Anti‐interleukin‐13 and anti‐interleukin‐4 agents versus placebo, anti‐interleukin‐5 or anti‐immunoglobulin‐E agents, for people with asthma

Andrew Gallagher; Michaela Edwards; Parameswaran Nair; Stewart Drew; Aashish Vyas; Rashmi Sharma; Paul A Marsden; Ran Wang; David JW Evans

doi:10.1002/14651858.CD012929.pub2

Inhibidores de la interleucina 13 y la interleucina 4 versus placebo, inhibidores de la interleucina 5 o sustancias antiinmunoglobulina E para personas con asma

Declaraciones de intereses de los autores

Versión publicada: 19 octubre 2021 Historial de versiones

https://doi.org/10.1002/14651858.CD012929.pub2

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Resumen

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Antecedentes

Actuar sobre la vía de la inmunoglobulina E y la de la interleucina 5 con anticuerpos monoclonales específicos dirigidos contra las citocinas o sus receptores es eficaz en pacientes con asma grave. Sin embargo, hay pacientes que tienen respuestas subóptimas a estos productos biológicos. Debido a que la interleucina 4 y la interleucina 13, que señalizan a través del receptor de la interleucina 4, tienen varios efectos en la biología del asma, se han desarrollado tratamientos dirigidos a la interleucina 4 y a la interleucina 13 (tanto de forma individual como combinada).

Objetivos

Evaluar la eficacia y la seguridad de los agentes inhibidores de la interleucina 13 o interleucina 4, en comparación con el placebo, los agentes antiinmunoglobulina E o los inhibidores de la interleucina 5, para el tratamiento de niños, adolescentes o adultos con asma.

Métodos de búsqueda

Se identificaron los estudios a partir del Registro de ensayos del Grupo Cochrane de Vías respiratorias (Cochrane Airways), que mantiene el documentalista del grupo y a través de búsquedas en el US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov y en la Plataforma de registros internacionales de ensayos clínicos de la Organización Mundial de la Salud. La búsqueda se realizó el 16 de octubre de 2020.

Criterios de selección

Se incluyeron los ensayos controlados aleatorizados de grupos paralelos que compararon inhibidores de la interleucina 13 o 4 (o sustancias que actúan tanto sobre la interleucina 13 como la interleucina 4) con placebo en adolescentes y adultos (de 16 años o más) o niños (menores de 16 años), con diagnóstico de asma; los participantes podían recibir su medicación habitual de acción corta o prolongada (p.ej., corticosteroides inhalados [CSI], agonistas beta adrenérgicos de acción prolongada [LABA], antagonistas muscarínicos de acción prolongada [LAMA] o antagonistas de los receptores de leucotrienos) siempre que no formaran parte del tratamiento asignado al azar.

Obtención y análisis de los datos

Se utilizaron los métodos estándar previstos por Cochrane.

Resultados principales

Se identificaron e incluyeron 41 ECA. De ellos, 29 estudios aportaron datos a los análisis cuantitativos, asignando al azar a 10 604 personas con asma a recibir un inhibidor de la interleucina 13 (intervención) o de la interleucina 4 (intervención), o un placebo (comparador). No se identificaron estudios relevantes en los que el comparador fuera un agente antiinmunoglobulina o un inhibidor de la interleucina 5. Los estudios tuvieron una duración de entre dos y 52 semanas (mediana de 16). La media de edad de los participantes en los estudios incluidos varió entre 22 y 55 años. Sólo cinco estudios permitieron la inclusión de niños y adolescentes, lo que representa menos del 5% del total de participantes que aportaron datos a la presente revisión. La mayoría de los participantes tenían asma moderada o grave no controlada. El uso concomitante de CSI se permitió o se exigió en la mayoría (21 de 29) de los estudios incluidos. El uso de corticosteroides sistémicos de mantenimiento no se permitió en 19 estudios y se permitió o requirió en cinco estudios (información no proporcionada en cinco estudios). En cuanto a los inhibidores de la interleucina 13/4 más comúnmente evaluados, cuatro estudios evaluaron el dupilumab (300 mg una vez por semana, 200 mg una vez cada dos semanas, 300 mg una vez cada dos semanas, 200 mg una vez cada cuatro semanas, 300 mg una vez cada cuatro semanas, cada uno administrado por inyección subcutánea [s.c.]); ocho estudios evaluaron el lebrikizumab (37,5 mg una vez cada cuatro semanas, 125 mg una vez cada cuatro semanas, 250 mg una vez cada cuatro semanas, cada uno administrado por inyección s.c.); y nueve estudios (3259 participantes) evaluaron el tralokinumab (75 mg una vez por semana, 150 mg una vez por semana, 300 mg una vez por semana, 150 mg una vez cada dos semanas, 300 mg una vez cada dos semanas, 600 mg una vez cada dos semanas, 300 mg una vez cada cuatro semanas, cada uno administrado por inyección s.c.; 1/5/10 mg/kg administrados por inyección intravenosa [i.v.]); todos los inhibidores de la interleucina 13 o 4 se compararon con placebo.

En general, el riesgo de sesgo se consideró bajo o incierto (no se proporcionaron daots suficientes); nueve estudios se consideraron con alto riesgo de sesgo de desgaste y tres estudios se consideraron con alto riesgo de sesgo de notificación.

Los siguientes resultados se refieren a los desenlaces principales. La tasa de exacerbaciones que requirieron hospitalización o visita al servicio de urgencias (SU) fue probablemente menor en los participantes que recibieron tralokinumab versus placebo (cociente de tasas 0,68; IC del 95%: 0,47 a 0,98; evidencia de certeza moderada; datos disponibles para tralokinumab [inhibidor de la interleucina 13] solamente). En los participantes que recibieron un inhibidor de la interleucina 13/4, la mejoría media comparado con el placebo en la puntuación ajustada del cuestionario de calidad de vida para el asma fue 0,18 unidades (IC del 95%: 0,12 a 0,24; evidencia de certeza alta); sin embargo, se consideró que este hallazgo no era una mejoría clínicamente relevante. Probablemente hubo poca o ninguna diferencia entre los grupos en la proporción de pacientes que notificaron eventos adversos graves por todas las causas (inhibidores de la interleucina 13/4 versus placebo, OR 0,91; IC del 95%: 0,76 a 1,09; evidencia de certeza moderada).

En cuanto a los desenlaces secundarios, podría haber poca o ninguna diferencia entre los grupos en la proporción de pacientes que presentaron exacerbaciones que requirieron corticosteroides orales (inhibidores de la interleucina 13/4 versus placebo, cociente de tasas 0,98; IC del 95%: 0,72 a 1,32; evidencia de certeza baja). Es probable que los inhibidores de la interleucina 13/4 mejoren el control del asma según la puntuación del cuestionario de control del asma (inhibidores de la interleucina 13/4 versus placebo, diferencia de medias ‐0,19; IC del 95%: ‐0,24 a ‐0,14); sin embargo, se consideró que la magnitud de este resultado no era una mejoría clínicamente relevante. La proporción de pacientes que presentaron algún evento adverso fue mayor en los que recibieron inhibidores de la interleucina 13/4 en comparación con los que recibieron placebo (OR 1,16; IC del 95%: 1,04 a 1,30; evidencia de certeza alta); los eventos adversos notificados con más frecuencia entre los participantes tratados con inhibidores de la interleucina 13/4 fueron infección de las vías respiratorias superiores, nasofaringitis, cefalea y reacción en el sitio de inyección. Los resultados agrupados para el desenlace exploratorio, la tasa de exacerbaciones que requirieron corticosteroides orales (CSO) u hospitalización o visita al servicio de urgencias, podrían ser menores en los participantes que recibieron inhibidores de la interleucina 13/4 versus placebo (cociente de tasas 0,71; IC del 95%: 0,65 a 0,77; evidencia de certeza baja).

Los resultados generalmente fueron consistentes en los subgrupos para las diferentes clases de inhibidores (de la interleucina 13 o de la interleucina 4), las duraciones del estudio y la gravedad de la enfermedad. El análisis de subgrupos basado en la categoría de la inflamación T helper 2 (TH2) indicó una mayor eficacia en los pacientes con mayores niveles de biomarcadores inflamatorios (eosinófilos en sangre, óxido nítrico exhalado y periostina en suero).

Conclusiones de los autores

Según la totalidad de la evidencia, en comparación con el placebo, los inhibidores de la interleucina 13/4 se asocian probablemente con una reducción de las exacerbaciones que requieren hospitalización o visita a urgencias, a costa de un aumento de los eventos adversos, en los pacientes con asma. No se identificaron mejorías clínicamente relevantes en la calidad de vida relacionada con la salud o el control del asma. Por lo tanto, los inhibidores de la interleucina 13 o de la interleucina 4 podrían ser apropiados para los adultos con asma no controlada de moderada a grave que no han respondido a otros tratamientos. Estas conclusiones se apoyan generalmente en evidencia de certeza moderada o alta basada en estudios con un periodo de observación de hasta un año.

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Resumen en términos sencillos

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Inhibidores de la interleucina 13 o de la interleucina 4 versus placebo, inhibidores de la interleucina 5 o agentes antiinmunoglobulina E, para niños y adultos con asma

Pregunta de la revisión

Se evaluó la eficacia y la seguridad de los inhibidores de la interleucina 13 o la interleucina 4, en comparación con el placebo, los agentes antiinmunoglobulina E o los inhibidores de la interleucina 5, para el tratamiento de niños, adolescentes o adultos con asma.

Antecedentes

La inmunoglobulina E y la interleucina 5 son sustancias químicas del organismo que favorecen la alergia (o una respuesta alérgica) en las vías respiratorias y provocan los síntomas del asma. Algunas personas con asma grave toman medicamentos que actúan sobre la inmunoglobulina E o a la interleucina 5, pero estos medicamentos no funcionan para todo el mundo. Debido a que la interleucina 4 y la interleucina 13 son también sustancias químicas de nuestro organismo que promueven la alergia (o una respuesta alérgica) en las vías respiratorias, se analizó si los medicamentos que actúan sobre ellas son seguros y eficaces (en comparación con el placebo, una sustancia que no tiene efecto terapéutico) para mejorar los síntomas o la calidad de vida de las personas con asma.

Características de los estudios

Se encontraron 41 estudios que compararon inhibidores de la interleucina 4 o de la interleucina 13 (o sustancias dirigidas tanto a la interleucina 13 como a la interleucina 4) con placebo en personas con asma. No se identificaron estudios relevantes en los que se compararan los inhibidores de la interleucina 4 o 13 con los inhibidores de la interleucina 5 o sustancias antiinmunoglobulina. Veintinueve de los estudios incluidos (10 604 participantes) aportaron información que sirvió para esta revisión. La evidencia presentada es actual hasta octubre de 2020. La mayoría de las personas que participaron en los estudios incluidos tenían asma moderada o grave no controlada y la media de edad de las personas en cada estudio varió entre 22 y 55 años. Sólo cuatro estudios permitieron el reclutamiento de niños y adolescentes y los participantes de este grupo de edad representaron menos del 5% de los que aportaron datos a la revisión. La mayoría de los estudios analizaron si el dupilumab, un inhibidor de la interleucina 4 (cuatro estudios), o los inhibidores de la interleucina 13 lebrikizumab (ocho estudios) o tralokinumab (nueve estudios), eran mejores que el placebo.

Resultados clave

Cuando se agrupó la información proporcionada por los 29 estudios, se mostró que estos medicamentos reducían el número de personas que sufrían crisis asmáticas y mejoraban la función pulmonar hasta un nivel en el que una persona podía sentir el beneficio. También se observaron pequeñas mejorías en la calidad de vida relacionada con la salud y el control del asma, pero la magnitud de estos efectos no fue lo suficientemente grande como para que una persona con asma sintiera el beneficio. También se observó una reducción del 16% en la dosis de corticosteroides orales, aunque la confianza en este hallazgo es baja. Aunque no se observó un aumento de los efectos secundarios graves (es decir, cualquier episodio médico adverso que provoque la muerte; que ponga en peligro la vida; que requiera hospitalización; que provoque una discapacidad/incapacidad persistente o significativa; o que sea un defecto congénito), el número de personas que tuvieron algún efecto secundario aumentó en comparación con las que tomaron placebo. Los efectos secundarios notificados con más frecuencia por los participantes tratados con inhibidores de la interleucina 13/4 fueron infección de las vías respiratorias superiores, resfriados, dolores de cabeza o reacciones en el sitio de inyección. Los resultados también mostraron que la información sobre los marcadores sanguíneos (eosinófilos en sangre y periostina en suero) y los niveles de óxido nítrico exhalado podrían ayudar a predecir la eficacia de estos medicamentos en un individuo con asma. En resumen, estos medicamentos probablemente son útiles para algunas personas con asma grave o no controlada cuando otros tratamientos no han funcionado y el propósito del tratamiento es reducir el número de crisis asmáticas experimentadas.

Calidad de la evidencia

En general, los estudios incluidos estaban bien diseñados y su información bien presentada. Las personas que participaron en los estudios y los que realizaron la investigación no sabían qué tratamiento estaban recibiendo, lo que garantiza una evaluación justa de los tratamientos. En general, es posible confiar en las conclusiones de esta revisión.

Authors' conclusions

Implications for practice

As the clinical development of lebrikizumab and tralokinumab for the treatment of patients with asthma has been halted indefinitely, the following conclusions focus on the use of dupilumab. The findings of the review support the use of dupilumab in adult patients with moderate‐to‐severe uncontrolled asthma. Given that the magnitude of the observed effect was relatively small (reduction in exacerbations without a clinically relevant improvement in asthma control, lung function or asthma‐related quality of life) the use of dupilumab is likely to be limited to a specific patient set. This is consistent with the approved indication for dupilumab, which is licensed for use in Europe for "adults and adolescents 12 years and older as add‐on maintenance treatment for severe asthma with type 2 inflammation characterised by raised blood eosinophils and/or raised FENO, who are inadequately controlled with high dose ICS plus another medicinal product for maintenance treatment" (EMA 2021) and in the USA "as an add‐on maintenance treatment in patients with moderate‐to‐severe asthma aged 12 years and older with an eosinophilic phenotype or with oral corticosteroid dependent asthma" (FDA 2021).

Implications for research

Given the number of published studies comparing anti‐interleukin‐13 or anti‐interleukin‐4 agents with placebo and the number of different agents studied, a future network meta‐analysis may be warranted. In this way, more specific clinical advice relating to individual agents and dose regimens could be derived (the present conclusions are relevant to the class of agents as a whole). Future updates of the review should include the outcome 'exacerbations requiring emergency department visit, hospitalisation or OCS use' as a primary outcome. Future updates of the review may also wish to examine the role of demographic characteristics (e.g. age or gender). Importantly, future clinical studies are required to evaluate the safety and efficacy of these agents in children and adolescents, as this population accounted for less than 5% of the participants contributing data to the present review. It is noteworthy that the exacerbation outcomes were poorly measured/analysed/reported in the individual studies. The use of core outcome sets across trials would improve uniformity and enable more powerful synthesis of results. Future studies of anti‐interleukin agents should also strive to use unified thresholds of biomarkers to define 'low' and 'high' inflammation groups. Future studies may also wish to include outcomes to examine effects on work or study (i.e. days lost). Future studies may also wish to compare the safety and efficacy of anti‐interleukin‐13/‐4 agents with that of anti‐interleukin‐5 agents or immunoglobulin‐E, in people with asthma.

Summary of findings

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Summary of findings 1. Anti‐IL13 or anti‐IL4 agents compared to placebo for children and adults with asthma

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Anti‐IL13 of anti‐IL4 agents compared to placebo for children and adults with asthma
Patient or population: children and adults with asthma Setting: community Intervention: anti‐IL13 of anti‐IL4 agents Comparison: placebo
Outcomes	Risk with placebo	Risk with anti‐IL13 of anti‐IL4 agents	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Exacerbation requiring hospitalisation or ED visit Follow‐up: 52 weeks	The mean AAER in the placebo group was 0.075¹	The AAER in the intervention group was 0.024 lower (0.002 lower to 0.04 lower)	Rate ratio 0.68 (0.47 to 0.98)	2039 (2 RCTs)	⊕⊕⊕⊝ MODERATE²
Health‐related quality of life (AQLQ) Scale: 1 to 7 (higher is better) Follow‐up: 12 weeks to 52 weeks	Where reported, the mean change in the placebo group ranged from 0.64 to 0.88	MD 0.18 higher (0.12 higher to 0.24 higher)	‐	4960 (7 RCTs)	⊕⊕⊕⊕ HIGH	MCID = 0.5; the treatment effect was not clinically relevant.
Serious adverse events Follow‐up: 3 to 52 weeks	81 per 1000	74 per 1000 (63 to 87)	OR 0.91 (0.76 to 1.09)	7739 (22 RCTs)	⊕⊕⊕⊝ MODERATE³
Exacerbation requiring OCS (rate ratio) Follow‐up: 52 weeks	The mean AAER in the placebo group was 0.90	The AAER in the intervention group was 0.08 lower (0.27 lower to 0.29 higher)	RR 0.98 (0.72 to 1.32)	452 (1 RCT)	⊕⊕⊝⊝ LOW^2,3
Change from baseline in ACQ score Scale: 0 to 6 (higher is worse) Follow‐up: 12 to 52 weeks	Where reported, the mean change from baseline in ACQ score in the placebo group ranged from ‐1.30 (SE 0.06) to ‐0.27 (error NR)	MD 0.19 lower (0.24 lower to 0.14 lower)	‐	6251 (14 RCTs)	⊕⊕⊕⊝ MODERATE⁴	MCID = 0.4; the treatment effect was not clinically relevant.
Adverse events (any) Follow‐up: 10 days to 52 weeks	707 per 1000	737 per 1000 (715 to 759 participants per 1000)	OR 1.16 (1.04 to 1.30)	7419 (18 RCTs)	⊕⊕⊕⊕ HIGH
Time off work or study	‐	‐	‐	‐	‐	No studies reported data for this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AAER: adjusted annualised exacerbation rate; ACQ: asthma control questionnaire; AQLQ: asthma quality of life questionnaire; CI: Confidence interval; ED: emergency department; MCID: minimally clinically important difference; MD: mean difference; OCS: oral corticosteroids; RR: Risk ratio; OR: Odds ratio; SD: standard deviation; RCT: randomised controlled trial; SE: standard error.
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Mean of the AAER in the placebo group of the two studies: 0.07 and 0.08 ²Downgraded once for indirectness (low number of studies of a single agent) ³Downgraded once for imprecision as the 95% confidence intervals for the treatment effect crossed 1.0 ⁴ Downgraded once for inconsistency (moderate heterogeneity of 30% to 60%) ⁶Downgraded twice for inconsistency (substantial heterogeneity of 50% to 90% or considerable heterogeneity of 75% to 100%)

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Summary of findings 2. Other secondary and post hoc exploratory outcomes

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Anti‐IL13 of anti‐IL4 agents compared to placebo for children and adults with asthma
Patient or population: children and adults with asthma Setting: community Intervention: anti‐IL13 of anti‐IL4 agents Comparison: placebo
Outcomes	Risk with placebo	Risk with anti‐IL13 of anti‐IL4 agents	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Change from baseline in pre‐bronchodilator FEV1 Follow‐up: 12 to 52 weeks	Where reported, the mean change from baseline in FEV1 in the placebo groups ranged from ‐0.02 L (SE 0.03) to 0.21 L (SE 0.02)	MD 0.1 L higher (0.08 higher to 0.12 higher)	‐	4829 (13 RCTs)	⊕⊕⊕⊝ MODERATE²	These changes were borderline clinically relevant (MCID is approximately 0.1 to 0.2 L).
Change from baseline in FENO (ppb) Follow‐up: 10 days to 52 weeks	Where reported, the mean change from baseline in FENO in the placebo groups ranged from ‐31.1 to 23.8 ppb	MD 14.68 ppb lower (16.56 lower to 12.8 ppb lower)	‐	3577 (11 RCTs)	⊕⊕⊕⊝ MODERATE²
Change from baseline in blood eosinophils (cells x 109/L) Follow‐up:* 12 to 52 weeks	Where reported, the mean change from baseline in blood eosinophil count in the placebo groups ranged from ‐0.048 (SD 0.347) to 0.003 (SD 0.313) cells x 10⁹/L	MD 0.06 cells x 10⁹/L higher (0.04 higher to 0.09 cells x 10⁹/L higher)	‐	2598 (6 RCTs)	⊕⊕⊕⊕ HIGH
Change from baseline in Periostin (ng/mL) Follow‐up: 12 to 52 weeks	Where reported, the mean change from baseline in periostin concentration in the placebo groups ranged from ‐5.05 (SD 27.89) to ‐0.3 (SD 1.0) ng/mL	MD 9.04 ng/mL lower (10.92 lower to 7.17 ng/mL lower)	‐	2106 (2 RCTs)	⊕⊕⊝⊝ LOW³
Percentage reduction from baseline in maintenance OCS dose Follow‐up: 24 to 40 weeks	Where reported, the mean reduction from baseline in OCS dose in the placebo groups ranged from ‐29.85 (SE 4.98) to ‐41.9 (SE 4.6)%	MD 15.58% lower (23.3% lower to 7.85% lower)	‐	350 (2 RCTs)	⊕⊕⊝⊝ LOW³
Post hoc exploratory endpoint: Exacerbation requiring hospitalisation/ED/OCS (rate ratio) Follow‐up: 24 weeks to 52 weeks	The mean AAER in the placebo groups was 1.00 (range 0.60 to 2.31)¹	The AAER in the intervention groups was 0.29 lower (0.35 lower to 0.23 lower)	Rate ratio 0.71 (0.65 to 0.77)	6998 (7 RCTs)	⊕⊕⊝⊝ LOW³
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AAER, adjusted annualised exacerbation rate; CI: Confidence interval; ED, emergency department; FENO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; MD, mean difference; OCS, oral corticosteroids; ppb, parts per billion; RR: Risk ratio; SD, standard deviation; RCT, randomised controlled trial; SE, standard error
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹Mean of the AAER in the placebo groups of the seven studies (1 study had two placebo arms): 2.31, 0.60, 0.82, 0.94, 0.61, 0.87, 0.97, 0.897 ² Downgraded once for inconsistency (moderate heterogeneity of 30% to 60%) ³Downgraded twice for inconsistency (substantial heterogeneity of 50% to 90% or considerable heterogeneity of 75% to 100%)

Background

Description of the condition

Asthma is a prevalent, noncommunicable, heterogeneous disease, typically characterised by chronic airway inflammation (GINA 2020). Common symptoms include wheezing, chest tightness, a cough, and shortness of breath, and they are frequently worse early in the morning or late at night (GINA 2020). Airflow limitation and symptoms vary over time and in intensity, and are known to be triggered by viral respiratory infections, changing weather, irritant and allergen exposure, and exercise (GINA 2020). Symptoms and airflow limitation can be absent for periods of weeks or months.

Asthma may affect up to 334 million individuals worldwide (Global Asthma Network 2014), and has been highlighted as one of the forum of international respiratory societies' 'Big 5' respiratory diseases (ERS 2017). It is noted as "the most common chronic condition in children, and is more severe in children in non‐affluent countries" (ERS 2017). Asthma is known to affect "1 to 18% of the population in different countries" (GINA 2020), and can carry a particularly serious burden in low‐ or middle‐income countries, which find it more difficult to afford the associated costs (Global Asthma Network 2014).

The goal of asthma treatment is to maintain good activity levels and control symptoms (GINA 2020). In addition, the use of maintenance medication can reduce the future risk of exacerbations (GINA 2020). Individuals should also be assessed for any relevant comorbidities (e.g. obstructive sleep apnoea, depression and anxiety, obesity, rhinosinusitis, rhinitis, and gastroesophageal reflux), which may contribute to asthma symptoms and poor control of asthma (GINA 2020).

It is increasingly accepted that asthma is a heterogeneous condition, with distinct clinical phenotypes. One of the better characterised phenotypes is that of eosinophilic asthma, where eosinophils infiltrate the bronchial mucosa and airways, and cause inflammation. Eosinophilic infiltration is a hallmark of both childhood‐onset allergic asthma and late‐onset non‐allergic asthma. In both cases, the cytokines interleukin‐4, ‐5, and ‐13 play a central role in the pathophysiology (De Groot 2015). Immunoglobulin E (IgE) also plays a role, and treatment with anti‐IgE therapies can reduce airway and blood eosinophils, and associated inflammation. However, some patients with uncontrolled asthma do not respond to anti‐IgE therapies, and continue to exhibit inflammation. Therefore, therapies targeting interleukin‐4, ‐5, and ‐13, have been developed; the evidence around anti‐interleukin‐5 therapies has recently been synthesised elsewhere (De Groot 2015; Farne 2017); anti‐interleukin‐5 agents were evaluated as active comparators, as they target the initiation and maintenance of eosinophilic airway inflammation (Ortega 2014).

Description of the intervention

The majority of anti‐interleukin‐13 and anti‐interleukin‐4 agents are humanised monoclonal antibodies (i.e. biological therapies) that bind to, and inhibit their respective inflammatory cytokines or their receptors (Bice 2014; Kau 2014). Antibodies targeting the interleukin‐13 pathway alone include lebrikizumab, GSK67958, tralokinumab, anrukinzumab, and IMA‐026. Antibodies inhibiting the interleukin‐4 pathway alone include pascolizumab and altrakincept. Antibodies inhibiting both the interleukin‐4 and ‐13 pathways include pitrakina, AMG‐317, and dupilumab (Bice 2014; Kau 2014). All of the agents are administered by subcutaneous injection once every several weeks. However, pitrakina can also be administered by nebulised inhalation.

