A Study of the Effect of IW-1973 on the Exercise Capacity of Patients With Heart Failure With Preserved Ejection Fraction (HFpEF)

• IW-1973 (Drug): Oral Tablet
• Placebo Oral Tablet (Drug): Oral Tablet

Primary outcomes

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Study Drug-related TEAEs [Day 1 up to Day 113]: An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TEAEs are defined as those adverse events (AEs) that started or worsened in severity after the administration of study drug. Causality relationship to study drug was per Investigator assessment. Number of participants with TEAEs and study drug-related TEAEs is presented.
• Change From Baseline in Peak Oxygen Consumption (VO2) at Week 12 [Baseline and Week 12]: Peak VO2 was obtained from Cardiopulmonary Exercise Test (CPET), which was used to evaluate the effect of praliciguat on peak exercise capacity. Baseline is defined as the last non-missing measurement prior to the first dose of study drug. Change from Baseline was calculated by subtracting Baseline value from the Week 12 value. Data were analyzed using an analysis of covariance (ANCOVA) model with treatment group and atrial fibrillation stratification factors as categorical variable terms and Baseline peak VO2 value as a covariate. Milliliter O2 per kilogram per minute = mL O2/kg/min

Secondary outcomes

• Change From Baseline in 6-minute Walk Test (6MWT) Distance at Week 12 [Baseline and Week 12]: 6MWT was a simple assessment of everyday functional capacity and provided a global evaluation of the organ/physiologic systems involved in exercise. 6MWT assessed the distance travelled in 6 minutes, measured at approximately the same time of day. Baseline is defined as the last non-missing measurement prior to the first dose of study drug. Change from Baseline was calculated by subtracting Baseline value from the Week 12 value. Data were analyzed using an ANCOVA model with treatment group, atrial fibrillation stratification factor and peak VO2 stratification factor as categorical variable terms and Baseline value as a covariate.
• Change From Baseline in Ventilatory Efficiency at Week 12 [Baseline and Week 12]: Ventilatory efficiency was defined as minute ventilation/carbon dioxide (VE/VCO2) slope, production and was obtained from CPET. Baseline is defined as the last non-missing measurement prior to the first dose of study drug. Change from Baseline was calculated by subtracting Baseline value from the Week 12 value. Data were analyzed using an ANCOVA model with treatment group, atrial fibrillation stratification factor and peak VO2 stratification factor as categorical variable terms and baseline value as a covariate.
• CPET Responders at Week 12 [At Week 12]: CPET responders were defined as participants who improved by at least 1.5 mL O2/kg/min in peak VO2 from Baseline to Week 12. Baseline is defined as the last non-missing measurement prior to the first dose of study drug.

Sex: All, ages: 45 Years to any

Inclusion Criteria:

1. Patient is an ambulatory male or female ≥45 years old at the Screening Visit
2. Patient has heart failure with ejection fraction (EF) of ≥40%
3. Patient has a peak VO2 measuring <80% of age- and sex-adjusted normal values
4. Patient has evidence in medical history supporting clinical heart failure syndrome consisting of at least 1 of the following:

   1. Hospitalization or emergency department visit for heart failure within the past year
   2. Elevated B-type natriuretic peptide (BNP) or N-terminal pro b-type natriuretic peptide (NT-proBNP) within the past 6 months
   3. Echocardiographic evidence within the past 12 months of at least 2 of the following: left ventricular (LV) hypertrophy, left atrial (LA) enlargement, or diastolic dysfunction
   4. Hemodynamic evidence of elevated filling pressures
5. Patient meets at least 2 of the following criteria at the Screening Visit:

   1. Diagnosis of type 2 diabetes mellitus or prediabetes
   2. History of hypertension
   3. Body mass index (BMI) >30 kg/m2
   4. Age ≥70 years

Exclusion Criteria:

1. Patient has had acute coronary syndrome or percutaneous coronary intervention within 30 days before Randomization
2. Patient has had cardiac transplantation or has cardiac transplantation planned during the study
3. Patient has had cardiac artery bypass graft, cardiac mechanical support implantation, or other cardiac surgery in the 3 months before the Screening Visit or planned during the study
4. Patient has severe chronic obstructive coronary disease as defined by chronic oxygen dependence
5. Patient had had heart failure hospitalization with discharge within 30 days before the Screening Visit
6. Patient has a history of clinically significant hypersensitivity or allergies to any of the inactive ingredients contained in the active or placebo drug products
7. Patient has previously received IW-1973 in a study, or received an investigational drug during the 30 days or 5 half lives of that investigational drug (whichever is longer) before the Screening Visit, or is planning to receive another investigational drug at any time during the study
8. Patient is taking specific inhibitors of phosphodiesterase 5 (PDE5), nonspecific inhibitors of PDE5, any supplements for the treatment of erectile dysfunction, riociguat, or nitrates or nitric oxide (NO) donors in any form
9. Patient is taking strong cytochrome P450 3A (CYP3A) inhibitors
10. Women of childbearing potential must have a negative pregnancy test prior to randomization and must agree to use protocol-specified contraception from the Screening Visit through 60 days after the final dose of study drug
11. Male patients must be surgically sterile by vasectomy (conducted ≥60 days before the Screening Visit or confirmed via sperm analysis) or must agree to use protocol-specified contraception from the Screening Visit through 60 days after the final dose of study drug
12. Other exclusion criteria per protocol

Participant flow

Outcome results

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Study Drug-related TEAEs (Primary), Count of participants, Participants: Placebo 61; Praliciguat 10 mg 4; Praliciguat 20 mg 6; Praliciguat 40 mg 72
• Change From Baseline in Peak Oxygen Consumption (VO2) at Week 12 (Primary), Least squares mean, mL O2/kg/min: Placebo 0.04 (-0.49 to 0.56); Praliciguat 40 mg -0.26 (-0.83 to 0.31) (p =0.3681)
• Change From Baseline in 6-minute Walk Test (6MWT) Distance at Week 12 (Secondary), Least squares mean, Meters: Placebo 58.12 (26.12 to 90.11); Praliciguat 40 mg 41.38 (8.25 to 74.50) (p =0.2817)
• Change From Baseline in Ventilatory Efficiency at Week 12 (Secondary), Least squares mean, VE/VCO2 Slope: Placebo 0.564 (-0.780 to 1.908); Praliciguat 40 mg 0.267 (-1.118 to 1.652) (p =0.6508)
• CPET Responders at Week 12 (Secondary), Count of participants, Participants: Placebo 17; Praliciguat 40 mg 13

Adverse events

Time frame: From first dose of study drug (Day 1) up to Follow-up Visit (Day 113)

Serious adverse events by term

Other adverse events by term

116 more terms not shown.

Limitations and caveats: Due to changes in study objectives and design (protocol amendment 3), all efficacy analyses was performed using only the praliciguat 40 mg and placebo groups; the praliciguat 10 mg and 20 mg groups were excluded from all efficacy analysis. For completeness, participants treated with both 10 mg and 20 mg praliciguat are included in the AE summaries for safety analyses, as well as for Participant Flow and Baseline Characteristics.

• Results publication: Udelson JE, Lewis GD, Shah SJ, Zile MR, Redfield MM, Burnett J Jr, Parker J, Seferovic JP, Wilson P, Mittleman RS, Profy AT, Konstam MA. Effect of Praliciguat on Peak Rate of Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction: The CAPACITY HFpEF Randomized Clinical Trial. JAMA. 2020 Oct 20;324(15):1522-1531. doi: 10.1001/jama.2020.16641. PMID 33079154
• Results publication: Udelson JE, Lewis GD, Shah SJ, Zile MR, Redfield MM, Burnett J Jr, Mittleman RS, Profy AT, Seferovic JP, Reasner D, Konstam MA. Rationale and design for a multicenter, randomized, double-blind, placebo-controlled, phase 2 study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator praliciguat over 12 weeks in patients with heart failure with preserved ejection fraction (CAPACITY HFpEF). Am Heart J. 2020 Apr;222:183-190. doi: 10.1016/j.ahj.2020.01.009. Epub 2020 Jan 21. PMID 32105984

• Study Protocol (PDF, 2018-06-27)
• Statistical Analysis Plan (PDF, 2019-06-13)

• Jelena Seferovic, MD PhD, Study director, Cyclerion Therapeutics, Inc.