Heart Failure
Conditions
Keywords
Worsening Heart Failure, Heart Failure with Reduced 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 therapy for heart failure with reduced ejection fraction (HFrEF).
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 in Log-Transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) to Week 12 | Baseline, Week 12 | Log-Transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) is a circulating plasma biomarker of cardiovascular function and prognosis in heart failure. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in Heart Function as Measured by Echocardiography, Left Ventricular Ejection Fraction (LVEF), From Baseline to Week 12 | Baseline, Week 12 | The left ventricular ejection fraction work index (LVEF) is a calculated echocardiography parameter. LVEF is derived from the directly measured parameters left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). These 2 parameters are acquired during a noninvasive echocardiography examination. Formula: LVEF = 100\*(LVEDV - LVESV)/LVEDV. |
| Change From Baseline in Systolic and Diastolic Blood Pressure to Week 12 | Baseline, Week 12 | Blood pressure was measured by monitor measurements after 10 minutes resting in a supine 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 in Heart Rate to Week 12 | Baseline, Week 12 | Heart rate was measured after 10 minutes resting in a supine position (3 measurements taken approximately 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 [HF] Hospitalization and Cardio-Vascular [CV] Mortality) | Baseline until 16 weeks | Clinical events (heart failure and mortality) were analyzed as CV death, and HF hospitalization at specified time points. |
| Number of Subjects With Implantable Cardioverter Defibrillators Cardiac Resynchronization Therapy With Defibrillation (ICD/CRT-D) Therapy | Baseline upto 16 weeks | ICD / CRT with defibrillation therapy (CRT-D) included previous appropriate interventions such as shocks or anti-tachycardic pacing (ATP) when diagnostic of sustained ventricular tachycardias in pre defined rapid zone. |
| Number of Subjects With Treatment-Emergent Adverse Events | From the start of study treatment upto 5 days after the last dose of study drug | An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; and another medically important serious event as judged by the investigator. AEs are considered to be treatment-emergent if they have started or worsened after first application of study drug up to 5 days after end of treatment with study drug. |
| Changes in Heart Function as Measured by Echocardiography, Left Ventricular End-Diastolic Volume (LVEDV), and Left Ventricular End-Systolic Volume (LVESV) From Baseline to Week 12 | Baseline, Week 12 | Left Ventricular End-Diastolic Volume (LVEDV) and Left ventricular end-systolic volume (LVESV) are measured echocardiography parameter. These are acquired during a non-invasive echocardiography examination. |
| Change in Biomarkers From Baseline to Week 12: TIMP-4 (pg/mL) | Baseline, Week 12 | TIMP-4: tissue inhibitor of matrix metalloproteinases 4 |
| Change in Biomarkers From Baseline to Week 12: cGMP (Pmol/mL) | Baseline, Week 12 | cGMP: cyclic guanosine monophosphate |
| Change in Biomarkers From Baseline to Week 12: PIIINP (mcg/L) | Baseline, Week 12 | PIIINP: pro-collagen III N-terminal peptide |
| Change in Biomarkers From Baseline to Week 12: GDF-15 (pg/mL) | Baseline, Week 12 | GDF-15: growth differentiation factor 15 |
| Change in Biomarkers From Baseline to Week 12: ST2 (pg/mL) | Baseline, Week 12 | ST2: suppression of tumorigenicity 2 |
| Change in Biomarkers From Baseline to Week 12: Gal-3 (μg/mL) | Baseline, Week 12 | Gal-3: Galectin-3 |
| Change in Biomarkers From Baseline to Week 12: Osteopontin (ng/mL) | Baseline, Week 12 | — |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, Czechia, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Japan, Netherlands, Poland, Singapore, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 144 centers in 24 countries between 29 November 2013 (first subject first visit) and 09 June 2015 (last subject last visit).
