Dornasa alfa para la fibrosis quística
Resumen
Antecedentes
La dornasa alfa se utiliza actualmente como mucolítico para tratar la enfermedad pulmonar (la principal causa de morbilidad y mortalidad) en la fibrosis quística. Reduce la viscosidad de la mucosidad en los pulmones, promoviendo una mejor depuración de las secreciones. Ésta es una actualización de una revisión publicada anteriormente.
Objetivos
Determinar si el uso de la dornasa alfa en la fibrosis quística se asocia con una mejoría de la mortalidad y la morbilidad en comparación con el placebo u otros fármacos que mejoran la depuración de las vías respiratorias e identificar cualquier evento adverso asociado con su uso.
Métodos de búsqueda
Se hicieron búsquedas en el registro de ensayos del Grupo Cochrane de Fibrosis quística y enfermedades genéticas (Cochrane Cystic Fibrosis and Genetic Disorders Group), que comprende referencias identificadas mediante búsquedas exhaustivas en bases de datos electrónicas, búsquedas manuales en revistas relevantes y en resúmenes de congresos. Fecha de la búsqueda más reciente en el Registro del Grupo de Fibrosis quística: 12 de octubre de 2020.
También se buscaron estudios en curso y no publicados en clinicaltrials.gov y en la Plataforma de registros internacionales de ensayos clínicos. Fecha de la búsqueda más reciente: 8 de febrero de 2021.
Criterios de selección
Todos los ensayos controlados aleatorizados y cuasialeatorizados que compararan dornasa alfa con placebo, tratamiento estándar u otros fármacos que mejoren la depuración de las vías respiratorias.
Obtención y análisis de los datos
Los autores de la revisión cotejaron de forma independiente los ensayos con los criterios de inclusión; dos autores realizaron el análisis de la calidad metodológica y extrajeron los datos. Se utilizó el método GRADE para evaluar el nivel de la evidencia.
Resultados principales
Las búsquedas identificaron 74 ensayos, de los cuales 19 (2565 participantes) cumplieron los criterios de inclusión. Quince ensayos compararon la dornasa alfa con placebo o ninguna dornasa alfa (2447 participantes); dos compararon la dornasa diaria con suero hipertónico (32 participantes); uno comparó la dornasa alfa diaria con suero hipertónico y dornasa alfa en días alternos (48 participantes); uno comparó la dornasa alfa con manitol y la combinación de ambos fármacos (38 participantes). La duración de los ensayos varió entre seis días y tres años.
Dornasa alfa en comparación con placebo o ningún tratamiento
La dornasa alfa probablemente mejora el volumen espiratorio forzado en un segundo (VEF1) al mes (cuatro ensayos, 248 participantes), a los tres meses (un ensayo, 320 participantes; evidencia de calidad moderada), a los seis meses (un ensayo, 647 participantes; evidencia de calidad alta) y a los dos años (un ensayo, 410 participantes). Evidencia limitada de calidad baja mostró que el tratamiento podría dar lugar a poca o ninguna diferencia en la calidad de vida. Es probable que la dornasa alfa reduzca el número de exacerbaciones pulmonares en ensayos de hasta dos años (evidencia de calidad moderada). Un ensayo que examinó el coste de la atención, incluido el coste de la dornasa alfa, encontró que el ahorro de costes de la dornasa alfa compensaba entre el 18% y el 38% de los costes de la medicación.
Dornasa alfa: diaria versus en días alternos
Un ensayo cruzado (cross‐over) (43 niños) encontró poca o ninguna diferencia entre los regímenes de tratamiento en la función pulmonar, la calidad de vida o las exacerbaciones pulmonares (evidencia de calidad baja).
Dornasa alfa comparada con otros medicamentos que mejoran la depuración de las vías respiratorias
Los resultados de estas comparaciones fueron variables. Un ensayo (43 niños) mostró que la dornasa alfa podría dar lugar a una mejoría mayor del VEF1 en comparación con el suero hipertónico (evidencia de calidad baja) y un ensayo (23 participantes) informó de poca o ninguna diferencia en la función pulmonar entre la dornasa alfa y el manitol o la dornasa alfa y la dornasa alfa más manitol (evidencia de calidad baja). Un ensayo (23 participantes) encontró que la dornasa alfa podría mejorar la calidad de vida en comparación con la dornasa alfa más manitol (evidencia de calidad baja); otras comparaciones encontraron poca o ninguna diferencia en este desenlace (evidencia de calidad baja). Ningún ensayo en ninguna comparación informó diferencias entre los grupos en el número de exacerbaciones pulmonares (evidencia de calidad baja).
Cuando se evaluaron todas las comparaciones, la dornasa alfa no causó significativamente más efectos adversos que otros tratamientos, excepto la alteración de la voz y la erupción cutánea.
Conclusiones de los autores
Hay evidencia que demuestra que, en comparación con el placebo, el tratamiento con dornasa alfa podría mejorar la función pulmonar en las personas con fibrosis quística en ensayos que duran de un mes a dos años. Hubo una disminución de las exacerbaciones pulmonares en los ensayos de seis meses o más, probablemente debido al tratamiento. La alteración de la voz y la erupción cutánea parecen ser los únicos eventos adversos informados con mayor frecuencia en los ensayos controlados aleatorizados. No hay evidencia suficiente para concluir firmemente si la dornasa alfa es superior a otros agentes hiperosmolares en la mejoría de la función pulmonar.
PICO
Resumen en términos sencillos
Dornasa alfa, un medicamento inhalado, para el tratamiento de la enfermedad pulmonar en la fibrosis quística
Pregunta de la revisión
Se revisó la evidencia acerca del efecto de la dornasa alfa inhalada para tratar la enfermedad pulmonar en personas con fibrosis quística.
Antecedentes
La fibrosis quística es un trastorno hereditario que afecta el movimiento de la sal a través de las células del cuerpo y afecta, por ejemplo, a las glándulas sudoríparas, las vías respiratorias, el páncreas y el sistema reproductivo masculino. La enfermedad pulmonar es la causa más común de muerte en las personas con fibrosis quística y, aunque la esperanza media de vida ha aumentado en los últimos 30 años, sigue siendo de sólo 48,5 años en los países de ingresos altos. Las personas con fibrosis quística desarrollan una enfermedad pulmonar crónica debido a la mucosidad espesa que se acumula en los pulmones y que provoca infecciones e inflamación. La dornasa alfa se desarrolló para diluir esta mucosidad, de modo que a las personas les resulte más fácil expulsarla de los pulmones a través de la tos; lo que a su vez, debería disminuir el número de infecciones y la cantidad de inflamación y prevenir la enfermedad pulmonar crónica.
Fecha de la búsqueda
La evidencia está actualizada hasta el 12 de octubre de 2020.
Características de los estudios
Se incluyeron 19 ensayos con 2565 personas con fibrosis quística; 15 ensayos (2447 personas) compararon la dornasa alfa con placebo (un tratamiento simulado sin medicación activa) o ningún tratamiento con dornasa alfa; dos ensayos (32 personas) compararon la dornasa alfa diaria con suero hipertónico; un ensayo (48 personas) comparó la dornasa alfa diaria con suero hipertónico y dornasa alfa en días alternos; y un ensayo (38 personas) comparó la dornasa alfa con manitol y la combinación de ambos medicamentos. Personas de todos los grupos de edad (desde lactantes hasta adultos) participaron en los ensayos, que duraron de seis días a tres años.
Resultados clave
Dornasa alfa en comparación con placebo o ningún tratamiento
Se encontró que la dornasa alfa probablemente mejora la función pulmonar en el transcurso de un mes en comparación con un placebo o ningún tratamiento y esta mejoría también se observó en ensayos con una duración más prolongada que duraron de seis meses a dos años (ocho ensayos; 1708 participantes). También hubo menos exacerbaciones pulmonares (brotes de inflamación pulmonar) en estos ensayos de mayor duración. Un ensayo encontró que el ahorro de costos de la dornasa alfa compensaba entre el 18% y el 38% de los costos de la medicación.
Dornasa alfa diaria frente a en días alternos
Un ensayo (43 niños) no encontró diferencias entre los regímenes de tratamiento en la función pulmonar, la calidad de vida o las exacerbaciones pulmonares.
Dornasa alfa comparada con otros medicamentos que mejoran la depuración de las vías respiratorias
Los resultados de los ensayos que compararon la dornasa alfa con el suero hipertónico o el manitol fueron variados. Un ensayo (43 niños) mostró una mejoría mayor en la función pulmonar con la dornasa alfa en comparación con el suero hipertónico y un ensayo (23 participantes) no informó diferencias en la función pulmonar entre la dornasa alfa y el manitol o la dornasa alfa y la dornasa alfa más manitol. En un ensayo (23 participantes) las puntuaciones de calidad de vida fueron mejores con la dornasa alfa sola en comparación con dornasa alfa más manitol; otras comparaciones de medicamentos no encontraron diferencias entre los tratamientos en la calidad de vida. Ningún ensayo en ninguna comparación de tratamientos informó diferencias entre los grupos en el número de exacerbaciones pulmonares.
En general, no se informaron efectos secundarios graves y sólo se observaron con más frecuencia sarpullidos y un cambio de voz en las personas que recibieron dornasa alfa. Sin embargo, la evidencia actual no permite determinar con certeza si la dornasa alfa es mejor que otros medicamentos como el suero hipertónico o el manitol.
Calidad de la evidencia
La calidad de la evidencia de los ensayos que compararon la dornasa alfa con placebo o ningún tratamiento fue moderada a alta para los resultados de la función pulmonar, pero sólo un ensayo informó de algún cambio en la calidad de vida, por lo que la evidencia para este desenlace es limitada.
Además, hubo pocos ensayos que compararan diferentes regímenes de tratamiento con dornasa alfa (p.ej., una vez al día frente a dos veces al día) o que compararan la dornasa alfa con otros medicamentos que ayudan a eliminar las secreciones, por lo que la evidencia actual de estos ensayos es limitada y de calidad baja.
Authors' conclusions
Summary of findings
| Dornase alfa compared with placebo or no dornase alfa treatment for cystic fibrosis | ||||||
| Patient or population: Adults and children with cystic fibrosis Settings: Outpatients Intervention: Dornase alfa Comparison: Placebo or no treatment | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo or no dornase alfa treatment | Dornase alfa | |||||
| Relative mean percentage change in FEV1 (% predicted) at 3 months | The relative mean percentage change in FEV1 (% predicted) was 2.10 | The relative mean percentage change in FEV1 (% predicted) was 7.30 higher (4.04 higher to 10.56 higher) | NA | 320 (1 study)1 | ⊕⊕⊕⊝ | |
| Relative mean percentage change in FEV1 (% predicted) at 6 months | The relative mean percentage change in FEV1 (% predicted) was 0.00 | The relative mean percentage change in FEV1 (% predicted) was 5.80 higher (3.99 higher to 7.61 higher) | NA | 647 (1 study)1 | ⊕⊕⊕⊕ | Result presented from once‐daily dornase alfa group. Significant benefit for dornase alfa also present in twice‐daily dornase alfa group |
| Relative mean percentage change in FVC (% predicted) at 3 months | The relative mean percentage change in FVC (% predicted) was 7.30 | The relative mean percentage change in FVC (% predicted) was 5.10 higher (1.23 higher to 8.97 higher) | NA | 318 (1 study)4 | ⊕⊕⊕⊝ | |
| Relative mean percentage change in FVC (% predicted) at 6 months | See comment | See comment | MD 3.80 (2.62 to 4.98) | 647 (1 study)1 | ⊕⊕⊕⊕ | Mean difference between groups only presented. Result presented from once‐daily dornase alfa group. Significant benefit for dornase alfa also present in twice‐daily dornase alfa group |
| Change in quality of life ‐ CFQ‐R respiratory at 1 month | See comment | See comment | MD 0.84 (‐10.74 to 12.42) | 19 (1 cross‐over study)5 | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa daily. Participants received both interventions in cross‐over design. |
| Change in quality of life ‐ CFQ‐R respiratory (parent) at 1 month | See comment | See comment | MD 9.78 (‐2.58 to 22.14) | 19 (1 cross‐over study)5 | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa daily. Participants received both interventions in cross‐over design. |
| Number of people experiencing exacerbations at up to 2 years | 252 per 1000 | 196 per 1000 | RR 0.78 (0.62 to 0.96) | 1157 (3 studies)8 | ⊕⊕⊕⊝ | RR <1 indicates an advantage for dornase alfa. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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). Assumed and corresponding risk not calculated for quality of life. Relative effect and 95% CI presented is adjusted for the cross‐over design of the study | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. Additionally four trials included in analysis at one month showed a significant advantage to dornase alfa over placebo or no dornase alfa treatment (Laube 1996; Ramsey 1993; Ranasinha 1993; Shah 1995a). Three studies not included in pooled analysis showed no difference between groups in relative FEV1(L) (Robinson 2000) and relative FEV1 (% predicted) (Wilmott 1996) or absolute FEV1 (% predicted) (Amin 2011) at one month. At one year, one study showed a significant advantage to dornase alfa over placebo or no dornase alfa treatment (Frederiksen 2006) and one study showed no difference between treatments (Robinson 2005). At one year, one study showed a significant advantage to dornase alfa over placebo or no dornase alfa treatment (Quan 2001) and at three years, one study showed no significant difference between treatments (Paul 2004). 2. Downgraded due to indirectness: participants in McCoy 1996 had severe lung disease (FVC below 40%). 3. No evidence of imprecision, inconsistency, indirectness, publication bias or serious risk of bias. 4. Additionally four trials included in analysis at one month (Laube 1996; Ramsey 1993; Ranasinha 1993; Shah 1995a) showed a significant advantage to dornase alfa over placebo or no dornase alfa treatment. One study not included in pooled analysis showed a significant advantage in relative FVC (L) to dornase alfa over placebo or no dornase alfa treatment (Robinson 2000) and one study showed no significant different in absolute FVC (% predicted) between groups (Amin 2011) at one month. No significant difference was found between groups at one year (Robinson 2005) and at two years (Quan 2001). 5. Additionally, four studies reported quality of life data which could not be included in pooled analysis. Wilmott 1996 showed no difference between groups in CFQ‐R. Ramsey reported that the frequency and magnitude of improvement across all quality of life questions was greater among participants receiving dornase alfa (Ramsey 1993). Ranasinha reported significant improvements in overall well‐being and significant improvements in general well‐being, cough frequency and chest congestion (Ranasinha 1993) and Fuchs reported significant improvements in well‐being score and dyspnoea score on dornase alfa compared to placebo (Fuchs 1994). 6. Downgraded once for lack of applicability: Amin included children only so results are not applicable to adults (Amin 2011). 7. Downgraded once for imprecision: wide confidence intervals around the effect size due to limited sample size of the trial. 8. Additionally, one study reported an age‐adjusted RR of having more than one respiratory exacerbation, but these data were not included in the pooled analysis (McCoy 1996). No significant difference was found between dornase alfa and control. 9. Downgraded once as data from one cross‐over trial was analysed as parallel data (Amin 2011), which is a conservative approach. | ||||||
| Dornase alfa daily compared with dornase alfa on alternate days for cystic fibrosis | ||||||
| Patient or population: Children with cystic fibrosis Settings: Outpatients Intervention: Dornase alfa daily Comparison: Dornase alfa alternate days | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Dornase alfa alternate days | Dornase alfa daily | |||||
| Mean relative percentage change in FEV1 (L) at 3 months | See comment | See comment | MD 2.00 (‐5.00 to 9.00) | 43 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa daily. Participants received both interventions in cross‐over design. |
| Mean relative percentage in FVC (L) at 3 months | See comment | See comment | MD 0.03 (‐0.06 to 0.12) | 43 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa daily. Participants received both interventions in cross‐over design. |
| Mean relative percentage in quality of life score at 3 months | See comment | See comment | MD 0.01 (‐0.02 to 0.04) | 43 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa daily. Participants received both interventions in cross‐over design. |
| Number of pulmonary exacerbations at 3 months | 17 exacerbations | 18 exacerbations | NA (see comment) | 43 (1 cross‐over study) | ⊕⊕⊝⊝ | No difference was found in the number of pulmonary exacerbations (no statistical comparison made) |
| *Assumed and corresponding risk not calculated lung function and quality of life. Relative effect and 95% CI presented is adjusted for the cross‐over design of the study. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. Downgraded once for lack of applicability: Suri included children only so results are not applicable to adults (Suri 2001). 2. Downgraded once for high risk of bias due to lack of blinding. | ||||||
| Dornase alfa compared with hypertonic saline for cystic fibrosis | ||||||
| Patient or population: Children with cystic fibrosis Settings: Outpatients Intervention: Dornase alfa (once daily) Comparison: Hypertonic saline | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Hypertonic Saline | Dornase alfa | |||||
| Mean relative percentage in FEV1 (L) at 3 months | See comment | See comment | MD 8.00 (2.00 to 14.00) | up to 431,2 (1 cross‐over study) (see comment) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Mean relative percentage in FVC (L) at 3 months | See comment | See comment | MD 0.08, (‐0.02 to 0.18) | up to 431,2 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Mean relative percentage in quality of life score at 3 months | See comment | See comment | MD 0.03, (‐0.01 to 0.07) | up to 431,2 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Number of pulmonary exacerbations at 3 months | 15 exacerbations | 17 exacerbations | NA (see comment) | up to 431,2 (1 cross‐over study) | ⊕⊕⊝⊝ | No difference was found in the number of pulmonary exacerbations (no statistical comparison made) |
