Trial Outcomes & Findings for A Study of the Effect of IW-1973 on the Exercise Capacity of Patients With Heart Failure With Preserved Ejection Fraction (HFpEF) (NCT NCT03254485)

Last Updated: 2022-09-15

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

196 participants

Primary outcome timeframe

Day 1 up to Day 113

Results posted on

2022-09-15

Participant Flow

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).

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.

Participant milestones

Participant milestones
Measure	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.	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.	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.	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.
Overall Study STARTED	90	7	7	92
Overall Study COMPLETED	78	7	7	77
Overall Study NOT COMPLETED	12	0	0	15

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study Adverse Event	3	6
Overall Study Protocol Violation	6	2
Overall Study Withdrawal by Subject	1	4
Overall Study Death	0	1
Overall Study Lost to Follow-up	1	0
Overall Study Other	1	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=90 Participants 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.	Praliciguat 10 mg n=7 Participants Participants were randomized to receive praliciguat 10 mg orally for 12 weeks: 2 weeks of BID dosing followed by 10 weeks of QD dosing.	Praliciguat 20 mg n=7 Participants Participants were randomized to receive praliciguat 20 mg orally for 12 weeks: 2 weeks of BID dosing followed by 10 weeks of QD dosing.	Praliciguat 40 mg n=92 Participants Participants were randomized to receive praliciguat 40 mg orally for 12 weeks: 2 weeks of BID dosing followed by 10 weeks of QD dosing.	Total n=196 Participants Total of all reporting groups
Age, Continuous	70.1 years STANDARD_DEVIATION 9.0 • n=93 Participants	67.3 years STANDARD_DEVIATION 9.6 • n=4 Participants	69.1 years STANDARD_DEVIATION 4.6 • n=27 Participants	70.8 years STANDARD_DEVIATION 9.1 • n=483 Participants	70.3 years STANDARD_DEVIATION 8.9 • n=36 Participants
Sex: Female, Male Female	40 Participants n=93 Participants	5 Participants n=4 Participants	3 Participants n=27 Participants	35 Participants n=483 Participants	83 Participants n=36 Participants
Sex: Female, Male Male	50 Participants n=93 Participants	2 Participants n=4 Participants	4 Participants n=27 Participants	57 Participants n=483 Participants	113 Participants n=36 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	20 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	20 Participants n=483 Participants	40 Participants n=36 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	69 Participants n=93 Participants	7 Participants n=4 Participants	7 Participants n=27 Participants	72 Participants n=483 Participants	155 Participants n=36 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	1 Participants n=36 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	1 Participants n=36 Participants
Race (NIH/OMB) Asian	1 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	1 Participants n=36 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	1 Participants n=36 Participants
Race (NIH/OMB) Black or African American	19 Participants n=93 Participants	1 Participants n=4 Participants	2 Participants n=27 Participants	17 Participants n=483 Participants	39 Participants n=36 Participants
Race (NIH/OMB) White	65 Participants n=93 Participants	6 Participants n=4 Participants	5 Participants n=27 Participants	72 Participants n=483 Participants	148 Participants n=36 Participants
Race (NIH/OMB) More than one race	2 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	1 Participants n=483 Participants	3 Participants n=36 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	2 Participants n=483 Participants	3 Participants n=36 Participants

PRIMARY outcome

Timeframe: Day 1 up to Day 113

Population: Safety Population consisted of all randomized participants who took at least 1 dose of study drug.

Outcome measures

Outcome measures
Measure	Placebo n=90 Participants 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.	Praliciguat 10 mg n=7 Participants Participants were randomized to receive praliciguat 10 mg orally for 12 weeks: 2 weeks of BID dosing followed by 10 weeks of QD dosing.	Praliciguat 20 mg n=7 Participants Participants were randomized to receive praliciguat 20 mg orally for 12 weeks: 2 weeks of BID dosing followed by 10 weeks of QD dosing.	Praliciguat 40 mg n=91 Participants Participants were randomized to receive praliciguat 40 mg orally for 12 weeks: 2 weeks of BID dosing followed by 10 weeks of QD dosing.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Study Drug-related TEAEs TEAEs	61 Participants	4 Participants	6 Participants	72 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Study Drug-related TEAEs Study drug-related TEAEs	9 Participants	1 Participants	0 Participants	22 Participants

PRIMARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Placebo n=72 Participants 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.	Praliciguat 10 mg n=64 Participants Participants were randomized to receive praliciguat 10 mg orally for 12 weeks: 2 weeks of BID dosing followed by 10 weeks of QD dosing.	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.	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.
Change From Baseline in Peak Oxygen Consumption (VO2) at Week 12	0.04 mL O2/kg/min Interval -0.49 to 0.56	-0.26 mL O2/kg/min Interval -0.83 to 0.31	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=72 Participants 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.	Praliciguat 10 mg n=63 Participants Participants were randomized to receive praliciguat 10 mg orally for 12 weeks: 2 weeks of BID dosing followed by 10 weeks of QD dosing.	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.	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.
Change From Baseline in 6-minute Walk Test (6MWT) Distance at Week 12	58.12 Meters Interval 26.12 to 90.11	41.38 Meters Interval 8.25 to 74.5	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=72 Participants 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.	Praliciguat 10 mg n=64 Participants Participants were randomized to receive praliciguat 10 mg orally for 12 weeks: 2 weeks of BID dosing followed by 10 weeks of QD dosing.	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.	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.
Change From Baseline in Ventilatory Efficiency at Week 12	0.564 VE/VCO2 Slope Interval -0.78 to 1.908	0.267 VE/VCO2 Slope Interval -1.118 to 1.652	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=78 Participants 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.	Praliciguat 10 mg n=65 Participants Participants were randomized to receive praliciguat 10 mg orally for 12 weeks: 2 weeks of BID dosing followed by 10 weeks of QD dosing.	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.	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.
CPET Responders at Week 12	17 Participants	13 Participants	—	—

Adverse Events

Placebo

Serious events: 9 serious events

Other events: 58 other events

Deaths: 0 deaths

Praliciguat 10 mg

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Praliciguat 20 mg

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Praliciguat 40 mg

Serious events: 10 serious events

Other events: 68 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Akebia Therapeutics

Phone: 6178446128

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place