Phase IIb Safety and Efficacy Study of Four Dose Regimens of BAY1021189 in Patients With Heart Failure With Reduced Ejection Fraction Suffering From Worsening Chronic Heart Failure (SOCRATES-REDUCED)

Sponsor
Bayer (Industry)
Overall Status
Completed
CT.gov ID
NCT01951625
Collaborator
(none)
456
157
5
18.3
2.9
0.2

Study Details

Study Description

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).

Condition or Disease Intervention/Treatment Phase
  • Drug: Vericiguat (BAY1021189) (1.25 mg)
  • Drug: Vericiguat (BAY1021189) (5 mg)
  • Drug: Placebo
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
456 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized Parallel-group, Placebo-controlled, Double-blind, Multi-center Dose Finding Phase II Trial Exploring the Pharmacodynamic Effects, Safety and Tolerability, and Pharmacokinetics of Four Dose Regimens of the Oral sGC Stimulator BAY1021189 Over 12 Weeks in Patients With Worsening Heart Failure With Reduced Ejection Fraction (HFrEF)
Actual Study Start Date :
Nov 29, 2013
Actual Primary Completion Date :
May 14, 2015
Actual Study Completion Date :
Jun 9, 2015

Arms and Interventions

Arm Intervention/Treatment
Experimental: Vericiguat (BAY1021189) (10 mg)

2.5 mg orally once daily for 2 weeks, up-titration to 5 mg orally once daily for 2 weeks, up-titration to 10 mg orally once daily for 8 weeks

Drug: Vericiguat (BAY1021189) (1.25 mg)
1.25 mg BAY1021189 tablets

Drug: Vericiguat (BAY1021189) (5 mg)
5 mg BAY1021189 tablets

Experimental: Vericiguat (BAY1021189) (5 mg)

2.5 mg orally once daily for 2 weeks, then 5 mg orally once daily for 10 weeks (with sham titration)

Drug: Vericiguat (BAY1021189) (1.25 mg)
1.25 mg BAY1021189 tablets

Drug: Vericiguat (BAY1021189) (5 mg)
5 mg BAY1021189 tablets

Experimental: Vericiguat (BAY1021189) (2.5 mg)

2.5 mg orally once daily for 12 weeks (with sham titrations)

Drug: Vericiguat (BAY1021189) (1.25 mg)
1.25 mg BAY1021189 tablets

Experimental: Vericiguat (BAY1021189) (1.25 mg)

1.25 mg orally once daily for 12 weeks (with sham titrations)

Drug: Vericiguat (BAY1021189) (1.25 mg)
1.25 mg BAY1021189 tablets

Placebo Comparator: Placebo

Orally once daily for 12 weeks (with sham titrations)

Drug: Placebo

Outcome Measures

Primary Outcome Measures

  1. 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 Outcome Measures

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Change in Biomarkers From Baseline to Week 12: Osteopontin (ng/mL) [Baseline, Week 12]

  9. Change in Biomarkers From Baseline to Week 12: TIMP-4 (pg/mL) [Baseline, Week 12]

    TIMP-4: tissue inhibitor of matrix metalloproteinases 4

  10. Change in Biomarkers From Baseline to Week 12: cGMP (Pmol/mL) [Baseline, Week 12]

    cGMP: cyclic guanosine monophosphate

  11. Change in Biomarkers From Baseline to Week 12: PIIINP (mcg/L) [Baseline, Week 12]

    PIIINP: pro-collagen III N-terminal peptide

  12. Change in Biomarkers From Baseline to Week 12: GDF-15 (pg/mL) [Baseline, Week 12]

    GDF-15: growth differentiation factor 15

  13. Change in Biomarkers From Baseline to Week 12: ST2 (pg/mL) [Baseline, Week 12]

    ST2: suppression of tumorigenicity 2

  14. Change in Biomarkers From Baseline to Week 12: Gal-3 (μg/mL) [Baseline, Week 12]

    Gal-3: Galectin-3

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts 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

