Heart Failure With Preserved Ejection Fraction
Conditions
Keywords
Heart Failure, Cardiovascular, HF, HFpEF
Brief summary
The objective of the CAPACITY-HFpEF study is to evaluate the safety and efficacy of IW-1973 compared with placebo when administered daily for approximately 12 weeks to patients with HFpEF. The study will evaluate the effect of oral IW-1973 on peak exercise capacity in patients with HFpEF, with or without permanent or persistent atrial fibrillation.
Interventions
DRUGIW-1973
Oral Tablet
DRUGPlacebo Oral Tablet
Oral Tablet
Sponsors
Cyclerion Therapeutics
Akebia Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Canada, United States
Participant flow
Recruitment details
This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and efficacy of different doses of praliciguat (IW-1973) compared with placebo in participants with heart failure with preserved ejection fraction (HFpEF).
Pre-assignment details
A total of 196 participants were enrolled in the study. Participants enrolled under protocol amendment 2 (or earlier) were randomized in a 1:1:1:1 ratio to 10 milligrams (mg) praliciguat, 20 mg praliciguat, 40 mg praliciguat, or placebo. Participants enrolled under protocol amendment 3 were randomized in a 1:1 ratio to either 40 mg praliciguat or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were randomized to receive matching placebo orally for 12 weeks: 2 weeks of twice daily (BID) dosing followed by 10 weeks of once daily (QD) dosing. | 90 |
| Praliciguat 10 mg Participants were randomized to receive praliciguat 10 mg orally for 12 weeks: 2 weeks of BID dosing followed by 10 weeks of QD dosing. | 7 |
| Praliciguat 20 mg Participants were randomized to receive praliciguat 20 mg orally for 12 weeks: 2 weeks of BID dosing followed by 10 weeks of QD dosing. | 7 |
| Praliciguat 40 mg Participants were randomized to receive praliciguat 40 mg orally for 12 weeks: 2 weeks of BID dosing followed by 10 weeks of QD dosing. | 92 |
| Total | 196 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 | 0 | 6 |
| Overall Study | Death | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Overall Study | Other | 1 | 0 | 0 | 2 |
| Overall Study | Protocol Violation | 6 | 0 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | Placebo | Praliciguat 10 mg | Praliciguat 20 mg | Praliciguat 40 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 70.1 years STANDARD_DEVIATION 9 | 67.3 years STANDARD_DEVIATION 9.6 | 69.1 years STANDARD_DEVIATION 4.6 | 70.8 years STANDARD_DEVIATION 9.1 | 70.3 years STANDARD_DEVIATION 8.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 0 Participants | 0 Participants | 20 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 69 Participants | 7 Participants | 7 Participants | 72 Participants | 155 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 1 Participants | 2 Participants | 17 Participants | 39 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 65 Participants | 6 Participants | 5 Participants | 72 Participants | 148 Participants |
| Sex: Female, Male Female | 40 Participants | 5 Participants | 3 Participants | 35 Participants | 83 Participants |
| Sex: Female, Male Male | 50 Participants | 2 Participants | 4 Participants | 57 Participants | 113 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 90 | 0 / 7 | 0 / 7 | 1 / 91 |
| other Total, other adverse events | 58 / 90 | 4 / 7 | 6 / 7 | 68 / 91 |
| serious Total, serious adverse events | 9 / 90 | 0 / 7 | 0 / 7 | 10 / 91 |
Outcome results
Primary
Change From Baseline in Peak Oxygen Consumption (VO2) at 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
Time frame: Baseline and Week 12
Population: Evaluable Population consisted of all participants in the modified (m)ITT population who completed 8 weeks of dosing (±3 days) and had at least 1 evaluable post-Baseline assessment and did not have a dose reduction. Only those participants with data available at the specified data points were analyzed. Following protocol amendment 3, efficacy analyses included only the praliciguat 40 mg and placebo groups; the praliciguat 10 mg and 20 mg groups were excluded from all efficacy analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Peak Oxygen Consumption (VO2) at Week 12 | 0.04 mL O2/kg/min |
| Praliciguat 10 mg | Change From Baseline in Peak Oxygen Consumption (VO2) at Week 12 | -0.26 mL O2/kg/min |
p-value: =0.368195% CI: [-0.95, 0.35]ANCOVA
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Study Drug-related TEAEs
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.
Time frame: Day 1 up to Day 113
Population: Safety Population consisted of all randomized participants who took at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Study Drug-related TEAEs | TEAEs | 61 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Study Drug-related TEAEs | Study drug-related TEAEs | 9 Participants |
| Praliciguat 10 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Study Drug-related TEAEs | Study drug-related TEAEs | 1 Participants |
| Praliciguat 10 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Study Drug-related TEAEs | TEAEs | 4 Participants |
| Praliciguat 20 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Study Drug-related TEAEs | TEAEs | 6 Participants |
| Praliciguat 20 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Study Drug-related TEAEs | Study drug-related TEAEs | 0 Participants |
| Praliciguat 40 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Study Drug-related TEAEs | TEAEs | 72 Participants |
| Praliciguat 40 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Study Drug-related TEAEs | Study drug-related TEAEs | 22 Participants |
Secondary
Change From Baseline in 6-minute Walk Test (6MWT) Distance at 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.
Time frame: Baseline and Week 12
Population: Evaluable Population. Only those participants with data available at the specified data points were analyzed. Following protocol amendment 3, efficacy analyses included only the praliciguat 40 mg and placebo groups; the praliciguat 10 mg and 20 mg groups were excluded from all efficacy analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in 6-minute Walk Test (6MWT) Distance at Week 12 | 58.12 Meters |
| Praliciguat 10 mg | Change From Baseline in 6-minute Walk Test (6MWT) Distance at Week 12 | 41.38 Meters |
p-value: =0.281795% CI: [-47.38, 13.9]ANCOVA
Secondary
Change From Baseline in Ventilatory Efficiency at 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.
Time frame: Baseline and Week 12
Population: Evaluable Population. Only those participants with data available at the specified data points were analyzed. Following protocol amendment 3, efficacy analyses included only the praliciguat 40 mg and placebo groups; the praliciguat 10 mg and 20 mg groups were excluded from all efficacy analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Ventilatory Efficiency at Week 12 | 0.564 VE/VCO2 Slope |
| Praliciguat 10 mg | Change From Baseline in Ventilatory Efficiency at Week 12 | 0.267 VE/VCO2 Slope |
p-value: =0.650895% CI: [-1.591, 0.997]ANCOVA
Secondary
CPET Responders 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.
Time frame: At Week 12
Population: Evaluable Population. Only those participants with data available at the specified data points were analyzed. Following protocol amendment 3, efficacy analyses included only the praliciguat 40 mg and placebo groups; the praliciguat 10 mg and 20 mg groups were excluded from all efficacy analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | CPET Responders at Week 12 | 17 Participants |
| Praliciguat 10 mg | CPET Responders at Week 12 | 13 Participants |