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Timing of dornase alfa inhalation for cystic fibrosis

  1. Ruth Dentice*,
  2. Mark Elkins

Editorial Group: Cochrane Cystic Fibrosis and Genetic Disorders Group

Published Online: 5 JUN 2013

Assessed as up-to-date: 2 MAY 2013

DOI: 10.1002/14651858.CD007923.pub3


How to Cite

Dentice R, Elkins M. Timing of dornase alfa inhalation for cystic fibrosis. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD007923. DOI: 10.1002/14651858.CD007923.pub3.

Author Information

  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.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 5 JUN 2013

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This is not the most recent version of the article. View current version (26 JUL 2016)

 
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.


Participants8 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.


NotesFurther 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.


OutcomesFEV1, 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.


NotesAdditional 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.


OutcomesFEV1, FVC, QOL (composite QWB).

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


NotesSubgroup 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.


OutcomesFEV1, FVC, symptom scores (VAS for cough and CSS day & night, sputum viscosity and amount).

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


NotesPEDro 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

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.


OutcomesFEV1, 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).


NotesPEDro 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

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 2007Does 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).

 
Comparison 1. Pre-ACT versus Post-ACT

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 FEV1 (L)4Mean Difference (Fixed, 95% CI)Subtotals only

    1.1 Over 1 week and up to 2 months
4Mean Difference (Fixed, 95% CI)-0.03 [-0.08, 0.03]

 2 FEV1 (% pred)4Mean Difference (Fixed, 95% CI)Subtotals only

    2.1 Over 1 week and up to 2 months
4Mean Difference (Fixed, 95% CI)-0.83 [-2.96, 1.31]

 3 FVC (L)2Mean Difference (Fixed, 95% CI)Subtotals only

    3.1 Over 1 week and up to 2 months
2Mean Difference (Fixed, 95% CI)0.01 [-0.05, 0.08]

 4 FVC (% pred)2Mean Difference (Fixed, 95% CI)Subtotals only

    4.1 Over 1 week and up to 2 months
2Mean Difference (Fixed, 95% CI)1.06 [-1.29, 3.41]

 5 FEF25-75 (% pred)1Mean Difference (Fixed, 95% CI)Totals not selected

    5.1 Over 1 week and up to 2 months
1Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]

 6 FEF25 (L)2Mean Difference (Fixed, 95% CI)Subtotals only

    6.1 Over 1 week and up to 2 months
2Mean Difference (Fixed, 95% CI)-0.17 [-0.28, -0.05]

 7 FEF25 (% pred)2Mean Difference (Fixed, 95% CI)Subtotals only

    7.1 Over 1 week and up to 2 months
2Mean Difference (Fixed, 95% CI)-5.44 [-9.23, -1.66]

 
Comparison 2. Morning versus Evening

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 FEV1 (L)1Mean Difference (Fixed, 95% CI)Totals not selected

    1.1 Over 1 week and up to 2 months
1Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]

 2 FEV1 (% pred)1Mean Difference (Fixed, 95% CI)Totals not selected

    2.1 Over 1 week and up to 2 months
1Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]

 3 FVC (L)1Mean Difference (Fixed, 95% CI)Totals not selected

    3.1 Over 1 week and up to 2 months
1Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]

 4 FVC (% pred)1Mean Difference (Fixed, 95% CI)Totals not selected

    4.1 Over 1 week and up to 2 months
1Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]

 5 FEF25 (% pred)1Mean Difference (Fixed, 95% CI)Totals not selected

    5.1 Over 1 week and up to 2 months
1Mean Difference (Fixed, 95% CI)0.0 [0.0, 0.0]

 
Table 1. Symptom Scores from van der Giessen 2007a

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

 Data are mean (or median if asterisked) and range
CSS: cough symptom score
VAS: visual analogue scale
 
Table 2. Symptom scores from van der Giessen 2007b

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

 Mean (SD)
CSS: cough symptom score
VAS: visual analogue scale