Contacts and Locations

Locations

Site City State Country Postal Code
1 Fountain Valley California United States 92708
2 Wilmington Delaware United States 19803
3 Fort Lauderdale Florida United States 33308
4 Jacksonville Florida United States 32209
5 Naples Florida United States 34102
6 Atlanta Georgia United States 30342
7 Macon Georgia United States 31201
8 New Orleans Louisiana United States 70112-1396
9 Detroit Michigan United States 48202
10 Minneapolis Minnesota United States 55422
11 Jackson Mississippi United States 39216-4505
12 Buffalo New York United States 14215
13 Columbus Ohio United States 43210
14 Fairfield Ohio United States 45014
15 Charleston South Carolina United States 29425
16 Germantown Tennessee United States 38138
17 Nashville Tennessee United States 37232-8802
18 Milwaukee Wisconsin United States 53215
19 Darlinghurst New South Wales Australia 2010
20 Hobart Tasmania Australia 7000
21 Prahran Victoria Australia 3181
22 St. Pölten Niederösterreich Austria 3100
23 Linz Oberösterreich Austria 4020
24 Graz Steiermark Austria 8036
25 Salzburg Austria 5020
26 Wien Austria 1220
27 Brugge Belgium 8000
28 Bruxelles - Brussel Belgium 1200
29 Gent Belgium 9000
30 Gilly Belgium 6060
31 HUY Belgium 4500
32 Mechelen Belgium 2800
33 MOL Belgium 2400
34 Roeselare Belgium 8800
35 Sofia Bulgaria 1202
36 Sofia Bulgaria 1233
37 Sofia Bulgaria 1309
38 Sofia Bulgaria 1527
39 Stara Zagora Bulgaria 6000
40 Toronto Ontario Canada M5B 1W8
41 Montreal Quebec Canada H1T 1C8
42 Montreal Quebec Canada H2W 1T8
43 Saint-Jean-sur-Richelieu Quebec Canada J3A 1C3
44 Sherbrooke Quebec Canada J1G 2E8
45 Quebec Canada G1V 4G5
46 Hradec kralove Czechia 500 05
47 Kromeriz Czechia 767 01
48 Fakultni nemocnice Ostrava Ostrava Czechia 708 52
49 Praha 10 Czechia 10034
50 Praha 2 Czechia 12808
51 Praha 4 Czechia 140 21
52 Praha 6 Czechia 169 02
53 Slany Czechia 274 01
54 Aalborg Denmark 9000
55 Aarhus N Denmark 8200
56 Hellerup Denmark DK-2900
57 Viborg Denmark 8800
58 BRON Cedex France 69677
59 La Tronche France 38700
60 Lille Cedex France 59037
61 Paris Cedex 15 France 75908
62 Pessac France 33604
63 Rouen France 76031
64 München Bayern Germany 80331
65 Bad Homburg Hessen Germany 61348
66 Frankfurt Hessen Germany 60596
67 Greifswald Mecklenburg-Vorpommern Germany 17475
68 Hannover Niedersachsen Germany 30625
69 Köln Nordrhein-Westfalen Germany 50924
70 Münster Nordrhein-Westfalen Germany 48149
71 Homburg Saarland Germany 66424
72 Erfurt Thüringen Germany 99089
73 Hamburg Germany 20246
74 Athens Greece 11527
75 Nea Ionia Greece 14233
76 Budapest Hungary 1032
77 Kistarcsa Hungary H-2143
78 Szekesfehervar Hungary 8000
79 Afula Israel 1834111
80 Ashkelon Israel 7830604
81 Hadera Israel 3810101
82 Jerusalem Israel 9103102
83 Petah Tikva Israel 4941492
84 Rehovot Israel 7610001
85 Tel Aviv Israel 6423906
86 Tiberias Israel 1528001
87 Zrifin Israel 7030000
88 Bergamo Lombardia Italy 24127
89 Brescia Lombardia Italy 25123
90 Como Lombardia Italy 22020
91 Milano Lombardia Italy 20017
92 Milano Lombardia Italy 20138
93 Milano Lombardia Italy 20149
94 Pavia Lombardia Italy 27100
95 Ancona Marche Italy 60126
96 Arezzo Toscana Italy 52040
97 Verona Veneto Italy 37045
98 Iizuka Fukuoka Japan 820-8505
99 Himeji Hyogo Japan 670-0981
100 Kanazawa Ishikawa Japan 920-8650
101 Sagamihara Kanagawa Japan 252-5188
102 Yokohama Kanagawa Japan 236-0051
103 Yokosuka Kanagawa Japan 238-8567
104 Sendai Miyagi Japan 981-3133
105 Naha Okinawa Japan 902-8511
106 Takatsuki Osaka Japan 569-1096
107 Yao Osaka Japan 581-0011
108 Ureshino Saga Japan 843-0393
109 Komatsushima Tokushima Japan 773-8502
110 Meguro-ku Tokyo Japan 152-8902
111 Minato-ku Tokyo Japan 106-0031
112 Fukui Japan 910-8526
113 Hiroshima Japan 734-8530
114 Kumamoto Japan 862-8505
115 Nagasaki Japan 850-8555
116 Tokushima Japan 770-8539
117 Toyama Japan 930-8550
118 Seoul Korea, Republic of 138-736
119 Amsterdam Netherlands 1105 AZ
120 Deventer Netherlands 7416 SE
121 Heerenveen Netherlands 8441 PW
122 Leeuwarden Netherlands 8901 BR
123 Veldhoven Netherlands 5504 DB
124 Bialystok Poland 15-276
125 Krakow Poland 31-202
126 Legnica Poland 59-220
127 Lodz Poland 92-213
128 Olsztyn Poland 10-010
129 Poznan Poland 61-848
130 Warszawa Poland 02-507
131 Singapore Singapore 119228
132 Singapore Singapore 169609
133 Singapore Singapore 308433
134 Singapore Singapore 768828
135 L'Hospitalet de Llobregat Barcelona Spain 08907
136 Santander Cantabria Spain 39008
137 Majadahonda Madrid Spain 28222
138 Barcelona Spain 08003
139 Barcelona Spain 08023
140 Valencia Spain 46010
141 Valencia Spain 46026
142 Helsingborg Sweden 251 87
143 Karlstad Sweden 651 85
144 Linköping Sweden 581 85
145 Malmö Sweden 205 02
146 Stockholm Sweden 118 83
147 Örebro Sweden 701 85
148 Liestal Basel-Landschaft Switzerland 4410
149 Bruderholz Switzerland 4101
150 Lugano Switzerland 6900
151 Zürich Switzerland 8091
152 Kaohsiung Taiwan 813
153 New Taipei City Taiwan 220
154 Taipei Taiwan 10016
155 Taipei Taiwan 11217
156 Chesterfield Derbyshire United Kingdom S44 5DX
157 Stevenage Hertfordshire United Kingdom SG1 4AB