Pre-assignment details
Overall 632 subjects were enrolled, of them 176 were screen failure and 456 were randomized. One subject did not receive study drug after randomization. Among the 455 subjects who received study drug 348 completed the study (that is completed both the treatment and follow-up periods) and 108 subjects did not complete the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. | 92 |
| BAY1021189 1.25 Milligram (mg) Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. | 91 |
| 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. | 91 |
| BAY1021189 From 2.5 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 once daily after 14 or 28 days. Sham titration included on Day 28. | 91 |
| BAY1021189 From 2.5 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. | 91 |
| Total | 456 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Follow Up Period | Adverse Event | 0 | 3 | 2 | 3 | 5 |
| Follow Up Period | Death | 1 | 3 | 2 | 2 | 1 |
| Follow Up Period | Logistical difficulties | 1 | 2 | 0 | 0 | 0 |
| Follow Up Period | Lost to Follow-up | 1 | 0 | 0 | 1 | 1 |
| Follow Up Period | Non-compliance with study drug | 1 | 0 | 0 | 0 | 0 |
| Follow Up Period | Withdrawal by Subject | 4 | 1 | 0 | 5 | 3 |
| Treatment Period | Adverse Event | 7 | 10 | 9 | 8 | 8 |
| Treatment Period | Death | 3 | 2 | 2 | 1 | 2 |
| Treatment Period | Lost to Follow-up | 1 | 0 | 0 | 1 | 0 |
| Treatment Period | Non compliance with study drug | 1 | 2 | 2 | 0 | 0 |
| Treatment Period | Physician Decision | 0 | 0 | 0 | 0 | 1 |
| Treatment Period | Protocol driven decision point | 0 | 5 | 0 | 2 | 1 |
| Treatment Period | Protocol Violation | 2 | 0 | 1 | 3 | 2 |
| Treatment Period | Withdrawal by Subject | 5 | 2 | 1 | 7 | 3 |
Baseline characteristics
| Characteristic | Placebo | BAY1021189 1.25 Milligram (mg) | BAY1021189 2.5 mg | BAY1021189 From 2.5 to 5 mg | BAY1021189 From 2.5 to 10 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 67 years STANDARD_DEVIATION 13.1 | 67.6 years STANDARD_DEVIATION 12.9 | 67.6 years STANDARD_DEVIATION 11.5 | 66.7 years STANDARD_DEVIATION 11.6 | 68.9 years STANDARD_DEVIATION 12.4 | 67.6 years STANDARD_DEVIATION 12.3 |
| Age, Customized <65 | 38 Participants | 38 Participants | 30 Participants | 38 Participants | 28 Participants | 172 Participants |
| Age, Customized 65-75 | 26 Participants | 19 Participants | 37 Participants | 32 Participants | 34 Participants | 148 Participants |
| Age, Customized > 75 | 28 Participants | 34 Participants | 24 Participants | 21 Participants | 29 Participants | 136 Participants |
| Sex: Female, Male Female | 19 Participants | 21 Participants | 19 Participants | 17 Participants | 14 Participants | 90 Participants |
| Sex: Female, Male Male | 73 Participants | 70 Participants | 72 Participants | 74 Participants | 77 Participants | 366 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 | 6 / 92 | 6 / 91 | 5 / 90 | 3 / 91 | 4 / 91 |
| other Total, other adverse events | 24 / 92 | 25 / 91 | 20 / 90 | 23 / 91 | 28 / 91 |
| serious Total, serious adverse events | 30 / 92 | 26 / 91 | 26 / 90 | 20 / 91 | 25 / 91 |
Outcome results
Primary
Change From Baseline in Log-Transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) to Week 12
Log-Transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) is a circulating plasma biomarker of cardiovascular function and prognosis in heart failure.
