Cochrane systematic reviews of mutation specific therapies for patients with cystic fibrosis

Patel, Sanjay
Cochrane systematic reviews of mutation specific therapies for patients with cystic fibrosis. Master of Philosophy thesis, University of Liverpool.

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Cystic Fibrosis (CF) is the most common inherited condition amongst people of European descent. It is caused by a mutation in the CFTR gene located on chromosome 7, and codes for the CFTR protein. Mutations in the CFTR gene lead to the characteristic features of CF, namely progressive and irreversible lung disease which is responsible for the majority of premature deaths in CF. Recently, research into the management of CF has shifted towards personalised genomic medicine. New classes of drugs called mutation-specific-therapies have been designed to target the mutation specific defects in CFTR protein synthesis or function. They have shown to restore the gating defect of class III mutations (CFTR potentiators) and intracellular processing defect of class II mutations (CFTR correctors) in cell studies. Both CFTR potentiators and CFTR correctors have progressed to human clinical trials. Cochrane systematic reviews are the gold standard for establishing the current evidence base for interventions. Objective To conduct two Cochrane systematic reviews to evaluate the benefits and harms of 1) CFTR potentiators (for class III-IV mutations) and 2) CFTR correctors (for class II mutations) on clinically important outcomes in children and adults with CF. Methods Systematic reviews were conducted according to peer assessed and published review protocol. Relevant studies were identified by searching the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and hand searching of journals and conference abstract books. We also searched the clinical trial registries maintained by the EMA, the US NIH and the WHO and contacted leading researches and industry for relevant trials. We included only RCTs of parallel design that met pre-defined eligibility criteria. Two authors independently extracted data and assessed the risk of bias in included trials. If appropriate, data were combined in a meta-analysis. Results Studies with patients with the G551D mutation demonstrated a clinically relevant impact of Ivacaftor on outcomes at 24 and 48 weeks providing evidence for the use of Ivacaftor (CFTR potentiator) in patients with G551D mutation (Class III). There is no evidence to support the short-term use of CFTR correctors, CFTR potentiators, or both as combination therapy in patients with the ΔF508 mutation (class II mutation). As patients with Class II mutations comprise a significant proportion of all CF patients, identifying an efficacious CFTR corrector (or CFTR corrector and CFTR potentiator combination) will have a profound impact on the field.

Item Type: Thesis (Master of Philosophy)
Additional Information: Date: 2014-08 (completed)
Depositing User: Symplectic Admin
Date Deposited: 10 Feb 2015 09:53
Last Modified: 17 Dec 2022 01:05
DOI: 10.17638/02003339