Phase 1B, Randomized, Double-Blinded, Dose Escalation, Single-Center, Repeat Dose Safety and Pharmacodynamics Study of the Oral NLRP3 Inhibitor Dapansutrile in Subjects With NYHA II-III Systolic Heart Failure

J Cardiovasc Pharmacol. 2020 Oct 24;77(1):49-60. doi: 10.1097/FJC.0000000000000931.


The NLRP3 inflammasome has been implicated in the development and progression of heart failure. The aim of this study was to determine the safety of an oral inhibitor of the NLRP3 inflammasome, dapansutrile (OLT1177), in patients with heart failure and reduced ejection fraction (HFrEF). This was a phase 1B, randomized, double-blind, dose escalation, single-center, repeat dose safety and pharmacodynamics study of dapansutrile in stable patients with HFrEF (New York Heart Association Class II-III). Subjects were randomized to treatment with dapansutrile for up to 14 days at a ratio of 4:1 into 1 of 3 sequential ascending dose cohorts (500, 1000, or 2000 mg) each including 10 patients. Subjects underwent clinical assessment, biomarker determination, transthoracic echocardiogram, and maximal cardiopulmonary exercise testing at baseline, day 14, and day 28 to ascertain changes in clinical status. Placebo cases (N = 2 per cohort) were used as a decoy to reduce bias and not for statistical comparisons. Thirty participants (20 men) were treated for 13 (12-14) days. No serious adverse events during the study were recorded. All clinical or laboratory parameters at day 14 compared with baseline suggested clinical stability without significant within-group differences in the dapansutrile-pooled group or the 3 dapansutrile cohorts. Improvements in left ventricular EF [from 31.5% (27.5-39) to 36.5% (27.5-45), P = 0.039] and in exercise time [from 570 (399.5-627) to 616 (446.5-688) seconds, P = 0.039] were seen in the dapansutrile 2000 mg cohort. Treatment with dapansutrile for 14 days was safe and well tolerated in patients with stable HFrEF.

Trial registration: NCT03534297.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Anti-Inflammatory Agents / administration & dosage*
  • Anti-Inflammatory Agents / adverse effects
  • Anti-Inflammatory Agents / pharmacokinetics
  • Double-Blind Method
  • Exercise Tolerance / drug effects
  • Female
  • Heart Failure, Systolic / diagnosis
  • Heart Failure, Systolic / drug therapy*
  • Heart Failure, Systolic / physiopathology
  • Humans
  • Male
  • Middle Aged
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
  • Nitriles / administration & dosage*
  • Nitriles / adverse effects
  • Nitriles / pharmacokinetics
  • Recovery of Function
  • Stroke Volume / drug effects
  • Time Factors
  • Treatment Outcome
  • Ventricular Function, Left / drug effects
  • Virginia


  • Anti-Inflammatory Agents
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nitriles
  • dapansutrile

Associated data