Timing of dornase alfa inhalation for cystic fibrosis

  • Review
  • Intervention

Authors

  • Ruth Dentice,

    Corresponding author
    1. Royal Prince Alfred Hospital, Department of Respiratory Medicine, Camperdown, New South Wales, Australia
    • Ruth Dentice, Department of Respiratory Medicine, Royal Prince Alfred Hospital, Level 11, E Block, Missenden Road, Camperdown, New South Wales, NSW 2050, Australia. ruth.dentice@sswahs.nsw.gov.au.

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  • Mark Elkins

    1. Royal Prince Alfred Hospital, Department of Respiratory Medicine, Camperdown, New South Wales, Australia
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Abstract

Background

Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis.

Objectives

To determine the effect of timing of dornase alfa inhalation on measures of clinical efficacy in people with cystic fibrosis (in relation to airway clearance techniques or time of day).

Search methods

Relevant randomised and quasi-randomised controlled trials were identified from the Cochrane Cystic Fibrosis Trials Register, Physiotherapy Evidence Database (PEDro), and international CF conference proceedings.

Date of the most recent search: 22 February 2013.

Selection criteria

Any trial of dornase alfa in people with cystic fibrosis where timing of inhalation was the randomised element in the study with either: inhalation before compared to after airway clearance techniques; or morning compared to evening inhalation.

Data collection and analysis

Both authors independently selected trials, assessed risk of bias and extracted data with disagreements resolved by discussion. Relevant data were extracted and, where possible, meta-analysed.

Main results

We identified 99 trial reports representing 48 studies, of which five studies (providing data on 122 participants) met our inclusion criteria. All five studies used a cross-over design. Intervention periods ranged from two to eight weeks. Four trials compared dornase alfa inhalation before versus after airway clearance techniques. Inhalation after instead of before airway clearance did not significantly change FEV1. Similarly, FVC and quality of life were not significantly affected; FEF25 was significantly worse with dornase alfa inhalation after airway clearance, MD -0.17 litres (95% CI -0.28 to -0.05), based on the pooled data from two small studies in children (7 to 19 years) with well-preserved lung function. All other secondary outcomes were statistically non-significant.

In one trial, morning versus evening inhalation had no impact on lung function or symptoms.

Authors' conclusions

The current evidence derived from a small number of participants does not indicate that inhalation of dornase alfa after airway clearance techniques is more or less effective than the traditional recommendation to inhale nebulised dornase alfa 30 minutes prior to airway clearance techniques, for most outcomes. For children with well-preserved lung function, inhalation before airway clearance may be more beneficial for small airway function than inhalation after. However, this result relied on a measure with high variability and studies with variable follow up. In the absence of strong evidence to indicate that one timing regimen is better than another, the timing of dornase alpha inhalation can be largely based on pragmatic reasons or individual preference with respect to the time of airway clearance and time of day. Further research is warranted.

Resumen

Antecedentes

Momento de administración de la inhalación de dornasa alfa para la fibrosis quística

La inhalación de la enzima dornasa alfa reduce la viscosidad del esputo y mejora los resultados clínicos de los pacientes con fibrosis quística.

Objetivos

Determinar el efecto del momento de administración de la inhalación de dornasa alfa sobre las medidas de eficacia clínica en los pacientes con fibrosis quística (relacionado con las técnicas de desobstrucción de las vías respiratorias y el momento del día).

Estrategia de búsqueda

Se identificaron ensayos controlados aleatorios y cuasialeatorios relevantes del Registro de ensayos del Grupo Cochrane de Fibrosis Quística (Cochrane Cystic Fibrosis), la Physiotherapy Evidence Database (PEDro) y las actas de congresos internacionales de FQ.

Fecha de la búsqueda: 6 octubre 2010.

Criterios de selección

Cualquier ensayo de dornasa alfa en pacientes con fibrosis quística donde el momento de administración de la inhalación fue el elemento aleatorio en el estudio con: inhalación antes de aplicar las técnicas de desobstrucción de las vías respiratorias en comparación con inhalación posterior; o inhalación matutina comparada con inhalación vespertina.

Obtención y análisis de los datos

Ambos autores seleccionaron los ensayos de forma independiente, 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.

Resultados principales

Se identificaron 92 informes de ensayos que representaban 47 estudios, de los cuales cinco estudios (que proporcionaron datos de 122 participantes) cumplieron los criterios de inclusión. Los cinco estudios utilizaron un diseño cruzado (crossover). Los períodos de intervención variaron entre dos y ocho semanas. Cuatro ensayos compararon la inhalación de dornasa alfa antes versus después de aplicar las técnicas de desobstrucción de las vías respiratorias. La inhalación posterior en lugar de la inhalación antes de la desobstrucción de las vías respiratorias no cambió significativamente el VEF1. De manera similar no se afectaron significativamente la CVF ni la calidad de vida; el FEF25 fue significativamente peor con la inhalación de dornasa alfa después de la desobstrucción de las vías respiratorias, DM −0,17 litros (IC del 95%: −0,28 a −0,05), según los datos agrupados de dos estudios pequeños realizados en niños (de siete a 19 años) con función pulmonar bien preservada. Los otros resultados secundarios no fueron estadísticamente significativos

En un ensayo, al comparar la inhalación matutina versus la inhalación vespertina no hubo repercusión sobre la función pulmonar ni los síntomas.

