Chronic Heart Failure With Preserved Ejection Fraction
Conditions
Brief summary
The primary hypothesis in this trial is that the treatment with vericiguat 10 mg or 15 mg in patients with HFpEF improves the KCCQ PLS (Kansas City Cardiomyopathy Questionnaire Physical limitation score) compared to placebo after 24 weeks of treatment.
Interventions
DRUGVericiguat (BAY1021189) 2.5 mg, 5 mg or 10 mg IR tablets
Oral use. Vericiguat, which will be started at 2.5 mg at randomization and up-titrated to 5 mg at week 2, and to 10 mg at week 4, with sham titration or up-titration to 15 mg at week 6.
DRUGPlacebo
Placebo and sham up-titration at weeks 2, 4, and 6
Sponsors
Merck Sharp & Dohme LLC
Canadian VIGOUR Centre
Duke Clinical Research Institute
Bayer
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
* Previous diagnosis of chronic heart failure (HF) * HF decompensation within 6 months prior to randomization, defined as hospitalization for HF or intravenous (IV) diuretic treatment for HF without hospitalization. * N-terminal pro brain natriuretic peptide (NT-proBNP) ≥300 or brain natriuretic peptide (BNP) ≥100 pg/mL in sinus rhythm, or NT-proBNP ≥600 or BNP ≥200 pg/mL in atrial fibrillation within 30 days prior to randomization * Diagnostic criteria of HFpEF by echocardiography assessed within 12 months prior to randomization (most recent measurement must be used to determine eligibility with no interim event signaling potential deterioration in ejection fraction) * Left ventricular ejection fraction (LVEF) ≥45% and * Structural changes indicated by at least one of the following parameters: * Left ventricle (LV) hypertrophy (any of the following: intraventricular septal or posterior wall thickness ≥1.1 cm, and/or LV mass index ≥115 g/m\*2 in male and ≥95 g/m\*2 in female), or * Left atrium (LA) enlargement (any of the following: left atrial volume (LAV) index ≥29 ml/m\*2, or LAV \>58 mL in male and \>52 mL in female patients, or LA area \>20 cm\*2, or LA diameter \>40 mm in male and \>38 mm in female patients) * NYHA class II or III at randomization
Exclusion criteria
* Clinical instability at randomization, defined by * Any IV treatment within 24h prior to randomization, and/or * SBP ≥160 mmHg * SBP \<110 mmHg and/or DBP \<40 mmHg and/or symptomatic hypotension * Resting heart rate (HR) \<50 or ≥100 beats per minute (bpm) * Use of IV inotropes at any time between qualifying HF event and randomization * Previous diagnosis of reduced ejection fraction (EF) (EF \<40%) * Hypertrophic obstructive cardiomyopathy, acute myocarditis, amyloidosis, sarcoidosis, or pericardial disease * Primary valvular heart disease requiring surgery or intervention, or within 3 months after valvular surgery or intervention, or active endocarditis * Acute coronary syndrome, including unstable angina, Non ST-elevation myocardial infarction or ST-elevation myocardial infarction, or Coronary artery bypass grafting (CABG) within 60 days prior to randomization, or indication for Percutaneous coronary intervention or CABG at the time of randomization * Symptomatic carotid stenosis, or transient ischemic attack or stroke within 60 days prior to randomization * Complex congenital heart disease * Non-cardiac comorbidity (any of the following) * Estimated glomerular filtration rate (eGFR) \<30 ml/min/1.73 m\*2 calculated by Modification of Diet in Renal Disease formula * Hepatic insufficiency classified as Child-Pugh B or C * Morbid obesity with a body mass index \>45 kg/m\*2 * Malignancy or other non-cardiac condition limiting life expectancy to \<1 year, per physician judgment * Requires continuous home oxygen for severe pulmonary disease or has interstitial lung disease * Patients with allergies, intolerance or hypersensitivity to investigational drug or any of the excipients * Concurrent or anticipated use of nitrates or NO donors, phosphodiesterase type V (PDE5) inhibitors, or a Soluble guanylate cyclase (sGC) stimulator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in KCCQ Physical Limitation Score From Baseline to Week 24 | From baseline to Week 24 | The City Cardiomyopathy Questionnaire (KCCQ) measures the impact of patients' heart failure, or its treatment, on 6 domains; Physical Limitation, Symptom (with subscores for frequency and burden), Quality of Life, Social Limitations, Symptom Stability and Self-Efficacy. Scores are calculated by summing domain responses and then transforming scores to a 0-100 unit scale with higher scores indicating better health status. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Six-minute Walk Test (6MWT) From Baseline to Week 24 | From baseline to Week 24 | 6MWT was conducted to test the physical limitations of the patient by assessing the patient's exercise capacity. The distance walked by the patient in 6 minutes was measured. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events | From first application of study drug up to 5 calendar days after end of treatment with study drug | An AE is any untoward medical occurrence (i.e. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a patient or clinical investigation patient after providing written informed consent for participation in the study. Adverse events are considered to be treatment-emergent if they have started or worsened after first application of study medication up to 5 calendar days after end of treatment with study medication. |
Countries
Argentina, Austria, Belgium, Bulgaria, Canada, Colombia, Germany, Greece, Hungary, Israel, Italy, Japan, Malaysia, Poland, Portugal, Russia, Singapore, South Africa, Spain, Taiwan, United States
Participant flow
Recruitment details
Study was conducted at 178 study centers worldwide, between 15-Jun-2018 (first subject first visit) and 04-Nov-2019 (last subject last visit).