Sponsors and Collaborators

  • Bayer

Investigators

  • Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Bayer
ClinicalTrials.gov Identifier:
NCT01951625
Other Study ID Numbers:
  • 15371
  • 2013-002287-11
First Posted:
Sep 26, 2013
Last Update Posted:
Mar 25, 2021
Last Verified:
Mar 1, 2021
Keywords provided by Bayer
Additional relevant MeSH terms:

Study Results

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 Detail 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.
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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.
Period Title: Treatment Period
STARTED 92 91 91 91 91
COMPLETED 73 70 76 69 74
NOT COMPLETED 19 21 15 22 17
Period Title: Treatment Period
STARTED 87 88 88 87 88
COMPLETED 79 79 84 76 78
NOT COMPLETED 8 9 4 11 10

Baseline Characteristics

Arm/Group Title 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
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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. Total of all reporting groups
Overall Participants 92 91 91 91 91 456
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
67
(13.1)
67.6
(12.9)
67.6
(11.5)
66.7
(11.6)
68.9
(12.4)
67.6
(12.3)
Age, Customized (Count of Participants)
<65
38
41.3%
38
41.8%
30
33%
38
41.8%
28
30.8%
172
37.7%
65-75
26
28.3%
19
20.9%
37
40.7%
32
35.2%
34
37.4%
148
32.5%
> 75
28
30.4%
34
37.4%
24
26.4%
21
23.1%
29
31.9%
136
29.8%
Sex: Female, Male (Count of Participants)
Female
19
20.7%
21
23.1%
19
20.9%
17
18.7%
14
15.4%
90
19.7%
Male
73
79.3%
70
76.9%
72
79.1%
74
81.3%
77
84.6%
366
80.3%