Conclusiones de los autores

Las pruebas actuales derivadas de un escaso número de participantes no indican que la inhalación de dornasa alfa después de aplicar las técnicas de desobstrucción de las vías respiratorias sea más o menos eficaz, para la mayoría de los resultados, que la recomendación tradicional de inhalar la dornasa alfa nebulizada 30 minutos antes de aplicar las técnicas de desobstrucción de las vías respiratorias. Para los niños con una función pulmonar bien preservada, la inhalación antes de la desobstrucción 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 estudios con un seguimiento variable. Además, el momento de administración de la inhalación de dornasa alfa puede estar relacionado en gran medida con motivos pragmáticos o con la preferencia individual con respecto al momento de la desobstrucción de las vías respiratorias y el momento del día. Se justifica la realización de estudios de investigación adicionales.

Traducción

Traducción realizada por el Centro Cochrane Iberoamericano

Résumé scientifique

Moment de l'inhalation de dornase alpha contre la mucoviscidose

Contexte

L'inhalation de l'enzyme dornase alpha réduit la viscosité des expectorations et améliore les critères de jugement cliniques des personnes atteintes de mucoviscidose.

Objectifs

Déterminer l'effet du moment de l'inhalation de dornase alpha sur les mesures de l'efficacité clinique chez les personnes atteintes de mucoviscidose (par rapport aux techniques de dégagement des voies respiratoires ou au moment de la journée).

Stratégie de recherche documentaire

Des essais contrôlés randomisés et quasi-randomisés pertinents ont été identifiés dans le registre d'essais cliniques du groupe Cochrane sur la mucoviscidose, dans la Physiotherapy Evidence Database (PEDro) et dans les actes des congrès internationaux sur la MV.

Date de la recherche la plus récente : 22 février 2013.

Critères de sélection

Tout essai portant sur la dornase alpha chez des personnes atteintes de mucoviscidose dans lequel le moment de l'inhalation était l'élément randomisé dans l'étude avec soit une inhalation avant comparé à après l'utilisation de techniques de dégagement des voies respiratoires, soit une inhalation le matin comparé à une inhalation le soir.

Recueil et analyse des données

Les deux auteurs ont sélectionné les essais, évalué les risques de biais et extrait les données des essais admissibles de manière indépendante, les désaccords ayant été résolus par la discussion. Les données pertinentes ont été extraites et soumises à une méta-analyse, lorsque cela a été possible.

Résultats principaux

Nous avons identifié 99 rapports d'essais représentant 48 études, dont cinq (fournissant des données sur 122 participants) ont répondu à nos critères d'inclusion. Les cinq études utilisaient un plan d'étude croisé. Les périodes d'intervention allaient de deux à huit semaines. Quatre essais comparaient l'inhalation de dornase alpha avant versus après l'utilisation de techniques de dégagement des voies respiratoires. L'inhalation après contrairement à avant le dégagement des voies respiratoires n'a pas modifié significativement le VEMS. De même, la CVF et la qualité de vie n'ont pas été significativement affectées ; le DEM25 a été significativement plus dégradé avec l'inhalation de dornase alpha après dégagement des voies respiratoires, DM -0,17 litre (IC à 95 % -0,28 à -0,05), d'après les données combinées de deux études de petite taille chez l'enfant (de 7 à 19 ans) ayant une fonction pulmonaire bien préservée. Aucun des autres critères de jugement secondaires n'a été statistiquement significatif.

Dans un essai, l'inhalation le matin versus le soir n'a eu aucun impact sur la fonction ou les symptômes pulmonaires.

Conclusions des auteurs

Les preuves actuelles, provenant d'un faible nombre de participants, n'indiquent pas que l'inhalation de dornase alpha après l'utilisation de techniques de dégagement des voies respiratoires est plus efficace ou moins efficace que la recommandation traditionnelle d'inhaler la dornase alpha nébulisée 30 minutes avant l'utilisation de techniques de dégagement des voies respiratoires, pour la plupart des critères de jugement. Pour les enfants ayant une fonction pulmonaire bien préservée, l'inhalation avant dégagement des voies respiratoires peut être plus bénéfique pour la fonction des petites voies aériennes que l'inhalation après dégagement. Cependant, ce résultat s'est basé sur une mesure présentant une forte variabilité et des études ayant des suivis différents. Cela mis à part, la détermination du moment de l'inhalation de dornase alpha peut se baser principalement sur des raisons pragmatiques ou des préférences individuelles par rapport au moment du dégagement des voies respiratoires et au moment de la journée. Des recherches supplémentaires sont nécessaires.

Plain language summary

The timing of inhalation of dornase alfa in people with cystic fibrosis

Inhaling the enzyme dornase alfa reduces the stickiness of sputum and improves clinical outcomes in people with cystic fibrosis. It is not certain whether it is better to inhale dornase alfa before or after clearing the airways with physical techniques. It is also not clear whether it is better to inhale it in the morning or in the evening. We included five trials with a total of 122 participants. In these trials the length of treatment ranged from two to eight weeks. Four of the trials compared inhaling before to inhaling after the airways had been cleared and found no overall difference in clinical outcomes. However, in children with well-preserved lung function, inhaling of dornase alfa after airway clearance techniques was better for small airways function. However, this did not affect quality of life or other outcomes. In the remaining trial, morning versus evening inhalation had no impact on lung function or symptoms. Therefore, for many people with CF, the timing of dornase alfa inhalation (before or after airway clearance or the time of day) can be based on practical reasons or individual preference. 

