J-EMPHASIS-HF: Clinical Study Of Eplerenone In Japanese Patients With Chronic Heart Failure

• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01115855
• Collaborator: (none)
• Enrollment: 221
• Locations: 54
• Arms: 2
• Duration (Months): 62
• Patients Per Site: 4.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

A study to compare the efficacy and safety of eplerenone in Japanese chronic heart failure patients with placebo.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: Eplerenone; Drug: Placebo	Phase 3

Detailed Description

The aim of this study was to show consistency with the EMPHASIS-HF trial (NCT00232180), which was defined as a HR of the primary endpoint of below 1.

Study Design

• Study Type: Interventional
• Actual Enrollment: 221 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Effect Of Eplerenone Versus Placebo On Cardiovascular Mortality And Heart Failure Hospitalization In Japanese Subjects With Chronic Heart Failure
• Study Start Date: Jul 1, 2010
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Eplerenone arm Add on standard heart failure therapy	Drug: Eplerenone; Eplerenone 25 mg once every other day, 25mg once daily or 50 mg once daily
Placebo Comparator: Placebo arm Add on standard heart failure therapy	Drug: Placebo; Placebo once daily or every once daily

Outcome Measures

Primary Outcome Measures

1. Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) [Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)]

   CV mortality was defined as any death due to HF, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident, other CV cause (such as aneurysm or pulmonary embolism). Hospitalization due to HF was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.

Secondary Outcome Measures

1. Number of Participants With First Occurrence of Cardiovascular (CV) Mortality, Hospitalization Due to Heart Failure (HF), or Addition/Increase of Heart Failure (HF) Medication [Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)]

   CV mortality was defined as any death due to HF, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident, other CV cause (such as aneurysm or pulmonary embolism). Hospitalization due to HF was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF. Addition/ increase of HF medications was defined as administration of new HF medication or increase of 50 percentage (%) or more in dose of HF medication for >= 3 days. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.

2. Number of Participants With With First Occurrence of All-Cause Mortality [Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)]

   All-cause mortality was defined as any CV mortality, Non-CV mortality, including malignant tumor, pulmonary disease and trauma.CV mortality was defined as death due to HF, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident, other CV cause (such as aneurysm or pulmonary embolism). Mortality during treatment, within 30 days of treatment discontinuation and after 30 days of discontinuation was reported. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.

3. Number of Participants With With First Occurrence of Cardiovascular Mortality [Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)]

   CV mortality was defined as death due to HF, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident, other CV cause (such as aneurysm or pulmonary embolism). Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.

4. Number of Participants With First Occurrence of All-cause Hospitalization [Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)]

   All cause hospitalization included all hospitalizations as CV hospitalization, which was defined as any hospitalization due to CV events including HF, myocardial infarction, arrhythmia, angina pectoris and non-CV hospitalizations which was defined as any hospitalization due to non-CV events including renal dysfunction, hyperkalaemia, malignant tumor and pulmonary disease. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.

5. Number of Participants With First Occurrence of Hospitalization Due to Heart Failure (HF) [Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)]

   Hospitalization due to HF was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.

6. Number of Participants With First Occurrence of All-cause Mortality or All-cause Hospitalization [Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)]

   All cause hospitalization included all hospitalizations as CV hospitalization, which was defined as any hospitalization due to CV events including HF, myocardial infarction, arrhythmia, angina pectoris and non-CV hospitalizations which was defined as any hospitalization due to non-CV events including renal dysfunction, hyperkalaemia, malignant tumor and pulmonary disease. All-cause mortality was defined as any CV mortality, Non-CV mortality, including malignant tumor, pulmonary disease and trauma.CV mortality was defined as death due to HF, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident, other CV cause (such as aneurysm or pulmonary embolism). Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.

7. Number of Participants With First Occurrence of Heart Failure (HF) Mortality or Heart Failure (HF) Hospitalization [Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)]

   HF mortality was defined as any death due to HF. Hospitalization due to HF was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.

8. Number of Participants With First Occurrence of Cardiovascular (CV) Hospitalization [Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)]

   CV hospitalization, which was defined as any hospitalization due to CV events including HF, myocardial infarction, arrhythmia, angina pectoris. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.

9. Number of Participants With First Occurrence of Addition/Increase of Heart Failure (HF) Medication Due to Heart Failure (HF) Worsening [Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)]

   Addition/ increase of HF medications was defined as administration of new HF medication or increase of 50 percent or more in dose of HF medication for >= 3 days. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.

10. Number of Participants With First Occurrence of Fatal/Non-Fatal Stroke [Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)]

    Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.

11. Number of Participants With First Occurrence of Fatal/Non-Fatal Myocardial Infarction (MI) [Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)]

    Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.

12. Number of Participants With First Occurrence of New Onset Atrial Fibrillation/Flutter [Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)]

    New onset of atrial fibrillation or flutter was defined as the diagnosis of atrial fibrillation or flutter in a participant after randomization. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.

13. Number of Participants With First Occurrence of New Onset Diabetes Mellitus [Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)]

    New onset diabetes mellitus was defined as the diagnosis of diabetes mellitus in a participant after randomization. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.

14. Number of Participants With First Occurrence of Hospitalisation Due to Worsening Renal Function [Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)]

    Hospitalization due to worsening renal function (as per physician's decision) was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to worsening renal function as the primary reason for hospitalization. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.

15. Number of Participants With First Occurrence of Hospitalization for Hyperkalemia [Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)]

    Hospitalization due to hyperkalemia (as per physician's decision) was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to hyperkalemia as the primary reason for hospitalization. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.

16. Change From Baseline in Plasma Concentration of Brain Natriuretic Peptide at Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48 and Final Visit [Baseline, Months 5,9,13,17,21,25,29,33,37,42,48, Final Visit (up to Month 48)]

17. Change From Baseline in Plasma Concentration of Serum N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) at Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48 and Final Visit [Baseline, Months 5, 9, 13, 17, 21 ,25, 29, 33, 37, 42, 48 and Final Visit (up to Month 48)]

18. Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48 and Final Visit [Baseline, Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48, Final Visit (up to Month 48)]

    LVEF was calculated based on end-diastolic volume measured by two-dimensional echocardiography.

19. Change From Baseline in Urine Albumin-to-Creatinine Ratio at Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48 and Final Visit [Baseline, Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48, Final Visit (up to Month 48)]

20. Number of Participants With Change From Baseline in New York Heart Association (NYHA) Classification at Weeks 1, 4, Months 2, 3, 4, 5, 9, 13, 17 21, 25, 29, 33, 37, 42, 48 and Final Visit [Baseline, Weeks 1, 4, Months 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48 and Final Visit (up to Month 48)]

    NYHA: classified as 'class I' (participants with cardiac disease but without resulting limitations of physical activity), 'class II' (participants with cardiac disease resulting in slight limitation of physical activity), 'class III' (participants with cardiac disease resulting in marked limitation of physical activity), 'class IV' (participants with cardiac disease resulting in inability to carry on any physical activity without discomfort). Participants with change from baseline were classified as 'improved' (positive change), 'no change' or 'worsened' (negative change).