How the intervention might work

Interleukins are a broad group of proteins, which are important in cell signalling. Interleukin‐13 is a pleiotropic cytokine produced by type 2 helper T cells (TH₂), and has been shown to drive airway eosinophilia and increase airway inflammation in asthma. Interleukin‐13 contributes to goblet cell metaplasia, subepithelial cell fibrosis, smooth muscle hyperplasia, and stimulation of periostin secretion (Woodruff 2007); periostin is a matricellular protein, which has a role in fibroblast activation and increasing collagen gel elasticity (Sidhu 2010). These pathophysiological processes are hallmarks of asthma. In preclinical models, interleukin‐13 has also been shown to increase airway hyper‐responsiveness (Chiba 2009). Interleukin‐4 is a closely related cytokine, which shares many of the biological and immunoregulatory functions of interleukin‐13 (Chomorat 1998). In particular, interleukin‐4 plays an important role in maintaining the TH₂ phenotype, leading to further secretion of interleukin‐4 and ‐13 in a positive feedback effect (Bice 2014). Interleukin‐4 also promotes B‐cell isotype switching, affects the production of chemokines by the airway epithelium, and increases IgE production (Li‐Weber 2003). Interleukin‐13 and interleukin‐4 have been shown to enhance bronchial smooth muscle proliferation (Ynuk 2008).

Anti‐interleukin‐13 and ‐4 agents target these pathways with the aim of reducing inflammation and airway remodelling, which are both features of asthma. Furthermore, these agents may be more effective in specific populations of people with asthma, such as those with eosinophilic asthma, where inhibition of these pathways may reduce infiltration of eosinophils into the airways. It is believed that blocking interleukin‐13 may reduce very late antigen‐4 expression, and thus, reduce the movement of eosinophils from circulation into airway tissue, and subsequently into the lumen (Pelaquini 2011). Glucorticosteroids have diverse effects on the airways, including inhibition of interleukin‐13 production; however, some patients with poorly controlled asthma continue to have elevated levels of interleukin‐13, despite the use of high‐dose inhaled or systemic glucocorticosteroids (Saha 2008). Therefore, direct inhibition of interleukin‐13 is a potential therapeutic target in this group of patients, and agents, such as lebrikizumab, have been shown to be effective in reducing interleukin‐13 levels following subcutaneous administration (Hanania 2016). Inhibition of the interleukin‐4 pathway by dupilumab has also been shown to reduce levels of TH₂‐associated inflammatory markers in patients with persistent, moderate to severe asthma, following the withdrawal of treatment with long‐acting beta‐adrenoceptor agonists (LABA) and glucocorticoid therapy (Wenzel 2013b).

Why it is important to do this review

Whilst severe or difficult to treat asthma represents only 5% to 10% of the total asthma population, these patients carry a disproportionate burden of healthcare, socioeconomic, and personal costs (Sullivan 2007). Around 1200 people die of asthma each year in the UK, and approximately 40% of deaths occur in individuals with severe asthma (BLF 2012; RCoP 2014). Therefore, it is imperative to find therapies that will offer improvements in disease control for this group of patients.

It is important to synthesise the available evidence on the safety and efficacy of anti‐interleukin‐13 and anti‐interleukin‐4 agents, given that data from phase III clinical trials are becoming available (Hanania 2016). Whilst improvements in laboratory markers, such as forced expiratory volume in 1 second (FEV1; (Corren 2011b)), and fraction of exhaled nitric oxide (FENO; (Noonan 2013b)) have been shown, a demonstration of consistent improvement in patient symptoms appear to be more elusive (Corren 2011b; De Boever 2014). Furthermore, some markers, such as elevated periostin levels, may identify a subset of patients who are more likely to have a favourable response. However, trial evidence is again mixed in this respect.

Objectives

To assess the efficacy and safety of anti‐interleukin‐13 or anti‐interleukin‐4 agents, compared with placebo, anti‐immunoglobulin E agents, or anti‐interleukin‐5 agents, for the treatment of children, adolescents, or adults with asthma.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs; parallel‐group). Cross‐over trials were excluded because the half‐life of these agents is in the order of a month, and thus trialists are unlikely to implement a sufficient washout period for eliminating a carry‐over effect (i.e. several times the half‐life). We included studies reported in full text, those published as an abstract only, and unpublished data. We excluded non‐randomised studies.

Types of participants

We included adolescents and adults (aged 16 years or older) and children (younger than 16 years), with a diagnosis of asthma. We excluded participants with other chronic respiratory comorbidities (e.g. COPD, bronchiectasis). If a study included a mixture of patients with COPD and asthma, we used or attempted to obtain data for the subgroup of patients with asthma; if this was not possible, the study was excluded.

If studies in adolescent or adult populations included a proportion of individuals under 16 years, and data were not reported separately, we included the study if the mean age in the intervention and comparator groups was 16 years or older.

Types of interventions

We included studies of adolescents and adults (aged 16 years or older) and studies of children (younger than 16 years) in separate comparisons. In each main comparison, we included studies that compared the following:

Anti‐interleukin‐13 or ‐4 agents* with placebo.
Anti‐interleukin‐13 or ‐4 agents* with anti‐immunoglobulin E (IgE) agents.
Anti‐interleukin‐13 or ‐4 agents* with anti‐interleukin‐5 agents.

*Some agents may inhibit both interleukin‐13 and ‐4, and we also included studies of these agents.

We selected anti‐interleukin‐5 agents as active comparators, as they target the initiation and maintenance of eosinophilic airway inflammation (Ortega 2014). We selected anti‐IgE agents as active comparators, as they target IgE‐mediated immune response, thought to be involved in severe allergic asthma (Busse 2001).

Co‐interventions were permitted, providing they were not part of the randomised treatment. For example, individuals' usual short‐ or long‐acting medications (e.g. inhaled corticosteroids, long‐acting beta adrenoceptor agonists (LABA), long‐acting muscarinic antagonists (LAMA), leukotriene receptor antagonists), oral corticosteroids (OCS) or macrolides.

If a study evaluated more than one dose of an anti‐interleukin‐13 or ‐4 agent (in separate arms), we considered the most clinically relevant dose. If the clinically relevant dose for a given agent was not clear, we extracted data for both doses, and used the most appropriate dataset for the meta‐analysis, based on the doses used in the majority of other included studies.

Types of outcome measures

Primary outcomes

Exacerbations requiring hospitalisation or emergency department visit (see section Unit of analysis issues for more details)
Quality of life (measured on a validated asthma scale, e.g. Asthma Quality of Life Questionnaire)
Serious adverse events (all causes; i.e. any untoward medical occurrence that results in death, is life threatening, requires inpatient hospitalisation, results in persistent or significant disability/incapacity; or is a congenital anomaly/birth defect)

Secondary outcomes

Exacerbations requiring oral corticosteroids
Lung function (e.g. change from baseline in forced expiratory volume in 1 second (FEV1; (L)); change from baseline in % predicted FEV1 (%); FEV1 bronchodilator reversibility (%); concentration of methacholine needed to produce a 20% fall in FEV1 from baseline (PC20 methacholine; (mg/mL))
Asthma control (measured on a validated scale, e.g. Asthma Control Questionnaire or Asthma Control Test)
Time off work or study
Adverse events (all causes)
Measures of airway inflammation (e.g. blood eosinophil (count ‐ absolute); sputum or bronchoalveolar lavage eosinophil (%); fraction of exhaled nitric oxide (FENO)
Reduction in maintenance oral corticosteroid dose

Additionally, we assessed the exploratory outcome "exacerbations requiring hospitalisation, emergency department visit or OCS". When we started to conduct the review, it was clear that the majority of studies reported this endpoint and that important evidence would be lost as a result of its omission from the published protocol. We plan to include this outcome as a primary outcome in future updates to the review.

We extracted data for each outcome at the time point closest to the end of the treatment period. Where multiple outcomes were proposed (i.e. as for lung function and measures of airway inflammation), we extracted data for all available measures.

Reporting one or more of the outcomes listed here in the study was not an inclusion criterion for the review.

Search methods for identification of studies

Electronic searches

We identified studies from the Cochrane Airways Trials Register, which is maintained by the Information Specialist for the Group. The Cochrane Airways Trials Register contains studies identified from several sources:

monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL), through the Cochrane Register of Studies (CRS) inception to October 2020;
weekly searches of MEDLINE Ovid SP 1946 to October 2020;
weekly searches of Embase Ovid SP 1974 to October 2020;
monthly searches of PsycINFO Ovid SP 1967 to October 2020;
monthly searches of CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature) 1937 to October 2020;
monthly searches of AMED EBSCO (Allied and Complementary Medicine) inception to October 2020;
handsearches of the proceedings of major respiratory conferences.

Studies contained in the Trials Register were identified through search strategies based on the scope of Cochrane Airways. Details of these strategies, as well as a list of handsearched conference proceedings are in Appendix 1. See Appendix 2 for search terms used to identify studies for this review.

We searched the following trials registries:

US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov)
World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch)

We searched the Cochrane Airways Trials Register and additional sources from inception to 16 October 2020, with no restriction on language of publication.

Searching other resources

We checked the reference lists of all selected studies for additional references. We searched relevant manufacturers' websites for study information.

We searched for errata or retractions from included studies published in full text on PubMed, on 26 February 2021.

Data collection and analysis

Selection of studies

Three review authors (DE, AG, ME) independently screened the titles and abstracts of the search results and coded them as 'retrieve' (eligible, potentially eligible, or unclear) or 'do not retrieve'. We retrieved the full‐text study reports of all potentially eligible studies, and three review authors (DE, AG, ME) independently screened them for inclusion, recording the reasons for exclusion of ineligible studies. We resolved any disagreement through discussion or, if required, we consulted a fourth review author (PM). We identified and excluded duplicates and collated multiple reports of the same study so that each study, rather than each report, was the unit of interest in the review. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram and Characteristics of excluded studies table (Moher 2009).

Data extraction and management

We used a data collection form for study characteristics and outcome data, which has been piloted on at least one study in the review. Two review authors (DE, RW) extracted the following study characteristics from included studies:

Methods: study design, total duration of study, details of any 'run‐in' period, number of study centres and location, study setting, withdrawals, and date of study.
Participants: N, mean age, age range, gender, severity of condition, diagnostic criteria, baseline lung function, baseline measures of airway inflammation, smoking history, inclusion criteria, and exclusion criteria.
Interventions: intervention (including dose), comparison, concomitant medications, and excluded medications.
Outcomes: primary and secondary outcomes specified and collected, and time points reported.
Notes: funding for studies and notable conflicts of interest of trial authors.

Two review authors (from DE, AG, ME) independently extracted outcome data from the included studies. We noted in the Characteristics of included studies table if outcome data were not reported in a usable way. We resolved disagreements by consensus, or by involving a fourth review author (RS). One review author (DE) transferred data into the Review Manager 5 file (RevMan 2014). We double‐checked that data were entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (SD) spot‐checked study characteristics for accuracy against the study report.

Assessment of risk of bias in included studies

Two review authors (from DE, ME, RW) independently assessed the risk of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreements by discussion, or by involving a third author (from DE, ME, RW). We assessed the risk of bias according to the following domains:

random sequence generation;
allocation concealment;
blinding of participants and personnel;
blinding of outcome assessment;
incomplete outcome data;
selective outcome reporting;
other bias.

We judged each potential source of bias as high, low, or unclear, and provided a quote from the study report together with a justification for our judgement in the risk of bias table. We summarised the risk of bias judgements across different studies for each of the domains listed. We considered blinding separately for different key outcomes where necessary (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a patient‐reported pain scale). Where information on risk of bias related to unpublished data or correspondence with a trialist, we noted this in the risk of bias table.

When considering treatment effects, we took into account the risk of bias for the studies that contributed to that outcome.

Assessment of bias in conducting the systematic review

We conducted the review according to the published protocol and justified any deviations from it in the Differences between protocol and review section of the systematic review.

Measures of treatment effect

We analysed dichotomous data as odds ratios (OR), and continuous data as rate ratios (RR), mean difference (MD), or standardised mean difference (SMD), which were presented with 95% confidence intervals (CI). If data from rating scales were combined in a meta‐analysis, we ensured that they were entered with a consistent direction of effect (e.g. lower scores always indicate improvement).

We undertook meta‐analyses only when this was meaningful; that is, if the treatments, doses, participants, and the underlying clinical question were similar enough for pooling to make sense.

Where multiple trial arms were reported in a single study, we included only the relevant arms. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) were combined in the same meta‐analysis, we either combined the active arms or halved the control group to avoid double‐counting.

If adjusted analyses were available (ANOVA or ANCOVA), we used these as a preference in our meta‐analyses. If both change from baseline and endpoint scores were available for continuous data, we used change from baseline, unless there was a low correlation between measurements in individuals. If a study reported outcomes at multiple time points, we used the latest available time point (i.e. corresponding to the end of the study) for studies with a duration of one year or less.

We used intention‐to‐treat (ITT) or 'full analysis set' analyses when they were reported (i.e. when data were imputed for participants who were randomly assigned but did not complete the study), instead of completer or per protocol analyses.

Unit of analysis issues

With the exception of outcomes relating to exacerbations, for dichotomous outcomes, we used participants, rather than events, as the unit of analysis (i.e. number of children admitted to hospital, rather than number of admissions per child). However, if data permitted the calculation of rate ratios, we analysed them on this basis. The majority of patients enrolled in studies of anti‐interleukin‐13 and anti‐interleukin‐4 agents had relatively severe or uncontrolled asthma, and experienced at least one exacerbation during the treatment period. Therefore, we synthesised data relating to exacerbations based on the number of exacerbations per patient during the treatment period, using rate ratios. We planned to only meta‐analyse data from cluster‐RCTs if the available data had been adjusted (or could be adjusted), to account for the clustering; however, no cluster‐RCTs were included in the review.

Dealing with missing data

We contacted investigators or study sponsors to verify key study characteristics and obtain missing numerical outcome data when possible (e.g. when a study was identified as an abstract only). If this was not possible, and the missing data were thought to introduce serious bias, we planned to take this into consideration in the GRADE rating for affected outcomes (however, this was not necessary). We did not contact investigators to obtain data for outcomes that were not prespecified in the trial protocols.

Assessment of heterogeneity

We used the I² statistic to measure heterogeneity among the studies in each analysis. An I² value of 30% to 60% may represent moderate heterogeneity, a value of 50% to 90% may represent substantial heterogeneity and a value of 75% to 100% may represent considerable heterogeneity. If we identified substantial heterogeneity, we reported it and explored the possible causes by our prespecified subgroup analysis.

Assessment of reporting biases

We did not explore possible small study and publication biases.

Data synthesis

We used a fixed‐effects model. We performed a sensitivity analysis with a random‐effects model. Rate ratios were combined using the generic inverse variance method.

Subgroup analysis and investigation of heterogeneity

We planned to carry out the following subgroup analyses for the primary outcomes (for each of the main comparisons in children, and adolescents and adults, respectively):

Individual anti‐interleukin‐13 or anti‐interleukin‐4 agent (e.g. including but not limited to lebrikizumab, tralokinumab, IMA‐026, GSK679586, anrukinzumab, pascolizumab, pitrakina, altrakincept, AMG‐317, dupilumab).
Agent class (anti‐interleukin‐13 only versus anti‐interleukin‐4 only versus drugs that inhibit both interleukin‐13 and ‐4 pathways).
Duration of therapy (up to 6 months versus longer than 6 months).
Severity of asthma as per Global Initiative for Asthma (GINA) or British Thoracic Society/Scottish Intercollegiate Guidelines Network (BTS/SIGN) definitions (mild or moderate versus severe).
Category of TH₂ inflammation (high versus low: e.g. as determined by serum IgE concentration (high: ≥ 300 kU/L%), exhaled nitric oxide (eNO; (high: ≥ 50 parts per billion (ppb)), airway eosinophil count (high: sputum eosinophilia ≥ 3%), serum periostin (high: ≥ 50 ng/mL), or direct assay of serum or sputum IL‐13 (high: ≥ 10 pg/mL)). Rationale: TH₂ cells play a central role in asthma; interleukin‐4 controls the development of TH₂ cells, and interleukin‐13 functions during the effector phase of immunity, mediating the physiological response to TH₂‐induced inflammation. Patients with greater levels of TH₂ inflammation may respond better to anti‐interleukin‐13 or ‐4 therapies than patients with lower levels of TH₂ inflammation.
Dose of corticosteroids (including prednisone) at randomisation. Rationale: there is some overlap in the mechanism of action between corticosteroids and anti‐interleukin agents; prior or concomitant corticosteroid use may potentially confound the results, with greater effects of the anti‐interleukin agents observed when corticosteroid doses are low. Equally, some patients may not respond to even high doses of corticosteroids, but may respond to anti‐interleukin‐13 or ‐4 therapies.

We used the formal test for subgroup interactions in Review Manager 5 (RevMan 2014).

Sensitivity analysis

We planned to carry out the following sensitivity analyses, removing the following from the primary outcome analyses:

Unpublished data.
Studies at high risk of bias for blinding of participants and personnel.
Studies at high risk for random sequence generation or allocation concealment.

We compared the results from a fixed‐effect model with the random‐effects model.

Summary of findings and assessment of the certainty of the evidence

We created summary of findings tables using the following outcomes: exacerbations requiring hospitalisation or emergency department visit, quality of life, serious adverse events (all causes), exacerbations requiring oral corticosteroids, asthma control, time off work or study, adverse events (all causes). We used the five considerations (risk of bias, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it related to the studies that contributed data for the prespecified outcomes. We used the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), using GRADEpro software (GRADEpro GDT). We justified all decisions to downgrade the quality of the evidence using footnotes, and we made comments to aid the reader's understanding of the review, where necessary.

Results

Description of studies

Details of the included studies are presented in the Characteristics of included studies tables and are summarised in Table 1. In the Characteristics of excluded studies table, we report reasons for the exclusion of studies considered during review of full‐text articles.

Open in table viewer

Table 1. Summary of included study characteristics

Study	Intervention	Treatment duration (weeks^c)	Asthma severity	ICS use	N randomised	Age range, years	Range % male	BL % pred. FEV1
Borish 1999	IL‐4R 500/1500 μg single dose	2	Moderate atopic	Discontinued prior to study drug	25 (17/8)	35 to 38	25 to 63	7 to 87
Borish 2001	IL‐4R 0.75/1.5/3.0 mg Q1W	12	Moderate‐to‐severe	Discontinued prior to study drug	62 (46/16)	36 to 46	25 to 37	75 to76
Brightling 2015 (NCT01402986)	Tralokinumab 300 mg Q2W or Q4W	52	Severe uncontrolled	Maintained through study	452 (376/76)	50 to 51	33 to 36	68 to 69
Burgess 2018 (NCT02473939)	VR492 0.5/10/20 mg as DPI	28	Mild	Maintained through study	45 (29/16)	29 to 30	100	77 to 89
Busse 2015 (NCT02281357)	Tralokinumab 300 mg Q2W	40	Severe	Maintained through study	140 (70/70)	54 to 55	32 to 44	NR
Castro 2018 (NCT02414854)	Dupilumab 200/300 mg SC Q2W	52	Severe uncontrolled	ICS permitted (≥ 500 μg FP or equiv.)	1902 (1264/638)	48	37	58
Corren 2010 (NCT 00436670)	Tralokinumab 75/150/300 mg Q1W	12	Moderate‐to‐severe	Stable doses of ICS (200 to 1000 μg FP or equiv.)	294 (220/74)	40 to 43	38 to 46	67 to 70
Corren 2011 (NCT00930163)	Lebrikizumab 250 mg SC Q4W	24	Moderate‐to‐severe uncontrolled	ICS maintained throughout study (≥ 200 and ≤ 1000 μg FP daily or equiv.)	218 (106/112)	44 to 45	33 to 35	64 to 66
De Boever 2014 (NCT00843193)	GSK679586 10 mg/kg IV Q4W	12	Severe refractory	Max recommended ICS doses maintained	198 (99/99)	51	48 to 51	55 to 58
Gauvreau 2011a (NCT00410280)	IMA‐638 4 mg/kg (2 doses, 1 week apart)	AC study (2)	Mild, allergic asthma	Not permitted	27 (14/13)	26 to 32	38 to 50	87 to 93
Gauvreau 2011b (NCT00725582)	IMA‐638 4 mg/kg (2 doses, 1 week apart)	AC study (2 )	Mild, allergic asthma	Not permitted	29 (14/15)	33 to 34	50 to 53	87 to 91
Hanania 2011	Lebrikizumab (dose not stated)	24	Uncontrolled by ICS	Maintained throughout study	180 (88/92)	NR	NR	NR
Hanania 2015a (NCT01545440)	Lebrikizumab 37.5/125/250 mg SC Q4W	52^a	Moderate‐to‐severe uncontrolled	SOC maintained (500 to 2000 μg/day FPA or equiv.)	463 (347/116)	47 to 50	39 to 57	61 to 63
Hanania 2015b (NCT01545453)	Lebrikizumab 37.5/125/250 mg SC Q4W	52^a	Moderate‐to‐severe uncontrolled	SOC maintained (500 to 2000 μg/day FPA or equiv.)	See Hanania 2015a^a
Hanania 2016a (NCT01867125)	Lebrikizumab 37.5/125 mg SC Q4W	52	Moderate‐to‐severe uncontrolled	SOC maintained (500 to 2000 μg/day FPA or equiv.)	1081 (719/362)	51	31 to 36	61
Hanania 2016b (NCT01868061)	Lebrikizumab 37.5/125 mg SC Q4W	52	Moderate‐to‐severe uncontrolled	SOC maintained (500 to 2000 μg/day FPA or equiv.)	1067 (713/354)	50 to 51	34 to 43	61
Hodsman 2013^b (NCT00411814)	GSK679586 2.5/10/20 mg/kg Q4W	12	Mild bronchial	Not permitted	28 (21/7)	25 to 32	100	102 to 105
Korenblat 2018 (NCT02104674)	Lebrikizumab 125 mg SC Q4W	12	Mild‐to‐moderate	Discontinued 30 days prior to study drug	211 (105/106)	43 to 45	37 to 39	72
NCT00425061	IMA‐638 0.2/0.6/2/ mg/kg SC D1/8/28/56/70/84	16	Moderate‐to‐severe persistent	Medium‐to‐high dose permitted	159 (98/61)	NR	39 to 45	NR
NCT00640016	Tralokinumab 1/5/10 mg/kg Q4W	12	Uncontrolled refractory	Maintained (≥ 800 μg BDP or equiv.)	14 (11/3)	34 to 41	0 to 75	NR
Noonan 2013 (NCT00971035)	Lebrikizumab 125/250/500 mg SC Q4W	12	Stable, mild‐to‐moderate	Not permitted	212 (160/52)	38 to 41	32 to 43	72 to 4
Pannetieri 2018A (NCT02161757)	Tralokinumab 300 mg SC Q2W or Q4W	52	Severe uncontrolled	Stable dose (≥ 500 μg FP or equiv.)	1207 (807/400)	49 to 51	30 to 37	60 to 62
Pannetieri 2018B (NCT02194699)	Tralokinumab 300 mg SC Q2W	52	Severe uncontrolled	Stable dose (≥ 500 μg FP or equiv.)	856 (428/428)	47 to 48	31 to 34	61
Piper 2013 (NCT00873860)	Tralokinumab 150/300/600 mg SC Q2W	12	Moderate‐to‐severe uncontrolled	Permitted	194 (146/48)	43 to 50	29 to 60	NR
Rabe 2018 (NCT02528214)	Dupilumab 300 mg SC Q2W	24	Severe asthma	Tapered down	210 (103/107)	51 to 52	39 to 40	NR
Russell 2018 (NCT02449473)	Tralokinumab 300 mg SC Q2W	12	Moderate‐to‐severe uncontrolled	Stable dose (≥ 250 μg FP daily or equiv.)	79 (39/40)	47 to 50	41 to 50	NR
Scheerens 2014 (NCT00781443)	Lebrikizumab 5 mg/kg SC Q4W	AC study (12)	Mild	Not stated	29 (13/16)	32 to 66	46 to 56	82‐84
Singh 2010^b (NCT00974675)	Tralokinumab 1/5/10 mg/kg IV Q4W	21	Mild well‐controlled	Permitted	23 (19/4)	35 to 43	67 to 100	NR
Tripp 2017^b (NCT00986037)	RPC4046 0.3/3 mg/kg IV Q1W	16	Mild‐to‐moderate controlled	Low‐to‐medium dose permitted	27 (20/7)	23 to 33	75 to 100	NR
Wenzel 2007a (NCT00535028)	Pitrakinra 25 mg SC once daily for 28 days	AC study (28 days)	Mild‐to‐moderate	Discontinued 1 month prior to study drug	24 (12/12)	30 to 31	42 to 58	100‐102
Wenzel 2007b (NCT00535031)	Pitrakinra 60 mg nebulised twice daily for 28 days	AC study (28 days)	Mild‐to‐moderate	Discontinued 1 month prior to study drug	32 (16/16)	25 to 29	47 to 80	96 to ‐99
Wenzel 2010 (NCT00801853)	Pitrakinra 1/3/10 mg	12	Moderate‐to‐severe uncontrolled	Fluticasone withdrawal from 6 weeks after initiation of blinded treatment	534 (397/137)	NR	NR	NR
Wenzel 2013 (NCT01312961)	Dupilumab 300 mg SC Q1W	12	Moderate‐to‐severe	Medium‐to‐high dose discontinued during weeks 6 to 9	104 (52/52)	38 to 42	50	72
Wenzel 2016 (NCT01854047)	Dupilumab 200/300 mg SC Q2/4W	24	Uncontrolled persistent asthma	Medium‐to‐high dose plus LABA	619 (461/158)	48 to 51	34 to 44	60 to 61

^aThis trial was designed to be 52 weeks; however, the trial was terminated early and the median duration of treatment was approximately 24 weeks. Pooled data are reported for the two replicate studies.

^bPhase 1 safety and PK study

^cUnless otherwise stated

Abbreviations: AC: allergen challenge; BDP: beclomethasone dipropionate; DPI: dry powder inhaler; FEV1: forced expiratory volume in one second; FP: fluticasone propionate; ICS: inhaled corticosteroids; IL‐4R: interleukin‐4 receptor; IL‐13: interleukin‐13; IV: intravenous; LABA: long‐acting beta‐agonist; NR: not reported; PK: pharmacokinetic; Q1/2/4W: every 1/2/4 weeks; SC: subcutaneous; SOC: standard of care.