Outcome Measures

1. Primary Outcome
Title Change From Baseline in Log-Transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) to Week 12
Description 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

Outcome Measure Data

Analysis Population Description
Per Protocol Set (PPS)
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg Pooled 2.5 mg up to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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. The three highest dose arms (BAY1021189 2.5 mg, 2.5-5 mg, and 2.5-10 mg) were pooled.
Measure Participants 69 69 73 67 73 213
Mean (Standard Deviation) [log-transformed picograms per milliliter]
-0.28
(0.8197)
-0.265
(0.7658)
-0.32
(0.7799)
-0.353
(0.8404)
-0.529
(0.9475)
-0.402
(0.8603)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Pooled 2.5 mg up to 10 mg
Comments 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.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value = 0.1506
Comments
Method t-test, 1 sided
Comments
Method of Estimation Estimation Parameter Log-Scale mean difference
Estimated Value -0.122
Confidence Interval (2-Sided) 90%
-0.32 to 0.07
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, BAY1021189 From 2.5 to 10 mg
Comments 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.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value = 0.0483
Comments
Method t-test, 1 sided
Comments
Method of Estimation Estimation Parameter Log-Scale mean difference
Estimated Value -0.2494
Confidence Interval (2-Sided) 90%
-0.5 to 0
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, BAY1021189 From 2.5 to 5 mg
Comments 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.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value = 0.3042
Comments
Method t-test, 1 sided
Comments
Method of Estimation Estimation Parameter Log-Scale mean difference
Estimated Value -0.0731
Confidence Interval (2-Sided) 90%
-0.31 to 0.16
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, BAY1021189 2.5 mg
Comments 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.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value = 0.3841
Comments
Method t-test, 1 sided
Comments
Method of Estimation Estimation Parameter Log-Scale mean difference
Estimated Value -0.0396
Confidence Interval (2-Sided) 90%
-0.26 to 0.18
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, BAY1021189 1.25 Milligram (mg)
Comments 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.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value = 0.5444
Comments
Method t-test, 1 sided
Comments
Method of Estimation Estimation Parameter Log-Scale mean difference
Estimated Value 0.0151
Confidence Interval (2-Sided) 90%
-0.21 to 0.24
Parameter Dispersion Type:
Value:
Estimation Comments
2. Other Pre-specified Outcome
Title 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
Description 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

Outcome Measure Data

Analysis Population Description
Evaluable subjects in full analysis set (FAS).
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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.
Measure Participants 92 91 91 91 91
Change in LVEDV
-7.259
(40.676)
-5.525
(34.75)
-9.632
(35.081)
-17.093
(53.307)
-7.324
(31.896)
Change in LVESV
-6.83
(32.407)
-8.585
(27.385)
-10.935
(27.146)
-15.485
(43.191)
-11.017
(26.525)
3. Other Pre-specified Outcome
Title Changes in Heart Function as Measured by Echocardiography, Left Ventricular Ejection Fraction (LVEF), From Baseline to Week 12
Description 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

Outcome Measure Data

Analysis Population Description
Evaluable subjects in full analysis set (FAS).
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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.
Measure Participants 92 91 91 91 91
Mean (Standard Deviation) [percentage]
1.515
(4.736)
2.84
(3.635)
2.741
(4.371)
2.07
(4.808)
3.682
(6.19)
4. Other Pre-specified Outcome
Title Change From Baseline in Systolic and Diastolic Blood Pressure to Week 12
Description 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

