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Intervention Review

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Topical cystic fibrosis transmembrane conductance regulator gene replacement for cystic fibrosis-related lung disease

  1. Tim WR Lee1,*,
  2. Kevin W Southern2

Editorial Group: Cochrane Cystic Fibrosis and Genetic Disorders Group

Published Online: 26 NOV 2013

Assessed as up-to-date: 19 SEP 2013

DOI: 10.1002/14651858.CD005599.pub4


How to Cite

Lee TWR, Southern KW. Topical cystic fibrosis transmembrane conductance regulator gene replacement for cystic fibrosis-related lung disease. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD005599. DOI: 10.1002/14651858.CD005599.pub4.

Author Information

  1. 1

    A Floor, Clarendon Wing, Leeds General Infirmary, Leeds Regional Paediatric Cystic Fibrosis Centre, Leeds, West Yorkshire, UK

  2. 2

    University of Liverpool, Department of Women's and Children's Health, Liverpool, Merseyside, UK

*Tim WR Lee, Leeds Regional Paediatric Cystic Fibrosis Centre, A Floor, Clarendon Wing, Leeds General Infirmary, Great George Street, Leeds, West Yorkshire, LS1 3EX, UK. timlee@doctors.org.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 26 NOV 2013

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This is not the most recent version of the article. View current version (17 JUN 2016)

 
Characteristics of included studies [ordered by study ID]
Alton 1999

MethodsDouble-blind randomised placebo-controlled trial, parallel design, intention-to-treat basis.

Single centre in UK.


Participants16 participants (all male). Treatment group n = 8, placebo group n = 8.

Mean age 26.9 years. Mean (SE) age: treatment group 27·5 (3·4) years, placebo group 26·3 (1·7) years.
Confirmed CF, FEV1 >70%, sterile.

Genotype (not split by treatment/placebo group):

∆F508/∆F508 n = 12

∆F508/W1282X n = 1

∆F508/other (ie, no mutation detected after screening for mutations present in 92–94% of UK patients with CF) n = 3.


InterventionsSingle dose of CFTR DNA+liposome, or liposome alone nebulised to lungs.


OutcomesAdverse events, gene expression, CFTR protein expression, airway potential difference.


NotesAdditional data requested from author, no additional data available.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised, but no further details given.

Allocation concealment (selection bias)Unclear riskNot discussed.

Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and outcome assessors blinded.

Incomplete outcome data (attrition bias)
All outcomes
High riskAll randomised participants assessed on intention-to-treat basis, although data incomplete for 4 reported endpoints.

Selective reporting (reporting bias)Unclear riskUnclear.

Other biasUnclear riskUnclear.

Moss 2004

MethodsDouble-blind randomised placebo controlled trial, parallel design, intention-to-treat basis.

Multicentre - 8 CF centres in the USA.


Participants37 participants (15 male, 22 female).

Treatment group n = 20 (6 male, 14 female), placebo group n = 17 (9 male, 8 female).
Mean age 23.7 years. Mean (SD) age: in treatment group 24.2 (8.7) years; in placebo group 23.2(11.1) years.
Confirmed CF, FEV1 >60%. Mean (SD) FEV1: in treatment group 82.2 (19.3) and in placebo group 84.4 (15.1),P = 0.70.

Genotype:

F508 homozygous: treatment group 5 (25%), placebo group 13 (77%).

F508 heterozygous: treatment group 12 (60%), placebo group 2 (12%).

Other/unknown: treatment group 3 (15%), placebo group 2 (12%).


Interventions1x10(13) particles tgAAVCF 3 times (30 day interval) or matching placebo, nebulised to lungs.


OutcomesRespiratory exacerbations, adverse events, lung function, inpatient episodes, acquisition of new pathogens, gene expression, change in CT score.


NotesAdditional data requested from author, original data provided.

Power calculation undertaken - paper states " Enrollment of 18 subjects per treatment group provided adequate power to test differences between treatment groups with respect to the primary and secondary protocol end points "


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised, but no further details given.

Allocation concealment (selection bias)Unclear riskNot discussed.

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, no further details.

Incomplete outcome data (attrition bias)
All outcomes
High risk42 participants randomised, 37 received at least one dose of study drug, 35 completed all 3 doses.
Not clear if withdrawals in placebo or active group, data pooled for 37 participants receiving at least 1 dose. Only 35 participants underwent HRCT lung scans, and just 10 had vector-specific CFTR gene expression assessed.

The first participant, who had received one dose of study medication, was withdrawn from the study as a result of a FDA hold on the research. The second participant was withdrawn prior to dosing, then later was re-screened and was re-randomized, but withdrew consent prior to dosing. 3 other participants withdrew consent after randomization but prior to starting treatment because of heavy work schedule, concern about potential risks, and a change of mind, respectively.

Selective reporting (reporting bias)Unclear riskUnclear.

Other biasHigh riskThe placebo group had significantly more ΔF508 homozygous participants (77%) than the CFTR gene replacement group (25%) (P = 0.01).