| *Assumed and corresponding risk not calculated lung function and quality of life. Relative effect and 95% CI presented is adjusted for the cross‐over design of the study. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. In the cross‐over trial, 43 participants completed the dornase alfa arm and 40 completed the hypertonic saline arm (Suri 2001). 2. Two additional cross‐over trials compared dornase alfa and hypertonic saline, no significant differences were found between the treatments for % change in FEV1 and other primary outcomes of the review were not recorded in these trials (Adde 2004; Ballmann 2002). 3. Downgraded once for lack of applicability: Suri included children only so results are not applicable to adults (Suri 2001). 4. Downgraded once for high risk of bias due to lack of blinding. | ||||||
| Dornase alfa compared with mannitol for cystic fibrosis | ||||||
| Patient or population: Children with cystic fibrosis Settings: Outpatients Intervention: Dornase alfa Comparison: Mannitol | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Mannitol | Dornase Alfa | |||||
| Mean absolute change in FEV1 (L) at 3 months | See comment | See comment | MD 0.02 (‐0.11 to 0.16) | up to 231 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Mean absolute change in FVC (L) at 3 months | See comment | See comment | MD ‐0.02, (‐0.23 to 0.19) | up to 231 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Change in quality of life ‐ CFQ‐R at 3 months | See comment | See comment | MD 10.61 (0.27 to 20.95) | up to 231 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Number of people experiencing exacerbations ‐ at 3 months | 130 per 1000 | 143 per 1000 | RR 1.10 (0.25 to 4.84) | up to 231 (1 cross‐over study) | ⊕⊕⊝⊝ | RR <1 indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| *Assumed and corresponding risk not calculated for lung function and quality of life. Relative effect and 95% CI presented is adjusted for the cross‐over design of the study. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. In the cross‐over trial, 21 participants completed the dornase alfa arm and 23 participants completed the mannitol arm (Minasian 2010). 2. Downgraded once for lack of applicability: Minasian included children only so results are not applicable to adults (Minasian 2010). 3. Downgraded once for high risk of bias due to lack of blinding. | ||||||
| Dornase alfa compared with dornase alfa and mannitol for cystic fibrosis | ||||||
| Patient or population: Children with cystic fibrosis Settings: Outpatients Intervention: Dornase alfa Comparison: Dornase alfa and Mannitol | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Dornase alfa and mannitol | Dornase alfa | |||||
| Mean absolute change in FEV1 (L) at 3 months | See comment | See comment | MD 0.10 (‐0.06 to 0.25) | up to 231 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Mean absolute change in FVC (L) at 3 months | See comment | See comment | MD 0.13 (‐0.11 to 0.37) | up to 231 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Change in quality of life ‐ CFQ‐R at 3 months | See comment | See comment | MD 10.61 (0.27 to 20.95) | up to 231 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Number of people experiencing exacerbations at 3 months | 261 per 1000 | 143 per 1000 | RR 0.55 (0.16 to 1.92) | up to 231 (1 cross‐over study) | ⊕⊕⊝⊝ | RR <1 indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| *Assumed and corresponding risk not calculated lung function and quality of life. Relative effect and 95% CI presented is adjusted for the cross‐over design of the study. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. In the crossover trial, 21 participants completed the dornase alfa arm and 23 participants completed the dornase alfa plus mannitol arm (Minasian 2010). 2. Downgraded once for lack of applicability: Minasian included children only so results are not applicable to adults (Minasian 2010). 3. Downgraded once for high risk of bias due to lack of blinding. | ||||||
Background
Description of the condition
Cystic fibrosis (CF) is the most common life‐limiting autosomal recessive disorder amongst people of Northern European descent, affecting about one in every 2300 births. Pulmonary disease is the major cause of morbidity and mortality in CF (Flume 2007).
People with CF inherit an abnormality in the cystic fibrosis transmembrane regulator protein leading to an abnormal movement of chloride and sodium across the airway epithelium. The reduced secretion of chloride into and the excessive absorption of sodium from the airway surface liquid results in a diminished airway surface liquid layer. Consequently, there is decreased mucociliary and cough clearance of airway secretions. The retained airway secretions allow development of a chronic endobronchial infection and induce an exuberant neutrophilic inflammatory response. The large influx of neutrophils into the airways release proteolytic enzymes and oxidants. When the neutrophils die, large quantities of deoxyribonucleic acid (DNA) are released causing the sputum to be thick and tenacious. The thick secretions lead to mucus plugging of the airways and further cycles of infection and inflammation. There is evidence that the initiation of significant airway damage occurs early with findings of pathogenic bacteria, airway inflammation and imaging changes in infants diagnosed by newborn screening (Sly 2009). The unremitting endobronchial infection and neutrophilic inflammation gradually result in irreversible bronchiectasis and eventual respiratory failure.
Description of the intervention
Dornase alfa (Pulmozyme®) is a highly purified solution of recombinant human deoxyribonuclease (rhDNase); it reduces mucus viscosity in the lungs, promoting improved clearance of secretions. The recommended dose for use in most people with CF is 2.5 mg (in one single‐use ampoule) inhaled once daily using a recommended nebuliser. Dornase alfa is used in conjunction with other standard CF therapies.
How the intervention might work
In the 1950s it was shown that the enzyme; bovine deoxyribonuclease (DNase) reduced the viscosity of sputum taken from people with CF by digesting the airway extracellular DNA released from neutrophils (Lieberman 1968). However, clinical trials of bovine DNase had to be stopped due to adverse effects. In 1990 dornase alfa was produced and since 1992 it has been used as a mucolytic to treat people with CF. In contrast, medications such as hypertonic saline and mannitol are osmotically active and are felt to improve mucociliary clearance by rehydrating the airway surface liquid.
Why it is important to do this review
In 2015, the average cost of dornase alfa per person, per year was CDN 14,300, while the cost of hypertonic saline (Nebusal™ 4 mL 7%) was CDN 880 (Cho E 2015 [pers comm]) and mannitol was CDN 11,374 (NICE 2012). In addition, the treatment burden of people with CF is increasingly being recognized with the average time spent on therapies being 108 minutes per day, with the use of two or more nebulised medications significantly adding to this burden (Sawicki 2009). It is important to understand the clinical benefits of medications in order to weigh the monetary and time costs of these therapies.
This is an update of a previously published review (Jones 2003; Jones 2010; Kearney 1998; Yang 2016; Yang 2018).
Objectives
To determine whether the use of dornase alfa in cystic fibrosis is associated with improved mortality and morbidity compared to placebo or other medications that improve airway clearance, and to identify any adverse events associated with its use.
Methods
Criteria for considering studies for this review
Types of studies
All randomised and quasi‐randomised controlled trials (published and unpublished) with either parallel or cross‐over design.
Types of participants
Children and adults, of any age, with CF diagnosed clinically and by sweat or genetic testing. Participants with all stages of lung disease were included.
Types of interventions
Dornase alfa administered at any dose, using any nebuliser, at any frequency and for any duration. We compared dornase alfa to placebo or other medications that are adjuncts to airway clearance (typically hyperosmotic agents such as hypertonic saline or mannitol).
Types of outcome measures
We grouped results for the following outcomes into those measured at up to one month, three, six and 12 months and annually thereafter.
Primary outcomes
-
Changes in lung function from baseline
-
forced expiratory volume at one second (FEV1)
-
forced vital capacity (FVC)
-
lung clearance index (LCI)
-
forced expiratory volume at 0.5 seconds (FEV0.5 )
-
-
Change from baseline in quality of life (QoL)
-
Mean number of exacerbations
Secondary outcomes
-
Number of deaths
-
Number of days treatment with intravenous (IV) antibiotics
-
Number of days treatment with oral antibiotics
-
Number of days in hospital due to respiratory exacerbations
-
Change in weight from baseline
-
Number of adverse events such as alteration in voice, haemoptysis, bronchospasm
-
Cost (including indirect costs of therapy)
Search methods for identification of studies
We searched for all relevant published and unpublished trials without restrictions on language, year or publication status.
Electronic searches
The Information Specialist at the Cystic Fibrosis and Genetic Disorders Group searched the Group's Cystic Fibrosis Trials Register for relevant trials using the term: dornase alfa.
The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library), weekly searches of MEDLINE, a search of Embase to 1995 and the prospective handsearching of two journals ‐ Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work is identified by searching the abstract books of three major cystic fibrosis conferences: the International Cystic Fibrosis Conference; the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. For full details of all searching activities for the register, please see the relevant sections of the Cystic Fibrosis and Genetic Disorders Group website.
Date of the most recent search of the Group's register: 12 October 2020.
We also searched the trials database Clinicaltrials.gov and attempted to search* the WHO International Clinical Trials Registry Platform (WHO ICTRP) to identify unpublished or ongoing trials using the terms dornase alfa (or dnase or pulmozyme) and cystic fibrosis. Date of most recent search: 08 February 2021.
* the trials registry was not available for searching on that date due to the Covid 19 pandemic
Searching other resources
We checked the bibliographies of included trials and any relevant systematic reviews identified for further references to relevant trials.
Data collection and analysis
Selection of studies
From the 2015 update, the lead author (CY) and a colleague (MC or MM) independently selected the trials to be included in the review. There were no disagreements about the selection of included trials, but if there are any such disagreements in the future, we will reach a consensus by discussion.
Data extraction and management
The lead author and a colleague (MC or MM) independently extracted data on lung function (FEV1, FVC, LCI, FEV0.5), QoL, exacerbations, deaths, days of oral and IV antibiotics, number of days in hospital, change in weight, adverse events and cost. There were no disagreements about the extracted data, but if there are any such disagreements in the future, we will reach a consensus by discussion.
In previous versions of this review, all trials that reported data at time points of one month or less were combined in a meta‐analysis (Jones 2003; Kearney 1998). It has since been decided that due to the fact that the trial by Wilmott was conducted over two weeks during an acute exacerbation (in contrast to the other trials which recruited participants with stable disease), it would be more appropriate to exclude the trial from this analysis and to analyse it separately (Wilmott 1996).
Assessment of risk of bias in included studies
The lead author (CY) and a colleague (MM, MC) assessed the risk of bias in the included trials using the Cochrane tool for this as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). In particular they recorded details for:
-
generation of allocation sequence;
-
concealment of allocation;
-
blinding;
-
incomplete outcome data;
-
selective reporting;
-
other potential sources of bias.
For each of these items the authors assessed the risk of bias for each trial as high, low or unclear.
Measures of treatment effect
For dichotomous data we used the risk ratio (RR) with 95% confidence intervals (CIs) as a measure of treatment effect, where appropriate. For continuous outcomes, we recorded mean change from baseline for each group and standard deviation (SD) for each group. We calculated a pooled estimate of treatment effect by calculating the mean difference (MD) with 95% CIs or the generic inverse variance as appropriate.
Unit of analysis issues
Where trials measured data longitudinally, we based the analysis on the final time point results. Jones discusses methods for the analysis of aggregate longitudinal data (Jones 2009); however, the information that is required to conduct these type of analyses is not available for the trials in this review. We analysed trials with a cross‐over design according to the methodology recommended by Elbourne (Elbourne 2002). We analysed the lung function data from the Amin trial using the generic inverse variance (GIV) and analysed the dichotomous outcomes as if it were a parallel trial (which is a conservative method) (Amin 2011). We were able to analyse the data from the Suri trial using GIV (Suri 2001), but were only able to analyse the data from the Castile trial and the Minasian trial as if they were parallel trials (conservative method) (Castile 2009, Minasian 2010). First‐arm data from the Castile cross‐over trial have been presented in an abstract and online at Clinicaltrials.gov; this site also reports that second‐arm data are not available and that the lead investigator is unavailable due to retirement. We were only able to report the data from the remaining cross‐over trials in narrative form (Adde 2004; Ballmann 2002; Robinson 2000).
Dealing with missing data
The authors requested individual patient data from all trials that are contained within this review. Genentech have not yet agreed to provide data on the trials that they funded, but we remain hopeful that this position may change (Fuchs 1994; Laube 1996; McCoy 1996; Quan 2001; Ramsey 1993; Ranasinha 1993; Robinson 2005; Shah 1995a; Wilmott 1996). We are grateful to Mrs Mary Dodd, Dr Fabíola Adde, Dr. Reshma Amin and Pharmaxis for providing individual patient data (Adde 2004; Amin 2011; Dodd 2000; Minasian 2010). We have included data from three of these trials in this review (Adde 2004; Amin 2011; Dodd 2000; Minasian 2010); however, we were not able to de‐code the raw data from the Dodd trial and therefore have not included these data (Dodd 2000).
Assessment of heterogeneity
We assessed heterogeneity using the I² statistic (Higgins 2003). Although the interpretation of I² depends on the magnitude and direction of the effect as well as the strength of evidence for heterogeneity, we used the following thresholds to assess I²:
-
0% to 40%: likely not important;
-
30% to 60%: moderate heterogeneity;
-
50% to 90%: substantial heterogeneity;
-
75% to 100%: considerable heterogeneity.
Assessment of reporting biases
Due to the chronic nature of the disease, in many CF trials investigators collect data longitudinally at different time points throughout the course of the trial. In all the included trials, we examined when data were collected during the trial and also which data were reported in the trial publication. For outcomes that included data from more than 10 trials, we planned to create a funnel plot to assess for publication bias.
Data synthesis
When we judged heterogeneity to likely be not important, we performed a fixed‐effect analysis. If heterogeneity between trials was more than moderate (i.e. more than 50% to 60%), we performed a random‐effects analysis.
In previous versions of this review, authors combined all trials which reported data at time points of one month or less in a meta‐analysis (Jones 2003; Kearney 1998). We have since decided that due to the fact that the trial by Wilmott was conducted over two weeks during an acute exacerbation (in contrast to the other trials which recruited participants with stable disease), it would be more appropriate to exclude the trial from this analysis and to analyse it separately (Wilmott 1996).
Subgroup analysis and investigation of heterogeneity
We defined the following subgroup analysis a priori to be performed if there were enough trials for inclusion in the analysis:
-
age group ‐ paediatric (0 to 18 years) versus adult (over 18 years);
-
disease severity ‐ severe (FEV1 or FVC less than 40% predicted) versus moderate (FEV1 or FVC 40% to 80% predicted) versus mild (FEV1 or FVC over 80% predicted);
-
dose of medication ‐ once‐daily versus twice‐daily administration.
Sensitivity analysis
In future updates (if possible) we will perform a sensitivity analysis based on the risk of bias of the included trials, including and excluding quasi‐randomised trials.
Summary of findings and assessment of the certainty of the evidence
In a post hoc change, the authors have presented five summary of findings tables; one for each comparison (Summary of findings table 1; Summary of findings table 2; Summary of findings table 3; Summary of findings table 4; summary of findings Table 5).
Primary outcomes of changes in lung function from baseline, change in QoL from baseline and number of pulmonary exacerbations are presented in the summary of findings tables at three or six months (or both) (or the nearest reported time point). For clarity in the tables, we chose to report relative changes in FEV1 and FVC as important lung function outcomes.
