Momento de la inhalación de la dornasa alfa para la fibrosis quística
Resumen
Antecedentes
La inhalación de la enzima dornasa alfa reduce la viscosidad del esputo y mejora los desenlaces clínicos de las personas con fibrosis quística. Esta es una actualización de una revisión Cochrane publicada anteriormente.
Objetivos
Determinar si el momento de inhalación de la dornasa alfa (relacionado con las técnicas de depuración de las vías respiratorias o la inhalación matutina versus la inhalación nocturna) tiene repercusión sobre medidas objetivas y subjetivas de eficacia clínica en las personas con fibrosis quística.
Métodos de búsqueda
Se identificaron ensayos controlados aleatorizados y cuasialeatorizados pertinentes en el Registro de Ensayos del Grupo Cochrane de Fibrosis quística (Cochrane Cystic Fibrosis), Physiotherapy Evidence Database (PEDro), registros de ensayos clínicos y actas de conferencias internacionales sobre fibrosis quística.
Fecha de la búsqueda más reciente: 12 de octubre de 2020.
Criterios de selección
Cualquier ensayo de dornasa alfa en personas con fibrosis quística en el que el momento de la inhalación fuera el elemento aleatorizado en el ensayo con: inhalación antes en comparación con después de las técnicas de depuración de las vías respiratorias; o la inhalación matutina en comparación con la nocturna.
Obtención y análisis de los datos
Ambos autores, de forma independiente, seleccionaron los ensayos, evaluaron el riesgo de sesgo y extrajeron los datos, resolviendo los desacuerdos mediante discusión. Se extrajeron los datos relevantes y de ser posible se realizó un metanálisis. La calidad de la evidencia se evaluó con GRADE.
Resultados principales
Se identificaron 115 artículos de ensayos que representaron 55 ensayos, de los cuales cinco estudios (que proporcionaron datos de 122 participantes) cumplieron los criterios de inclusión. Los cinco ensayos utilizaron un diseño cruzado. Los períodos de intervención variaron entre dos y ocho semanas. Cuatro ensayos (98 participantes) compararon la inhalación de la dornasa alfa antes versus después de aplicar las técnicas de depuración de las vías respiratorias. La inhalación después en vez de antes de la depuración de las vías respiratorias no cambió significativamente el volumen espiratorio forzado en un segundo (evidencia de calidad muy baja). De manera similar, la capacidad vital forzada (evidencia de calidad baja) y la calidad de vida (evidencia de calidad muy baja) no se vieron afectadas de manera significativa; el flujo espiratorio forzado del 25% fue significativamente peor con la inhalación de dornasa alfa después de la depuración de las vías respiratorias, diferencia de medias ‐0,17 litros (intervalo de confianza del 95%: ‐0,28 a ‐0,05), sobre la base de los datos agrupados de dos ensayos pequeños en niños (7 a 19 años) con una función pulmonar bien conservada. Los otros desenlaces secundarios no fueron estadísticamente significativos.
En un ensayo (25 participantes), la inhalación matutina versus la nocturna no tuvo impacto en la función pulmonar ni en los síntomas (evidencia de calidad baja).
Conclusiones de los autores
La evidencia actual derivada de un escaso número de participantes no indica que la inhalación de la dornasa alfa después de las técnicas de depuración de las vías respiratorias sea más o menos eficaz que la recomendación tradicional de inhalar la dornasa alfa nebulizada 30 minutos antes de las técnicas de depuración de las vías respiratorias, en la mayoría de los desenlaces. En los niños con una función pulmonar bien preservada, la inhalación antes de la depuración de las vías respiratorias puede ser más beneficiosa para la función de las vías respiratorias pequeñas que la inhalación posterior. Sin embargo, este resultado dependió de una medida con gran variabilidad y de ensayos con un seguimiento variable. A falta de evidencia sólida que indique que un régimen temporal es mejor que otro, el momento de inhalación de la dornasa alfa se puede basar en gran medida en razones pragmáticas o en la preferencia individual con respecto al momento de depuración de las vías respiratorias y el momento del día. La realización de estudios de investigación adicionales está justificada.
PICO
Resumen en términos sencillos
Momento de la inhalación de la dornasa alfa en personas con fibrosis quística
Pregunta de la revisión
Determinar el efecto del momento de inhalación de la dornasa alfa sobre las medidas de efectividad clínica en personas con fibrosis quística (relacionado con las técnicas de depuración de las vías respiratorias y el momento del día). Esta es una actualización de una revisión Cochrane publicada anteriormente.
Antecedentes
La inhalación de la enzima dornasa alfa reduce la viscosidad del esputo y mejora los desenlaces clínicos en las personas con fibrosis quística. No hay seguridad con respecto a si es mejor inhalar la dornasa alfa antes o después de la depuración de las vías respiratorias con técnicas físicas. Tampoco está claro si es mejor la inhalación matutina o la inhalación nocturna.
Fecha de la búsqueda
La evidencia está actualizada hasta el 12 de octubre de 2020.
Características de los estudios
Se incluyeron cinco ensayos con un total de 122 participantes. En estos ensayos la duración del tratamiento varió de dos a ocho semanas.
Resultados clave
Cuatro de los ensayos compararon la inhalación antes versus después de la depuración de las vías respiratorias y en general no encontraron diferencias en los desenlaces clínicos. Sin embargo, en los niños con función pulmonar bien preservada, la inhalación de la dornasa alfa antes de la depuración de las vías respiratorias fue mejor para la función de las vías respiratorias pequeñas. No obstante, lo anterior no afectó la calidad de vida ni otros resultados. En el ensayo restante, al comparar la inhalación matutina versus la inhalación nocturna no hubo repercusión sobre la función pulmonar ni los síntomas. Por lo tanto, en muchas personas con fibrosis quística el momento de inhalación de la dornasa alfa (antes o después de la depuración de las vías respiratorias o en un momento del día) se puede basar en motivos prácticos o en la preferencia individual.
Calidad de la evidencia
Aparte de un ensayo publicado sólo en forma de resumen, la calidad de la evidencia varió de baja a muy baja. Ello se debió a cuestiones relacionadas con la asignación a los grupos, el cegamiento, el informe incompleto de los datos de desenlaces y el limitado rango de edad de los participantes.