Time frame: Baseline, Week 12
Population: Per Protocol Set (PPS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Log-Transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) to Week 12 | -0.28 log-transformed picograms per milliliter | Standard Deviation 0.8197 |
| BAY1021189 1.25 Milligram (mg) | Change From Baseline in Log-Transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) to Week 12 | -0.265 log-transformed picograms per milliliter | Standard Deviation 0.7658 |
| BAY1021189 2.5 mg | Change From Baseline in Log-Transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) to Week 12 | -0.32 log-transformed picograms per milliliter | Standard Deviation 0.7799 |
| BAY1021189 From 2.5 to 5 mg | Change From Baseline in Log-Transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) to Week 12 | -0.353 log-transformed picograms per milliliter | Standard Deviation 0.8404 |
| BAY1021189 From 2.5 to 10 mg | Change From Baseline in Log-Transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) to Week 12 | -0.529 log-transformed picograms per milliliter | Standard Deviation 0.9475 |
| Pooled 2.5 mg up to 10 mg | Change From Baseline in Log-Transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) to Week 12 | -0.402 log-transformed picograms per milliliter | Standard Deviation 0.8603 |
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 at the significance level of 5 percent (%). Results are reported including 90% confidence intervals (CI) for the difference of means. The difference between the pooled treatment group and the placebo group is difference of means on the log scale.p-value: =0.150690% CI: [-0.32, 0.07]t-test, 1 sided
Comparison: In case of a significant result in the primary analysis of the primary endpoint, 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 case of non-significance of the primary analyses, these secondary analyses were specified as exploratory only, since the primary analyses were not significant.p-value: =0.048390% CI: [-0.5, 0]t-test, 1 sided
Comparison: In case of a significant result in the primary analysis of the primary endpoint, 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 case of non-significance of the primary analyses, these secondary analyses were specified as exploratory only, since the primary analyses were not significant.p-value: =0.304290% CI: [-0.31, 0.16]t-test, 1 sided
Comparison: In case of a significant result in the primary analysis of the primary endpoint, 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 case of non-significance of the primary analyses, these secondary analyses were specified as exploratory only, since the primary analyses were not significant.p-value: =0.384190% CI: [-0.26, 0.18]t-test, 1 sided
Comparison: In case of a significant result in the primary analysis of the primary endpoint, 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 case of non-significance of the primary analyses, these secondary analyses were specified as exploratory only.p-value: =0.544490% CI: [-0.21, 0.24]t-test, 1 sided
Other Pre-specified
Change From Baseline in Heart Rate to Week 12
Heart rate was measured after 10 minutes resting in a supine position (3 measurements taken approximately 2 minutes apart). The changes in heart rate were recorded and the mean of the three measurements was analyzed.
