A monthly inhaled gene therapy is being tested in 120 cystic fibrosis patients to see if repeated doses can stabilise or improve lung function over a year. Cystic fibrosis is caused by a faulty gene that makes mucus in the lungs thick and sticky, leading to repeated infections and gradual lung damage. Existing drugs target only specific genetic mutations, leaving many patients without effective treatment. This trial uses a formulation called pGM169/GL67A, which delivers a working copy of the CFTR gene directly into lung cells via a nebuliser, regardless of the patient’s underlying mutation. If it works, it could offer a universal, mutation-agnostic therapy that slows or halts lung decline, reducing hospitalisations and extending life expectancy for people with cystic fibrosis. The primary outcome is a 6% improvement in FEV1, a standard measure of lung function, which clinicians consider meaningful. The trial is double-blind and placebo-controlled, with 60 patients receiving the gene therapy and 60 receiving saline, dosed monthly for 12 months. Results are expected in 2014.
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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).
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