We determined the quality of the evidence using the GRADE approach; and downgraded evidence in the presence of a high risk of bias in at least one trial, indirectness of the evidence, unexplained heterogeneity or inconsistency, imprecision of results, high probability of publication bias. We downgraded evidence by one level if for a serious limitation and by two levels if very serious.
Results
Description of studies
For further details, please see the tables (Characteristics of included studies; Characteristics of excluded studies).
Results of the search
The searches identified 74 trials, of which 19 trials with a total of 2565 participants met our inclusion criteria. We excluded four trials immediately on title alone, excluded 50 trials with reasons and listed one trial as ongoing (seeFigure 1).
Study flow diagram.
Included studies
We included 19 trials with a total of 2565 participants in the review (Table 1). Three papers analysed the healthcare costs of using dornase alfa (Menzin 1996; Oster 1995; von der Schulenburg 1995) using the data from the included Fuchs trial (Fuchs 1994). Three trials were available in abstract form only (Adde 2004; Castile 2009; Dodd 2000); but the remaining included trials were published as full papers.
| Study | Comparison group | Duration of treatment | Frequency of dornase treatment | Study design |
|---|---|---|---|---|
| Placebo | 4 weeks | once daily | cross‐over | |
| Placebo | 6 months | once daily | cross‐over | |
| Placebo | 2 weeks | once daily | cross‐over | |
| No treatment | 1 year | once daily | parallel | |
| Placebo and twice‐daily dornase | 6 months | once or twice daily | parallel | |
| Placebo | 6 days | twice a day | parallel | |
| Placebo | 3 months | once daily | parallel | |
| No treatment | 3 years | twice a day | parallel | |
| Placebo | 2 years | once a day | parallel | |
| Placebo | 10 days | twice a day (0.6 mg, 2.5 mg or 10 mg) | parallel | |
| Placebo | 10 days | twice a day | parallel | |
| Placebo | 7 days | once a day | cross‐over | |
| Placebo | 1 year | once a day | parallel | |
| Placebo | 2 weeks | twice a day | parallel | |
| Placebo | 15 days | twice a day | parallel | |
| Hypertonic saline and alternate day dornase | 3 months | once a day, alternate day | cross‐over | |
| Hypertonic saline | 4 weeks | once daily | cross‐over | |
| Hypertonic saline | 3 weeks | once daily | cross‐over | |
| Mannitol and mannitol plus dornase | 3 months | once daily | cross‐over |
*Trial done during acute exacerbation
15 trials (n = 2447) compared dornase alfa to placebo or no dornase alfa treatment (Amin 2011; Castile 2009; Dodd 2000; Frederiksen 2006; Fuchs 1994; Laube 1996; McCoy 1996; Paul 2004; Quan 2001; Ramsey 1993; Ranasinha 1993; Robinson 2000; Robinson 2005; Shah 1995a; Wilmott 1996). One trial (n = 48) compared daily dornase alfa to hypertonic saline and to alternate day dornase alfa (Suri 2001), and two trials (n = 32) compared dornase alfa to hypertonic saline (Adde 2004; Ballmann 2002). The remaining trial (n = 38) compared dry powder mannitol to dornase alfa and to a combination of both drugs (Minasian 2010).
Dornase alfa versus placebo or no dornase alfa treatment
There were 15 trials (n = 2447) included in this comparison (Amin 2011; Castile 2009; Dodd 2000; Frederiksen 2006; Fuchs 1994; Laube 1996; McCoy 1996; Paul 2004; Quan 2001; Ramsey 1993; Ranasinha 1993; Robinson 2000; Robinson 2005; Shah 1995a; Wilmott 1996).
Trial design
Most of these trials were of parallel design, but we included four trials of cross‐over design (Amin 2011; Castile 2009; Dodd 2000; Robinson 2000). Amin used two four‐week treatment periods with a four‐week washout period (Amin 2011); Castile used six‐month treatment periods with no washout although only data for the first period was available (Castile 2009); Dodd had two‐week treatment periods with a seven‐day washout period (Dodd 2000); and Robinson used seven‐day treatment periods with a two‐week washout (Robinson 2000). The duration of the trials varied from six days (Laube 1996) to three years (Paul 2004) (Table 1). Duration of treatment was less than or equal to one month in eight trials (Amin 2011; Dodd 2000; Laube 1996; Ramsey 1993; Ranasinha 1993; Robinson 2000; Shah 1995a; Wilmott 1996), three months in one trial (McCoy 1996), six months in two trials (Castile 2009; Fuchs 1994), one year in two trials (Frederiksen 2006; Robinson 2005), two years in one trial (Quan 2001) and three years in one trial (Paul 2004).
The size of trials varied from 19 participants (Amin 2011) to 968 participants (Fuchs 1994).
Participants
Four trials included adults only (Dodd 2000; Laube 1996; Ranasinha 1993; Robinson 2000). Four trials included children only; one trial enrolled children aged six to 10 years (Quan 2001), two trials enrolled participants aged six to 18 years (Amin 2011; Robinson 2005) and the remaining trial recruited infants with a mean (SD) age of 42 (32) weeks (Castile 2009). Seven trials included mixed adult and paediatric populations. One trial included participants aged one year and over (Frederiksen 2006), four trials included participants aged five years or older (Fuchs 1994; Paul 2004; Shah 1995a; Wilmott 1996), one trial included participants aged seven years or older (McCoy 1996) and a further trial included participants aged eight years or older (Ramsey 1993).
All trials except for one included participants with stable lung disease; only Wilmott looked at the effects of dornase alfa during treatment for a respiratory exacerbation (Wilmott 1996).
Severity of lung disease varied across the trials. Two trials recruited only participants with severe lung disease (FVC less than 40% predicted) (McCoy 1996; Shah 1995a). Five trials studied participants who had mild to moderate disease (FVC greater than 35% to 40% predicted) (Fuchs 1994; Quan 2001; Ramsey 1993; Ranasinha 1993; Wilmott 1996). One trial looked at participants with moderate disease (FVC between 35% and 75% predicted) (Laube 1996). Three trials included participants with mild lung disease, defined as FVC greater than or equal to 85% in one trial (Robinson 2005), or FEV1 greater than 80% in two trials (Amin 2011; Paul 2004). Three trials did not report information on severity of disease (Castile 2009; Dodd 2000; Frederiksen 2006). The participants in the Castile trial were all infants, so this information would not be available and the abstract simply stated that the participants were all clinically well.
Interventions
The dose and frequency of dornase alfa received by participants varied. Six trials used 2.5 mg dornase alfa twice daily in the treatment group (Laube 1996; Paul 2004; Ranasinha 1993; Robinson 2000; Shah 1995a; Wilmott 1996). Seven trials used used 2.5 mg dornase alfa once daily (Amin 2011; Castile 2009; Dodd 2000; Frederiksen 2006; McCoy 1996; Quan 2001; Robinson 2005). Ramsey gave three different doses of dornase alfa as a twice‐daily regimen: 0.6 mg; 2.5 mg; and 10 mg (Ramsey 1993). Fuchs administered a dose of 2.5 mg dornase alfa either once or twice daily (Fuchs 1994).
In two trials the placebo used was normal saline solution (Dodd 2000; Robinson 2005), six trials stated that the placebo used was excipient alone (Fuchs 1994; Laube 1996; Ranasinha 1993; Shah 1995a; Wilmott 1996; Robinson 2000) and five trials stated that a placebo was used but did not give a formal definition (Amin 2011; Castile 2009; McCoy 1996; Quan 2001; Ramsey 1993).
Outcomes
All trials assessed lung function parameters (FEV1 % predicted, FVC % predicted) with one trial examining FEV0.5 in infants (Castile 2009). Three trials assessed QoL; however, only one trial used a validated measure (CFQ‐R) (Amin 2011). None of the trials reported respiratory exacerbations expressed as mean number per period of follow up. Adverse events and deaths were reported in nine trials (Amin 2011; Castile 2009; Fuchs 1994; McCoy 1996; Quan 2001; Ramsey 1993; Ranasinha 1993; Shah 1995a; Wilmott 1996). One trial reported on the use of IV antibiotics and the days in hospital (McCoy 1996), one trial reported the number of days of antibiotics but did not specify the route of administration (Castile 2009) and one trial reported on weight (Quan 2001).
Dornase alfa versus hyperosmolar agents
Trial design
Four trials are included in this comparison and all of these trials had a cross‐over design (Adde 2004; Ballmann 2002; Minasian 2010; Suri 2001). Adde used two four‐week treatment periods with a two‐week washout period (Adde 2004). Ballmann used two three‐week treatment periods with a three‐week washout period (Ballmann 2002). Both Minasian and Suri employed three treatment periods, each lasting 12 weeks, with a two‐week washout period between each treatment period (Minasian 2010; Suri 2001). Miniasian was the only trial to compare the combination of dornase and mannitol to each of these agents alone (Minasian 2010).
Participants
Two trials enrolled only children; in one trial ages ranged from nine to 17 years (Minasian 2010) and in the second trial they ranged from five to 18 years (Suri 2001). Ballmann did not specify the age of participants for recruitment purposes, but did state that the mean age of included participants was 13.3 years (Ballmann 2002). The remaining trial recruited both adults and children, age range 8.7 years to 25.8 years (Adde 2004).
One trial included participants with moderate lung disease, FEV1 between 40% and 70% predicted (Minasian 2010). A second trial recruited participants with FEV1 over 70% predicted (Suri 2001). The remaining two trials did not report on lung function as a measure of disease severity (Adde 2004; Ballmann 2002), but Ballmann described participants as a 'group of mild to moderately severely ill children' (Ballmann 2002).
Interventions
Three trials compared dornase alfa to hypertonic saline (Adde 2004; Ballmann 2002; Suri 2001). The first trial compared 2.5 mg dornase alfa once daily to 10 ml hypertonic saline (6%) once daily (Adde 2004), while the second trial compared 2.5 mg dornase alfa once daily to 10 ml hypertonic saline (5.8%) once daily (Ballmann 2002). Suri compared dornase alfa 2.5 mg once daily to dornase alfa 2.5 mg on alternate days and also to twice‐daily 5 ml hypertonic saline (7%) (Suri 2001). Minasian ran a three‐arm trial comparing 2.5 mg dornase alfa twice daily to 400 mg mannitol twice daily and to a combination of both agents (again twice daily) (Minasian 2010).
Outcomes assessed
All of the trials looked at improvements in lung function (FEV1 % predicted or L, FVC % predicted or L) (Adde 2004; Ballmann 2002; Minasian 2010; Suri 2001). Two trials reported on QoL; one used a self‐administered quality of well‐being score (Suri 2001) and the second used the CFQ‐R (Minasian 2010). The same two trials reported on pulmonary exacerbations (Minasian 2010; Suri 2001), but only one of these defined what was meant by the term (Suri 2001). A further trial reported the number of days of antibiotics, but did not specify the route of administration (Castile 2009). Two trials reported on adverse events (Castile 2009; Minasian 2010) and only one trial reported on weight, number of days in hospital and cost (Suri 2001).
Excluded studies
We have excluded 50 trials, details are given in the tables (Characteristics of excluded studies) and the PRISMA diagram (Figure 1).
We excluded 10 trials due to trial methodology: eight because they were not clearly RCTs (Furuya 2001; Hubbard 1992; NCT00311506; NCT02722122; NCT02682290; NCT00843817; Shah 1995b; Shah 1995c); one because it was a longitudinal qualitative study linked to the ongoing SIMPLIFY randomised withdrawal RCT (QUEST); and one because it was an 'N‐of‐1' trial design (Weck 1999).
Two trials were excluded as the participants did not have CF (Riethmueller 2006; EUCTR2006‐002098‐30‐NL) and two trials were excluded as the participants were already on dornase alfa at entry to trial (Dab 2000; EUCTR2007‐000935‐25‐NL). One trial was excluded because it included people who were post lung transplant and although some of these people had CF, the intervention is not expected to work the same in non‐CF lungs transplanted into a person with CF (Tarrant 2019).
We excluded 31 trials on account of the interventions. One did not use dornase alfa as part of the intervention (Laube 2005) and one trial compared mannitol to control (Bilton 2011). A further trial did not randomise participants by dornase alfa use, investigators studied vitamin E in people with CF and presented results stratified by dornase alfa use (Kelijo 2001). One trial studied in vitro elasticity in CF sputum (King 1997). Three trials assessed interventions to improve adherence to dornase alfa therapy (NCT01025258; NCT01232478; NCT02301377). Four trials compared different nebulisers (Elkins 2006; Johnson 2006; Sawicki 2014; Shah 1997) and three compared the dispensing methods or delivery technique of the drug (Bakker 2010; Hagelberg 2008; Potter 2008); a further six trials were excluded as they looked at the timing of administration (Anderson 2009; Bishop 2011; Fitzgerald 2005; van der Giessen 2007a; van der Giessen 2007b; Wilson 2007). Five trials were excluded because dornase alfa was given intranasally after sinus surgery or for sinusitis (Cimmino 2005; Lahiri 2012; Mainz 2011; Mainz 2014; NCT01155752). One trial compared sputum characteristics following either dornase alfa or normal saline with airway clearance techniques (Majaesic 1996) and a further trial studied sputum rheology after dornase alfa therapy (Griese 1997). Two trials looked at the utility of using CT scan changes as an outcome measure (Nasr 2001; Robinson 2002). One trial was excluded because it was designed to produce an objective means of selecting those people with CF who would benefit most from dornase alfa (Bollert 1999). Finally, one trial was excluded because it compared dornase alfa to a biosimilar medication (Tigerase) which was not the intent of this review (Amelina 2019).
One trial was excluded after the authors were contacted to confirm that no outcomes relevant to this review were collected; although this trial looked at infant pulmonary function they only measured FRC and maximal flow at FRC (ten Berge 2003). One trial examining the use of dornase alfa in pre‐school children was terminated without results because of difficulty obtaining reliable lung function data (NCT00680316) and a further trial assessing the effect of dornase alfa withdrawal on exercise tolerance in people with CF was terminated for administrative reasons (NCT00434278).
In one trial all participants received dornase alfa and there was no control intervention (Heijerman 1995).
Ongoing studies
We have listed one open‐label two‐arm non‐inferiority RCT of parallel design as ongoing (SIMPLIFY). Investigators are looking at the effects of withdrawing inhaled hypertonic saline (Study A) or dornase alfa (Study B) in those who are also taking the triple combination CFTR modulator therapy of elexacaftor/tezacaftor/ivacaftor (approved for people with CF who have at least one F508del mutation). Only data from Study B are relevant to this Cochrane Review. An estimated 800 clinically stable participants aged 12 years and older will be recruited to the trial and for Study B participants will be randomised to either continue with dornase alfa as well as elexacaftor/tezacaftor/ivacaftor or to stop dornase alfa treatment.
The trial consists of a two‐week screening period, randomisation 1:1 to continue or discontinue dornase alfa, followed by a six‐week study period. Participants taking both hypertonic saline and dornase alfa at study entry will be randomized to participate in either Study A or Study B; after completion of the first trial, they may subsequently enrol in the alternative trial.
Clinical outcomes to be measured at the end of the trial include lung function (absolute change in FEV1 % predicted), safety (adverse events), absolute change in respiratory symptoms, antibiotic use, pulmonary exacerbations and self‐reported outcomes such as perception of how stopping dornase alfa would impact their daily life. Additional outcome measurements of multiple breath washout (for changes in LCI) and mucociliary clearance will be conducted in a subset of participants at selected trial centres.
Risk of bias in included studies
In order to assess the risk of bias, we examined the following: generation of treatment allocation schedule; concealment of treatment allocation schedule; blinding; incomplete outcome data; selective reporting; and other potential sources of bias. Please see the tables for details for each of these for each trial (Characteristics of included studies). A summary of the risk of bias for each trial is presented as a figure (Figure 2).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Generation of allocation sequence
Dornase alfa versus placebo or no dornase alfa treatment
It was clear in only three trials that generation of allocation schedule was adequate and there was a low risk of bias (Amin 2011; Quan 2001; Ranasinha 1993). In the remaining 12 included trials for this comparison, while each trial was described as randomised no details of the randomisation method were stated; therefore, we judged the risk of bias to be unclear (Castile 2009; Dodd 2000; Frederiksen 2006; Fuchs 1994; Laube 1996; McCoy 1996; Paul 2004; Ramsey 1993; Robinson 2000; Robinson 2005; Shah 1995a; Wilmott 1996).
