A Comparison Of Outcomes In Patients In New York Heart Association (NYHA) Class II Heart Failure When Treated With Eplerenone Or Placebo In Addition To Standard Heart Failure Medicines (EMPHASIS-HF)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT00232180
First received: September 30, 2005
Last updated: March 28, 2013
Last verified: March 2013
Results First Received: May 20, 2011  
Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Endpoint Classification: Safety Study;   Intervention Model: Single Group Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Heart Failure
Intervention: Drug: Eplerenone

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
A total of 1597 participants who completed the double-blind phase, 1246 entered into the open-label phase and 351 participants were ineligible to participate the open-label phase.

Reporting Groups
  Description
Eplerenone: Double-blind Phase Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo: Double-blind Phase Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Eplerenone: Open Label Phase Participants from double blind phase received eplerenone 25 mg tablet orally once daily on top of standard heart failure therapy for 12 months. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an eGFR between 30 to 49 ml/min/1.73m^2 in the double blind phase, initial dose was 25 mg orally once every other day; at Week 4, dose might had been increased to a maximum of 25 mg once daily based on serum potassium level.

Participant Flow for 2 periods

Period 1:   Double-blind (DB) Phase
    Eplerenone: Double-blind Phase     Placebo: Double-blind Phase     Eplerenone: Open Label Phase  
STARTED     1367 [1]   1376 [1]   0  
Treated     1364     1372     0  
COMPLETED     826     771     0  
NOT COMPLETED     541     605     0  
Death                 186                 222                 0  
Lost to Follow-up                 34                 28                 0  
Withdrawal by Subject                 131                 148                 0  
Protocol Violation                 28                 21                 0  
Adverse Event                 83                 100                 0  
Unspecified                 70                 75                 0  
Randomized but not treated                 3                 4                 0  
Laboratory abnormality                 6                 7                 0  
[1] Three participants in each arm were enrolled after data cut-off.

Period 2:   Open Label Phase
    Eplerenone: Double-blind Phase     Placebo: Double-blind Phase     Eplerenone: Open Label Phase  
STARTED     0     0     1246  
Treated     0     0     1245  
COMPLETED     0     0     1098  
NOT COMPLETED     0     0     148  
Death                 0                 0                 48  
Lost to Follow-up                 0                 0                 5  
Protocol Violation                 0                 0                 3  
Study terminated by sponsor                 0                 0                 3  
Withdrawal by Subject                 0                 0                 37  
Unspecified                 0                 0                 16  
Adverse Event                 0                 0                 25  
Laboratory abnormality                 0                 0                 10  
Randomized but not treated                 0                 0                 1  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Eplerenone Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.
Total Total of all reporting groups

Baseline Measures
    Eplerenone     Placebo     Total  
Number of Participants  
[units: participants]
  1367     1376     2743  
Age, Customized  
[units: participants]
     
Less than (<) 65 years     443     441     884  
65 to 74 years     594     607     1201  
75 to 84 years     302     299     601  
Greater than or equal to (>=) 85 years     28     29     57  
Gender  
[units: participants]
     
Female     309     302     611  
Male     1058     1074     2132  



  Outcome Measures
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1.  Primary:   Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) (Adjudicated): Up to Cut-off Date   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010) ]

2.  Primary:   Number of Participants With First Occurrence of Cardiovascular (CV) Mortality or Hospitalization Due to Heart Failure (HF) (Adjudicated)   [ Time Frame: Baseline (30 March 2006) up to 59.5 months (complete DB phase: 18 March 2011) ]

3.  Secondary:   Number of Participants With First Occurrence of All-Cause Mortality or Heart Failure (HF) Hospitalization (Adjudicated)   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

4.  Secondary:   Number of Participants With First Occurrence of All-Cause Mortality (Adjudicated)   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

5.  Secondary:   Number of Participants With First Occurrence of Cardiovascular (CV) Mortality (Adjudicated)   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

6.  Secondary:   Number of Participants With First Occurrence of All-Cause Hospitalization (Adjudicated)   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

7.  Secondary:   Number of Participants With First Occurrence of Heart Failure (HF) Hospitalization (Adjudicated)   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

8.  Secondary:   Number of Participants With First Occurrence of All-Cause Mortality or All-Cause Hospitalization (Adjudicated)   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

9.  Secondary:   Number of Participants With First Occurrence Of Heart Failure (HF) Mortality or Heart Failure (HF) Hospitalization (Adjudicated)   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]
  Hide Outcome Measure 9

Measure Type Secondary
Measure Title Number of Participants With First Occurrence Of Heart Failure (HF) Mortality or Heart Failure (HF) Hospitalization (Adjudicated)
Measure Description Death due to HF or first occurrence of HF hospitalization. Hospitalization due to HF is 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 as the primary reason for hospitalization as determined by the endpoint committee adjudicator.
Time Frame Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011)  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
FAS using ITT principle: All randomized participants, followed for mortality and other major endpoints for the duration of the double blind treatment period, regardless of compliance with the study drug and the protocol. Here “n” signifies participants evaluated at that time point.