Résumé simplifié

Détermination du moment de l'inhalation de dornase alpha chez les personnes atteintes de mucoviscidose

L'inhalation de l'enzyme dornase alpha réduit la viscosité des expectorations et améliore les critères d'évaluation cliniques chez les personnes atteintes de mucoviscidose (MV). On ignore s'il est préférable d'inhaler la dornase alpha avant ou après dégagement des voies respiratoires à l'aide de techniques physiques. On ignore également s'il est préférable de l'inhaler le matin ou le soir. Nous avons inclus cinq essais totalisant 122 participants. Dans ces essais, la durée du traitement allait de deux à huit semaines. Quatre des essais comparaient l'inhalation avant à l'inhalation après dégagement des voies respiratoires et n'ont trouvé aucune différence globale concernant les critères d'évaluation cliniques. Cependant, chez les enfants ayant une fonction pulmonaire bien préservée, l'inhalation de dornase alpha après l'utilisation de techniques de dégagement des voies respiratoires a été plus efficace pour la fonction des petites voies aériennes. Cependant, cela n'a pas affecté la qualité de vie ou d'autres critères d'évaluation. Dans l'essai restant, l'inhalation le matin versus le soir n'a eu aucun impact sur la fonction ou les symptômes pulmonaires. Par conséquent, pour de nombreuses personnes atteintes de MV, la détermination du moment de l'inhalation de dornase alpha (avant ou après dégagement des voies respiratoires ou la détermination du moment de la journée) peut se baser sur des raisons pratiques ou une préférence individuelle.

Notes de traduction

Traduit par: French Cochrane Centre 22nd February, 2013
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Background

Description of the condition

Cysic fibrosis (CF) is the most common life-limiting autosomal recessive disorder amongst Caucasians (Cutting 2002). Cystic fibrosis-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 twelve-month period is associated with an improvement in lung function in CF (Jones 2010).

A single daily dose of 2.5 mg of dornase alfa is not less effective than higher dosing regimens (Ramsey 1993; Fuchs 1994).

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

Cystic fibrosis 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.

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 study protocol:

  1. inhalation up to six hours before airway clearance techniques compared to inhalation up to six hours after airway clearance techniques;

  2. 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
  1. Lung function (absolute change and change in per cent predicted)

    1. forced expiratory volume at one second (FEV1)

    2. forced vital capacity (FVC)

  2. Measures of quality of life and symptom scores (including cough or subjective ease of clearance)

Secondary outcomes
  1. Measures of sputum clearance, including measures of mucociliary clearance and objective measures of sputum volume

  2. Measures of exercise capacity

  3. Mortality

  4. Other pulmonary parameters

    1. forced expiratory flow between 25% and 75% of the vital capacity (FEF25-75)

    2. maximal instantaneous forced flow when 25% of the forced vital capacity remains to be exhaled (FEF25)

    3. total lung capacity (TLC)

    4. residual volume (RV)

    5. functional residual capacity (FRC)

  5. Frequency of exacerbations of respiratory infection where a clear definition is described demonstrating an increase in symptoms or a decline in pulmonary function

    1. admission rates to hospital (defined as either number of inpatient hospital admissions or days as a hospital inpatient)

    2. courses of IV antibiotics (whether received in hospital or in the home)

    3. outpatient treatments (presentations to hospital, unscheduled visits to the doctor)

  6. Adherence to treatment along with other treatments while the protocol for inhalation timing is followed

  7. Adverse effects such as bronchospasm, cough and acute decline in pulmonary function

Search methods for identification of studies

Electronic searches

We identified relevant trials from the Group's Cystic Fibrosis Trials Register 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), quarterly 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 was 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 Module.

Date of last search of the Group's Cystic Fibrosis Register: 22 February 2013.

In addition, we searched the Physiotherapy Evidence Database (PEDro) for all years available (Appendix 1; Appendix 2; Appendix 3; Appendix 4).

Date of the most recent search: 23 January 2013.

Searching other resources

We hand-searched the Australia and New Zealand CF Conference Proceedings (1999 to 2009).

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 studies 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 trialists in an attempt to gain the information required to evaluate study 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 studies 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 studies 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 5.1.0 (Higgins 2011). We assessed the following domains as having either a low risk, unclear risk or high risk of bias:

  1. randomisation;

  2. concealment of allocation;

  3. blinding (of participants, personnel and outcome assessors);

  4. incomplete outcome data;

  5. selective outcome reporting;

  6. 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 trialists. 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 trialists 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 trialists to find out if they measured and analysed an outcome and obtained the data. We contacted experts in the field to ensure unpublished studies 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.

Results

Description of studies

Results of the search

The electronic searches identified 113 trial reports which represented 53 studies. Of these, four studies met our inclusion criteria (Fitzgerald 2005; Bishop 2011; van der Giessen 2007a; van der Giessen 2007b). A further study was identified in international CF conference proceedings in poster format (Anderson 2009). The five included studies provided data for 122 participants. Fifteen trial reports (representing 6 trials) were disregarded on title alone and we excluded 43 studies, predominantly because they did not address the timing issue of dornase alfa inhalation (Excluded studies). One of these studies 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 studies, which provided data for 122 participants; one study has not yet been published in full but has been presented as a poster at a conference (Anderson 2009). Four studies investigated the impact of timing in relation to airway clearance physiotherapy (Anderson 2009; Fitzgerald 2005; Bishop 2011; van der Giessen 2007a). One study 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 (Fitzgerald 2005; Bishop 2011), three weeks (van der Giessen 2007a) and eight weeks (Anderson 2009). One study had a two-week washout between intervention arms (Fitzgerald 2005). The longest study (four months duration with two eight-week intervention arms) was small in sample size and experienced significant dropouts (3 out of 8 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 studies.

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 studies (Fitzgerald 2005; van der Giessen 2007a) and at time of entry in one study (Anderson 2009).

One study 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 study.

Participants were on maintenance dornase alfa in two studies (Anderson 2009; van der Giessen 2007a). In the remaining two studies the participants were dornase alfa naive (Fitzgerald 2005; Bishop 2011).

Interventions

The duration of each timing intervention ranged from two to eight weeks; two studies had an intervention block of two weeks, one of three weeks and one of eight weeks.