Dornase alfa versus hyperosmolar agents
In three trials in this comparison, it was clear that the generation of allocation schedule had a low risk of bias (Adde 2004; Minasian 2010; Suri 2001). One trial stated that allocation was randomised but did not provide details and was therefore judged as unclear (Ballmann 2002).
Concealment of allocation
Dornase alfa versus placebo or no dornase alfa treatment
The concealment of treatment allocation was adequate, and hence the risk of bias was low, in three trials (Amin 2011; Quan 2001; Ranasinha 1993); the risk of bias was unclear in the remaining 12 trials (Castile 2009; Dodd 2000; Frederiksen 2006; Fuchs 1994; Laube 1996; McCoy 1996; Paul 2004; Ramsey 1993; Robinson 2000; Robinson 2005; Shah 1995a; Wilmott 1996).
Dornase alfa versus hyperosmolar agents
In the Suri trial, an independent trial co‐ordinator concealed the allocation schedule, so the risk of bias was judged to be low (Suri 2001). The details of concealment of treatment allocation schedule, and thus also the risk of bias, was unclear in the remaining trials (Adde 2004; Ballmann 2002; Minasian 2010).
Blinding
Dornase alfa versus placebo or no dornase alfa treatment
Two trials stated that all participants, clinicians and research personnel were blinded to the treatments (Amin 2011; Castile 2009) and 12 trials stated that the design was double blinded and the risk of bias was low in these trials. In one trial no information was provided about the blinding and the risk of bias was therefore unclear (Frederiksen 2006).
Dornase alfa versus hyperosmolar agents
In all four trial reports, it is stated that the trial was not blinded due to the taste of either the hypertonic saline or mannitol (Adde 2004; Ballmann 2002; Minasian 2010; Suri 2001). In one trial, it was stated that the technicians performing the testing were blinded to the intervention (Adde 2004). The four trials reported a mixture of objective outcome measurements (lung function measurement) (Adde 2004; Ballmann 2002) and subjective outcomes determined by the participant (e.g. QoL, adverse events) (Minasian 2010; Suri 2001), therefore risk of bias was deemed high for all four trials.
Incomplete outcome data
Dornase alfa versus placebo or no dornase alfa treatment
We judged 10 trials to have a low risk of bias due to incomplete outcome data. An intention‐to‐treat analysis was performed in seven trials and these were judged to have a low risk of bias (Fuchs 1994; Laube 1996; Paul 2004; Quan 2001; Ramsey 1993; Robinson 2005; Wilmott 1996). In the 2000 trial by Robinson, 15 participants were randomised, but data were only included for 13 participants (no intention‐to‐treat analysis). Two participants withdrew due to pulmonary exacerbations (an a priori protocol violation), one of these was from the placebo group and the other from the dornase alfa group, given that the withdrawals were balanced between treatment groups, there is a low risk of bias (Robinson 2000). In the trials by Shah and McCoy, the risk of bias was considered low since there were few missing data (Shah 1995a; McCoy 1996). An intention‐to‐treat analysis was not possible in the Shah trial where five (out of 70) participants did not complete the 14‐day trial period: one received a heart‐lung transplant; two withdrew consent; and two from the dornase alfa group died. Changes in lung function could therefore not be analysed on an intention‐to‐treat basis; however, adverse events and deaths were analysed on this basis (Shah 1995a). In the McCoy trial, two participants from the dornase alfa group did not have lung function recorded (McCoy 1996). Furthermore, three participants inadvertently received dornase alfa instead of placebo; the lung function data for these participants were analysed on an intention‐to‐treat basis. For analysis of safety data McCoy published results for these participants as if they had been randomised to dornase alfa (McCoy 1996). One of the authors (CA Johnson) has since been contacted and has kindly provided data enabling intention‐to‐treat analysis for the purpose of this review. This did not significantly alter the results.
The risk of bias due to incomplete outcome data is deemed to be unclear in four trials (Amin 2011; Dodd 2000; Frederiksen 2006; Ranasinha 1993). Amin (n = 19) states results were analysed based on the intention‐to‐treat principle; however, only data from 17 participants who provided data for all four trial visits were included (Amin 2011). One participant withdrew after two trial visits because of a pulmonary exacerbation requiring IV antibiotics and a second participant did not have an acceptable LCI during one visit; but it was not clear which treatment these participants had received. It was not clear whether an intention‐to‐treat analysis was performed in the remaining three trials (Dodd 2000; Frederiksen 2006; Ranasinha 1993).
In the trial performed by Castile, follow‐up lung function data were only presented for 19 out of 24 recruited participants in the published abstract and the reasons for dropping out were not clear; while some additional data are available from ClinicalTrials.gov, results are very limited and therefore, the risk of bias due to incomplete outcome data was considered high (Castile 2009).
Dornase alfa versus hyperosmolar agents
Withdrawals were discussed in detail by Suri and Minasian (seeCharacteristics of included studies), and hence the risk of bias is judged to be low with regards to incomplete outcome data in these two trials (Minasian 2010; Suri 2001). The published data for the Minasian trial only included the 20 participants who completed all three arms of the trial; however, Pharmaxis provided the data analysed by intention‐to‐treat which were used in this review (Minasian 2010). In the remaining two trials, it was not clear whether there had been any withdrawals as these were not discussed (Adde 2004; Ballmann 2002). The risk of bias is therefore judged to be unclear in these two trials.
Selective reporting
Dornase alfa versus placebo or no dornase alfa treatment
Due to the chronic nature of the disease, in many CF trials data are collected longitudinally at different time points throughout the course of the trial. For all the trials we included in this review, we examined when data were collected during the trial and also which data were reported in the trial publication(s). Nine trials reported all time points as well as all outcomes identified in the protocol and we judged these to have a low risk of bias (Amin 2011; Dodd 2000; Frederiksen 2006; Laube 1996, Paul 2004; Ranasinha 1993; Robinson 2000; Robinson 2005; Shah 1995a). Five of the trials reported measuring outcomes at time points which were then not presented in the 'Results' section of the published papers, which may lead to a risk of bias (Fuchs 1994; McCoy 1996; Quan 2001; Ramsey 1993; Wilmott 1996). Castile reported all time points; limited results for the number of antibiotic days were reported on ClinicalTrials.gov (omitted from the published abstract) but only reported together for all routes of administration and for the first arm of the cross‐over trial only and we judged this to constitute an unclear risk of bias (Castile 2009).
Dornase alfa versus hyperosmolar agent
Outcomes were reported for all time points in all four trials and we judged these to have a low risk of bias (Adde 2004; Ballmann 2002; Suri 2001; Minasian 2010). Miniasian did not report all outcomes as intended in the protocol; however, none of these affected the main outcomes of interest, so the risk of bias was judged as low (Minasian 2010).
Other potential sources of bias
Dornase alfa versus placebo or no dornase alfa treatment
There was an unclear risk of bias for one trial in this comparison where the type of antibiotic used was a potential confounder: eight out of 36 participants in the placebo group received an oral antibiotic versus eight out of the 44 in the treatment group (Wilmott 1996).
Four trials in this group were cross‐over in design with varying washout periods ranging from no washout to four weeks (Amin 2011; Castile 2009; Dodd 2000; Robinson 2000). Data from the Ranasinha trial provides information on the duration of treatment effect with dornase alfa used twice daily (Ranasinha 1993). Participants in that trial were followed weekly after treatment was discontinued and FEV1 and FVC returned to baseline measures 11 to 18 days and 4 to 11 days after treatment discontinuation, respectively. Therefore a washout period of between two and three weeks should be adequate for trials of dornase alfa and we judged two trials to have a low risk of bias despite the cross‐over design (Amin 2011; Robinson 2000). Of the two trials with washout periods less than this, one did not provide any data for this review, so we judged this trial to have an unclear risk of bias (Dodd 2000); and the second did not show a difference between the placebo and dornase alfa group (Castile 2009). It might be expected that a lingering treatment effect of dornase alfa in the Castile trial would lead to a greater decline in lung function in the placebo group and we judged this trial to have a high risk of bias.
We judged the remaining trials in this comparison to have a low risk of bias from any other potential sources as we were unable to identify any.
Dornase alfa versus hyperosmolar agents
All four trials in this group were cross‐over in design, with washout periods ranging from two to three weeks (Adde 2004; Ballmann 2002; Minasian 2010; Suri 2001). The appropriate washout period for dornase alfa is discussed above and data from previous mannitol trials suggest that lung function returns to baseline two weeks after discontinuation of mannitol (Jacques 2008); however, similar data are not available for hypertonic saline. Given that all trials had an appropriate washout period, we do not think this would have led to any bias.
Effects of interventions
See: Summary of findings 1 Dornase alfa versus placebo or no dornase alfa treatment; Summary of findings 2 Dornase alfa daily versus alternate days; Summary of findings 3 Dornase alfa versus hypertonic saline; Summary of findings 4 Dornase alfa versus mannitol; Summary of findings 5 Dornase alfa versus dornase alfa and mannitol
In the summary of findings tables, the quality of the evidence has been graded for pre‐defined outcomes (see above) and definitions of these gradings provided.
Dornase alfa versus placebo or no dornase alfa treatment
Results that are reported in the graphs for Fuchs were from the once‐daily group (results from the twice‐daily group have been reported where possible) (Fuchs 1994). Also, Ramsey investigated three doses of dornase alfa, the results in the graphs are from the treatment group that were randomised to 2.5 mg of dornase alfa. A summary of key findings for this comparison has been presented in a table (summary of findings Table 1).
Primary outcomes
1. Changes in lung function (FEV1, FVC, LCI, FEV0.5) from baseline
The changes in FEV1, FVC and LCI for Quan and Amin were reported as absolute differences and the results for the other trials were reported as relative differences (seePublished notes) (Amin 2011; Quan 2001). It was not clear if the change in FEV0.5 reported by Castile was an absolute or relative difference (Castile 2009).
Results for FEV1 from the Wilmott and Ranasinha trials were estimated from the graphs that were included in the primary papers (Ranasinha 1993; Wilmott 1996). One trial provided data for outcomes at both three and 12 months; both data sets are included in the analysis (Robinson 2005).
a. Mean percentage change in FEV1 ‐ in participants with stable disease
i. at one month
This outcome was reported in six trials at the one‐month time point (dornase alfa n = 151, control n = 157) (Amin 2011; Laube 1996; Ramsey 1993; Ranasinha 1993; Robinson 2000; Shah 1995a). However, data from two trials were not included in the pooled analysis because one trial reported absolute and not relative changes in FEV1 (Amin 2011) and another trial reported results in litres and not % predicted (Robinson 2000); therefore, the pooled analysis includes a total of 248 participants (dornase alfa n = 121, control n = 127). When analysed, data showed a difference in percentage change in FEV1, MD 9.51% (95% CI 0.67 to 18.35) (Analysis 1.1). Due to the substantial heterogeneity between the four trials in the pooled analysis (I² = 88%), we employed a random‐effects model; we also considered the planned subgroup analyses based on age of participants, disease severity and frequency of dosing (once daily versus twice daily).
A subgroup analysis could not be undertaken for paediatric versus adult participants because there were no trials including only children and trials with both paediatric and adult participants did not report the data for these groups separately. We were able to undertake a subgroup analysis based on disease severity with three trials including participants with moderate disease (dornase n = 90, control n = 93) (Laube 1996; Ramsey 1993; Ranasinha 1993) and one trial including participants with severe disease (dornase n = 31, control n = 34) (Shah 1995a). Those with moderate disease had significant improvements in FEV1, MD 14.26 (95% CI 10.79 to 17.74), whereas those with severe disease did not, MD ‐2.81 (95% CI ‐8.77 to 3.15). In addition the heterogeneity in the subgroup analysis decreased to I² = 0 suggesting that disease severity accounted for the heterogeneity in the original analysis (Analysis 1.2).
A subgroup analysis based on frequency of drug administration was not possible, because all four trials used dornase twice daily.
There was no absolute difference between groups in FEV1 in the Amin trial, MD 0.08% (95% CI ‐5.59 to 5.74) (Analysis 1.3). There was no significant difference reported in FEV1 (L) between the dornase group (7.5% change) and the placebo group (3.4 % change) (Robinson 2000) (Table 2).
| Pre dornase alfa | Post dornase alfa | Pre placebo | Post placebo | |
|---|---|---|---|---|
| FEV1 (L) mean (SD) | 2.63 (0.31) | 2.8 (0.32) | 2.63 (0.32) | 2.70 (0.32) |
| FVC (L) mean (SD) | 4.03 (0.35) | 4.21 (0.35) | 4.12 (0.36) | 4.06 (0.38) |
FEV1: forced expiratory volume at one second
FVC: forced vital capacity
SD: standard deviation
ii. at three months
This was reported in one trial in which participants had severe lung disease (FVC below 40%) (dornase alfa n = 158, control n = 162) (McCoy 1996). The MD in percentage change in FEV1 was 7.30% (95% CI 4.04 to 10.56) (Analysis 1.1) (moderate‐quality evidence).
iii. at six months
This outcome was reported in one trial at the six‐month time point (dornase alfa n = 322, control n = 325) (Fuchs 1994). The MD in percentage change in FEV1 for the once‐daily treatment group was 5.80% (95% CI 3.99 to 7.61) (high‐quality evidence). For the twice‐daily dosage group mean improvement was 5.60 (95% CI 4.90 to 6.29) (Analysis 1.1).
iv. at one year
Analysable data for this outcome were reported in one trial at the one‐year time point (dornase alfa n = 8, control n = 11) (Robinson 2005). The MD in percentage change in FEV1 was 0.70 (95% CI ‐11.26 to 12.66) (Analysis 1.1). A second trial reported a median increase in FEV1 of 7.3% in the treatment group compared to 0.9% in the placebo group (P < 0.05) (Frederiksen 2006).
v. at two years
One trial reported on this outcome at the two‐year time point (dornase alfa n = 204, control n = 206) (Quan 2001); and showed a MD 3.24% (95% CI 1.03 to 5.45) (Analysis 1.4).
vi. at three years
One trial which was designed to assess lung inflammation reported on this outcome at the three‐year time point (dornase alfa n = 46, control n = 39) (Paul 2004). Trialists reported the median rate of decline in FEV1 at ‐1.99% in the dornase group and ‐3.26% in those not receiving dornase; this result was not significantly different (Paul 2004).
b. Mean percentage change in FEV1 ‐ in participants with acute pulmonary exacerbations
i. at one month
This outcome was reported in one trial at the one‐month time point (dornase alfa n = 43, control n = 37) (Wilmott 1996). Our analysis showed no difference between groups, MD 1.00 (95% CI ‐13.93 to 15.93) (Analysis 1.5).
c. Mean percentage change in FVC ‐ in participants with stable disease
i. at one month
This outcome was reported in six trials at the one‐month time point (dornase alfa n = 151, control n = 157) (Amin 2011; Laube 1996; Ramsey 1993; Ranasinha 1993; Shah 1995a; Robinson 2000). As for the results for FEV1, the data from Amin were not included in the pooled analysis because the trial reported absolute and not relative changes and the data from the Robinson trial were not included because the trial reported FVC in litres and not % predicted (pooled analysis dornase alfa n = 121, control n = 127).
The pooled analysis showed a difference in relative percentage change in FVC, MD 7.52% (95% CI 1.34 to 13.69) (Analysis 1.6). There was substantial heterogeneity between the trials (I² = 69%), therefore a random‐effects model was used.
We originally planned to undertake subgroup analyses based on age of participants, disease severity and dose frequency (once‐daily versus twice‐daily dosing). A subgroup analysis with paediatric versus adult participants was not possible because there were no trials including only children. We were able to perform a subgroup analysis on disease severity with three trials including participants with moderate disease (dornase alfa n = 90, control n = 93) (Laube 1996; Ramsey 1993; Ranasinha 1993) and one trial including participants with severe disease (dornase alfa n = 31, control n = 34) (Shah 1995a). Similar to the findings for FEV1, those with moderate disease showed significant improvements in FVC, MD 10.98 (95% CI 7.68 to 14.29), whereas those with severe disease did not, MD ‐4.90 (95% CI ‐15.15 to 5.35). In addition, the heterogeneity in this subgroup analysis decreased to I² = 0% suggesting that disease severity accounted for some of the heterogeneity in the original analysis (Analysis 1.8). A subgroup analysis based on frequency of drug administration was not possible because all four trials administered dornase alfa twice daily.