21. Change From Baseline in Specific Activity Scale (SAS) Score at Week 4, Months 2, 3, 4, 5, 9, 13, 17 21, 25, 29, 33, 37, 42, 48 and Final Visit [Baseline, Week 4, Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48, Final Visit (up to Month 48)]

    Specific activity scale was estimated by pre-specified questionnaire (for different activities) to assess the exercise capability of the participants. Answers provided by participants were transformed in terms of number of metabolic equivalents (METs).1 MET was defined as the amount of oxygen consumed while sitting at rest and is equal to 3.5 ml oxygen per kg body weight* minute. Scale ranged from 1 (less than (<) 2 METs) = lowest level of exercise tolerance to 6 (>=8METs) = highest level of tolerance and higher score indicated more tolerance.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Japanese chronic systolic heart failure patients with LVEF =<30% by echocardiography and NYHA II or more

• Patients who receive standard therapy (Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blocker or diuretic)

Exclusion Criteria:

• Patients with a myocardial infarction, stroke, cardiac surgery or percutaneous coronary intervention within 30 days prior to randomization.

• Patients with serum potassium >5.0 mmol/L or eGFR <30 ml/min/1.73 m2.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Chubu Rosai Hospital	Nagoya	Aichi	Japan	455-8530
2	Tosei General Hospital	Seto	Aichi	Japan	489-8642
3	National Hospital Organization Chiba Medical Center	Chiba-shi	Chiba-ken	Japan	260-8606
4	Asahi General Hospital	Asahi	Chiba	Japan	289-2511
5	Nippon Medical School Chiba Hokusou Hospital	Inzai	Chiba	Japan	270-1694
6	Ehime Prefectural Central Hospital	Matuyama-shi	Ehime	Japan	790-0024
7	Kyushu University Hospital	Fukuoka-shi	Fukuoka-ken	Japan	812-8582
8	Aso Iizuka Hospital	Iizuka-shi	Fukuoka-ken	Japan	820-8505
9	Kurume University Hospital	Kurume-shi	Fukuoka-ken	Japan	830-0011
10	Southern TOHOKU Research Institute for Neuroscience Southern TOHOKU Medical Clinic	Koriyama	Fukushima	Japan	963-8052
11	Ogaki Municipal Hospital	Ogaki	Gifu	Japan	503-8502
12	National Hospital Organization Hakodate National Hospital	Hakodate-shi	Hokkai-do	Japan	041-8512
13	Hakodate City Hospital	Hakodate	Hokkaido	Japan	041-8680
14	Teine Keijinkai Clinic	Sapporo	Hokkaido	Japan	006-0811
15	Hokkaido University Hospital	Sapporo	Hokkaido	Japan	060-8648
16	National Hospital Organization Hokkaido Medical Center	Sapporo	Hokkaido	Japan	063-0005
17	Hyogo Brain and Heart Center	Himeji	Hyogo	Japan	670-0981
18	Japanease Red Cross Society Himeji Hospital	Himeji	Hyogo	Japan	670-8540
19	The Hospital of Hyogo College of Medicine	Nishinomiya	Hyogo	Japan	663-8501
20	Toride Kyodo General Hospital	Toride-shi	Ibaraki	Japan	302-0022
21	Mitoyo General Hospital	Kannonji	Kagawa	Japan	769-1695
22	Fujisawa City Hospital	Fujisawa	Kanagawa	Japan	251-8550
23	Kitasato University Hospital	Sagamihara	Kanagawa	Japan	252-0375
24	Mie University Hospital	Tsu	MIE	Japan	514-8507
25	National Hospital Organization Sendai Medical Center	Sendai-shi	Miyagi-ken	Japan	983-8520
26	Nara Medical University Hospital	Kashihara	Nara	Japan	634-8522
27	National Cerebral and Cardiovascular Center Hospital	Suita-shi	Osaka-fu	Japan	565-8565
28	Kishiwada Tokushukai Hospital	Kishiwada	Osaka	Japan	596-0042
29	Sakai City Medical Center	Sakai-shi	Osaka	Japan	593-8304
30	Gokeikai Osaka Kaisei Hospital	Yodogawa-ku	Osaka	Japan	532-0003
31	Shuwa General Hospital	Kasukabe-shi	Saitama	Japan	344-0035
32	Saitama Medical Center Jichi Medical University	Saitama-shi	Saitama	Japan	330-0834
33	Kusatsu General Hospital	Kusatsu-shi	Shiga-ken	Japan	525-8585
34	Hamamatsu Rosai Hospital	Hamamatsu-shi	Shizuoka	Japan	430-8525
35	Jichi Medical University Hospital	Shimotsuke-shi	Tochigi	Japan	329-0498
36	Tokushima Red Cross Hospital	Komatsushima	Tokushima	Japan	773-8502
37	Juntendo University Hospital	Bunkyo-ku	Tokyo	Japan	113-8431
38	Mitsui Memorial Hospital	Chiyoda-Ku	Tokyo	Japan	101-8643
39	Tokyo Women's Medical University Hospital	Shinjuku-ku	Tokyo	Japan	162-8666
40	Tottori University Hospital	Yonago-shi	Tottori	Japan	683-8504
41	Ube-kohsan Central Hospital Corp.	Ube-city	Yamaguchi	Japan	755-0151
42	Yamaguchi University Hospital	Ube	Yamaguchi	Japan	755-8505
43	University of Yamanashi Hospital	Chuo	Yamanashi	Japan	409-3898
44	Hamanomachi Hospital	Fukuoka		Japan	810-8539
45	Fukushima Medical University Hospital	Fukushima		Japan	960-1295
46	Gifu Prefectural General Medical Center	Gifu		Japan	500-8727
47	Kumamoto University Hospital	Kumamoto		Japan	860-8556
48	Saiseikai Kumamoto Hospital	Kumamoto		Japan	861-4101
49	Japanese Red Cross Okayama Hospital	Okayama		Japan	700-8607
50	National Hospital Organization Osaka National Hospital	Osaka		Japan	540-0006
51	Osaka Police Hospital	Osaka		Japan	543-0035
52	Osaka General Medical Center	Osaka		Japan	558-8558
53	National Hospital Organization Takasaki General Medical Center	Takasaki-shi		Japan	370-0829
54	Toyama University Hospital	Toyama		Japan	930-0152

Sponsors and Collaborators

• Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
• ClinicalTrials.gov Identifier: NCT01115855
• Other Study ID Numbers: A6141114
• First Posted: May 4, 2010
• Last Update Posted: Dec 22, 2020
• Last Verified: Dec 1, 2020

• Keywords provided by Pfizer's Upjohn has merged with Mylan to form Viatris Inc.: Double-blind; eplerenone; Japanese
• Additional relevant MeSH terms: Heart Failure; Eplerenone

Study Results

Participant Flow

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with estimated glomerular filtration rate (eGFR) greater than or equal to (>=) 50 milliliter per minute divided by 1.73 squared meter (mL/min/1.73m^2) received eplerenone 25 milligram (mg) tablet once daily up to Week 4 and participants with eGFR 30 to less than (<) 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. . From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Period Title: Overall Study
STARTED	111	110
COMPLETED	75	74
NOT COMPLETED	36	36