Authors' conclusions
Summary of findings
| DNase inhalation before versus after ACTs for cystic fibrosis | ||||||
| Patient or population: adults and children with cystic fibrosis Settings: outpatients Intervention: DNase inhalation before ACT Comparison: DNase inhalation after ACT | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Inhalation after airway clearance | Inhalation before airway clearance | |||||
| FEV1 (% predicted) change from baseline Follow‐up: up to 4 weeks | See comments. | MD 0.83% (95% CI ‐2.96% to 1.31%) | 102 (4 cross‐over trials) | ⊕⊖⊖⊖ very low1,2,3 | Positive MD indicates an advantage for DNase inhalation before ACT, but difference is not statistically significant. FEV1 (L) also showed no significant difference between groups. Participants received both ACTs as cross‐over design. | |
| FVC (% predicted) change from baseline Follow‐up: up to 4 weeks | See comments. | MD 1.06% (95% CI ‐1.29% to 3.41%) | 77 (2 cross‐over trials) | ⊕⊕⊖⊖ low3,4 | Positive MD indicates an advantage for DNase inhalation before ACT, but difference is not statistically significant. FVC (L) also showed no significant difference between groups. Participants received both ACTs as cross‐over design. | |
| Measures of QoL and symptom scores Follow‐up: up to 4 weeks | See comments. | NA | 102 (4 cross‐over trials) | ⊕⊖⊖⊖ very low1,2,3, | 4 trials reported a variety of QoL scores (CFQ and QWB) and symptom scores covering well‐being, sputum (volume, viscosity and ease of clearance), and cough (daytime and nighttime). No outcome showed a difference due to timing of DNase inhalation in relation to ACTs. | |
| FEF25-75 (% predicted) Follow‐up: up to 4 weeks | See comments. | MD ‐6.71% (95% CI ‐14.66% to 1.24%) | 25 (1 cross‐over trial) | ⊕⊕⊖⊖ low3,4 | Negative MD indicates an advantage for DNase inhalation after ACT, but difference is not statistically significant. Participants received both ACTs as cross‐over design. | |
| Adverse effects Follow‐up: up to 4 weeks | See comments. | NA (see comment) | 102 (4 cross‐over trials) | ⊕⊖⊖⊖ very low1,2,3 | No statistical comparisons were made. Narrative reports included a single episode of haemoptysis after 2 weeks of DNase inhalation which resolved spontaneously with continued treatment. A further trial reported 34 adverse events (27 of these were for pulmonary exacerbations, 4 for musculoskeletal injuries and 3 gastrointestinal events) in 26 out of 52 participants, but we do not know which treatment group these occurred in. 2 trials monitored nighttime cough frequency but the timing of the interventions had no impact on nocturnal cough. | |
| Relative effect and 95% CI presented is adjusted for the cross‐over design of the trials. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. Downgraded once for high risk of bias due to lack of allocation concealment. 2. Downgraded once for high risk of bias due to lack of blinding. 3. Downgraded once for high risk of bias due to incomplete outcome data. 4. Downgraded once for lack of applicability as trials included only children so results are not applicable to adults. | ||||||
| Morning versus evening inhalation of DNase for cystic fibrosis | ||||||
| Patient or population: adults and children with cystic fibrosis Settings: outpatients Intervention: morning DNase inhalation Comparison: evening DNase inhalation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Evening inhalation | Morning inhalation | |||||
| FEV1 (% predicted) change from baseline Follow‐up: up to 4 weeks | See comments. | MD ‐1.30% (95% CI ‐4.18% to 1.58%) | 25 (1 cross‐over trial) | ⊕⊕⊖⊖ low1,2 | Negative MD indicates an advantage for evening DNase inhalation, but difference is not statistically significant. FEV1 (L) also showed no significant difference between groups. Participants received both morning and evening DNase inhalation as cross‐over design. | |
| FVC (% predicted) change from baseline Follow‐up: up to 4 weeks | See comments. | MD ‐0.10% (95% CI ‐5.98% to 5.78%) | 25 (1 cross‐over trial) | ⊕⊕⊖⊖ low1,2 | Negative MD indicates an advantage for evening DNase inhalation, but difference is not statistically significant FVC (L) also showed no significant difference between groups. Participants received both morning and evening DNase inhalation as cross‐over design. | |
| Measures of QoL and symptom scores Follow‐up: up to 4 weeks | See comments. | NA | 25 (1 cross‐over trial) | ⊕⊕⊖⊖ low1,2 | A variety of VAS scores reported on cough (day and night), sputum (volume and viscosity), appetite and sleep quality; none of which were significantly different as a result of the time of day the DNase was inhaled. | |
| FEF25-75 (% predicted) Follow‐up: up to 4 weeks | Outcome not reported. | NA | NA | NA | ||
| Adverse effects Follow‐up: up to 4 weeks | See comments. | NA (see comment) | 25 (1 cross‐over trial) | ⊕⊕⊖⊖ low1,2 | No statistical comparisons made. Narrative reports indicated that evening DNase inhalation did not adversely impact overnight oximetry or cough per hour recordings (but between‐group comparisons were not provided for this outcome). | |
| Relative effect and 95% CI presented is adjusted for the cross‐over design of the trials. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. Downgraded once for lack of applicability as the trial only included children so results are not applicable to adults. 2. Downgraded once due to incomplete outcome data. | ||||||
Background
Description of the condition
Cystic fibrosis (CF) is the most common life‐limiting autosomal recessive disorder amongst Caucasians (Cutting 2002). CF‐related pulmonary disease is the major cause of morbidity and mortality (Buzzetti 2009).
Description of the intervention
The enzyme recombinant human deoxyribonuclease (dornase alfa), has been shown to reduce the viscosity of sputum taken from people with CF by digesting the deoxyribonucleic acid (DNA) released from neutrophils (Lieberman 1968). The proprietary name of dornase alfa is Pulmozyme® (produced by Genentech Inc.). Therapy with dornase alfa over a one‐, six‐ or 12‐month period is associated with an improvement in lung function in CF (Yang 2018).
A single daily dose of 2.5 mg of dornase alfa is not less effective than higher dosing regimens (Fuchs 1994; Ramsey 1993).
How the intervention might work
Traditionally, people with CF have been advised to nebulise dornase alfa 30 minutes prior to airway clearance techniques. This recommendation is based on evidence that Pulmozyme® makes CF sputum pourable within 30 minutes (Shak 1990). Alternatively, it is also hypothesised that dornase alfa deposition to peripheral airways may be improved after airway clearance techniques have cleared the larger central airways.
Theoretical arguments can also be put forward to support morning inhalation of dornase alfa. Given that spontaneous mucociliary clearance is faster during waking hours than sleep (Bateman 1978), morning inhalation of dornase alfa may capitalise on faster daytime mucociliary clearance and on the clearance effects of daytime activities such as exercise (Wolff 1977). Some people with CF find evening inhalation more convenient or report that it improves ease of expectoration the following morning. Since mucociliary clearance and coughing are suppressed overnight, evening inhalation of dornase alfa may increase its dwell time in the airways, possibly increasing its clinical efficacy. However, evening inhalation could theoretically induce cough and impair sleep quality.
Why it is important to do this review
CF is associated with a high treatment burden in terms of time and money for both people with the disease and for their care providers. Given the high costs specifically associated with dornase alfa therapy, efforts to optimise the timing of inhalation for optimal clinical efficacy are important. This is an update of a previously published Cochrane Review (Dentice 2011; Dentice 2013; Dentice 2018).
Objectives
To determine whether the timing of dornase alfa inhalation (in relation to airway clearance techniques or morning versus evening inhalation) has an impact on objective and subjective measures of clinical efficacy in people with CF.
Methods
Criteria for considering studies for this review
Types of studies
Controlled clinical trials (published and unpublished). Trials with either random allocation and quasi‐random allocation (e.g. where there is alternate allocation to groups) were included.
Types of participants
People of all ages and of both sexes with CF diagnosed by genetic testing or evidence on sweat chloride or nasal potential difference, including all degrees of disease severity.
Types of interventions
Any dornase alfa trial in people with CF where timing of inhalation was the randomised element in the trial protocol:
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inhalation up to six hours before airway clearance techniques compared to inhalation up to six hours after airway clearance techniques;
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morning compared to evening inhalation with any definition provided by the author. If not defined, we accepted midnight to midday as morning and midday to midnight as evening.
Dornase alfa treatment given as a minimum of a single dose of at least 2.5 mg.