Time frame: Baseline, Week 12
Population: Evaluable subjects in safety analysis set (SAF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Heart Rate to Week 12 | -0.562 Beats per minute | Standard Deviation 12.897 |
| BAY1021189 1.25 Milligram (mg) | Change From Baseline in Heart Rate to Week 12 | -0.352 Beats per minute | Standard Deviation 10.153 |
| BAY1021189 2.5 mg | Change From Baseline in Heart Rate to Week 12 | -1.556 Beats per minute | Standard Deviation 10.2 |
| BAY1021189 From 2.5 to 5 mg | Change From Baseline in Heart Rate to Week 12 | -0.99 Beats per minute | Standard Deviation 11.295 |
| BAY1021189 From 2.5 to 10 mg | Change From Baseline in Heart Rate to Week 12 | 0.545 Beats per minute | Standard Deviation 10.636 |
Other Pre-specified
Change From Baseline in Systolic and Diastolic Blood Pressure to Week 12
Blood pressure was measured by monitor measurements after 10 minutes resting in a supine 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
Population: Evaluable subjects in safety analysis set (SAF).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Systolic and Diastolic Blood Pressure to Week 12 | Change in SBP | -5.142 millimeter of mercury (mmHg) | Standard Deviation 12.829 |
| Placebo | Change From Baseline in Systolic and Diastolic Blood Pressure to Week 12 | Change in DBP | -4.173 millimeter of mercury (mmHg) | Standard Deviation 8.6 |
| BAY1021189 1.25 Milligram (mg) | Change From Baseline in Systolic and Diastolic Blood Pressure to Week 12 | Change in SBP | -4.033 millimeter of mercury (mmHg) | Standard Deviation 13.3 |
| BAY1021189 1.25 Milligram (mg) | Change From Baseline in Systolic and Diastolic Blood Pressure to Week 12 | Change in DBP | -0.486 millimeter of mercury (mmHg) | Standard Deviation 9.298 |
| BAY1021189 2.5 mg | Change From Baseline in Systolic and Diastolic Blood Pressure to Week 12 | Change in SBP | -3.733 millimeter of mercury (mmHg) | Standard Deviation 16.509 |
| BAY1021189 2.5 mg | Change From Baseline in Systolic and Diastolic Blood Pressure to Week 12 | Change in DBP | -2.938 millimeter of mercury (mmHg) | Standard Deviation 11.101 |
| BAY1021189 From 2.5 to 5 mg | Change From Baseline in Systolic and Diastolic Blood Pressure to Week 12 | Change in DBP | -1.338 millimeter of mercury (mmHg) | Standard Deviation 9.528 |
| BAY1021189 From 2.5 to 5 mg | Change From Baseline in Systolic and Diastolic Blood Pressure to Week 12 | Change in SBP | -3.043 millimeter of mercury (mmHg) | Standard Deviation 15.934 |
| BAY1021189 From 2.5 to 10 mg | Change From Baseline in Systolic and Diastolic Blood Pressure to Week 12 | Change in SBP | -5.64 millimeter of mercury (mmHg) | Standard Deviation 15.509 |
| BAY1021189 From 2.5 to 10 mg | Change From Baseline in Systolic and Diastolic Blood Pressure to Week 12 | Change in DBP | -4.045 millimeter of mercury (mmHg) | Standard Deviation 10.604 |
Other Pre-specified
Change in Biomarkers From Baseline to Week 12: cGMP (Pmol/mL)
cGMP: cyclic guanosine monophosphate
Time frame: Baseline, Week 12
Population: Evaluable subjects in FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Biomarkers From Baseline to Week 12: cGMP (Pmol/mL) | 78.874 picomole(s)/milliliter (pmol/mL) | Standard Deviation 143.321 |
| BAY1021189 1.25 Milligram (mg) | Change in Biomarkers From Baseline to Week 12: cGMP (Pmol/mL) | 79.767 picomole(s)/milliliter (pmol/mL) | Standard Deviation 123.031 |
