A multicenter randomized, double-blind, placebo-controlled pilot study to assess the efficacy and safety of riociguat in systemic sclerosis-associated digital ulcers

Abstract

Background: To determine the effect of riociguat, an oral, selective soluble guanylate cyclase stimulator, on the net digital ulcer (DU) burden in systemic sclerosis (SSc).

Methods: Participants with SSc-related active or painful indeterminate DUs were recruited in a multicenter, double-blind, randomized, placebo-controlled, proof-of-concept trial. Eligible participants were required to have at least one visible, active ischemic DU or painful indeterminate DU at screening, located at or distal to the proximal interphalangeal joint and that developed or worsened within 8 weeks prior to screening. Participants were randomized 1:1 to placebo or riociguat in individualized doses (maximum of 2.5 mg three times daily) during an 8-week titration period, followed by an 8-week stable dosing period. This was followed by an optional 16-week open-label extension phase for participants with active DU/reoccurrence of DUs within 1 month of the end of the main treatment phase. The primary endpoint was the change from baseline to week 16 in net ulcer burden (NUB), analyzed using ANCOVA. Other endpoints included plasma biomarkers and proportion of participants with treatment-emergent adverse events (AEs).

Results: Seventeen participants (eight placebo, nine riociguat) were randomized at five centers. Six participants in each group transitioned to the open-label extension. Baseline characteristics were comparable between the treatment groups, except participants randomized to placebo were older and had longer disease duration (p < 0.05). At baseline, the mean (SD) NUB was 2.5 (2.0) in the placebo and 2.4 (1.4) in the riociguat. No significant treatment difference was observed in the change from baseline to 16 weeks in NUB (adjusted mean treatment difference - 0.24, 95% CI (- 1.46, 0.99), p = 0.70). Four participants experienced five serious AE (four in riociguat and one in placebo); none was considered related to study medication. Statistically significant elevation of cGMP was observed at 16 weeks in the riociguat group (p = 0.05); no other biomarkers showed significant changes. In the open-label extension, participants in the riociguat-riociguat arm had complete healing of their DUs.

Conclusion: In participants with SSc-DU, treatment with riociguat did not reduce the number of DU net burden compared with placebo at 16 weeks. Open-label extension suggests that longer duration is needed to promote DU healing, which needs to be confirmed in a new trial.

Trial registration: ClinicalTrials.gov, NCT02915835 . Registered on September 27, 2016.

Keywords: Clinical trial; Digital ulcers; Riociguat; Systemic sclerosis.

Conflict of interest statement

Dr. Robyn Domsic has worked as a consultant for paid consultant for Eicos Sciences Inc. and Boehringer-Ingelheim. Dr. Robert Lafyatis has received grant support from PRISM Biolab, Regeneron, Elpidera, and Kiniksa. He has served as a consultant for PRISM Biolab, Merck, Bristol Myers Squibb, Biocon, UCB, Formation, Sanofi, and Genentech/Roche. Dr. Jessica Gordon has received grant support from Corbus Pharmaceuticals and Cumberland Pharmaceuticals. Dr. Dinesh Khanna has served as a consultant for Actelion, Acceleron, BMS, Blade Therapeutics, Boehringer Ingelham, Bayer, ChemomAB, Cytori, Celgene, Curzion, Corbus Pharmaceuticals, CSL Behring, GSK, Genentech, Mitsubishi Tanabe Pharma Development America, Sanofi-Aventis, and UCB. He has stocks in Eicos Sciences, Inc. and has employment with CiviBio Pharma, Inc. He has received grant support from Bristol Myers Squibb, Pfizer, Bayer, and Horizon. The rest of the authors declare that they have no competing interests.

Figures

Fig. 1

Consort diagram

Fig. 2

Study design

Fig. 3

Mean trend over time: change in net ulcer burden. Digital ulcer net burden is defined as the total number of “active” and indeterminate digital ulcers at an assessment. LS, least squares; SE, standard error; CI, confidence interval. Estimates are from an ANCOVA model with terms for the treatment group and baseline digital net ulcer burden. Modified intent-to-treat population is defined as all participants randomized, receiving at least one dose of treatment, and having at least one post-baseline efficacy assessment