Moss 2007

MethodsDouble-blind randomised placebo controlled trial, parallel design, intention-to-treat basis.

Multicentre - 12 centres in USA.


Participants122 people screened, 109 randomised and 102 participants (54 male, 48 female) received treatment. 98 completed study and 4 stopped early (reasons given - see below).

Treatment group n = 51 (26 male), placebo group n = 51 (28 male).
Mean age 22.6 years, all aged over 12 years. Mean (SD) age: treatment group 23.9 (10.9) years, placebo group 21.3 (8.7) years.
Confirmed CF, FEV1 >60% predicted. Mean (SD) FEV1 % predicted: treatment group 84.7 (13.7), placebo group 87.9 (15.5).

Genotype:

AF508 homozygous: treatment group 27 (53%), placebo group 27 (53%).

AF508 heterozygous: treatment group 18 (35%), placebo group 20 (39%).


Interventions1x10(13) particles tgAAVCF 2 times (30 day interval) or matching placebo, nebulised to lungs.


OutcomesRespiratory exacerbations, adverse events, lung function.


NotesAdditional data requested from author, original data provided.

Sample size calculation based on the initial phase 2 multidose aerosol study. "Enrollment of 100 subjects, 50 in each treatment arm, would provide 93% power to detect a 0.14- liter difference in the 30-day change in FEV1 between treatment groups, assuming a standard deviation of the change of 0.20 liter in each group. This sample size would also provide adequate power for detecting 0.3 log10-ng/ml differences between treatment groups in IL-8."


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as randomised, but no further details given.

Allocation concealment (selection bias)Unclear riskNot discussed.

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, no further details.

Incomplete outcome data (attrition bias)
All outcomes
Low risk109 participants randomised, of whom 102 received at least 1 dose of study drug, 98 completed trial - 4 participants stopped early. Of these, 1 was in the tgAAVCF treatment group and 3 were in the placebo group. The reason the participant from the tgAAVCF group discontinued was loss to follow-up. Reasons for discontinuation in the 3 placebo recipients included experiencing an adverse event (unlikely to be related pulmonary exacerbation), death (unrelated motorcycle accident), and other (no response to day 210 phone call).

Selective reporting (reporting bias)High riskSome relevant secondary endpoints, such as number of days of oral antibiotic use, remain unreported

Other biasUnclear riskUnclear.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Davies 2011Not a randomised controlled trial

Flotte 1996Not a randomised controlled trial

Gill 1997Applied to nose not to lungs

Harvey 1999Not a randomised controlled trial

Hyde 2000Applied to nose not to lungs

Joseph 2001Not a randomised controlled trial

Knowles 1995Applied to nose not to lungs

Noone 2000Not a randomised controlled trial

Porteous 1997Applied to nose not to lungs

Wagner 1999Applied to sinuses not lungs

Wagner 2002Applied to sinuses not lungs

Zabner 1996Not randomised controlled trial

Zabner 1997Not randomised controlled trial

Zuckerman 1999Not a randomised controlled trial

 
Characteristics of ongoing studies [ordered by study ID]
Alton 2012

Trial name or titleA randomised, double-blind, placebo-controlled phase 2B clinical trial of repeated application of gene therapy in patients with CF.

MethodsDouble-blind, randomised, placebo-controlled, parallel design.

ParticipantsApproximately 130 individuals with confirmed CF aged 12 years and over.

InterventionsAerosolised delivery of pGM169/GL67A, or placebo (0.9% saline) to lungs, 12 doses per patient, 4 weeks apart over 48 weeks.

OutcomesLung function, lung clearance index, HRCT score, respiratory exacerbations, safety.

Starting date2013.

Contact informationProf Eric Alton (e.alton@imperial.ac.uk), Professor of Gene Therapy, Imperial College, London, UK.

NotesLikely to report late 2014 or early 2015.

 
Comparison 1. CFTR gene replacement therapy versus placebo

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

 1 Respiratory exacerbations (episodes)2Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 5 - 6 months
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 7 - 10 months
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Change in FEV1 (L) from baseline3Mean Difference (IV, Fixed, 95% CI)Subtotals only

    2.1 At <24 hours
116Mean Difference (IV, Fixed, 95% CI)-1.40 [-3.07, 0.27]

    2.2 At 1 - 30 days
2139Mean Difference (IV, Fixed, 95% CI)0.06 [-0.00, 0.13]

    2.3 At 1 - 2 months
2138Mean Difference (IV, Fixed, 95% CI)-0.05 [-0.12, 0.02]

 3 Change in FEV1 % predicted from baseline2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    3.1 At 1 - 30 days
2139Mean Difference (IV, Fixed, 95% CI)1.48 [-0.43, 3.39]

