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

NCT05592275 | Terminated Phase 2 Results FDA Drug

• 3 other identifiers: 18473J3E-MC-EZDB2023-505902-40-00
• Study Type: interventional
• Target: 332
• Locations: 12 countries
• Sites: 137

Brief Summary

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

Conditions

Heart Failure; Heart Failure With Preserved Ejection Fraction

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Left Atrial Reservoir Strain (LARS) at Week 26

  Results are estimated using least squares (LS) mean from the mixed model repeated measures (MMRM) model: Change from baseline = Baseline + Strata + Gender + Treatment + Time + Treatment\*Time + Baseline\*Treatment.

  Baseline, Week 26

Secondary Outcomes (13)

• Change From Baseline in Left Atrial Reservoir Strain (LARS) at Week 12

  Baseline, Week 12

• Change From Baseline in Log-transformed N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) at Week 12

  Baseline, Week 12

• Change From Baseline in Log-transformed N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) at Week 26

  Baseline, Week 26

• Change From Baseline in Left Atrial End-Diastolic Volume Index (LAEDVI) at Week 12

  Baseline, Week 12

• Change From Baseline in Left Atrial End-Diastolic Volume Index (LAEDVI) at Week 26

  Baseline, Week 26

Study Arms (4)

25 mg LY3540378

EXPERIMENTAL

Participants received 25 mg LY3540378 administered once weekly as subcutaneous (SC) injection for 26 weeks.

Drug: LY3540378

50 mg LY3540378

EXPERIMENTAL

Participants received 50 mg LY3540378 administered once weekly as SC injection for 26 weeks.

Drug: LY3540378

100 mg LY3540378

EXPERIMENTAL

Participants received 100 mg LY3540378 administered once weekly as SC injection for 26 weeks.

Drug: LY3540378

Placebo

PLACEBO COMPARATOR

Participants received placebo administered once weekly as SC injection for 26 weeks.

Drug: Placebo

Interventions

LY3540378 DRUG

Administered SC

100 mg LY3540378; 25 mg LY3540378; 50 mg LY3540378

Placebo DRUG

Administered SC

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Experienced an index event, defined as a recent hospitalization for HF requiring ≥1 bolus doses of intravenous diuretics or an out- of- hospital encounter (for example, Emergency Room, clinic visit, infusion clinic, etc.) for HF requiring ≥1 bolus doses of intravenous diuretics.
• 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.
• 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

You may not qualify if:

• 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 V2. (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.
• Uncorrected thyroid disease.

Sponsors & Collaborators

• Eli Lilly and Company: lead

Study Sites (137)

Pima Heart

Tucson, Arizona, 85719, United States

Location

Valley Clinical Trials, Inc.

Covina, California, 91723, United States

Location

Valley Clinical Trials, Inc.

Northridge, California, 91325, United States

Location

University of California Irvine Medical Center

Orange, California, 92868, United States

Location

Pasadena Clinical Research

Pasadena, California, 91105, United States

Location

Velocity Clinical Research, Coastal Heart Medical Group

Santa Ana, California, 92704, United States

Location

Excel Medical Clinical Trials

Boca Raton, Florida, 33434, United States

Location

Infinite Clinical Research

Miami, Florida, 33133, United States

Location

South Florida Research Solutions - North Flamingo Road

Pembroke Pines, Florida, 33028, United States

Location

University Medical Center New Orleans

New Orleans, Louisiana, 70112, United States

Location

Boston Medical Center

Boston, Massachusetts, 02118, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

Mayo Clinic in Rochester, Minnesota

Rochester, Minnesota, 55905, United States

Location

University of North Carolina Medical Center

Chapel Hill, North Carolina, 27514, United States

Location

Abington Memorial Hospital

Abington, Pennsylvania, 19001, United States

Location

PharmaTex Research

Amarillo, Texas, 79109, United States

Location

Baylor Scott & White Health-Advanced Heart and Lung Disease

Dallas, Texas, 75246, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

University of Texas Medical Branch

Galveston, Texas, 77555-0553, United States

Location

West Houston Area Clinical Trial Consultants

Houston, Texas, 77094, United States

Location

Texas Institute of Cardiology, PA

McKinney, Texas, 75071, United States

Location

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, 53792, United States

Location

Centro de Investigaciones Metabólicas (CINME)

