Irbesartan in Heart Failure With Preserved Systolic Function (I-Preserve)

Study Overview
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Brief Summary
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The purpose of this clinical research study is to learn if Irbesartan is superior to placebo in reducing mortality and cardiovascular morbidity in subjects with heart failure with preserved systolic function. The safety of this treatment will also be studied.

Official Title
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Irbesartan in Heart Failure With Preserved Systolic Function (I-Preserve)

Conditions
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Congestive Heart Failure

Intervention / Treatment
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* Drug: Irbesartan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female age >= 60 years with current symptoms of heart failure consistent with New York Heart Association (NYHA) class II-IV Left ventricular ejection fraction (LVEF) > = 45% Willing to provide written informed consent AND hospitalization for heart failure within the past 6 months OR various abnormalities in electrocardiogram, echocardiogram or chest x-ray indicating heart disease. Exclusion Criteria: Acute myocardial infarction within 3 months; Heart revascularization procedure within 3 months; Hospitalization for angina within 3 months; Other heart surgery Life-threatening or uncontrolled arrhythmia Subjects with an implantable cardioverter-defibrillator that has discharged in the past 3 months; Stroke or surgery of the arteries in the brain within 3 months; Serious lung disease which requires use of home oxygen. Significantly low blood pressure Significantly high blood pressure Other known diseases that may limit life expectancy to <3 years; Known or suspected bilateral kidney artery narrowing; Geographic or social factors making study participation and follow-up impractical.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br> | Drug: Irbesartan<br>* Tablets, Oral, titration from 75 to 300 mg, once daily up to 6 years<br>|
| Placebo Comparator: 2<br> | Drug: Placebo<br>* Tablets, Oral, titration from 75 to 300 mg, once daily up to 6 years<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With First Occurrence of the Composite Outcome of Death (All Cause) or Protocol-Specified Cardiovascular (CV) Hospitalization at Given Timepoints | Treatment comparisons for time to first occurrence of composite outcome of all-cause death (composite outcome of death) or protocol-specified CV hospitalization. Protocol-specified CV hospitalizations include those ≥24 hrs or involving a calendar date change for a primary cause of worsening heart failure, unstable angina, myocardial infarction, ventricular or atrial dysrhythmia, or stroke, that also require intravenous or intramuscular therapy or a related procedure or significant augmentation of oral therapy. In addition, MI or stroke during any hospitalization are included. | Year 1, Year 2, Year 3, Year 4, Year 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Heart Failure Mortality or Heart Failure Hospitalization at Given Time Points | Treatment comparisons for time to heart failure mortality or heart failure hospitalization | Year 1, Year 2, Year 3, Year 4, Year 5 | 
| Minnesota Living With Heart Failure (MLwHF) Total Score (Sum of Questions 1-21) at Month 6 and Month 14 | Mean score and adjusted mean change from baseline in Minnesota Living with Heart Failure (MLWHF) questionnaire, a 21-item, patient-reported, 6-point (ranging from 0-5; higher score=poorer quality of life; highest possible score=105) measurement of quality of life in persons with heart failure. | Baseline, Month 6, Month 14 | 
| Minnesota Living With Heart Failure (MLwHF) Total Score (Sum of Questions 1-21) at Final Visit | Mean score at baseline and final visit in Minnesota Living with Heart Failure (MLWHF) questionnaire, a 21-item, patient-reported, 6-point (ranging from 0-5; higher score=poorer quality of life; highest possible score=105) measurement of quality of life in persons with heart failure. | Baseline, Final Visit=last scheduled visit specified in the protocol at conclusion of the entire study by the sponsor. The trial was designed to end after 1440 primary endpoint events, projected duration=6.0 ± 0.5 years. | 
| Change From Baseline in B-Type Natriuretic Peptide (Pro-BNP) at Month 6 and Month 14 | Adjusted ratio to baseline in geometric mean in Pro-BNP in the blood. Ratio to Baseline = On-therapy geometric mean divided by baseline geometric mean. A lower score signifies improvement. Change from baseline adjusted for baseline value and angiotensin converting enzyme inhibitor use at baseline. Analysis uses natural logarithms of excretion rate values. | Baseline, Month 6, Month 14 | 
| Percentage of Participants Experiencing CV Death, Non-Fatal Myocardial Infarction (MI), or Non-Fatal Stroke at Given Timepoints | Treatment comparisons for time to cardiovascular death, non-fatal MI, or non-fatal stroke. | Year 1, Year 2, Year 3, Year 4, Year 5 | 
| Percentage of Participants Experiencing Cardiovascular Death at Given Timepoints | Treatment comparisons for time to cardiovascular death | Year 1, Year 2, Year 3, Year 4, Year 5 | 
| Percentage of Participants Experiencing All-cause Death at Given Time Points | Treatment comparisons for time to all-cause death | Year 1, Year 2, Year 3, Year 4, Year 5 | 
| Change From Baseline in the New York Heart Association (NYHA) Functional Class at Month 6, Month 10, Month 14, and Final Visit | NYHA functional classification=4-tiered system relating symptoms to everyday activities & quality of life. (See Reporting Groups for description of each class.) Change of NYHA functional class from baseline was grouped into 3 categories: improved, unchanged, or worsened (based on case report form [CRF] assessment). If a post-randomization CRF assessment was missing or participant died, was hospitalized for worsening heart failure or discontinued study medication for worsening heart failure, the participant was classified as Major Event. | Baseline, Month 6, Month 10, Month 14, Final Visit. The trial was designed to end after 1440 primary endpoint events, projected duration=6.0 ± 0.5 years. | 