Results of the search

We identified 472 records by conducting electronic searches of bibliographic databases on the 16 October 2020. Of a total of 446 records (26 duplicates removed), we excluded 261 records upon screening titles and abstracts. We examined full‐text articles of the remaining 185 records and excluded a further 22 records (reporting 18 studies; see Excluded studies). The remaining 163 records reported the findings of 41 studies, which we included in this review (n = 34 studies included in the narrative analyses; n = 6 studies awaiting classification; n = 1 study ongoing). A total of 29 studies were included in the quantitative analyses. Figure 1 presents the flow of information through this systematic review.

Figure 1

Study flow diagram.

Included studies

A total of 41 studies met the inclusion criteria, of which 29 contributed to the quantitative analyses (Borish 1999; Borish 2001; Brightling 2015; Burgess 2018; Busse 2015; Castro 2018; Corren 2010; Corren 2011; De Boever 2014; Hanania 2011; Hanania 2015a; Hanania 2015b; Hanania 2016a; Hanania 2016b; Hodsman 2013; Korenblat 2018; NCT00425061; NCT00640016; Noonan 2013; Pannetieri 2018A; Pannetieri 2018B; Piper 2013; Rabe 2018; Russell 2018; Singh 2010; Tripp 2017; Wenzel 2010; Wenzel 2013; Wenzel 2016); five were included in qualitative analyses (narrative synthesis only Gauvreau 2011a; Gauvreau 2011b; Scheerens 2014; Wenzel 2007a; Wenzel 2007b), six were awaiting classification (having completed, but no data reported Euctr 2015‐001572‐22; NCT00024544; NCT01987492; NCT02948959; NCT03112577; NCT03387852); and one was ongoing (NCT03782532). Regarding the replicate studies Hanania 2015a and Hanania 2015b, following the discovery of a host‐cell impurity in the study drug material, protocols were amended to convert from phase III to phase IIb. Subsequently, dosing of study medication was discontinued early as a precautionary measure. The data collected for analysis were from a placebo‐controlled period of variable duration and pooled across both studies. Therefore, pooled data for the two studies have herein been included under Hanania 2015a.

The studies Hanania 2016a; Hanania 2016b were reported in a single publication, as were the studies Pannetieri 2018A; Pannetieri 2018B.

Methods

All of the 29 included studies contributing to the quantitative analyses were randomised, placebo‐controlled trials; eight were phase 3 studies, fifteen were phase 2 studies, and six were phase 1 dose‐ranging studies (Borish 1999; Borish 2001; Burgess 2018; Hodsman 2013; Singh 2010; Tripp 2017). The majority (24 of 29) were multi‐centre studies. Overall geographical coverage was broad; the majority of studies were performed in Europe, North America and Oceania and several large studies enrolled participants from South America, Russia, Asia, and South Africa (Brightling 2015; Castro 2018; Hanania 2015a; Hanania 2015b; Hanania 2016a; Hanania 2016b; Rabe 2018; Wenzel 2016). Studies had a randomly assigned treatment period ranging from two weeks to 52 weeks (mean 18 weeks; median 16 weeks; mode 12 weeks). The study setting was poorly reported, but appeared, principally, to comprise of academic and clinical research centres.

Additionally, five studies were allergen challenge studies and did not contribute data to the quantitative analyses (Gauvreau 2011a; Gauvreau 2011b; Scheerens 2014; Wenzel 2007a; Wenzel 2007b). Of these studies, all were randomised, controlled trials (phase 1, n = 2; phase 2, n = 3); two were single‐centre studies conducted in the UK (Wenzel 2007a; Wenzel 2007b), two studies were conducted at four centres in Canada (Gauvreau 2011a; Gauvreau 2011b) and the number of centres and location was not reported for Scheerens 2014. Four of the studies had a duration of approximately four weeks and one study had a duration of 12 weeks (Scheerens 2014). Where declared, all of the included studies were sponsored by pharmaceutical companies (two studies did not declare the source of funding).

Participants

The 29 studies contributing quantitative data randomised a total of 10,604 participants (Table 1). The majority of studies (23 of 29) enrolled individuals with moderate or severe uncontrolled asthma; four studies enrolled individuals with mild‐to‐moderate asthma (Korenblat 2018; Noonan 2013; Singh 2010; Tripp 2017) and two enrolled individuals with mild asthma (Burgess 2018; Hodsman 2013). The mean ages of participants across the relevant arms of all included studies ranged from 22 to 55 years. Only five studies permitted enrolment of children/adolescents (defined by the authors as aged between 12 and 18 years )(Busse 2015; Castro 2018; Pannetieri 2018A; Pannetieri 2018B; Rabe 2018); participants in this age group accounted for less than 5% of the total participants contributing data to the present review. In approximately half of the trials, less than 50 per cent of participants were male (range across studies 25% to 63%, with the exception of Burgess 2018 and Hodsman 2013 where all participants were male, and NCT00640016; Singh 2010, and Tripp 2017, where the proportion of males across treatment arms ranged from 0 to 75, 67 to 100 and 75 to 100, respectively). Where reported, post‐bronchodilator per cent predicted FEV1 ranged from 55% to 87% (with the exception of Hodsman 2013 where the range was 102 to 105% across groups). ICS were not permitted or discontinued prior to study initiation in six studies; were maintained/permitted in 21 studies; and were tapered during the double‐blind period in two studies. The use of maintenance systemic corticosteroids was not permitted in 19 studies and was permitted or required in five studies (this information was not reported in five studies).

The five allergen challenge studies randomised a total of 141 participants to receive either anti‐interleukin‐13 or anti‐interleukin‐13/‐4 (pitrakinra) agents or placebo. Participants had mild or mild‐to‐moderate asthma, were aged between 26 and 36 years of age and approximately half were male; post‐bronchodilator per cent predicted FEV1 ranged from 82% to 102%.

Intervention

Of the 10,604 participants randomised across the 29 studies contributing quantitative data, a total of 2560 participants were randomised to receive an anti‐interleukin‐4 agent (soluble IL‐4R, dupilumab, pitrakinra), 4401 participants were randomised to receive an anti‐interleukin‐13 agent (GSK679586, IMA‐638 [anrukinzumab], lebrikizumab, RPC4046, tralokinumab, VR492) and 3643 were randomised to receive placebo. The authors noted that pitrakinra and dupilumab also have some interleukin‐13 activity. No relevant studies were identified where the comparator was an anti‐immunoglobulin agent or an anti‐interleukin‐5 agent.

Across the 29 studies, four studies (2835 participants) evaluated dupilumab (300 mg once every week (Q1W), 200 mg once every 2 weeks (Q2W), 300 mg Q2W, 200 mg once every 4 weeks (Q4W), 300 mg Q4W, each administered by subcutaneous injection), eight studies (3432 participants) evaluated lebrikizumab (37.5 mg Q4W, 125 mg Q4W, 250 mg Q4W), and nine studies (3259 participants) evaluated tralokinumab (75 mg Q1W, 150 mg Q1W, 300 mg Q1W, 150 mg Q2W, 300 mg Q2W, 600 mg Q2W, 300 mg Q4W, each administered by SC injection; 1/5/10 mg/kg administered by IV injection). Additionally, two studies evaluated a soluble IL‐4R (Borish 1999; Borish 2001), two studies evaluated GSK679586 (De Boever 2014; Hodsman 2013), and one study valuated each of IMA‐638 (NCT00425061), VR492 (Burgess 2018), RPC4046 (Tripp 2017) and pitrakinra (Wenzel 2010). Concomitant inhaled corticosteroid (ICS) use was permitted or required in most of the included studies, with the exception of five (Borish 1999; Borish 2001; Hodsman 2013; Korenblat 2018; Noonan 2013).

Of the five allergen challenge studies, two evaluated IMA‐638 (Gauvreau 2011a; Gauvreau 2011b), two evaluated pitrakinra (Wenzel 2007a; Wenzel 2007b) and one evaluated lebrikizumab (Scheerens 2014).

Outcomes

Most prespecified outcomes were reported by at least seven of the included studies (reporting data for ≥ 4960 participants). The proportion of participants experiencing an exacerbation requiring an emergency department visit or hospitalisation was reported by two large studies (reporting data for 2039 participants) and the proportion of patients experiencing an exacerbation requiring a course of OCS was only reported by one study (reporting data from 452 participants). However, a post hoc exploratory endpoint combining the two prespecified outcomes relating to exacerbations (i.e. the proportion of patients requiring emergency department visit, hospitalisation or OCS) was evaluated by seven studies (reporting data for 6998 participants). Health‐related quality of life (measured using the Asthma Quality of Life Questionnaire (AQLQ)) was evaluated by seven studies, lung function (change from baseline in FEV1) was evaluated by 13 studies, asthma control (measured by the Asthma Control Questionnaire (ACQ)‐5) was evaluated by 14 studies and adverse events and serious adverse events by 18 and 22 studies, respectively (summary of findings Table 1 and Table 2). Time off work or study was not reported by any of the included studies. Changes from baseline in FENO, blood eosinophils and periostin were evaluated by 11, six and two studies, respectively.

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Table 2. Sensitivity analysis: random effects versus fixed effects

Outcome	Fixed‐effect model	Random‐effects model
Exacerbation requiring hospitalisation or ED visit	RR 0.68, 95% CI 0.47 to 0.98 (participants = 2039; studies = 2)	RR 0.68, 95% CI 0.47 to 0.98
HRQoL (AQLQ)	MD 0.18, 95% CI 0.12 to 0.24 (participants = 4960; studies = 7)	MD 0.18, 95% CI 0.12 to 0.24
Serious adverse events	OR 0.91, 95% CI 0.76 to 1.09 (participants = 7739; studies = 22)	OR 0.91, 95% CI 0.76 to 1.09

Abbreviations: AQLQ: asthma quality of life questionnaire; CI: confidence interval; ED: emergency department; HRQoL: health‐related quality of life; MD: mean difference; OR: odds ratio; RR: rate ratio.

Five studies contributed data to the subanalysis of the post hoc outcome 'proportion of patients requiring emergency department visit, hospitalisation or OCS' according to levels of blood eosinophils (Castro 2018; Hanania 2016a; Hanania 2016b; Rabe 2018; Wenzel 2016), FENO (Castro 2018) or periostin (Hanania 2015a; Hanania 2015b; Hanania 2016a; Hanania 2016b).

With the exception of FEV1, the allergen challenge studies did not evaluate prespecified outcomes of interest.

Excluded studies

We excluded 18 studies from the review following examination of full‐text reports. Nine studies used a control arm not relevant to this review (i.e. not placebo or a prespecified active comparator) (NCT00339872; NCT00638989; NCT00785668; NCT01592396; NCT02085473; NCT02134028; NCT02546869; NCT02902809; Nsouli 2018); in five studies, the study population was not relevant to this review (e.g. participants had respiratory comorbidities or were healthy volunteers) (Bachert 2016; Bachert 2019; NCT01875003; Oh 2009; Weinstein 2017); in one study, patients received an intervention (omalizumab) not relevant to this review (Djukanovic 2004); in one study patients were not randomised (Banfield 2008); and one study used a sequential study design (Parsey 2004). The CLAVIER study (NCT02099656) was terminated early and drug dosing was terminated and enrolment closed before the planned sample size was achieved; therefore, this study was excluded (as only an article reporting bronchoscopy data from this study was available (Austin 2020)).

Risk of bias in included studies

Please refer to the Characteristics of included studies tables for details on risk of bias and for supporting evidence for each study. Figure 2 provides a summary of risk of bias judgements, presented by study and domain (sequence generation, allocation concealment, blinding, incomplete data, selective reporting and 'other'). Figure 3 depicts the risk of bias for each domain, presented as percentages across all included studies. Across 306 assessments (34 studies, nine risk of bias domains), 23 6 were considered to be at a low risk of bias, 15 at a high risk of bias and 5 5 to have an unclear risk of bias.

Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Approximately a third of the included studies (12 of 34) provided insufficient information regarding methods of random sequence generation and approximately half (15 of 34 studies) provided insufficient information regarding concealment of treatment allocation to allow a judgement on risk of bias; the risk of bias for these studies was rated as unclear. Twenty‐two studies employed adequate methods of random sequence generation and were considered to be at low risk of bias, and 19 of 34 studies reported adequate methods of allocation concealment. No studies were considered to have a high risk of selection bias.

Blinding

We considered the risk of performance and detection bias for objective and subjective outcomes separately. For objective outcomes (all‐cause mortality, serious adverse events (SAEs), exacerbations, lung function, time off work or study, reduction in corticosteroid dose, Adverse events (AEs) and measures of airway inflammation) we considered that a lack of blinding would not result in a risk of detection or performance bias; therefore, all studies were considered to be at low risk of bias with respect to these outcomes. The only subjective outcomes relevant to this review were health‐related quality of life (HRQoL) based on assessment of AQLQ, and asthma control determined by the ACQ; for these outcomes, 28 of 34 studies were considered to be at low risk of performance bias and the risk unclear in the remaining six studies (Borish 1999; Hanania 2011; Hanania 2015a; Hanania 2015b; Singh 2010; Wenzel 2010). The risk of detection bias for the HRQoL and asthma control outcomes was considered to be low for 2 7 of 34 studies and unclear in the remaining seven studies (Borish 1999; Hanania 2011; Hanania 2015a; Hanania 2015b; Singh 2010; Tripp 2017; Wenzel 2010).

Incomplete outcome data

We considered 22 of 34 studies to be at low risk of attrition bias on the basis of low and balanced rates of participant withdrawal, which were adequately documented in the trial reports. Nine studies (Borish 1999; Borish 2001; Hanania 2015a; Hanania 2015b; Hodsman 2013; NCT00425061; NCT00640016; Singh 2010; Wenzel 2013) were considered to be at high risk for attrition bias based on either a high proportion of withdrawals in one or more treatment arms, an uneven proportion of withdrawals between treatment arms, or both; in some instances, high or imbalanced withdrawal rate arose due to early study termination (Hanania 2015a; Hanania 2015b; Singh 2010). Insufficient information was reported for three studies (Hanania 2011; Russell 2018; Wenzel 2010), resulting in a rating of unclear risk of attrition bias.

Selective reporting

We considered 24 of 34 studies to be at low risk of reporting bias. Three studies were considered to be at high risk of reporting bias; in one instance, the study was stopped early due to futility of the interim efficacy analysis results and the sponsor decided to only analyse safety results and key efficacy data (NCT00425061); and in two instances, outcomes were reported by biomarker level, which was not prespecified in the trial registry (Hanania 2016a; Hanania 2016b). Seven studies (Borish 1999; Borish 2001; De Boever 2014; Hanania 2011; NCT00640016; Russell 2018; Wenzel 2010) provided insufficient information (i.e. comparison of prespecified and reported outcomes was not possible).

Other potential sources of bias

No 'other' sources of bias were identified in 26 of the included studies. Five studies were rated as 'unclear' for other risk of bias, where insufficient information was available (abstract only; Hanania 2011; Wenzel 2010) or it was uncertain how the anomaly would affect the results (lack of formal sample size calculation and lower than planned dose of allergen received [Gauvreau 2011a]; or imbalance in baseline characteristics where the effect on treatment effect was uncertain [Corren 2011; Wenzel 2013]). We considered there to be potential sources of bias present in three of the studies: in one study (Borish 1999) the authors stated that baseline characteristics were balanced, but there appeared to be a trend towards better baseline lung function and fewer symptoms in the placebo group versus IL‐4R groups, which would tend to favour placebo with regards to treatment effect; and in two studies (Hanania 2015a; Hanania 2015b), the protocol underwent substantial modification after study initiation because the study drug was found to contain an impurity that required a manufacturing change and the study was downgraded to a phase IIb (from phase III) and planned enrolment was greatly reduced.

Effects of interventions

See: Summary of findings 1 Anti‐IL13 or anti‐IL4 agents compared to placebo for children and adults with asthma; Summary of findings 2 Other secondary and post hoc exploratory outcomes

Structure of the meta‐analysis

We performed a meta‐analysis only when interventions and outcomes were sufficiently similar to permit the pooling of data. In each forest plot, we subgrouped the data according to type and dose of anti‐interleukin‐13 or anti‐interleukin‐4 agent. A number of comparisons should be interpreted with caution due to the relatively small number of trials for each subgroup, heterogeneity in study design (i.e. length of study, and eligibility criteria), or a low number of events (e.g. SAEs).

Structure of the narrative synthesis

In the following sections, we present a narrative summary of the effects of the interventions according to the prespecified outcomes of interest (primary: exacerbations requiring hospitalisation or emergency department visit, respiratory health‐related quality of life, SAEs; secondary: exacerbations requiring OCS, lung function, asthma control, time off work or study, AEs, measures of airway inflammation, reduction in OCS dose; exploratory outcome: exacerbation requiring OCS/hospitalisation/emergency department visit). For each outcome, we described the overall effect of the intervention irrespective of anti‐interleukin‐13/‐4 agent or dose, followed by the effect of the intervention in subgroups according to anti‐interleukin‐13/‐4 agent and dose.

Several studies examined the response to anti‐interleukin‐13/‐4 agents following allergen challenge (Gauvreau 2011a; Gauvreau 2011b; Scheerens 2014; Wenzel 2007a; Wenzel 2007b). Data from these studies were not included in the meta‐analyses as these studies posed a different clinical question.

Primary outcomes

Exacerbations requiring hospitalisation or emergency department visit

Two studies (2039 participants) reported exacerbations requiring hospitalisation or emergency department visit; both studies compared tralokinumab with placebo (Pannetieri 2018A; Pannetieri 2018B ). The rate of exacerbations requiring hospitalisation or emergency department visit was lower in participants receiving tralokinumab versus placebo (rate ratio 0.68, 95% CI 0.47 to 0.98; Analysis 1.1). The overall certainty of the evidence for this outcome was rated as moderate, having been downgraded once for indirectness (low number studies of a single anti‐interleukin‐13 agent).

Evaluation of the results by agent and dose showed that a reduction in the rate of exacerbations requiring hospitalisation or emergency department visit was achieved in participants receiving tralokinumab 300 mg subcutaneous (SC) every two weeks (Q2W; rate ratio 0.63, 95% CI 0.41 to 0.99; P = 0.04; n = 2 studies; n = 1435 participants); in participants receiving tralokinumab 300 mg SC Q4W, the 95% confidence intervals included no difference (rate ratio 0.78, 95% CI 0.41 to 1.49; P = 0.45; n = 1 study; n = 604 participants) (Figure 4). The test for subgroup differences was not significant (P = 0.61).

Figure 4

Forest plot of comparison: 1 Anti‐interleukin‐13 or ‐4 agents with placebo, outcome: 1.1 Exacerbation requiring hospitalisation or ED visit.

Respiratory health‐related quality of life

Seven studies (4960 participants) reported adjusted respiratory HRQoL at the end of treatment (i.e. change from baseline in HRQoL), as assessed using the AQLQ ( Brightling 2015; Castro 2018; Corren 2010; Korenblat 2018; Pannetieri 2018A; Pannetieri 2018B; Wenzel 2016). An increase in AQLQ score represents an improvement in quality of life, with a change of 0.5 units considered as the minimally clinically important difference (MCID). In participants receiving an anti‐interleukin‐13/‐4 agent, the mean improvement versus placebo in adjusted AQLQ score was 0.18 (95% CI 0.12 to 0.24; Analysis 1.2); however, this finding did not exceed the MCID and was thus deemed not to be a clinically relevant improvement. The overall certainty of the evidence for this outcome was rated as high.

The results were generally consistent across different anti‐interleukin‐13/‐4 agents and doses, with mean differences versus placebo ranging from 0.11 with tralokinumab 300 mg SC Q2W, to 0.30 with dupilumab 300 mg SC Q4W. Although some statistically significant effects were observed with individual agents (dupilumab 200 mg SC Q2W [MD 0.29, 95% CI 0.16 to 0.42; P < 0.0001; participants = 1111; studies = 2]; dupilumab 300 mg SC Q2W [MD 0.27, 95% CI 0.14 to 0.40; P < 0.0001; participants = 1127; studies = 2]; tralokinumab 300 mg SC Q2W [MD 0.11, 95% CI ‐0.00 to 0.23; P = 0.06; participants = 1262; studies = 3]), none of the improvements exceeded the MCID and were thus not considered to be clinically relevant (Analysis 1.2). Furthermore, the overall test for subgroup differences was negative (P = 0.17).

Serious adverse events

Twenty‐two studies (7739 participants) reported the number of participants experiencing SAEs during the study period; there was probably little or no difference between groups (anti‐interleukin‐13/‐4 agents versus placebo; OR 0.91, 95% CI 0.76 to 1.09; I² = 0%; Analysis 1.3). Compared with taking placebo, we estimated that taking an anti‐interleukin‐13/‐4 agent would result in seven fewer people per 1000 experiencing an SAE, but the confidence intervals ranged from 18 fewer to six more people per 1000. The overall certainty of the evidence for this outcome was rated as moderate, having been downgraded once for imprecision (95% CI for the treatment effect crossed 1.0).

The results were consistent across the different anti‐interleukin‐13/‐4 agents and doses, with ORs ranging from 0.16 with lebrikizumab 37.5 mg SC Q4W to 2.59 with IMA‐638 IV 200 mg SC (Figure 5); the overall test for subgroup differences was negative (P = 0.99).

Figure 5

Forest plot of comparison: 1 Anti‐interleukin‐13 or ‐4 agents with placebo, outcome: 1.2 Health‐related quality of life (adjusted mean diff versus placebo). A change of 0.5 is considered the minimum clinically significant difference (MCID).

Secondary outcomes

Exacerbations requiring OCS

One study (452 participants) reported annualised rates of exacerbations requiring treatment with OCS (Brightling 2015); compared with placebo, there may be little or no difference in the rate of exacerbations requiring OCS in patients receiving tralokinumab (rate ratio 0.98, 95% CI 0.72 to 1.32; Analysis 1.4). The rate ratio was consistent for both dose regimens of tralokinumab examined (300 mg SC Q2W: rate ratio 0.94, 95% CI 0.62 to 1.42; 300 mg SC Q4W: rate ratio 1.02, 95% CI 0.65 to 1.59) (overall test for subgroup differences was negative (P = 0.79)) . The overall certainty of the evidence for this outcome was rated as low, having been downgraded once for imprecision (95% CI for the treatment effect crossed 1.0) and once for indirectness (low number studies of a single anti‐interleukin‐13 agent).

Two studies reported the number of participants experiencing an exacerbation requiring treatment with OCS (Corren 2010; NCT00425061) . There was no clear difference in the number of participants experiencing an exacerbation requiring OCS between those receiving an anti‐interleukin‐13 agent and those receiving placebo (OR 0.93, 95% CI 0.49 to 1.78; participants = 453; I² = 29%; Analysis 1.5), although confidence intervals were wide. Acknowledging the small sample sizes per study, this finding was consistent for both agents examined, regardless of dose. Where estimable, the odds ratio versus placebo ranged from 0.47 to 1.14 across doses of AMG317, from 6.38 to 19.29 with SC doses of IMA638, and from 0.09 to 0.33 with IV doses of IMA638. The overall test for subgroup differences was negative (P = 0.20).

Lung function (adjusted trough FEV1)

A total of 13 studies (n = 4829 participants) reported adjusted trough FEV1 at the end of treatment (i.e. change from baseline in FEV1). In participants receiving an anti‐interleukin‐13/4 agent, the mean difference versus placebo in adjusted trough FEV1 was 0.10 L (95% CI 0.08 to 0.12; I² = 36%; Analysis 1.6). The MCID in FEV₁ has not been definitively established for asthma, but it is likely that changes of 100 mL to 200 mL in FEV₁ are clinically important (Santanello 1999). Therefore, improvements in adjusted trough FEV1 observed in participants receiving anti‐interleukin‐13/4 agents are borderline clinically relevant. The overall certainty of the evidence for this outcome was rated as moderate, having been downgraded once for inconsistency (moderate heterogeneity of 36%).

The results were generally consistent across the different anti‐interleukin‐13/4 agents and doses examined. An exception to the general trend was observed with GSK679586 10 mg/kg IV Q1W where a statistically significant decrease in trough FEV1 was observed (MD ‐0.10, 95% CI ‐0.19 to ‐0.01; participants = 198), although this result was based on a single study and did not exceed the MCID. The overall test for subgroup differences was significant (P = 0.005), largely driven by this outlying result.

Asthma control

Fourteen studies (n = 6251 participants) reported adjusted ACQ scores at the end of treatment (i.e. change from baseline in ACQ score). In participants receiving an anti‐interleukin‐13/‐4 agent versus placebo, there is probably a greater improvement in the mean adjusted ACQ score (MD ‐0.19, 95% CI ‐0.24 to ‐0.14; I² = 14%; Analysis 1.7); however, the magnitude of the improvement did not exceed the MCID of 0.40 (Nguyen 2014). The overall certainty of the evidence for this outcome was rated as moderate, having been downgraded once for inconsistency (moderate heterogeneity of 14%).

Results were generally consistent across the different anti‐interleukin‐13/‐4 agents and doses examined, but the effect never exceeded the MCID of 0.40 (Analysis 1.7) (overall test for subgroup differences P = 0.07).

Time off work or study

No studies reported data for this outcome.

Adverse events (all causes)

A total of 18 studies (n = 7419 participants) reported the number of participants reporting any adverse event during the study period. The proportion of patients experiencing any AE was greater in those receiving anti‐interleukin‐13/‐4 agents compared with those receiving placebo (OR 1.16, 95% CI 1.04 to 1.30; participants = 7419; I² = 0%; Analysis 1.8). The most commonly reported adverse events in participants treated with anti‐interleukin‐13/‐4 agents were upper respiratory tract infection, nasopharyngitis, headache and injection site reaction. The overall certainty of the evidence for this outcome was rated as high. Examination of the results across different agents and doses (Analysis 1.8) revealed little or no difference versus placebo for all agents and doses, with the exception of tralokinumab 300 mg SC Q2W (OR 1.37, 95% CI 1.11 to 1.69; P = 0.004); the weighting of this subgroup (25.9%) appeared to account for the statistical significance of the pooled effect. The overall test for subgroup differences was negative (P = 0.81).

