PMID- 31481106 OWN - NLM STAT- MEDLINE DCOM- 20200826 LR - 20200826 IS - 1478-6362 (Electronic) IS - 1478-6354 (Print) IS - 1478-6354 (Linking) VI - 21 IP - 1 DP - 2019 Sep 3 TI - A multicenter randomized, double-blind, placebo-controlled pilot study to assess the efficacy and safety of riociguat in systemic sclerosis-associated digital ulcers. PG - 202 LID - 10.1186/s13075-019-1979-7 [doi] LID - 202 AB - 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. FAU - Nagaraja, Vivek AU - Nagaraja V AD - Division of Rheumatology/Department of Internal Medicine, University of Michigan Scleroderma Program, Suite 7C27, 300 North Ingalls Street, SPC 5422, Ann Arbor, MI, 48109, USA. FAU - Spino, Cathie AU - Spino C AD - Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA. FAU - Bush, Erica AU - Bush E AD - Division of Rheumatology/Department of Internal Medicine, University of Michigan Scleroderma Program, Suite 7C27, 300 North Ingalls Street, SPC 5422, Ann Arbor, MI, 48109, USA. FAU - Tsou, Pei-Suen AU - Tsou PS AD - Division of Rheumatology/Department of Internal Medicine, University of Michigan Scleroderma Program, Suite 7C27, 300 North Ingalls Street, SPC 5422, Ann Arbor, MI, 48109, USA. FAU - Domsic, Robyn T AU - Domsic RT AD - Division of Rheumatology and Clinical Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. FAU - Lafyatis, Robert AU - Lafyatis R AD - Division of Rheumatology and Clinical Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. FAU - Frech, Tracy AU - Frech T AD - Division of Rheumatology, University of Utah, Salt Lake City, UT, USA. FAU - Gordon, Jessica K AU - Gordon JK AD - Division of Rheumatology, Hospital of Special Surgery, New York, NY, USA. FAU - Steen, Virginia D AU - Steen VD AD - Division of Rheumatology, Georgetown University Medical Center, Washington, DC, USA. FAU - Khanna, Dinesh AU - Khanna D AD - Division of Rheumatology/Department of Internal Medicine, University of Michigan Scleroderma Program, Suite 7C27, 300 North Ingalls Street, SPC 5422, Ann Arbor, MI, 48109, USA. khannad@med.umich.edu. LA - eng SI - ClinicalTrials.gov/NCT02915835 GR - K24 AR063120/AR/NIAMS NIH HHS/United States GR - none/Merck Sharp and Dohme/International PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20190903 PL - England TA - Arthritis Res Ther JT - Arthritis research & therapy JID - 101154438 RN - 0 (Enzyme Activators) RN - 0 (Pyrazoles) RN - 0 (Pyrimidines) RN - RU3FE2Y4XI (riociguat) SB - IM MH - Adult MH - Dose-Response Relationship, Drug MH - Double-Blind Method MH - Enzyme Activators/therapeutic use MH - Female MH - Finger Phalanges MH - Follow-Up Studies MH - Humans MH - Male MH - Middle Aged MH - Pilot Projects MH - Pyrazoles/*therapeutic use MH - Pyrimidines/*therapeutic use MH - Scleroderma, Systemic/*complications/diagnosis/drug therapy MH - Skin Ulcer/chemically induced/diagnosis/*drug therapy MH - Treatment Outcome PMC - PMC6724329 OTO - NOTNLM OT - Clinical trial OT - Digital ulcers OT - Riociguat OT - Systemic sclerosis COIS- 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. EDAT- 2019/09/05 06:00 MHDA- 2020/08/28 06:00 PMCR- 2019/09/03 CRDT- 2019/09/05 06:00 PHST- 2019/06/10 00:00 [received] PHST- 2019/08/16 00:00 [accepted] PHST- 2019/09/05 06:00 [entrez] PHST- 2019/09/05 06:00 [pubmed] PHST- 2020/08/28 06:00 [medline] PHST- 2019/09/03 00:00 [pmc-release] AID - 10.1186/s13075-019-1979-7 [pii] AID - 1979 [pii] AID - 10.1186/s13075-019-1979-7 [doi] PST - epublish SO - Arthritis Res Ther. 2019 Sep 3;21(1):202. doi: 10.1186/s13075-019-1979-7.