Heart Failure
Conditions
Keywords
Worsening Heart Failure, Heart Failure with Preserved Ejection Fraction
Brief summary
Objective of the study is to find the optimal dose of the once daily oral soluble guanylate cyclase stimulator (sGC) BAY1021189 for Phase III that can be given in addition to standard diuretic and comorbidity treatment for heart failure with preserved ejection fraction (HFpEF)
Interventions
1.25 mg BAY1021189 tablets
5 mg BAY1021189 tablets
DRUGPlacebo
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Worsening chronic heart failure (WCHF) requiring hospitalization (or intravenous diuretic treatment for HF without hospitalization) with initiation of study treatment after clinical stabilization * Left ventricular ejection fraction (LVEF) \>/= 45% by echocardiography at randomization
Exclusion criteria
* Intravenous inotropes at any time after hospitalization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in Log-transformed N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | Baseline, Week 12 (end of treatment [EOT]) | NTproBNP is a circulating plasma biomarker of cardiovascular function and prognosis in heart failure (HF). |
| Change From Baseline to Week 12 in Left Atrial Volume (LAV) | Baseline, Week 12 (EOT) | Left atrial volume was measured by echocardiography. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Baseline, Week 12 (EOT) | Blood pressure was measured after at least 10 minutes resting in a sitting position (3 measurements taken approximately 2 minutes apart).The changes in blood pressure were recorded and the mean of the three measurements was analyzed. |
| Change From Baseline to Week 12 in Heart Rate | Baseline, Week 12 (EOT) | Heart rate was measured after 10 minutes resting in a sitting position (3 measurements taken approximatly 2 minutes apart). The changes in heart rate were recorded and the mean of the three measurements was analyzed. |
| Number of Subjects With Clinical Events (Heart Failure Hospitalization and Cardio-vascular [CV] Mortality) | Baseline up to Week 16 including 12 week treatment period and 4 week follow-up period | Clinical events (heart failure and mortality) were analyzed as CV death, and HF hospitalization at specified time points. |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, Czechia, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Japan, Netherlands, Poland, Portugal, Singapore, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 158 centers in 25 countries between 06 November 2013 (first subject first visit) and 16 September 2015 (last subject last visit).
Pre-assignment details
Overall, 632 subjects were enrolled, of them 477 were randomized and 475 were treated. Among the 477 subjects who were randomized, 404 subjects completed both treatment and follow-up \[FU\] periods. All arms in FU period were mutually exclusive, this question below is ticked No because of database validation rule constraints.
Participants by arm
| Arm | Count |
|---|---|
| BAY1021189 1.25 mg Subjects received vericiguat (Verquvo, BAY1021189) 1.25 milligram (mg) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. | 96 |
| Placebo Subjects received placebo matched to vericiguat (BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. | 93 |
| BAY1021189 2.5 mg Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. | 96 |
| BAY1021189 2.5 mg to 5 mg Subjects received vericiguat (Verquvo, BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg after 14 or 28 days. Sham titration included on Day 28. | 96 |
| BAY1021189 2.5 mg to 10 mg Subjects received vericiguat (Verquvo, BAY1021189) for 12 weeks, starting on 2.5 mg once daily with potential up-titration to 5 mg once daily after 14 days, and up-titration to 10 mg once daily after 28 days. | 96 |
| Total | 477 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Follow-up Period | Adverse Event | 0 | 1 | 2 | 1 | 1 |
| Follow-up Period | Death | 1 | 0 | 1 | 4 | 1 |
| Follow-up Period | Logistical difficulties | 0 | 2 | 0 | 0 | 1 |
| Follow-up Period | Lost to Follow-up | 0 | 1 | 0 | 1 | 0 |
| Follow-up Period | Protocol Violation | 0 | 0 | 0 | 1 | 0 |
| Follow-up Period | Withdrawal by Subject | 1 | 5 | 2 | 1 | 2 |
| Treatment Period | Adverse Event | 3 | 4 | 8 | 6 | 5 |
| Treatment Period | Death | 0 | 0 | 0 | 3 | 1 |
| Treatment Period | Logistical difficulties | 0 | 1 | 1 | 0 | 0 |