One study provided limited information other than the description 'delivery before airway clearance techniques compared to delivery after airway clearance' (Anderson 2009).

In the three remaining studies, 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 studies (Bishop 2011; van der Giessen 2007a) and 30 minutes after in one study (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 studies 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; Fitzgerald 2005; Bishop 2011; 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 study. It was a study 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 study. Participants were on maintenance dornase alfa.

Interventions

Each intervention block in this study lasted for two weeks; there was no washout period reported.

The clearance technique used in this study 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 study 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

Eighty-eight papers representing 43 studies were added to the Excluded studies section, predominantly because they did not address timing of dornase alfa inhalation. Furthermore, eight 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 5.1 (Higgins 2011). 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, see PEDro Scale).

Among the studies of dornase alfa inhalation before versus after airway clearance, PEDro scores ranged from three (Anderson 2009) to nine (Fitzgerald 2005; Bishop 2011). The single study 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.

Inhalation before versus after airway clearance techniques

Allocation  
Generation of sequence

No trials reported the method of generation of the random sequence. Two studies reported using block randomisation (Fitzgerald 2005; Bishop 2011) and thus have a low risk of bias. However, two studies stated the study was 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 studies of dornase alfa inhalation before versus after airway clearance techniques, allocation was concealed in two studies which both used independent distant pharmacies and which we judged to have a low risk of bias (Fitzgerald 2005; Bishop 2011). Allocation concealment was unclear in one study which we judged to have an unclear risk of bias (van der Giessen 2007a), and was unconcealed in the final study which we judged to have a high risk of bias (Anderson 2009). We judged the risk of bias due to unconcealed allocation across all studies to be moderate.

Blinding  

Among the studies of dornase alfa inhalation before versus after airway clearance techniques, blinding was adequate in three studies that used a double-dummy placebo (Fitzgerald 2005; Bishop 2011; van der Giessen 2007a). Thus risk of bias due to lack of blinding was low in these studies. Blinding was not used in one study, giving a high risk of bias (Anderson 2009), but the proportion of data contributed by this study was very small due to its small sample size. The overall risk of bias due to lack of blinding was therefore low.

Incomplete outcome data

Among the studies of dornase alfa inhalation before versus after airway clearance techniques, the number (%) of dropouts was low in three studies: 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 study: 3 (37%) (Anderson 2009), giving a high risk of bias. 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.

Selective reporting

Although we did not review the study protocols, we contacted trialists on the included studies requesting confirmation that the data they provided includes all outcomes measured in the studies. The authors have confirmed this for all studies, therefore giving no risk of bias due to outcome measures being omitted completely (Anderson 2009; Fitzgerald 2005; Bishop 2011; van der Giessen 2007a). However, a small number of outcomes in each study 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.

Other potential sources of bias

No other potential sources of bias were identified for any of the studies, suggesting a low risk of bias across studies.

Morning versus evening inhalation

Allocation
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

The single study 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

There was one (4%) dropout in this study and intention-to-treat analysis was used (van der Giessen 2007b). Therefore the risk of bias was low.

Selective reporting

We have contacted trialists on the included study requesting confirmation that the data provided includes all outcome measured in the study (van der Giessen 2007b). The trialists 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

No other potential sources were identified, suggesting a low risk of bias.

Effects of interventions

Inhalation before versus after airway clearance techniques

There are four studies included for this comparison with a total of 102 participants (Anderson 2009; Fitzgerald 2005; Bishop 2011; van der Giessen 2007a).

Primary outcomes
1. Lung function (absolute change and change in per cent predicted)
a. FEV1

Four studies provided data that could be included in the meta-analysis regarding the change in FEV1 in litres (Anderson 2009; Fitzgerald 2005; Bishop 2011; 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 per cent predicted, this between-group difference equated to MD - 0.83% predicted (95% CI -2.96 to 1.31) (Analysis 1.2).

Fitzgerald performed a post-hoc subgroup analysis of the 17 participants who were colonised with Pseudomonas aeruginosa persistently for the two years preceding the study (Fitzgerald 2005). In this subgroup, FEV1 improved significantly more when dornase alfa was inhaled after airway clearance techniques (P = 0.034).

b. FVC

Two studies 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 per cent predicted, this between-group difference equated to MD 1.06% predicted (95% CI -1.29 to 3.41) (Analysis 1.4).

One further study 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 studies reported a variety of quality of life and symptom scores. None changed significantly as a result of timing in relation to airway clearance techniques. 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 studies reported only that the between-group comparison was non-significant. However, the symptom data from one study are presented in Table 1 (van der Giessen 2007a).

Table 1. Symptom Scores from van der Giessen 2007a
  1. Data are mean (or median if asterisked) and range
    CSS: cough symptom score
    VAS: visual analogue scale

 DNase before ACTDNase after ACTP 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 Cough1.7 (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 Daytime1.4 (0 to 3)1.6 (0 to 3.1)0.28
CSS Nighttime0.4 (0 to 2)0.7 (0 to 2.6)0.06
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 studies reported on this outcome.

2. Measures of exercise capacity

Two studies reported non-significant changes in VO2 max measured by 20 or 10 metre shuttle tests (Fitzgerald 2005; Bishop 2011).

