Heart Failure With Preserved Ejection Fraction (HFpEF), Obesity
Conditions
Keywords
Heart Failure with Preserved Ejection Fraction (HFpEF)
Brief summary
The main purpose of this study is to assess the efficacy and safety of Tirzepatide (LY3298176) in participants with heart failure with preserved ejection fraction and obesity.
Detailed description
The study will continue until approximately 52 weeks after the last participant is randomized. The maximum duration of an individual's participation is estimated to be \ 120 weeks and will depend on duration of study enrollment.
Interventions
DRUGTirzepatide
Administered SC
OTHERPlacebo
Administered SC
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have a diagnosis of stable heart failure (NYHA class II-IV) and left ventricular ejection fraction (LVEF) ≥50% * Elevated NT-proBNP (N-terminal pro B-type natriuretic peptide) \> 200 picogram/milliliter (pg/ml) for participants without atrial fibrillation (AF), or \>600 pg/ml for participants with AF, Structural heart disease (Left atrial enlargement) or Elevated left ventricular filling pressure * Estimated glomerular filtration rate (eGFR) \<70 milliliter (ml)/minute (min)/1.73m² at screening, or HF decompensation within 12 months of screening, * Stable dose of heart failure medications within 4 weeks of screening * Body mass index (BMI) ≥30 kilograms per meter squared (kg/m²) * 6MWD 100-425 meters * KCCQ CSS ≤80
Exclusion criteria
* Have had a major cardiovascular event within the last 90 days of screening * Have had acute decompensated heart failure within 4 weeks of screening * Have non cardiac causes of functional impairment such as pulmonary arterial hypertension (PAH), severe chronic obstructive pulmonary disease (COPD), anemia, thyroid disease, musculoskeletal disease or orthopedic conditions * Presence of cardiac amyloidosis, cardiac accumulation disease, cardiomyopathy and severe valvular heart disease * HbA1c ≥9.5% or uncontrolled diabetes * History of proliferative diabetic retinopathy or diabetic maculopathy * Have a history of pancreatitis * eGFR \<15 mL/min/1.73 m² or requiring dialysis at screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) | Baseline, Week 52 | The KCCQ is a 23-item, participant self-administered questionnaire that assesses impacts of heart failure over the past 2 weeks on the following 7 domains: * Physical Limitation (6) * Symptom Stability (1) * Symptom Frequency (4) * Symptom Burden (3) * Self-Efficacy (2) * Quality of Life (3) * Social Limitation (4) Each of the 23 individual items are answered on Likert scales of varying lengths (5, 6, or 7-point scales). KCCQ-CSS includes the symptom and physical limitation domains of the KCCQ. Scores are obtained by averaging the associated individual items and transforming the score to a 0 to 100 range. Higher scores indicate better health status. Least Square (LS) mean was determined using ANCOVA model with Baseline + HF Decompensation Within 12 Months of Screening + T2DM Status + Baseline BMI group (\<35, \>=35 kg/m2) + Treatment (Type III sum of squares) as variables . |
| First Occurrence of the Composite Endpoint of Heart Failure (HF) Outcomes | Baseline Up To 160 weeks | Clinical Endpoint Committe confirmed Occurrences of CV outcomes were reported here. HF outcomes consisted of cardiovascular death and HF events. The HF events were defined as worsening clinical symptoms or signs related to HF, which are meaningful to the participant and require intensification of treatment characterized by 1 or more of the following: * hospitalization for heart failure regardless of duration or treatment received * use of intravenous drug, usually an intravenous diuretic, but may include intravenous vasodilators or positive inotropic drugs, or * augmentation or increase in oral diuretic therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) | Baseline, Week 52 | Percent change from baseline in hsCRP was reported. LS Mean was determined using ANCOVA model with log (actual measurement/baseline) = log (baseline) + HF decompensation within 12 months of screening + T2DM status + baseline BMI group (\<35, \>=35 kg/m2) + Treatment (Type III sum of squares) as variables. |