Reporting Groups
  Description
Eplerenone: Double-blind Phase Eplerenone 25 milligram (mg) tablet orally once daily on top of standard heart failure therapy. Dose might have been increased at Week 4 to 50 mg once daily. For participants with an estimated glomerular filtration rate (eGFR) between 30 to 49 milliliter per minute divided by 1.73 squared meter (ml/min/1.73m^2), initial dose was 25 mg orally once every other day; at Week 4, dose might have been increased to a maximum of 25 mg once daily based on serum potassium level.
Placebo: Double-blind Phase Placebo matching to eplerenone 25 mg orally once daily on top of standard heart failure therapy.

Measured Values
    Eplerenone: Double-blind Phase     Placebo: Double-blind Phase  
Number of Participants Analyzed  
[units: participants]
  1367     1376  
Number of Participants With First Occurrence Of Heart Failure (HF) Mortality or Heart Failure (HF) Hospitalization (Adjudicated)  
[units: participants]
   
Up to 50 months (cut-off) (n= 1364, 1373)     170     262  
Up to 59.5 months (complete DB) (n= 1367, 1376)     194     287  


Statistical Analysis 1 for Number of Participants With First Occurrence Of Heart Failure (HF) Mortality or Heart Failure (HF) Hospitalization (Adjudicated)
Groups [1] All groups
Method [2] Cox proportional hazard model
P Value [3] <0.0001
Hazard Ratio (HR) [4] 0.577
95% Confidence Interval ( 0.475 to 0.701 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The statistical analysis was only performed on the adjudicated endpoint data up to cut-off. Cox proportional hazard model includes treatment as the major factor, adjusting for age, estimated glomerular filtration rate, left ventricular ejection fraction, body mass index, hemoglobin, heart rate, systolic blood pressure, diabetes, history of hypertension, prior myocardial infarction, baseline left bundle branch block, QRS complex and atrial fibrillation as covariates.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Statistically significant if p-value <0.01
[4] Other relevant estimation information:
  No text entered.



10.  Secondary:   Number of Participants With First Occurrence of Cardiovascular (CV) Hospitalization (Adjudicated)   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

11.  Secondary:   Number of Participants With First Occurrence of Fatal or Non-fatal Myocardial Infarction (Adjudicated)   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

12.  Secondary:   Number of Participants With First Occurrence of Fatal or Non-fatal Stroke (Adjudicated)   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

13.  Secondary:   Number of Participants With First Occurrence of Implantation of Cardiac Defibrillator (ICD) (Adjudicated)   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

14.  Secondary:   Number of Participants With First Occurrence of Implantation of Resynchronization Device (Cardiac Resynchronization Therapy [CRT]) (Adjudicated)   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

15.  Secondary:   Number of Participants With First Occurrence of Hospitalization Due to Worsening Renal Function (Adjudicated)   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

16.  Secondary:   Number of Participants With First Occurrence of Hospitalization Due to Hyperkalemia (Adjudicated)   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

17.  Secondary:   Number of Participants With New Onset Atrial Fibrillation or Flutter   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]

18.  Secondary:   Number of Participants With New Onset Diabetes Mellitus (DM)   [ Time Frame: Baseline (30 March 2006) up to 50 months (cut-off date: 25 May 2010), 59.5 months (complete DB phase: 18 March 2011) ]


  Serious Adverse Events


  Other Adverse Events


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Limitations and Caveats
Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.  


Results Point of Contact:  
Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
phone: 1-800-718-1021
e-mail: ClinicalTrials.gov_Inquiries@pfizer.com


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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00232180     History of Changes
Other Study ID Numbers: A6141079
Study First Received: September 30, 2005
Results First Received: May 20, 2011
Last Updated: March 28, 2013
Health Authority: United States: Food and Drug Administration