Safety & Efficacy of VX-371 in CF patients Homozygous for F508del-CFTR
Research type
Research Study
Full title
A Phase 2a, Randomized, Double-blind, Placebo-controlled, Incomplete Block, Crossover Study to Evaluate the Safety and Efficacy of VX-371 in Subjects Aged 12 Years or Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation, and Being Treated With Orkambi
IRAS ID
200188
Contact name
Alex Horsley
Contact email
Sponsor organisation
Vertex Pharmaceuticals, Inc.
Eudract number
2015-004841-13
Duration of Study in the UK
0 years, 10 months, 13 days
Research summary
Cystic fibrosis (CF) is a genetic disease that affects an estimated 70,000 children and adults worldwide, it is characterised by thick, sticky mucus making sufferers prone to respiratory infections. Healthy airways are protected by a thin layer of mucus which defends the airway by trapped inhaled particles, bacteria and pollutants. This is then moved out of the lung by a process known as mucocilliary clearance. Small hairs (cillia) on the surface of airway cells move the mucus to the mouth where it is expectorated or swallowed. In CF, the airway mucus is dehydrated, which prevents the action of cillia and leads to mucus accumulation in the lungs. A vicious cycle of airway blockage, infection and subsequently airway destruction is established. In patients with CF average life expectancy with currently available therapies is mid-40s.
CF is caused by an abnormal CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, the most common mutation is known as DF508 mutation. Current treatments work to increase fluidity of the mucus by decreasing the thickness or hydrating the cell surface using a variety of methods; Orkambi, is a combination oral therapy which increases mucus fluidity and corrects the CTFR mutation. Amiloride, an Inhaled therapy, inhibits ENaC (an airway sodium channel that is inappropriately upregulated in CF due to lack of inhibition by faulty CFTR), but has several characteristics that make it impractical as a therapy. Newer generations have additional features that more specifically target the ENaC channel and do not have as many side effects.
VX-371 is a unique, new chemical entity belonging to amiloride family that inhibits ENaC by directly blocking it. A laboratory study found that, when compared to a control substance, VX-371 combined with Orkambi significantly increased mucus fluidity at 8 and 48 hours when compared to the control substance and VX-371 alone. Significantly increased functioning of the cillia at 48 hours was also found when compared to Orkambi alone.This study will evaluate the safety and efficacy of VX-371 formulated with 4.2% Hypertonic Saline (HS), in comparison to 4.2% HS alone plus standard of care drugs on lung function over 28 days of treatment in CF patients, over 12, with the F508del-CFTR mutation. Participants will be randomized to 1 of the 4 treatment sequences comprised of ‘treatment Period 1’, ‘Washout’ and ‘Treatment Period 2’.
REC name
North West - Greater Manchester South Research Ethics Committee
REC reference
16/NW/0262
Date of REC Opinion
8 Jun 2016
REC opinion
Further Information Favourable Opinion