Types of outcome measures
Primary outcomes
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Lung function (absolute change and change in per cent (%) predicted)
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forced expiratory volume at one second (FEV1)
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forced vital capacity (FVC)
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Measures of quality of life and symptom scores (including cough or subjective ease of clearance)
Secondary outcomes
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Measures of sputum clearance, including measures of mucociliary clearance and objective measures of sputum volume
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Measures of exercise capacity
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Mortality
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Other pulmonary parameters
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forced expiratory flow between 25% and 75% of the vital capacity (FEF25-75)
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maximal instantaneous forced flow when 25% of the forced vital capacity remains to be exhaled (FEF25)
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total lung capacity (TLC)
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residual volume (RV)
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functional residual capacity (FRC)
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Frequency of exacerbations of respiratory infection where a clear definition is described demonstrating an increase in symptoms or a decline in pulmonary function
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admission rates to hospital (defined as either number of inpatient hospital admissions or days as a hospital inpatient)
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courses of IV antibiotics (whether received in hospital or in the home)
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outpatient treatments (presentations to hospital, unscheduled visits to the doctor)
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Adherence to treatment along with other treatments while the protocol for inhalation timing is followed
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Adverse effects such as bronchospasm, cough and acute decline in pulmonary function
Search methods for identification of studies
We formulated a comprehensive search strategy in an attempt to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).
Electronic searches
The Cochrane Cystic Fibrosis and Genetic Disorders Group's Information Specialist conducted a systematic search of the Group's Cystic Fibrosis Trials Register for relevant trials using the following 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 CF 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 section of the Cochrane Cystic Fibrosis and Genetic Disorders Group's website.
Date of last search of the Group's Cystic Fibrosis Register: 12 October 2020.
We also searched the Physiotherapy Evidence Database (PEDro) for all years available (17 December 2020) (Appendix 1; Appendix 2; Appendix 3; Appendix 4).
In addition to the above, we carried out further searches of the following clinical trial registers (17 December 2020):
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ClinicalTrials.gov (www.ClinicalTrials.gov);
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World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) Search Portal (apps.who.int/trialsearch/) (Appendix 5).
Searching other resources
We hand‐searched the Australia and New Zealand CF Conference Proceedings (1999 to 2019).
We also contacted Roche in an attempt to identify further relevant trials. Experts in the use of dornase alfa inhalation were also contacted.
Data collection and analysis
Selection of studies
Both authors independently selected the trials to be included in the review, with disagreements resolved by discussion.
Data extraction and management
Each author independently extracted data from included trials using a standardised data extraction form. We resolved any disagreements by discussion. Where data were absent or difficult to interpret in the presented form the authors contacted the trial author in an attempt to gain the information required to evaluate trial quality or facilitate data analysis, or both.
For change‐from‐baseline data:
Where the mean difference (MD) and standard error (SE) of the MD were available, we entered these directly into the meta‐analysis. If only group means and standard deviations (SD) were available, we planned the following analysis. We planned to calculate the MD by subtraction of one group mean from the other. We planned to impute the SD of the differences from that obtained from raw data in another included trial that used the same measurement scale, and was most similar in terms of the degree of measurement error and the time period between baseline and final value measurement. We then planned to calculate the SEs using the formula: imputed SD / √n. However, we obtained MD and SE of the MD for all included trials in the current review.
For final‐value data:
Where the between‐group MD and SE of the MD were available, we entered these directly into the meta‐analysis. Where these were not available, we used the MD and the P value from the paired t‐test to calculate the SE around the MD.
We planned to report outcomes at up to one week, between one week and two months, and more than two months. However, the included trials all had intervention arms of two to eight weeks and thus outcomes were reported within a single subdivision. We plan to use the other subdivisions if trials of shorter or longer duration are included in future updates of this review.
Assessment of risk of bias in included studies
Each author independently determined the risk of bias for each trial following the domain‐based evaluation as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020). We assessed the following domains as having either a low risk, unclear risk or high risk of bias:
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randomisation;
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concealment of allocation;
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blinding (of participants, personnel and outcome assessors);
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incomplete outcome data;
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selective outcome reporting;
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other sources of bias.
We resolved any disagreements by discussion. In addition, each author independently rated each trial on the PEDro Scale (Maher 2003), using published and unpublished data from the trial authors. Note that these scores may differ slightly from those on the PEDro database as those are based on the published versions only.
Measures of treatment effect
For dichotomous data we used the risk ratio (RR) with 95% confidence intervals (95% CIs) as a measure of treatment effect with an intention‐to‐treat analysis. For continuous data we recorded the difference in mean change from baseline and SD (or SEs) for each group, or the final group means and SDs if change data were unavailable. We calculated a pooled estimate of treatment effect using the MD with 95% CIs.
Unit of analysis issues
We incorporated data from cross‐over trials into the meta‐analyses using the generic inverse variance method, involving expression of data in terms of the paired MDs between treatments and their SE. We calculated these values either from paired individual patient data provided by authors, or by calculation of MDs between interventions and their SE from means, SDs and P values reported in the manuscript (Elbourne 2002). If parallel trials are included in future versions of this review, we intend to combine data from parallel‐designed trials with those from cross‐over trials in the meta‐analyses where appropriate. Otherwise we will consider parallel‐designed and cross‐over trials separately. If necessary, we will calculate the SEs in parallel‐designed trials from the MDs between treatments and their CIs.
Dealing with missing data
Where data were absent or difficult to interpret in the presented form, the authors contacted the trial authors in an attempt to obtain the data in a form that would facilitate data analysis.
Assessment of heterogeneity
We estimated the statistical heterogeneity using the I² value (Higgins 2003). We considered heterogeneity of 0% to 40% as low, 30% to 60% as moderate, 50% to 90% as substantial and 75% to 100% as considerable.
Assessment of reporting biases
We planned to assess publication bias using a funnel plot had we been able to identify 10 trials, bearing in mind that there are other reasons for funnel plot asymmetry, so this should be interpreted with caution. Due to insufficient data we are currently unable to do this, but plan to undertake this analysis if we include sufficient trials in future updates of this review. If we suspected outcome reporting bias, we contacted the trial authors to find out if they measured and analysed an outcome and obtained the data. We contacted experts in the field to ensure unpublished trials were located.
Data synthesis
We performed meta‐analyses using a fixed‐effect model. In future versions of the review, if we observe substantial heterogeneity, as defined above, we will use a random‐effects model.
Subgroup analysis and investigation of heterogeneity
We planned a subgroup analysis excluding trials delivering dornase alfa more than 30 minutes either side of physiotherapy in a subgroup analysis, but no eligible trial warranted this action.
Sensitivity analysis
We performed sensitivity analyses by excluding trials of low quality (less than 5/10 on the PEDro Scale (de Morton 2009; Maher 2003)). We planned sensitivity analysis by excluding cross‐over trials, however, our current search did not identify any eligible parallel trials.
Summary of findings and assessment of the certainty of the evidence
In a post hoc change, we have presented two summary of findings tables, one for each comparison (summary of findings Table 1, summary of findings Table 2). We have included the following outcomes: FEV1, FVC, measures of quality of life and symptoms scores, FEF25-75, and adverse events.
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 we considered the limitation to be serious and by two levels if very serious.
Results
Description of studies
Results of the search
The electronic searches identified 125 trial reports which represented 58 trials. Of these, four trials met our inclusion criteria (Bishop 2011; Fitzgerald 2005; van der Giessen 2007a; van der Giessen 2007b). A further trial was identified in international CF conference proceedings in poster format (Anderson 2009). The five included trials provided data for 122 participants. Eighteen reports (representing nine trials) were disregarded on title alone and we excluded 48 trials, predominantly because they did not address the timing issue of dornase alfa inhalation (Excluded studies). One of these trials did not precisely match either of the two comparisons specified for this review, i.e. before versus after airway clearance techniques and morning versus evening inhalation (Wilson 2007). However, the comparison it examined (short versus long dwell time) is relevant to the broad topic of this review. Therefore, we intend to add an additional comparison to the next version of this review to allow inclusion of trials comparing long versus short dwell time. This is discussed further in the Discussion section of this review.