Baseline Characteristics

Arm/Group Title	Eplerenone	Placebo	Total
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.	Total of all reporting groups
Overall Participants	111	110	221
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.0 (8.7)	68.4 (7.7)	68.7 (8.2)
Sex: Female, Male (Count of Participants)
FEMALE	26 23.4%	19 17.3%	45 20.4%
MALE	85 76.6%	91 82.7%	176 79.6%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF)
Description	CV mortality was defined as any death due to HF, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident, other CV cause (such as aneurysm or pulmonary embolism). Hospitalization due to HF was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.
Time Frame	Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Number [participants]	33 29.7%	36 32.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Cox Proportional Hazard Model with baseline New York Heart Association (NYHA) cohort (II, III/IV) and baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) covariates.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.53 to 1.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants With First Occurrence of Cardiovascular (CV) Mortality, Hospitalization Due to Heart Failure (HF), or Addition/Increase of Heart Failure (HF) Medication
Description	CV mortality was defined as any death due to HF, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident, other CV cause (such as aneurysm or pulmonary embolism). Hospitalization due to HF was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF. Addition/ increase of HF medications was defined as administration of new HF medication or increase of 50 percentage (%) or more in dose of HF medication for >= 3 days. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.
Time Frame	Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Number [participants]	42 37.8%	45 40.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Cox Proportional Hazard Model with baseline NYHA cohort (II, III/IV) and baseline eGFR (30--<50 ml/min/1.73 m^2, >-=50 ml/min/1.73 m^2) covariates.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.56 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants With With First Occurrence of All-Cause Mortality
Description	All-cause mortality was defined as any CV mortality, Non-CV mortality, including malignant tumor, pulmonary disease and trauma.CV mortality was defined as death due to HF, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident, other CV cause (such as aneurysm or pulmonary embolism). Mortality during treatment, within 30 days of treatment discontinuation and after 30 days of discontinuation was reported. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.
Time Frame	Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
During treatment	6 5.4%	5 4.5%
Within 30 days of treatment discontinuation	1 0.9%	1 0.9%
After 30 days of treatment discontinuation	10 9%	4 3.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Cox Proportional Hazard Model with baseline NYHA cohort (II, III/IV) and baseline eGFR (30--<50 ml/min/1.73 m^2, >-=50 ml/min/1.73 m^2) covariates.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.77
	Confidence Interval	(2-Sided) 95%; 0.81 to 3.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Participants With With First Occurrence of Cardiovascular Mortality
Description	CV mortality was defined as death due to HF, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident, other CV cause (such as aneurysm or pulmonary embolism). Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.
Time Frame	Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Number [participants]	14 12.6%	6 5.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Cox Proportional Hazard Model with baseline NYHA cohort (II, III/IV) and baseline eGFR (30--<50 ml/min/1.73 m^2, >-=50 ml/min/1.73 m^2) covariates.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.40
	Confidence Interval	(2-Sided) 95%; 0.92 to 6.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Participants With First Occurrence of All-cause Hospitalization
Description	All cause hospitalization included all hospitalizations as CV hospitalization, which was defined as any hospitalization due to CV events including HF, myocardial infarction, arrhythmia, angina pectoris and non-CV hospitalizations which was defined as any hospitalization due to non-CV events including renal dysfunction, hyperkalaemia, malignant tumor and pulmonary disease. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.
Time Frame	Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Number [participants]	45 40.5%	58 52.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Cox Proportional Hazard Model with baseline NYHA cohort (II, III/IV) and baseline eGFR (30--<50 ml/min/1.73 m^2, >-=50 ml/min/1.73 m^2) covariates.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.44 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Number of Participants With First Occurrence of Hospitalization Due to Heart Failure (HF)
Description	Hospitalization due to HF was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.
Time Frame	Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Number [participants]	27 24.3%	33 30%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Cox Proportional Hazard Model with baseline NYHA cohort (II, III/IV) and baseline eGFR (30--<50 ml/min/1.73 m^2, >-=50 ml/min/1.73 m^2) covariates.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.45 to 1.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Number of Participants With First Occurrence of All-cause Mortality or All-cause Hospitalization
Description	All cause hospitalization included all hospitalizations as CV hospitalization, which was defined as any hospitalization due to CV events including HF, myocardial infarction, arrhythmia, angina pectoris and non-CV hospitalizations which was defined as any hospitalization due to non-CV events including renal dysfunction, hyperkalaemia, malignant tumor and pulmonary disease. All-cause mortality was defined as any CV mortality, Non-CV mortality, including malignant tumor, pulmonary disease and trauma.CV mortality was defined as death due to HF, myocardial infarction, cardiac arrhythmia, stroke or cerebral vascular accident, other CV cause (such as aneurysm or pulmonary embolism). Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.
Time Frame	Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Number [participants]	48 43.2%	61 55.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Cox Proportional Hazard Model with baseline NYHA cohort (II, III/IV) and baseline eGFR (30--<50 ml/min/1.73 m^2, >-=50 ml/min/1.73 m^2) covariates.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Number of Participants With First Occurrence of Heart Failure (HF) Mortality or Heart Failure (HF) Hospitalization
Description	HF mortality was defined as any death due to HF. Hospitalization due to HF was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to HF. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.
Time Frame	Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Number [participants]	29 26.1%	33 30%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Cox Proportional Hazard Model with baseline NYHA cohort (II, III/IV) and baseline eGFR (30--<50 ml/min/1.73 m^2, >=-50 ml/min/1.73 m^2) covariates.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.49 to 1.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Number of Participants With First Occurrence of Cardiovascular (CV) Hospitalization
Description	CV hospitalization, which was defined as any hospitalization due to CV events including HF, myocardial infarction, arrhythmia, angina pectoris. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.
Time Frame	Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Number [participants]	35 31.5%	44 40%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Cox Proportional Hazard Model with baseline NYHA cohort (II, III/IV) and baseline eGFR (30--<50 ml/min/1.73 m^2, >-=50 ml/min/1.73 m^2) covariates.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.45 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Number of Participants With First Occurrence of Addition/Increase of Heart Failure (HF) Medication Due to Heart Failure (HF) Worsening
Description	Addition/ increase of HF medications was defined as administration of new HF medication or increase of 50 percent or more in dose of HF medication for >= 3 days. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.
Time Frame	Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Number [participants]	38 34.2%	43 39.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Cox Proportional Hazard Model with baseline NYHA cohort (II, III/IV) and baseline eGFR (30--<50 ml/min/1.73 m^2, >-=50 ml/min/1.73 m^2) covariates.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.53 to 1.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Number of Participants With First Occurrence of Fatal/Non-Fatal Stroke
Description	Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.
Time Frame	Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Number [participants]	3 2.7%	4 3.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Cox Proportional Hazard Model with baseline NYHA cohort (II, III/IV) and baseline eGFR (30--<50 ml/min/1.73 m^2, >-=50 ml/min/1.73 m^2) covariates.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.18 to 3.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Number of Participants With First Occurrence of Fatal/Non-Fatal Myocardial Infarction (MI)
Description	Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.
Time Frame	Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Number [participants]	1 0.9%	1 0.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Cox Proportional Hazard Model with baseline NYHA cohort (II, III/IV) and baseline eGFR (30--<50 ml/min/1.73 m^2, >-=50 ml/min/1.73 m^2) covariates.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 95%; 0.07 to 17.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Number of Participants With First Occurrence of New Onset Atrial Fibrillation/Flutter
Description	New onset of atrial fibrillation or flutter was defined as the diagnosis of atrial fibrillation or flutter in a participant after randomization. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.
Time Frame	Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Number [participants]	4 3.6%	2 1.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Cox Proportional Hazard Model with baseline NYHA cohort (II, III/IV) and baseline eGFR (30--<50 ml/min/1.73 m^2, >-=50 ml/min/1.73 m^2) covariates.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.11
	Confidence Interval	(2-Sided) 95%; 0.39 to 11.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Number of Participants With First Occurrence of New Onset Diabetes Mellitus
Description	New onset diabetes mellitus was defined as the diagnosis of diabetes mellitus in a participant after randomization. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.
Time Frame	Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Number [participants]	1 0.9%	2 1.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Cox Proportional Hazard Model with baseline NYHA cohort (II, III/IV) and baseline eGFR (30--<50 ml/min/1.73 m^2, >-=50 ml/min/1.73 m^2) covariates.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95%; 0.05 to 5.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Number of Participants With First Occurrence of Hospitalisation Due to Worsening Renal Function
Description	Hospitalization due to worsening renal function (as per physician's decision) was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to worsening renal function as the primary reason for hospitalization. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.
Time Frame	Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Number [participants]	2 1.8%	2 1.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Cox Proportional Hazard Model with baseline NYHA cohort (II, III/IV) and baseline eGFR (30--<50 ml/min/1.73 m^2, >-=50 ml/min/1.73 m^2) covariates.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; 0.16 to 8.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Number of Participants With First Occurrence of Hospitalization for Hyperkalemia
Description	Hospitalization due to hyperkalemia (as per physician's decision) was defined as an overnight stay, or longer, in a hospital environment (emergency room, observation unit or in-patient care, or similar facility including admission to a day care facility) due to hyperkalemia as the primary reason for hospitalization. Hazard ratio of Eplerenone versus placebo for first occurrence of the event was obtained from a Cox proportional hazards model.
Time Frame	Randomization up to the date when the last enrolled participant had been followed up for 1 year (up to 1744 days)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Number [participants]	0 0%	0 0%