Measures of airway inflammation

Change from baseline in FENO

Eleven studies (n = 3577 participants) reported adjusted FENO levels at the end of treatment. In participants receiving an anti‐interleukin‐13/‐4 agent, the mean difference versus placebo in adjusted FENO levels at the end of treatment was ‐14.68 (95% CI ‐16.56 to ‐12.80; I² = 46%; Analysis 1.9). The overall certainty of the evidence for this outcome was rated as moderate, having been downgraded once for inconsistency (moderate heterogeneity of 46%). This effect was generally consistent across individual agents and doses with the magnitude of the observed difference versus placebo ranging from ‐40 ppb with GSK679586 10 mg/kg IV Q4W, to ‐3.8 ppb with VR492 0.5 mg (Analysis 1.9). The relative reduction in FENO was statistically significant for all subgroups with the exception of the lebrikizumab 500 mg SC Q4W, dupilumab 200 mg SC Q4W, VR492 0.5 mg and nebulised soluble IL‐4R 500 μg and 1500 μg groups (acknowledging the low number of participants in the soluble IL‐R4 and VR492 groups). The overall test for subgroup differences was significant at P = 0.03, but should be interpreted with caution, given the small size and low participant numbers in many of the individual subgroups.

Change from baseline in blood eosinophil count

Six studies (n = 2598 participants) reported data on adjusted blood eosinophil count at the end of treatment (Castro 2018; Corren 2011; De Boever 2014; NCT00425061; Russell 2018; Wenzel 2013). In participants receiving an anti‐interleukin‐13/‐4 agent, the mean difference versus placebo in adjusted blood eosinophil count at the end of treatment was 0.06 x 10*9 cells/L (95% CI 0.04 to 0.09 x 10*9 cells/L; I² = 13%; Analysis 1.10); however, this increase is not considered to be clinically relevant. The overall certainty of the evidence for this outcome was rated as high. A consistent effect was observed across agents and doses examined (Analysis 1.10) (overall test for subgroup differences, P = 0.32), with increases from baseline versus placebo ranging from 0.02 x 10*9 cells/L with dupilumab 200 mg SC Q2W, to 0.20 x 10*9 cells/L with IMA‐638 0.6 mg/kg IV and 75 mg SC.

Change from baseline in periostin concentration

Two studies (n = 2106 participants) reported data‐adjusted periostin levels at the end of treatment (Castro 2018; Korenblat 2018). In participants receiving either lebrikizumab or dupilumab, the mean difference versus placebo in adjusted periostin concentration at the end of treatment was ‐9.04 ng/mL (95% CI ‐10.92 to ‐7.17 ng/mL; I² = 92%; Analysis 1.11). The overall certainty of the evidence for this outcome was rated as low, having been downgraded twice for inconsistency (considerable heterogeneity of 92%). The magnitude of the relative reduction in adjusted periostin levels was greater for dupilumab with SC doses of 200 or 300 mg Q2W (MD ‐14 ng/mL) than with lebrikizumab at a dose of 125 mg Q4W (MD ‐4.2 ng/mL) (overall test for subgroup differences P < 0.00001).

Reduction in maintenance oral corticosteroid dose

Two studies (350 participants) reported the percentage reduction from baseline in OCS use (Busse 2015; Rabe 2018). In participants receiving either lebrikizumab or dupilumab, the mean reduction in OCS dose versus placebo at end of treatment was ‐15.58% (95% CI ‐23.30 to ‐7.85; I² = 84%; Analysis 1.12). The overall certainty of the evidence for this outcome was rated as low, having been downgraded twice for inconsistency (considerable heterogeneity of 84%). In terms of subgroups, one study reported a non‐significant 7.8% reduction in OCS dose in patients receiving tralokinumab 300 mg SC Q2W versus placebo (MD ‐7.77, 95% CI ‐17.60 to 2.06; participants = 140), whereas a statistically significant 28% reduction in OCS dose was reported in the second study for patients receiving dupilumab 300 mg SC Q2W versus placebo (MD ‐28.20, 95% CI ‐40.70 to ‐15.70; P < 0.00001; participants = 210). However, the overall test for subgroup differences was negative (P = 0.32).

Post hoc exploratory outcome

Exacerbations requiring hospitalisation, emergency department visit or OCS

Seven studies (6998 participants) reported exacerbations requiring OCS or hospitalisation or emergency department visit (Busse 2015; Castro 2018; Hanania 2016a; Hanania 2016b; Pannetieri 2018A; Pannetieri 2018B; Wenzel 2016). The rate of exacerbations requiring OCS or hospitalisation or emergency department visit may be lower in participants receiving anti‐13/‐4 agents versus placebo (rate ratio 0.71, 95% CI 0.65 to 0.77; participants = 6998; I² = 67%; Analysis 1.13). The overall certainty of the evidence for this outcome was rated as low, having been downgraded twice for inconsistency (substantial heterogeneity of 67%).

Evaluation of the results by agent and dose showed that, although a reduction in the rate of exacerbations requiring hospitalisation or emergency department visit was seen for all agents and doses, the magnitude and certainty of this reduction was greater in participants receiving lebrikizumab 37.5 mg SC Q4W (rate ratio 0.68, 95% CI 0.53 to 0.87; n = 2 studies; participants = 1074), lebrikizumab 125 mg SC Q4W (rate ratio 0.74, 95% CI 0.59 to 0.93; n = 2 studies; participants = 1074), dupilumab 200 mg SC Q2W (rate ratio 0.51, 95% CI 0.40 to 0.64; n = 2 studies; participants = 1135) and dupilumab 300 mg SC Q2W (rate ratio 0.52, 95% CI 0.42 to 0.65; n = 2 studies participants = 1144). The reduced rates of exacerbations requiring OCS, hospitalisation or emergency department visit were uncertain with tralokinumab 300 mg SC (either Q2W or Q4W) or with dupilumab SC Q4W (either 200 mg or 300 mg) (Analysis 1.13). This is reflected in the overall test for subgroup differences (P < 0.00001), although cautious interpretation is required due to the small size and low participant numbers in many of the individual subgroups.

Prespecified subgroup analyses

Individual anti‐interleukin‐13 or anti‐interleukin‐4 agent

The effect of individual agents is reported in the main analyses of the primary and secondary outcomes (see above).

Agent class

This subgroup analysis evaluated the effect of agents directly targeting IL13 (tralokinumab, lebrikizumab, GSK679‐586, IMA‐638, RPC‐4046) versus the effects of agents directly targeting IL4R (dupilumab, AMG‐317, pitrakinra, soluble IL‐4R).

For the primary outcome, exacerbations requiring hospitalisation or emergency department (ED) visit, only two studies of tralokinumab, which targets interleukin‐13, contributed data to the meta‐analysis. Therefore, a comparison between agents directly targeting interleukin‐13 and IL‐4R, could not be performed for this outcome as no data for agents directly targeting IL‐4 were available.

For the primary outcome, health‐related quality of life, agents directly targeting interleukin‐13 resulted in an improvement in respiratory health‐related quality of life versus placebo, as assessed by AQLQ (MD 0.10, 95% CI 0.01 to 0.18; participants = 2105; Analysis 2.2), as did agents directly targeting IL‐4R (MD 0.26, 95% CI 0.17 to 0.34; participants = 2855; Analysis 3.1); neither improvement versus placebo exceeded the MCID for AQLQ.

For the primary outcome, SAEs, subgroup analyses by agent class were consistent with the primary analyses (agents directly targeting interleukin‐13 versus placebo: OR 0.84, 95% CI 0.67 to 1.05; participants = 4443; Analysis 2.3; agents directly targeting IL4R versus placebo: OR 1.05, 95% CI 0.78 to 1.40; participants = 3296; Analysis 3.2).

Studies of three agents (dupilumab, lebrikizumab, tralokinumab) contributed data to the meta‐analyses for the exploratory outcome, exacerbations requiring hospitalisation/ED/OCS. The rate of exacerbations requiring OCS or hospitalisation or emergency department visit was lower in participants receiving agents directly targeting interleukin‐13 (tralokinumab or lebrikizumab; rate ratio 0.83, 95% CI 0.74 to 0.92; participants = 4327; Analysis 2.4) compared with placebo. The rate of exacerbations requiring OCS or hospitalisation or emergency department visit was also lower in participants receiving agents directly targeting IL‐4R (dupilumab; rate ratio 0.52, 95% CI 0.44 to 0.61; participants = 2671; Analysis 3.3) compared with placebo. The magnitude of the improvement versus placebo appeared to be greater with dupilumab compared with agents directly targeting interleukin‐13; however, formal statistical comparison was not performed.

Duration of therapy

This subgroup analysis examined the effect of treatment duration (≤ six months versus > six months).

For the primary outcome, exacerbations requiring hospitalisation or ED visit, only two 52‐week studies of tralokinumab contributed data to the meta‐analysis. Therefore, a comparison between studies of duration ≤ six months or > six months could not be performed for this outcome.

For the primary outcome, health‐related quality of life, considering data from studies with a duration of six months or less demonstrated an improvement in respiratory health‐related quality of life versus placebo, as assessed by AQLQ (MD 0.13, 95% CI ‐0.00 to 0.26; participants = 1162; Analysis 4.1); this was also the case when considering data from studies with a duration greater than six months (MD 0.19, 95% CI 0.13 to 0.26; participants = 3798; Analysis 5.2); neither improvement versus placebo exceeded the MCID for AQLQ.

For the primary outcome, SAEs, subgroup analyses by study duration were consistent with the primary analyses. There was no clear difference between anti‐interleukin‐13/‐4 agents versus placebo, when considering data from studies of duration ≤ six months (OR 1.09, 95% CI 0.73 to 1.63; participants = 2738; Analysis 4.2) or > six months (OR 0.87, 95% CI 0.72 to 1.06; participants = 5001; Analysis 5.3). However, confidence intervals did not exclude an effect.

For the exploratory outcome, exacerbations requiring hospitalisation/ED/OCS, only one of the studies contributing to the primary analyses had a duration of six months or less. Results from this study showed that the rate of exacerbations was lower in participants receiving dupilumab versus placebo (rate ratio 0.43, 95% CI 0.27 to 0.68; participants = 769; Analysis 4.3). Considering data from studies of a duration greater than six months also showed that the rate of exacerbations was lower in participants receiving anti‐IL13/‐4 agents versus placebo (rate ratio 0.72, 95% CI 0.66 to 0.79; participants = 6229; Analysis 5.4).

Severity of asthma

This subgroup analysis examined the effect of asthma severity (mild‐to‐moderate versus severe) as per Global Initiative for Asthma (GINA) or British Thoracic Society/Scottish Intercollegiate Guidelines Network (BTS/SIGN) definitions. We note that this approach excludes consideration of data from studies that enrolled participants with moderate‐to‐severe asthma.

The two studies contributing data to the meta‐analysis for the primary outcome, exacerbations requiring hospitalisation or ED visit, enrolled participants with severe, uncontrolled asthma (Pannetieri 2018A; Pannetieri 2018B); thus, no subgroup analysis could be performed for this outcome.

For the primary outcome, health‐related quality of life, an improvement in respiratory health‐related quality of life versus placebo, as assessed by AQLQ, was observed in participants with severe asthma (MD 0.21, 95% CI 0.14 to 0.27; participants = 4457; Analysis 7.2), but was not observed in the relatively small subgroup of participants with mild‐to‐moderate asthma (MD ‐0.06, 95% CI ‐0.29 to 0.17; participants = 209; Analysis 7.1). However, formal statistical comparison was not performed and the MCID for AQLQ was not exceeded in either subgroup.

For the primary outcome, SAEs, subgroup analyses by asthma severity were consistent with the primary analyses. There was no clear difference between anti‐interleukin‐13/‐4 agents versus placebo, in participants with mild or moderate asthma, although confidence intervals were wide (OR 1.41, 95% CI 0.49 to 4.01; participants = 664; Analysis 6.2) or in participants with severe asthma (OR 0.94, 95% CI 0.78 to 1.13; participants = 5946; Analysis 7.3).

For the exploratory outcome, exacerbations requiring hospitalisation/ED/OCS, all of the studies contributing data to the meta‐analysis enrolled participants with either severe or moderate‐to‐severe asthma. Therefore, a subgroup analysis examining this outcome in participants with mild or moderate versus severe asthma could not be performed.

Dose of corticosteroids (including prednisone), at randomisation

To some extent, the dose of corticosteroids at randomisation reflects the severity of asthma experienced (see previous subanalysis). Therefore, we considered the effect of concomitant ICS use versus no concomitant ICS use during the study. Only five of the included studies discontinued ICS prior to study start or enrolled participants who were not previously taking ICS (Borish 1999; Borish 2001; Hodsman 2013; Korenblat 2018; Noonan 2013).

The two studies contributing data to the meta‐analysis for the primary outcome, exacerbations requiring hospitalisation or ED visit, permitted participants to receive ICS during the study. Therefore, subgroup analysis by ICS use could not be performed for this outcome.

For the primary outcome, respiratory health‐related quality of life, an improvement versus placebo, as assessed by AQLQ, was observed in participants who received concomitant ICS (MD 0.20, 95% CI 0.13 to 0.26; participants = 4751; Analysis 9.2) but was not observed in the single study that prohibited the use of concomitant ICS (MD ‐0.06, 95% CI ‐0.29 to 0.17; participants = 209; Analysis 8.1). However, formal statistical comparison was not performed and the MCID for AQLQ was not exceeded in either subgroup.

For the primary outcome, SAEs, subgroup analyses by concomitant ICS use were consistent with the primary analyses. There was no clear difference versus placebo in participants who were not receiving concomitant ICS during the study, although confidence intervals were wide (OR 1.73, 95% CI 0.40 to 7.48; participants = 470; Analysis 8.2) or in those who were permitted to receive concomitant ICS (OR 0.90, 95% CI 0.76 to 1.08; participants = 7269; Analysis 9.3).

All of the studies contributing data to the meta‐analysis for the exploratory outcome, exacerbations requiring hospitalisation/ED/OCS, permitted participants to receive ICS during the study. Therefore, subgroup analysis by ICS use could not be performed for this outcome.

Category of TH₂ inflammation

The influence of several markers of TH2 inflammation was examined by a number of the included studies.

Blood eosinophils

No studies reported data subgrouped by patients with high and low blood eosinophil levels for any of the primary outcomes.

Five studies reported data on the rate of exacerbations requiring hospitalisation/ED visit/OCS (exploratory outcome) by high and low blood eosinophil levels (Castro 2018; Hanania 2016a; Hanania 2016b; Rabe 2018; Wenzel 2016) based on the threshold of 300 cells/μL; additionally Castro 2018 reported data for low blood eosinophils > 150 and < 300 cells/μL. The studies reported data for dupilumab 200 mg Q2W, 200 mg Q4W and 300 mg Q2W, all versus placebo (Castro 2018; Rabe 2018), and for lebrikizumab 37.5 mg Q4W and 125 mg Q4W, both versus placebo (Hanania 2016a; Hanania 2016b). Overall, the subanalyses by blood eosinophil levels showed that a reduction in the rate of exacerbations requiring hospitalisation or emergency department visits or OCS was achieved in patients with high blood eosinophil levels (≥ 300 cells/μL: rate ratio 0.47, 95% CI 0.40 to 0.55; participants = 2052; studies = 5; Analysis 10.1) and low blood eosinophil levels (< 300 cells/μL: (rate ratio 0.75, 95% CI 0.65 to 0.87; participants = 1881; studies = 4; Analysis 10.2). For patients with high blood eosinophil levels, treatment with dupilumab 200 mg Q2W and 300 mg Q2W led to a large reduction in the rate of exacerbations requiring hospitalisation or emergency department visits or OCS (rate ratios 0.34, 95% CI 0.24 to 0.47 and (rate ratio 0.46, 95% CI 0.36 to 0.59, respectively). A similar reduction was observed with dupilumab 200 mg Q4W or 300 mg Q4W, but with more uncertainty. Both lebrikizumab doses were superior to placebo (37.5 mg Q4W: rate ratio 0.54, 95% CI 0.38 to 0.76; 125 mg Q4W: rate ratio 0.59, 95% CI 0.42 to 0.83). The overall test for subgroup difference was negative (P = 0.27). For patients with low blood eosinophil levels, all doses and agents resulted in a reduction in the rate of exacerbations compared to placebo, but the size and certainty of the effect varied. The overall test for subgroup differences was negative (P = 0.51).

Airway eosinophils (sputum eosinophilia ≥ 3%)

No studies reported data subgrouped by patients with high and low airway eosinophil levels for any of the primary outcomes, or the exploratory efficacy outcome.

FENO (high: ≥ 50 ppb)

No studies reported data subgrouped by patients with high and low FENO levels for any of the primary outcomes.

One study reported data on the rate of exacerbations requiring hospitalisation/ED visit/OCS (exploratory outcome) by high, medium and low serum FENO levels (Castro 2018). The study reported data for dupilumab 200 mg Q2W and 300 mg Q2W, both versus placebo. Overall, the subanalyses by FENO serum levels showed that a reduction in the rate of exacerbations requiring hospitalisation or emergency department visits or OCS use was achieved in patients with high FENO levels (≥ 50 ppb: rate ratio 0.31, 95% CI 0.22 to 0.45; participants = 389; Analysis 11.1), medium FENO levels (≥ 25 to < 50 ppb: rate ratio 0.42, 95% CI 0.30 to 0.58; participants = 554; Analysis 11.2) and low FENO levels (< 25 ppb: rate ratio 0.77, 95% CI 0.61 to 0.97; participants = 935 Analysis 11.3).

Subgroup data on the rate of exacerbations requiring hospitalisation/ED visit/OCS with tralokinumab were reported by Pannetieri 2018A and Pannetieri 2018B, but could not be used as a threshold of 37 ppb was used to separate the low and high FENO groups, in contrast to the threshold of 50 ppb prespecified in this review.

Periostin (high: ≥ 50 ng/mL)

No studies reported data subgrouped by patients with high and low serum periostin levels for any of the primary outcomes.

Four studies reported data on the rate of exacerbations requiring hospitalisation/ED visit/OCS (exploratory outcome) by high and low serum periostin levels (Hanania 2015a; Hanania 2015b; Hanania 2016a; Hanania 2016b); the results of the two VERSE trials (Hanania 2015a; Hanania 2015b) were reported in combined fashion and are entered into the analyses under Hanania 2015a. The four studies reported data for lebrikizumab 37 mg Q4W and 125 mg Q4W, both versus placebo; two studies also reported data for lebrikizumab 250 mg Q4W. Overall, the subanalyses by periostin serum levels showed that a reduction in the rate of exacerbations requiring hospitalisation or emergency department visits or OCS use was achieved in patients with high serum periostin levels (≥ 50 ng/mL: rate ratio 0.63, 95% CI 0.51 to 0.77; participants = 1499; studies = 3; Analysis 12.1); in patients with low serum periostin levels the 95% confidence intervals included no difference (< 50 ng/mL: rate ratio 0.87, 95% CI 0.68 to 1.11; participants = 1212; studies = 3; Analysis 12.2). For patients with high serum periostin levels, both the 37.5 mg and 125 mg Q4W doses reduced exacerbation rates compared with placebo (rate ratio 0.59, 95% CI 0.43 to 0.79 and 0.66, 95% CI 0.49 to 0.89, respectively). The difference versus placebo was more uncertain for the 250 mg Q4W dose (rate ratio 0.78, 95% CI 0.27 to 2.24).

Subgroup data on the rate of exacerbations requiring hospitalisation/ED visit/OCS with tralokinumab were reported by Brightling 2015 but were not compatible with the present subgroup analyses as the threshold used to differentiate between low and high serum periostin levels was based on the median periostin levels at baseline (~23 ng/mL), in contrast to the threshold of 50 ng/mL prespecified in this review.

Sensitivity analyses

The following sensitivity analyses were performed for the primary outcomes.

Unpublished data

No unpublished data (i.e. not publicly available) were included in this review, so it was not possible to perform this prespecified sensitivity analysis.

Fixed‐ versus random‐effect models

The results were consistent regardless of choice of analysis model (fixed‐ versus random‐effects model) (Table 2).

Risk of bias assessments

None of the included studies were considered to be at high risk of bias for blinding of participants and personnel, or high risk of bias for random sequence generation or allocation concealments; therefore, these sensitivity analyses could not be conducted.

Discussion

Summary of main results

Twenty‐nine studies with a median duration of 16 weeks contributed data to the quantitative analyses in the present review; these studies randomised a total of 10,604 participants to receive either an anti‐interleukin‐13 agent (n = 4401 participants), an anti‐interleukin‐4 agent (n = 2560 participants), or placebo (n = 3643 participants). Most participants were adults with moderate or severe uncontrolled asthma. The majority of studies were well designed and considered to be at low risk of bias.

Our findings support a benefit for anti‐interleukin‐13/‐4 agents over placebo in adult patients with asthma. For the primary endpoint "exacerbations requiring hospitalisation or OCS", only data for tralokinumab, an anti‐interleukin‐13 agent, were available. Compared with placebo, tralokinumab was likely associated with a reduction in the adjusted annualised exacerbation rate (moderate‐certainty evidence). For the primary endpoint "health‐related quality of life", anti‐interleukin‐13/‐4 agents were associated with a small improvement over placebo; however, the improvement did not exceed the minimal clinically important difference such that the improvement in HRQoL was not considered to be clinically relevant (high‐certainty evidence). There was likely little or no difference between groups (anti‐interleukin‐13/‐4 versus placebo) in the proportion of patients experiencing serious adverse events (moderate‐certainty evidence).

In terms of secondary endpoints, compared with placebo, there was a likely improvement in lung function with anti‐interleukin‐13/‐4 agents (100 mL measured with trough FEV1) that was borderline clinically relevant (moderate‐certainty evidence); a likely improvement in asthma control with anti‐interleukin‐13/‐4 agents that was deemed not to be clinically relevant (moderate‐certainty evidence); and there may be a reduction in oral corticosteroid dose (~16%) in participants receiving anti‐interleukin‐13/‐4 agents (low‐certainty evidence) driven by the reduction in OCS observed in single study with dupilumab. The proportion of patients experiencing any adverse event was higher in participants receiving anti‐interleukin‐13/‐4 agents compared with those receiving placebo (high‐certainty evidence). The most commonly reported adverse events in participants treated with anti‐interleukin‐13/‐4 agents were upper respiratory tract infection, nasopharyngitis, headache and injection site reaction. There may be little or no difference between groups (anti‐interleukin‐13/‐4 versus placebo) in the proportions of patients with exacerbations requiring OCS (low‐certainty evidence), and there were no studies that reported data for the outcome "time off work or study". Reductions in inflammatory biomarkers were observed in participants receiving anti‐interleukin‐13/‐4 agents compared with those receiving placebo, including in FENO (moderate‐certainty evidence) and periostin concentrations (low‐certainty evidence). Notably, treatment with anti‐interleukin‐13/‐4 agents was associated with a small increase in blood eosinophil levels (high‐certainty evidence).

We also analysed data for an exploratory (post hoc) endpoint "Exacerbations requiring hospitalisation, emergency department visit or OCS" as this endpoint was reported by a number of the studies, particularly in relation to biomarker levels. As the endpoint essentially combines two of the prespecified endpoints of the review, we deemed it important to examine these data. The rate of exacerbations requiring OCS or hospitalisation or emergency department visit may be lower in participants receiving anti‐13/‐4 agents versus placebo (low‐certainty evidence).

The results of the subgroup analyses by agent class (anti interleukin‐13 versus anti‐interleukin‐4 agent), study duration (up to six months versus six months or longer), disease severity (mild‐to‐moderate versus severe) and inhaled corticosteroid use at baseline (concomitant use versus non‐concomitant use; i.e. a proxy for disease severity), were generally consistent with those of the primary analyses.

Subgroup analyses by category of TH2 inflammation support the notion that anti‐interleukin‐13/‐4 agents provide greater clinical benefit in patients with higher levels of inflammatory biomarkers. Subanalysis by high and low blood eosinophil levels based on the threshold of 300 cells/μL showed that a reduction in the rate of exacerbations requiring hospitalisation/emergency department visit/OCS (post hoc exploratory outcome) was achieved in patients with high blood eosinophil levels (rate ratio 0.47, 95% CI 0.40 to 0.55) and low blood eosinophil levels (rate ratio 0.75, 95% CI 0.65 to 0.87). A similar trend was observed for FENO, where a reduction in the rate of exacerbations requiring hospitalisation or emergency department or OCS use was achieved in patients with high FENO levels (≥ 50 ppb: rate ratio 0.31, 95% CI 0.22 to 0.45), medium FENO levels (≥ 25 to < 50 ppb: rate ratio 0.42, 95% CI 0.30 to 0.58) and low FENO levels (< 25 ppb: rate ratio 0.77, 95% CI 0.61 to 0.97), with the greatest treatment effect observed in patients with high FENO levels. Finally, subanalyses by periostin serum levels showed that a clear reduction in the rate of exacerbations requiring hospitalisation or emergency department visit or OCS use was only achieved in patients with high serum periostin levels (≥ 50 ng/mL: rate ratio 0.63, 95% CI 0.51 to 0.77) but not in patients with low serum periostin levels (< 50 ng/mL: rate ratio 0.87, 95% CI 0.68 to 1.11), although we did not perform a formal statistical comparison.

The results of the review were consistent regardless of choice of analysis model (fixed‐ versus random‐effects model).

Overall completeness and applicability of evidence

The findings of this review are principally applicable to people with moderate‐to‐severe, uncontrolled asthma (95 per cent of the participants in the included studies contributing data to the quantitative analyses had moderate or severe asthma). Furthermore, studies evaluating dupilumab, lebrikizumab and tralokinumab accounted for 90 per cent of participants randomised to the studies contributing quantitative data to this review and thus the findings are most relevant to these drugs. At the time of writing, the clinical development of lebrikizumab and tralokinumab for the treatment of patients with asthma has been halted indefinitely.