| BAY1021189 2.5 mg | Change in Biomarkers From Baseline to Week 12: cGMP (Pmol/mL) | 92.352 picomole(s)/milliliter (pmol/mL) | Standard Deviation 121.477 |
| BAY1021189 From 2.5 to 5 mg | Change in Biomarkers From Baseline to Week 12: cGMP (Pmol/mL) | 80.888 picomole(s)/milliliter (pmol/mL) | Standard Deviation 114.09 |
| BAY1021189 From 2.5 to 10 mg | Change in Biomarkers From Baseline to Week 12: cGMP (Pmol/mL) | 63.563 picomole(s)/milliliter (pmol/mL) | Standard Deviation 127.448 |
Other Pre-specified
Change in Biomarkers From Baseline to Week 12: Gal-3 (μg/mL)
Gal-3: Galectin-3
Time frame: Baseline, Week 12
Population: Evaluable subjects in FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Biomarkers From Baseline to Week 12: Gal-3 (μg/mL) | 0.802 mcg/L | Standard Deviation 13.818 |
| BAY1021189 1.25 Milligram (mg) | Change in Biomarkers From Baseline to Week 12: Gal-3 (μg/mL) | 0.233 mcg/L | Standard Deviation 6.208 |
| BAY1021189 2.5 mg | Change in Biomarkers From Baseline to Week 12: Gal-3 (μg/mL) | -0.287 mcg/L | Standard Deviation 3.729 |
| BAY1021189 From 2.5 to 5 mg | Change in Biomarkers From Baseline to Week 12: Gal-3 (μg/mL) | 0.064 mcg/L | Standard Deviation 5.64 |
| BAY1021189 From 2.5 to 10 mg | Change in Biomarkers From Baseline to Week 12: Gal-3 (μg/mL) | -0.38 mcg/L | Standard Deviation 4.551 |
Other Pre-specified
Change in Biomarkers From Baseline to Week 12: GDF-15 (pg/mL)
GDF-15: growth differentiation factor 15
Time frame: Baseline, Week 12
Population: Evaluable subjects in FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Biomarkers From Baseline to Week 12: GDF-15 (pg/mL) | 429.432 pg/mL | Standard Deviation 3212.229 |
| BAY1021189 1.25 Milligram (mg) | Change in Biomarkers From Baseline to Week 12: GDF-15 (pg/mL) | 496.456 pg/mL | Standard Deviation 3132.738 |
| BAY1021189 2.5 mg | Change in Biomarkers From Baseline to Week 12: GDF-15 (pg/mL) | 285.472 pg/mL | Standard Deviation 2837.237 |
| BAY1021189 From 2.5 to 5 mg | Change in Biomarkers From Baseline to Week 12: GDF-15 (pg/mL) | 468.369 pg/mL | Standard Deviation 1786.062 |
| BAY1021189 From 2.5 to 10 mg | Change in Biomarkers From Baseline to Week 12: GDF-15 (pg/mL) | 244.63 pg/mL | Standard Deviation 2906.763 |
Other Pre-specified
Change in Biomarkers From Baseline to Week 12: Osteopontin (ng/mL)
Time frame: Baseline, Week 12
Population: Evaluable subjects in FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Biomarkers From Baseline to Week 12: Osteopontin (ng/mL) | 2.79 nanogram(s)/milliliter (ng/mL) | Standard Deviation 42.049 |
| BAY1021189 1.25 Milligram (mg) | Change in Biomarkers From Baseline to Week 12: Osteopontin (ng/mL) | 3.812 nanogram(s)/milliliter (ng/mL) | Standard Deviation 39.248 |
| BAY1021189 2.5 mg | Change in Biomarkers From Baseline to Week 12: Osteopontin (ng/mL) | 3.266 nanogram(s)/milliliter (ng/mL) | Standard Deviation 52.957 |
| BAY1021189 From 2.5 to 5 mg | Change in Biomarkers From Baseline to Week 12: Osteopontin (ng/mL) | 8.485 nanogram(s)/milliliter (ng/mL) | Standard Deviation 41.97 |
| BAY1021189 From 2.5 to 10 mg | Change in Biomarkers From Baseline to Week 12: Osteopontin (ng/mL) | 3.709 nanogram(s)/milliliter (ng/mL) | Standard Deviation 36.048 |
Other Pre-specified
Change in Biomarkers From Baseline to Week 12: PIIINP (mcg/L)
