A Study of LY3540378 in Participants With Worsening Chronic Heart Failure With Preserved Ejection Fraction (HFpEF)

Study Overview
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Brief Summary
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The main purpose of this study is to assess the efficacy and safety of LY3540378 in adults with worsening heart failure with preserved ejection fraction

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and Safety of LY3540378 in Adults With Worsening Chronic Heart Failure With Preserved Ejection Fraction (HFpEF)

Conditions
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Heart Failure, Heart Failure With Preserved Ejection Fraction

Intervention / Treatment
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* Drug: LY3540378
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Prior chronic treatment, or prescription, with a loop diuretic (for example, furosemide, torsemide, bumetanide) for ≥30 days prior to the index event. Medical records, discharge notes and physician referral letters may serve as documentation for prior chronic treatment with a loop diuretic. Experienced an index event, defined as a recent hospitalization for HF requiring ≥2 bolus doses of intravenous diuretics or an out- of- hospital encounter (for example, Emergency Room, clinic visit, infusion clinic, etc.) for HF requiring ≥2 bolus doses of intravenous diuretics. Chronic HF diagnosed for at least 3 months before V1 (screening) Documented LVEF of ≥50% within 12 months prior to screening; as measured by echocardiography, radionuclide ventriculography, invasive angiography, magnetic resonance imaging (MRI), or computerized tomograph (CT). Evidence of documentation of LVEF of ≥50% may also include participant medical records, discharge notes or a referral letter from the participant's physician or referring physician that details the participant's medical history. Had evidence of clinical HF syndrome consisting of Hospitalization for worsening heart failure (WHF) with intravascular volume overload (the index event), as determined by the investigator, based on appropriate supportive documentation at randomization, and defined by ≥2 of the following: dyspnea jugular venous distention pitting edema in lower extremities (>1+) ascites pulmonary congestion on chest X-ray pulmonary rales AND participant received treatment with IV diuretics. OR Treatment for an urgent visit outside of of being hospitalized with WHF and intravascular volume overload (the index visit) requiring treatment with IV diuretics (defined as ≥2 IV doses) such as in the outpatient setting/emergency room/observation unit/infusion clinic with a clinical response within the past 2 weeks prior to randomization. Urgent visit is defined as an unplanned visit for HF defined by ≥2 of the following: dyspnea jugular venous distention pitting edema in lower extremities (>1+) ascites pulmonary rales on lung examination. NT-proBNP (>300 [sinus rhythm] or 900 picograms/milliliter (pg/mL) [atrial fibrillation or atrial flutter] OR brain natriuretic (BNP) (>100 [sinus rhythm] or 300 pg/mL [atrial fibrillation or atrial flutter]) at screening. Note: The presence or absence of atrial fibrillation or atrial flutter to determine the appropriate cut-off for a given BNP or NT-proBNP sample should be evaluated using electrocardiogram (ECG) performed at screening prior to the collection of the BNP or NT-proBNP sample. Exclusion Criteria Prior documentation of low ventricle ejection fraction (LVEF) ≤45% in the past 12 months. Have had acute coronary syndrome or percutaneous coronary intervention, coronary artery bypass graft, cardiac mechanical support implantation, within 3 months prior to day 2. (randomization), or any other cardiac surgery planned during the study. Have had Left Ventricular assist device (LVAD) or cardiac transplantation or have cardiac transplantation planned during the study. Have hypertrophic cardiomyopathy (obstructive or nonobstructive), restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, cardiac sarcoidosis, known amyloid cardiomyopathy, or inherited cardiomyopathy. Have severe chronic obstructive pulmonary disease (COPD), (pulmonary arterial hypertension, etc) as defined by chronic oxygen dependence. Night-time oxygen is not exclusionary. Uncorrected thyroid disease.

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Experimental: LY3540378 Dose 1<br>Participants will receive LY3540378 subcutaneously (SC). | Drug: LY3540378<br>* Administered SC<br>|
| Experimental: LY3540378 Dose 2<br>Participants will receive LY3540378 SC. | Drug: LY3540378<br>* Administered SC<br>|
| Experimental: LY3540378 Dose 3<br>Participants will receive LY3540378 SC. | Drug: LY3540378<br>* Administered SC<br>|
| Placebo Comparator: Placebo<br>Participants will be given placebo SC. | Drug: Placebo<br>* Administered SC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Left Atrial Reservoir Strain (LARS) |  | Baseline, Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Log-transformed N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) |  | Baseline, Week 26 | 
| Change from Baseline in Left Atrial End-Diastolic Volume Index (LAEDVI) |  | Baseline, Week 26 | 
| Change from Baseline Left Atrial End-Systolic Volume Index (LAESVI) |  | Baseline, Week 26 | 
| Change from Baseline in Estimated Glomerular Filtration Rate (eGFR) | eGFR calculated by creatinine and cystatin C | Baseline, Week 26 | 
| Change from Baseline in Serum Creatinine |  | Baseline, Week 26 | 
| Change from Baseline in cystatin-C |  | Baseline, Week 26 |