| Treatment Period | Protocol-driven decision point | 1 | 3 | 0 | 0 | 0 |
| Treatment Period | Protocol Violation | 0 | 0 | 0 | 2 | 0 |
| Treatment Period | Withdrawal by Subject | 9 | 6 | 4 | 5 | 4 |
Baseline characteristics
| Characteristic | BAY1021189 1.25 mg | Placebo | BAY1021189 2.5 mg | BAY1021189 2.5 mg to 5 mg | BAY1021189 2.5 mg to 10 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 73.8 years STANDARD_DEVIATION 10 | 73.7 years STANDARD_DEVIATION 9.1 | 72 years STANDARD_DEVIATION 10.7 | 73.9 years STANDARD_DEVIATION 7.9 | 72.5 years STANDARD_DEVIATION 10.2 | 73.2 years STANDARD_DEVIATION 9.6 |
| Sex: Female, Male Female | 51 Participants | 46 Participants | 43 Participants | 43 Participants | 44 Participants | 227 Participants |
| Sex: Female, Male Male | 45 Participants | 47 Participants | 53 Participants | 53 Participants | 52 Participants | 250 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 93 | 0 / 96 | 1 / 95 | 7 / 95 | 2 / 96 |
| other Total, other adverse events | 21 / 93 | 33 / 96 | 40 / 95 | 38 / 95 | 33 / 96 |
| serious Total, serious adverse events | 20 / 93 | 20 / 96 | 24 / 95 | 18 / 95 | 21 / 96 |
Outcome results
Primary
Change From Baseline to Week 12 in Left Atrial Volume (LAV)
Left atrial volume was measured by echocardiography.
Time frame: Baseline, Week 12 (EOT)
Population: PPS Left Atrial Volume (LAV) included all subjects randomized to treatment who had a valid measurement of LAV at baseline and at Week 12 (Visit 5) and showed no major protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in Left Atrial Volume (LAV) | -3.361 milliliter | Standard Deviation 12.654 |
| BAY1021189 1.25 mg | Change From Baseline to Week 12 in Left Atrial Volume (LAV) | -2.163 milliliter | Standard Deviation 7.895 |
| BAY1021189 2.5 mg | Change From Baseline to Week 12 in Left Atrial Volume (LAV) | -2.142 milliliter | Standard Deviation 11.931 |
| BAY1021189 2.5 mg to 5 mg | Change From Baseline to Week 12 in Left Atrial Volume (LAV) | -1.252 milliliter | Standard Deviation 16.139 |
| BAY1021189 2.5 mg to 10 mg | Change From Baseline to Week 12 in Left Atrial Volume (LAV) | -1.654 milliliter | Standard Deviation 10.245 |
Comparison: For the primary analysis, the three highest active treatment groups (BAY1021189 2.5mg, BAY1021189 2.5 to 5mg, BAY1021189 2.5 to 10mg) were pooled and compared to the assigned placebo treatment group with a one-sided two-sample t-test. The Hochberg procedure was used to test the two primary end points at study-wise significance level of 5%. Results are reported including 90% confidence intervals (CI) for the difference of means.p-value: =0.815690% CI: [-1.36, 4.62]t-test, 1 sided
Comparison: Pairwise comparisons to placebo were performed in a hierarchical manner (from BAY1021189 from 2.5 to 10mg dose arm to BAY1021189 1.25mg dose arm). In accordance with the specification in the protocol these secondary analyses are considered exploratory only, since the primary analyses were not significant.p-value: =0.794595% CI: [-2.39, 5.8]t-test, 1 sided
Comparison: Pairwise comparisons to placebo were performed in a hierarchical manner (from BAY1021189 from 2.5 to 10mg dose arm to BAY1021189 1.25mg dose arm). In accordance with the specification in the protocol these secondary analyses are considered exploratory only, since the primary analyses were not significant.p-value: =0.791795% CI: [-3.01, 7.23]t-test, 1 sided
Comparison: Pairwise comparisons to placebo were performed in a hierarchical manner (from BAY1021189 from 2.5 to 10mg dose arm to BAY1021189 1.25mg dose arm). In accordance with the specification in the protocol these secondary analyses are considered exploratory only, since the primary analyses were not significant.p-value: =0.724195% CI: [-2.82, 5.26]t-test, 1 sided
Comparison: Pairwise comparisons to placebo were performed in a hierarchical manner (from BAY1021189 from 2.5 to 10mg dose arm to BAY1021189 1.25mg dose arm). In accordance with the specification in the protocol these secondary analyses are considered exploratory only, since the primary analyses were not significant.p-value: =0.754695% CI: [-2.23, 4.63]t-test, 1 sided
Primary
Change From Baseline to Week 12 in Log-transformed N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)
NTproBNP is a circulating plasma biomarker of cardiovascular function and prognosis in heart failure (HF).
