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Original Investigation
June 4, 2019

Effect of Neladenoson Bialanate on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial

Author Affiliations
  • 1Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 2University of Groningen, Groningen, the Netherlands
  • 3University of Glasgow, Glasgow, Scotland
  • 4Wake Forest School of Medicine, Winston-Salem, North Carolina
  • 5Bayer AG, Leverkusen, Germany
  • 6Bayer United States, Whippany, New Jersey
  • 7Brigham and Women’s Hospital, Boston, Massachusetts
JAMA. 2019;321(21):2101-2112. doi:10.1001/jama.2019.6717
Key Points

Question  In patients with heart failure with preserved ejection fraction, what is the effect of neladenoson bialanate, a partial adenosine A1 receptor agonist, on exercise capacity?

Findings  In this phase 2b randomized clinical trial that included 305 patients randomized to receive neladenoson (5 mg, 10 mg, 20 mg, 30 mg, or 40 mg) or placebo, there was no significant dose-response relationship detected for neladenoson with regard to the change in the 6-minute walk test distance from baseline to 20 weeks.

Meaning  In light of these findings, novel approaches will be needed if further development of neladenoson for the treatment of patients with heart failure with preserved ejection fraction is pursued.

Abstract

Importance  Heart failure with preserved ejection fraction (HFpEF) lacks effective treatments. Based on preclinical studies, neladenoson bialanate, a first-in-class partial adenosine A1 receptor agonist, has the potential to improve several heart failure–related cardiac and noncardiac abnormalities but has not been evaluated to treat HFpEF.

Objectives  To determine whether neladenoson improves exercise capacity, physical activity, cardiac biomarkers, and quality of life in patients with HFpEF and to find the optimal dose.

Design, Setting, and Participants  Phase 2b randomized clinical trial conducted at 76 centers in the United States, Europe, and Japan. Patients (N = 305) with New York Heart Association class II or III HFpEF with elevated natriuretic peptide levels were enrolled between May 10, 2017, and December 7, 2017 (date of final follow-up: June 20, 2018).

Interventions  Participants were randomized (1:2:2:2:2:3) to neladenoson (n = 27 [5 mg], n = 50 [10 mg], n = 51 [20 mg], n = 50 [30 mg], and n = 51 [40 mg]) or matching placebo (n = 76) for 20 weeks of treatment.

Main Outcomes and Measures  The primary end point was change in 6-minute walk test distance from baseline to 20 weeks (minimal clinically important difference, 40 m). Key safety measures included bradyarrhythmias and adverse events. To evaluate the effects of varying doses of neladenoson, a multiple comparison procedure with 5 modeling techniques (linear, Emax, 2 variations of sigmoidal Emax, and quadratic) was used to evaluate diverse dose-response profiles.

Results  Among 305 patients who were randomized (mean age, 74 years; 160 [53%] women; mean 6-minute walk test distance, 321.5 m), 261 (86%) completed the trial and were included in the primary analysis. After 20 weeks of treatment, the mean absolute changes from baseline in 6-minute walk test distance were 0.2 m (95% CI, −12.1 to 12.4 m) for the placebo group; 19.4 m (95% CI, −10.8 to 49.7 m) for the 5 mg of neladenoson group; 29.4 m (95% CI, 3.0 to 55.8 m) for 10 mg of neladenoson group; 13.8 m (95% CI, −2.3 to 29.8 m) for 20 mg of neladenoson group; 16.3 m (95% CI, −1.1 to 33.6 m) for 30 mg of neladenoson group; and 13.0 m (95% CI, −5.9 to 31.9 m) for 40 mg of neladenoson group. Because none of the neladenoson groups achieved the clinically relevant 40-m increase in 6-minute walk test distance from baseline, an optimal dose of neladenoson was not identified. There was no significant dose-response relationship for the change in 6-minute walk test distance among the 5 different dose-response models (P = .05 for Emax; P = .18 for quadratic; P = .21 for sigmoidal Emax 1; P = .39 for linear; and P = .52 for sigmoidal Emax 2). Serious adverse events were similar among the neladenoson groups (61/229 [26.6%]) and the placebo group (21/76 [27.6%]).

Conclusions and Relevance  Among patients with HFpEF, there was no significant dose-response relationship detected for neladenoson with regard to the change in exercise capacity from baseline to 20 weeks. In light of these findings, novel approaches will be needed if further development of neladenoson for the treatment of patients with HFpEF is pursued.

Trial Registration  ClinicalTrials.gov Identifier: NCT03098979

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