Ciudad Autónoma de Buenos Aires, Buenos Aires, C1056ABI, Argentina

Location

Instituto de Investigaciones Clinicas Zarate

Zárate, Buenos Aires, B2800DGH, Argentina

Location

Investigaciones Medicas Imoba Srl

Balvanera, Buenos Aires F.D., C1056ABH, Argentina

Location

Sanatorio Anchorena Recoleta

Buenos Aires, Buenos Aires F.D., 1425, Argentina

Location

Mautalen Salud e Investigación

Buenos Aires, Buenos Aires F.D., C1128AAF, Argentina

Location

Centro Medico Dra. Laura Maffei- Investigacion Clinica Aplicada

Buenos Aires, Buenos Aires F.D., C1425AGC, Argentina

Location

Instituto Médico Río Cuarto

Río Cuarto, Córdoba Province, 5800, Argentina

Location

Hospital Provincial del Centenario

Rosario, Santa Fe Province, 2002, Argentina

Location

Instituto de Investigaciones Clinicas Rosario

Rosario, Santa Fe Province, S2000CVD, Argentina

Location

Sanatorio San Martin

Venado Tuerto, Santa Fe Province, 2600, Argentina

Location

Investigaciones Clínicas Tucumán

San Miguel de Tucumán, Tucumán Province, 4000, Argentina

Location

CEMEDIC

Buenos Aires, 1407, Argentina

Location

Fundación Respirar

Buenos Aires, C1426ABP, Argentina

Location

Centro de Investigaciones Clinicas del Litoral

Santa Fe, 3000, Argentina

Location

Clínica de Nefrología, Urología y Enfermedades Cardiovasculares

Santa Fe, 3000, Argentina

Location

Centro de Pesquisa Silvestre Santé

Rio Branco, Acre, 69915-030, Brazil

Location

Universidade Federal de Goias

Goiânia, Goiás, 74605-020, Brazil

Location

PUC Trials- Nucleo de Pesquisa clinica da Escola de Medicina da PUCPR

Curitiba, Paraná, 80230-130, Brazil

Location

Centro de Pesquisa Clinica do Coracao

Acaraju, Sergipe, 49055-530, Brazil

Location

Centro de Pesquisa Sao Lucas

Campinas, São Paulo, 13034-685, Brazil

Location

Instituto de Pesquisa clinica de Campinas

Campinas, São Paulo, 13060-080, Brazil

Location

Instituto Do Coracao De Marilia

Marília, São Paulo, 17515-000, Brazil

Location

CAPED Centro Avancado Pesquisa e Diagnostica

Ribeirão Preto, São Paulo, 14026-900, Brazil

Location

Pesquisare Saude

Santo André, São Paulo, 09080-110, Brazil

Location

Hospital Santa Paula

São Paulo, São Paulo, 04556-100, Brazil

Location

Incor - Instituto do Coracao

São Paulo, São Paulo, 05403-900, Brazil

Location

Instituto de Molestias Cardiovasculares de Tatui

Tatuí, São Paulo, 18270-170, Brazil

Location

Integral Pesquisa e Ensino

Votuporanga, São Paulo, 15501-405, Brazil

Location

Hospital São Lucas de Copacabana

Rio de Janeiro, 22061-080, Brazil

Location

Instituto D'Or Pesquisa e Ensino

Rio de Janeiro, 22281-100, Brazil

Location

SMH Cardiology Clinical Trials

Surrey, British Columbia, V3V 0C6, Canada

Location

Private Practice - Dr. Saul Vizel

Cambridge, Ontario, N1R 7R1, Canada

Location

PACE Cardiology

Newmarket, Ontario, L3Y 2P6, Canada

Location

North York Diagnostic and Cardiac Centre

North York, Ontario, M6B 3H7, Canada

Location

Oakville Trafalgar Memorial Hospital

Oakville, Ontario, L6M 1M1, Canada

Location

Heart Health Institute - Scarborough Office

Scarborough Village, Ontario, M1B 4Z8, Canada

Location

Medicus MFC Research Clinic

Toronto, Ontario, M4P 1E4, Canada

Location

CPS Research

Waterloo, Ontario, N2T 0C1, Canada

Location

Centre Hospitalier Universite de Sherbrooke - Hôtel-Dieu Hospital

Sherbrooke, Quebec, J1G 2E8, Canada

Location

Fakultní nemocnice Brno Bohunice

Brno, Brno-město, 62500, Czechia

Location

Fakultni Nemocnice u sv. Anny v Brne

Brno, South Moravian, 60200, Czechia

Location

Vseobecna fakultni nemocnice v Praze

Prague, 12808, Czechia

Location

Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ

Szeged, Csongrád megye, 6720, Hungary

Location

Medifarma 98 Kft

Nyíregyháza, Nyíregyháza, 4400, Hungary

Location

Kistarcsai Flor Ferenc Korhaz

Kistarcsa, Pest County, 2143, Hungary

Location

Belvárosi Egészségház

Zalaegerszeg, Zala County, 8900, Hungary

Location

Dél-Pesti Centrumkórház

Budapest, 1097, Hungary

Location

Semmelweis University

Budapest, 1122, Hungary

Location

Yitzhak Shamir Medical Center

Ẕerifin, Central District, 609300, Israel

Location

Hadassah Medical Center

Jerusalem, Jerusalem, 9112001, Israel

Location

Rambam Health Care Campus

Haifa, Northern District, 3109601, Israel