Outcome Measure Data

Analysis Population Description
Evaluable subjects in safety analysis set (SAF).
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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.
Measure Participants 92 91 90 91 91
Change in SBP
-5.142
(12.829)
-4.033
(13.3)
-3.733
(16.509)
-3.043
(15.934)
-5.64
(15.509)
Change in DBP
-4.173
(8.6)
-0.486
(9.298)
-2.938
(11.101)
-1.338
(9.528)
-4.045
(10.604)
5. Other Pre-specified Outcome
Title Change From Baseline in Heart Rate to Week 12
Description 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

Outcome Measure Data

Analysis Population Description
Evaluable subjects in safety analysis set (SAF).
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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.
Measure Participants 92 91 90 91 91
Mean (Standard Deviation) [Beats per minute]
-0.562
(12.897)
-0.352
(10.153)
-1.556
(10.2)
-0.99
(11.295)
0.545
(10.636)
6. Other Pre-specified Outcome
Title Number of Subjects With Clinical Events (Heart Failure [HF] Hospitalization and Cardio-Vascular [CV] Mortality)
Description Clinical events (heart failure and mortality) were analyzed as CV death, and HF hospitalization at specified time points.
Time Frame Baseline until 16 weeks

Outcome Measure Data

Analysis Population Description
FAS
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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.
Measure Participants 92 91 91 91 91
HF hospitalizations
21
22.8%
18
19.8%
20
22%
10
11%
9
9.9%
CV death
6
6.5%
5
5.5%
4
4.4%
2
2.2%
4
4.4%
7. Other Pre-specified Outcome
Title Number of Subjects With Implantable Cardioverter Defibrillators Cardiac Resynchronization Therapy With Defibrillation (ICD/CRT-D) Therapy
Description 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

Outcome Measure Data

Analysis Population Description
No analysis was performed for this end point.
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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.
Measure Participants 0 0 0 0 0
8. Other Pre-specified Outcome
Title Number of Subjects With Treatment-Emergent Adverse Events
Description 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

Outcome Measure Data

Analysis Population Description
SAF
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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.
Measure Participants 92 91 90 91 91
Count of Participants [Participants]
66
71.7%
60
65.9%
62
68.1%
62
68.1%
56
61.5%
9. Other Pre-specified Outcome
Title Change in Biomarkers From Baseline to Week 12: Osteopontin (ng/mL)
Description
Time Frame Baseline, Week 12

Outcome Measure Data

Analysis Population Description
Evaluable subjects in FAS
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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.
Measure Participants 73 69 73 65 71
Mean (Standard Deviation) [nanogram(s)/milliliter (ng/mL)]
2.79
(42.049)
3.812
(39.248)
3.266
(52.957)
8.485
(41.97)
3.709
(36.048)
10. Other Pre-specified Outcome
Title Change in Biomarkers From Baseline to Week 12: TIMP-4 (pg/mL)
Description TIMP-4: tissue inhibitor of matrix metalloproteinases 4
Time Frame Baseline, Week 12

Outcome Measure Data

Analysis Population Description
Evaluable subjects in FAS
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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.
Measure Participants 73 69 72 67 72
Mean (Standard Deviation) [picogram(s)/millilitre (pg/mL)]
451.889
(1392.03)
1128.635
(1949.351)
643.626
(1441.954)
876.584
(1559.768)
397.603
(1420.223)
11. Other Pre-specified Outcome
Title Change in Biomarkers From Baseline to Week 12: cGMP (Pmol/mL)
Description cGMP: cyclic guanosine monophosphate
Time Frame Baseline, Week 12

Outcome Measure Data

Analysis Population Description
Evaluable subjects in FAS
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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.
Measure Participants 73 69 73 66 71
Mean (Standard Deviation) [picomole(s)/milliliter (pmol/mL)]
78.874
(143.321)
79.767
(123.031)
92.352
(121.477)
80.888
(114.09)
63.563
(127.448)
12. Other Pre-specified Outcome
Title Change in Biomarkers From Baseline to Week 12: PIIINP (mcg/L)
Description PIIINP: pro-collagen III N-terminal peptide
Time Frame Baseline, Week 12