17. Secondary Outcome

Title	Change From Baseline in Plasma Concentration of Brain Natriuretic Peptide at Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48 and Final Visit
Time Frame	Baseline, Months 5,9,13,17,21,25,29,33,37,42,48, Final Visit (up to Month 48)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants. Here, 'n' signifies those participants who were evaluable at specified time point for each arm, respectively.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Baseline (n=111,110)	469.29 (375.43)	435.61 (391.49)
Change at Month 5 (n=105,106)	-169.75 (424.40)	-36.36 (413.73)
Change at Month 9 (n=99,104)	-208.54 (405.74)	-76.23 (442.47)
Change at Month 13 (n=95,101)	-258.66 (395.05)	-93.99 (409.87)
Change at Month 17 (n=81,82)	-242.92 (431.59)	-69.74 (535.05)
Change at Month 21 (n=72,73)	-241.33 (429.24)	-57.31 (515.76)
Change at Month 25 (n=63,63)	-249.76 (473.68)	-83.99 (506.79)
Change at Month 29 (n=53,48)	-269.07 (502.78)	-95.33 (350.51)
Change at Month 33 (n=45,40)	-228.84 (575.05)	-43.98 (500.78)
Change at Month 37 (n=40,33)	-211.86 (597.30)	-73.73 (626.13)
Change at Month 42 (n=30,26)	-155.65 (320.44)	-22.31 (689.26)
Change at Month 48 (n=16,16)	-200.85 (357.51)	-122.33 (450.87)
Change at Final Visit (n=109,110)	-149.75 (473.95)	-57.45 (509.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 5 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-102.93
	Confidence Interval	(2-Sided) 95%; -195.92 to -9.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 47.13
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 9 :Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-95.77
	Confidence Interval	(2-Sided) 95%; -184.51 to -7.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 44.54
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 13 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-125.09
	Confidence Interval	(2-Sided) 95%; -195.50 to -54.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 35.15
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 17 :Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-31.94
	Confidence Interval	(2-Sided) 95%; -232.77 to -31.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 51.12
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 21 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-132.39
	Confidence Interval	(2-Sided) 95%; -240.94 to -23.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 52.77
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 25 :Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-117.18
	Confidence Interval	(2-Sided) 95%; -221.49 to -12.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 51.76
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 29 :Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-101.50
	Confidence Interval	(2-Sided) 95%; -267.36 to 64.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 61.05
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 33 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-110.78
	Confidence Interval	(2-Sided) 95%; -307.49 to 85.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 92.42
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 37 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-119.62
	Confidence Interval	(2-Sided) 95%; -2137.82 to 1898.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 158.84
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 42 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-144.60
	Confidence Interval	(2-Sided) 90%; -2692.95 to 2403.76
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 200.56
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 48 :Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-77.26
	Confidence Interval	(2-Sided) 95%; -2131.88 to 1977.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 966.09
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 13 : ANCOVA with treatment effect and covariates of the NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-102.30
	Confidence Interval	(2-Sided) 95%; -172.61 to -32.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 35.67
	Estimation Comments