Pre-assignment details
Overall, 979 participants were screened, of whom 789 participants were randomized in the study. 788 of the randomized participants were allocated to study treatment, of whom 672 participants completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Vericiguat up to 10 mg Participants received vericiguat (BAY1021189) for 24 weeks, starting at 2.5 mg once daily at randomization and up-titrated to 5 mg at week 2, to 10 mg at week 4, with sham titration at week 6. | 263 |
| Vericiguat up to 15 mg Participants received vericiguat (BAY1021189) for 24 weeks, starting at 2.5 mg once daily at randomization and up-titrated to 5 mg at week 2, to 10 mg at week 4, and to 15 mg at week 6 week. | 264 |
| Placebo Participants received placebo once daily and sham up-titration at weeks 2, 4, and 6. | 262 |
| Total | 789 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 16 | 11 | 10 |
| Overall Study | Death | 11 | 7 | 4 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Non-compliance with study drug | 0 | 0 | 1 |
| Overall Study | Other | 2 | 2 | 3 |
| Overall Study | Physician Decision | 1 | 0 | 3 |
| Overall Study | Protocol Violation | 2 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 12 | 19 | 10 |
Baseline characteristics
| Characteristic | Vericiguat up to 10 mg | Vericiguat up to 15 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 72.2 years STANDARD_DEVIATION 9.7 | 73.1 years STANDARD_DEVIATION 9.1 | 72.8 years STANDARD_DEVIATION 9.4 | 72.7 years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 28 Participants | 21 Participants | 23 Participants | 72 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 235 Participants | 242 Participants | 238 Participants | 715 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Kansas City Cardiopathy Questionnaire Physical limitation score (KCCQ PLS) | 57.30 Scores STANDARD_DEVIATION 24.77 | 60.03 Scores STANDARD_DEVIATION 24.64 | 59.03 Scores STANDARD_DEVIATION 24 | 58.79 Scores STANDARD_DEVIATION 24.46 |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 4 Participants | 4 Participants | 11 Participants |
| Race (NIH/OMB) Asian | 24 Participants | 26 Participants | 25 Participants | 75 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 7 Participants | 9 Participants | 21 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 228 Participants | 224 Participants | 222 Participants | 674 Participants |
| Sex: Female, Male Female | 124 Participants | 140 Participants | 121 Participants | 385 Participants |
| Sex: Female, Male Male | 139 Participants | 124 Participants | 141 Participants | 404 Participants |
| Six-minute walk test | 292.13 Meters STANDARD_DEVIATION 107.75 | 294.99 Meters STANDARD_DEVIATION 118 | 295.80 Meters STANDARD_DEVIATION 106.27 | 294.32 Meters STANDARD_DEVIATION 110.72 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 15 / 262 | 10 / 264 | 7 / 262 |
| other Total, other adverse events | 121 / 262 | 134 / 264 | 131 / 262 |
| serious Total, serious adverse events | 46 / 262 | 54 / 264 | 48 / 262 |
Outcome results
Primary
Change in KCCQ Physical Limitation Score From Baseline to Week 24
The City Cardiomyopathy Questionnaire (KCCQ) measures the impact of patients' heart failure, or its treatment, on 6 domains; Physical Limitation, Symptom (with subscores for frequency and burden), Quality of Life, Social Limitations, Symptom Stability and Self-Efficacy. Scores are calculated by summing domain responses and then transforming scores to a 0-100 unit scale with higher scores indicating better health status.