Amin reported the absolute difference in FVC, but analysis of the data showed no difference between treatment groups, MD ‐3.61% (95% CI ‐10.02 to 2.80) (Amin 2011) (Analysis 1.9). Robinson reported a significant difference in FVC between the placebo group (‐2.2% change) and the dornase alfa group (5.4% change) (P < 0.02) (Robinson 2000) (Table 2).
ii. at three months
The mean percentage change in FVC was reported in one trial at the three‐month time point (dornase alfa n = 156, control n = 162) (McCoy 1996). Analysis showed a difference between groups, MD 5.10% (95% CI 1.23 to 8.97) (Analysis 1.6) (moderate‐quality evidence).
iii. at six months
One trial of once‐daily and twice‐daily dornase alfa compared to placebo reported on this outcome at the six‐month time point (once‐daily dornase alfa n = 322, twice‐daily dornase alfa n = 321, control n = 325) (Fuchs 1994). In participants receiving once‐daily dornase alfa, FVC improved by MD 3.80 (95% CI 2.62 to 4.98) compared to control (high‐quality evidence); and for those on the twice‐daily regimen by MD 3.00 (95% CI 1.82 to 4.18) compared to control (Analysis 1.7).
iv. at one year
This outcome was reported in one trial at the one‐year time point (dornase alfa n = 8, control n = 11) (Robinson 2005). Analysis showed no difference between treatment groups, MD ‐5.70 (95% CI ‐15.87 to 4.47) (Analysis 1.6).
v. at two years
One trial reported the absolute mean difference between the two groups at two years (dornase alfa n = 204, control n = 206), showing MD 0.70 (95% CI ‐1.24 to 2.64) (Quan 2001) (Analysis 1.10).
vi. at three years
One trial, whose primary objective was to assess lung inflammation, reported on the change in FVC at three years (dornase alfa n = 46, control n = 39) (Paul 2004). The trial reported a significant decrease in the annual median decline in FVC in the group not receiving dornase alfa; whereas, the participants receiving dornase alfa did not have a significant decrease in FVC over time.
d. LCI
One trial reported on LCI at one month (dornase alfa n = 17, control n = 17) (Amin 2011). Our analysis produced a non‐significant result, MD ‐0.90 (95% CI ‐1.87 to 0.07) (Analysis 1.11). However, the published paper reports a significant difference in LCI between the groups (P = 0.02) (Amin 2011). This is likely due to the fact the investigators used a model that took participants' baseline lung function into account when analysing the data which we are not able to do when analysing data in RevMan. It should be noted that, contrary to other measures of lung function, a decrease in LCI is beneficial.
e. FEV0.5 z score
Only one cross‐over trial involving 24 infants (dornase alfa n = 12, control n = 12) reported on this outcome at the six‐month time point. Only first‐arm data are available and have been analyzed as a parallel group comparison (Castile 2009). The score declined in both groups and the difference in mean reduction was not significant, MD 0.10 (95% CI ‐0.74 to 0.94) (Analysis 1.12).
2. Mean percentage change in QoL score
Many of the trials did not use the same QoL measurements precluding pooling of data. Although Ranasinha and Fuchs described similar measures of quality of life, Ranasinha did not report specific QoL scores (Fuchs 1994; Ranasinha 1993).
Wilmott and Amin reported that the QoL scores they obtained showed no significant difference between the groups, in terms of improvement in cough and congestion, activity limitation, emotional well‐being, fatigue, days of restriction to bed and general health perception (Wilmott 1996) or in either version of the CFQ‐R (Amin 2011) (Analysis 1.13; Analysis 1.14) (low‐quality evidence). Fuchs used a five‐point well‐being score and also evaluated a CF symptom score and dyspnoea scale. There was a significant improvement in the well‐being score and dyspnoea score compared to placebo in the once‐daily dornase alfa group but not in the twice‐daily dornase alfa group; both groups reported an improvement in the CF symptom score (Fuchs 1994). Ranasinha stated that there was a non‐significant improvement in dyspnoea, and overall well‐being and significant improvements in general well‐being, cough frequency and chest congestion (Ranasinha 1993). Ramsey reported that the frequency and magnitude of improvement across all QoL questions was greater among participants receiving dornase alfa (Ramsey 1993).
3. Mean number of respiratory exacerbations
Trials included participants with stable lung disease. None of the included trials reported respiratory exacerbations expressed as a mean number per period of follow up. However, three trials reported either the RR or the number of people experiencing respiratory exacerbations, therefore these data have been included within the review (Amin 2011; Fuchs 1994; Quan 2001). Additionally, one trial reported an age‐adjusted RR of having more than one respiratory exacerbation, but these data were not included in the pooled analysis (McCoy 1996).
The definition of a respiratory (pulmonary) exacerbation varied in the trials. Fuchs defined an exacerbation as the need for parenteral antibiotics because of any four of the following 12 signs or symptoms: change in sputum; new or increased haemoptysis; increased cough; increased dyspnoea; malaise, fatigue or lethargy; temperature above 38°C; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical exam of the chest; decrease in pulmonary function by 10% or more from a previously recorded value; or radiographic changes indicative of pulmonary infection (Fuchs 1994). Quan defined an exacerbation as respiratory symptoms requiring IV antibiotics (Quan 2001). The remaining two trials did not include a specific definition for pulmonary exacerbations (Amin 2011; McCoy 1996). The Amin trial planned to withdraw participants who had a pulmonary exacerbation requiring IV antibiotics and one participant was withdrawn for this reason, but it was not reported which treatment group this participant was from (Amin 2011).
We included data for this outcome from trials lasting one month (Amin 2011), six months (Fuchs 1994) and two years (Quan 2001) (dornase alfa n = 575, control n = 576). This yielded a RR of 0.78 (95% CI 0.62 to 0.96) in favour of dornase alfa (Analysis 1.15) (moderate‐quality evidence). In the trial by Fuchs, it was noted that participants aged 17 to 23 years had a higher incidence of exacerbations regardless of treatment group, and the once‐daily group had a higher percentage of participants in this age range; therefore, they calculated an age‐adjusted RR for the once‐daily group at 0.72 (95% CI 0.52 to 0.98) and for the twice‐daily group at 0.63 (95% CI 0.46 to 0.87) (Fuchs 1994).
A three‐month trial including participants with severe disease (dornase alfa n = 158, control n = 162) reported the age‐adjusted RR of having more than one respiratory exacerbation during the trial as 0.93 (95%CI 0.69 to 1.21) (McCoy 1996).
Secondary outcomes
1. Mortality
This outcome was reported in seven trials in total (dornase alfa n = 841, control n = 849): in four trials at one month (Laube 1996; Ramsey 1993; Ranasinha 1993; Shah 1995a); in one trial at three months (McCoy 1996); in one trial at six months (Fuchs 1994); and in one trial at two years (Quan 2001). The RR of death was 1.70 (95% CI 0.70 to 4.14) with 12 deaths in the dornase alfa group and seven deaths in the control group (Analysis 1.16). The majority of deaths (17 of 19 deaths) were reported from two trials which enrolled participants with severe lung disease (Shah 1995a; McCoy 1996).
2. Mean number of days IV antibiotics used
One trial reported the use of antibiotics and did not specify the route of administration; however we have chosen to report the results here (Castile 2009). After six months, there was no difference in the number of days of antibiotic use between groups, MD ‐4.60 days (95% CI ‐22.53 to 13.33) (Analysis 1.17).
a. at three months
One trial reported on this outcome at three months (dornase alfa n = 158, control n = 162) (McCoy 1996). Analysis showed the difference between the treated and control groups was MD ‐2.96 (95% ‐7.29 to 1.37) (Analysis 1.18).
3. Mean number of days oral antibiotics used
No trial reported on this outcome.
4. Mean number of days of inpatient treatment
a. at three months
One trial reported on this outcome at three months (dornase alfa n = 158, control n = 162) (McCoy 1996). The difference between the groups was not statistically significant, MD 0.93 (95% CI ‐2.19 to 4.05) (Analysis 1.19).
b. at six months
One trial reported the mean number of inpatient days at six months (dornase alfa n = 322, control n = 325) (Fuchs 1994). Participants treated with the once‐daily regimen spent 1.3 fewer days in hospital compared to placebo (P = 0.06) and participants receiving twice‐daily dornase alfa spent 1.0 fewer days in hospital compared to placebo (P < 0.05).
5. Mean change in weight from baseline
a. at two years
Only Quan reported on the mean change in weight from baseline at two years (dornase alfa n = 236, control n = 234) (Quan 2001). The weight‐for‐age percentile decreased in both groups from baseline to the end of the trial; the difference between the treatment groups was not statistically significant, MD ‐0.20 (95% CI ‐2.42 to 2.02) (Analysis 1.20).
6. Number of participants experiencing adverse events by end of the trial
a. haemoptysis (blood stained sputum)
This outcome was reported in three trials (dornase alfa n = 393, control = 395) with trial durations of one month (Ranasinha 1993; Shah 1995a) and six months (Fuchs 1994). There was no increased risk of haemoptysis with dornase alfa treatment, RR 0.88 (95% CI 0.50 to 1.55) (Analysis 1.21).
b. dyspnoea (shortness of breath)
This outcome was reported in four trials (dornase alfa n = 551, control = 557) with trial durations of one month (Ranasinha 1993; Shah 1995a), three months (McCoy 1996) and six months (Fuchs 1994). There was no increased risk of dyspnoea with dornase alfa treatment, RR 1.00 (95% CI 0.85 to 1.18) (Analysis 1.22).
c. pneumothorax
Three trials of participants with stable disease reported on this outcome (dornase alfa n = 393, control = 395) with trial durations of one month (Ranasinha 1993; Shah 1995a) and six months (Fuchs 1994). There was no increased risk of pneumothorax with dornase alfa treatment, RR 0.60 (95% CI 0.08 to 4.50) (Analysis 1.23).
The trial which enrolled participants with an acute exacerbation also reported this outcome (dornase alfa n = 43, control n = 37) (Wilmott 1996), with one participants in the treatment group having a pneumothorax, RR 2.65 (95% CI 0.10 to 66.96) (Analysis 1.24).
d. voice alteration
Seven trials of participants with stable disease reported on this outcome (dornase alfa n = 831, control n = 839) with durations of one month (Ramsey 1993; Ranasinha 1993; Shah 1995a), three months (McCoy 1996), six months (Fuchs 1994) and two years (Quan 2001). Participants were more likely to experience voice alteration with dornase alfa compared to placebo, RR 1.69 (95% CI 1.20 to 2.39) and this was seen more commonly in trials lasting between one and three months, but not in longer trials (Analysis 1.25). In the trial that compared once‐daily to twice‐daily use of dornase alfa over six months, there was no difference in voice alteration between the two groups, RR 1.34 (95% 0.64 to 2.78) (Fuchs 1994) (Analysis 1.26).
The trial in people with an acute exacerbation also reported on this outcome (dornase alfa n = 43, control n = 37) (Wilmott 1996), but found no statistically significant difference between the treatment or control groups, RR 2.58 (95% CI 0.55 to 12.03) (Analysis 1.27).
e. rash
Occurence of a rash was reported in two trials (dornase alfa n = 558, control n = 559) of six months (Fuchs 1994) and two years duration (Quan 2001). There was an increased risk of rash in participants taking dornase alfa, RR 2.40 (95% CI 1.16 to 4.99) (Analysis 1.28).
f. other adverse events
A number of other adverse events were documented and are presented in the analysis; in no case was there an increased risk in participants treated with dornase alfa: three trials reported chest pain (Analysis 1.29); two trials reported cough (Analysis 1.30); one trial reported increased sputum production (Analysis 1.31); one trial reported dry throat (Analysis 1.32); six trials reported pharyngitis (Analysis 1.33); three trials reported laryngitis (Analysis 1.34); two trials reported conjunctivitis (Analysis 1.35); four trials reported wheeze (Analysis 1.36), one of the these reported this as a serious adverse event after the participant was admitted to hospital ; and one trial reported facial oedema (Analysis 1.37).
7. Cost of treatment
Three papers examined the cost of health care for participants involved in the Fuchs trial, which lasted for 20 weeks (Fuchs 1994).
The report by Oster prospectively documented how participants used health care and then, using secondary data sources, estimated the cost of hospitalisation and outpatient antibiotic treatment for participants in the trial. This information was then used to compare the cost of all respiratory tract infection‐related health care (including non‐protocol defined respiratory tract infections) between the two treatment groups and the control group. The authors estimated that the mean total cost of respiratory tract infection‐related care was USD 6443, USD 4761 and USD 5628 for the placebo, once‐daily and twice‐daily dosage regimens respectively. This cost included all outpatient antibiotic therapy, as well as estimates of cost for any inpatient care. The estimates did not include the cost of dornase alfa itself, as this was not marketed at the time of the trial. Once dornase alfa was marketed, at a cost of USD 27 per ampoule, they were able to estimate that the reduced cost of respiratory tract infection‐related care would offset between 18.3% and 37.5% of the cost of therapy itself (Oster 1995).
The report by von der Schulenburg used the same data from the Fuchs trial, but used health insurance costs to estimate what would have been the costs of healthcare treatment in German CF centres for participants receiving once daily dornase alfa versus those participants receiving placebo (von der Schulenburg 1995). The total cost for the health care of participants, if they had been treated in a German CF centre, was DM 5879 (USD 3551) for the group receiving once‐daily dornase alfa versus DM 7849 (USD 4742) for the placebo group. This included the cost of inpatient admissions, outpatient appointments and investigations. The cost of all antibiotics used was DM 2954 (USD 1784) per participant in the treated group versus DM 4213 (USD 2545) in the placebo group. The estimates did not include the cost of dornase alfa itself, as this was not marketed at the time of the trial.
Similarly, the Menzin report analysed data from the Fuchs trial to estimate the reduction in cost of respiratory tract infection‐related care (excluding the cost of dornase alfa itself) in the UK, France, Italy and Germany (Fuchs 1994; Menzin 1996). Variations in medical practice in these countries led to a range of cost reductions from GBP 434 (USD 700) in the UK to a maximum of FF 13,872 (USD 2100) in France. The estimates did not include the cost of dornase alfa itself, as this was not marketed at the time of the trial.
Dornase alfa daily versus alternate days
One cross‐over trial compared the use of once‐daily dornase alfa to alternate‐day use over two separate three‐month treatment periods (daily use n = 43, alternate day use n = 43) (Suri 2001). A summary of key findings for this comparison has been presented in a table (summary of findings Table 2).
Primary outcomes
1. Changes in lung function (FEV1, FVC) from baseline
Changes in FEV1 and FVC were expressed as relative % change (seePublished notes). There was no difference found between the two groups in FEV1, MD 2.00 (95% CI ‐5.00 to 9.00) (Analysis 2.1) or FVC, MD 0.03 (95% CI ‐0.06 to 0.12) (Analysis 2.2) (both low‐quality evidence).
2. Mean percentage change in QoL score
There was no difference found between the two groups in QoL score, MD 0.01 (95% CI ‐0.02 to 0.04) (Analysis 2.3) (low‐quality evidence).
3. Number of respiratory exacerbations
There was no difference found between the two groups in the number of participants experiencing one or more pulmonary exacerbations (18 in the once‐daily group and 17 in the alternate‐day group) (low‐quality evidence).
Secondary outcomes
1. Mortality
The trial did not measure this outcome.
2. Mean number of days IV antibiotics used
The trial did not measure this outcome.
3. Mean number of days oral antibiotics used
The trial did not measure this outcome.
4. Mean number of days inpatient treatment
There was no difference found between the two groups in the number of days of inpatient treatment, MD ‐0.93 (95%CI ‐3.24 to 1.38) (Analysis 2.4).
5. Mean change in weight from baseline
There was no difference found between the two groups in the change in weight from baseline, MD ‐0.09 kg (95% CI ‐0.73 to 0.55) (Analysis 2.5).