Quality of the evidence

The certainty of the evidence was generally considered to be moderate or high with the exceptions of the secondary outcomes "exacerbations requiring OCS" and the exploratory outcome "exacerbations requiring emergency department visit, hospitalisation or OCS use" which were both considered to be low certainty.

We downgraded the outcome "exacerbations requiring hospitalisation or ED visit" once for indirectness, "serious adverse events" for imprecision, "exacerbations requiring OCS" for both indirectness and imprecision and "change from baseline in ACQ score" for inconsistency.

Risk of bias in the included studies was generally considered to be low or was unclear due to the lack of necessary information provided in the study reports. Across 306 assessments (34 studies, nine domains each), over three‐quarters were considered to be at a low risk of bias, and only 15 were considered to be at a high risk of bias. Risk of bias was considered unclear in the remaining 5 5 assessments. Nine studies were considered to be at high risk for attrition bias based on either a high proportion of withdrawals in one or more treatment arms, an uneven proportion of withdrawals between treatment arms, or both; in some instances, high or imbalanced withdrawal rates arose due to early study termination (Hanania 2015a; Hanania 2015b; Singh 2010). Three studies were considered to be at high risk for reporting bias; in one instance, the study was stopped early due to futility of the interim efficacy analysis results and the sponsor decided to only analyse safety results and key efficacy data (NCT00425061); and in two instances, outcomes were reported by biomarker level, which was not prespecified in the trial registry (Hanania 2016a; Hanania 2016b). We did not examine whether the results were robust to the removal of studies with any domain considered to be at high risk of attrition or reporting bias as this was not a prespecified sensitivity analysis. However, no downgrading of the strength of the evidence (by GRADE) was performed on the basis of risk of bias.

Potential biases in the review process

The review was conducted to the Cochrane's MECIR standards (MECIR 2020) and in accordance with the published protocol (Edwards 2018). In particular, two authors independently screened the search results, determined studies for inclusion, assessed the risk of bias, extracted the relevant data, and performed the GRADE assessment (i.e. all steps involving subjective decisions).

There were three deviations from the protocol (see Differences between protocol and review). First, as few studies reported data on the prespecified primary endpoint for efficacy (exacerbations requiring hospitalisation or ED visit) and more studies reported the rate of exacerbations requiring hospitalisation, ED visit, or OCS use, this outcome was investigated as an exploratory outcome. For future updates of the review, we would suggest that this outcome is selected as a primary efficacy outcome. Additionally, the present review considered patients with any severity of asthma. Given that these agents are only likely to be used clinically in selected patients with uncontrolled asthma, despite the use of other medications, it would perhaps be appropriate to exclude patients with mild asthma from future updates to this review. Second, the main analyses were conducted using a fixed‐effect model, and the sensitivity analyses were conducted using a random‐effects model; comparison of the data derived using the two models showed no difference in findings for the primary endpoints. Finally, we did not explore possible small study and publication biases, as planned in the original protocol.

It is unlikely that any relevant studies were missed, as a skilled information specialist conducted the main electronic searches. Additionally, the main searches were supplemented by manual searches of reference lists of associated studies and reviews. Finally, this review has undergone editorial and peer review and thus considers the opinions of independent external experts. In summary, the review was conducted in a manner that should ensure that our conclusions fairly and accurately represent the results synthesised during the review process.

Agreements and disagreements with other studies or reviews

Our findings with respect to anti‐interleukin‐13 agents are consistent with those from a recent systematic review which examined lebrikizumab and tralokinumab for uncontrolled asthma (Li 2019). The authors reported that anti‐interleukin‐13 treatments were associated with a significant improvement in asthma exacerbations, FEV1 and AQLQ scores, and a reduction in rescue medication use (Li 2019).

Our findings with respect to dupilumab are consistent with three systematic reviews conducted by the European Academy of Allergy and Clinical Immunology task force that evaluated dupilumab (and other biologicals) for the treatment of severe asthma (Agache 2020), severe eosinophilic asthma (Agache 2020b) and severe allergic asthma (Agache 2020). The authors reported high‐certainty evidence in patients with severe asthma that dupilumab reduced the rate of severe exacerbations and that the magnitude of the reduction was significantly greater in patients with high levels of eosinophils (≥ 300 cells/μL) or high levels of FENO (≥ 50 ppb) at baseline (Agache 2020). Improvements in asthma control, asthma‐related quality of life and lung function and reduced OCS use were also observed but did not exceed the MCID for each measure (Agache 2020). Similar findings were reported with respect to patients with severe eosinophilic asthma where high‐certainty evidence showed that dupilumab reduced exacerbation rates and OCS use; observed improvements in asthma control and asthma‐related quality of life did not exceed the MCID (Agache 2020b). Similarly, Agache and colleagues reported high‐certainty evidence that dupilumab as an add‐on to standard of care reduces exacerbation rates for patients aged 12 years and over with severe allergic asthma; again, improvements in asthma control and lung function were demonstrated but did not exceed the MCID (Agache 2020).

Interestingly, anti‐interleukin‐13/‐4 agents were not found to have an anti‐eosinophilic effect; in fact, a small, statistically significant increase in blood eosinophils was observed (high‐certainty evidence). The direction of this treatment effect (i.e. an increase) was consistent across all agents contributing data (tralokinumab, dupilumab, lebrikizumab, IMA‐638) but was not always statistically significant for each contributing study. The effect of anti‐interleukin‐4 and anti‐interleukin‐13 inhibitors on blood eosinophil levels may depend on the duration of treatment and time points analysed. A recent analysis of eosinophil kinetics in a large cohort of patients with asthma showed that blood eosinophils increased from baseline by 9.2% at week 4, returned to baseline by week 24, and fell below baseline by week 52 (Wechsler 2021). These findings suggest that the benefit of treatment with anti‐interleukin‐13 or anti‐interleukin‐4 agents is mediated through multiple pathways, perhaps particularly on mucus clearing as demonstrated in the EXPEDITION study (NCT02573233).

Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 4

Forest plot of comparison: 1 Anti‐interleukin‐13 or ‐4 agents with placebo, outcome: 1.1 Exacerbation requiring hospitalisation or ED visit.

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Figure 5

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Analysis 1.1

Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 1: Exacerbation requiring hospitalisation or ED visit

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Analysis 1.2

Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 2: Health‐related quality of life (adjusted mean diff versus placebo)

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Analysis 1.3

Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 3: Serious adverse events

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Analysis 1.4

Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 4: Exacerbation requiring OCS (rate ratio)

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Analysis 1.5

Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 5: Exacerbation requiring OCS (dichotomous)

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Analysis 1.6

Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 6: Change from baseline in pre‐bronchodilator FEV1

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Analysis 1.7

Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 7: Change from baseline in ACQ score

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Analysis 1.8

Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 8: Adverse events

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Analysis 1.9

Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 9: Change from baseline in FENO, ppb

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Analysis 1.10

Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 10: Change from baseline in blood eosinophils, cells x 10*9/L

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Analysis 1.11

Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 11: Change from baseline in periostin, ng/mL

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Analysis 1.12

Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 12: Percentage reduction from baseline in OCS use

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Analysis 1.13

Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 13: Exacerbation requiring hospitalisation/ED/OCS (rate ratio)

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Analysis 1.14

Comparison 1: Anti‐interleukin‐13 or ‐4 agents with placebo, Outcome 14: Exacerbation requiring hospitalisation/ED/OCS (relative risk)

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Analysis 2.1

Comparison 2: Subanalysis: agents directly targeting IL‐13, Outcome 1: Exacerbation requiring hospitalisation or ED visit

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Analysis 2.2

Comparison 2: Subanalysis: agents directly targeting IL‐13, Outcome 2: Health‐related quality of life (adjusted mean diff versus placebo)

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Analysis 2.3

Comparison 2: Subanalysis: agents directly targeting IL‐13, Outcome 3: Serious adverse events

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Analysis 2.4

Comparison 2: Subanalysis: agents directly targeting IL‐13, Outcome 4: Exacerbation requiring hospitalisation/ED/OCS (rate ratio)

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Analysis 3.1

Comparison 3: Subanalysis: agents directly targeting IL‐4R, Outcome 1: Health‐related quality of life (adjusted mean diff versus placebo)

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Analysis 3.2

Comparison 3: Subanalysis: agents directly targeting IL‐4R, Outcome 2: Serious adverse events

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Analysis 3.3

Comparison 3: Subanalysis: agents directly targeting IL‐4R, Outcome 3: Exacerbation requiring hospitalisation/ED/OCS (rate ratio)

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Analysis 4.1

Comparison 4: Subanalysis: study duration <= 6 months, Outcome 1: Health‐related quality of life (adjusted mean diff versus placebo)

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Analysis 4.2

Comparison 4: Subanalysis: study duration <= 6 months, Outcome 2: Serious adverse events

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Analysis 4.3

Comparison 4: Subanalysis: study duration <= 6 months, Outcome 3: Exacerbation requiring hospitalisation/ED/OCS (rate ratio)

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Analysis 5.1

Comparison 5: Subanalysis: study duration > 6 months, Outcome 1: Exacerbation requiring hospitalisation or ED visit

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Analysis 5.2

Comparison 5: Subanalysis: study duration > 6 months, Outcome 2: Health‐related quality of life (adjusted mean diff versus placebo)

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Analysis 5.3

Comparison 5: Subanalysis: study duration > 6 months, Outcome 3: Serious adverse events

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Analysis 5.4

Comparison 5: Subanalysis: study duration > 6 months, Outcome 4: Exacerbation requiring hospitalisation/ED/OCS (rate ratio)

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Analysis 6.1

Comparison 6: Subanalysis: asthma severity mild‐to‐moderate, Outcome 1: Health‐related quality of life (adjusted mean diff versus placebo)

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Analysis 6.2

Comparison 6: Subanalysis: asthma severity mild‐to‐moderate, Outcome 2: Serious adverse events

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Analysis 7.1

Comparison 7: Subanalysis: asthma severity severe, Outcome 1: Exacerbation requiring hospitalisation or ED visit

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Analysis 7.2

Comparison 7: Subanalysis: asthma severity severe, Outcome 2: Health‐related quality of life (adjusted mean diff versus placebo)

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Analysis 7.3

Comparison 7: Subanalysis: asthma severity severe, Outcome 3: Serious adverse events

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Analysis 7.4

Comparison 7: Subanalysis: asthma severity severe, Outcome 4: Exacerbation requiring hospitalisation/ED/OCS (rate ratio)

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Analysis 8.1

Comparison 8: Subanalysis: no concomitant ICS, Outcome 1: Health‐related quality of life (adjusted mean diff versus placebo)

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Analysis 8.2

Comparison 8: Subanalysis: no concomitant ICS, Outcome 2: Serious adverse events

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Analysis 9.1

Comparison 9: Subanalysis: concomitant ICS, Outcome 1: Exacerbation requiring hospitalisation or ED visit

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Analysis 9.2

Comparison 9: Subanalysis: concomitant ICS, Outcome 2: Health‐related quality of life (adjusted mean diff versus placebo)

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Analysis 9.3

Comparison 9: Subanalysis: concomitant ICS, Outcome 3: Serious adverse events

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Analysis 9.4

Comparison 9: Subanalysis: concomitant ICS, Outcome 4: Exacerbation requiring hospitalisation/ED/OCS (rate ratio)

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Analysis 10.1

Comparison 10: Subanalysis by blood eosinophil count: exacerbations requiring hospitalisation/ED/OCS, Outcome 1: Blood eosinophils high (> 300 cells/uL)

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Analysis 10.2

Comparison 10: Subanalysis by blood eosinophil count: exacerbations requiring hospitalisation/ED/OCS, Outcome 2: Blood eosinophils low (< 300 cells/uL)

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Analysis 10.3

Comparison 10: Subanalysis by blood eosinophil count: exacerbations requiring hospitalisation/ED/OCS, Outcome 3: Blood eosinophils low (> 150 < 300 cells/uL)

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Analysis 10.4

Comparison 10: Subanalysis by blood eosinophil count: exacerbations requiring hospitalisation/ED/OCS, Outcome 4: Blood eosinophils low (< 150 cells/uL)

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Analysis 11.1

Comparison 11: Subanalysis by FENO: exacerbations requiring hospitalisation/ED/OCS, Outcome 1: FENO high (≥ 50 ppb)

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Analysis 11.2

Comparison 11: Subanalysis by FENO: exacerbations requiring hospitalisation/ED/OCS, Outcome 2: FENO medium (≥ 25 to < 50 ppb)

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Analysis 11.3

Comparison 11: Subanalysis by FENO: exacerbations requiring hospitalisation/ED/OCS, Outcome 3: FENO low (< 25 ppb)

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Analysis 12.1

Comparison 12: Subanalysis by periostin level: exacerbations requiring hospitalisation/ED/OCS, Outcome 1: Periostin high (≥ 50 ng/mL)

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Analysis 12.2

Comparison 12: Subanalysis by periostin level: exacerbations requiring hospitalisation/ED/OCS, Outcome 2: Periostin low (< 50 ng/mL)

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Analysis 13.1

Comparison 13: Sensitvity analysis ‐ random‐effects, Outcome 1: Exacerbation requiring hospitalisation or ED visit

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Analysis 13.2

Comparison 13: Sensitvity analysis ‐ random‐effects, Outcome 2: Health‐related quality of life (adjusted mean diff versus placebo)

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Analysis 13.3

Comparison 13: Sensitvity analysis ‐ random‐effects, Outcome 3: Serious adverse events

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Summary of findings 1. Anti‐IL13 or anti‐IL4 agents compared to placebo for children and adults with asthma

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Anti‐IL13 of anti‐IL4 agents compared to placebo for children and adults with asthma
Patient or population: children and adults with asthma Setting: community Intervention: anti‐IL13 of anti‐IL4 agents Comparison: placebo
Outcomes	Risk with placebo	Risk with anti‐IL13 of anti‐IL4 agents	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Exacerbation requiring hospitalisation or ED visit Follow‐up: 52 weeks	The mean AAER in the placebo group was 0.075¹	The AAER in the intervention group was 0.024 lower (0.002 lower to 0.04 lower)	Rate ratio 0.68 (0.47 to 0.98)	2039 (2 RCTs)	⊕⊕⊕⊝ MODERATE²
Health‐related quality of life (AQLQ) Scale: 1 to 7 (higher is better) Follow‐up: 12 weeks to 52 weeks	Where reported, the mean change in the placebo group ranged from 0.64 to 0.88	MD 0.18 higher (0.12 higher to 0.24 higher)	‐	4960 (7 RCTs)	⊕⊕⊕⊕ HIGH	MCID = 0.5; the treatment effect was not clinically relevant.
Serious adverse events Follow‐up: 3 to 52 weeks	81 per 1000	74 per 1000 (63 to 87)	OR 0.91 (0.76 to 1.09)	7739 (22 RCTs)	⊕⊕⊕⊝ MODERATE³
Exacerbation requiring OCS (rate ratio) Follow‐up: 52 weeks	The mean AAER in the placebo group was 0.90	The AAER in the intervention group was 0.08 lower (0.27 lower to 0.29 higher)	RR 0.98 (0.72 to 1.32)	452 (1 RCT)	⊕⊕⊝⊝ LOW^2,3
Change from baseline in ACQ score Scale: 0 to 6 (higher is worse) Follow‐up: 12 to 52 weeks	Where reported, the mean change from baseline in ACQ score in the placebo group ranged from ‐1.30 (SE 0.06) to ‐0.27 (error NR)	MD 0.19 lower (0.24 lower to 0.14 lower)	‐	6251 (14 RCTs)	⊕⊕⊕⊝ MODERATE⁴	MCID = 0.4; the treatment effect was not clinically relevant.
Adverse events (any) Follow‐up: 10 days to 52 weeks	707 per 1000	737 per 1000 (715 to 759 participants per 1000)	OR 1.16 (1.04 to 1.30)	7419 (18 RCTs)	⊕⊕⊕⊕ HIGH
Time off work or study	‐	‐	‐	‐	‐	No studies reported data for this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AAER: adjusted annualised exacerbation rate; ACQ: asthma control questionnaire; AQLQ: asthma quality of life questionnaire; CI: Confidence interval; ED: emergency department; MCID: minimally clinically important difference; MD: mean difference; OCS: oral corticosteroids; RR: Risk ratio; OR: Odds ratio; SD: standard deviation; RCT: randomised controlled trial; SE: standard error.
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Mean of the AAER in the placebo group of the two studies: 0.07 and 0.08 ²Downgraded once for indirectness (low number of studies of a single agent) ³Downgraded once for imprecision as the 95% confidence intervals for the treatment effect crossed 1.0 ⁴ Downgraded once for inconsistency (moderate heterogeneity of 30% to 60%) ⁶Downgraded twice for inconsistency (substantial heterogeneity of 50% to 90% or considerable heterogeneity of 75% to 100%)

Summary of findings 1. Anti‐IL13 or anti‐IL4 agents compared to placebo for children and adults with asthma

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Summary of findings 2. Other secondary and post hoc exploratory outcomes

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Anti‐IL13 of anti‐IL4 agents compared to placebo for children and adults with asthma
Patient or population: children and adults with asthma Setting: community Intervention: anti‐IL13 of anti‐IL4 agents Comparison: placebo
Outcomes	Risk with placebo	Risk with anti‐IL13 of anti‐IL4 agents	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Change from baseline in pre‐bronchodilator FEV1 Follow‐up: 12 to 52 weeks	Where reported, the mean change from baseline in FEV1 in the placebo groups ranged from ‐0.02 L (SE 0.03) to 0.21 L (SE 0.02)	MD 0.1 L higher (0.08 higher to 0.12 higher)	‐	4829 (13 RCTs)	⊕⊕⊕⊝ MODERATE²	These changes were borderline clinically relevant (MCID is approximately 0.1 to 0.2 L).
Change from baseline in FENO (ppb) Follow‐up: 10 days to 52 weeks	Where reported, the mean change from baseline in FENO in the placebo groups ranged from ‐31.1 to 23.8 ppb	MD 14.68 ppb lower (16.56 lower to 12.8 ppb lower)	‐	3577 (11 RCTs)	⊕⊕⊕⊝ MODERATE²
Change from baseline in blood eosinophils (cells x 109/L) Follow‐up:* 12 to 52 weeks	Where reported, the mean change from baseline in blood eosinophil count in the placebo groups ranged from ‐0.048 (SD 0.347) to 0.003 (SD 0.313) cells x 10⁹/L	MD 0.06 cells x 10⁹/L higher (0.04 higher to 0.09 cells x 10⁹/L higher)	‐	2598 (6 RCTs)	⊕⊕⊕⊕ HIGH
Change from baseline in Periostin (ng/mL) Follow‐up: 12 to 52 weeks	Where reported, the mean change from baseline in periostin concentration in the placebo groups ranged from ‐5.05 (SD 27.89) to ‐0.3 (SD 1.0) ng/mL	MD 9.04 ng/mL lower (10.92 lower to 7.17 ng/mL lower)	‐	2106 (2 RCTs)	⊕⊕⊝⊝ LOW³
Percentage reduction from baseline in maintenance OCS dose Follow‐up: 24 to 40 weeks	Where reported, the mean reduction from baseline in OCS dose in the placebo groups ranged from ‐29.85 (SE 4.98) to ‐41.9 (SE 4.6)%	MD 15.58% lower (23.3% lower to 7.85% lower)	‐	350 (2 RCTs)	⊕⊕⊝⊝ LOW³
Post hoc exploratory endpoint: Exacerbation requiring hospitalisation/ED/OCS (rate ratio) Follow‐up: 24 weeks to 52 weeks	The mean AAER in the placebo groups was 1.00 (range 0.60 to 2.31)¹	The AAER in the intervention groups was 0.29 lower (0.35 lower to 0.23 lower)	Rate ratio 0.71 (0.65 to 0.77)	6998 (7 RCTs)	⊕⊕⊝⊝ LOW³
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AAER, adjusted annualised exacerbation rate; CI: Confidence interval; ED, emergency department; FENO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; MD, mean difference; OCS, oral corticosteroids; ppb, parts per billion; RR: Risk ratio; SD, standard deviation; RCT, randomised controlled trial; SE, standard error
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹Mean of the AAER in the placebo groups of the seven studies (1 study had two placebo arms): 2.31, 0.60, 0.82, 0.94, 0.61, 0.87, 0.97, 0.897 ² Downgraded once for inconsistency (moderate heterogeneity of 30% to 60%) ³Downgraded twice for inconsistency (substantial heterogeneity of 50% to 90% or considerable heterogeneity of 75% to 100%)

Summary of findings 2. Other secondary and post hoc exploratory outcomes

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Table 1. Summary of included study characteristics

Study	Intervention	Treatment duration (weeks^c)	Asthma severity	ICS use	N randomised	Age range, years	Range % male	BL % pred. FEV1
Borish 1999	IL‐4R 500/1500 μg single dose	2	Moderate atopic	Discontinued prior to study drug	25 (17/8)	35 to 38	25 to 63	7 to 87
Borish 2001	IL‐4R 0.75/1.5/3.0 mg Q1W	12	Moderate‐to‐severe	Discontinued prior to study drug	62 (46/16)	36 to 46	25 to 37	75 to76
Brightling 2015 (NCT01402986)	Tralokinumab 300 mg Q2W or Q4W	52	Severe uncontrolled	Maintained through study	452 (376/76)	50 to 51	33 to 36	68 to 69
Burgess 2018 (NCT02473939)	VR492 0.5/10/20 mg as DPI	28	Mild	Maintained through study	45 (29/16)	29 to 30	100	77 to 89
Busse 2015 (NCT02281357)	Tralokinumab 300 mg Q2W	40	Severe	Maintained through study	140 (70/70)	54 to 55	32 to 44	NR
Castro 2018 (NCT02414854)	Dupilumab 200/300 mg SC Q2W	52	Severe uncontrolled	ICS permitted (≥ 500 μg FP or equiv.)	1902 (1264/638)	48	37	58
Corren 2010 (NCT 00436670)	Tralokinumab 75/150/300 mg Q1W	12	Moderate‐to‐severe	Stable doses of ICS (200 to 1000 μg FP or equiv.)	294 (220/74)	40 to 43	38 to 46	67 to 70
Corren 2011 (NCT00930163)	Lebrikizumab 250 mg SC Q4W	24	Moderate‐to‐severe uncontrolled	ICS maintained throughout study (≥ 200 and ≤ 1000 μg FP daily or equiv.)	218 (106/112)	44 to 45	33 to 35	64 to 66
De Boever 2014 (NCT00843193)	GSK679586 10 mg/kg IV Q4W	12	Severe refractory	Max recommended ICS doses maintained	198 (99/99)	51	48 to 51	55 to 58
Gauvreau 2011a (NCT00410280)	IMA‐638 4 mg/kg (2 doses, 1 week apart)	AC study (2)	Mild, allergic asthma	Not permitted	27 (14/13)	26 to 32	38 to 50	87 to 93
Gauvreau 2011b (NCT00725582)	IMA‐638 4 mg/kg (2 doses, 1 week apart)	AC study (2 )	Mild, allergic asthma	Not permitted	29 (14/15)	33 to 34	50 to 53	87 to 91
Hanania 2011	Lebrikizumab (dose not stated)	24	Uncontrolled by ICS	Maintained throughout study	180 (88/92)	NR	NR	NR
Hanania 2015a (NCT01545440)	Lebrikizumab 37.5/125/250 mg SC Q4W	52^a	Moderate‐to‐severe uncontrolled	SOC maintained (500 to 2000 μg/day FPA or equiv.)	463 (347/116)	47 to 50	39 to 57	61 to 63
Hanania 2015b (NCT01545453)	Lebrikizumab 37.5/125/250 mg SC Q4W	52^a	Moderate‐to‐severe uncontrolled	SOC maintained (500 to 2000 μg/day FPA or equiv.)	See Hanania 2015a^a
Hanania 2016a (NCT01867125)	Lebrikizumab 37.5/125 mg SC Q4W	52	Moderate‐to‐severe uncontrolled	SOC maintained (500 to 2000 μg/day FPA or equiv.)	1081 (719/362)	51	31 to 36	61
Hanania 2016b (NCT01868061)	Lebrikizumab 37.5/125 mg SC Q4W	52	Moderate‐to‐severe uncontrolled	SOC maintained (500 to 2000 μg/day FPA or equiv.)	1067 (713/354)	50 to 51	34 to 43	61
Hodsman 2013^b (NCT00411814)	GSK679586 2.5/10/20 mg/kg Q4W	12	Mild bronchial	Not permitted	28 (21/7)	25 to 32	100	102 to 105
Korenblat 2018 (NCT02104674)	Lebrikizumab 125 mg SC Q4W	12	Mild‐to‐moderate	Discontinued 30 days prior to study drug	211 (105/106)	43 to 45	37 to 39	72
NCT00425061	IMA‐638 0.2/0.6/2/ mg/kg SC D1/8/28/56/70/84	16	Moderate‐to‐severe persistent	Medium‐to‐high dose permitted	159 (98/61)	NR	39 to 45	NR
NCT00640016	Tralokinumab 1/5/10 mg/kg Q4W	12	Uncontrolled refractory	Maintained (≥ 800 μg BDP or equiv.)	14 (11/3)	34 to 41	0 to 75	NR
Noonan 2013 (NCT00971035)	Lebrikizumab 125/250/500 mg SC Q4W	12	Stable, mild‐to‐moderate	Not permitted	212 (160/52)	38 to 41	32 to 43	72 to 4
Pannetieri 2018A (NCT02161757)	Tralokinumab 300 mg SC Q2W or Q4W	52	Severe uncontrolled	Stable dose (≥ 500 μg FP or equiv.)	1207 (807/400)	49 to 51	30 to 37	60 to 62
Pannetieri 2018B (NCT02194699)	Tralokinumab 300 mg SC Q2W	52	Severe uncontrolled	Stable dose (≥ 500 μg FP or equiv.)	856 (428/428)	47 to 48	31 to 34	61
Piper 2013 (NCT00873860)	Tralokinumab 150/300/600 mg SC Q2W	12	Moderate‐to‐severe uncontrolled	Permitted	194 (146/48)	43 to 50	29 to 60	NR
Rabe 2018 (NCT02528214)	Dupilumab 300 mg SC Q2W	24	Severe asthma	Tapered down	210 (103/107)	51 to 52	39 to 40	NR
Russell 2018 (NCT02449473)	Tralokinumab 300 mg SC Q2W	12	Moderate‐to‐severe uncontrolled	Stable dose (≥ 250 μg FP daily or equiv.)	79 (39/40)	47 to 50	41 to 50	NR
Scheerens 2014 (NCT00781443)	Lebrikizumab 5 mg/kg SC Q4W	AC study (12)	Mild	Not stated	29 (13/16)	32 to 66	46 to 56	82‐84
Singh 2010^b (NCT00974675)	Tralokinumab 1/5/10 mg/kg IV Q4W	21	Mild well‐controlled	Permitted	23 (19/4)	35 to 43	67 to 100	NR
Tripp 2017^b (NCT00986037)	RPC4046 0.3/3 mg/kg IV Q1W	16	Mild‐to‐moderate controlled	Low‐to‐medium dose permitted	27 (20/7)	23 to 33	75 to 100	NR
Wenzel 2007a (NCT00535028)	Pitrakinra 25 mg SC once daily for 28 days	AC study (28 days)	Mild‐to‐moderate	Discontinued 1 month prior to study drug	24 (12/12)	30 to 31	42 to 58	100‐102
Wenzel 2007b (NCT00535031)	Pitrakinra 60 mg nebulised twice daily for 28 days	AC study (28 days)	Mild‐to‐moderate	Discontinued 1 month prior to study drug	32 (16/16)	25 to 29	47 to 80	96 to ‐99
Wenzel 2010 (NCT00801853)	Pitrakinra 1/3/10 mg	12	Moderate‐to‐severe uncontrolled	Fluticasone withdrawal from 6 weeks after initiation of blinded treatment	534 (397/137)	NR	NR	NR
Wenzel 2013 (NCT01312961)	Dupilumab 300 mg SC Q1W	12	Moderate‐to‐severe	Medium‐to‐high dose discontinued during weeks 6 to 9	104 (52/52)	38 to 42	50	72
Wenzel 2016 (NCT01854047)	Dupilumab 200/300 mg SC Q2/4W	24	Uncontrolled persistent asthma	Medium‐to‐high dose plus LABA	619 (461/158)	48 to 51	34 to 44	60 to 61
^aThis trial was designed to be 52 weeks; however, the trial was terminated early and the median duration of treatment was approximately 24 weeks. Pooled data are reported for the two replicate studies. ^bPhase 1 safety and PK study ^cUnless otherwise stated Abbreviations: AC: allergen challenge; BDP: beclomethasone dipropionate; DPI: dry powder inhaler; FEV1: forced expiratory volume in one second; FP: fluticasone propionate; ICS: inhaled corticosteroids; IL‐4R: interleukin‐4 receptor; IL‐13: interleukin‐13; IV: intravenous; LABA: long‐acting beta‐agonist; NR: not reported; PK: pharmacokinetic; Q1/2/4W: every 1/2/4 weeks; SC: subcutaneous; SOC: standard of care.