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 per cent predicted was reported to be non-significant (P = 0.07) in one study (van der Giessen 2007a).

b. FEF25

Two studies provided data that could be included in the meta-analysis regarding the change in FEF25 in litres/sec (Anderson 2009; van der Giessen 2007a), with a significant between-group difference overall, MD -0.17 litres/sec (95% CI -0.28 to -0.05) (Analysis 1.6). In per cent 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 studies 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 study withdrawal. In the study by van der Giessen, one out of 25 developed a pulmonary exacerbation in the first arm of the study, 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 study (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 studies (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 study reported a 98% adherence rate (range 83% to 100%) (van der Giessen 2007a). A further study 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

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 per cent predicted)
a. FEV1

The change in FEV1 in litres was reported in one study to be non-significant (van der Giessen 2007b), MD 0.04 (95% CI -0.04 to 0.12) (Analysis 2.1). In per cent predicted, this between-group difference equated to MD -1.30 (95% CI -4.18 to 1.58) (Analysis 2.2).

b. FVC

The change in FVC in litres was reported in one study to be non-significant (van der Giessen 2007b), MD 0.07 (95% CI -0.02 to 0.15) (Analysis 2.3). In per cent predicted, this between-group difference equated to MD -0.10 (95% CI -5.98 to 5.78) (Analysis 2.4).

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). The symptom data are presented in Table 2.

Table 2. Symptom scores from van der Giessen 2007b
  1. Mean (SD)
    CSS: cough symptom score
    VAS: visual analogue scale

 EveningMorningP value
VAS Viscosity2.1 (1.6)2.5 (1.6)0.22
VAS Sputum amount1.9 (1.8)2.1 (1.6)0.26
VAS Daytime coughing2.2 (1.6)2.5 (1.7)0.27
VAS Nighttime coughing1 (1)1.3 (1.4)0.08
VAS Appetite3 (2.7)3.3 (2.6)0.35
VAS Sleep quality1.1 (1)1.5 (1.3)0.08
CSS Daytime1.3 (0.9)1.6 (0.9)0.07
CSS Nighttime0.8 (0.8)1 (0.9)0.27
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 per cent 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 study 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).

Assessment of heterogeneity  

Meta-analysis was possible for several outcomes (FEV1 in litres and per cent predicted, FVC in litres and per cent predicted and FEF25 in litres and per cent predicted). For all these meta-analyses, there was low heterogeneity between trials.

Discussion

Summary of main results

The searches identified 99 trial reports, of which five trials (providing data on 122 participants) met our inclusion criteria. All five studies 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 studies (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 study has examined this comparison further trials would improve the precision of these estimates.

Overall completeness and applicability of evidence

The identified studies were of relatively short duration with a timing intervention ranging from two or three weeks, to a maximum of eight weeks in one study with very small numbers (Anderson 2009). In addition, none of the studies 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 studies was conducted in adults (Bishop 2011).

Observations about participants with chronic Pseudomonas 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 (Fitzgerald 2005; Bishop 2011). 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 study will increase the variability in both groups. This will reduce the ability of the study 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 studies. Therefore, there is the potential for this effect to introduce further bias.

One additional cross-over study 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 studies 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 study has a different mechanism of therapeutic effect than the timing regimen we have examined in the studies comparing inhalation of dornase alfa before versus after airway clearance techniques. In vivo studies 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 study published only in abstract form (Anderson 2009), the quality of the included studies was moderate.

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 (Jones 2010).

Authors' conclusions

Implications for practice

For children with well preserved lung function, data derived from a small number of participants indicate that inhalation of dornase alfa before airway clearance techniques may be more beneficial for small airway function, but does not affect other outcomes. In the absence of strong evidence to indicate that one timing regimen is better than another, the timing of of dornase alpha inhalation can be largely based on pragmatic reasons or individual preference with respect to the time of airway clearance and time of day.

Implications for research

The primary outcome examined by this review (FEV1) was not affected by the timing of dornase alfa inhalation with respect to airway clearance or time of day. For the other outcomes of this review, there were some significant findings in individual studies, but further evidence is required in well-designed studies of longer duration. To better investigate the effect on small airway function, a more sensitive measure, such as nitrogen washout, might be used.

This review has identified few RCTs that consider the timing of dornase alfa inhalation. Given the expense in both time and money to both patients and care providers, further research is warranted to attempt to clarify an optimal regimen for dornase alfa therapy. Interestingly, in the current trials no follow up information regarding what participants opted to continue when the trial finished was included, this may have provided valuable insights into subjective treatment efficacy.

Acknowledgements

We thank Tracey Remmington and Nikki Jahnke from the Cochrane Cystic Fibrosis and Genetic Disorders Group for their editorial support and guidance. This systematic review has been possible due to the willingness of the authors of the included studies to give generously of their data and time. We thank them for providing unpublished data. We thank Christine Wilson for providing unpublished data and detailed protocol information that will permit the inclusion of this trial under a new timing comparison in future updates of this review.

Data and analyses

Download statistical data

Comparison 1. Pre-ACT versus Post-ACT
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 FEV1 (L)4 Mean Difference (Fixed, 95% CI)Subtotals only
1.1 Over 1 week and up to 2 months4 Mean Difference (Fixed, 95% CI)-0.03 [-0.08, 0.03]
2 FEV1 (% pred)4 Mean Difference (Fixed, 95% CI)Subtotals only
2.1 Over 1 week and up to 2 months4 Mean Difference (Fixed, 95% CI)-0.83 [-2.96, 1.31]
3 FVC (L)2 Mean Difference (Fixed, 95% CI)Subtotals only
3.1 Over 1 week and up to 2 months2 Mean Difference (Fixed, 95% CI)0.01 [-0.05, 0.08]
4 FVC (% pred)2 Mean Difference (Fixed, 95% CI)Subtotals only
4.1 Over 1 week and up to 2 months2 Mean Difference (Fixed, 95% CI)1.06 [-1.29, 3.41]
5 FEF25-75 (% pred)1 Mean Difference (Fixed, 95% CI)Totals not selected
5.1 Over 1 week and up to 2 months1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
6 FEF25 (L)2 Mean Difference (Fixed, 95% CI)Subtotals only
6.1 Over 1 week and up to 2 months2 Mean Difference (Fixed, 95% CI)-0.17 [-0.28, -0.05]
7 FEF25 (% pred)2 Mean Difference (Fixed, 95% CI)Subtotals only
7.1 Over 1 week and up to 2 months2 Mean Difference (Fixed, 95% CI)-5.44 [-9.23, -1.66]
Analysis 1.1.