PIIINP: pro-collagen III N-terminal peptide
Time frame: Baseline, Week 12
Population: Evaluable subjects in FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Biomarkers From Baseline to Week 12: PIIINP (mcg/L) | -0.701 microgram(s)/liter (mcg/L) | Standard Deviation 7.246 |
| BAY1021189 1.25 Milligram (mg) | Change in Biomarkers From Baseline to Week 12: PIIINP (mcg/L) | 0.092 microgram(s)/liter (mcg/L) | Standard Deviation 3.958 |
| BAY1021189 2.5 mg | Change in Biomarkers From Baseline to Week 12: PIIINP (mcg/L) | 0.106 microgram(s)/liter (mcg/L) | Standard Deviation 5.145 |
| BAY1021189 From 2.5 to 5 mg | Change in Biomarkers From Baseline to Week 12: PIIINP (mcg/L) | -0.71 microgram(s)/liter (mcg/L) | Standard Deviation 3.774 |
| BAY1021189 From 2.5 to 10 mg | Change in Biomarkers From Baseline to Week 12: PIIINP (mcg/L) | -0.321 microgram(s)/liter (mcg/L) | Standard Deviation 4.452 |
Other Pre-specified
Change in Biomarkers From Baseline to Week 12: ST2 (pg/mL)
ST2: suppression of tumorigenicity 2
Time frame: Baseline, Week 12
Population: Evaluable subjects in FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Biomarkers From Baseline to Week 12: ST2 (pg/mL) | 9457.677 pg/mL | Standard Deviation 54702.45 |
| BAY1021189 1.25 Milligram (mg) | Change in Biomarkers From Baseline to Week 12: ST2 (pg/mL) | 1623.869 pg/mL | Standard Deviation 25086.72 |
| BAY1021189 2.5 mg | Change in Biomarkers From Baseline to Week 12: ST2 (pg/mL) | -1217.77 pg/mL | Standard Deviation 35166.41 |
| BAY1021189 From 2.5 to 5 mg | Change in Biomarkers From Baseline to Week 12: ST2 (pg/mL) | 6933.941 pg/mL | Standard Deviation 20747.71 |
| BAY1021189 From 2.5 to 10 mg | Change in Biomarkers From Baseline to Week 12: ST2 (pg/mL) | 3681.668 pg/mL | Standard Deviation 32293.77 |
Other Pre-specified
Change in Biomarkers From Baseline to Week 12: TIMP-4 (pg/mL)
TIMP-4: tissue inhibitor of matrix metalloproteinases 4
Time frame: Baseline, Week 12
Population: Evaluable subjects in FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Biomarkers From Baseline to Week 12: TIMP-4 (pg/mL) | 451.889 picogram(s)/millilitre (pg/mL) | Standard Deviation 1392.03 |
| BAY1021189 1.25 Milligram (mg) | Change in Biomarkers From Baseline to Week 12: TIMP-4 (pg/mL) | 1128.635 picogram(s)/millilitre (pg/mL) | Standard Deviation 1949.351 |
| BAY1021189 2.5 mg | Change in Biomarkers From Baseline to Week 12: TIMP-4 (pg/mL) | 643.626 picogram(s)/millilitre (pg/mL) | Standard Deviation 1441.954 |
| BAY1021189 From 2.5 to 5 mg | Change in Biomarkers From Baseline to Week 12: TIMP-4 (pg/mL) | 876.584 picogram(s)/millilitre (pg/mL) | Standard Deviation 1559.768 |
| BAY1021189 From 2.5 to 10 mg | Change in Biomarkers From Baseline to Week 12: TIMP-4 (pg/mL) | 397.603 picogram(s)/millilitre (pg/mL) | Standard Deviation 1420.223 |
Other Pre-specified
Changes in Heart Function as Measured by Echocardiography, Left Ventricular Ejection Fraction (LVEF), From Baseline to Week 12
The left ventricular ejection fraction work index (LVEF) is a calculated echocardiography parameter. LVEF is derived from the directly measured parameters left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). These 2 parameters are acquired during a noninvasive echocardiography examination. Formula: LVEF = 100\*(LVEDV - LVESV)/LVEDV.