18. Secondary Outcome

Title	Change From Baseline in Plasma Concentration of Serum N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) at Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48 and Final Visit
Time Frame	Baseline, Months 5, 9, 13, 17, 21 ,25, 29, 33, 37, 42, 48 and Final Visit (up to Month 48)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants. Here, 'n' signifies those participants who were evaluable at specified time point for each arm, respectively.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Baseline (n=111,110)	2635.78 (2143.64)	2354.31 (1874.30)
Change at Month 5 (n=105,106)	-770.51 (2172.88)	-205.18 (1801.42)
Change at Month 9 (n=99,104)	-884.76 (2265.57)	-425.47 (1883.54)
Change at Month 13 (n=95,101)	-1066.86 (2088.51)	-452.02 (1878.98)
Change at Month 17 (n=81,82)	-1126.96 (2384.14)	-109.59 (3380.42)
Change at Month 21 (n=72,73)	-957.86 (2601.47)	-250.85 (2508.01)
Change at Month 25 (n=63,63)	-453.57 (4894.51)	-128.02 (2627.01)
Change at Month 29 (n=53,48)	-1013.83 (3167.91)	-187.08 (2524.52)
Change at Month 33 (n=45,40)	-168.36 (5404.82)	434.35 (5134.98)
Change at Month 37 (n=40,33)	-9.64 (5188.24)	171.21 (5081.43)
Change at Month 42 (n=30,26)	-246.77 (4753.87)	928.35 (6494.32)
Change at Month 48 (n=16,16)	-970.71 (4833.60)	-450.69 (1487.78)
Change at Final Visit (n=109,110)	-177.00 (3780.44)	296.35 (3823.59)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 5 :Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-364.65
	Confidence Interval	(2-Sided) 95%; -1863.06 to 1133.76
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 763.83
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 9 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-247.14
	Confidence Interval	(2-Sided) 95%; -1642.43 to 1148.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 711.26
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 13 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-370.14
	Confidence Interval	(2-Sided) 95%; -1742.51 to 1002.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 699.58
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 17 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-664.09
	Confidence Interval	(2-Sided) 95%; -141189.93 to 139861.75
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11059.62
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 21 :Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-414.99
	Confidence Interval	(2-Sided) 95%; -39445.52 to 38615.54
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3071.77
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 25 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	23.86
	Confidence Interval	(2-Sided) 95%; -21649.89 to 21697.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10794.85
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 29 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-245.23
	Confidence Interval	(2-Sided) 95%; -85358.69 to 84868.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6698.57
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 33 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	170.49
	Confidence Interval	(2-Sided) 95%; -21375.69 to 21716.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10730.38
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 37 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-58.77
	Confidence Interval	(2-Sided) 95%; -30160.25 to 30042.70
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12765.30
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 42 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-212.25
	Confidence Interval	(2-Sided) 90%; -22723.82 to 22299.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11073.11
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 48 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-80.16
	Confidence Interval	(2-Sided) 95%; -146026.28 to 145865.96
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11486.21
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 13 : ANCOVA with treatment effect and covariates of the NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-187.72
	Confidence Interval	(2-Sided) 95%; -662.67 to 287.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 240.96
	Estimation Comments

19. Secondary Outcome

Title	Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48 and Final Visit
Description	LVEF was calculated based on end-diastolic volume measured by two-dimensional echocardiography.
Time Frame	Baseline, Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48, Final Visit (up to Month 48)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants. Here, 'n' signifies those participants who were evaluable at specified time point for each arm, respectively.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Baseline (n=111,110)	25.64 (4.95)	26.64 (3.97)
Change at Month 5 (n=105,106)	5.98 (8.87)	4.01 (7.59)
Change at Month 9 (n=99,104)	33.89 (10.64)	31.37 (9.19)
Change at Month 13 (n=94,101)	9.62 (9.70)	4.86 (10.13)
Change at Month 17 (n=81,82)	11.36 (11.45)	5.50 (10.74)
Change at Month 21 (n=72,73)	12.73 (12.04)	6.37 (11.88)
Change at Month 25 (n=63,64)	12.18 (12.18)	6.60 (10.94)
Change at Month 29 (n=53,48)	11.95 (12.28)	6.45 (12.83)
Change at Month 33 (n=45,39)	13.67 (13.94)	5.20 (10.19)
Change at Month 37 (n=40,33)	13.34 (14.59)	7.18 (10.49)
Change at Month 42 (n=30,26)	12.15 (14.38)	5.13 (10.36)
Change at Month 48 (n=16,16)	10.18 (16.02)	8.41 (11.51)
Change at Final Visit (n=109,110)	9.50 (12.03)	5.99 (11.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 5 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	1.71
	Confidence Interval	(2-Sided) 95%; -0.55 to 3.96
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.14
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 9 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	2.74
	Confidence Interval	(2-Sided) 95%; 0.07 to 5.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.36
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 13 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	3.86
	Confidence Interval	(2-Sided) 95%; 1.11 to 6.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.39
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 17 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	4.86
	Confidence Interval	(2-Sided) 95%; 1.81 to 7.90
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.54
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 21 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	5.65
	Confidence Interval	(2-Sided) 95%; 2.36 to 8.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.67
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 25 :Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	3.44
	Confidence Interval	(2-Sided) 95%; 0.12 to 6.75
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.68
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 29 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	3.60
	Confidence Interval	(2-Sided) 95%; -0.06 to 7.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.85
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 33 :Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	4.65
	Confidence Interval	(2-Sided) 95%; 0.86 to 8.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.92
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 37 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	3.85
	Confidence Interval	(2-Sided) 95%; 0.02 to 7.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.94
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 42 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	4.67
	Confidence Interval	(2-Sided) 90%; 0.08 to 9.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.31
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 48 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	4.13
	Confidence Interval	(2-Sided) 95%; -1.82 to 10.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.98
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 13 : ANCOVA with treatment effect and covariates of the NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	3.18
	Confidence Interval	(2-Sided) 95%; 0.56 to 5.80
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.33
	Estimation Comments

20. Secondary Outcome

Title	Change From Baseline in Urine Albumin-to-Creatinine Ratio at Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48 and Final Visit
Time Frame	Baseline, Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48, Final Visit (up to Month 48)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants. Here, 'n' signifies those participants who were evaluable at specified time point for each arm, respectively.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Baseline (n=111,108)	169.82 (787.32)	154.93 (366.44)
Change at Month 5 (n=104,103)	-21.14 (359.53)	46.23 (377.56)
Change at Month 9 (n=98,101)	-11.10 (249.68)	23.79 (362.35)
Change at Month 13 (n=94,98)	-41.56 (322.12)	-19.04 (253.57)
Change at Month 17 (n=80,82)	-13.66 (247.48)	79.28 (530.74)
Change at Month 21 (n=72,73)	-63.65 (498.00)	28.84 (431.48)
Change at Month 25 (n=62,63)	17.17 (489.08)	30.08 (350.86)
Change at Month 29 (n=50,47)	18.51 (454.75)	-4.58 (504.53)
Change at Month 33 (n=43,39)	-47.07 (506.66)	-3.38 (417.43)
Change at Month 37 (n=39,33)	-80.21 (743.85)	34.20 (393.95)
Change at Month 42 (n=27,25)	-162.18 (921.61)	-29.95 (187.19)
Change at Month 48 (n=16,16)	-303.19 (1211.28)	-41.03 (113.70)
Change at Final Visit (n=109,110)	-29.30 (597.07)	-31.56 (271.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 5: Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-61.53
	Confidence Interval	(2-Sided) 95%; -186.44 to 63.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 59.75
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 9 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-24.94
	Confidence Interval	(2-Sided) 95%; -131.27 to 81.39
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 54.20
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 13 :Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-12.57
	Confidence Interval	(2-Sided) 95%; -97.28 to 72.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 43.18
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 17 :Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-78.47
	Confidence Interval	(2-Sided) 95%; -221.25 to 64.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 72.78
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 21 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-79.63
	Confidence Interval	(2-Sided) 95%; -211.88 to 52.63
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 67.42
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 25 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	19.35
	Confidence Interval	(2-Sided) 95%; -230.01 to 268.71
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 88.95
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 29: Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-21.05
	Confidence Interval	(2-Sided) 95%; -194.21 to 152.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 88.27
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 33: Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-40.79
	Confidence Interval	(2-Sided) 95%; -197.55 to 115.97
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 79.91
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 37 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-44.48
	Confidence Interval	(2-Sided) 95%; -247.11 to 158.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 103.29
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 42 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-27.69
	Confidence Interval	(2-Sided) 90%; -238.31 to 182.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 107.06
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 48: Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-31.46
	Confidence Interval	(2-Sided) 95%; -221.17 to 158.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 96.48
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 13 :ANCOVA with treatment effect and covariates of the NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-2.04
	Confidence Interval	(2-Sided) 95%; -58.91 to 54.83
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 28.85
	Estimation Comments