Time frame: From baseline to Week 24
Population: FAS KCCQ: All patients randomized and treated (at least one dose of the study treatment), and had at least one observed KCCQ PLS assessment at both baseline and during post-baseline (excluding safety follow-up) were valid for this analysis set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vericiguat up to 10 mg | Change in KCCQ Physical Limitation Score From Baseline to Week 24 | 6.41 Scores on a scale | Standard Error 1.592 |
| Vericiguat up to 15 mg | Change in KCCQ Physical Limitation Score From Baseline to Week 24 | 5.47 Scores on a scale | Standard Error 1.538 |
| Placebo | Change in KCCQ Physical Limitation Score From Baseline to Week 24 | 6.93 Scores on a scale | Standard Error 1.535 |
Comparison: The analysis of each imputed dataset will be performed using mixed-effects model for repeated measures (MMRM), including treatment, region, heart rhythm, study visit as fixed effects, interaction between study visit and treatment group, and adjustment for the baseline PLS values as covariates.p-value: =0.800897.5% CI: [-5.17, 4.13]Mixed model repeated-measures
Comparison: The analysis of each imputed dataset will be performed using mixed-effects model for repeated measures (MMRM), including treatment, region, heart rhythm, study visit as fixed effects, interaction between study visit and treatment group, and adjustment for the baseline PLS values as covariates.p-value: =0.472297.5% CI: [-6.02, 3.1]Mixed model repeated-measures
Secondary
Change in the Six-minute Walk Test (6MWT) From Baseline to Week 24
6MWT was conducted to test the physical limitations of the patient by assessing the patient's exercise capacity. The distance walked by the patient in 6 minutes was measured.
Time frame: From baseline to Week 24
Population: FAS 6MWT: All patients randomized and treated (at least one dose of the study treatment), and who were able to perform at least one 6MWT assessment at both baseline and post-baseline (excluding safety follow-up) were valid for this analysis set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vericiguat up to 10 mg | Change in the Six-minute Walk Test (6MWT) From Baseline to Week 24 | 8.68 Meters | Standard Error 5.841 |
| Vericiguat up to 15 mg | Change in the Six-minute Walk Test (6MWT) From Baseline to Week 24 | 5.00 Meters | Standard Error 5.718 |
| Placebo | Change in the Six-minute Walk Test (6MWT) From Baseline to Week 24 | 10.49 Meters | Standard Error 5.512 |
Comparison: The analysis of each imputed dataset will be performed using mixed-effects model for repeated measures (MMRM), including treatment, region, heart rhythm, study visit as fixed effects, interaction between study visit and treatment group, and adjustment for the baseline 6MWT values as covariates.p-value: =0.805497.5% CI: [-18.3, 14.67]Mixed model repeated-measures
Comparison: The analysis of each imputed dataset will be performed using mixed-effects model for repeated measures (MMRM), including treatment, region, heart rhythm, study visit as fixed effects, interaction between study visit and treatment group, and adjustment for the baseline 6MWT values as covariates.p-value: =0.450297.5% CI: [-21.77, 10.8]mixed model repeated measures
Other Pre-specified
Number of Participants With Treatment Emergent Adverse Events
An AE is any untoward medical occurrence (i.e. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a patient or clinical investigation patient after providing written informed consent for participation in the study. Adverse events are considered to be treatment-emergent if they have started or worsened after first application of study medication up to 5 calendar days after end of treatment with study medication.
Time frame: From first application of study drug up to 5 calendar days after end of treatment with study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vericiguat up to 10 mg | Number of Participants With Treatment Emergent Adverse Events | Any study drug related TEAE | 38 Participants |
| Vericiguat up to 10 mg | Number of Participants With Treatment Emergent Adverse Events | Any TEAE | 163 Participants |
| Vericiguat up to 10 mg | Number of Participants With Treatment Emergent Adverse Events | Any TESAE | 46 Participants |
| Vericiguat up to 15 mg | Number of Participants With Treatment Emergent Adverse Events | Any study drug related TEAE | 42 Participants |
| Vericiguat up to 15 mg | Number of Participants With Treatment Emergent Adverse Events | Any TEAE | 172 Participants |
| Vericiguat up to 15 mg | Number of Participants With Treatment Emergent Adverse Events | Any TESAE | 54 Participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events | Any TEAE | 172 Participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events | Any TESAE | 48 Participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events | Any study drug related TEAE | 24 Participants |