Included studies
We included five trials, which provided data for 122 participants; one trial has not yet been published in full but has been presented as a poster at a conference (Anderson 2009). Four trials investigated the impact of timing in relation to airway clearance physiotherapy (Anderson 2009; Fitzgerald 2005; Bishop 2011; van der Giessen 2007a). One trial investigated the issue of morning versus evening inhalation (van der Giessen 2007b).
Inhalation before versus after airway clearance techniques
Trial characteristics
Four cross‐over trials (98 participants) investigated the impact of timing in relation to airway clearance techniques. The duration of intervention blocks were two weeks (Bishop 2011; Fitzgerald 2005), three weeks (van der Giessen 2007a) and eight weeks (Anderson 2009). One trial had a two‐week washout between intervention arms (Fitzgerald 2005). The longest trial (four months duration with two eight‐week intervention arms) was small in sample size and experienced significant dropouts (three out of eight participants); limited data were provided in conference poster proceedings and additional information was provided by the author (Anderson 2009).
Participants
Clarification of participant data was requested from the authors of the four trials.
Three trials included children (Anderson 2009; Fitzgerald 2005; van der Giessen 2007a). The participants had mean ages of 10.7 years (Fitzgerald 2005), 11 years (Anderson 2009), and 12 years (van der Giessen 2007a). In these participants, FEV1 was well preserved at 83%, 81% and 88% predicted respectively. The children had a clinically stable baseline for two to four weeks leading into two trials (Fitzgerald 2005; van der Giessen 2007a) and at time of entry in one trial (Anderson 2009).
One trial included adults only; mean age 27 years, but with a broad age range (19 to 67 years) (Bishop 2011). The adult trial included participants with a broad range of lung function (FEV1 20% to 97% predicted), who were clinically stable for the two weeks leading into the trial.
Participants were on maintenance dornase alfa in two trials (Anderson 2009; van der Giessen 2007a). In the remaining two trials the participants were dornase alfa naive (Bishop 2011; Fitzgerald 2005).
Interventions
The duration of each timing intervention ranged from two to eight weeks; two trials had an intervention block of two weeks, one of three weeks and one of eight weeks.
One trial provided limited information other than the description "delivery before airway clearance techniques compared to delivery after airway clearance" (Anderson 2009).
In the three remaining trials, when dornase alfa was delivered first, it was inhaled 30 minutes before airway clearance techniques (Bishop 2011; Fitzgerald 2005; van der Giessen 2007a). Inhalation after airway clearance was immediate in two trials (Bishop 2011; van der Giessen 2007a) and 30 minutes after in one trial (Fitzgerald 2005). All three included a placebo, thus two inhalations were performed for a single session of airway clearance techniques. The clearance technique was stated as positive expiratory pressure (PEP) in the majority, but some also noted active cycle of breathing techniques, Flutter, autogenic drainage, or postural drainage and percussion.
Outcomes measured
All four trials looked at improvements in lung function (FEV1) at the conclusion of the intervention arm. Some reported data for FVC, FEF25-75 and FEF25. A variety of quality of life and symptom scores were reported. All trials reported the incidence of any adverse events. All trials except one reported adherence (Anderson 2009). Data were supplied by the investigators of all trials to supplement the information that was available in their abstract and poster (Anderson 2009; Bishop 2011; Fitzgerald 2005; van der Giessen 2007a).
Morning versus evening inhalation
Trial characteristics
One randomised, blinded, cross‐over, placebo‐controlled trial (providing data for 24 participants) investigated the issue of morning (on waking) versus evening (pre‐bedtime) inhalation (van der Giessen 2007b).
Participants
We requested clarification of participant data from the authors of this trial. It was a trial of children whose mean age was 13 years old (range 6 years to 19 years). Their mean FEV1 was 75% predicted and they were described as clinically stable in the month prior to the trial. Participants were on maintenance dornase alfa.
Interventions
Each intervention block in this trial lasted for two weeks; there was no washout period reported.
The clearance technique used in this trial was predominantly PEP mask (62%), with autogenic drainage (17%), Flutter (13%) or a combination in smaller numbers. The clearance technique was performed for 30 minutes post morning inhalation, with a placebo being used so that inhalations were performed twice daily.
Outcomes measured
This trial reported on lung function (FEV1, FVC, FEF25), symptom scores (VAS for cough and cough symptom scoring (CSS) day and night, sleep quality, sputum viscosity and amount), adherence and adverse events.
Excluded studies
A total of 93 papers representing 48 trials were added to the Excluded studies section, predominantly because they did not address timing of dornase alfa inhalation. Furthermore, nine were not RCTs, two did not study people with CF, and three did not involve dornase alfa. A further trial considered the impact of dornase alfa dwell time in the lung before airway clearance techniques. It compared a short dwell (median of 0.25 hours) to a long dwell (median of 11.1 hours) (Wilson 2007). While participants were randomised to morning or evening inhalation of dornase alfa, the data were not analysed in relation to this. We considered that long or short dwell time is a separate issue. This is discussed further in the Discussion section.
Risk of bias in included studies
We assessed the risk of bias of each trial using criteria as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020). For each trial we assessed the following: randomisation; concealment of allocation; blinding (of participants, personnel and outcome assessors); outcome data reporting (incomplete or selective). We also completed the PEDro Scale for the included trials (de Morton 2009; Maher 2003). The PEDro Scale assesses whether allocation was truly random, whether allocation was concealed, whether the groups were comparable at baseline, whether participants, therapists and assessors were blinded, whether follow‐up exceeded 85% for any outcome, whether analysis was by intention‐to‐treat and whether between group comparisons were made and reported with point estimates and measures of variability (for more detail, seePEDro Scale).
Among the trials of dornase alfa inhalation before versus after airway clearance, PEDro scores ranged from three (Anderson 2009) to nine (Bishop 2011; Fitzgerald 2005). The single trial of dornase alfa inhalation in the morning versus the evening also scored nine (van der Giessen 2007b). All these scores are included in the table Characteristics of included studies.
Allocation
Inhalation before versus after airway clearance techniques
Generation of sequence
No trials reported the method of generation of the random sequence. Two trials reported using block randomisation (Bishop 2011; Fitzgerald 2005) and thus have a low risk of bias. However, two trials stated that they were randomised but did not provide methodology (Anderson 2009; van der Giessen 2007a). Thus the overall risk of bias due to the method of generation of the random sequence is unclear.
Concealment of allocation
Among the trials of dornase alfa inhalation before versus after airway clearance techniques, allocation was concealed in two trials which both used independent distant pharmacies and which we judged to have a low risk of bias (Bishop 2011; Fitzgerald 2005). Allocation concealment was unclear in one trial which we judged to have an unclear risk of bias (van der Giessen 2007a), and was unconcealed in the final trial which we judged to have a high risk of bias (Anderson 2009). We judged the risk of bias due to unconcealed allocation across all trials to be moderate.
Morning versus evening inhalation
Generation of sequence
The included trial did not report the method of sequence generation (van der Giessen 2007b). Thus the risk of bias due to this is unclear.
Allocation concealment
The method for concealing allocation and hence risk of bias is unclear (van der Giessen 2007b).
Blinding
Inhalation before versus after airway clearance techniques
Among the trials of dornase alfa inhalation before versus after airway clearance techniques, blinding was adequate in three trials that used a double‐dummy placebo (Bishop 2011; Fitzgerald 2005; van der Giessen 2007a). Thus, the risk of bias due to lack of blinding was low in these trials. Blinding was not used in one trial, giving a high risk of bias (Anderson 2009), but the proportion of data contributed by this trial was very small due to its small sample size. The overall risk of bias due to lack of blinding was therefore low.