| Win Percentage of the Hierarchical Composite Endpoint | Baseline Up To 160 Weeks | Hierarchical Composite Endpoint included time to all-cause death, number of HF events, time to first HF events, KCCQ-CSS, 6MWD. The winner was determined in each pair-wise comparison in the following order: * A delayed first occurrence of all-cause death * If the pair cannot be differentiated based on death, winner has fewer HF events * If the pair cannot be differentiated by number of HF events, winner has delayed time to occurrence of first HF event * If the pair still cannot be differentiated, winner has a more favorable category for change from baseline in 6MWD * If the pair still cannot be differentiated, winner has a more favorable category for change from baseline in KCCQ-CSS * Otherwise the pair will be recorded as tied. Reported unit is the total percent of wins for each treatment group from performing such a hierarchical comparison across stratification factors in the study. |
| Percentage of Participants With New York Heart Association (NYHA) Class Change | Week 52 | Percentage of participants with NYHA class change at Week 52 was reported. |
| Change From Baseline in Exercise Capacity as Measured by 6-Minute Walk Distance (6MWD) | Baseline, Week 52 | Participants performed an exercise capacity assessment using the 6-Minute Walk Test (6MWT) and the distance covered (6MWD) was assessed in meters. The 6MWT was performed indoors on a straight, flat, hard surface that is at least 30 meters in length. The greater distance walked meant better physical capacity. LS Mean was determined using ANCOVA model with Baseline + HF Decompensation Within 12 Months of Screening + T2DM Status + Baseline BMI group (\<35, \>=35 kg/m2) + Treatment (Type III sum of squares) as variables. |
| Number of Participants With Time to First Occurrence of HF Events | Baseline Up To 160 Weeks | Number of participants with time to first occurrence of HF events are reported. |
| Number of HF Events and All-Cause Death | Baseline Up To 160 Weeks. | Number of HF events and all-cause death are reported. |
| Number of Recurrent HF Events | Baseline Up To 160 Weeks. | Number of recurrent HF events were reported. |
| Number of Participants With Time to All-Cause Death | Baseline Up To 160 Weeks | All-cause mortality is death due to any cause. Number of participants with time to all-cause mortality are presented. |
| Percent Change From Baseline in Body Weight | Baseline, Week 52 | Percent change in bodyweight was reported. LS mean was determined using ANCOVA model with Baseline + HF Decompensation Within 12 Months of Screening + T2DM Status + Baseline BMI group (\<35, \>=35 kg/m2) + Treatment (Type III sum of squares) as variables. |
Countries
Argentina, Brazil, China, India, Israel, Mexico, Puerto Rico, Russia, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tirzepatide - MTD Participants received a starting dose of 2.5 mg tirzepatide administered SC QW and escalated by 2.5 mg every 4 weeks to a maximum of 15 mg QW or MTD tolerated by the participant (5 mg QW or 10 mg QW). | 364 |
| Placebo Participants received placebo administered SC QW. | 367 |
| Total | 731 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 19 | 15 |
| Overall Study | Lost to Follow-up | 3 | 6 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 8 | 14 |
Baseline characteristics
| Characteristic | Tirzepatide - MTD | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 65.50 years STANDARD_DEVIATION 10.53 | 65.20 years STANDARD_DEVIATION 10.7 | 65.00 years STANDARD_DEVIATION 10.87 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 195 Participants | 400 Participants | 205 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 164 Participants | 323 Participants | 159 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 8 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 24 Participants | 47 Participants | 23 Participants |
| Race (NIH/OMB) Asian | 58 Participants | 131 Participants | 73 Participants |
| Race (NIH/OMB) Black or African American | 22 Participants | 36 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 256 Participants | 512 Participants | 256 Participants |
| Region of Enrollment Argentina | 101 Participants | 204 Participants | 103 Participants |
| Region of Enrollment Brazil | 51 Participants | 105 Participants | 54 Participants |
| Region of Enrollment China | 25 Participants | 55 Participants | 30 Participants |
| Region of Enrollment India | 9 Participants | 20 Participants | 11 Participants |
| Region of Enrollment Israel | 17 Participants | 38 Participants | 21 Participants |
| Region of Enrollment Mexico | 41 Participants | 81 Participants | 40 Participants |
