Riociguat for the Treatment of Raynaud's Phenomenon: A Single-Dose, Double-Blind, Randomized, Placebo-Controlled Cross-Over Pilot Study (DIGIT)

Clin Drug Investig. 2018 Nov;38(11):1061-1069. doi: 10.1007/s40261-018-0698-1.


Background and objective: Raynaud's phenomenon (RP) is characterized by transient digital ischemia and is commonly associated with connective tissue disease. Treatment remains unsatisfactory. Here we evaluate the efficacy, safety, and pharmacokinetics of a single dose of the soluble guanylate cyclase stimulator riociguat in RP.

Methods: DIGIT was a double-blind, randomized, placebo-controlled pilot study. Patients with primary or secondary RP were randomized to a single oral dose of riociguat 2 mg or placebo in a cross-over design (7 ± 3 days). Efficacy was assessed as placebo-corrected change in digital blood flow 2 h post-dose at room temperature (RT) or following cold exposure (CE), measured by laser-speckle contrast analysis. Patients were regarded as responders if placebo-corrected digital blood flow increased by ≥ 10% from baseline at RT or after CE.

Results: Of 20 eligible patients, 17 (85%) were female and mean [standard deviation (SD)] age was 52 (13.8) years. Placebo-corrected changes in digital blood flow were + 46% [90% confidence interval (CI) - 6 to + 98] at RT and - 9% (90% CI - 63 to + 44) after CE, with high inter-individual variability. Eight patients (40%) were responders at RT, and 12 (60%) after CE. Riociguat increased mean (SD) digital blood flow in responders at RT by + 136% (114) and in responders following CE by + 39% (53). Riociguat was well tolerated, with few adverse events.

Conclusion: In this pilot study, single-dose riociguat was well tolerated in patients with RP and resulted in improved digital blood flow in some patient subsets, with high inter-individual variability. Long-term evaluation is warranted.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Blood Flow Velocity / drug effects*
  • Blood Flow Velocity / physiology
  • Cross-Over Studies
  • Double-Blind Method
  • Enzyme Activators / administration & dosage*
  • Female
  • Fingers / blood supply*
  • Humans
  • Male
  • Middle Aged
  • Pilot Projects
  • Pyrazoles / administration & dosage*
  • Pyrimidines / administration & dosage*
  • Raynaud Disease / diagnosis
  • Raynaud Disease / drug therapy*
  • Raynaud Disease / physiopathology
  • Treatment Outcome


  • Enzyme Activators
  • Pyrazoles
  • Pyrimidines
  • riociguat