Morning versus evening inhalation
The single trial of dornase alfa inhalation in the morning versus the evening blinded participants, therapists and assessors (van der Giessen 2007b). Therefore, the risk of bias was low.
Incomplete outcome data
Inhalation before versus after airway clearance techniques
Among the trials of dornase alfa inhalation before versus after airway clearance techniques, the number (%) of dropouts was low in three trials: 2 (4%) (Fitzgerald 2005); 0 (0%) (Bishop 2011); 1 (4%) (van der Giessen 2007a), giving a low risk of bias. The number (%) of dropouts was high in one trial: 3 (37%) (Anderson 2009), giving a high risk of bias. An intention‐to‐treat analysis was performed in two trials, giving a low risk of bias (Fitzgerald 2005; Bishop 2011). Intention‐to‐treat analysis was not performed in two trials due to dropouts as a consequence of pulmonary exacerbations, giving a high risk of bias (Anderson 2009; van der Giessen 2007a). The overall risk of bias was moderate.
Morning versus evening inhalation
There was one (4%) dropout in this trial and intention‐to‐treat analysis was used (van der Giessen 2007b). Therefore, the risk of bias was low.
Selective reporting
Inhalation before versus after airway clearance techniques
Although we did not review the trial protocols, we contacted the trial authors of the included trials requesting confirmation that the data they provided includes all outcomes measured in the trials. The authors have confirmed this for all trials, therefore giving no risk of bias due to outcome measures being omitted completely (Anderson 2009; Bishop 2011; Fitzgerald 2005; van der Giessen 2007a). However, a small number of outcomes in each trial that did not significantly differ between groups were only reported as "non‐significant" and further data could not be obtained. Therefore, overall the risk of bias due to selective reporting is low.
Morning versus evening inhalation
We have contacted trial authors of the included trial requesting confirmation that the data provided includes all outcome measured in the trial (van der Giessen 2007b). The trial authors confirmed that all of the outcomes measured were reported, therefore, there was no risk of bias due to outcome measures being omitted completely. However, some outcomes were only described as non‐significant without provision of data. Therefore, the overall risk of bias due to selective reporting is low.
Other potential sources of bias
Inhalation before versus after airway clearance techniques
No other potential sources of bias were identified for any of the trials, suggesting a low risk of bias across trials (Anderson 2009; Bishop 2011; Fitzgerald 2005; van der Giessen 2007a).
Morning versus evening inhalation
No other potential sources were identified, suggesting a low risk of bias (van der Giessen 2007b).
Effects of interventions
See: Summary of findings 1 Inhalation of dornase alfa before versus after airway clearance techniques; Summary of findings 2 Morning versus evening inhalation of dornase alfa
The quality of the evidence has been graded for those outcomes included in the summary of findings tables. For the definitions of these gradings, please refer to the summary of findings tables (summary of findings Table 1; summary of findings Table 2).
Inhalation before versus after airway clearance techniques
There are four trials included for this comparison with a total of 102 participants (Anderson 2009; Bishop 2011; Fitzgerald 2005; van der Giessen 2007a).
Primary outcomes
1. Lung function (absolute change and change in % predicted)
a. FEV1
Four trials provided data that could be included in the meta‐analysis regarding the change in FEV1 in litres (Anderson 2009; Bishop 2011; Fitzgerald 2005; van der Giessen 2007a). There was no significant between‐group difference overall, MD ‐0.03 litres (95% CI ‐0.08 to 0.03) with the trend favouring inhalation before airway clearance (Analysis 1.1). In % predicted, this between‐group difference equated to MD ‐ 0.83% predicted (95% CI ‐2.96 to 1.31) (Analysis 1.2) (very low‐quality evidence).
Fitzgerald performed a post‐hoc subgroup analysis of the 17 participants who were colonised with Pseudomonas aeruginosa persistently for the two years preceding the trial (Fitzgerald 2005). In this subgroup, FEV1 improved significantly more when dornase alfa was inhaled after airway clearance techniques (P = 0.034).
b. FVC
Two trials provided data regarding the change in FVC in litres (Fitzgerald 2005; van der Giessen 2007a). There was no significant between‐group difference overall, MD 0.01 litres (95% CI ‐0.05 to 0.08) with the trend favouring inhalation after airway clearance (Analysis 1.3). In % predicted, this between‐group difference equated to MD 1.06% predicted (95% CI ‐1.29 to 3.41) (Analysis 1.4) (low‐quality evidence).
One further trial reported a non‐significant change in FVC; however, data were not provided (Bishop 2011).
2. Measures of quality of life and symptom scores
The four trials reported a variety of quality of life and symptom scores. None changed significantly as a result of timing in relation to airway clearance techniques (very low‐quality evidence). The quality of life questionnaires included the Cystic Fibrosis Questionnaire (CFQ) (Bishop 2011), the Quality of Wellbeing ("a composite of mobility scale, physical and social activity scales") (Fitzgerald 2005) and a bespoke subjective questionnaire (Anderson 2009). A visual analogue scale (VAS) was frequently used to report symptom scores including: well being (Bishop 2011); cough (Bishop 2011; van der Giessen 2007a); sputum volume (Bishop 2011; van der Giessen 2007a); sputum viscosity (van der Giessen 2007a); and ease of clearance (Bishop 2011). The paper by van der Giessen also reported a cough VAS and cough symptom score for day and night (van der Giessen 2007a). Most trials reported only that the between‐group comparison was non‐significant. However, the symptom data from one trial are presented in Table 1 (van der Giessen 2007a).
| DNase before ACT | DNase after ACT | P value (paired t‐test) | |
|---|---|---|---|
| VAS viscosity* | 1.3 (0.2 to 8.4) | 1.3 (0.2 to 8.4) | 0.73 |
| VAS sputum amount* | 0.7 (0 to 5.1) | 1.1 (0.1 to 6.6) | 0.14 |
| VAS daytime cough | 1.7 (0 to 5.3) | 1.9 (1 to 7.4) | 0.51 |
| VAS nightime cough* | 0.1 (0 to 3.4) | 0.2 (0 to 5.7) | 0.14 |
| CSS daytime | 1.4 (0 to 3) | 1.6 (0 to 3.1) | 0.28 |
| CSS nighttime | 0.4 (0 to 2) | 0.7 (0 to 2.6) | 0.06 |
Data are mean (or median if asterisked) and range
ACT: airway clearance technique
CSS: cough symptom score
VAS: visual analogue scale
Secondary outcomes
1. Measures of sputum clearance, including measures of mucociliary clearance and objective measures of sputum volume
The Middleton trial reported that 24‐hour wet sputum weight and the percentage cleared during physiotherapy did not change in response to timing in relation to airway clearance techniques (Bishop 2011). No other trials reported on this outcome.
2. Measures of exercise capacity
Two trials reported non‐significant changes in VO2 max measured by 20 or 10 metre shuttle tests (Bishop 2011; Fitzgerald 2005).
3. Mortality
No trial reported this outcome.
4. Other pulmonary parameters
a. FEF25-75
The impact of timing with airway clearance techniques on FEF25-75 in % predicted was reported to be non‐significant (P = 0.07) in one trial (van der Giessen 2007a) (low‐quality evidence).
b. FEF25
Two trials provided data that could be included in the meta‐analysis regarding the change in FEF25 in litres per second (Anderson 2009; van der Giessen 2007a), with a significant between‐group difference overall, MD ‐0.17 litres per second (95% CI ‐0.28 to ‐0.05) (Analysis 1.6). In % predicted, this between‐group difference equated to MD ‐5.44 % predicted (95% CI ‐9.23 to ‐1.66) (Analysis 1.7). The participants in these trials were children aged 7 years to 19 years.
c. TLC
No trial reported this outcome.
d. RV
No trial reported this outcome.
e. FRC
No trial reported this outcome.
