Repeated Application of Gene Therapy in CF Patients
Cystic fibrosis is a genetic condition where epithelial cells, including from the respiratory tract, have an abnormal function of a surface protein, the cystic fibrosis transmembrane conductance regulator (CFTR) protein resulting from abnormal gene expression. The trial will assess the clinical efficacy, safety & tolerability and gene expression following repeated nebulised doses of a gene product coding for a normal CFTR protein, with the primary outcome of the trial assessing lung function.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Official Title:||A Randomised, Double-blind, Placebo-controlled Phase 2B Clinical Trial of Repeated Application of Gene Therapy in Patients With Cystic Fibrosis|
- Relative change in percent predicted FEV1 after 12 doses of gene product [ Time Frame: 12-months ] [ Designated as safety issue: Yes ]
- EFFICACY [ Time Frame: 12-months ] [ Designated as safety issue: No ]Relative change in other spirometric measures; lung clearance index; chest CT scan; Quality of Life Questionnaires; exercise capacity; activity monitoring; serum calprotectin; sputum culture; sputum weight, cell counts and inflammatory markers; frequency of antibiotics for increased chest symptoms
- SAFETY [ Time Frame: 12-months ] [ Designated as safety issue: Yes ]The above efficacy measures; clinical examination; transcutaneous oxygen saturation; serum inflammatory markers (CRP, white blood cell count,cytokines); renal and hepatic function; gas transfer; immune response markers (anti-nuclear and double-stranded DNA antibodies, CFTR-specific T cell responses); endobronchial histology (subgroup only)
- GENE EXPRESSION(subgroups only) [ Time Frame: 12-months ] [ Designated as safety issue: No ]Transgene mRNA expression in nasal and lower airway brushing samples; potential difference measurements in nose and bronchi.
|Study Start Date:||May 2012|
|Estimated Primary Completion Date:||June 2014 (Final data collection date for primary outcome measure)|
|Active Comparator: pGM169/GL67A (CFTR Gene/Lipid Vector)||
5ml Gene Product/Lipid Vector pGM169/GL67A nebulised; 2ml nasal application of pGM169/GL67A in addition to 5ml nebulised gene product (Nasal Subgroup)
|Placebo Comparator: Placebo||
5ml Nebulised non-active placebo; 2ml nasal administration of non-active placebo (nasal subgroup)
Cystic fibrosis (CF), a common, genetically inherited disease, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This gene encodes the CFTR protein, which is expressed on the apical surface of epithelial cells, and which has many functions, the most important of which is thought to be ion transport. Abnormal ion transport leads to thick secretions in the airways, infection, inflammation and eventually irreversible lung damage. There is currently no treatment that halts the natural progression of the disease; all available successful therapies merely slow the rate of decline in clinical condition.
To date, no viral gene transfer agents retain efficacy upon repeated administration. Our study will assess the safety and efficacy of a lipid-mediated vector harbouring a normal CFTR gene in repeated nebulised administrations. We have completed a single dose safety study which evaluated the safety and gene expression of a single dose of pGM169/GL67A administered to the nose and lung of individuals with cystic fibrosis.
This trial is will randomise 130-patients to receive either a gene product (pGM169/GL67A)encoding for CFTR or placebo in a double-blinded fashion. All subjects will receive 12 doses of nebulised gene therapy at intervals of 4 weeks over a 48 week period. After dose 12 there will be 2 formal follow up visits, at 14 and 28 days post-dose. In addition, patients will be followed up long-term.
Subgroups of patients will be enrolled for gene expression measurement in both nose (at least n=20) and lower airway via bronchoscopy (at least n=20).
The primary outcome of the trial is to evaluate the relative change in predicted Forced Expiratory Volume in 1-second (FEV1) after 12-doses. Secondary outcome measures will assess the efficacy of the gene product (by assessment of patients' physiological function, serological indices, radiological appearances of the lungs and self-reported assessment of quality of life), on the degree of gene expression and on the product safely.
|Royal Hospital for Sick Children|
|Edinburgh, United Kingdom, EH9 1LF|
|Western General Hospital|
|Edinburgh, United Kingdom, EH4 2XU|
|Royal Brompton Hospital|
|London, United Kingdom, SW3 6NP|
|Study Director:||Eric Alton, MD, FMedSci||Imperial College London|
|Principal Investigator:||Jane Davies, MD||Imperial College London|
|Principal Investigator:||Uta Griesenbach, PhD||Imperial College London|
|Principal Investigator:||Steve Hyde, MA, DPhil||Oxford University|
|Principal Investigator:||Deborah Gill, PhD||Oxford University|
|Principal Investigator:||Chris Boyd, PhD||Edinburgh University|
|Principal Investigator:||David Porteous, FMedSci||Edinburgh University|
|Principal Investigator:||Alastair Innes, PhD||Edinburgh University|
|Principal Investigator:||Steve Cunningham, PhD||Edinburgh University|