Time frame: Baseline, Week 12 (end of treatment [EOT])
Population: Per Protocol Set (PPS) NT-pro BNP: included all subjects randomized to treatment who had a valid measurement of NT-pro BNP at baseline and at Week 12 (Visit 5) and showed no major protocol deviations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in Log-transformed N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | -0.098 log-transformed picograms per milliliter | Standard Deviation 0.778 |
| BAY1021189 1.25 mg | Change From Baseline to Week 12 in Log-transformed N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | -0.047 log-transformed picograms per milliliter | Standard Deviation 0.788 |
| BAY1021189 2.5 mg | Change From Baseline to Week 12 in Log-transformed N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | 0.071 log-transformed picograms per milliliter | Standard Deviation 0.818 |
| BAY1021189 2.5 mg to 5 mg | Change From Baseline to Week 12 in Log-transformed N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | 0.057 log-transformed picograms per milliliter | Standard Deviation 0.819 |
| BAY1021189 2.5 mg to 10 mg | Change From Baseline to Week 12 in Log-transformed N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | -0.023 log-transformed picograms per milliliter | Standard Deviation 0.705 |
Comparison: For the primary analysis, the three highest active treatment groups BAY1021189 (2.5mg, 2.5 to 5mg, 2.5 to 10mg) were pooled and compared to the assigned placebo treatment group with a one-sided two-sample t-test. The Hochberg procedure was used to test the two primary end points at study-wise significance level of 5%. Results are reported including 90% confidence intervals (CI) for the difference of means. The difference between the comparison groups is difference of means on the log scale.p-value: =0.899190% CI: [-0.04, 0.31]t-test, 1 sided
Comparison: Pairwise comparisons to placebo were performed in a hierarchical manner (from BAY1021189 from 2.5 to 10mg dose arm to BAY1021189 1.25mg dose arm). In accordance with the specification in the protocol these secondary analyses are considered exploratory only, since the primary analyses were not significant.p-value: =0.719495% CI: [-0.18, 0.33]t-test, 1 sided
Comparison: Pairwise comparisons to placebo were performed in a hierarchical manner (from BAY1021189 from 2.5 to 10mg dose arm to BAY1021189 1.25mg dose arm). In accordance with the specification in the protocol these secondary analyses are considered exploratory only, since the primary analyses were not significant.p-value: =0.865395% CI: [-0.12, 0.43]t-test, 1 sided
Comparison: Pairwise comparisons to placebo were performed in a hierarchical manner (from BAY1021189 from 2.5 to 10mg dose arm to BAY1021189 1.25mg dose arm). In accordance with the specification in the protocol these secondary analyses are considered exploratory only, since the primary analyses were not significant.p-value: =0.904195% CI: [-0.09, 0.43]t-test, 1 sided
Comparison: Pairwise comparisons to placebo were performed in a hierarchical manner (from BAY1021189 from 2.5 to 10mg dose arm to BAY1021189 1.25mg dose arm). In accordance with the specification in the protocol these secondary analyses are considered exploratory only, since the primary analyses were not significant.p-value: =0.657295% CI: [-0.2, 0.3]t-test, 1 sided
Other Pre-specified
Change From Baseline to Week 12 in Heart Rate
Heart rate was measured after 10 minutes resting in a sitting position (3 measurements taken approximatly 2 minutes apart). The changes in heart rate were recorded and the mean of the three measurements was analyzed.
Time frame: Baseline, Week 12 (EOT)
Population: Safety Analysis Set (SAF) with evaluable subjects for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in Heart Rate | 3.287 beats per minute | Standard Deviation 13.582 |
| BAY1021189 1.25 mg | Change From Baseline to Week 12 in Heart Rate | 1.776 beats per minute | Standard Deviation 11.42 |
| BAY1021189 2.5 mg | Change From Baseline to Week 12 in Heart Rate | -0.373 beats per minute | Standard Deviation 9.845 |
| BAY1021189 2.5 mg to 5 mg | Change From Baseline to Week 12 in Heart Rate | 1.055 beats per minute | Standard Deviation 13.331 |
| BAY1021189 2.5 mg to 10 mg | Change From Baseline to Week 12 in Heart Rate | -2.623 beats per minute | Standard Deviation 9.639 |
Other Pre-specified
Change From Baseline to Week 12 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Blood pressure was measured after at least 10 minutes resting in a sitting position (3 measurements taken approximately 2 minutes apart).The changes in blood pressure were recorded and the mean of the three measurements was analyzed.