| Region of Enrollment Russia | 13 Participants | 21 Participants | 8 Participants |
| Region of Enrollment Taiwan | 24 Participants | 56 Participants | 32 Participants |
| Region of Enrollment United States | 83 Participants | 151 Participants | 68 Participants |
| Sex: Female, Male Female | 200 Participants | 393 Participants | 193 Participants |
| Sex: Female, Male Male | 164 Participants | 338 Participants | 174 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 19 / 364 | 15 / 367 |
| other Total, other adverse events | 221 / 364 | 137 / 367 |
| serious Total, serious adverse events | 96 / 364 | 94 / 367 |
Outcome results
Primary
Change From Baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS)
The KCCQ is a 23-item, participant self-administered questionnaire that assesses impacts of heart failure over the past 2 weeks on the following 7 domains: * Physical Limitation (6) * Symptom Stability (1) * Symptom Frequency (4) * Symptom Burden (3) * Self-Efficacy (2) * Quality of Life (3) * Social Limitation (4) Each of the 23 individual items are answered on Likert scales of varying lengths (5, 6, or 7-point scales). KCCQ-CSS includes the symptom and physical limitation domains of the KCCQ. Scores are obtained by averaging the associated individual items and transforming the score to a 0 to 100 range. Higher scores indicate better health status. Least Square (LS) mean was determined using ANCOVA model with Baseline + HF Decompensation Within 12 Months of Screening + T2DM Status + Baseline BMI group (\<35, \>=35 kg/m2) + Treatment (Type III sum of squares) as variables .
Time frame: Baseline, Week 52
Population: All participants who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tirzepatide - MTD | Change From Baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) | 19.51 Score on a scale | Standard Error 1.24 |
| Placebo | Change From Baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) | 12.68 Score on a scale | Standard Error 1.25 |
p-value: <0.00195% CI: [3.3, 10.6]Stratified Wilcoxon
Primary
First Occurrence of the Composite Endpoint of Heart Failure (HF) Outcomes
Clinical Endpoint Committe confirmed Occurrences of CV outcomes were reported here. HF outcomes consisted of cardiovascular death and HF events. The HF events were defined as worsening clinical symptoms or signs related to HF, which are meaningful to the participant and require intensification of treatment characterized by 1 or more of the following: * hospitalization for heart failure regardless of duration or treatment received * use of intravenous drug, usually an intravenous diuretic, but may include intravenous vasodilators or positive inotropic drugs, or * augmentation or increase in oral diuretic therapy.
Time frame: Baseline Up To 160 weeks
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tirzepatide - MTD | First Occurrence of the Composite Endpoint of Heart Failure (HF) Outcomes | 36 Number of events |
| Placebo | First Occurrence of the Composite Endpoint of Heart Failure (HF) Outcomes | 56 Number of events |
Comparison: Heart Failure Outcomesp-value: 0.02695% CI: [0.41, 0.95]Regression, Cox
Secondary
Change From Baseline in Exercise Capacity as Measured by 6-Minute Walk Distance (6MWD)
Participants performed an exercise capacity assessment using the 6-Minute Walk Test (6MWT) and the distance covered (6MWD) was assessed in meters. The 6MWT was performed indoors on a straight, flat, hard surface that is at least 30 meters in length. The greater distance walked meant better physical capacity. LS Mean was determined using ANCOVA model with Baseline + HF Decompensation Within 12 Months of Screening + T2DM Status + Baseline BMI group (\<35, \>=35 kg/m2) + Treatment (Type III sum of squares) as variables.
Time frame: Baseline, Week 52
Population: All participants who received at least one dose of study drug and had evaluable data for this outcome,
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tirzepatide - MTD | Change From Baseline in Exercise Capacity as Measured by 6-Minute Walk Distance (6MWD) | 26.04 meters | Standard Error 3.81 |
| Placebo | Change From Baseline in Exercise Capacity as Measured by 6-Minute Walk Distance (6MWD) | 10.10 meters | Standard Error 3.94 |
p-value: <0.00195% CI: [9.9, 26.7]Stratified Wilcoxon
Secondary
Number of HF Events and All-Cause Death
Number of HF events and all-cause death are reported.
Time frame: Baseline Up To 160 Weeks.
