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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Shah reported receiving personal fees from Amgen, Bayer, Boehringer-Ingelheim, Cardiora, Eisai, Ionis, Ironwood, MyoKardia, Merck, Sanofi, and United Therapeutics; receiving grants and personal fees from Actelion, AstraZeneca, and Novartis; and receiving grants from the National Institutes of Health, the American Heart Association, and Corvia. Dr Voors reported receiving personal fees from Amgen, Applied Therpautics, AstraZeneca, Bayer, Boehringer-Ingelheim, Cytokinetics, GlaxoSmithKline, Myokardia, Novartis, and Servier; and receiving grants and personal fees from Roche Diagnostics. Dr McMurray reported receiving personal fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Cardurion, DalCor Pharmaceuticals, GlaxoSmithKline, Merck, Novartis, and Theracos. Glasgow University was paid by Bayer for Dr McMurray’s time spent as a steering committee member for the PANACHE trial. These payments were made through a consultancy with Glasgow University, but Dr McMurray was not paid personal payments in relation to this trial or drug. Dr Kitzman reported receiving grants and personal fees from Bayer, Novartis, and St Luke’s Medical; and receiving personal fees from Merck, Boerhinger Ingelheim, Corvia, Abbvie, CinRx, Akros, AstraZeneca, GlaxoSmithKlein, Duke Clinical Research Institute, and Gilead. Dr Viethen reported being an employee of Bayer AG (sponsor of the study). Dr Bomfim Wirtz reported reported being an employee and receiving personal fees from Bayer AG. Dr Huang reported being an employee of Bayer AG. Mr Pap reported reported being an employee and receiving personal fees from Bayer AG. Dr Solomon reported receiving grants and personal fees from Bayer; receiving grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, the National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and receiving personal fees from Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. No other disclosures were reported.

Figures

Figure 1.. Study Participant Disposition Flowchart

Information about the number of patients approached was not collected. No study drug was administered during the run-in period, which was only used for familiarization testing for the 6-minute walk test and for collecting data on the continuous electrocardiographic monitoring patch. According to the trial protocol, certain exclusion criteria could be evaluated during the run-in period (eg, 6-minute walk test distance, blood pressure, heart rate); patients who met these exclusion criteria were excluded during the run-in period. Participants were randomized (1:2:2:2:2:3) to neladenoson (5 mg, 10 mg, 20 mg, 30 mg, and 40 mg) or matching placebo for 20 weeks of treatment. All participants enrolled in the study received at least 1 dose of their assigned treatment.

Figure 2.. Changes in Primary and Secondary Efficacy End Points From Baseline to 20 Weeks

Box-and-whisker plots display median (middle line in the box), 25th percentile (lower end of box), 75th percentile (upper end of box) and 1.5 × the interquartile range (whiskers). KCCQ indicates Kansas City Cardiomyopathy Questionnaire.