Outcome Measure Data

Analysis Population Description
Evaluable subjects in FAS
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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.
Measure Participants 70 69 72 67 73
Mean (Standard Deviation) [microgram(s)/liter (mcg/L)]
-0.701
(7.246)
0.092
(3.958)
0.106
(5.145)
-0.71
(3.774)
-0.321
(4.452)
13. Other Pre-specified Outcome
Title Change in Biomarkers From Baseline to Week 12: GDF-15 (pg/mL)
Description GDF-15: growth differentiation factor 15
Time Frame Baseline, Week 12

Outcome Measure Data

Analysis Population Description
Evaluable subjects in FAS
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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.
Measure Participants 73 69 73 66 71
Mean (Standard Deviation) [pg/mL]
429.432
(3212.229)
496.456
(3132.738)
285.472
(2837.237)
468.369
(1786.062)
244.63
(2906.763)
14. Other Pre-specified Outcome
Title Change in Biomarkers From Baseline to Week 12: ST2 (pg/mL)
Description ST2: suppression of tumorigenicity 2
Time Frame Baseline, Week 12

Outcome Measure Data

Analysis Population Description
Evaluable subjects in FAS
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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.
Measure Participants 73 69 72 67 72
Mean (Standard Deviation) [pg/mL]
9457.677
(54702.45)
1623.869
(25086.72)
-1217.77
(35166.41)
6933.941
(20747.71)
3681.668
(32293.77)
15. Other Pre-specified Outcome
Title Change in Biomarkers From Baseline to Week 12: Gal-3 (μg/mL)
Description Gal-3: Galectin-3
Time Frame Baseline, Week 12

Outcome Measure Data

Analysis Population Description
Evaluable subjects in FAS
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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.
Measure Participants 72 68 73 64 71
Mean (Standard Deviation) [mcg/L]
0.802
(13.818)
0.233
(6.208)
-0.287
(3.729)
0.064
(5.64)
-0.38
(4.551)