Comparison 1 Pre-ACT versus Post-ACT, Outcome 1 FEV1 (L).

Analysis 1.2.

Comparison 1 Pre-ACT versus Post-ACT, Outcome 2 FEV1 (% pred).

Analysis 1.3.

Comparison 1 Pre-ACT versus Post-ACT, Outcome 3 FVC (L).

Analysis 1.4.

Comparison 1 Pre-ACT versus Post-ACT, Outcome 4 FVC (% pred).

Analysis 1.5.

Comparison 1 Pre-ACT versus Post-ACT, Outcome 5 FEF25-75 (% pred).

Analysis 1.6.

Comparison 1 Pre-ACT versus Post-ACT, Outcome 6 FEF25 (L).

Analysis 1.7.

Comparison 1 Pre-ACT versus Post-ACT, Outcome 7 FEF25 (% pred).

Comparison 2. Morning versus Evening
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 FEV1 (L)1 Mean Difference (Fixed, 95% CI)Totals not selected
1.1 Over 1 week and up to 2 months1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
2 FEV1 (% pred)1 Mean Difference (Fixed, 95% CI)Totals not selected
2.1 Over 1 week and up to 2 months1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
3 FVC (L)1 Mean Difference (Fixed, 95% CI)Totals not selected
3.1 Over 1 week and up to 2 months1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
4 FVC (% pred)1 Mean Difference (Fixed, 95% CI)Totals not selected
4.1 Over 1 week and up to 2 months1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
5 FEF25 (% pred)1 Mean Difference (Fixed, 95% CI)Totals not selected
5.1 Over 1 week and up to 2 months1 Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 2.1.

Comparison 2 Morning versus Evening, Outcome 1 FEV1 (L).

Analysis 2.2.

Comparison 2 Morning versus Evening, Outcome 2 FEV1 (% pred).

Analysis 2.3.

Comparison 2 Morning versus Evening, Outcome 3 FVC (L).

Analysis 2.4.

Comparison 2 Morning versus Evening, Outcome 4 FVC (% pred).

Analysis 2.5.

Comparison 2 Morning versus Evening, Outcome 5 FEF25 (% pred).

Appendices

Appendix 1. PEDro search strategy 'deoxyribonuclease'

Date of last search for all years available: 20 May 2009. Using the option 'Advanced search', the following search terms were entered into the following fields:
Field Search term
Abstract & titledeoxyribonuclease
Problemdifficulty with sputum clearance
Subdiscipline cardiothoracics

Appendix 2. PEDro search strategy 'DNase'

Date of last search for all years available: 20 May 2009. Using the option 'Advanced search', the following search terms were entered into the following fields:
Field Search term
Abstract & titleDNase
Problemdifficulty with sputum clearance
Subdiscipline cardiothoracics

Appendix 3. PEDro search strategy 'Dornase'

Date of last search for all years available: 20 May 2009. Using the option 'Advanced search', the following search terms were entered into the following fields:
Field Search term
Abstract & titleDornase
Problemdifficulty with sputum clearance
Subdiscipline cardiothoracics

Appendix 4. PEDro search strategy 'Pulmozyme'

Date of last search for all years available: 20 May 2009. Using the option 'Advanced search', the following search terms were entered into the following fields:
Field Search term
Abstract & titlePulmozyme
Problemdifficulty with sputum clearance
Subdiscipline cardiothoracics

What's new

Last assessed as up-to-date: 2 May 2013.

DateEventDescription
2 May 2013New search has been performedThe searches identified: a full paper publication to an already included study (Bishop 2011); four additional references to an already excluded study (Bakker 2011); and one new excluded study (Lahiri 2012). A further six trials (15 trials reports) identified were disregarded from inclusion on title alone.
2 May 2013New citation required but conclusions have not changedMinor changes have been made throughout this updated version of the review.

Contributions of authors

RD and ME outlined the protocol and each performed the search for studies, appraisal and data extraction.

RD or ME contacted the authors of trials where data are absent or difficult to interpret in the presented form.

RD and ME performed the data analysis.

Declarations of interest

ME has received funding for attending international conferences and honorariums for giving talks from Roche Pharmaceuticals.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Anderson 2009

MethodsRandomised, cross-over trial with 2-month interventions.
Measurements were taken at 0, 2, 4 months.
Generation of allocation schedule and concealment of treatment allocation were unclear.
ITT analysis was not used.
Participants

8 stable children randomised (mean 11 years, range 8 - 14 years) mean FEV1 81% (range 63% - 98%).

Dornase alfa maintenance via eFlow rapid.
There were 3 withdrawals due to exacerbations, time of withdrawal not stated.

InterventionsDelivery before airway clearance techniques compared to delivery after airway clearance.
Times in relation to ACT (PEP or AD) unclear.
No placebo or washout.
Maintenance DNase.
OutcomesFEV1, QOL (Bespoke subjective questionnaire), FEF25.
Notes

Further data obtained from author.