    3.2 At 1 - 2 months
2138Mean Difference (IV, Fixed, 95% CI)-2.03 [-4.21, 0.14]

 4 Change in FVC3Mean Difference (IV, Fixed, 95% CI)Subtotals only

    4.1 At <24 hours
116Mean Difference (IV, Fixed, 95% CI)-1.70 [-3.27, -0.13]

    4.2 At 1 - 30 days
2139Mean Difference (IV, Fixed, 95% CI)0.02 [-0.05, 0.09]

    4.3 At 1 - 2 months
2138Mean Difference (IV, Fixed, 95% CI)-0.06 [-0.13, 0.02]

 5 Number of inpatient episodes1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    5.1 Within 5 - 6 months
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Adverse events3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Mild airway symptoms (Alton-pooled: Cough, wheeze, tight chest)
116Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.57, 1.76]

    6.2 Rhinitis
2139Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.67, 1.14]

    6.3 Pharyngitis
2139Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.76, 1.70]

    6.4 Headache
2139Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.51, 1.45]

    6.5 Sinusitis
2139Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.53, 1.54]

    6.6 Moderate: Influenza type symptoms (Alton: pooled)
116Risk Ratio (M-H, Fixed, 95% CI)7.0 [1.10, 44.61]

    6.7 Abdominal pain
2139Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.36, 1.20]

    6.8 Asthma
2139Risk Ratio (M-H, Fixed, 95% CI)1.94 [0.48, 7.91]

    6.9 Chest pain
2139Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.50, 1.57]

    6.10 Cough
137Risk Ratio (M-H, Fixed, 95% CI)6.0 [0.33, 108.56]

    6.11 Increased cough
2139Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.71, 1.10]

    6.12 Dyspnoea
2139Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.38, 2.84]

    6.13 Fatigue
137Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.44, 2.12]

    6.14 Fever
2139Risk Ratio (M-H, Fixed, 95% CI)1.36 [0.79, 2.36]

    6.15 Decreased lung function
2139Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.63, 2.18]

    6.16 Increased Sputum
2139Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.61, 1.20]

    6.17 Severe (Alton: pooled)
116Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.18 CF lung exacerbation
2139Risk Ratio (M-H, Fixed, 95% CI)1.40 [0.75, 2.61]

    6.19 Hemoptysis
2139Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.32, 2.47]

    6.20 Lung disorder
137Risk Ratio (M-H, Fixed, 95% CI)1.28 [0.43, 3.78]

 7 Lower airway potential difference change from baseline1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    7.1 Day 1 - 30
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Lower airway potential difference change from baseline (amiloride and low chloride)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    8.1 Response to perfusion with amiloride
116Mean Difference (IV, Fixed, 95% CI)3.90 [-9.76, 17.56]

    8.2 Response to perfusion with zero chloride solution
116Mean Difference (IV, Fixed, 95% CI)6.86 [3.77, 9.95]

 9 Measurement of CFTR protein expression (SPQ chloride efflux)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

 10 Change in validated computerised tomogram (CT) score1Mean Difference (IV, Fixed, 95% CI)Subtotals only

 
Table 1. Primary outcomes measured

Study nameRespiratory exacerbationsLung functionDays in hospitalSurvival

Alton 1999Not measured.Measured, but only at 6 hours post-dose to monitor for adverse effects.

Reported in this review.
Not measured.Not measured.

Moss 2004Measured respiratory exacerbations requiring IV antibiotics within 150 days.

Reported in this review.
Measured FEV1, FEV1 % predicted, FVC, at baseline, 30, 60, 90 and 150 days.

Day 30 and 60 data reported in this review.
Not measured, although number of inpatient episodes within 150 days measured.

Reported in this review.
Not measured.

Moss 2007Measured respiratory exacerbations requiring IV antibiotics within 210 days.

Reported in this review.
Measured FEV1, FEV1 % predicted, FVC, at baseline, 14, 30, 45, 60, 75 and 90 days.

Day 30 and 60 data reported in this review.
Not measured.Not measured.

 FEV1: forced expiratory volume in one second
FVC: forced expiratory volume
IV: intravenous
 
Table 2. Secondary outcomes measured

Study nameExtra treatmentAdverse eventsQuality of lifeSchool or work daysNutritionNew pathogensSputum rheologyMucus clearanceAirway PD

Alton 1999Not measured.Measured.

Reported in this review.
Not measured.Not measured.Not measured.Not measured.Not measured.Only measured saccharine nasal mucociliary clearance, this is not an efficacy measure for CFTR gene replacement therapy to the lung.

Not reported.
Measured baseline potential difference, response to perfusion with amiloride, and response to low chloride solution and isoprenaline, measured at baseline and 2 days after study drug.

Reported in review.

Moss 2004Not measured.Measured to 150 days.

Reported in this review.
Not measured.Not measured.Not measured.Measured Pseudomonas aeruginosa and Staphylococcus aureus, (at baseline and Day 90) but data is incomplete.

Reported in review.
Not measured.Not measured.Not measured.

Moss 2007Not measured.Measured to 210 days.

Reported in this review.
Not measured.Not measured.Not measured.Not measured.Not measured.Not measured.Not measured.