21. Secondary Outcome

Title	Number of Participants With Change From Baseline in New York Heart Association (NYHA) Classification at Weeks 1, 4, Months 2, 3, 4, 5, 9, 13, 17 21, 25, 29, 33, 37, 42, 48 and Final Visit
Description	NYHA: classified as 'class I' (participants with cardiac disease but without resulting limitations of physical activity), 'class II' (participants with cardiac disease resulting in slight limitation of physical activity), 'class III' (participants with cardiac disease resulting in marked limitation of physical activity), 'class IV' (participants with cardiac disease resulting in inability to carry on any physical activity without discomfort). Participants with change from baseline were classified as 'improved' (positive change), 'no change' or 'worsened' (negative change).
Time Frame	Baseline, Weeks 1, 4, Months 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48 and Final Visit (up to Month 48)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants. Here, 'n' signifies those participants who were evaluable at specified time point for each arm, respectively.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Week 1 (n=111, 110) : Improved	4 3.6%	2 1.8%
Week 1 (n=111, 110) : Unchanged	107 96.4%	107 97.3%
Week 1 (n=111, 110) : Worse	0 0%	1 0.9%
Week 4 (n=111, 108) : Improved	10 9%	14 12.7%
Week 4 (n=111, 108) : Unchanged	101 91%	92 83.6%
Week 4 (n=111, 108) : Worse	0 0%	2 1.8%
Month 2 (n=109, 109) : Improved	15 13.5%	14 12.7%
Month 2 (n=109, 109) : Unchanged	94 84.7%	95 86.4%
Month 2 (n=109, 109) : Worse	0 0%	0 0%
Month 3 (n=106, 107) : Improved	18 16.2%	16 14.5%
Month 3 (n=106, 107) : Unchanged	88 79.3%	91 82.7%
Month 3 (n=106, 107) : Worse	0 0%	0 0%
Month 4 (n=106, 106) : Improved	22 19.8%	20 18.2%
Month 4 (n=106, 106) : Unchanged	82 73.9%	86 78.2%
Month 4 (n=106, 106) : Worse	2 1.8%	0 0%
Month 5 (n=104, 106) : Improved	24 21.6%	22 20%
Month 5 (n=104, 106) : Unchanged	76 68.5%	83 75.5%
Month 5 (n=104, 106) : Worse	4 3.6%	1 0.9%
Month 9 (n=99, 105) : Improved	27 24.3%	20 18.2%
Month 9 (n=99, 105) : Unchanged	71 64%	81 73.6%
Month 9 (n=99, 105) : Worse	1 0.9%	4 3.6%
Month 13 (n=94, 102) : Improved	31 27.9%	19 17.3%
Month 13 (n=94, 102) : Unchanged	62 55.9%	82 74.5%
Month 13 (n=94, 102) : Worse	1 0.9%	1 0.9%
Month 17 (n=81, 82) : Improved	25 22.5%	18 16.4%
Month 17 (n=81, 82) : Unchanged	55 49.5%	61 55.5%
Month 17 (n=81, 82) : Worse	1 0.9%	3 2.7%
Month 21 (n=72, 73) : Improved	21 18.9%	19 17.3%
Month 21 (n=72, 73) : Unchanged	50 45%	51 46.4%
Month 21 (n=72, 73) : Worse	1 0.9%	3 2.7%
Month 25 (n=63, 64) : Improved	23 20.7%	14 12.7%
Month 25 (n=63, 64) : Unchanged	38 34.2%	48 43.6%
Month 25 (n=63, 64) : Worse	2 1.8%	2 1.8%
Month 29 (n=53, 48) : Improved	17 15.3%	12 10.9%
Month 29 (n=53, 48) : Unchanged	36 32.4%	35 31.8%
Month 29 (n=53, 48) : Worse	0 0%	1 0.9%
Month 33 (n=46, 39) : Improved	14 12.6%	10 9.1%
Month 33 (n=46, 39) : Unchanged	31 27.9%	27 24.5%
Month 33 (n=46, 39) : Worse	1 0.9%	2 1.8%
Month 37 (n=40, 33) : Improved	12 10.8%	10 9.1%
Month 37 (n=40, 33) : Unchanged	28 25.2%	22 20%
Month 37 (n=40, 33) : Worse	0 0%	1 0.9%
Month 42 (n=30, 26) : Improved	7 6.3%	7 6.4%
Month 42 (n=30, 26) : Unchanged	23 20.7%	18 16.4%
Month 42 (n=30, 26) : Worse	0 0%	1 0.9%
Month 48 (n=16, 16) : Improved	2 1.8%	6 5.5%
Month 48 (n=16, 16) : Unchanged	14 12.6%	9 8.2%
Month 48 (n=16, 16) : Worse	0 0%	1 0.9%
Final Visit (n=111, 110) : Improved	25 22.5%	26 23.6%
Final Visit (n=111, 110) : Unchanged	80 72.1%	80 72.7%
Final Visit (n=111, 110) : Worse	6 5.4%	4 3.6%

22. Secondary Outcome

Title	Change From Baseline in Specific Activity Scale (SAS) Score at Week 4, Months 2, 3, 4, 5, 9, 13, 17 21, 25, 29, 33, 37, 42, 48 and Final Visit
Description	Specific activity scale was estimated by pre-specified questionnaire (for different activities) to assess the exercise capability of the participants. Answers provided by participants were transformed in terms of number of metabolic equivalents (METs).1 MET was defined as the amount of oxygen consumed while sitting at rest and is equal to 3.5 ml oxygen per kg body weight* minute. Scale ranged from 1 (less than (<) 2 METs) = lowest level of exercise tolerance to 6 (>=8METs) = highest level of tolerance and higher score indicated more tolerance.
Time Frame	Baseline, Week 4, Months 5, 9, 13, 17, 21, 25, 29, 33, 37, 42, 48, Final Visit (up to Month 48)