PEDro 3/10 (Eligibility criteria: Yes; Random allocation: Yes; Concealed allocation: No; Baseline comparability: Yes; Blind participants: No; Blind therapists: No; Blind assessors: No (because not clearly stated); Adequate follow up: No; Intention-to-treat analysis: No; Between-group comparisons: Yes; Point estimates and variability: No).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised for 18 participants who were identified as potential participants, 8 were subsequently enrolled. The method of randomisation was not described.
Allocation concealment (selection bias)High riskInformation from the author suggests the assessor was aware of the allocation sequence.
Blinding (performance bias and detection bias)
All outcomes
High riskNo placebo. Unclear if the assessor blinded.
Incomplete outcome data (attrition bias)
All outcomes
High riskNot ITT. Unclear from which group the 3 dropouts occurred.
Selective reporting (reporting bias)Low riskQOL was reported as non-significant in the publication but data were not provided by authors.

Bishop 2011

MethodsRandomised, blinded, cross-over placebo-controlled trial with 2-week interventions, no washout.
Measurements were taken at: -14; 0;14; and 28 days.
Generation of allocation schedule and concealment of treatment allocation were clear.
ITT analysis was used.
Participants17 stable (monitored 2 weeks previously) adults randomised; mean (SD) age 27 years (range 19 years - 67 years), mean (SD) FEV1 63 (23) % predicted (range 20% - 97%).
InterventionsDelivery 30 minutes before airway clearance techniques compared to delivery immediately after airway clearance.
ACT= PEP or PD/percussion.
Dornase alfa naive.
Outcomes

FEV1, FVC, QOL (CFQ, VAS for well-being, cough, sputum volume, ease of clearance).

24 hr wet sputum weight, VO2max (10 or 20 minute shuttle), adherence (diary), adverse events.

Notes

Additional data from authors, manuscript pending publication (Bishop 2011).

PEDro 9/10 (Eligibility criteria: Yes; Random allocation: Yes; Concealed allocation: Yes; Baseline comparability: Yes; Blind participants: Yes; Blind therapists: Yes; Blind assessors: Yes; Adequate follow up: Yes; Intention-to-treat analysis: Yes; Between-group comparisons: Yes; Point estimates and variability: No).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBlock randomisation by an independent was used.
Allocation concealment (selection bias)Low riskIndependent distant pharmacy.
Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo used; participants, therapists and assessors blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskRaw data available.
Selective reporting (reporting bias)Low riskQOL, 24 hr wet sputum weight, VO2max, adherence and adverse events were reported as non-significant in the publication but data were not provided by authors.

Fitzgerald 2005

MethodsRandomised, blinded, cross-over placebo-controlled trial with 2-week interventions and 2-weeks washout.
Measurements were taken at 0, 2, 4 and 6 weeks.
Generation of allocation schedule and concealment of treatment allocation were clear.
ITT analysis was used.
Participants52 stable children randomised; mean (SD) age 10.7 (3.2) years; mean (SD) FEV1 83 (18) % predicted.
There were 2 withdrawals due to protocol violations (one nebulisation instead of two) in the second arm while inhaling dornase alfa after airway clearance.
InterventionsDelivery 30 minutes before airway clearance techniques compared to delivery 30 minutes after airway clearance.
ACT = 'physiotherapy' or PEP mask.
DNase naive.
Outcomes

FEV1, FVC, QOL (composite QWB).

VO2max (Shuttle), FEF25-75, adherence (vials returned), adverse events (34 in 26 participants including diverse symptoms - intervention group unclear).

Notes

Subgroup analysis FEV1 for those with Pseudomonas aeruginosa in the preceding 2 years (n = 17)

PEDro 9/10 (Eligibility criteria: Yes; Random allocation: Yes; Concealed allocation: Yes; Baseline comparability: No; Blind participants: Yes; Blind therapists: Yes; Blind assessors: Yes; Adequate follow up: Yes; Intention-to-treat analysis: Yes; Between-group comparisons: Yes; Point estimates and variability: Yes).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBlock randomisation by an independent investigator was used.
Allocation concealment (selection bias)Low riskIndependent distant pharmacy.
Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo used; participants, therapists and assessors blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low risk2 participants did not take both medications in the second arm.
Selective reporting (reporting bias)Low riskQOL, VO2max, FEF25-75 and adverse events and were reported as non-significant in the publication but data were not provided by authors.

van der Giessen 2007a

MethodsRandomised, blinded, cross-over placebo-controlled trial with 3-week interventions, no washout.
Measurements were taken at 0, 14, 21, 35 and 42 days.
Generation of allocation schedule and concealment of treatment allocation were unclear.
ITT analysis was not used.
Participants25 stable (no IV treatment 1 month previously) children randomised: mean age 12 years (range 7 years - 19 years), mean FEV1 88% predicted. One child dropped out while inhaling dornase alfa before airway clearance.
InterventionsDelivery 30 minutes before airway clearance techniques compared to delivery immediately after airway clearance.
ACT = PEP mask in 75%, Flutter in 13%, ACBT in 4%, AD in 4% and combination 4%.
Maintenance dornase alfa.
Outcomes

FEV1, FVC, symptom scores (VAS for cough and CSS day & night, sputum viscosity and amount).

FEF25-75, FEF25, Rint, adherence (vials), adverse events.

