Title: A randomised double-blind placebo controlled Phase 2B clinical trial of repeated application of gene therapy in patients with Cystic Fibrosis
Funder: Department of Health (England)

Abstract: RESEARCH DESIGN: Double-blind placebo controlled parallel group study of monthly aerosol of gene therapy formulation over 12 months. POPULATION: Inclusion: a) Confirmed diagnosis of Cystic Fibrosis; b) 12 years or older; c) Mild to moderate lung disease based on FEV1 of 50-90% predicted; d) Any CFTR mutation; e) Clinical stability for 4 weeks prior to first dose; f) Written informed consent from patient (16 years or older) or parent if younger child; assent from a child; g) Willing to adhere to contraceptive requirements. Exclusion: a) Current participation in another interventional trial; b) Infection with Burkholderia cepacia complex organisms Mycobacterium abscessus or MRSA; c) Previous spontaneous pneumothorax unless pleurodesed (bronchoscopic group only); d) Recurrent severe haemoptysis; e) Current smoker; f) Significant comorbidity; g) Using second line immunosuppressants; h) Pregnant or breast-feeding. INTERVENTIONS: Twelve 5 ml doses of pGM169/GL67A or placebo (0.9% saline) delivered via an AeroEclipse nebuliser at four weekly intervals; subgroup (n=24) to be dosed nasally. OUTCOME MEASURES: a) Primary: Percent change in percent predicted FEV1 from baseline to after the 12th dose. b) Secondary: Lung clearance index chest CT scan Quality of Life measures (using CFQ-UK validated questionnaire) other spirometric markers exercise capacity activity monitoring serum calprotectin sputum microbiology cell counts and soluble inflammatory markers. Gene expression: Transgene mRNA and potential difference in nose and lung (subgroup only). ASSESSMENT AND FOLLOW UP: Subjects will undergo: screening 12 x dosing and 2 x follow up at 14 and 28 days after the 12th dose. The first 20 patients will undergo visits on Day 2 post-dosing for the first three doses. SAMPLE SIZE: Based on our extensive data from the Run-in Study we estimate the standard deviation (SD) of the percent change in percent predicted FEV1 over 12 months to be 10.0%. 120 evaluable patients (60 active 60 placebo) will give us 90% power at the 5% significance level (2-sided) to detect a difference of 6% between the randomised groups in the mean change from baseline. This is widely considered clinically relevant. STATISTICAL ANALYSIS: Comparison of the two randomised groups in terms of mean percent change in percent predicted FEV1 from baseline to end of treatment. An analysis of covariance (ANCOVA) model will include baseline percent predicted FEV1 together with the other variables used in the randomisation algorithm as covariates. The treatment effect will be presented as an adjusted difference in mean percent change along with its corresponding 95% confidence interval. TIMETABLE: Start March 2012 with first dosing May 2012; the majority of the patients are already recruited. Completion of: three doses in first 20 subjects (Aug 2012); all patients receiving one dose (Dec 2012); final dosing in all patients (Dec 2013); data analysis (Mar 2014).


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;5.2 CELLULAR AND GENE THERAPIES
Health categories: CONGENITAL DISORDERS