Adverse Events

Time Frame Treatment-emergent AEs were collected after first application of study medication up to 5 calendar days after end of treatment with study medication.
Adverse Event Reporting Description
Arm/Group Title Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Arm/Group Description Subjects received placebo matched to vericiguat (Verquvo, BAY1021189) orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 1.25 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. Subjects received vericiguat (Verquvo, BAY1021189) 2.5 mg orally once daily for 12 weeks. Sham titrations included on Days 14 and 28. 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. 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.
All Cause Mortality
Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 6/92 (6.5%) 6/91 (6.6%) 5/90 (5.6%) 3/91 (3.3%) 4/91 (4.4%)
Serious Adverse Events
Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 30/92 (32.6%) 26/91 (28.6%) 26/90 (28.9%) 20/91 (22%) 25/91 (27.5%)
Blood and lymphatic system disorders
Anaemia 1/92 (1.1%) 1 1/91 (1.1%) 1 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Thrombocytopenia 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Cardiac disorders
Angina pectoris 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Atrial fibrillation 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 2/91 (2.2%) 2
Cardiac arrest 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Cardiac failure 8/92 (8.7%) 14 13/91 (14.3%) 14 10/90 (11.1%) 11 3/91 (3.3%) 4 3/91 (3.3%) 4
Cardiac failure acute 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1 0/91 (0%) 0
Cardiac failure chronic 5/92 (5.4%) 5 2/91 (2.2%) 3 5/90 (5.6%) 5 3/91 (3.3%) 6 4/91 (4.4%) 4
Cardiac failure congestive 1/92 (1.1%) 1 2/91 (2.2%) 3 3/90 (3.3%) 3 2/91 (2.2%) 2 3/91 (3.3%) 4
Ventricular fibrillation 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1 0/91 (0%) 0
Ventricular tachycardia 1/92 (1.1%) 1 1/91 (1.1%) 1 0/90 (0%) 0 1/91 (1.1%) 1 0/91 (0%) 0
Ischaemic cardiomyopathy 0/92 (0%) 0 1/91 (1.1%) 1 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Left ventricular dysfunction 0/92 (0%) 0 0/91 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0 0/91 (0%) 0
Acute left ventricular failure 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1 0/91 (0%) 0
Gastrointestinal disorders
Abdominal pain 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Abdominal pain upper 0/92 (0%) 0 0/91 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0 0/91 (0%) 0
Diarrhoea 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Gastrointestinal haemorrhage 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1 0/91 (0%) 0
Melaena 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Small intestinal obstruction 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1 0/91 (0%) 0
Upper gastrointestinal haemorrhage 0/92 (0%) 0 0/91 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0 0/91 (0%) 0
Mechanical ileus 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Incarcerated umbilical hernia 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
General disorders
Chest pain 0/92 (0%) 0 1/91 (1.1%) 1 0/90 (0%) 0 1/91 (1.1%) 1 1/91 (1.1%) 1
Death 0/92 (0%) 0 0/91 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0 0/91 (0%) 0
Multi-organ failure 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1 0/91 (0%) 0
Oedema peripheral 0/92 (0%) 0 1/91 (1.1%) 1 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Sudden death 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1 1/91 (1.1%) 1
General physical health deterioration 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Device dislocation 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1 0/91 (0%) 0
Hepatobiliary disorders
Cholangitis 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Cholecystitis 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Infections and infestations
Bronchitis 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1 2/91 (2.2%) 2
Escherichia sepsis 0/92 (0%) 0 1/91 (1.1%) 1 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Pneumonia 1/92 (1.1%) 1 1/91 (1.1%) 1 0/90 (0%) 0 2/91 (2.2%) 2 1/91 (1.1%) 1
Gastroenteritis 0/92 (0%) 0 0/91 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0 0/91 (0%) 0
Urinary tract infection 0/92 (0%) 0 1/91 (1.1%) 1 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Pneumococcal sepsis 0/92 (0%) 0 0/91 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0 0/91 (0%) 0
Injury, poisoning and procedural complications
Fall 2/92 (2.2%) 2 2/91 (2.2%) 2 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Hip fracture 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Contusion 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Incision site haemorrhage 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 2
Investigations
Transplant evaluation 0/92 (0%) 0 1/91 (1.1%) 1 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Metabolism and nutrition disorders