5. Frequency of exacerbations of respiratory infection
An exacerbation of respiratory symptoms was reported by some authors as a cause of trial withdrawal. In the trial by van der Giessen, one out of 25 developed a pulmonary exacerbation in the first arm of the trial, during which they inhaled dornase alfa before performing airway clearance techniques. The participant was withdrawn and did not provide data for the second half of the trial (van der Giessen 2007a). Two of three dropouts in the Anderson trial were due to exacerbations (one from each group at the end of the first intervention) (Anderson 2009).
a. admission rates to hospital
We defined this as either number of inpatient hospital admissions or days as a hospital inpatient. The Fitzgerald paper reported this data as an adverse event (see below), but the intervention arm at the time of the event was not stated (Fitzgerald 2005).
b. courses of IV antibiotics (whether received in hospital or in the home)
Fitzgerald reported three of 52 participants required hospitalisation for intravenous antibiotics; two for exacerbations of suppurative lung disease and one with streptococcal septicaemia. The intervention group at the time of the event was not stated (Fitzgerald 2005).
c. outpatient treatments (presentations to hospital, unscheduled visits to the doctor)
No trial reported this outcome.
6. Adherence to treatment along with other treatments while the protocol for inhalation timing is followed
The number of returned vials was reported in two trials (Fitzgerald 2005; van der Giessen 2007a). Fitzgerald had two out of 52 withdraw as a result of protocol violations (for failing to take both inhalations) but continued analysis as intention‐to‐treat (Fitzgerald 2005). The second trial reported a 98% adherence rate (range 83% to 100%) (van der Giessen 2007a). A further trial recorded adherence for airway clearance techniques and inhalation with a daily diary but the adherence rate was not reported (Bishop 2011).
7. Adverse effects such as bronchospasm, cough and acute decline in pulmonary function
Four trials reported on adverse events, but we were not able to meta‐analyse the results (very low‐quality evidence). The Middleton trial reported one single episode of haemoptysis after two weeks of dornase alfa inhalation that resolved spontaneously despite continued dornase alfa treatment (Bishop 2011). Fitzgerald reported 34 adverse events that occurred among 26 participants (27 were due to exacerbations with previously isolated sputum pathogens, three required hospitalisation for intravenous antibiotics, four were due to musculoskeletal injuries during usual sporting activities and three were gastrointestinal in nature); the intervention group at the time of the event was not stated (Fitzgerald 2005). Cough frequency during the night was monitored by two authors as a potential adverse event without a significant impact of the intervention (Anderson 2009; van der Giessen 2007a).
Morning versus evening inhalation
One cross‐over trial investigated the issue of morning (on waking) versus evening (before bedtime) inhalation with two‐week intervention periods (van der Giessen 2007b).
Primary outcomes
1. Lung function (absolute change and change in % predicted)
a. FEV1
The change in FEV1 in litres was reported in one trial to be non‐significant (van der Giessen 2007b), MD 0.04 (95% CI ‐0.04 to 0.12) (Analysis 2.1). In % predicted, this between‐group difference equated to MD ‐1.30 (95% CI ‐4.18 to 1.58) (Analysis 2.2) (low‐quality evidence).
b. FVC
The change in FVC in litres was reported in one trial to be non‐significant (van der Giessen 2007b), MD 0.07 (95% CI ‐0.02 to 0.15) (Analysis 2.3). In % predicted, this between‐group difference equated to MD ‐0.10 (95% CI ‐5.98 to 5.78) (Analysis 2.4) (low‐quality evidence).
2. Measures of quality of life and symptom scores
A variety of VAS scores were also reported in the van der Giessen paper: cough and CSS day and night; sputum viscosity and amount; none of which were significantly different as a result of the time of day the inhalation was performed (van der Giessen 2007b) (low‐quality evidence). The symptom data are presented in Table 2.
| Evening Mean (SD) | Morning Mean (SD) | P value | |
|---|---|---|---|
| VAS viscosity | 2.1 (1.6) | 2.5 (1.6) | 0.22 |
| VAS sputum amount | 1.9 (1.8) | 2.1 (1.6) | 0.26 |
| VAS daytime coughing | 2.2 (1.6) | 2.5 (1.7) | 0.27 |
| VAS nighttime coughing | 1 (1) | 1.3 (1.4) | 0.08 |
| VAS appetite | 3 (2.7) | 3.3 (2.6) | 0.35 |
| VAS sleep quality | 1.1 (1) | 1.5 (1.3) | 0.08 |
| CSS daytime | 1.3 (0.9) | 1.6 (0.9) | 0.07 |
| CSS nighttime | 0.8 (0.8) | 1 (0.9) | 0.27 |
CSS: cough symptom score
SD: standard deviation
VAS: visual analogue scale
Secondary outcomes
1. Measures of sputum clearance, including measures of mucociliary clearance and objective measures of sputum volume
The included trial did not report this outcome.
2. Measures of exercise capacity
The included trial did not report this outcome.
3. Mortality
The included trial did not report this outcome.
4. Other pulmonary parameters
a. FEF25-75
The included trial did not report this outcome.
b. FEF25
The change in FEF25 in % predicted was reported to be non‐significant (van der Giessen 2007b), MD ‐3.40 (95% CI ‐9.18 to 2.38) (Analysis 2.5).
c. TLC
The included trial did not report this outcome.
d. RV
The included trial did not report this outcome.
e. FRC
The included trial did not report this outcome.
5. Frequency of exacerbations of respiratory infection
The included trial had one withdrawal out of 25 as a result of a respiratory exacerbation, but did apply an intention‐to‐treat analysis (van der Giessen 2007b).
a. admission rates to hospital
The included trial did not report this outcome.
b. courses of IV antibiotics (whether received in hospital or in the home)
The included trial did not report this outcome.
c. outpatient treatments (presentations to hospital, unscheduled visits to the doctor)
The included trial did not report this outcome.
6. Adherence to treatment along with other treatments while the protocol for inhalation timing is followed
The number of returned vials was reported by van der Giessen to give a 97% adherence rate (range 82% to 100%), but no between‐group comparison was reported (van der Giessen 2007b).
7. Adverse effects such as bronchospasm, cough and acute decline in pulmonary function
Bedtime inhalation did not adversely impact overnight oximetry (mean (SD) in the morning group was 96.2 (1.4) and in the evening group was 96.1 (1.6), P = 0.78). Bedtime inhalation did not adversely impact cough per hour recordings (mean (SD) in the morning group was 3.7 (8) and in the evening group was 3.3 (5), P = 0.85), but between‐group comparison SDs were not provided (van der Giessen 2007b) (low‐quality evidence).
Assessment of heterogeneity
Meta‐analysis was possible for several outcomes (FEV1 in litres and % predicted, FVC in litres and % predicted and FEF25 in litres and % predicted). For all these meta‐analyses, there was low heterogeneity between trials.
Discussion
Summary of main results
The searches identified 115 trial reports, of which five trials (providing data on 122 participants) met our inclusion criteria. All five trials used a cross‐over design. Intervention periods ranged from two to eight weeks.