6. Number of participants experiencing adverse events by end of trial
The trial did not measure this outcome.
7. Cost of treatment
The Suri trial also examined the cost of therapy including intervention and non‐intervention drugs, hospital and community care (Suri 2001). The cost of daily dornase alfa over the 12‐week treatment period was GBP 1749 and the cost of alternate day dornase alfa was GBP 857. Total costs were on average GBP 513.00 (95% CI ‐546.00 to 1510.00) higher in the daily use group.
Dornase alfa versus hyperosmolar agents (hypertonic saline or mannitol)
Comparator medications for improving mucus clearance which were included in this review were hypertonic saline (HS) in three trials and mannitol in one trial. For HS, one trial used 5 ml of 7% HS twice daily (Suri 2001), a second trial used 10 ml of 5.8% HS once daily (Ballmann 2002) and the third trial used 10 ml of 6% HS twice daily (Adde 2004). These doses of HS were compared with once‐daily dornase alfa (Adde 2004; Ballmann 2002; Suri 2001). Minasian compared twice‐daily 400 mg mannitol to twice‐daily 2.5 mg dornase alfa (Minasian 2010). A summary of key findings for these comparisons have been presented in the tables (summary of findings Table 3; summary of findings Table 4; summary of findings Table 5).
Primary outcomes
1. Changes in lung function (FEV1 and FVC) from baseline
Four trials lasting three weeks (Ballmann 2002), four weeks (Adde 2004) and three months (Minasian 2010; Suri 2001) reported on changes in lung function. Data from the Suri and Minasian trials were not pooled because Suri reported lung function in % predicted; whereas, Minasian reported lung function in litres (Minasian 2010; Suri 2001). Data from Ballman and Adde could not be pooled because only group means and SDs were provided. Two trials reported the relative change in lung function (Minasian 2010; Suri 2001), but the remaining two trials did not specify whether data were for absolute or relative changes (Adde 2004; Ballmann 2002).
a. mean percentage change or change in L in FEV1
At the time point of up to one month, one trial (dornase alfa n = 14, HS n = 14) reported the mean (SD) increase in FEV1 was 7.7% (14%) with HS versus 9.3% (11.7%) with dornase alfa (no significant difference between groups) (Ballmann 2002). In this trial, the number of participants that had at least a 10% increase in FEV1 from baseline was four in the dornase alfa group, and four in the HS group, with two participants improving with either treatment (Ballmann 2002). At the same time point, a second trial (dornase alfa n = 18, HS n = 18) reported that FEV1 did not significantly change after treatment with either HS or dornase alfa (Adde 2004) (Table 3).
| Pre‐hypertonic saline | Post hypertonic saline | Pre dornase alfa | Post dornase alfa | P value | |
|---|---|---|---|---|---|
| FEV1 (% predicted) mean (SD) | 47 (18) | 46 (18) | 49 (15) | 50 (21) | NS |
FEV1: forced expiratory volume at one second
NS: non‐significant
SD: standard deviation
At three months, Suri (dornase alfa n = 43, HS n = 40) reported an advantage for daily dornase alfa over HS, MD 8.00% (95% CI 2.00% to 14.00%) (Suri 2001) (Analysis 3.1) (low‐quality evidence). Within the trial there were varying individual responses to dornase alfa and HS, with 50% of participants experiencing a 10% improvement in FEV1 with dornase alfa and 35% having a 10% improvement in FEV1 with HS.
The trial comparing dornase alfa and mannitol (dornase alfa n = 21, mannitol n = 23) did not report a significant difference between the two interventions for FEV1 MD 0.02 L (95% CI ‐0.11 to 0.16) (Minasian 2010) (Analysis 4.1) (low‐quality evidence).
b. mean percentage change or change in L in FVC
Two trials did not report on the change in FVC (Adde 2004; Ballmann 2002). At three months, Suri (dornase alfa n = 43, HS n = 40) reported that the difference between the once‐daily treatment group and the HS treatment group was 0.08% (95% CI ‐0.02 to 0.18) (Suri 2001) (Analysis 3.2) (low‐quality evidence).
The trial comparing dornase alfa and mannitol (dornase alfa n = 21, mannitol n = 23) reported no difference in change in FVC between groups, MD ‐0.02 L (95% CI ‐0.23 to 0.19) (Minasian 2010) (Analysis 4.2) (low‐quality evidence).
2. Mean percentage change in QoL score
Two trials measured QoL, but used different tools precluding pooling of results (Minasian 2010; Suri 2001). Suri reported that the difference between the once‐daily dornase alfa and HS was MD 0.03% (95% CI ‐0.01% to 0.07%) (Suri 2001) (Analysis 3.3) (low‐quality evidence). Miniasian used the CFQ‐R to assess QoL and expressed this as the absolute change from baseline; investigators did not find a difference between the mannitol and dornase alfa groups, MD 4.1 (95% CI ‐6.40 to 14.6) (Minasian 2010) (Analysis 4.3) (low‐quality evidence).
3. Number of respiratory exacerbations
Suri measured the mean number of respiratory exacerbations reported these as not being statistically significant (Suri 2001). The absolute number of people who experienced one or more exacerbations whilst taking HS was 15 and for the once‐daily dornase alfa participants it was 18 (Suri 2001) (low‐quality evidence). Miniasian reported on exacerbations which required IV antibiotics in terms of absolute numbers per participant (Minasian 2010). Investigators did not find a difference between the two groups, RR 1.10 (95% CI 0.25 to 4.84) (Analysis 4.4) (low‐quality evidence).
Secondary outcomes
1. Mortality
There were no deaths reported in any of the trials (Adde 2004; Ballmann 2002; Minasian 2010; Suri 2001).
2. Mean number of days IV antibiotics used
No trials looked at this outcome.
3. Mean number of days oral antibiotics used
No trials looked at this outcome.
4. Mean number of days inpatient treatment
One trial reported on this outcome and found no difference between the once‐daily dornase alfa and the HS groups, MD ‐0.40 (95% CI ‐2.32 to 1.52) (Suri 2001) (Analysis 3.4).
5. Mean change in weight from baseline
Again, only one trial reported on this outcome (Suri 2001). There was no difference found between the once‐daily dornase alfa and the HS groups, MD ‐0.42 (95% CI ‐1.04 to 0.2) (Analysis 3.5).
6. Number of participants experiencing adverse events by end of trial
Two trial reported adverse events (Minasian 2010; Suri 2001).
Suri reported no significant difference in the number of adverse effects between the different groups (Suri 2001). In the HS group, with the initial dose three participants (6%) experienced significant bronchospasm (a greater than 15% decrease in FEV1 despite initial treatment with bronchodilators) requiring withdrawal from the trial. A further five participants reported a salty taste, but this was not severe enough for them to drop out of the trial. It was found that HS tended to make the participants cough during administration. The 10 most frequent adverse events were increased cough, coryza, throat infection, allergic reaction to antibiotic, wheeze, breathlessness, haemoptysis, chest pain, eye irritation and oral thrush (Suri 2001).
Minasian reported the following side effects were not more common in either treatment group (Analysis 4.5): cough, RR 0.08 (95% CI 0.01 to 1.40); ear infection, RR 0.36 (95% CI 0.02 to 8.47); musculoskeletal pain, RR 0.36 (95% CI 0.02 to 8.47); or pharyngitis, RR 0.36 (95% CI 0.02 to 8.47). However, nine out of 38 (24%) participants screened had significant bronchoconstriction (at least a 15% decrease in FEV1) with the mannitol challenge, even when pre‐treated with bronchodilators and were not included in the trial (Minasian 2010).
7. Cost of treatment
Only Suri investigated the mean cost difference between daily dornase alfa and HS at 12 weeks. The drug cost per day was reported to be GBP 0.38 (USD 0.59) for HS and GBP 20.39 (USD 31.85) for once‐daily dornase alfa. The average total cost of an occupied bed per day ranged from GBP 280 (USD 438) to GBP 397 (USD 620). Over the 12‐week treatment period the mean drug cost of daily dornase alfa was GBP 1755 (USD 2741) compared with GBP 37 (USD 58) for HS. The difference in the total health service cost between daily dornase alfa and HS was calculated, MD GBP 1409.00 (95% CI 440.00 to 2318.00) (MD USD 2200 (95% CI 687 to 3620)) (Suri 2001).
*USD equivalent not reported in paper but estimated based on conversion of GBP 1 to USD 1.56.
Dornase versus a combination of dornase and a hyperosmolar agent
Only one trial compared mannitol (400 mg twice daily) with a combination of mannitol (400 mg twice daily) and dornase alfa (2.5 mg twice daily) (Minasian 2010).
Primary outcomes
1. Changes in lung function (FEV1, FVC ) from baseline
There was no difference between the two groups in either FEV1, MD 0.10 L (95% CI ‐0.06 to 0.25) (Analysis 5.1) or FVC, MD 0.13 L (95% CI ‐0.11 to 0.37) (Analysis 5.2) (both low‐quality evidence).
2. Mean percentage change in QoL score
The change in QoL using the CFQ‐R was just in favour of dornase alfa, MD 10.61 (95% CI 0.27 to 20.95) (Analysis 5.3) (low‐quality evidence).
3. Number of respiratory exacerbations
There was no difference found between the two groups in the number of participants experiencing pulmonary exacerbations, RR 0.55 (95% CI 0.16 to 1.92) (Analysis 5.4) (low‐quality evidence).
Secondary outcomes
1. Mortality
The trial did not measure this outcome.
2. Mean number of days IV antibiotics used
The trial did not measure this outcome.
3. Mean number of days oral antibiotics used
The trial did not measure this outcome.
4. Mean number of days inpatient treatment
The trial did not measure this outcome.
5. Mean change in weight from baseline
The trial did not measure this outcome.
6. Number of participants experiencing adverse events by end of trial
There was no difference found between the two groups in the rates of adverse events of: cough, RR 0.22 (95% CI 0.01 to 4.30); headache, RR 0.36 (95% CI 0.02 to 8.47); nausea, RR 0.36 (95% CI 0.02 to 8.47); or rash, RR 0.36 (95% CO 0.02 to 8.47) (Analysis 5.5).
7. Cost of treatment
The trial did not measure this outcome.
Discussion
Summary of main results
Dornase alfa versus placebo or no treatment
Dornase alfa improved lung function in trials of up to one month duration compared to placebo, MD in FEV1 % predicted 9.51% (95% CI 0.67 to 18.35). This overall improvement was due to the improvement in participants with moderate disease severity, as demonstrated by a subgroup analysis of this group which showed an improvement, MD 14.26% (95% CI 10.79 to 17.74), compared to the group with severe disease which did not show any improvement, MD ‐2.81% (95% CI ‐8.77 to 3.15). Unfortunately there was only one trial which included participants with severe disease. We were not able to include participants with mild disease in the pooled result; however, one small trial including only participants with mild disease showed no change in FEV1, MD 0.08% (95% CI ‐5.59 to 5.74) (Amin 2011). The Amin trial also looked at LCI and identified a decrease in LCI of ‐0.90 (95% CI ‐1.87 to 0.07) in the dornase alfa group compared to placebo. This decrease was significant when baseline lung function was taken into account, which emphasizes the importance of using more sensitive measures of lung function in people with mild lung disease. There were fewer trials of longer duration, but FEV1 was significantly better in the dornase alfa group in trials ranging from three months to two years. This included trials involving participants with severe disease (McCoy 1996) as well as mild to moderate disease (Fuchs 1994; Quan 2001). It was not possible to perform a subgroup analysis comparing trials using once‐daily versus twice‐daily dornase alfa, but the single large trial which compared these two interventions directly, did not find a difference in FEV1 between the groups (Fuchs 1994).
Dornase alfa also decreased the number of participants experiencing pulmonary exacerbations, which is an important outcome measure in CF. We calculated the RR of a pulmonary exacerbation as 0.78 (95% CI 0.62 to 0.96) in participants receiving dornase alfa compared to control. QoL improved in some trials and was unchanged in others. Dornase alfa was well‐tolerated and other than voice alteration, RR 1.69 (95% CI 1.2 to 2.39), and rash, RR 2.4 (95% CI 1.16 to 4.99), side effects were not more common than in the control group.
There have not been new trials examining the cost effectiveness of dornase alfa, but as concluded with earlier versions of this review, the healthcare costs of people treated with dornase alfa are lower (Oster 1995; von der Schulenburg 1995). However, this saving only offsets between 18.3% to 37.5% of the cost of dornase alfa (Oster 1995). Given that the cost of dornase alfa has not decreased since 2010, these cost estimates are still relevant. One difficulty in interpreting the cost effectiveness of dornase alfa is that the cost benefits of improving lung function over the long term are difficult to model.
Dornase alfa daily versus alternate days
One cross‐over trial compared the use of once‐daily dornase alfa to alternate‐day use over two separate three‐month treatment periods (daily use n = 43, alternate day use n = 43) (Suri 2001). This trial did not find a difference in lung function (either FEV1 or FVC) between the different regimens. Similarly, there were no differences observed in QoL score, number of respiratory exacerbations, days of inpatient treatment or change in weight. The cost of daily dornase alfa over the 12‐week treatment period was higher (GBP 1749) than in the alternate‐day group (GBP 857). Total costs were on average GBP 513.00 (95% CI ‐546.00 to 1510.00) higher in the daily use group (Suri 2001).
Dornase alfa versus hyperosmolar agents
Mucolytic and hyperosmolar agents are the most common groups of medications that help with mucous clearance. Unfortunately there are few high‐quality trials comparing these two types of medication and none of the results could be pooled in this review because of differences in how outcomes were reported.
Trials of one month or less did not find a significant difference in FEV1 between HS and dornase alfa (Adde 2004; Ballmann 2002); whereas a three‐month trial reported an improvement with dornase compared to HS, MD 8.00% (95% CI 2.00% to 14.00%) (Suri 2001). The only trial comparing dornase alfa to mannitol did not find a difference in FEV1 between the two interventions, MD 0.02 L (95% CI ‐0.11 to 0.16); neither did this trial find a difference in FEV1 when mannitol combined with dornase alfa was compared to dornase alfa alone, MD 0.10 L (95% CI ‐0.06 to 0.25) (Minasian 2010).
The two trials reporting on the number of participants experiencing exacerbations found no difference between treatment groups (Minasian 2010; Suri 2001). QoL improved in some trials, but was unchanged in others.
Adverse events were not significantly different between the groups receiving dornase alfa and hyperosmolar agents, although 6% and 24% of potential participants experienced bronchoconstriction with the initial doses of HS and mannitol respectively, and were excluded from the trials.
Given that the cost of dornase alfa is 10 times that of HS, it is not surprising that the difference in the total health service cost was GBP 1409 (95% CI GBP 440 to GBP 2318) higher for the daily dornase alfa group compared to the HS group (Suri 2001). However, this trial was only three months in duration and differences in the numbers of exacerbations were not significant, which would be expected to affect health service costs.
Overall completeness and applicability of evidence
The objectives of this review were to determine if there was an improvement in morbidity or mortality with the use of dornase alfa, to identify any adverse events associated with the use of dornase alfa and to determine the efficacy of dornase alfa compared with other medications for improving airway clearance.
There is evidence to support the short‐term benefit of dornase alfa in improving lung function; however, other outcomes such as the frequency of pulmonary exacerbations require trials of longer duration. The trial by Fuchs used data from a CF registry to determine that a trial lasting 48 weeks was needed to assess pulmonary exacerbations and only two of the included trials in this Cochrane Review reporting on exacerbations as an outcome were of sufficient duration (Fuchs 1994; Quan 2001). Given the improvement in prognosis for people with CF, it is difficult to detect differences in mortality unless trials include participants with severe disease and are long enough in duration. Only two trials included participants with severe disease making it difficult to reach firm conclusions on the effect of dornase alfa on mortality (McCoy 1996; Shah 1995a).
Dornase alfa is approved for use as a once‐daily medication in most countries. Different dose‐frequency regimens of dornase alfa were used in this review; ranging from alternate‐day use to twice‐daily use; only two trials compared these regimens directly (Fuchs 1994; Suri 2001). In the trial comparing once‐daily to twice‐daily dornase alfa, there was a similar improvement in lung function between the groups, although only the twice‐daily group showed a significant decrease in the number of participants experiencing an exacerbation. It is not clear from the current evidence if an alternate‐day regimen would be equally efficacious as this has only been studied in one small trial of three months duration.