Fluid overload 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Gout 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Hyperglycaemia 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Hyperkalaemia 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Hypoglycaemia 0/92 (0%) 0 0/91 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0 0/91 (0%) 0
Hypokalaemia 0/92 (0%) 0 1/91 (1.1%) 1 2/90 (2.2%) 2 0/91 (0%) 0 0/91 (0%) 0
Metabolic acidosis 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Type 2 diabetes mellitus 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1 0/91 (0%) 0
Musculoskeletal and connective tissue disorders
Arthralgia 0/92 (0%) 0 0/91 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0 0/91 (0%) 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastric cancer 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Intra-abdominal haemangioma 0/92 (0%) 0 0/91 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0 0/91 (0%) 0
Non-small cell lung cancer 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1 0/91 (0%) 0
Nervous system disorders
Cerebrovascular accident 0/92 (0%) 0 0/91 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0 0/91 (0%) 0
Cervicobrachial syndrome 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Subarachnoid haemorrhage 0/92 (0%) 0 0/91 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0 0/91 (0%) 0
Headache 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Syncope 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Renal and urinary disorders
Renal failure 0/92 (0%) 0 0/91 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0 0/91 (0%) 0
Urinary retention 0/92 (0%) 0 0/91 (0%) 0 1/90 (1.1%) 1 0/91 (0%) 0 0/91 (0%) 0
Acute kidney injury 3/92 (3.3%) 3 4/91 (4.4%) 4 2/90 (2.2%) 2 1/91 (1.1%) 1 3/91 (3.3%) 3
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema 0/92 (0%) 0 1/91 (1.1%) 1 0/90 (0%) 0 1/91 (1.1%) 1 0/91 (0%) 0
Acute respiratory failure 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Chronic obstructive pulmonary disease 0/92 (0%) 0 1/91 (1.1%) 1 1/90 (1.1%) 1 0/91 (0%) 0 0/91 (0%) 0
Dyspnoea 0/92 (0%) 0 1/91 (1.1%) 1 0/90 (0%) 0 1/91 (1.1%) 1 1/91 (1.1%) 1
Pneumonia aspiration 0/92 (0%) 0 1/91 (1.1%) 1 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Pulmonary congestion 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Pulmonary oedema 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 1/91 (1.1%) 1 0/91 (0%) 0
Skin and subcutaneous tissue disorders
Rash 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Rash pruritic 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Surgical and medical procedures
Catheter placement 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Vascular disorders
Hypertension 1/92 (1.1%) 1 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Hypotension 0/92 (0%) 0 0/91 (0%) 0 0/90 (0%) 0 0/91 (0%) 0 1/91 (1.1%) 1
Deep vein thrombosis 0/92 (0%) 0 1/91 (1.1%) 1 0/90 (0%) 0 0/91 (0%) 0 0/91 (0%) 0
Other (Not Including Serious) Adverse Events
Placebo BAY1021189 1.25 Milligram (mg) BAY1021189 2.5 mg BAY1021189 From 2.5 to 5 mg BAY1021189 From 2.5 to 10 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 24/92 (26.1%) 25/91 (27.5%) 20/90 (22.2%) 23/91 (25.3%) 28/91 (30.8%)
Cardiac disorders
Cardiac failure chronic 4/92 (4.3%) 5 1/91 (1.1%) 1 5/90 (5.6%) 5 2/91 (2.2%) 2 0/91 (0%) 0
Gastrointestinal disorders
Abdominal pain upper 2/92 (2.2%) 2 5/91 (5.5%) 6 1/90 (1.1%) 1 1/91 (1.1%) 1 0/91 (0%) 0
Dyspepsia 0/92 (0%) 0 1/91 (1.1%) 1 0/90 (0%) 0 1/91 (1.1%) 1 5/91 (5.5%) 7
Nausea 3/92 (3.3%) 4 5/91 (5.5%) 6 3/90 (3.3%) 3 1/91 (1.1%) 1 1/91 (1.1%) 1
General disorders
Asthenia 3/92 (3.3%) 3 0/91 (0%) 0 2/90 (2.2%) 2 5/91 (5.5%) 5 2/91 (2.2%) 2
Metabolism and nutrition disorders
Hyperuricaemia 1/92 (1.1%) 1 0/91 (0%) 0 2/90 (2.2%) 2 5/91 (5.5%) 5 0/91 (0%) 0
Hypokalaemia 3/92 (3.3%) 3 5/91 (5.5%) 5 2/90 (2.2%) 2 2/91 (2.2%) 2 5/91 (5.5%) 6
Nervous system disorders
Dizziness 5/92 (5.4%) 6 3/91 (3.3%) 3 2/90 (2.2%) 2 2/91 (2.2%) 2 5/91 (5.5%) 5
Respiratory, thoracic and mediastinal disorders
Dyspnoea 5/92 (5.4%) 5 1/91 (1.1%) 1 3/90 (3.3%) 3 2/91 (2.2%) 3 4/91 (4.4%) 4
Cough 6/92 (6.5%) 7 8/91 (8.8%) 8 4/90 (4.4%) 4 4/91 (4.4%) 4 4/91 (4.4%) 4
Vascular disorders
Hypotension 6/92 (6.5%) 6 5/91 (5.5%) 5 5/90 (5.6%) 6 4/91 (4.4%) 4 14/91 (15.4%) 17

Limitations/Caveats

Endpoints of "Change in 'health-related quality of life', 'Composite Congestion Score', 'NYHA function class', and 'background heart failure therapies' were assessed as exploratory. "Incidence of atrial fibrillation" is reported in AE summary.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Therapeutic Area Head
Organization Bayer AG
Phone (+) 1-888-8422937
Email clinical-trials-contact@bayer.com
Responsible Party:
Bayer
ClinicalTrials.gov Identifier:
NCT01951625
Other Study ID Numbers:
  • 15371
  • 2013-002287-11
First Posted:
Sep 26, 2013
Last Update Posted:
Mar 25, 2021
Last Verified:
Mar 1, 2021