Four trials examined inhalation of dornase alfa before versus after airway clearance techniques. Despite theoretical arguments that one timing regimen may be better than another, meta‐analysis of all the available data showed that inhalation after instead of before airway clearance did not change FEV1, MD ‐0.03 litres (95% CI ‐0.08 to 0.03). Similarly, FVC and quality of life were unaffected. Most of the secondary outcomes were also statistically non‐significant. However, FEF25 was significantly better with dornase alfa inhalation before airway clearance, based on the pooled data from two small trials (Anderson 2009; van der Giessen 2007a). This evidence of a benefit in small airway function was reinforced by a similar result in FEF25-75 (van der Giessen 2007a), although this did not reach statistical significance. However, it is difficult to judge the importance of this finding for several reasons. Unlike the well‐established prognostic value of FEV1, we are unaware of evidence for the prognostic value of FEF25. Therefore, it is difficult to interpret whether or not the magnitude of the effect on FEF25 is clinically important, although it did not lead to improvements in symptom scores or quality of life. Furthermore, a decrease in flow at low lung volumes is not necessarily specific for small airway disease and interpretation is hazardous if FEV1 or FVC are abnormal or have varied, or if their ratio is abnormal (Pellegrino 2005). Also, FEF25 is a highly variable measure in healthy adults (Pellegrino 2005) and has poor repeatability in children and adolescents with CF (Cooper 1990). This high variability and the lack of significant effects on all other outcomes make it uncertain how relevant the observed benefits in small airway function are to the clinical well being of people with CF, especially into adulthood.
In one trial, morning versus evening inhalation had no impact on lung function or symptoms (van der Giessen 2007b). Bedtime inhalation had previously been considered a relative contraindication given the hypothesised risk of a reduced therapeutic effect with the absence of an opportunity to expectorate. Concerns had also been raised concerning side effects of nocturnal cough and impaired sleep quality. Given the potential to improve the time burden and acceptability of therapy with the possibility of evening inhalation, this may have significant implications for patient compliance with therapy. Given that only one trial has examined this comparison further trials would improve the precision of these estimates.
Overall completeness and applicability of evidence
The identified trials were of relatively short duration with a timing intervention ranging from two or three weeks, to a maximum of eight weeks in one trial with very small numbers (Anderson 2009). In addition, none of the trials reported which timing regimen was chosen by participants after trial completion, which may reflect the relative acceptability of the timing regimens overall.
The included trials in this review encompassed a diverse CF patient population in age and disease severity as reflected in FEV1, however, only one of the included trials was conducted in adults (Bishop 2011).
Observations about participants with chronic P aeruginosa colonisation on post hoc analysis in the Fitzgerald trial should be interpreted with caution (Fitzgerald 2005).
Two of the trials included only participants who were naive to dornase alfa (Bishop 2011; Fitzgerald 2005). It is well‐recognised that some individuals have a marked response when commencing therapy with dornase alfa while others do not (Ramsey 1993). The large response of these participants during the first arm of the trial will increase the variability in both groups. This will reduce the ability of the trial to identify a treatment effect due to the timing of dornase alfa. Furthermore, there are no data to confirm whether participants with a large response to dornase alfa were evenly distributed between the groups in these trials. Therefore, there is the potential for this effect to introduce further bias.
One additional cross‐over trial with two‐week intervention periods did not meet the type of intervention specified in our protocol (Wilson 2007). Twenty participants were randomised to morning or evening dornase alfa inhalation to create a lung dwell time of long or short duration, since airway clearance techniques were performed in the morning. The data were analysed to assess the effect of long versus short dwell time. Allowing dornase alfa to dwell in the lungs longer (mean 11 hours) before airway clearance improved FEF25-75 and quality of life significantly more than a short dwell time (0.2 hours). We believe this differs importantly from trials of pre‐ versus post‐airway clearance techniques, because the long dwell time is more than six hours after the previous session of airway clearance techniques. The dornase alfa would therefore not be influenced by several factors that occur immediately after airway clearance. The first is that the airways ‐ particularly the large central airways ‐ are presumably at their most cleared state. The second is that airway clearance techniques can cause transient bronchoconstriction. Finally, airway clearance techniques can cause a transient increase in mucociliary clearance after the techniques are completed. The combination of these effects may affect the pattern of deposition of the dornase alfa and how quickly it is cleared. It is likely that a long dwell time as used in the Wilson trial has a different mechanism of therapeutic effect than the timing regimen we have examined in the trials comparing inhalation of dornase alfa before versus after airway clearance techniques. In vivo trials demonstrate continued enzymatic activity at six hours, and animal studies at 11 hours (Roche 2005). A longer dwell time therefore, has the potential to maximise the mucolytic effect. It remains unclear if this is optimal if airway clearance is too distant from drug delivery and the liquefied mucus is not cleared. We plan to include this type of intervention in the next update of this review.
Quality of the evidence
Apart from one trial published only in abstract form (Anderson 2009), in relation to the risk of bias domains, the quality of the included trials was moderate.
The quality of the evidence as assessed by GRADE ranged from low to very low. Reasons for downgrading the evidence included risks of bias (due to allocation concealment, blinding and incomplete outcome data) and inapplicability due to the limited age range of participants.
Potential biases in the review process
No potential biases in the review process were identified.
Agreements and disagreements with other studies or reviews
A current Cochrane Review considers the evidence for dornase alfa for people with CF, but timing of inhalation is not considered (Yang 2018).
Comparison 1: Pre‐ACT versus Post‐ACT, Outcome 1: FEV1 (L)
Comparison 1: Pre‐ACT versus Post‐ACT, Outcome 2: FEV1 (% pred)
Comparison 1: Pre‐ACT versus Post‐ACT, Outcome 3: FVC (L)
Comparison 1: Pre‐ACT versus Post‐ACT, Outcome 4: FVC (% pred)
Comparison 1: Pre‐ACT versus Post‐ACT, Outcome 5: FEF25-75 (% pred)
Comparison 1: Pre‐ACT versus Post‐ACT, Outcome 6: FEF25 (L)
Comparison 1: Pre‐ACT versus Post‐ACT, Outcome 7: FEF25 (% pred)
Comparison 2: Morning versus Evening, Outcome 1: FEV1 (L)
Comparison 2: Morning versus Evening, Outcome 2: FEV1 (% pred)
Comparison 2: Morning versus Evening, Outcome 3: FVC (L)
Comparison 2: Morning versus Evening, Outcome 4: FVC (% pred)
Comparison 2: Morning versus Evening, Outcome 5: FEF25 (% pred)
| DNase inhalation before versus after ACTs for cystic fibrosis | ||||||
| Patient or population: adults and children with cystic fibrosis Settings: outpatients Intervention: DNase inhalation before ACT Comparison: DNase inhalation after ACT | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Inhalation after airway clearance | Inhalation before airway clearance | |||||