Time frame: Baseline, Week 12
Population: Evaluable subjects in full analysis set (FAS).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Heart Function as Measured by Echocardiography, Left Ventricular Ejection Fraction (LVEF), From Baseline to Week 12 | 1.515 percentage | Standard Deviation 4.736 |
| BAY1021189 1.25 Milligram (mg) | Changes in Heart Function as Measured by Echocardiography, Left Ventricular Ejection Fraction (LVEF), From Baseline to Week 12 | 2.84 percentage | Standard Deviation 3.635 |
| BAY1021189 2.5 mg | Changes in Heart Function as Measured by Echocardiography, Left Ventricular Ejection Fraction (LVEF), From Baseline to Week 12 | 2.741 percentage | Standard Deviation 4.371 |
| BAY1021189 From 2.5 to 5 mg | Changes in Heart Function as Measured by Echocardiography, Left Ventricular Ejection Fraction (LVEF), From Baseline to Week 12 | 2.07 percentage | Standard Deviation 4.808 |
| BAY1021189 From 2.5 to 10 mg | Changes in Heart Function as Measured by Echocardiography, Left Ventricular Ejection Fraction (LVEF), From Baseline to Week 12 | 3.682 percentage | Standard Deviation 6.19 |
Other Pre-specified
Changes in Heart Function as Measured by Echocardiography, Left Ventricular End-Diastolic Volume (LVEDV), and Left Ventricular End-Systolic Volume (LVESV) From Baseline to Week 12
Left Ventricular End-Diastolic Volume (LVEDV) and Left ventricular end-systolic volume (LVESV) are measured echocardiography parameter. These are acquired during a non-invasive echocardiography examination.
Time frame: Baseline, Week 12
Population: Evaluable subjects in full analysis set (FAS).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Changes in Heart Function as Measured by Echocardiography, Left Ventricular End-Diastolic Volume (LVEDV), and Left Ventricular End-Systolic Volume (LVESV) From Baseline to Week 12 | Change in LVEDV | -7.259 milliliter | Standard Deviation 40.676 |
| Placebo | Changes in Heart Function as Measured by Echocardiography, Left Ventricular End-Diastolic Volume (LVEDV), and Left Ventricular End-Systolic Volume (LVESV) From Baseline to Week 12 | Change in LVESV | -6.83 milliliter | Standard Deviation 32.407 |
| BAY1021189 1.25 Milligram (mg) | Changes in Heart Function as Measured by Echocardiography, Left Ventricular End-Diastolic Volume (LVEDV), and Left Ventricular End-Systolic Volume (LVESV) From Baseline to Week 12 | Change in LVEDV | -5.525 milliliter | Standard Deviation 34.75 |
| BAY1021189 1.25 Milligram (mg) | Changes in Heart Function as Measured by Echocardiography, Left Ventricular End-Diastolic Volume (LVEDV), and Left Ventricular End-Systolic Volume (LVESV) From Baseline to Week 12 | Change in LVESV | -8.585 milliliter | Standard Deviation 27.385 |
| BAY1021189 2.5 mg | Changes in Heart Function as Measured by Echocardiography, Left Ventricular End-Diastolic Volume (LVEDV), and Left Ventricular End-Systolic Volume (LVESV) From Baseline to Week 12 | Change in LVEDV | -9.632 milliliter | Standard Deviation 35.081 |
| BAY1021189 2.5 mg | Changes in Heart Function as Measured by Echocardiography, Left Ventricular End-Diastolic Volume (LVEDV), and Left Ventricular End-Systolic Volume (LVESV) From Baseline to Week 12 | Change in LVESV | -10.935 milliliter | Standard Deviation 27.146 |
| BAY1021189 From 2.5 to 5 mg | Changes in Heart Function as Measured by Echocardiography, Left Ventricular End-Diastolic Volume (LVEDV), and Left Ventricular End-Systolic Volume (LVESV) From Baseline to Week 12 | Change in LVESV | -15.485 milliliter | Standard Deviation 43.191 |
| BAY1021189 From 2.5 to 5 mg | Changes in Heart Function as Measured by Echocardiography, Left Ventricular End-Diastolic Volume (LVEDV), and Left Ventricular End-Systolic Volume (LVESV) From Baseline to Week 12 | Change in LVEDV | -17.093 milliliter | Standard Deviation 53.307 |