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tirzepatide - MTD | Number of HF Events and All-Cause Death | 61 Events |
| Placebo | Number of HF Events and All-Cause Death | 82 Events |
95% CI: [0.46, 1.14]
Secondary
Number of Participants With Time to All-Cause Death
All-cause mortality is death due to any cause. Number of participants with time to all-cause mortality are presented.
Time frame: Baseline Up To 160 Weeks
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tirzepatide - MTD | Number of Participants With Time to All-Cause Death | 19 Participants |
| Placebo | Number of Participants With Time to All-Cause Death | 15 Participants |
95% CI: [0.633, 2.452]
Secondary
Number of Participants With Time to First Occurrence of HF Events
Number of participants with time to first occurrence of HF events are reported.
Time frame: Baseline Up To 160 Weeks
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tirzepatide - MTD | Number of Participants With Time to First Occurrence of HF Events | 29 Participants |
| Placebo | Number of Participants With Time to First Occurrence of HF Events | 52 Participants |
95% CI: [0.342, 0.85]
Secondary
Number of Recurrent HF Events
Number of recurrent HF events were reported.
Time frame: Baseline Up To 160 Weeks.
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tirzepatide - MTD | Number of Recurrent HF Events | 44 Events |
| Placebo | Number of Recurrent HF Events | 68 Events |
95% CI: [0.37, 1.05]
Secondary
Percentage of Participants With New York Heart Association (NYHA) Class Change
Percentage of participants with NYHA class change at Week 52 was reported.
Time frame: Week 52
Population: All participant who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tirzepatide - MTD | Percentage of Participants With New York Heart Association (NYHA) Class Change | 33.27 Percentage of participants |
| Placebo | Percentage of Participants With New York Heart Association (NYHA) Class Change | 20.39 Percentage of participants |
95% CI: [1.53, 3.4]
Secondary
Percent Change From Baseline in Body Weight
Percent change in bodyweight was reported. LS mean was determined using ANCOVA model with Baseline + HF Decompensation Within 12 Months of Screening + T2DM Status + Baseline BMI group (\<35, \>=35 kg/m2) + Treatment (Type III sum of squares) as variables.
Time frame: Baseline, Week 52
Population: All participants who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tirzepatide - MTD | Percent Change From Baseline in Body Weight | -13.85 Percent change | Standard Error 0.43 |
| Placebo | Percent Change From Baseline in Body Weight | -2.24 Percent change | Standard Error 0.46 |
p-value: <0.00195% CI: [-12.85, -10.38]ANCOVA
Secondary
Percent Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP)
Percent change from baseline in hsCRP was reported. LS Mean was determined using ANCOVA model with log (actual measurement/baseline) = log (baseline) + HF decompensation within 12 months of screening + T2DM status + baseline BMI group (\<35, \>=35 kg/m2) + Treatment (Type III sum of squares) as variables.
Time frame: Baseline, Week 52
Population: All participants who received at least one dose of study drug and had evaluable data for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tirzepatide - MTD | Percent Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) | -38.76 Percent change | Standard Error 4.47 |
| Placebo | Percent Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) | -5.88 Percent change | Standard Error 5.25 |
p-value: <0.00195% CI: [-45.6, -22.17]ANCOVA
Secondary
Win Percentage of the Hierarchical Composite Endpoint
Hierarchical Composite Endpoint included time to all-cause death, number of HF events, time to first HF events, KCCQ-CSS, 6MWD. The winner was determined in each pair-wise comparison in the following order: * A delayed first occurrence of all-cause death * If the pair cannot be differentiated based on death, winner has fewer HF events * If the pair cannot be differentiated by number of HF events, winner has delayed time to occurrence of first HF event * If the pair still cannot be differentiated, winner has a more favorable category for change from baseline in 6MWD * If the pair still cannot be differentiated, winner has a more favorable category for change from baseline in KCCQ-CSS * Otherwise the pair will be recorded as tied. Reported unit is the total percent of wins for each treatment group from performing such a hierarchical comparison across stratification factors in the study.
Time frame: Baseline Up To 160 Weeks
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tirzepatide - MTD | Win Percentage of the Hierarchical Composite Endpoint | 57.90 Win percentage |
| Placebo | Win Percentage of the Hierarchical Composite Endpoint | 35.43 Win percentage |
95% CI: [1.17, 2.28]