| FEV1 (% predicted) change from baseline Follow‐up: up to 4 weeks | See comments. | MD 0.83% (95% CI ‐2.96% to 1.31%) | 102 (4 cross‐over trials) | ⊕⊖⊖⊖ very low1,2,3 | Positive MD indicates an advantage for DNase inhalation before ACT, but difference is not statistically significant. FEV1 (L) also showed no significant difference between groups. Participants received both ACTs as cross‐over design. | |
| FVC (% predicted) change from baseline Follow‐up: up to 4 weeks | See comments. | MD 1.06% (95% CI ‐1.29% to 3.41%) | 77 (2 cross‐over trials) | ⊕⊕⊖⊖ low3,4 | Positive MD indicates an advantage for DNase inhalation before ACT, but difference is not statistically significant. FVC (L) also showed no significant difference between groups. Participants received both ACTs as cross‐over design. | |
| Measures of QoL and symptom scores Follow‐up: up to 4 weeks | See comments. | NA | 102 (4 cross‐over trials) | ⊕⊖⊖⊖ very low1,2,3, | 4 trials reported a variety of QoL scores (CFQ and QWB) and symptom scores covering well‐being, sputum (volume, viscosity and ease of clearance), and cough (daytime and nighttime). No outcome showed a difference due to timing of DNase inhalation in relation to ACTs. | |
| FEF25-75 (% predicted) Follow‐up: up to 4 weeks | See comments. | MD ‐6.71% (95% CI ‐14.66% to 1.24%) | 25 (1 cross‐over trial) | ⊕⊕⊖⊖ low3,4 | Negative MD indicates an advantage for DNase inhalation after ACT, but difference is not statistically significant. Participants received both ACTs as cross‐over design. | |
| Adverse effects Follow‐up: up to 4 weeks | See comments. | NA (see comment) | 102 (4 cross‐over trials) | ⊕⊖⊖⊖ very low1,2,3 | No statistical comparisons were made. Narrative reports included a single episode of haemoptysis after 2 weeks of DNase inhalation which resolved spontaneously with continued treatment. A further trial reported 34 adverse events (27 of these were for pulmonary exacerbations, 4 for musculoskeletal injuries and 3 gastrointestinal events) in 26 out of 52 participants, but we do not know which treatment group these occurred in. 2 trials monitored nighttime cough frequency but the timing of the interventions had no impact on nocturnal cough. | |
| Relative effect and 95% CI presented is adjusted for the cross‐over design of the trials. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. Downgraded once for high risk of bias due to lack of allocation concealment. 2. Downgraded once for high risk of bias due to lack of blinding. 3. Downgraded once for high risk of bias due to incomplete outcome data. 4. Downgraded once for lack of applicability as trials included only children so results are not applicable to adults. | ||||||
| Morning versus evening inhalation of DNase for cystic fibrosis | ||||||
| Patient or population: adults and children with cystic fibrosis Settings: outpatients Intervention: morning DNase inhalation Comparison: evening DNase inhalation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Evening inhalation | Morning inhalation | |||||
| FEV1 (% predicted) change from baseline Follow‐up: up to 4 weeks | See comments. | MD ‐1.30% (95% CI ‐4.18% to 1.58%) | 25 (1 cross‐over trial) | ⊕⊕⊖⊖ low1,2 | Negative MD indicates an advantage for evening DNase inhalation, but difference is not statistically significant. FEV1 (L) also showed no significant difference between groups. Participants received both morning and evening DNase inhalation as cross‐over design. | |
| FVC (% predicted) change from baseline Follow‐up: up to 4 weeks | See comments. | MD ‐0.10% (95% CI ‐5.98% to 5.78%) | 25 (1 cross‐over trial) | ⊕⊕⊖⊖ low1,2 | Negative MD indicates an advantage for evening DNase inhalation, but difference is not statistically significant FVC (L) also showed no significant difference between groups. Participants received both morning and evening DNase inhalation as cross‐over design. | |
| Measures of QoL and symptom scores Follow‐up: up to 4 weeks | See comments. | NA | 25 (1 cross‐over trial) | ⊕⊕⊖⊖ low1,2 | A variety of VAS scores reported on cough (day and night), sputum (volume and viscosity), appetite and sleep quality; none of which were significantly different as a result of the time of day the DNase was inhaled. | |
| FEF25-75 (% predicted) Follow‐up: up to 4 weeks | Outcome not reported. | NA | NA | NA | ||
| Adverse effects Follow‐up: up to 4 weeks | See comments. | NA (see comment) | 25 (1 cross‐over trial) | ⊕⊕⊖⊖ low1,2 | No statistical comparisons made. Narrative reports indicated that evening DNase inhalation did not adversely impact overnight oximetry or cough per hour recordings (but between‐group comparisons were not provided for this outcome). | |
| Relative effect and 95% CI presented is adjusted for the cross‐over design of the trials. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. Downgraded once for lack of applicability as the trial only included children so results are not applicable to adults. 2. Downgraded once due to incomplete outcome data. | ||||||
| DNase before ACT | DNase after ACT | P value (paired t‐test) | |
|---|---|---|---|
| VAS viscosity* | 1.3 (0.2 to 8.4) | 1.3 (0.2 to 8.4) | 0.73 |
| VAS sputum amount* | 0.7 (0 to 5.1) | 1.1 (0.1 to 6.6) | 0.14 |
| VAS daytime cough | 1.7 (0 to 5.3) | 1.9 (1 to 7.4) | 0.51 |
| VAS nightime cough* | 0.1 (0 to 3.4) | 0.2 (0 to 5.7) | 0.14 |
| CSS daytime | 1.4 (0 to 3) | 1.6 (0 to 3.1) | 0.28 |
| CSS nighttime | 0.4 (0 to 2) | 0.7 (0 to 2.6) | 0.06 |
| Data are mean (or median if asterisked) and range | |||
| Evening Mean (SD) | Morning Mean (SD) | P value | |
|---|---|---|---|
| VAS viscosity | 2.1 (1.6) | 2.5 (1.6) | 0.22 |
| VAS sputum amount | 1.9 (1.8) | 2.1 (1.6) | 0.26 |
| VAS daytime coughing | 2.2 (1.6) | 2.5 (1.7) | 0.27 |
| VAS nighttime coughing | 1 (1) | 1.3 (1.4) | 0.08 |
| VAS appetite | 3 (2.7) | 3.3 (2.6) | 0.35 |
| VAS sleep quality | 1.1 (1) | 1.5 (1.3) | 0.08 |
| CSS daytime | 1.3 (0.9) | 1.6 (0.9) | 0.07 |
| CSS nighttime | 0.8 (0.8) | 1 (0.9) | 0.27 |
| CSS: cough symptom score | |||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 FEV1 (L) Show forest plot | 4 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.1.1 Over 1 week and up to 2 months | 4 | Mean Difference (IV, Fixed, 95% CI) | ‐0.03 [‐0.08, 0.03] | |
| 1.2 FEV1 (% pred) Show forest plot | 4 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.2.1 Over 1 week and up to 2 months | 4 | Mean Difference (IV, Fixed, 95% CI) | ‐0.83 [‐2.96, 1.31] | |
| 1.3 FVC (L) Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.3.1 Over 1 week and up to 2 months | 2 | Mean Difference (IV, Fixed, 95% CI) | 0.01 [‐0.05, 0.08] | |
| 1.4 FVC (% pred) Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.4.1 Over 1 week and up to 2 months | 2 | Mean Difference (IV, Fixed, 95% CI) | 1.06 [‐1.29, 3.41] | |
| 1.5 FEF25-75 (% pred) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.5.1 Over 1 week and up to 2 months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.6 FEF25 (L) Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.6.1 Over 1 week and up to 2 months | 2 | Mean Difference (IV, Fixed, 95% CI) | ‐0.17 [‐0.28, ‐0.05] | |
| 1.7 FEF25 (% pred) Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.7.1 Over 1 week and up to 2 months | 2 | Mean Difference (IV, Fixed, 95% CI) | ‐5.44 [‐9.23, ‐1.66] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 FEV1 (L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.1.1 Over 1 week and up to 2 months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.2 FEV1 (% pred) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.2.1 Over 1 week and up to 2 months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.3 FVC (L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.3.1 Over 1 week and up to 2 months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.4 FVC (% pred) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.4.1 Over 1 week and up to 2 months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.5 FEF25 (% pred) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.5.1 Over 1 week and up to 2 months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
