Safety, tolerability and early signs of efficacy with riociguat for the treatment of adult Phe508del homozygous cystic fibrosis patients: study design and rationale for the Rio-CF study

Objectives: The only available CFTR-modulating therapy for CF patients homozygous for the Phe508del mutation is ivacaftor + lumacaftor. Preclinical data indicate that the soluble guanylate cyclase stimulator riociguat may improve CFTR channel function. The primary objectives of the Rio-CF study are to assess safety, tolerability and early signs of efficacy of riociguat in patients not receiving CFTR modulator therapy; secondary objectives include safety and efficacy in patients on background ivacaftor + lumacaftor therapy, and PK of riociguat in CF patients. Methods: Rio-CF is a sequential group, multicentre, international, Phase II trial. Eligibility criteria include adult CF patients homozygous for Phe508del with mild-to-moderate obstructive disease (predicted FEV1 of 40–100% and stable lung disease). In part 1, patients were randomised (1:2) to placebo or riociguat 0.5 mg tid for 14 days followed by 1 mg tid for 14 days. In part 2, following positive review by an independent Data Safety Monitoring Board, 24 patients will be enrolled and separated equally into two groups: a) patients not on ivacaftor + lumacaftor and b) patients receiving ivacaftor + lumacaftor. Patients will receive four dose levels of riociguat (0.25, 0.5, 1, 2 mg tid) for 14 days each. Safety and tolerability will be continuously monitored according to AEs; efficacy will be explored by change in sweat chloride content. Results: Recruitment to part 1 is complete with 21 patients (mean age 27.8 [range 19–40] years; 16 [76%] men) randomised. Conclusion: The study will yield preliminary data on the safety, tolerability and ability of riociguat to improve Phe508del CFTR function as a potential CF therapy