Table 1. Summary of included study characteristics

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Table 2. Sensitivity analysis: random effects versus fixed effects

Outcome	Fixed‐effect model	Random‐effects model
Exacerbation requiring hospitalisation or ED visit	RR 0.68, 95% CI 0.47 to 0.98 (participants = 2039; studies = 2)	RR 0.68, 95% CI 0.47 to 0.98
HRQoL (AQLQ)	MD 0.18, 95% CI 0.12 to 0.24 (participants = 4960; studies = 7)	MD 0.18, 95% CI 0.12 to 0.24
Serious adverse events	OR 0.91, 95% CI 0.76 to 1.09 (participants = 7739; studies = 22)	OR 0.91, 95% CI 0.76 to 1.09
Abbreviations: AQLQ: asthma quality of life questionnaire; CI: confidence interval; ED: emergency department; HRQoL: health‐related quality of life; MD: mean difference; OR: odds ratio; RR: rate ratio.

Table 2. Sensitivity analysis: random effects versus fixed effects

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Comparison 1. Anti‐interleukin‐13 or ‐4 agents with placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Exacerbation requiring hospitalisation or ED visit Show forest plot	2	2039	Rate Ratio (IV, Fixed, 95% CI)	0.68 [0.47, 0.98]

1.1.1 Tralokinumab 300 mg SC Q2W	2	1435	Rate Ratio (IV, Fixed, 95% CI)	0.63 [0.41, 0.99]
1.1.2 Tralokinumab 300 mg SC Q4W	1	604	Rate Ratio (IV, Fixed, 95% CI)	0.78 [0.41, 1.49]
1.2 Health‐related quality of life (adjusted mean diff versus placebo) Show forest plot	7	4960	Mean Difference (IV, Fixed, 95% CI)	0.18 [0.12, 0.24]

1.2.1 Lebrikizumab 125 mg SC Q4W	1	209	Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐0.29, 0.17]
1.2.2 Dupilumab 200 mg SC Q2W	2	1111	Mean Difference (IV, Fixed, 95% CI)	0.29 [0.16, 0.42]
1.2.3 Dupilumab 200 mg SC Q4W	1	159	Mean Difference (IV, Fixed, 95% CI)	0.23 [‐0.13, 0.59]
1.2.4 Dupilumab 300 mg SC Q2W	2	1127	Mean Difference (IV, Fixed, 95% CI)	0.27 [0.14, 0.40]
1.2.5 Dupilumab 300 mg SC Q4W	1	164	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐0.06, 0.66]
1.2.6 Tralokinumab 300 mg SC Q2W	3	1262	Mean Difference (IV, Fixed, 95% CI)	0.11 [‐0.00, 0.23]
1.2.7 Tralokinumab 300 mg SC Q4W	2	634	Mean Difference (IV, Fixed, 95% CI)	0.14 [‐0.02, 0.30]
1.2.8 AMG317 75 mg SC Q1W	1	98	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.60, 0.36]
1.2.9 AMG317 150 mg SC Q1W	1	98	Mean Difference (IV, Fixed, 95% CI)	0.07 [‐0.44, 0.58]
1.2.10 AMG317 300 mg SC Q1W	1	98	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.44, 0.64]
1.3 Serious adverse events Show forest plot	22	7739	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.76, 1.09]

1.3.1 Soluble IL‐4R 500 ug nebulised	1	12	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3.2 Soluble IL‐4R 1500 ug nebulised	1	13	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3.3 Tralokinumab 1 mg/kg IV Q4W	2	12	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3.4 Tralokinumab 5 mg/kg IV Q4W	2	14	Odds Ratio (M‐H, Fixed, 95% CI)	0.60 [0.02, 23.07]
1.3.5 Tralokinumab 10 mg/kg IV Q4W	2	10	Odds Ratio (M‐H, Fixed, 95% CI)	1.29 [0.03, 53.51]
1.3.6 Tralokinumab 150 mg SC Q2W	1	62	Odds Ratio (M‐H, Fixed, 95% CI)	0.62 [0.05, 7.39]
1.3.7 Tralokinumab 300 mg SC Q2W	6	1955	Odds Ratio (M‐H, Fixed, 95% CI)	0.78 [0.58, 1.05]
1.3.8 Tralokinumab 300 mg SC Q4W	2	831	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.58, 1.40]
1.3.9 Tralokinumab 600 mg SC Q2W	1	64	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.02, 5.42]
1.3.10 Lebrikizumab 37.5 mg SC Q4W	1	155	Odds Ratio (M‐H, Fixed, 95% CI)	0.16 [0.01, 1.76]
1.3.11 Lebrikizumab 125 mg SC Q4W	3	428	Odds Ratio (M‐H, Fixed, 95% CI)	1.47 [0.43, 5.05]
1.3.12 Lebrikizumab 250 mg SC Q4W	3	445	Odds Ratio (M‐H, Fixed, 95% CI)	0.72 [0.28, 1.86]
1.3.13 Lebrikizumab 500 mg SC Q4W	1	70	Odds Ratio (M‐H, Fixed, 95% CI)	1.08 [0.04, 27.64]
1.3.14 AMG317 75 mg SC Q1W	1	97	Odds Ratio (M‐H, Fixed, 95% CI)	0.69 [0.06, 7.91]
1.3.15 AMG317 150 mg SC Q1W	1	98	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3.16 AMG317 300 mg SC Q1W	1	96	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3.17 GSK679586 2.5 mg/kg IV Q4W	1	8	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3.18 GSK679586 10 mg/kg IV Q4W	2	206	Odds Ratio (M‐H, Fixed, 95% CI)	1.65 [0.52, 5.24]
1.3.19 GSK679586 20 mg/kg IV Q4W	1	12	Odds Ratio (M‐H, Fixed, 95% CI)	1.24 [0.04, 38.30]
1.3.20 RPC4046 0.3 mg/kg IV Q1W	1	6	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3.21 RPC4046 3 mg/kg IV Q1W	1	6	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3.22 Dupilumab 300 mg SC Q1W	1	104	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.03, 3.18]
1.3.23 Dupilumab 200 mg SC Q2W	2	1131	Odds Ratio (M‐H, Fixed, 95% CI)	0.96 [0.60, 1.54]
1.3.24 Dupilumab 200 mg SC Q4W	1	189	Odds Ratio (M‐H, Fixed, 95% CI)	0.77 [0.15, 3.98]
1.3.25 Dupilumab 300 mg SC Q2W	3	1359	Odds Ratio (M‐H, Fixed, 95% CI)	1.16 [0.76, 1.77]
1.3.26 Dupilumab 300 mg SC Q4W	1	197	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [0.39, 5.06]
1.3.27 IMA‐638 IV 0.2 mg/kg (D1/8/28/56/84)	1	21	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.3.28 IMA‐638 IV 0.6 mg/kg (D1/8/28/56/84)	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	1.00 [0.04, 28.30]
1.3.29 IMA‐638 IV 2 mg/kg (D1/8/28/56/84)	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.05, 9.70]
1.3.30 IMA‐638 IV 200 mg SC (D1/8/28/42/56/70/84)	1	67	Odds Ratio (M‐H, Fixed, 95% CI)	2.59 [0.12, 56.20]
1.3.31 IMA‐638 IV 75 mg SC (D1/8/28/42/56/70/84)	1	27	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.4 Exacerbation requiring OCS (rate ratio) Show forest plot	1	452	Rate Ratio (IV, Fixed, 95% CI)	0.98 [0.72, 1.32]

1.4.1 Tralokinumab 300 mg SC Q2W	1	225	Rate Ratio (IV, Fixed, 95% CI)	0.94 [0.62, 1.42]
1.4.2 Tralokinumab 300 mg SC Q4W	1	227	Rate Ratio (IV, Fixed, 95% CI)	1.02 [0.65, 1.59]
1.5 Exacerbation requiring OCS (dichotomous) Show forest plot	2	453	Odds Ratio (M‐H, Fixed, 95% CI)	0.93 [0.49, 1.78]

1.5.1 AMG317 75 mg SC	1	98	Odds Ratio (M‐H, Fixed, 95% CI)	1.14 [0.33, 3.88]
1.5.2 AMG317 150 mg SC	1	98	Odds Ratio (M‐H, Fixed, 95% CI)	0.47 [0.12, 1.83]
1.5.3 AMG317 300 mg SC	1	98	Odds Ratio (M‐H, Fixed, 95% CI)	0.62 [0.14, 2.69]
1.5.4 IMA638 75 mg SC	1	68	Odds Ratio (M‐H, Fixed, 95% CI)	6.38 [0.34, 120.65]
1.5.5 IMA638 200 mg SC	1	26	Odds Ratio (M‐H, Fixed, 95% CI)	19.29 [0.65, 573.83]
1.5.6 IMA638 0.2 mg/kg IV	1	21	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.5.7 IMA638 0.6 mg/kg IV	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	0.09 [0.00, 2.48]
1.5.8 IMA638 2 mg/kg IV	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	0.33 [0.02, 6.37]
1.6 Change from baseline in pre‐bronchodilator FEV1 Show forest plot	13	4829	Mean Difference (IV, Fixed, 95% CI)	0.10 [0.08, 0.12]

1.6.1 Tralokinumab 150 mg SC Q2W	1	58	Mean Difference (IV, Fixed, 95% CI)	0.09 [‐0.17, 0.35]
1.6.2 Tralokinumab 300 mg SC Q2W	3	331	Mean Difference (IV, Fixed, 95% CI)	0.13 [0.03, 0.22]
1.6.3 Tralokinumab 300 mg SC Q4W	1	185	Mean Difference (IV, Fixed, 95% CI)	0.04 [‐0.06, 0.14]
1.6.4 Tralokinumab 600 mg SC Q2W	1	58	Mean Difference (IV, Fixed, 95% CI)	0.20 [‐0.07, 0.47]
1.6.5 AMG317 75 mg SC Q1W	1	98	Mean Difference (IV, Fixed, 95% CI)	‐0.04 [‐0.18, 0.10]
1.6.6 AMG317 150 mg SC Q1W	1	98	Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.15, 0.21]
1.6.7 AMG317 300 mg SC Q1W	1	98	Mean Difference (IV, Fixed, 95% CI)	0.11 [‐0.03, 0.25]
1.6.8 Lebrikizumab 125 mg SC Q4W	2	279	Mean Difference (IV, Fixed, 95% CI)	0.08 [0.01, 0.16]
1.6.9 Lebrikizumab 250 mg SC Q4W	2	288	Mean Difference (IV, Fixed, 95% CI)	0.11 [0.03, 0.19]
1.6.10 Lebrikizumab 500 mg SC Q4W	1	70	Mean Difference (IV, Fixed, 95% CI)	0.06 [‐0.11, 0.22]
1.6.11 GSK679586 10 mg/kg IV Q4W	1	198	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.19, ‐0.01]
1.6.12 Dupilumab 300 mg SC Q1W	1	104	Mean Difference (IV, Fixed, 95% CI)	0.27 [0.11, 0.43]
1.6.13 Dupilumab 200 mg SC Q2W	2	1114	Mean Difference (IV, Fixed, 95% CI)	0.14 [0.09, 0.20]
1.6.14 Dupilumab 300 mg SC Q2W	3	1329	Mean Difference (IV, Fixed, 95% CI)	0.14 [0.10, 0.19]
1.6.15 Dupilumab 200 mg SC Q4W	1	157	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.04, 0.24]
1.6.16 Dupilumab 300 mg SC Q4W	1	164	Mean Difference (IV, Fixed, 95% CI)	0.13 [‐0.01, 0.27]
1.6.17 IMA‐638 0.2 mg/kg IV	1	21	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.20, 0.40]
1.6.18 IMA‐638 0.6 mg/kg IV	1	22	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐0.28, 0.28]
1.6.19 IMA‐638 2 mg/kg IV	1	22	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐0.31, 0.31]
1.6.20 IMA‐638 75 mg SC	1	49	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.11, 0.31]
1.6.21 IMA‐638 200 mg SC	1	86	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐0.13, 0.13]
1.7 Change from baseline in ACQ score Show forest plot	14	6251	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐0.24, ‐0.14]

1.7.1 Tralokinumab 150 mg SC Q2W	1	61	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.72, 0.48]
1.7.2 Tralokinumab 300 mg SC Q2W	5	1484	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.21, ‐0.03]
1.7.3 Tralokinumab 300 mg SC Q4W	2	685	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.27, 0.02]
1.7.4 Tralokinumab 600 mg SC Q2W	1	63	Mean Difference (IV, Fixed, 95% CI)	‐0.25 [‐0.82, 0.32]
1.7.5 AMG317 75 mg SC Q1W	1	98	Mean Difference (IV, Fixed, 95% CI)	0.06 [‐0.33, 0.45]
1.7.6 AMG317 150 mg SC Q1W	1	97	Mean Difference (IV, Fixed, 95% CI)	‐0.09 [‐0.51, 0.33]
1.7.7 AMG317 300 mg SC Q1W	1	98	Mean Difference (IV, Fixed, 95% CI)	‐0.21 [‐0.57, 0.15]
1.7.8 Lebrikizumab 125 mg SC Q4W	1	70	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.68, 0.28]
1.7.9 Lebrikizumab 250 mg SC Q4W	2	288	Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐0.30, 0.17]
1.7.10 Lebrikizumab 500 mg SC Q4W	1	70	Mean Difference (IV, Fixed, 95% CI)	‐0.40 [‐0.86, 0.06]
1.7.11 GSK679586 10 mg/kg IV Q4W	1	198	Mean Difference (IV, Fixed, 95% CI)	‐0.08 [‐0.31, 0.15]
1.7.12 Dupilumab 300 mg SC Q1W	1	104	Mean Difference (IV, Fixed, 95% CI)	‐0.73 [‐1.15, ‐0.31]
1.7.13 Dupilumab 200 mg SC Q2W	2	1114	Mean Difference (IV, Fixed, 95% CI)	‐0.38 [‐0.51, ‐0.25]
1.7.14 Dupilumab 300 mg SC Q2W	3	1341	Mean Difference (IV, Fixed, 95% CI)	‐0.27 [‐0.39, ‐0.15]
1.7.15 Dupilumab 200 mg SC Q4W	1	158	Mean Difference (IV, Fixed, 95% CI)	‐0.18 [‐0.53, 0.17]
1.7.16 Dupilumab 300 mg SC Q4W	1	163	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.54, 0.14]
1.7.17 IMA‐638 0.2 mg/kg IV	1	21	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐1.12, 0.92]
1.7.18 IMA‐638 0.6 mg/kg IV	1	22	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.75, 0.95]
1.7.19 IMA‐638 2 mg/kg IV	1	22	Mean Difference (IV, Fixed, 95% CI)	‐0.40 [‐1.25, 0.45]
1.7.20 IMA‐638 75 mg SC	1	8	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐0.65, 1.85]
1.7.21 IMA‐638 200 mg SC	1	86	Mean Difference (IV, Fixed, 95% CI)	0.20 [‐0.23, 0.63]
1.8 Adverse events Show forest plot	18	7419	Odds Ratio (M‐H, Fixed, 95% CI)	1.16 [1.04, 1.30]

1.8.1 Tralokinumab 150 mg SC Q2W	1	62	Odds Ratio (M‐H, Fixed, 95% CI)	1.48 [0.44, 5.01]
1.8.2 Tralokinumab 300 mg SC Q2W	5	1816	Odds Ratio (M‐H, Fixed, 95% CI)	1.37 [1.11, 1.69]
1.8.3 Tralokinumab 600 mg SC Q2W	1	64	Odds Ratio (M‐H, Fixed, 95% CI)	1.81 [0.57, 5.78]
1.8.4 Tralokinumab 300 mg SC Q4W	2	831	Odds Ratio (M‐H, Fixed, 95% CI)	1.31 [0.95, 1.81]
1.8.5 Tralokinumab 1 mg/kg IV	1	9	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.8.6 Tralokinumab 5 mg/kg IV	1	9	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.8.7 Tralokinumab 10 mg/kg IV	1	4	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.8.8 AMG317 75 mg SC Q1W	1	97	Odds Ratio (M‐H, Fixed, 95% CI)	2.16 [0.73, 6.37]
1.8.9 AMG317 150 mg SC Q1W	1	98	Odds Ratio (M‐H, Fixed, 95% CI)	1.50 [0.53, 4.26]
1.8.10 AMG317 300 mg SC Q1W	1	96	Odds Ratio (M‐H, Fixed, 95% CI)	2.07 [0.66, 6.46]
1.8.11 Lebrikizumab 37.5 mg SC Q4W	1	155	Odds Ratio (M‐H, Fixed, 95% CI)	1.18 [0.52, 2.67]
1.8.12 Lebrikizumab 125 mg SC Q4W	3	428	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.70, 1.64]
1.8.13 Lebrikizumab 250 mg SC Q4W	3	445	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.58, 1.44]
1.8.14 Lebrikizumab 500 mg SC Q4W	1	70	Odds Ratio (M‐H, Fixed, 95% CI)	1.50 [0.47, 4.80]
1.8.15 GSK679586 10 mg/kg IV Q4W	1	198	Odds Ratio (M‐H, Fixed, 95% CI)	1.13 [0.65, 1.97]
1.8.16 Dupilumab 300 mg SC Q1W	1	104	Odds Ratio (M‐H, Fixed, 95% CI)	1.26 [0.49, 3.24]
1.8.17 Dupilumab 200 mg SC Q2W	2	1131	Odds Ratio (M‐H, Fixed, 95% CI)	0.96 [0.70, 1.33]
1.8.18 Dupilumab 300 mg SC Q2W	3	1358	Odds Ratio (M‐H, Fixed, 95% CI)	0.89 [0.67, 1.18]
1.8.19 Dupilumab 200 mg SC Q4W	1	190	Odds Ratio (M‐H, Fixed, 95% CI)	1.02 [0.45, 2.28]
1.8.20 Dupilumab 300 mg SC Q4W	1	197	Odds Ratio (M‐H, Fixed, 95% CI)	1.60 [0.70, 3.67]
1.8.21 VR492 0.5 mg	1	11	Odds Ratio (M‐H, Fixed, 95% CI)	0.67 [0.06, 7.35]
1.8.22 VR492 10 mg	1	11	Odds Ratio (M‐H, Fixed, 95% CI)	0.33 [0.03, 3.93]
1.8.23 VR492 20 mg	1	23	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [0.28, 12.07]
1.8.24 RPC4046 0.3 mg/kg IV Q1W	1	6	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.8.25 RPC4046 3 mg/kg IV Q1W	1	6	Odds Ratio (M‐H, Fixed, 95% CI)	1.00 [0.03, 29.81]
1.9 Change from baseline in FENO, ppb Show forest plot	11	3577	Mean Difference (IV, Fixed, 95% CI)	‐14.68 [‐16.56, ‐12.80]

1.9.1 Lebrikizumab 125 mg SC Q4W	2	279	Mean Difference (IV, Fixed, 95% CI)	‐21.25 [‐29.12, ‐13.37]
1.9.2 Lebrikizumab 250 mg SC Q4W	2	288	Mean Difference (IV, Fixed, 95% CI)	‐11.70 [‐17.34, ‐6.05]
1.9.3 Lebrikizumab 500 mg SC Q4W	1	70	Mean Difference (IV, Fixed, 95% CI)	‐14.10 [‐32.86, 4.66]
1.9.4 Tralokinumab 300 mg Q2W	1	76	Mean Difference (IV, Fixed, 95% CI)	‐11.67 [‐20.32, ‐3.02]
1.9.5 Dupilumab 200 mg SC Q2W	2	1088	Mean Difference (IV, Fixed, 95% CI)	‐14.21 [‐17.27, ‐11.16]
1.9.6 Dupilumab 300 mg SC Q2W	3	1317	Mean Difference (IV, Fixed, 95% CI)	‐12.52 [‐16.61, ‐8.43]
1.9.7 Dupilumab 200 mg SC Q4W	1	132	Mean Difference (IV, Fixed, 95% CI)	‐16.39 [‐40.06, 7.28]
1.9.8 Dupilumab 300 mg SC Q4W	1	145	Mean Difference (IV, Fixed, 95% CI)	‐27.53 [‐51.21, ‐3.85]
1.9.9 Soluble IL‐4R 500 ug nebulised	1	12	Mean Difference (IV, Fixed, 95% CI)	‐15.50 [‐57.42, 26.42]
1.9.10 Soluble IL‐4R 1500 ug nebulised	1	13	Mean Difference (IV, Fixed, 95% CI)	‐26.40 [‐67.03, 14.23]
1.9.11 GSK679586 2.5 mg/kg IV Q4W	2	8	Mean Difference (IV, Fixed, 95% CI)	‐28.00 [‐52.29, ‐3.71]
1.9.12 GSK679586 10 mg/kg IV Q4W	2	8	Mean Difference (IV, Fixed, 95% CI)	‐40.00 [‐55.96, ‐24.04]
1.9.13 GSK679586 20 mg/kg IV Q4W	2	96	Mean Difference (IV, Fixed, 95% CI)	‐24.14 [‐32.12, ‐16.15]
1.9.14 VR492 0.5 mg	1	11	Mean Difference (IV, Fixed, 95% CI)	‐3.80 [‐15.80, 8.20]
1.9.15 VR492 10 mg	1	11	Mean Difference (IV, Fixed, 95% CI)	‐17.50 [‐29.50, ‐5.50]
1.9.16 VR492 20 mg	1	23	Mean Difference (IV, Fixed, 95% CI)	‐11.60 [‐20.50, ‐2.70]
1.10 Change from baseline in blood eosinophils, cells x 109/L Show forest plot*	6	2598	Mean Difference (IV, Fixed, 95% CI)	0.06 [0.04, 0.09]

1.10.1 Tralokinumab 300 mg Q2W	1	76	Mean Difference (IV, Fixed, 95% CI)	0.08 [‐0.02, 0.18]
1.10.2 Lebrikizumab 250 mg SC Q4W	1	218	Mean Difference (IV, Fixed, 95% CI)	0.11 [0.06, 0.16]
1.10.3 Dupilumab 300 mg SC Q1W	1	87	Mean Difference (IV, Fixed, 95% CI)	0.17 [‐0.02, 0.36]
1.10.4 Dupilumab 200 mg SC Q2W	1	944	Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.03, 0.06]
1.10.5 Dupilumab 300 mg SC Q2W	1	953	Mean Difference (IV, Fixed, 95% CI)	0.04 [‐0.01, 0.09]
1.10.6 IMA‐638 0.2 mg/kg IV	1	21	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.10, 0.30]
1.10.7 IMA‐638 0.6 mg/kg IV	1	22	Mean Difference (IV, Fixed, 95% CI)	0.20 [0.00, 0.40]
1.10.8 IMA‐638 2 mg/kg IV	1	22	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.09, 0.29]
1.10.9 IMA‐638 75 mg SC	1	8	Mean Difference (IV, Fixed, 95% CI)	0.20 [‐1.13, 1.53]
1.10.10 IMA‐638 200 mg SC	1	49	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.10, 0.30]
1.10.11 GSK679586 10 mg/kg IV	1	198	Mean Difference (IV, Fixed, 95% CI)	0.08 [‐0.00, 0.16]
1.11 Change from baseline in periostin, ng/mL Show forest plot	2	2106	Mean Difference (IV, Fixed, 95% CI)	‐9.04 [‐10.92, ‐7.17]