More data are needed comparing dornase to hyperosmolar agents before definitive conclusions can be reached.
With the advent of modulator treatment for people with CF (Shteinberg 2020), the results of this review may become less applicable to the CF population as a whole as the intervention may work differently in people on modulator therapy. A study assessing the impact of discontinuing long‐term treatment with dornase alfa in people with CF who are on modulator therapy is underway (SIMPLIFY).
Quality of the evidence
Most trials were judged to have a low risk of performance, detection, reporting and attrition bias. Many of the included trials did not have enough information in the publication to determine if there was a risk of selection bias. This reduces the strength of evidence available. Also, the pooled results for lung function from the shorter trials showed considerable heterogeneity and although this may be explained by the subgroup analysis by disease severity; this heterogeneity reduces the strength of evidence in favour of using dornase alfa.
According to the GRADE approach, the quality of the evidence in the trials which compared dornase alfa to placebo or no dornase alfa treatment was judged to be moderate to high quality for lung function outcomes and exacerbations. The quality of the evidence for quality of life was limited for this comparison and therefore judged to be low. The quality of the evidence for dornase alfa compared to other controls (HS, mannitol or daily dornase alfa compared to alternate days) was limited and from open‐label trials and therefore judged to be low.
Potential biases in the review process
For this review, we searched all relevant sources for potential trials and the inclusion of hand‐searching abstracts from the North American and European Cystic Fibrosis Conferences increases the likelihood that all relevant trials have been identified.
Agreements and disagreements with other studies or reviews
No other systematic reviews have been identified which compare the use of dornase alfa to placebo or control in people with CF. The Cochrane Review of hypertonic saline for people with CF included trials comparing dornase alfa to hypertonic saline and identified the same trials as were included in this review (Wark 2018). The authors of that review concluded that hypertonic saline should be recommended for use in CF, but not in preference to dornase alfa given that there was insufficient evidence of superiority and less evidence for long‐term benefit in lung function.
Study flow diagram.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1: Dornase alfa versus placebo, Outcome 1: Relative mean % change in FEV1 (% predicted)
Comparison 1: Dornase alfa versus placebo, Outcome 2: Relative mean % change in FEV1 (% predicted) at one month ‐ subgroup analysis by disease severity
Comparison 1: Dornase alfa versus placebo, Outcome 3: Absolute mean % change in FEV1 (% predicted)
Comparison 1: Dornase alfa versus placebo, Outcome 4: Absolute mean % change in FEV1 (% predicted)
Comparison 1: Dornase alfa versus placebo, Outcome 5: Relative mean % change in FEV1 (in participants with acute exacerbations)
Comparison 1: Dornase alfa versus placebo, Outcome 6: Relative mean % change in FVC (% predicted)
Comparison 1: Dornase alfa versus placebo, Outcome 7: Relative mean % change in FVC (% predicted)
Comparison 1: Dornase alfa versus placebo, Outcome 8: Relative mean % change in FVC at one month ‐ subgroup analysis by disease severity
Comparison 1: Dornase alfa versus placebo, Outcome 9: Absolute mean % change in FVC (% predicted)
Comparison 1: Dornase alfa versus placebo, Outcome 10: Absolute mean % change in FVC (% predicted)
Comparison 1: Dornase alfa versus placebo, Outcome 11: Absolute mean change in LCI
Comparison 1: Dornase alfa versus placebo, Outcome 12: Absolute change in FEV0.5 (z score)
Comparison 1: Dornase alfa versus placebo, Outcome 13: Quality of life ‐ CFQ‐R respiratory
Comparison 1: Dornase alfa versus placebo, Outcome 14: Quality of life ‐ CFQ‐R Parent respiratory
Comparison 1: Dornase alfa versus placebo, Outcome 15: Number of people experiencing exacerbations
Comparison 1: Dornase alfa versus placebo, Outcome 16: Number of deaths
Comparison 1: Dornase alfa versus placebo, Outcome 17: Mean number of days of antibiotics (inhaled, oral or IV)
Comparison 1: Dornase alfa versus placebo, Outcome 18: Mean number of days IV antibiotics used
Comparison 1: Dornase alfa versus placebo, Outcome 19: Mean number of days inpatient treatment
Comparison 1: Dornase alfa versus placebo, Outcome 20: Mean change in weight from baseline
Comparison 1: Dornase alfa versus placebo, Outcome 21: Adverse event ‐ haemoptysis (blood‐stained sputum)
Comparison 1: Dornase alfa versus placebo, Outcome 22: Adverse event ‐ dyspnoea (shortness of breath)
Comparison 1: Dornase alfa versus placebo, Outcome 23: Adverse event ‐ pneumothorax
Comparison 1: Dornase alfa versus placebo, Outcome 24: Adverse event ‐ pneumothorax (in participants with acute exacerbations)
Comparison 1: Dornase alfa versus placebo, Outcome 25: Adverse event ‐ voice alteration
Comparison 1: Dornase alfa versus placebo, Outcome 26: Adverse event ‐ voice alteration (1x versus 2x daily treatment)
Comparison 1: Dornase alfa versus placebo, Outcome 27: Adverse event ‐ voice alteration (in participants with acute exacerbations)
Comparison 1: Dornase alfa versus placebo, Outcome 28: Adverse event ‐ rash
Comparison 1: Dornase alfa versus placebo, Outcome 29: Adverse event ‐ chest pain
Comparison 1: Dornase alfa versus placebo, Outcome 30: Adverse event ‐ cough (new or increased)
Comparison 1: Dornase alfa versus placebo, Outcome 31: Adverse event ‐ increased sputum production
Comparison 1: Dornase alfa versus placebo, Outcome 32: Adverse event ‐ dry throat
Comparison 1: Dornase alfa versus placebo, Outcome 33: Adverse event ‐ pharyngitis
Comparison 1: Dornase alfa versus placebo, Outcome 34: Adverse event ‐ laryngitis
Comparison 1: Dornase alfa versus placebo, Outcome 35: Adverse event ‐ conjunctivitis
Comparison 1: Dornase alfa versus placebo, Outcome 36: Adverse event ‐ wheeze
Comparison 1: Dornase alfa versus placebo, Outcome 37: Adverse event ‐ facial oedema
Comparison 2: Dornase alfa once daily versus dornase alfa on alternate days, Outcome 1: Mean % change in FEV1
Comparison 2: Dornase alfa once daily versus dornase alfa on alternate days, Outcome 2: Mean % change in FVC
Comparison 2: Dornase alfa once daily versus dornase alfa on alternate days, Outcome 3: Mean % change in quality of life score
Comparison 2: Dornase alfa once daily versus dornase alfa on alternate days, Outcome 4: Mean number of days inpatient treatment
Comparison 2: Dornase alfa once daily versus dornase alfa on alternate days, Outcome 5: Mean change in weight (kg) from baseline
Comparison 3: Dornase alfa daily versus hypertonic saline, Outcome 1: Mean % change in FEV1
Comparison 3: Dornase alfa daily versus hypertonic saline, Outcome 2: Mean % change in FVC
Comparison 3: Dornase alfa daily versus hypertonic saline, Outcome 3: Mean % change in quality of life score
Comparison 3: Dornase alfa daily versus hypertonic saline, Outcome 4: Mean number of days inpatient treatment
Comparison 3: Dornase alfa daily versus hypertonic saline, Outcome 5: Mean change in weight (kg) from baseline
Comparison 4: Dornase alfa versus mannitol, Outcome 1: Mean absolute change in FEV1 (L)
Comparison 4: Dornase alfa versus mannitol, Outcome 2: Mean absolute change in FVC (L)
Comparison 4: Dornase alfa versus mannitol, Outcome 3: Quality of life ‐ CFQ‐R
Comparison 4: Dornase alfa versus mannitol, Outcome 4: Number of people experiencing exacerbations
Comparison 4: Dornase alfa versus mannitol, Outcome 5: Adverse events at 3 months
Comparison 5: Dornase alfa versus dornase alfa and mannitol, Outcome 1: Mean absolute change in FEV1 (L)
Comparison 5: Dornase alfa versus dornase alfa and mannitol, Outcome 2: Mean absolute change in FVC (L)
Comparison 5: Dornase alfa versus dornase alfa and mannitol, Outcome 3: Quality of life ‐ CFQ‐R
Comparison 5: Dornase alfa versus dornase alfa and mannitol, Outcome 4: Number of people experiencing exacerbations
Comparison 5: Dornase alfa versus dornase alfa and mannitol, Outcome 5: Adverse events at 3 months
| Dornase alfa compared with placebo or no dornase alfa treatment for cystic fibrosis | ||||||
| Patient or population: Adults and children with cystic fibrosis Settings: Outpatients Intervention: Dornase alfa Comparison: Placebo or no treatment | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo or no dornase alfa treatment | Dornase alfa | |||||
| Relative mean percentage change in FEV1 (% predicted) at 3 months | The relative mean percentage change in FEV1 (% predicted) was 2.10 | The relative mean percentage change in FEV1 (% predicted) was 7.30 higher (4.04 higher to 10.56 higher) | NA | 320 (1 study)1 | ⊕⊕⊕⊝ | |
| Relative mean percentage change in FEV1 (% predicted) at 6 months | The relative mean percentage change in FEV1 (% predicted) was 0.00 | The relative mean percentage change in FEV1 (% predicted) was 5.80 higher (3.99 higher to 7.61 higher) | NA | 647 (1 study)1 | ⊕⊕⊕⊕ | Result presented from once‐daily dornase alfa group. Significant benefit for dornase alfa also present in twice‐daily dornase alfa group |
| Relative mean percentage change in FVC (% predicted) at 3 months | The relative mean percentage change in FVC (% predicted) was 7.30 | The relative mean percentage change in FVC (% predicted) was 5.10 higher (1.23 higher to 8.97 higher) | NA | 318 (1 study)4 | ⊕⊕⊕⊝ | |
| Relative mean percentage change in FVC (% predicted) at 6 months | See comment | See comment | MD 3.80 (2.62 to 4.98) | 647 (1 study)1 | ⊕⊕⊕⊕ | Mean difference between groups only presented. Result presented from once‐daily dornase alfa group. Significant benefit for dornase alfa also present in twice‐daily dornase alfa group |
| Change in quality of life ‐ CFQ‐R respiratory at 1 month | See comment | See comment | MD 0.84 (‐10.74 to 12.42) | 19 (1 cross‐over study)5 | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa daily. Participants received both interventions in cross‐over design. |
| Change in quality of life ‐ CFQ‐R respiratory (parent) at 1 month | See comment | See comment | MD 9.78 (‐2.58 to 22.14) | 19 (1 cross‐over study)5 | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa daily. Participants received both interventions in cross‐over design. |
| Number of people experiencing exacerbations at up to 2 years | 252 per 1000 | 196 per 1000 | RR 0.78 (0.62 to 0.96) | 1157 (3 studies)8 | ⊕⊕⊕⊝ | RR <1 indicates an advantage for dornase alfa. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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). Assumed and corresponding risk not calculated for quality of life. Relative effect and 95% CI presented is adjusted for the cross‐over design of the study | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. Additionally four trials included in analysis at one month showed a significant advantage to dornase alfa over placebo or no dornase alfa treatment (Laube 1996; Ramsey 1993; Ranasinha 1993; Shah 1995a). Three studies not included in pooled analysis showed no difference between groups in relative FEV1(L) (Robinson 2000) and relative FEV1 (% predicted) (Wilmott 1996) or absolute FEV1 (% predicted) (Amin 2011) at one month. At one year, one study showed a significant advantage to dornase alfa over placebo or no dornase alfa treatment (Frederiksen 2006) and one study showed no difference between treatments (Robinson 2005). At one year, one study showed a significant advantage to dornase alfa over placebo or no dornase alfa treatment (Quan 2001) and at three years, one study showed no significant difference between treatments (Paul 2004). 2. Downgraded due to indirectness: participants in McCoy 1996 had severe lung disease (FVC below 40%). 3. No evidence of imprecision, inconsistency, indirectness, publication bias or serious risk of bias. 4. Additionally four trials included in analysis at one month (Laube 1996; Ramsey 1993; Ranasinha 1993; Shah 1995a) showed a significant advantage to dornase alfa over placebo or no dornase alfa treatment. One study not included in pooled analysis showed a significant advantage in relative FVC (L) to dornase alfa over placebo or no dornase alfa treatment (Robinson 2000) and one study showed no significant different in absolute FVC (% predicted) between groups (Amin 2011) at one month. No significant difference was found between groups at one year (Robinson 2005) and at two years (Quan 2001). 5. Additionally, four studies reported quality of life data which could not be included in pooled analysis. Wilmott 1996 showed no difference between groups in CFQ‐R. Ramsey reported that the frequency and magnitude of improvement across all quality of life questions was greater among participants receiving dornase alfa (Ramsey 1993). Ranasinha reported significant improvements in overall well‐being and significant improvements in general well‐being, cough frequency and chest congestion (Ranasinha 1993) and Fuchs reported significant improvements in well‐being score and dyspnoea score on dornase alfa compared to placebo (Fuchs 1994). 6. Downgraded once for lack of applicability: Amin included children only so results are not applicable to adults (Amin 2011). 7. Downgraded once for imprecision: wide confidence intervals around the effect size due to limited sample size of the trial. 8. Additionally, one study reported an age‐adjusted RR of having more than one respiratory exacerbation, but these data were not included in the pooled analysis (McCoy 1996). No significant difference was found between dornase alfa and control. 9. Downgraded once as data from one cross‐over trial was analysed as parallel data (Amin 2011), which is a conservative approach. | ||||||
| Dornase alfa daily compared with dornase alfa on alternate days for cystic fibrosis | ||||||
| Patient or population: Children with cystic fibrosis Settings: Outpatients Intervention: Dornase alfa daily Comparison: Dornase alfa alternate days | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Dornase alfa alternate days | Dornase alfa daily | |||||
| Mean relative percentage change in FEV1 (L) at 3 months | See comment | See comment | MD 2.00 (‐5.00 to 9.00) | 43 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa daily. Participants received both interventions in cross‐over design. |
| Mean relative percentage in FVC (L) at 3 months | See comment | See comment | MD 0.03 (‐0.06 to 0.12) | 43 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa daily. Participants received both interventions in cross‐over design. |
| Mean relative percentage in quality of life score at 3 months | See comment | See comment | MD 0.01 (‐0.02 to 0.04) | 43 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa daily. Participants received both interventions in cross‐over design. |
| Number of pulmonary exacerbations at 3 months | 17 exacerbations | 18 exacerbations | NA (see comment) | 43 (1 cross‐over study) | ⊕⊕⊝⊝ | No difference was found in the number of pulmonary exacerbations (no statistical comparison made) |
| *Assumed and corresponding risk not calculated lung function and quality of life. Relative effect and 95% CI presented is adjusted for the cross‐over design of the study. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. Downgraded once for lack of applicability: Suri included children only so results are not applicable to adults (Suri 2001). 2. Downgraded once for high risk of bias due to lack of blinding. | ||||||
| Dornase alfa compared with hypertonic saline for cystic fibrosis | ||||||
| Patient or population: Children with cystic fibrosis Settings: Outpatients Intervention: Dornase alfa (once daily) Comparison: Hypertonic saline | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Hypertonic Saline | Dornase alfa | |||||
| Mean relative percentage in FEV1 (L) at 3 months | See comment | See comment | MD 8.00 (2.00 to 14.00) | up to 431,2 (1 cross‐over study) (see comment) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Mean relative percentage in FVC (L) at 3 months | See comment | See comment | MD 0.08, (‐0.02 to 0.18) | up to 431,2 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Mean relative percentage in quality of life score at 3 months | See comment | See comment | MD 0.03, (‐0.01 to 0.07) | up to 431,2 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Number of pulmonary exacerbations at 3 months | 15 exacerbations | 17 exacerbations | NA (see comment) | up to 431,2 (1 cross‐over study) | ⊕⊕⊝⊝ | No difference was found in the number of pulmonary exacerbations (no statistical comparison made) |