| BAY1021189 From 2.5 to 10 mg | Changes in Heart Function as Measured by Echocardiography, Left Ventricular End-Diastolic Volume (LVEDV), and Left Ventricular End-Systolic Volume (LVESV) From Baseline to Week 12 | Change in LVEDV | -7.324 milliliter | Standard Deviation 31.896 |
| BAY1021189 From 2.5 to 10 mg | Changes in Heart Function as Measured by Echocardiography, Left Ventricular End-Diastolic Volume (LVEDV), and Left Ventricular End-Systolic Volume (LVESV) From Baseline to Week 12 | Change in LVESV | -11.017 milliliter | Standard Deviation 26.525 |
Other Pre-specified
Number of Subjects With Clinical Events (Heart Failure [HF] 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 until 16 weeks
Population: FAS
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Subjects With Clinical Events (Heart Failure [HF] Hospitalization and Cardio-Vascular [CV] Mortality) | CV death | 6 Participants |
| Placebo | Number of Subjects With Clinical Events (Heart Failure [HF] Hospitalization and Cardio-Vascular [CV] Mortality) | HF hospitalizations | 21 Participants |
| BAY1021189 1.25 Milligram (mg) | Number of Subjects With Clinical Events (Heart Failure [HF] Hospitalization and Cardio-Vascular [CV] Mortality) | CV death | 5 Participants |
| BAY1021189 1.25 Milligram (mg) | Number of Subjects With Clinical Events (Heart Failure [HF] Hospitalization and Cardio-Vascular [CV] Mortality) | HF hospitalizations | 18 Participants |
| BAY1021189 2.5 mg | Number of Subjects With Clinical Events (Heart Failure [HF] Hospitalization and Cardio-Vascular [CV] Mortality) | HF hospitalizations | 20 Participants |
| BAY1021189 2.5 mg | Number of Subjects With Clinical Events (Heart Failure [HF] Hospitalization and Cardio-Vascular [CV] Mortality) | CV death | 4 Participants |
| BAY1021189 From 2.5 to 5 mg | Number of Subjects With Clinical Events (Heart Failure [HF] Hospitalization and Cardio-Vascular [CV] Mortality) | HF hospitalizations | 10 Participants |
| BAY1021189 From 2.5 to 5 mg | Number of Subjects With Clinical Events (Heart Failure [HF] Hospitalization and Cardio-Vascular [CV] Mortality) | CV death | 2 Participants |
| BAY1021189 From 2.5 to 10 mg | Number of Subjects With Clinical Events (Heart Failure [HF] Hospitalization and Cardio-Vascular [CV] Mortality) | HF hospitalizations | 9 Participants |
| BAY1021189 From 2.5 to 10 mg | Number of Subjects With Clinical Events (Heart Failure [HF] Hospitalization and Cardio-Vascular [CV] Mortality) | CV death | 4 Participants |
Other Pre-specified
Number of Subjects With Implantable Cardioverter Defibrillators Cardiac Resynchronization Therapy With Defibrillation (ICD/CRT-D) Therapy
ICD / CRT with defibrillation therapy (CRT-D) included previous appropriate interventions such as shocks or anti-tachycardic pacing (ATP) when diagnostic of sustained ventricular tachycardias in pre defined rapid zone.
Time frame: Baseline upto 16 weeks
Population: No analysis was performed for this end point.
Other Pre-specified
Number of Subjects With Treatment-Emergent Adverse Events
An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; and another medically important serious event as judged by the investigator. AEs are considered to be treatment-emergent if they have started or worsened after first application of study drug up to 5 days after end of treatment with study drug.
Time frame: From the start of study treatment upto 5 days after the last dose of study drug
Population: SAF
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Subjects With Treatment-Emergent Adverse Events | 66 Participants |
| BAY1021189 1.25 Milligram (mg) | Number of Subjects With Treatment-Emergent Adverse Events | 60 Participants |
| BAY1021189 2.5 mg | Number of Subjects With Treatment-Emergent Adverse Events | 62 Participants |
| BAY1021189 From 2.5 to 5 mg | Number of Subjects With Treatment-Emergent Adverse Events | 62 Participants |
| BAY1021189 From 2.5 to 10 mg | Number of Subjects With Treatment-Emergent Adverse Events | 56 Participants |