1.11.1 Lebrikizumab 125 mg SC Q4W	1	209	Mean Difference (IV, Fixed, 95% CI)	‐4.20 [‐6.84, ‐1.56]
1.11.2 Dupilumab 200 mg SC Q2W	1	944	Mean Difference (IV, Fixed, 95% CI)	‐14.06 [‐17.70, ‐10.42]
1.11.3 Dupilumab 300 mg SC Q2W	1	953	Mean Difference (IV, Fixed, 95% CI)	‐13.85 [‐17.73, ‐9.97]
1.12 Percentage reduction from baseline in OCS use Show forest plot	2	350	Mean Difference (IV, Fixed, 95% CI)	‐15.58 [‐23.30, ‐7.85]

1.12.1 Tralokinumab 300 mg SC Q2W	1	140	Mean Difference (IV, Fixed, 95% CI)	‐7.77 [‐17.60, 2.06]
1.12.2 Dupilumab 300 mg SC Q2W	1	210	Mean Difference (IV, Fixed, 95% CI)	‐28.20 [‐40.70, ‐15.70]
1.13 Exacerbation requiring hospitalisation/ED/OCS (rate ratio) Show forest plot	7	6998	Rate Ratio (IV, Fixed, 95% CI)	0.71 [0.65, 0.77]

1.13.1 Tralokinumab 300 mg SC Q2W	3	1575	Rate Ratio (IV, Fixed, 95% CI)	0.94 [0.80, 1.11]
1.13.2 Tralokinumab 300 mg SC Q4W	1	604	Rate Ratio (IV, Fixed, 95% CI)	0.90 [0.66, 1.22]
1.13.3 Lebrikizumab 37.5 mg SC Q4W	2	1074	Rate Ratio (IV, Fixed, 95% CI)	0.68 [0.53, 0.87]
1.13.4 Lebrikizumab 125 mg SC Q4W	2	1074	Rate Ratio (IV, Fixed, 95% CI)	0.74 [0.59, 0.93]
1.13.5 Dupilumab 200mg SC Q2W	2	1135	Rate Ratio (IV, Fixed, 95% CI)	0.51 [0.40, 0.64]
1.13.6 Dupilumab 200 mg SC Q4W	1	195	Rate Ratio (IV, Fixed, 95% CI)	0.46 [0.18, 1.16]
1.13.7 Dupilumab 300mg SC Q2W	2	1144	Rate Ratio (IV, Fixed, 95% CI)	0.52 [0.42, 0.65]
1.13.8 Dupilumab 300 mg SC Q4W	1	197	Rate Ratio (IV, Fixed, 95% CI)	0.67 [0.29, 1.55]
1.14 Exacerbation requiring hospitalisation/ED/OCS (relative risk) Show forest plot	1	210	Risk Ratio (IV, Fixed, 95% CI)	0.41 [0.26, 0.63]

1.14.1 Dupilumab 300mg SC Q2W	1	210	Risk Ratio (IV, Fixed, 95% CI)	0.41 [0.26, 0.63]

Comparison 1. Anti‐interleukin‐13 or ‐4 agents with placebo

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Comparison 2. Subanalysis: agents directly targeting IL‐13

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Exacerbation requiring hospitalisation or ED visit Show forest plot	2		Rate Ratio (IV, Fixed, 95% CI)	0.68 [0.47, 0.98]

2.1.1 Tralokinumab 300 mg SC Q2W	2		Rate Ratio (IV, Fixed, 95% CI)	0.63 [0.41, 0.99]
2.1.2 Tralokinumab 300 mg SC Q4W	1		Rate Ratio (IV, Fixed, 95% CI)	0.78 [0.41, 1.49]
2.2 Health‐related quality of life (adjusted mean diff versus placebo) Show forest plot	4		Mean Difference (IV, Fixed, 95% CI)	0.10 [0.01, 0.18]

2.2.1 Lebrikizumab 125 mg SC Q4W	1		Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐0.29, 0.17]
2.2.2 Tralokinumab 300 mg SC Q2W	3		Mean Difference (IV, Fixed, 95% CI)	0.11 [‐0.00, 0.23]
2.2.3 Tralokinumab 300 mg SC Q4W	2		Mean Difference (IV, Fixed, 95% CI)	0.14 [‐0.02, 0.30]
2.3 Serious adverse events Show forest plot	16	4443	Odds Ratio (M‐H, Fixed, 95% CI)	0.84 [0.67, 1.05]

2.3.1 Tralokinumab 1 mg/kg IV Q4W	2	12	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.3.2 Tralokinumab 5 mg/kg IV Q4W	2	14	Odds Ratio (M‐H, Fixed, 95% CI)	0.60 [0.02, 23.07]
2.3.3 Tralokinumab 10 mg/kg IV Q4W	2	10	Odds Ratio (M‐H, Fixed, 95% CI)	1.29 [0.03, 53.51]
2.3.4 Tralokinumab 150 mg SC Q2W	1	62	Odds Ratio (M‐H, Fixed, 95% CI)	0.62 [0.05, 7.39]
2.3.5 Tralokinumab 300 mg SC Q2W	6	1955	Odds Ratio (M‐H, Fixed, 95% CI)	0.78 [0.58, 1.05]
2.3.6 Tralokinumab 300 mg SC Q4W	2	831	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.58, 1.40]
2.3.7 Tralokinumab 600 mg SC Q2W	1	64	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.02, 5.42]
2.3.8 Lebrikizumab 37.5 mg SC Q4W	1	155	Odds Ratio (M‐H, Fixed, 95% CI)	0.16 [0.01, 1.76]
2.3.9 Lebrikizumab 125 mg SC Q4W	3	428	Odds Ratio (M‐H, Fixed, 95% CI)	1.47 [0.43, 5.05]
2.3.10 Lebrikizumab 250 mg SC Q4W	3	445	Odds Ratio (M‐H, Fixed, 95% CI)	0.72 [0.28, 1.86]
2.3.11 Lebrikizumab 500 mg SC Q4W	1	70	Odds Ratio (M‐H, Fixed, 95% CI)	1.08 [0.04, 27.64]
2.3.12 GSK679586 2.5 mg/kg IV Q4W	1	8	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.3.13 GSK679586 10 mg/kg IV Q4W	2	206	Odds Ratio (M‐H, Fixed, 95% CI)	1.65 [0.52, 5.24]
2.3.14 GSK679586 20 mg/kg IV Q4W	1	12	Odds Ratio (M‐H, Fixed, 95% CI)	1.24 [0.04, 38.30]
2.3.15 RPC4046 0.3 mg/kg IV Q1W	1	6	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.3.16 RPC4046 3 mg/kg IV Q1W	1	6	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.3.17 IMA‐638 IV 0.2 mg/kg (D1/8/28/56/84)	1	21	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.3.18 IMA‐638 IV 0.6 mg/kg (D1/8/28/56/84)	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	1.00 [0.04, 28.30]
2.3.19 IMA‐638 IV 2 mg/kg (D1/8/28/56/84)	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.05, 9.70]
2.3.20 IMA‐638 IV 200 mg SC (D1/8/28/42/56/70/84)	1	67	Odds Ratio (M‐H, Fixed, 95% CI)	2.59 [0.12, 56.20]
2.3.21 IMA‐638 IV 75 mg SC (D1/8/28/42/56/70/84)	1	27	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.4 Exacerbation requiring hospitalisation/ED/OCS (rate ratio) Show forest plot	5		Rate Ratio (IV, Fixed, 95% CI)	0.83 [0.74, 0.92]

2.4.1 Tralokinumab 300 mg SC Q2W	3		Rate Ratio (IV, Fixed, 95% CI)	0.94 [0.80, 1.11]
2.4.2 Tralokinumab 300 mg SC Q4W	1		Rate Ratio (IV, Fixed, 95% CI)	0.90 [0.66, 1.22]
2.4.3 Lebrikizumab 37.5 mg SC Q4W	2		Rate Ratio (IV, Fixed, 95% CI)	0.68 [0.53, 0.87]
2.4.4 Lebrikizumab 125 mg SC Q4W	2		Rate Ratio (IV, Fixed, 95% CI)	0.74 [0.59, 0.93]

Comparison 2. Subanalysis: agents directly targeting IL‐13

Ir a la tabla de la revisión

Comparison 3. Subanalysis: agents directly targeting IL‐4R

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Health‐related quality of life (adjusted mean diff versus placebo) Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	0.26 [0.17, 0.34]

3.1.1 Dupilumab 200 mg SC Q2W	2		Mean Difference (IV, Fixed, 95% CI)	0.29 [0.16, 0.42]
3.1.2 Dupilumab 200 mg SC Q4W	1		Mean Difference (IV, Fixed, 95% CI)	0.23 [‐0.13, 0.59]
3.1.3 Dupilumab 300 mg SC Q2W	2		Mean Difference (IV, Fixed, 95% CI)	0.27 [0.14, 0.40]
3.1.4 Dupilumab 300 mg SC Q4W	1		Mean Difference (IV, Fixed, 95% CI)	0.30 [‐0.06, 0.66]
3.1.5 AMG317 75 mg SC Q1W	1		Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.60, 0.36]
3.1.6 AMG317 150 mg SC Q1W	1		Mean Difference (IV, Fixed, 95% CI)	0.07 [‐0.44, 0.58]
3.1.7 AMG317 300 mg SC Q1W	1		Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.44, 0.64]
3.2 Serious adverse events Show forest plot	6	3296	Odds Ratio (M‐H, Fixed, 95% CI)	1.05 [0.78, 1.40]

3.2.1 Soluble IL‐4R 500 ug nebulised	1	12	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.2.2 Soluble IL‐4R 1500 ug nebulised	1	13	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.2.3 AMG317 75 mg SC Q1W	1	97	Odds Ratio (M‐H, Fixed, 95% CI)	0.69 [0.06, 7.91]
3.2.4 AMG317 150 mg SC Q1W	1	98	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.2.5 AMG317 300 mg SC Q1W	1	96	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.2.6 Dupilumab 300 mg SC Q1W	1	104	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.03, 3.18]
3.2.7 Dupilumab 200 mg SC Q2W	2	1131	Odds Ratio (M‐H, Fixed, 95% CI)	0.96 [0.60, 1.54]
3.2.8 Dupilumab 200 mg SC Q4W	1	189	Odds Ratio (M‐H, Fixed, 95% CI)	0.77 [0.15, 3.98]
3.2.9 Dupilumab 300 mg SC Q2W	3	1359	Odds Ratio (M‐H, Fixed, 95% CI)	1.16 [0.76, 1.77]
3.2.10 Dupilumab 300 mg SC Q4W	1	197	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [0.39, 5.06]
3.3 Exacerbation requiring hospitalisation/ED/OCS (rate ratio) Show forest plot	2		Rate Ratio (IV, Fixed, 95% CI)	0.52 [0.44, 0.61]

3.3.1 Dupilumab 200mg SC Q2W	2		Rate Ratio (IV, Fixed, 95% CI)	0.51 [0.40, 0.64]
3.3.2 Dupilumab 200 mg SC Q4W	1		Rate Ratio (IV, Fixed, 95% CI)	0.46 [0.18, 1.16]
3.3.3 Dupilumab 300mg SC Q2W	2		Rate Ratio (IV, Fixed, 95% CI)	0.52 [0.42, 0.65]
3.3.4 Dupilumab 300 mg SC Q4W	1		Rate Ratio (IV, Fixed, 95% CI)	0.67 [0.29, 1.55]

Comparison 3. Subanalysis: agents directly targeting IL‐4R

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Comparison 4. Subanalysis: study duration <= 6 months

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Health‐related quality of life (adjusted mean diff versus placebo) Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	0.13 [‐0.00, 0.26]

4.1.1 Lebrikizumab 125 mg SC Q4W	1		Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐0.29, 0.17]
4.1.2 Dupilumab 200 mg SC Q2W	1		Mean Difference (IV, Fixed, 95% CI)	0.31 [‐0.06, 0.68]
4.1.3 Dupilumab 200 mg SC Q4W	1		Mean Difference (IV, Fixed, 95% CI)	0.23 [‐0.13, 0.59]
4.1.4 Dupilumab 300 mg SC Q2W	1		Mean Difference (IV, Fixed, 95% CI)	0.36 [‐0.02, 0.74]
4.1.5 Dupilumab 300 mg SC Q4W	1		Mean Difference (IV, Fixed, 95% CI)	0.30 [‐0.06, 0.66]
4.1.6 AMG317 75 mg SC Q1W	1		Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.60, 0.36]
4.1.7 AMG317 150 mg SC Q1W	1		Mean Difference (IV, Fixed, 95% CI)	0.07 [‐0.44, 0.58]
4.1.8 AMG317 300 mg SC Q1W	1		Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.44, 0.64]
4.2 Serious adverse events Show forest plot	16	2738	Odds Ratio (M‐H, Fixed, 95% CI)	1.09 [0.73, 1.63]

4.2.1 Soluble IL‐4R 500 ug nebulised	1	12	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.2.2 Soluble IL‐4R 1500 ug nebulised	1	13	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.2.3 Tralokinumab 1 mg/kg IV Q4W	2	12	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.2.4 Tralokinumab 5 mg/kg IV Q4W	2	14	Odds Ratio (M‐H, Fixed, 95% CI)	0.60 [0.02, 23.07]
4.2.5 Tralokinumab 10 mg/kg IV Q4W	2	10	Odds Ratio (M‐H, Fixed, 95% CI)	1.29 [0.03, 53.51]
4.2.6 Tralokinumab 150 mg SC Q2W	1	62	Odds Ratio (M‐H, Fixed, 95% CI)	0.62 [0.05, 7.39]
4.2.7 Tralokinumab 300 mg SC Q2W	2	145	Odds Ratio (M‐H, Fixed, 95% CI)	0.19 [0.02, 1.89]
4.2.8 Tralokinumab 600 mg SC Q2W	1	64	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.02, 5.42]
4.2.9 Lebrikizumab 125 mg SC Q4W	2	277	Odds Ratio (M‐H, Fixed, 95% CI)	2.18 [0.33, 14.31]
4.2.10 Lebrikizumab 250 mg SC Q4W	2	288	Odds Ratio (M‐H, Fixed, 95% CI)	0.69 [0.19, 2.53]
4.2.11 Lebrikizumab 500 mg SC Q4W	1	70	Odds Ratio (M‐H, Fixed, 95% CI)	1.08 [0.04, 27.64]
4.2.12 AMG317 75 mg SC Q1W	1	97	Odds Ratio (M‐H, Fixed, 95% CI)	0.69 [0.06, 7.91]
4.2.13 AMG317 150 mg SC Q1W	1	98	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.2.14 AMG317 300 mg SC Q1W	1	96	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.2.15 GSK679586 2.5 mg/kg IV Q4W	1	8	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.2.16 GSK679586 10 mg/kg IV Q4W	2	206	Odds Ratio (M‐H, Fixed, 95% CI)	1.65 [0.52, 5.24]
4.2.17 GSK679586 20 mg/kg IV Q4W	1	12	Odds Ratio (M‐H, Fixed, 95% CI)	1.24 [0.04, 38.30]
4.2.18 RPC4046 0.3 mg/kg IV Q1W	1	6	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.2.19 RPC4046 3 mg/kg IV Q1W	1	6	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.2.20 Dupilumab 300 mg SC Q1W	1	104	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.03, 3.18]
4.2.21 Dupilumab 200 mg SC Q2W	1	187	Odds Ratio (M‐H, Fixed, 95% CI)	1.34 [0.28, 6.39]
4.2.22 Dupilumab 200 mg SC Q4W	1	189	Odds Ratio (M‐H, Fixed, 95% CI)	0.77 [0.15, 3.98]
4.2.23 Dupilumab 300 mg SC Q2W	2	406	Odds Ratio (M‐H, Fixed, 95% CI)	1.65 [0.69, 3.97]
4.2.24 Dupilumab 300 mg SC Q4W	1	197	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [0.39, 5.06]
4.2.25 IMA‐638 IV 0.2 mg/kg (D1/8/28/56/84)	1	21	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.2.26 IMA‐638 IV 0.6 mg/kg (D1/8/28/56/84)	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	1.00 [0.04, 28.30]
4.2.27 IMA‐638 IV 2 mg/kg (D1/8/28/56/84)	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.05, 9.70]
4.2.28 IMA‐638 IV 200 mg SC (D1/8/28/42/56/70/84)	1	67	Odds Ratio (M‐H, Fixed, 95% CI)	2.59 [0.12, 56.20]
4.2.29 IMA‐638 IV 75 mg SC (D1/8/28/42/56/70/84)	1	27	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.3 Exacerbation requiring hospitalisation/ED/OCS (rate ratio) Show forest plot	1		Rate Ratio (IV, Fixed, 95% CI)	0.43 [0.27, 0.68]

4.3.1 Dupilumab 200mg SC Q2W	1		Rate Ratio (IV, Fixed, 95% CI)	0.30 [0.11, 0.82]
4.3.2 Dupilumab 200 mg SC Q4W	1		Rate Ratio (IV, Fixed, 95% CI)	0.46 [0.18, 1.16]
4.3.3 Dupilumab 300mg SC Q2W	1		Rate Ratio (IV, Fixed, 95% CI)	0.29 [0.11, 0.78]
4.3.4 Dupilumab 300 mg SC Q4W	1		Rate Ratio (IV, Fixed, 95% CI)	0.67 [0.29, 1.55]

Comparison 4. Subanalysis: study duration <= 6 months

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Comparison 5. Subanalysis: study duration > 6 months

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Exacerbation requiring hospitalisation or ED visit Show forest plot	2		Rate Ratio (IV, Fixed, 95% CI)	0.68 [0.47, 0.98]

5.1.1 Tralokinumab 300 mg SC Q2W	2		Rate Ratio (IV, Fixed, 95% CI)	0.63 [0.41, 0.99]
5.1.2 Tralokinumab 300 mg SC Q4W	1		Rate Ratio (IV, Fixed, 95% CI)	0.78 [0.41, 1.49]
5.2 Health‐related quality of life (adjusted mean diff versus placebo) Show forest plot	4		Mean Difference (IV, Fixed, 95% CI)	0.19 [0.13, 0.26]

5.2.1 Dupilumab 200 mg SC Q2W	1		Mean Difference (IV, Fixed, 95% CI)	0.29 [0.15, 0.43]
5.2.2 Dupilumab 300 mg SC Q2W	1		Mean Difference (IV, Fixed, 95% CI)	0.26 [0.12, 0.40]
5.2.3 Tralokinumab 300 mg SC Q2W	3		Mean Difference (IV, Fixed, 95% CI)	0.11 [‐0.00, 0.23]
5.2.4 Tralokinumab 300 mg SC Q4W	2		Mean Difference (IV, Fixed, 95% CI)	0.14 [‐0.02, 0.30]
5.3 Serious adverse events Show forest plot	6	5001	Odds Ratio (M‐H, Fixed, 95% CI)	0.87 [0.72, 1.06]

5.3.1 Tralokinumab 300 mg SC Q2W	4	1810	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.59, 1.09]
5.3.2 Tralokinumab 300 mg SC Q4W	2	831	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.58, 1.40]
5.3.3 Lebrikizumab 37.5 mg SC Q4W	1	155	Odds Ratio (M‐H, Fixed, 95% CI)	0.16 [0.01, 1.76]
5.3.4 Lebrikizumab 125 mg SC Q4W	1	151	Odds Ratio (M‐H, Fixed, 95% CI)	1.05 [0.20, 5.42]
5.3.5 Lebrikizumab 250 mg SC Q4W	1	157	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.19, 3.08]
5.3.6 Dupilumab 200 mg SC Q2W	1	944	Odds Ratio (M‐H, Fixed, 95% CI)	0.93 [0.57, 1.53]
5.3.7 Dupilumab 200 mg SC Q4W	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.3.8 Dupilumab 300 mg SC Q2W	1	953	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.64, 1.68]
5.4 Exacerbation requiring hospitalisation/ED/OCS (rate ratio) Show forest plot	6		Rate Ratio (IV, Fixed, 95% CI)	0.72 [0.66, 0.79]

5.4.1 Tralokinumab 300 mg SC Q2W	3		Rate Ratio (IV, Fixed, 95% CI)	0.94 [0.80, 1.11]
5.4.2 Tralokinumab 300 mg SC Q4W	1		Rate Ratio (IV, Fixed, 95% CI)	0.90 [0.66, 1.22]
5.4.3 Lebrikizumab 37.5 mg SC Q4W	2		Rate Ratio (IV, Fixed, 95% CI)	0.68 [0.53, 0.87]
5.4.4 Lebrikizumab 125 mg SC Q4W	2		Rate Ratio (IV, Fixed, 95% CI)	0.74 [0.59, 0.93]
5.4.5 Dupilumab 200mg SC Q2W	1		Rate Ratio (IV, Fixed, 95% CI)	0.52 [0.41, 0.66]
5.4.6 Dupilumab 300mg SC Q2W	1		Rate Ratio (IV, Fixed, 95% CI)	0.54 [0.43, 0.68]

Comparison 5. Subanalysis: study duration > 6 months

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Comparison 6. Subanalysis: asthma severity mild‐to‐moderate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Health‐related quality of life (adjusted mean diff versus placebo) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐0.29, 0.17]

6.1.1 Lebrikizumab 125 mg SC Q4W	1		Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐0.29, 0.17]
6.2 Serious adverse events Show forest plot	7	664	Odds Ratio (M‐H, Fixed, 95% CI)	1.41 [0.49, 4.01]

6.2.1 Soluble IL‐4R 500 ug nebulised	1	12	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.2.2 Soluble IL‐4R 1500 ug nebulised	1	13	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.2.3 Tralokinumab 1 mg/kg IV Q4W	1	9	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.2.4 Tralokinumab 5 mg/kg IV Q4W	1	9	Odds Ratio (M‐H, Fixed, 95% CI)	0.60 [0.02, 23.07]
6.2.5 Tralokinumab 10 mg/kg IV Q4W	1	5	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.2.6 Lebrikizumab 125 mg SC Q4W	2	277	Odds Ratio (M‐H, Fixed, 95% CI)	2.18 [0.33, 14.31]
6.2.7 Lebrikizumab 250 mg SC Q4W	1	70	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.2.8 Lebrikizumab 500 mg SC Q4W	1	70	Odds Ratio (M‐H, Fixed, 95% CI)	1.08 [0.04, 27.64]
6.2.9 GSK679586 2.5 mg/kg IV Q4W	1	8	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.2.10 GSK679586 10 mg/kg IV Q4W	1	8	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.2.11 GSK679586 20 mg/kg IV Q4W	1	12	Odds Ratio (M‐H, Fixed, 95% CI)	1.24 [0.04, 38.30]
6.2.12 RPC4046 0.3 mg/kg IV Q1W	1	6	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.2.13 RPC4046 3 mg/kg IV Q1W	1	6	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.2.14 IMA‐638 IV 0.2 mg/kg (D1/8/28/56/84)	1	21	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.2.15 IMA‐638 IV 0.6 mg/kg (D1/8/28/56/84)	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	1.00 [0.04, 28.30]
6.2.16 IMA‐638 IV 2 mg/kg (D1/8/28/56/84)	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.05, 9.70]
6.2.17 IMA‐638 IV 200 mg SC (D1/8/28/42/56/70/84)	1	67	Odds Ratio (M‐H, Fixed, 95% CI)	2.59 [0.12, 56.20]
6.2.18 IMA‐638 IV 75 mg SC (D1/8/28/42/56/70/84)	1	27	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable

Comparison 6. Subanalysis: asthma severity mild‐to‐moderate

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Comparison 7. Subanalysis: asthma severity severe

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Exacerbation requiring hospitalisation or ED visit Show forest plot	2		Rate Ratio (IV, Fixed, 95% CI)	0.68 [0.47, 0.98]

7.1.1 Tralokinumab 300 mg SC Q2W	2		Rate Ratio (IV, Fixed, 95% CI)	0.63 [0.41, 0.99]
7.1.2 Tralokinumab 300 mg SC Q4W	1		Rate Ratio (IV, Fixed, 95% CI)	0.78 [0.41, 1.49]
7.2 Health‐related quality of life (adjusted mean diff versus placebo) Show forest plot	5		Mean Difference (IV, Fixed, 95% CI)	0.21 [0.14, 0.27]

7.2.1 Dupilumab 200 mg SC Q2W	2		Mean Difference (IV, Fixed, 95% CI)	0.29 [0.16, 0.42]
7.2.2 Dupilumab 200 mg SC Q4W	1		Mean Difference (IV, Fixed, 95% CI)	0.23 [‐0.13, 0.59]
7.2.3 Dupilumab 300 mg SC Q2W	2		Mean Difference (IV, Fixed, 95% CI)	0.27 [0.14, 0.40]
7.2.4 Dupilumab 300 mg SC Q4W	1		Mean Difference (IV, Fixed, 95% CI)	0.30 [‐0.06, 0.66]
7.2.5 Tralokinumab 300 mg SC Q2W	3		Mean Difference (IV, Fixed, 95% CI)	0.11 [‐0.00, 0.23]
7.2.6 Tralokinumab 300 mg SC Q4W	2		Mean Difference (IV, Fixed, 95% CI)	0.14 [‐0.02, 0.30]
7.3 Serious adverse events Show forest plot	10	5946	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.78, 1.13]