| Physician Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline | This was an assessment of the change in overall physician opinion of change from baseline status. Assessments are directly based on the Case Report Form (CRF). If the post-randomization CRF assessment was missing and the subject died, was hospitalized for worsening heart failure, or discontinued study medication for worsening heart failure, the subject was considered as having a Major Event. Participants who are summarized under Major Events are categorized as Worsened Markedly. | Baseline, Month 6, Month 14, Final Visit. The trial was designed to end after 1440 primary endpoint events, projected duration=6.0 ± 0.5 years. | 
| Participant Assessment of Heart Failure Status at Month 6, Month 14, and Final Visit Compared With Baseline | Assessments are directly based on the Case Report Form (CRF). If the post-randomization CRF assessment was missing and the subject died, was hospitalized for worsening heart failure, or discontinued study medication for worsening heart failure, the subject was considered as having a Major Event. Participants who are summarized under Major Events are categorized as Worsened Markedly. | Baseline, Month 6, Month 14, Final Visit. The trial was designed to end after 1440 primary endpoint events, projected duration=6.0 ± 0.5 years. | 
| Participant Assessment of Fatigue at Month 6, Month 14, and Final Visit Compared With Baseline | Assessments are directly based on the Case Report Form (CRF). If the post-randomization CRF assessment was missing and the subject died, was hospitalized for worsening heart failure, or discontinued study medication for worsening heart failure, the subject was considered as having a Major Event. Participants who are summarized under Major Events are categorized as Worsened Markedly. | Baseline, Month 6, Month 14, Final Visit. The trial was designed to end after 1440 primary endpoint events, projected duration=6.0 ± 0.5 years. | 
| Participant Assessment of Dyspnea at Month 6, Month 14, and Final Visit Compared With Baseline | Assessments are directly based on the Case Report Form (CRF). If the post-randomization CRF assessment was missing and the subject died, was hospitalized for worsening heart failure, or discontinued study medication for worsening heart failure, the subject was considered as having a Major Event. Participants who are summarized under Major Events are categorized as Worsened Markedly. | Baseline, Month 6, Month 14, Final Visit. The trial was designed to end after 1440 primary endpoint events, projected duration=6.0 ± 0.5 years. | 
| Percentage of Participants Experiencing CV Death or CV Hospitalization at Given Timepoints | Treatment comparisons for time to CV death or CV hospitalization. Protocol-specified CV hospitalizations include hospitalizations ≥24 hrs or involve a calendar date change for a primary cause of worsening heart failure, unstable angina, myocardial infarction, ventricular dysrhythmia, atrial dysrhythmia or stroke that also requires intravenous or intramuscular therapy or a related procedure or significant augmentation of oral therapy. Protocol specified CV hospitalizations also include myocardial infarction or stroke occurring during any hospitalization. | Year 1, Year 2, Year 3, Year 4, Year 5 | 
| Percentage of Participants Experiencing Protocol-specified Cardiovascular (CV) Hospitalization at Given Timepoints | Treatment comparisons for time to protocol-specified CV hospitalization. Protocol-specified CV hospitalizations include hospitalizations ≥24 hrs or involve a calendar date change for a primary cause of worsening heart failure, unstable angina, myocardial infarction, ventricular dysrhythmia, atrial dysrhythmia or stroke that also requires intravenous or intramuscular therapy or a related procedure or significant augmentation of oral therapy. Protocol specified CV hospitalizations also include myocardial infarction or stroke occurring during any hospitalization. | Year 1, Year 2, Year 3, Year 4, Year 5 | 
| Percentage of Participants With New Onset of Diabetes Among Subjects With No Prior Diabetes History at Given Timepoints | Treatment comparisons for time to new onset of diabetes (from adverse event reporting) among subjects with no prior history of diabetes. | Year 1, Year 2, Year 3, Year 4, Year 5 | 
| Mean Change From Baseline in Glomerular Filtration Rate (GFR) at Month 6, Month 18, and Month 30 | Based on the Cockcroft-Gault formula calculation, a commonly used surrogate marker to estimate creatinine clearance, which in turn is an approximate measure of GFR. It employs serum creatinine measurements and a patient's weight to predict the creatinine clearance. Adjusted for baseline GFR and angiotensin-converting enzyme inhibitor use at baseline (ACE-I). A decrease from baseline signifies worsening. The adjusted mean change from baseline value is from the model (calculated prior to rounding), whereas the other two points are the baseline mean and post mean. | Baseline, Month 6, Month 18, Month 30 | 
| Mean Change From Baseline in Glomerular Filtration Rate (GFR)at Month 42, Month 54, Month 66 | Based on the Cockcroft-Gault formula calculation, a commonly used surrogate marker to estimate creatinine clearance, which in turn is an approximate measure of GFR. It employs serum creatinine measurements and a patient's weight to predict the creatinine clearance. Adjusted for baseline GFR and angiotensin-converting enzyme inhibitor use at baseline (ACE-I). A decrease from baseline signifies worsening. The adjusted mean change from baseline value is from the model (calculated prior to rounding), whereas the other two points are the baseline mean and post mean. | Baseline, Month 42, Month 54, Month 66 | 
| Number of Participants With New Onset Atrial Fibrillation (AF) Among Those With No Prior AF History or Evidence of AF on Baseline Electrocardiograph (ECG) | Frequency of new onset AF in participants with no prior AF history or evidence of AF on baseline ECG. Stratified by use of angiotensin-converting enzyme (ACE) inhibitors and measured by adverse events reporting and final ECG recording read by the investigator. | Baseline, Final Visit |