The UK CF GTC 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 administration would be required, and that therefore a non-viral approach was needed. We demonstrated in laboratory and preclinical models that GL67A (Genzyme Corp) was the optimal gene transfer agent, and designed a plasmid, pGM169, completely depleted of pro-inflammatory CpG motifs and driven by the novel hCEFI promoter, designed for prolonged expression. 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 a) choose our primary outcome (FEV1), b) secondary efficacy outcomes (lung clearance index, various parameters on CT scan, Quality of life questionnaire [CFQ-R], exercise 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). We have recently completed a single-dose safety and dose ranging study.
In this trial, 130 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. 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. Patients will be invited to participate in either one or two substudies, 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 recruitment, projected time-lines and progress.
Funded by the MRC and NIHR through the EME programme.