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants. Here, 'n' signifies those participants who were evaluable at specified time point for each arm, respectively.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.	Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
Measure Participants	111	110
Baseline (n=111,110)	4.85 (1.51)	4.89 (1.54)
Change at Week 4 (n= 111,108)	0.15 (0.79)	0.27 (1.08)
Change at Month 5 (n=104,106)	0.46 (1.15)	0.33 (1.19)
Change at Month 9 (n=99,104)	0.41 (1.16)	0.37 (1.39)
Change at Month 13 (n=94,102)	0.52 (1.18)	0.44 (1.45)
Change at Month 17 (n=81,82)	0.46 (1.38)	0.47 (1.81)
Change at Month 21 (n=72,73)	0.34 (1.33)	0.59 (1.64)
Change at Month 25 (n=63,63)	0.48 (1.08)	0.63 (1.72)
Change at Month 29 (n=53,48)	0.42 (1.14)	0.65 (1.56)
Change at Month 33 (n=46,40)	0.37 (1.28)	0.51 (1.80)
Change at Month 37 (n=40,33)	0.53 (1.47)	0.68 (1.39)
Change at Month 42 (n=30,26)	0.39 (1.70)	0.47 (1.83)
Change at Month 48 (n=16,16)	-0.13 (1.57)	0.64 (1.59)
Change at Final Visit (n=111,110)	0.14 (1.56)	0.25 (1.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 5 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -0.21 to 0.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.15
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 9 :Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.34 to 0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.16
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 13: Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.27 to 0.39
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.17
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 17 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.41 to 0.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.22
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 21 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.56 to 0.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.20
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 25 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.55 to 0.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.20
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 29 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.49 to 0.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.20
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 33 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.57 to 0.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.26
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 37 :Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.50 to 0.54
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.26
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 42 :Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	0.20
	Confidence Interval	(2-Sided) 90%; -0.44 to 0.83
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.32
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Month 48 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 95%; -0.63 to 0.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.38
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Eplerenone, Placebo
	Comments	Change from baseline at Week 4 : Mixed effect model of repeated measurements with covariates of the treatment, Week, interaction between treatment and week, baseline NYHA cohort (II, III/IV), baseline eGFR (30-<50 ml/min/1.73 m^2, >=50 ml/min/1.73 m^2) and baseline value.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean Difference
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Adverse Events