7.3.1 Tralokinumab 1 mg/kg IV Q4W	1	3	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.3.2 Tralokinumab 5 mg/kg IV Q4W	1	5	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
7.3.3 Tralokinumab 10 mg/kg IV Q4W	1	5	Odds Ratio (M‐H, Fixed, 95% CI)	1.29 [0.03, 53.51]
7.3.4 Tralokinumab 300 mg SC Q2W	4	1810	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.59, 1.09]
7.3.5 Tralokinumab 300 mg SC Q4W	2	831	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.58, 1.40]
7.3.6 Lebrikizumab 250 mg SC Q4W	1	218	Odds Ratio (M‐H, Fixed, 95% CI)	0.69 [0.19, 2.53]
7.3.7 GSK679586 10 mg/kg IV Q4W	1	198	Odds Ratio (M‐H, Fixed, 95% CI)	1.65 [0.52, 5.24]
7.3.8 Dupilumab 200 mg SC Q2W	2	1131	Odds Ratio (M‐H, Fixed, 95% CI)	0.96 [0.60, 1.54]
7.3.9 Dupilumab 200 mg SC Q4W	1	189	Odds Ratio (M‐H, Fixed, 95% CI)	0.77 [0.15, 3.98]
7.3.10 Dupilumab 300 mg SC Q2W	3	1359	Odds Ratio (M‐H, Fixed, 95% CI)	1.16 [0.76, 1.77]
7.3.11 Dupilumab 300 mg SC Q4W	1	197	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [0.39, 5.06]
7.4 Exacerbation requiring hospitalisation/ED/OCS (rate ratio) Show forest plot	7		Rate Ratio (IV, Fixed, 95% CI)	0.71 [0.65, 0.77]

7.4.1 Tralokinumab 300 mg SC Q2W	3		Rate Ratio (IV, Fixed, 95% CI)	0.94 [0.80, 1.11]
7.4.2 Tralokinumab 300 mg SC Q4W	1		Rate Ratio (IV, Fixed, 95% CI)	0.90 [0.66, 1.22]
7.4.3 Lebrikizumab 37.5 mg SC Q4W	2		Rate Ratio (IV, Fixed, 95% CI)	0.68 [0.53, 0.87]
7.4.4 Lebrikizumab 125 mg SC Q4W	2		Rate Ratio (IV, Fixed, 95% CI)	0.74 [0.59, 0.93]
7.4.5 Dupilumab 200mg SC Q2W	2		Rate Ratio (IV, Fixed, 95% CI)	0.51 [0.40, 0.64]
7.4.6 Dupilumab 200 mg SC Q4W	1		Rate Ratio (IV, Fixed, 95% CI)	0.46 [0.18, 1.16]
7.4.7 Dupilumab 300mg SC Q2W	2		Rate Ratio (IV, Fixed, 95% CI)	0.52 [0.42, 0.65]
7.4.8 Dupilumab 300 mg SC Q4W	1		Rate Ratio (IV, Fixed, 95% CI)	0.67 [0.29, 1.55]

Comparison 7. Subanalysis: asthma severity severe

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Comparison 8. Subanalysis: no concomitant ICS

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Health‐related quality of life (adjusted mean diff versus placebo) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐0.29, 0.17]

8.1.1 Lebrikizumab 125 mg SC Q4W	1		Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐0.29, 0.17]
8.2 Serious adverse events Show forest plot	4	470	Odds Ratio (M‐H, Fixed, 95% CI)	1.73 [0.40, 7.48]

8.2.1 Soluble IL‐4R 500 ug nebulised	1	12	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.2.2 Soluble IL‐4R 1500 ug nebulised	1	13	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.2.3 Lebrikizumab 125 mg SC Q4W	2	277	Odds Ratio (M‐H, Fixed, 95% CI)	2.18 [0.33, 14.31]
8.2.4 Lebrikizumab 250 mg SC Q4W	1	70	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.2.5 Lebrikizumab 500 mg SC Q4W	1	70	Odds Ratio (M‐H, Fixed, 95% CI)	1.08 [0.04, 27.64]
8.2.6 GSK679586 2.5 mg/kg IV Q4W	1	8	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.2.7 GSK679586 10 mg/kg IV Q4W	1	8	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.2.8 GSK679586 20 mg/kg IV Q4W	1	12	Odds Ratio (M‐H, Fixed, 95% CI)	1.24 [0.04, 38.30]

Comparison 8. Subanalysis: no concomitant ICS

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Comparison 9. Subanalysis: concomitant ICS

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Exacerbation requiring hospitalisation or ED visit Show forest plot	2		Rate Ratio (IV, Fixed, 95% CI)	0.68 [0.47, 0.98]

9.1.1 Tralokinumab 300 mg SC Q2W	2		Rate Ratio (IV, Fixed, 95% CI)	0.63 [0.41, 0.99]
9.1.2 Tralokinumab 300 mg SC Q4W	1		Rate Ratio (IV, Fixed, 95% CI)	0.78 [0.41, 1.49]
9.2 Health‐related quality of life (adjusted mean diff versus placebo) Show forest plot	6		Mean Difference (IV, Fixed, 95% CI)	0.20 [0.13, 0.26]

9.2.1 Dupilumab 200 mg SC Q2W	2		Mean Difference (IV, Fixed, 95% CI)	0.29 [0.16, 0.42]
9.2.2 Dupilumab 200 mg SC Q4W	1		Mean Difference (IV, Fixed, 95% CI)	0.23 [‐0.13, 0.59]
9.2.3 Dupilumab 300 mg SC Q2W	2		Mean Difference (IV, Fixed, 95% CI)	0.27 [0.14, 0.40]
9.2.4 Dupilumab 300 mg SC Q4W	1		Mean Difference (IV, Fixed, 95% CI)	0.30 [‐0.06, 0.66]
9.2.5 Tralokinumab 300 mg SC Q2W	3		Mean Difference (IV, Fixed, 95% CI)	0.11 [‐0.00, 0.23]
9.2.6 Tralokinumab 300 mg SC Q4W	2		Mean Difference (IV, Fixed, 95% CI)	0.14 [‐0.02, 0.30]
9.2.7 AMG317 75 mg SC Q1W	1		Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.60, 0.36]
9.2.8 AMG317 150 mg SC Q1W	1		Mean Difference (IV, Fixed, 95% CI)	0.07 [‐0.44, 0.58]
9.2.9 AMG317 300 mg SC Q1W	1		Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.44, 0.64]
9.3 Serious adverse events Show forest plot	18	7269	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.76, 1.08]

9.3.1 Tralokinumab 1 mg/kg IV Q4W	2	12	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.3.2 Tralokinumab 5 mg/kg IV Q4W	2	14	Odds Ratio (M‐H, Fixed, 95% CI)	0.60 [0.02, 23.07]
9.3.3 Tralokinumab 10 mg/kg IV Q4W	2	10	Odds Ratio (M‐H, Fixed, 95% CI)	1.29 [0.03, 53.51]
9.3.4 Tralokinumab 150 mg SC Q2W	1	62	Odds Ratio (M‐H, Fixed, 95% CI)	0.62 [0.05, 7.39]
9.3.5 Tralokinumab 300 mg SC Q2W	6	1955	Odds Ratio (M‐H, Fixed, 95% CI)	0.78 [0.58, 1.05]
9.3.6 Tralokinumab 300 mg SC Q4W	2	831	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.58, 1.40]
9.3.7 Tralokinumab 600 mg SC Q2W	1	64	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.02, 5.42]
9.3.8 Lebrikizumab 37.5 mg SC Q4W	1	155	Odds Ratio (M‐H, Fixed, 95% CI)	0.16 [0.01, 1.76]
9.3.9 Lebrikizumab 125 mg SC Q4W	1	151	Odds Ratio (M‐H, Fixed, 95% CI)	1.05 [0.20, 5.42]
9.3.10 Lebrikizumab 250 mg SC Q4W	2	375	Odds Ratio (M‐H, Fixed, 95% CI)	0.72 [0.28, 1.86]
9.3.11 AMG317 75 mg SC Q1W	1	97	Odds Ratio (M‐H, Fixed, 95% CI)	0.69 [0.06, 7.91]
9.3.12 AMG317 150 mg SC Q1W	1	98	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.3.13 AMG317 300 mg SC Q1W	1	96	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.3.14 GSK679586 10 mg/kg IV Q4W	1	198	Odds Ratio (M‐H, Fixed, 95% CI)	1.65 [0.52, 5.24]
9.3.15 RPC4046 0.3 mg/kg IV Q1W	1	6	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.3.16 RPC4046 3 mg/kg IV Q1W	1	6	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.3.17 Dupilumab 300 mg SC Q1W	1	104	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.03, 3.18]
9.3.18 Dupilumab 200 mg SC Q2W	2	1131	Odds Ratio (M‐H, Fixed, 95% CI)	0.96 [0.60, 1.54]
9.3.19 Dupilumab 200 mg SC Q4W	1	189	Odds Ratio (M‐H, Fixed, 95% CI)	0.77 [0.15, 3.98]
9.3.20 Dupilumab 300 mg SC Q2W	3	1359	Odds Ratio (M‐H, Fixed, 95% CI)	1.16 [0.76, 1.77]
9.3.21 Dupilumab 300 mg SC Q4W	1	197	Odds Ratio (M‐H, Fixed, 95% CI)	1.40 [0.39, 5.06]
9.3.22 IMA‐638 IV 0.2 mg/kg (D1/8/28/56/84)	1	21	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.3.23 IMA‐638 IV 0.6 mg/kg (D1/8/28/56/84)	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	1.00 [0.04, 28.30]
9.3.24 IMA‐638 IV 2 mg/kg (D1/8/28/56/84)	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.05, 9.70]
9.3.25 IMA‐638 IV 200 mg SC (D1/8/28/42/56/70/84)	1	67	Odds Ratio (M‐H, Fixed, 95% CI)	2.59 [0.12, 56.20]
9.3.26 IMA‐638 IV 75 mg SC (D1/8/28/42/56/70/84)	1	27	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.4 Exacerbation requiring hospitalisation/ED/OCS (rate ratio) Show forest plot	7		Rate Ratio (IV, Fixed, 95% CI)	0.71 [0.65, 0.77]

9.4.1 Tralokinumab 300 mg SC Q2W	3		Rate Ratio (IV, Fixed, 95% CI)	0.94 [0.80, 1.11]
9.4.2 Tralokinumab 300 mg SC Q4W	1		Rate Ratio (IV, Fixed, 95% CI)	0.90 [0.66, 1.22]
9.4.3 Lebrikizumab 37.5 mg SC Q4W	2		Rate Ratio (IV, Fixed, 95% CI)	0.68 [0.53, 0.87]
9.4.4 Lebrikizumab 125 mg SC Q4W	2		Rate Ratio (IV, Fixed, 95% CI)	0.74 [0.59, 0.93]
9.4.5 Dupilumab 200mg SC Q2W	2		Rate Ratio (IV, Fixed, 95% CI)	0.51 [0.40, 0.64]
9.4.6 Dupilumab 200 mg SC Q4W	1		Rate Ratio (IV, Fixed, 95% CI)	0.46 [0.18, 1.16]
9.4.7 Dupilumab 300mg SC Q2W	2		Rate Ratio (IV, Fixed, 95% CI)	0.52 [0.42, 0.65]
9.4.8 Dupilumab 300 mg SC Q4W	1		Rate Ratio (IV, Fixed, 95% CI)	0.67 [0.29, 1.55]

Comparison 9. Subanalysis: concomitant ICS

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Comparison 10. Subanalysis by blood eosinophil count: exacerbations requiring hospitalisation/ED/OCS

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Blood eosinophils high (> 300 cells/uL) Show forest plot	5	2052	Rate Ratio (IV, Fixed, 95% CI)	0.47 [0.40, 0.55]

10.1.1 Dupilumab 200 mg Q2W	2	494	Rate Ratio (IV, Fixed, 95% CI)	0.34 [0.24, 0.47]
10.1.2 Dupilumab 200 mg Q4W	1	77	Rate Ratio (IV, Fixed, 95% CI)	0.34 [0.07, 1.63]
10.1.3 Dupilumab 300 mg Q2W	3	589	Rate Ratio (IV, Fixed, 95% CI)	0.46 [0.36, 0.59]
10.1.4 Dupilumab 300 mg Q4W	1	83	Rate Ratio (IV, Fixed, 95% CI)	0.65 [0.17, 2.44]
10.1.5 Lebrikizumab 37.5 mg Q4W	2	398	Rate Ratio (IV, Fixed, 95% CI)	0.54 [0.38, 0.76]
10.1.6 Lebrikizumab 125 mg Q4W	2	411	Rate Ratio (IV, Fixed, 95% CI)	0.59 [0.42, 0.83]
10.2 Blood eosinophils low (< 300 cells/uL) Show forest plot	4	1881	Rate Ratio (IV, Fixed, 95% CI)	0.75 [0.65, 0.87]

10.2.1 Dupilumab 200 mg Q2W	1	107	Rate Ratio (IV, Fixed, 95% CI)	0.32 [0.09, 1.21]
10.2.2 Dupilumab 200 mg Q4W	1	114	Rate Ratio (IV, Fixed, 95% CI)	0.57 [0.19, 1.75]
10.2.3 Dupilumab 300 mg Q2W	2	237	Rate Ratio (IV, Fixed, 95% CI)	0.69 [0.56, 0.86]
10.2.4 Dupilumab 300 mg Q4W	1	114	Rate Ratio (IV, Fixed, 95% CI)	0.63 [0.21, 1.85]
10.2.5 Lebrikizumab 37.5 mg Q4W	2	645	Rate Ratio (IV, Fixed, 95% CI)	0.79 [0.58, 1.08]
10.2.6 Lebrikizumab 125 mg Q4W	2	664	Rate Ratio (IV, Fixed, 95% CI)	0.92 [0.68, 1.23]
10.3 Blood eosinophils low (> 150 < 300 cells/uL) Show forest plot	1	527	Rate Ratio (IV, Fixed, 95% CI)	0.60 [0.43, 0.83]

10.3.1 Dupilumab 200 mg Q2W	1	257	Rate Ratio (IV, Fixed, 95% CI)	0.64 [0.41, 1.00]
10.3.2 Dupilumab 300 mg Q2W	1	270	Rate Ratio (IV, Fixed, 95% CI)	0.56 [0.35, 0.90]
10.4 Blood eosinophils low (< 150 cells/uL) Show forest plot	1	542	Rate Ratio (IV, Fixed, 95% CI)	1.05 [0.76, 1.43]

10.4.1 Dupilumab 200 mg Q2W	1	278	Rate Ratio (IV, Fixed, 95% CI)	0.93 [0.58, 1.49]
10.4.2 Dupilumab 300 mg Q2W	1	264	Rate Ratio (IV, Fixed, 95% CI)	1.15 [0.75, 1.76]

Comparison 10. Subanalysis by blood eosinophil count: exacerbations requiring hospitalisation/ED/OCS

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Comparison 11. Subanalysis by FENO: exacerbations requiring hospitalisation/ED/OCS

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 FENO high (≥ 50 ppb) Show forest plot	1	389	Rate Ratio (IV, Fixed, 95% CI)	0.31 [0.22, 0.45]

11.1.1 Dupilumab 200 mg Q2W	1	190	Rate Ratio (IV, Fixed, 95% CI)	0.31 [0.18, 0.53]
11.1.2 Dupilumab 300 mg Q2W	1	199	Rate Ratio (IV, Fixed, 95% CI)	0.31 [0.19, 0.51]
11.2 FENO medium (≥ 25 to < 50 ppb) Show forest plot	1	554	Rate Ratio (IV, Fixed, 95% CI)	0.42 [0.30, 0.58]

11.2.1 Dupilumab 200 mg Q2W	1	271	Rate Ratio (IV, Fixed, 95% CI)	0.39 [0.24, 0.63]
11.2.2 Dupilumab 300 mg Q2W	1	283	Rate Ratio (IV, Fixed, 95% CI)	0.44 [0.28, 0.69]
11.3 FENO low (< 25 ppb) Show forest plot	1	935	Rate Ratio (IV, Fixed, 95% CI)	0.77 [0.61, 0.97]

11.3.1 Dupilumab 200 mg Q2W	1	474	Rate Ratio (IV, Fixed, 95% CI)	0.75 [0.54, 1.04]
11.3.2 Dupilumab 300 mg Q2W	1	461	Rate Ratio (IV, Fixed, 95% CI)	0.79 [0.57, 1.09]

Comparison 11. Subanalysis by FENO: exacerbations requiring hospitalisation/ED/OCS

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Comparison 12. Subanalysis by periostin level: exacerbations requiring hospitalisation/ED/OCS

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 Periostin high (≥ 50 ng/mL) Show forest plot	3	1499	Rate Ratio (IV, Fixed, 95% CI)	0.63 [0.51, 0.77]

12.1.1 Lebrikizumab 37.5 mg	3	717	Rate Ratio (IV, Fixed, 95% CI)	0.59 [0.43, 0.79]
12.1.2 Lebrikizumab 125 mg	3	715	Rate Ratio (IV, Fixed, 95% CI)	0.66 [0.49, 0.89]
12.1.3 Lebrikizumab 250 mg	1	67	Rate Ratio (IV, Fixed, 95% CI)	0.78 [0.27, 2.24]
12.2 Periostin low (< 50 ng/mL) Show forest plot	3	1212	Rate Ratio (IV, Fixed, 95% CI)	0.87 [0.68, 1.11]

12.2.1 Lebrikizumab 37.5 mg	3	562	Rate Ratio (IV, Fixed, 95% CI)	0.79 [0.54, 1.15]
12.2.2 Lebrikizumab 125 mg	3	560	Rate Ratio (IV, Fixed, 95% CI)	0.93 [0.66, 1.32]
12.2.3 Lebrikizumab 250 mg	1	90	Rate Ratio (IV, Fixed, 95% CI)	0.95 [0.30, 3.00]

Comparison 12. Subanalysis by periostin level: exacerbations requiring hospitalisation/ED/OCS

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Comparison 13. Sensitvity analysis ‐ random‐effects

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
13.1 Exacerbation requiring hospitalisation or ED visit Show forest plot	2		Rate Ratio (IV, Random, 95% CI)	0.68 [0.47, 0.98]

13.1.1 Tralokinumab 300 mg SC Q2W	2		Rate Ratio (IV, Random, 95% CI)	0.63 [0.41, 0.99]
13.1.2 Tralokinumab 300 mg SC Q4W	1		Rate Ratio (IV, Random, 95% CI)	0.78 [0.41, 1.49]
13.2 Health‐related quality of life (adjusted mean diff versus placebo) Show forest plot	7		Mean Difference (IV, Random, 95% CI)	0.18 [0.12, 0.24]

13.2.1 Lebrikizumab 125 mg SC Q4W	1		Mean Difference (IV, Random, 95% CI)	‐0.06 [‐0.29, 0.17]
13.2.2 Dupilumab 200 mg SC Q2W	2		Mean Difference (IV, Random, 95% CI)	0.29 [0.16, 0.42]
13.2.3 Dupilumab 200 mg SC Q4W	1		Mean Difference (IV, Random, 95% CI)	0.23 [‐0.13, 0.59]
13.2.4 Dupilumab 300 mg SC Q2W	2		Mean Difference (IV, Random, 95% CI)	0.27 [0.14, 0.40]
13.2.5 Dupilumab 300 mg SC Q4W	1		Mean Difference (IV, Random, 95% CI)	0.30 [‐0.06, 0.66]
13.2.6 Tralokinumab 300 mg SC Q2W	3		Mean Difference (IV, Random, 95% CI)	0.11 [‐0.00, 0.23]
13.2.7 Tralokinumab 300 mg SC Q4W	2		Mean Difference (IV, Random, 95% CI)	0.14 [‐0.02, 0.30]
13.2.8 AMG317 75 mg SC Q1W	1		Mean Difference (IV, Random, 95% CI)	‐0.12 [‐0.60, 0.36]
13.2.9 AMG317 150 mg SC Q1W	1		Mean Difference (IV, Random, 95% CI)	0.07 [‐0.44, 0.58]
13.2.10 AMG317 300 mg SC Q1W	1		Mean Difference (IV, Random, 95% CI)	0.10 [‐0.44, 0.64]
13.3 Serious adverse events Show forest plot	22	7739	Odds Ratio (M‐H, Random, 95% CI)	0.91 [0.76, 1.09]

13.3.1 Soluble IL‐4R 500 ug nebulised	1	12	Odds Ratio (M‐H, Random, 95% CI)	Not estimable
13.3.2 Soluble IL‐4R 1500 ug nebulised	1	13	Odds Ratio (M‐H, Random, 95% CI)	Not estimable
13.3.3 Tralokinumab 1 mg/kg IV Q4W	2	12	Odds Ratio (M‐H, Random, 95% CI)	Not estimable
13.3.4 Tralokinumab 5 mg/kg IV Q4W	2	14	Odds Ratio (M‐H, Random, 95% CI)	0.60 [0.02, 23.07]
13.3.5 Tralokinumab 10 mg/kg IV Q4W	2	10	Odds Ratio (M‐H, Random, 95% CI)	1.29 [0.03, 53.51]
13.3.6 Tralokinumab 150 mg SC Q2W	1	62	Odds Ratio (M‐H, Random, 95% CI)	0.62 [0.05, 7.39]
13.3.7 Tralokinumab 300 mg SC Q2W	6	1955	Odds Ratio (M‐H, Random, 95% CI)	0.78 [0.58, 1.06]
13.3.8 Tralokinumab 300 mg SC Q4W	2	831	Odds Ratio (M‐H, Random, 95% CI)	0.89 [0.58, 1.39]
13.3.9 Tralokinumab 600 mg SC Q2W	1	64	Odds Ratio (M‐H, Random, 95% CI)	0.32 [0.02, 5.42]
13.3.10 Lebrikizumab 37.5 mg SC Q4W	1	155	Odds Ratio (M‐H, Random, 95% CI)	0.16 [0.01, 1.76]
13.3.11 Lebrikizumab 125 mg SC Q4W	3	428	Odds Ratio (M‐H, Random, 95% CI)	1.43 [0.41, 4.94]
13.3.12 Lebrikizumab 250 mg SC Q4W	3	445	Odds Ratio (M‐H, Random, 95% CI)	0.72 [0.28, 1.87]
13.3.13 Lebrikizumab 500 mg SC Q4W	1	70	Odds Ratio (M‐H, Random, 95% CI)	1.08 [0.04, 27.64]
13.3.14 AMG317 75 mg SC Q1W	1	97	Odds Ratio (M‐H, Random, 95% CI)	0.69 [0.06, 7.91]
13.3.15 AMG317 150 mg SC Q1W	1	98	Odds Ratio (M‐H, Random, 95% CI)	Not estimable
13.3.16 AMG317 300 mg SC Q1W	1	96	Odds Ratio (M‐H, Random, 95% CI)	Not estimable
13.3.17 GSK679586 2.5 mg/kg IV Q4W	1	8	Odds Ratio (M‐H, Random, 95% CI)	Not estimable
13.3.18 GSK679586 10 mg/kg IV Q4W	2	206	Odds Ratio (M‐H, Random, 95% CI)	1.65 [0.52, 5.24]
13.3.19 GSK679586 20 mg/kg IV Q4W	1	12	Odds Ratio (M‐H, Random, 95% CI)	1.24 [0.04, 38.30]
13.3.20 RPC4046 0.3 mg/kg IV Q1W	1	6	Odds Ratio (M‐H, Random, 95% CI)	Not estimable
13.3.21 RPC4046 3 mg/kg IV Q1W	1	6	Odds Ratio (M‐H, Random, 95% CI)	Not estimable
13.3.22 Dupilumab 300 mg SC Q1W	1	104	Odds Ratio (M‐H, Random, 95% CI)	0.32 [0.03, 3.18]
13.3.23 Dupilumab 200 mg SC Q2W	2	1131	Odds Ratio (M‐H, Random, 95% CI)	0.96 [0.60, 1.54]
13.3.24 Dupilumab 200 mg SC Q4W	1	189	Odds Ratio (M‐H, Random, 95% CI)	0.77 [0.15, 3.98]
13.3.25 Dupilumab 300 mg SC Q2W	3	1359	Odds Ratio (M‐H, Random, 95% CI)	1.16 [0.76, 1.76]
13.3.26 Dupilumab 300 mg SC Q4W	1	197	Odds Ratio (M‐H, Random, 95% CI)	1.40 [0.39, 5.06]
13.3.27 IMA‐638 IV 0.2 mg/kg (D1/8/28/56/84)	1	21	Odds Ratio (M‐H, Random, 95% CI)	Not estimable
13.3.28 IMA‐638 IV 0.6 mg/kg (D1/8/28/56/84)	1	22	Odds Ratio (M‐H, Random, 95% CI)	1.00 [0.04, 28.30]
13.3.29 IMA‐638 IV 2 mg/kg (D1/8/28/56/84)	1	22	Odds Ratio (M‐H, Random, 95% CI)	0.71 [0.05, 9.70]
13.3.30 IMA‐638 IV 200 mg SC (D1/8/28/42/56/70/84)	1	67	Odds Ratio (M‐H, Random, 95% CI)	2.59 [0.12, 56.20]
13.3.31 IMA‐638 IV 75 mg SC (D1/8/28/42/56/70/84)	1	27	Odds Ratio (M‐H, Random, 95% CI)	Not estimable

Comparison 13. Sensitvity analysis ‐ random‐effects

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Idioma de la Revisión Cochrane

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Resumen

Antecedentes

Objetivos

Métodos de búsqueda

Criterios de selección

Obtención y análisis de los datos

Resultados principales

Conclusiones de los autores

PICO

PICO

Population

Intervention

Comparison

Outcome

Resumen en términos sencillos

Inhibidores de la interleucina 13 o de la interleucina 4 versus placebo, inhibidores de la interleucina 5 o agentes antiinmunoglobulina E, para niños y adultos con asma

Resumen visual

Authors' conclusions

Implications for practice

Implications for research

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Assessment of bias in conducting the systematic review

Measures of treatment effect

Unit of analysis issues

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Assessment of heterogeneity

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Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

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Included studies

Methods

Participants

Intervention

Outcomes

Excluded studies

Risk of bias in included studies

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Structure of the meta‐analysis

Structure of the narrative synthesis

Primary outcomes

Exacerbations requiring hospitalisation or emergency department visit

Respiratory health‐related quality of life

Serious adverse events

Secondary outcomes

Exacerbations requiring OCS

Lung function (adjusted trough FEV1)

Asthma control