Notes PEDro 8/10 (Eligibility criteria: Yes; Random allocation: Yes; Concealed allocation: No; Baseline comparability: Yes; Blind participants: Yes; Blind therapists: Yes; Blind assessors: Yes; Adequate follow up: Yes; Intention-to-treat analysis: No; Between-group comparisons: Yes; Point estimates and variability: Yes).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStated as randomised but no method was described.
Allocation concealment (selection bias)Unclear riskMethod unclear.
Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo used; participants, therapists and assessors blinded.
Incomplete outcome data (attrition bias)
All outcomes
High riskNot analysed as ITT, one drop out due to exacerbation.
Selective reporting (reporting bias)Low riskAdherence data were only provided for the whole study cohort and not by study arm.

van der Giessen 2007b

  1. a

    ACT: airway clearance technique
    AD: autogenic drainage
    CFQ: cystic fibrosis questionnaire
    CSS: cough symptom score
    SD: standard deviation
    FEF25-75: mid-expiratory flow
    FEV1: forced expiratory volume at one second
    FVC: forced vital capacity
    ITT: intention-to-treat
    IV: intravenous
    FEF25: forced expiratory flow at 25% of FVC
    PD: postural drainage
    PEP: positive expiratory pressure
    QOL: quality of life
    QWB: quality of well-being scale
    Rint: resistance measured by the interrupter technique
    VAS: visual analogue scales
    VO2max: measure of the peak volume of oxygen (VO2) you can consume and use in a minute

MethodsRandomised, blinded, cross-over placebo-controlled trial with 2-week interventions, no washout.
Measurements were taken at 0, 14, 21 and 28 days.
Generation of allocation schedule was clear but concealment of treatment allocation was unclear.
ITT analysis was used.
Participants25 stable (no IV treatment 1 month previously) children randomised: mean age 13 years (range 6 years - 19 years); mean FEV1 75% predicted. One child dropped out while inhaling dornase alfa in the evening.
InterventionsMorning (on waking) compared to evening (before bedtime). ACT performed for 30 minutes post morning inhalation.
ACT not described.
Maintenance dornase alfa.
Outcomes

FEV1, FVC, symptom scores (VAS for cough and CSS day & night, sleep quality, sputum viscosity and amount).

FEF25, Rint, adherence (vials), adverse events (overnight oximetry and cough per hour recordings).

Notes PEDro 9/10 (Eligibility criteria: Yes; Random allocation: Yes; Concealed allocation: No; Baseline comparability: Yes; Blind participants: Yes; Blind therapists: Yes; Blind assessors: Yes; Adequate follow up: Yes; Intention-to-treat analysis: Yes; Between-group comparisons: Yes; Point estimates and variability: Yes).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStated as randomised but no method was described.
Allocation concealment (selection bias)Unclear riskMethod unclear.
Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo used; participants, therapists and assessors blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low risk1 drop out due to exacerbation, ITT applied.
Selective reporting (reporting bias)Low riskAdherence data were only provided for the whole study cohort and not by study arm.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    CF: cystic fibrosis
    RCT: randomised controlled trial

Adde 2004Not timing of dornase alfa.
Bakker 2011Not timing of dornase alfa.
Ballmann 2002Not timing of dornase alfa.
Bollert 1999Not an RCT, not dornase alfa, not timing of dornase alfa.
Dodd 2000Not timing of dornase alfa.
Frederiksen 2006Not timing of dornase alfa.
Fuchs 1994Timing of dornase alfa not addressed by the study.
Furuya 2001Timing of dornase alfa not addressed by the study.
Grassemann 2004Timing of dornase alfa not addressed by the study.
Griese 1997Timing of dornase alfa not addressed by the study.
Hagelberg 2008Timing of dornase alfa not addressed by the study.
Heijerman 1995Timing of dornase alfa not addressed by the study.
Hjelte 1997Timing of dornase alfa not addressed by the study.
Hubbard 1992Timing of dornase alfa not addressed by the study.
Lahiri 2012Timing of dornase alfa not addressed by the study.
Laube 1996Timing of dornase alfa not addressed by the study.
Laube 2005Timing of dornase alfa not addressed by the study.
Mainz 2008Timing of dornase alfa not addressed by the study.
Mainz 2010Timing of dornase alfa not addressed by the study.
Majaesic 1996Timing of dornase alfa not addressed by the study.
Malfroot 1999Dornase alfa not assessed in the study.
McCoy 1996Timing of dornase alfa not addressed by the study.
Minasian 2010Timing of dornase alfa not addressed by the study.
Nasr 2001Timing of dornase alfa not addressed by the study.
Quan 2001Timing of dornase alfa not addressed by the study.
Ramsey 1993Timing of dornase alfa not addressed by the study.
Ranasinha 1993Timing of dornase alfa not addressed by the study.
Riethmueller 2006Not CF participants, timing of dornase alfa not addressed in the study.
Robinson 2000Timing of dornase alfa not addressed by the study.
Robinson 2003Timing of dornase alfa not addressed by the study.
Shah 1994aTiming of dornase alfa not addressed by the study.
Shah 1994bTiming of dornase alfa not addressed by the study.
Shah 1995aNot an RCT, timing of dornase alfa not addressed by the study.
Shah 1995bTiming of dornase alfa not addressed by the study.
Shah 1995cTiming of dornase alfa not addressed by the study.
Smith 1994Timing of dornase alfa not addressed by the study.
Suri 2001aTiming of dornase alfa not addressed by the study.
ten Berge 1999Timing of dornase alfa not addressed by the study.
ten Berge 2003Timing of dornase alfa not addressed by the study.
Ungewitter 2000Timing of dornase alfa not addressed by the study.
Weck 1999Not an RCT, timing of dornase alfa not addressed in the study.
Wilmott 1996Timing of dornase alfa not addressed by the study.
Wilson 2007

Does not fit the timing interventions specified in this version of the protocol. Likely inclusion as a new timing intervention in future updates.

PEDro 6/10 (Eligibility criteria: Yes; Random allocation: Yes; Concealed allocation: Yes; Baseline comparability: No; Blind subjects: No; Blind therapists: No; Blind assessors: Yes; Adequate follow up: Yes; Intention-to-treat analysis: No; Between-group comparisons: Yes; Point estimates and variability: Yes).

Ancillary