Adverse Event Reporting Description	The same event may appear as both an adverse event and an serious adverse event. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non serious event during the study.
Arm/Group Title	Eplerenone		Placebo
Arm/Group Description	Participants with eGFR >=50 mL/min/1.73m^2 received eplerenone 25 mg tablet once daily up to Week 4 and participants with eGFR 30 to < 50 mL/min/1.73m^2 received eplerenone 25 mg tablet every other day up to Week 4. From Week 4 onward, the dose of eplerenone was limited to 50 mg once daily for participants with eGFR >=50 mL/min/1.73 m^2 and 25 mg once daily for participants with eGFR 30 to <50 mL/min/1.73 m^2 up to Month 48.		Participants with eGFR >=50 mL/min/1.73m^2 received placebo matched with eplerenone tablet orally once daily from up to Week 4 and participants with eGFR 30 to <50 mL/min/1.73m^2 received placebo matched with eplerenone tablet every other day up to Week 4. From Week 4 onward, all participants received placebo matched with eplerenone tablet once daily up to Month 48.
All Cause Mortality
	Eplerenone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Eplerenone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/111 (46.8%)		65/110 (59.1%)
Blood and lymphatic system disorders
Anaemia	1/111 (0.9%)		0/110 (0%)
Bone marrow failure	1/111 (0.9%)		0/110 (0%)
Disseminated intravascular coagulation	2/111 (1.8%)		0/110 (0%)
Haemorrhagic diathesis	1/111 (0.9%)		0/110 (0%)
Cardiac disorders
Angina pectoris	2/111 (1.8%)		4/110 (3.6%)
Angina unstable	0/111 (0%)		1/110 (0.9%)
Arrhythmia	0/111 (0%)		1/110 (0.9%)
Atrial fibrillation	1/111 (0.9%)		2/110 (1.8%)
Atrial flutter	0/111 (0%)		1/110 (0.9%)
Bradycardia	0/111 (0%)		1/110 (0.9%)
Cardiac failure	27/111 (24.3%)		31/110 (28.2%)
Cardiac failure acute	1/111 (0.9%)		0/110 (0%)
Cardiac failure chronic	2/111 (1.8%)		1/110 (0.9%)
Cardiac failure congestive	2/111 (1.8%)		2/110 (1.8%)
Cardiac sarcoidosis	1/111 (0.9%)		0/110 (0%)
Cardio-respiratory arrest	1/111 (0.9%)		0/110 (0%)
Congestive cardiomyopathy	1/111 (0.9%)		0/110 (0%)
Coronary artery stenosis	2/111 (1.8%)		2/110 (1.8%)
Intracardiac thrombus	0/111 (0%)		1/110 (0.9%)
Mitral valve incompetence	0/111 (0%)		1/110 (0.9%)
Myocardial infarction	1/111 (0.9%)		0/110 (0%)
Ventricular fibrillation	1/111 (0.9%)		1/110 (0.9%)
Ventricular tachycardia	5/111 (4.5%)		3/110 (2.7%)
Eye disorders
Cataract	2/111 (1.8%)		3/110 (2.7%)
Retinal detachment	1/111 (0.9%)		0/110 (0%)
Gastrointestinal disorders
Abdominal pain upper	1/111 (0.9%)		0/110 (0%)
Gastric ulcer	1/111 (0.9%)		0/110 (0%)
Gastric ulcer haemorrhage	0/111 (0%)		1/110 (0.9%)
Gastrointestinal haemorrhage	1/111 (0.9%)		2/110 (1.8%)
Inguinal hernia	0/111 (0%)		1/110 (0.9%)
Large intestine polyp	1/111 (0.9%)		0/110 (0%)
Pancreatitis acute	1/111 (0.9%)		0/110 (0%)
Protein-losing gastroenteropathy	1/111 (0.9%)		0/110 (0%)
General disorders
Chest discomfort	1/111 (0.9%)		1/110 (0.9%)
Chest pain	0/111 (0%)		1/110 (0.9%)
Malaise	0/111 (0%)		1/110 (0.9%)
Multi-organ failure	1/111 (0.9%)		0/110 (0%)
Sudden cardiac death	1/111 (0.9%)		2/110 (1.8%)
Sudden death	1/111 (0.9%)		0/110 (0%)
Hepatobiliary disorders
Cholecystitis	0/111 (0%)		3/110 (2.7%)
Infections and infestations
Appendicitis	0/111 (0%)		1/110 (0.9%)
Bronchitis	1/111 (0.9%)		0/110 (0%)
Bronchopneumonia	1/111 (0.9%)		0/110 (0%)
Cellulitis	0/111 (0%)		1/110 (0.9%)
Device related infection	0/111 (0%)		2/110 (1.8%)
Disseminated tuberculosis	0/111 (0%)		1/110 (0.9%)
Endocarditis bacterial	0/111 (0%)		1/110 (0.9%)
Gastroenteritis	2/111 (1.8%)		1/110 (0.9%)
Influenza	1/111 (0.9%)		0/110 (0%)
Peritonitis	1/111 (0.9%)		0/110 (0%)
Pneumonia	4/111 (3.6%)		5/110 (4.5%)
Pneumonia bacterial	0/111 (0%)		2/110 (1.8%)
Pneumonia staphylococcal	1/111 (0.9%)		0/110 (0%)
Pyelonephritis	0/111 (0%)		1/110 (0.9%)
Sepsis	3/111 (2.7%)		0/110 (0%)
Injury, poisoning and procedural complications
Brain contusion	0/111 (0%)		1/110 (0.9%)
Femur fracture	0/111 (0%)		1/110 (0.9%)
Muscle injury	1/111 (0.9%)		0/110 (0%)
Postoperative ileus	1/111 (0.9%)		0/110 (0%)
Road traffic accident	0/111 (0%)		1/110 (0.9%)
Spinal compression fracture	2/111 (1.8%)		0/110 (0%)
Spinal cord injury cervical	0/111 (0%)		1/110 (0.9%)
Investigations
Blood pressure decreased	0/111 (0%)		1/110 (0.9%)
Metabolism and nutrition disorders
Dehydration	1/111 (0.9%)		0/110 (0%)
Diabetes mellitus	1/111 (0.9%)		2/110 (1.8%)
Fluid retention	1/111 (0.9%)		0/110 (0%)
Metabolic acidosis	0/111 (0%)		1/110 (0.9%)
Musculoskeletal and connective tissue disorders
Arthritis reactive	1/111 (0.9%)		0/110 (0%)
Lumbar spinal stenosis	1/111 (0.9%)		0/110 (0%)
Muscle haemorrhage	0/111 (0%)		1/110 (0.9%)
Rhabdomyolysis	1/111 (0.9%)		0/110 (0%)
Spinal column stenosis	1/111 (0.9%)		0/110 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	1/111 (0.9%)		0/110 (0%)
Colon adenoma	0/111 (0%)		1/110 (0.9%)
Colon cancer	1/111 (0.9%)		0/110 (0%)
Gastric cancer	1/111 (0.9%)		0/110 (0%)
Lung neoplasm malignant	2/111 (1.8%)		2/110 (1.8%)
Metastases to bone	0/111 (0%)		1/110 (0.9%)
Oesophageal carcinoma recurrent	0/111 (0%)		1/110 (0.9%)
Prostate cancer	0/111 (0%)		1/110 (0.9%)
Prostate cancer metastatic	0/111 (0%)		1/110 (0.9%)
Rectal cancer	0/111 (0%)		1/110 (0.9%)
Thyroid cancer metastatic	1/111 (0.9%)		0/110 (0%)
Nervous system disorders
Cerebellar infarction	0/111 (0%)		1/110 (0.9%)
Cerebral haemorrhage	0/111 (0%)		1/110 (0.9%)
Cerebral infarction	3/111 (2.7%)		2/110 (1.8%)
Cerebrovascular accident	1/111 (0.9%)		0/110 (0%)
Cervical myelopathy	1/111 (0.9%)		0/110 (0%)
Loss of consciousness	0/111 (0%)		1/110 (0.9%)
Spondylitic myelopathy	0/111 (0%)		1/110 (0.9%)
Subarachnoid haemorrhage	1/111 (0.9%)		0/110 (0%)
Syncope	0/111 (0%)		1/110 (0.9%)
Transient ischaemic attack	0/111 (0%)		1/110 (0.9%)
Renal and urinary disorders
Acute kidney injury	0/111 (0%)		1/110 (0.9%)
Chronic kidney disease	1/111 (0.9%)		0/110 (0%)
Renal failure	2/111 (1.8%)		1/110 (0.9%)
Renal impairment	0/111 (0%)		3/110 (2.7%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/111 (0.9%)		0/110 (0%)
Organising pneumonia	0/111 (0%)		1/110 (0.9%)
Pleurisy	1/111 (0.9%)		0/110 (0%)
Pneumonia aspiration	0/111 (0%)		1/110 (0.9%)
Pneumothorax	1/111 (0.9%)		0/110 (0%)
Sleep apnoea syndrome	0/111 (0%)		1/110 (0.9%)
Upper respiratory tract inflammation	0/111 (0%)		1/110 (0.9%)
Vascular disorders
Extremity necrosis	1/111 (0.9%)		0/110 (0%)
Haemorrhage	1/111 (0.9%)		0/110 (0%)
Hypotension	0/111 (0%)		1/110 (0.9%)
Peripheral arterial occlusive disease	0/111 (0%)		2/110 (1.8%)
Peripheral artery aneurysm	1/111 (0.9%)		0/110 (0%)
Other (Not Including Serious) Adverse Events
	Eplerenone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	89/111 (80.2%)		87/110 (79.1%)
Blood and lymphatic system disorders
Anaemia	7/111 (6.3%)		6/110 (5.5%)
Cardiac disorders
Cardiac failure	21/111 (18.9%)		32/110 (29.1%)
Gastrointestinal disorders
Chronic gastritis	6/111 (5.4%)		3/110 (2.7%)
Constipation	8/111 (7.2%)		18/110 (16.4%)
Diarrhoea	7/111 (6.3%)		10/110 (9.1%)
Haemorrhoids	2/111 (1.8%)		6/110 (5.5%)
Hepatobiliary disorders
Hepatic function abnormal	4/111 (3.6%)		7/110 (6.4%)
Infections and infestations
Bronchitis	6/111 (5.4%)		8/110 (7.3%)
Conjunctivitis	7/111 (6.3%)		5/110 (4.5%)
Nasopharyngitis	37/111 (33.3%)		40/110 (36.4%)
Upper respiratory tract infection	5/111 (4.5%)		6/110 (5.5%)
Injury, poisoning and procedural complications
Contusion	12/111 (10.8%)		5/110 (4.5%)
Fall	20/111 (18%)		20/110 (18.2%)
Investigations
Blood pressure decreased	6/111 (5.4%)		4/110 (3.6%)
Metabolism and nutrition disorders
Dehydration	10/111 (9%)		5/110 (4.5%)
Diabetes mellitus	7/111 (6.3%)		7/110 (6.4%)
Hyperkalaemia	8/111 (7.2%)		6/110 (5.5%)
Hyperuricaemia	11/111 (9.9%)		14/110 (12.7%)
Hypokalaemia	2/111 (1.8%)		11/110 (10%)
Musculoskeletal and connective tissue disorders
Back pain	11/111 (9.9%)		9/110 (8.2%)
Pain in extremity	6/111 (5.4%)		3/110 (2.7%)
Nervous system disorders
Dizziness	8/111 (7.2%)		5/110 (4.5%)
Renal and urinary disorders
Renal impairment	5/111 (4.5%)		7/110 (6.4%)
Reproductive system and breast disorders
Atrophic vulvovaginitis	0/26 (0%)		1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders
Cough	8/111 (7.2%)		9/110 (8.2%)
Sleep apnoea syndrome	0/111 (0%)		6/110 (5.5%)
Upper respiratory tract inflammation	1/111 (0.9%)		8/110 (7.3%)
Skin and subcutaneous tissue disorders
Eczema	4/111 (3.6%)		6/110 (5.5%)
Vascular disorders
Hypertension	9/111 (8.1%)		3/110 (2.7%)
Hypotension	4/111 (3.6%)		6/110 (5.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.