Time frame: Baseline, Week 12 (EOT)
Population: Safety Analysis Set (SAF) with evaluable subjects for this endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to Week 12 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Change in SBP | 1.458 millimeter of mercury | Standard Deviation 18.865 |
| Placebo | Change From Baseline to Week 12 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Change in DBP | 1.887 millimeter of mercury | Standard Deviation 11.435 |
| BAY1021189 1.25 mg | Change From Baseline to Week 12 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Change in SBP | 0.703 millimeter of mercury | Standard Deviation 16.993 |
| BAY1021189 1.25 mg | Change From Baseline to Week 12 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Change in DBP | 0.911 millimeter of mercury | Standard Deviation 10.037 |
| BAY1021189 2.5 mg | Change From Baseline to Week 12 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Change in SBP | -1.819 millimeter of mercury | Standard Deviation 19.438 |
| BAY1021189 2.5 mg | Change From Baseline to Week 12 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Change in DBP | -2.173 millimeter of mercury | Standard Deviation 11.249 |
| BAY1021189 2.5 mg to 5 mg | Change From Baseline to Week 12 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Change in DBP | -1.142 millimeter of mercury | Standard Deviation 11.4 |
| BAY1021189 2.5 mg to 5 mg | Change From Baseline to Week 12 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Change in SBP | -1.486 millimeter of mercury | Standard Deviation 17.179 |
| BAY1021189 2.5 mg to 10 mg | Change From Baseline to Week 12 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Change in SBP | -0.913 millimeter of mercury | Standard Deviation 15.498 |
| BAY1021189 2.5 mg to 10 mg | Change From Baseline to Week 12 Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Change in DBP | -0.629 millimeter of mercury | Standard Deviation 10.271 |
Other Pre-specified
Number of Subjects With Clinical Events (Heart Failure Hospitalization and Cardio-vascular [CV] Mortality)
Clinical events (heart failure and mortality) were analyzed as CV death, and HF hospitalization at specified time points.
Time frame: Baseline up to Week 16 including 12 week treatment period and 4 week follow-up period
Population: Full Analysis Set (FAS) included all subjects who were randomized to treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Subjects With Clinical Events (Heart Failure Hospitalization and Cardio-vascular [CV] Mortality) | HF hospitalizations | 8 Participants |
| Placebo | Number of Subjects With Clinical Events (Heart Failure Hospitalization and Cardio-vascular [CV] Mortality) | CV Mortality | 1 Participants |
| BAY1021189 1.25 mg | Number of Subjects With Clinical Events (Heart Failure Hospitalization and Cardio-vascular [CV] Mortality) | HF hospitalizations | 6 Participants |
| BAY1021189 1.25 mg | Number of Subjects With Clinical Events (Heart Failure Hospitalization and Cardio-vascular [CV] Mortality) | CV Mortality | 0 Participants |
| BAY1021189 2.5 mg | Number of Subjects With Clinical Events (Heart Failure Hospitalization and Cardio-vascular [CV] Mortality) | HF hospitalizations | 11 Participants |
| BAY1021189 2.5 mg | Number of Subjects With Clinical Events (Heart Failure Hospitalization and Cardio-vascular [CV] Mortality) | CV Mortality | 0 Participants |
| BAY1021189 2.5 mg to 5 mg | Number of Subjects With Clinical Events (Heart Failure Hospitalization and Cardio-vascular [CV] Mortality) | CV Mortality | 5 Participants |
| BAY1021189 2.5 mg to 5 mg | Number of Subjects With Clinical Events (Heart Failure Hospitalization and Cardio-vascular [CV] Mortality) | HF hospitalizations | 8 Participants |
| BAY1021189 2.5 mg to 10 mg | Number of Subjects With Clinical Events (Heart Failure Hospitalization and Cardio-vascular [CV] Mortality) | HF hospitalizations | 5 Participants |
| BAY1021189 2.5 mg to 10 mg | Number of Subjects With Clinical Events (Heart Failure Hospitalization and Cardio-vascular [CV] Mortality) | CV Mortality | 1 Participants |