| *Assumed and corresponding risk not calculated lung function and quality of life. Relative effect and 95% CI presented is adjusted for the cross‐over design of the study. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. In the cross‐over trial, 43 participants completed the dornase alfa arm and 40 completed the hypertonic saline arm (Suri 2001). 2. Two additional cross‐over trials compared dornase alfa and hypertonic saline, no significant differences were found between the treatments for % change in FEV1 and other primary outcomes of the review were not recorded in these trials (Adde 2004; Ballmann 2002). 3. Downgraded once for lack of applicability: Suri included children only so results are not applicable to adults (Suri 2001). 4. Downgraded once for high risk of bias due to lack of blinding. | ||||||
| Dornase alfa compared with mannitol for cystic fibrosis | ||||||
| Patient or population: Children with cystic fibrosis Settings: Outpatients Intervention: Dornase alfa Comparison: Mannitol | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Mannitol | Dornase Alfa | |||||
| Mean absolute change in FEV1 (L) at 3 months | See comment | See comment | MD 0.02 (‐0.11 to 0.16) | up to 231 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Mean absolute change in FVC (L) at 3 months | See comment | See comment | MD ‐0.02, (‐0.23 to 0.19) | up to 231 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Change in quality of life ‐ CFQ‐R at 3 months | See comment | See comment | MD 10.61 (0.27 to 20.95) | up to 231 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Number of people experiencing exacerbations ‐ at 3 months | 130 per 1000 | 143 per 1000 | RR 1.10 (0.25 to 4.84) | up to 231 (1 cross‐over study) | ⊕⊕⊝⊝ | RR <1 indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| *Assumed and corresponding risk not calculated for lung function and quality of life. Relative effect and 95% CI presented is adjusted for the cross‐over design of the study. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. In the cross‐over trial, 21 participants completed the dornase alfa arm and 23 participants completed the mannitol arm (Minasian 2010). 2. Downgraded once for lack of applicability: Minasian included children only so results are not applicable to adults (Minasian 2010). 3. Downgraded once for high risk of bias due to lack of blinding. | ||||||
| Dornase alfa compared with dornase alfa and mannitol for cystic fibrosis | ||||||
| Patient or population: Children with cystic fibrosis Settings: Outpatients Intervention: Dornase alfa Comparison: Dornase alfa and Mannitol | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Dornase alfa and mannitol | Dornase alfa | |||||
| Mean absolute change in FEV1 (L) at 3 months | See comment | See comment | MD 0.10 (‐0.06 to 0.25) | up to 231 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Mean absolute change in FVC (L) at 3 months | See comment | See comment | MD 0.13 (‐0.11 to 0.37) | up to 231 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Change in quality of life ‐ CFQ‐R at 3 months | See comment | See comment | MD 10.61 (0.27 to 20.95) | up to 231 (1 cross‐over study) | ⊕⊕⊝⊝ | Positive MD indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| Number of people experiencing exacerbations at 3 months | 261 per 1000 | 143 per 1000 | RR 0.55 (0.16 to 1.92) | up to 231 (1 cross‐over study) | ⊕⊕⊝⊝ | RR <1 indicates an advantage for dornase alfa. Participants received both interventions in cross‐over design. |
| *Assumed and corresponding risk not calculated lung function and quality of life. Relative effect and 95% CI presented is adjusted for the cross‐over design of the study. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. In the crossover trial, 21 participants completed the dornase alfa arm and 23 participants completed the dornase alfa plus mannitol arm (Minasian 2010). 2. Downgraded once for lack of applicability: Minasian included children only so results are not applicable to adults (Minasian 2010). 3. Downgraded once for high risk of bias due to lack of blinding. | ||||||
| Study | Comparison group | Duration of treatment | Frequency of dornase treatment | Study design |
|---|---|---|---|---|
| Placebo | 4 weeks | once daily | cross‐over | |
| Placebo | 6 months | once daily | cross‐over | |
| Placebo | 2 weeks | once daily | cross‐over | |
| No treatment | 1 year | once daily | parallel | |
| Placebo and twice‐daily dornase | 6 months | once or twice daily | parallel | |
| Placebo | 6 days | twice a day | parallel | |
| Placebo | 3 months | once daily | parallel | |
| No treatment | 3 years | twice a day | parallel | |
| Placebo | 2 years | once a day | parallel | |
| Placebo | 10 days | twice a day (0.6 mg, 2.5 mg or 10 mg) | parallel | |
| Placebo | 10 days | twice a day | parallel | |
| Placebo | 7 days | once a day | cross‐over | |
| Placebo | 1 year | once a day | parallel | |
| Placebo | 2 weeks | twice a day | parallel | |
| Placebo | 15 days | twice a day | parallel | |
| Hypertonic saline and alternate day dornase | 3 months | once a day, alternate day | cross‐over | |
| Hypertonic saline | 4 weeks | once daily | cross‐over | |
| Hypertonic saline | 3 weeks | once daily | cross‐over | |
| Mannitol and mannitol plus dornase | 3 months | once daily | cross‐over | |
| *Trial done during acute exacerbation | ||||
| Pre dornase alfa | Post dornase alfa | Pre placebo | Post placebo | |
|---|---|---|---|---|
| FEV1 (L) mean (SD) | 2.63 (0.31) | 2.8 (0.32) | 2.63 (0.32) | 2.70 (0.32) |
| FVC (L) mean (SD) | 4.03 (0.35) | 4.21 (0.35) | 4.12 (0.36) | 4.06 (0.38) |
| FEV1: forced expiratory volume at one second | ||||
| Pre‐hypertonic saline | Post hypertonic saline | Pre dornase alfa | Post dornase alfa | P value | |
|---|---|---|---|---|---|
| FEV1 (% predicted) mean (SD) | 47 (18) | 46 (18) | 49 (15) | 50 (21) | NS |
| FEV1: forced expiratory volume at one second | |||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Relative mean % change in FEV1 (% predicted) Show forest plot | 7 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.1.1 At 1 month | 4 | 248 | Mean Difference (IV, Random, 95% CI) | 9.51 [0.67, 18.35] |
| 1.1.2 At 3 months | 1 | 320 | Mean Difference (IV, Random, 95% CI) | 7.30 [4.04, 10.56] |
| 1.1.3 At 6 months | 1 | 647 | Mean Difference (IV, Random, 95% CI) | 5.80 [3.99, 7.61] |
| 1.1.4 At 12 months | 1 | 19 | Mean Difference (IV, Random, 95% CI) | 0.70 [‐11.26, 12.66] |
| 1.2 Relative mean % change in FEV1 (% predicted) at one month ‐ subgroup analysis by disease severity Show forest plot | 4 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.2.1 Moderate | 3 | 183 | Mean Difference (IV, Fixed, 95% CI) | 14.26 [10.79, 17.74] |
| 1.2.2 Severe | 1 | 65 | Mean Difference (IV, Fixed, 95% CI) | ‐2.81 [‐8.77, 3.15] |
| 1.3 Absolute mean % change in FEV1 (% predicted) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.3.1 At 1 month | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.08 [‐5.59, 5.74] | |
| 1.4 Absolute mean % change in FEV1 (% predicted) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.4.1 At 2 years | 1 | 410 | Mean Difference (IV, Fixed, 95% CI) | 3.24 [1.03, 5.45] |
| 1.5 Relative mean % change in FEV1 (in participants with acute exacerbations) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.5.1 Up to 1 month | 1 | 80 | Mean Difference (IV, Fixed, 95% CI) | 1.00 [‐13.93, 15.93] |
| 1.6 Relative mean % change in FVC (% predicted) Show forest plot | 6 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.6.1 At 1 month | 4 | 248 | Mean Difference (IV, Random, 95% CI) | 7.52 [1.34, 13.69] |
| 1.6.2 At 3 months | 1 | 318 | Mean Difference (IV, Random, 95% CI) | 5.10 [1.23, 8.97] |
| 1.6.3 At 12 months | 1 | 19 | Mean Difference (IV, Random, 95% CI) | ‐5.70 [‐15.87, 4.47] |
| 1.7 Relative mean % change in FVC (% predicted) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.7.1 At 6 months (once daily) | 1 | 2 | Mean Difference (IV, Random, 95% CI) | 3.80 [2.62, 4.98] |
| 1.7.2 At 6 months (twice daily) | 1 | 2 | Mean Difference (IV, Random, 95% CI) | 3.00 [1.82, 4.18] |
| 1.8 Relative mean % change in FVC at one month ‐ subgroup analysis by disease severity Show forest plot | 4 | 248 | Mean Difference (IV, Fixed, 95% CI) | 9.49 [6.34, 12.63] |
| 1.8.1 Moderate | 3 | 183 | Mean Difference (IV, Fixed, 95% CI) | 10.98 [7.68, 14.29] |
| 1.8.2 Severe | 1 | 65 | Mean Difference (IV, Fixed, 95% CI) | ‐4.90 [‐15.15, 5.35] |
| 1.9 Absolute mean % change in FVC (% predicted) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.9.1 At 1 month | 1 | Mean Difference (IV, Fixed, 95% CI) | ‐3.61 [‐10.02, 2.80] | |
| 1.10 Absolute mean % change in FVC (% predicted) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.10.1 At 2 years | 1 | 410 | Mean Difference (IV, Random, 95% CI) | 0.70 [‐1.24, 2.64] |
| 1.11 Absolute mean change in LCI Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.11.1 At 1 month | 1 | 34 | Mean Difference (IV, Fixed, 95% CI) | ‐0.90 [‐1.87, 0.07] |
| 1.12 Absolute change in FEV0.5 (z score) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.12.1 At 6 months | 1 | 24 | Mean Difference (IV, Fixed, 95% CI) | 0.10 [‐0.74, 0.94] |
| 1.13 Quality of life ‐ CFQ‐R respiratory Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.13.1 At 1 month | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.84 [‐10.74, 12.42] | |
| 1.14 Quality of life ‐ CFQ‐R Parent respiratory Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.14.1 At 1 month | 1 | Mean Difference (IV, Fixed, 95% CI) | 9.78 [‐2.58, 22.14] | |
| 1.15 Number of people experiencing exacerbations Show forest plot | 3 | 1151 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.62, 0.96] |
| 1.16 Number of deaths Show forest plot | 7 | 1690 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.70 [0.70, 4.14] |
| 1.16.1 At 1 month | 4 | 253 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.00 [0.25, 100.53] |
| 1.16.2 At 3 months | 1 | 320 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.54 [0.56, 4.22] |
| 1.16.3 At 6 months | 1 | 647 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.06, 16.07] |
| 1.16.4 At 2 years | 1 | 470 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 1.17 Mean number of days of antibiotics (inhaled, oral or IV) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.17.1 At six months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.18 Mean number of days IV antibiotics used Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.18.1 At 3 months | 1 | 320 | Mean Difference (IV, Fixed, 95% CI) | ‐2.96 [‐7.29, 1.37] |
| 1.19 Mean number of days inpatient treatment Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.19.1 At 3 months | 1 | 320 | Mean Difference (IV, Fixed, 95% CI) | 0.93 [‐2.19, 4.05] |
| 1.20 Mean change in weight from baseline Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.20.1 At 2 years | 1 | 470 | Mean Difference (IV, Fixed, 95% CI) | ‐0.20 [‐2.42, 2.02] |
| 1.21 Adverse event ‐ haemoptysis (blood‐stained sputum) Show forest plot | 3 | 788 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.50, 1.55] |
| 1.22 Adverse event ‐ dyspnoea (shortness of breath) Show forest plot | 4 | 1108 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.85, 1.18] |
| 1.23 Adverse event ‐ pneumothorax Show forest plot | 3 | 788 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.08, 4.50] |
| 1.24 Adverse event ‐ pneumothorax (in participants with acute exacerbations) Show forest plot | 1 | 80 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.59 [0.11, 61.75] |
| 1.25 Adverse event ‐ voice alteration Show forest plot | 6 | 1670 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.69 [1.20, 2.39] |
| 1.26 Adverse event ‐ voice alteration (1x versus 2x daily treatment) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.27 Adverse event ‐ voice alteration (in participants with acute exacerbations) Show forest plot | 1 | 80 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.58 [0.55, 12.03] |
| 1.28 Adverse event ‐ rash Show forest plot | 2 | 1117 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.40 [1.16, 4.99] |
| 1.29 Adverse event ‐ chest pain Show forest plot | 3 | 1151 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.59, 1.70] |
| 1.30 Adverse event ‐ cough (new or increased) Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.31 Adverse event ‐ increased sputum production Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.32 Adverse event ‐ dry throat Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.33 Adverse event ‐ pharyngitis Show forest plot | 6 | 1612 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.15 [0.91, 1.46] |
| 1.34 Adverse event ‐ laryngitis Show forest plot | 3 | 1187 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.58 [0.68, 3.68] |
| 1.35 Adverse event ‐ conjunctivitis Show forest plot | 2 | 1117 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.25 [0.50, 3.13] |
| 1.36 Adverse event ‐ wheeze Show forest plot | 4 | 199 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.24, 2.73] |
| 1.37 Adverse event ‐ facial oedema Show forest plot | 1 | 92 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.62 [0.40, 143.52] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Mean % change in FEV1 Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.1.1 At 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 2.00 [‐5.00, 9.00] | |
| 2.2 Mean % change in FVC Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.2.1 At 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.03 [‐0.06, 0.12] | |
| 2.3 Mean % change in quality of life score Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.3.1 At 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.01 [‐0.02, 0.04] | |
| 2.4 Mean number of days inpatient treatment Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.4.1 At 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | ‐0.93 [‐3.24, 1.38] | |
| 2.5 Mean change in weight (kg) from baseline Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.5.1 At 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | ‐0.09 [‐0.73, 0.55] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Mean % change in FEV1 Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.1.1 At 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 8.00 [2.00, 14.00] | |
| 3.2 Mean % change in FVC Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.2.1 At 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.08 [‐0.02, 0.18] | |
| 3.3 Mean % change in quality of life score Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.3.1 At 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.03 [‐0.01, 0.07] | |
| 3.4 Mean number of days inpatient treatment Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.4.1 At 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | ‐0.40 [‐2.32, 1.52] | |
| 3.5 Mean change in weight (kg) from baseline Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.5.1 At 3 months | 1 | Mean Difference (IV, Fixed, 95% CI) | ‐0.42 [‐1.04, 0.20] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 Mean absolute change in FEV1 (L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 4.1.1 At 3 months | 1 | 44 | Mean Difference (IV, Fixed, 95% CI) | 0.02 [‐0.11, 0.16] |
| 4.2 Mean absolute change in FVC (L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 4.2.1 At 3 months | 1 | 44 | Mean Difference (IV, Fixed, 95% CI) | ‐0.02 [‐0.23, 0.19] |
| 4.3 Quality of life ‐ CFQ‐R Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 4.3.1 At 3 months | 1 | 56 | Mean Difference (IV, Fixed, 95% CI) | 4.10 [‐6.40, 14.60] |
| 4.4 Number of people experiencing exacerbations Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.4.1 At 3 months | 1 | 44 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.25, 4.84] |
| 4.5 Adverse events at 3 months Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.5.1 Cough | 1 | 44 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.08 [0.01, 1.40] |
| 4.5.2 Ear infection | 1 | 44 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.02, 8.47] |
| 4.5.3 Musculoskeletal pain | 1 | 44 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.02, 8.47] |
| 4.5.4 Pharyngitis | 1 | 44 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.02, 8.47] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 5.1 Mean absolute change in FEV1 (L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 5.1.1 At 3 months | 1 | 44 | Mean Difference (IV, Fixed, 95% CI) | 0.10 [‐0.06, 0.25] |
| 5.2 Mean absolute change in FVC (L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 5.2.1 At 3 months | 1 | 44 | Mean Difference (IV, Fixed, 95% CI) | 0.13 [‐0.11, 0.37] |
| 5.3 Quality of life ‐ CFQ‐R Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 5.3.1 At 3 months | 1 | 53 | Mean Difference (IV, Fixed, 95% CI) | 10.61 [0.27, 20.95] |
| 5.4 Number of people experiencing exacerbations Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.5 Adverse events at 3 months Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.5.1 Cough | 1 | 44 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.22 [0.01, 4.30] |
| 5.5.2 Headache | 1 | 44 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.02, 8.47] |
| 5.5.3 Nausea | 1 | 44 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.02, 8.47] |
| 5.5.4 Rash | 1 | 44 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.02, 8.47] |
