Pediatic Pulmonology, 47 S35 Abstract 245
The North American Cystic Fibrosis Conference, Orlando, 2012
The UK CF Gene Therapy Consortium has been working for several years to determine the clinical benefit of CFTR gene therapy. Our premise was that for such a therapy to achieve clinical benefit, repeated administra- tion would be required, and that therefore a non-viral approach was needed. We demonstrated in laboratory and preclinical animal models that the cationic lipid, GL67A, originally developed by Genzyme Corp, was the optimal gene transfer agent, and designed a plasmid, pGM169, completely depleted of pro-inflammatory CpG motifs and driven by the EF1α promot- er designed for prolonged expression (Hyde SC et al. Nat Biotech 2008). In a longitudinal observational study (the Run-in) we measured the variability of multiple outcome measures, both conventional and novel. These data have allowed us to perform power calculations and choose a) our primary outcome (FEV1), b) secondary efficacy outcomes (lung clearance index, various parameters on CT scan, quality of life questionnaire [CFQ-R], exer- cise capacity and activity, and selected sputum and serum inflammatory markers), and c) safety measures (clinical findings, exacerbation rate, gas transfer, sputum culture, serum inflammatory markers, renal and hepatic markers). The Run-in study also allowed us to identify the patients most suitable to progress to the trial. We excluded two subgroups a) too severe: those with such heterogeneity of pulmonary deposition on isotope scanning that successful delivery of the topical agent was considered unlikely or who had significant impairment of FEV1 (<50% predicted) and b) too mild: FEV1 > 90% predicted, in whom a primary outcome signal might not be achiev- able. One hundred patients, aged 12 years, and above are being randomised in a 1:1 fashion to active treatment or placebo and will receive the nebulised agent at monthly intervals for 12 doses at a dose determined from our recently completed single dose (Pilot) study. The group size was determined on the basis of a 6% relative improvement in FEV1. An adaptive design will be used for additional safety; the first 20 patients will receive 3 doses ahead of the rest of the cohort. Safety data will be examined by an independent committee following which, should there be no major concerns, the rest of the group will begin dosing. If safety is an issue, the administered dose will be halved. Patients will be invited to participate in either one, or both, sub- studies, being conducted to explore mechanisms; a) nasal administration followed by nasal potential difference (PD) and brushings for mRNA expression and b) pre- and post-treatment bronchoscopies for lower airway PD, gene expression and histology. The double-blinded nature of the trial means that final outcome data will only be available upon completion of the study. The trial was initiated in April 2012; here we will update on recruit- ment, projected time-lines and progress. Funded by the Cystic Fibrois Trust and the MRC and NIHR through the EME programme.