Location

Sourasky Medical Center

Tel Aviv, Tell Abīb, 6423906, Israel

Location

Kasugai Municipal Hospital

Kasugai, Aichi-ken, 486-8510, Japan

Location

Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital

Nagoya, Aichi-ken, 466-8650, Japan

Location

Saiseikai Futsukaichi Hospital

Chikushino-shi, Fukuoka, 818-8516, Japan

Location

Nakamura Cardiovascular Clinic

Itoshima, Fukuoka, 819-1104, Japan

Location

Gunma University Hospital

Maebashi, Gunma, 371-8511, Japan

Location

National Hospital Organization Takasaki General Medical Centar

Takasaki, Gunma, 370-0829, Japan

Location

Yokohama City University Medical Center

Yokohama, Kanagawa, 232-0024, Japan

Location

Yokohama Minami Kyosai Hospital

Yokohama, Kanagawa, 236-0037, Japan

Location

Kanagawa Cardiovascular and Respiratory Center

Yokohama, Kanagawa, 236-0051, Japan

Location

Minamino Cardiovascular Hospital

Hachiōji, Tokyo, 192-0918, Japan

Location

Ome Medical Center

Ōme, Tokyo, 198-0042, Japan

Location

Yamanashi Prefectural Central Hospital

Kofu, Yamanashi, 400-8506, Japan

Location

Harasanshin Hospital

Fukuoka, 812-0033, Japan

Location

Rakuwakai Otowa Hospital

Kyoto, 607-8062, Japan

Location

National Hospital Organization Okayama Medical Center

Okayama, 701-1154, Japan

Location

Sakurabashi Watanabe Advanced Healthcare Hospital

Osaka, 530-0005, Japan

Location

Yodogawa Christian Hospital

Osaka, 533-0024, Japan

Location

National Hospital Organization - Osaka National Hospital - Institute For Clinical Research

Osaka, 540-0006, Japan

Location

Toyama Prefectural Central Hospital

Toyama, 930-0975, Japan

Location

NZOZ Centrum Medyczne KERmed

Bydgoszcz, Kuyavian-Pomeranian Voivodeship, 85-231, Poland

Location

INTERCOR

Bydgoszcz, Kuyavian-Pomeranian Voivodeship, 85-605, Poland

Location

Private Practice - Dr. Ewa Mirek Bryniarska

Krakow, Lesser Poland Voivodeship, 30-082, Poland

Location

MEDICOME Centrum Badań Klinicznych Oświęcimskie

Oświęcim, Lesser Poland Voivodeship, 32-660, Poland

Location

1 Wojskowy Szpital Kliniczny w Lublinie

Lublin, Lublin Voivodeship, 20-043, Poland

Location

CenterMed Lublin NZOZ

Lublin, Lublin Voivodeship, 20-044, Poland

Location

Balsam Medica

Warsaw, Masovian Voivodeship, 01-249, Poland

Location

Wojewodzki Szpital im. Sw. Ojca Pio w Przemyslu

Przemyśl, Podkarpackie Voivodeship, 37-700, Poland

Location

Uniwersytecki Szpital Kliniczny w Białymstoku

Bialystok, Podlaskie Voivodeship, 15-540, Poland

Location

KLIMED Marek Klimkiewicz

Bialystok, Podlaskie Voivodeship, 15-704, Poland

Location

SPZOZ Uniwersytecki Szpital Kliniczny Im. Wojskowej Akademii Medycznej UM W Łodzi Centralny Szpital Wetera -T

Lodz, Łódź Voivodeship, 90-549, Poland

Location

Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi

Lodz, Łódź Voivodeship, 93-513, Poland

Location

IRMED Osrodek Badan Klinicznych

Piotrkow Trybunalski, Łódź Voivodeship, 97-300, Poland

Location

Provita Profamilia

Piotrkow Trybunalski, Łódź Voivodeship, 97-300, Poland

Location

CHUS - Hospital Clinico Universitario

Santiago de Compostela, A Coruña [La Coruña], 15706, Spain

Location

Hospital de Denia Marina Salud

Denia, Alicante, 03700, Spain

Location

Hospital Universitario Reina Sofia

Córdoba, Andalusia, 14004, Spain

Location

Hospital Universitario Virgen de Valme

Seville, Andalusia, 41014, Spain

Location

Hospital Germans Trias i Pujol

Badalona, Barcelona [Barcelona], 08916, Spain

Location

Hospital Universitari de Bellvitge

L'Hospitalet de Llobregat, Catalunya [Cataluña], 08907, Spain

Location

Hospital San Juan de la Cruz

Úbeda, Jaén, 23400, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, Madrid, Comunidad de, 28034, Spain

Location

Hospital Clínico Universitario Virgen de la Arrixaca

El Palmar, Murcia, Murcia, Región de, 30120, Spain

Location

Hospital Universitario Virgen de la Victoria

Málaga, Málaga, 29010, Spain

Location

Hospital Clinico de Valencia

Valencia, Valenciana, Comunitat, 46010, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Bursa Yüksek İhtisas Eğitim Ve Araştırma Hastanesi

Yıldırım, Bursa, 16310, Turkey (Türkiye)

Location

Eskisehir Osmangazi University

Eskişehir, Eskişehir, 26480, Turkey (Türkiye)

Location

Ege Universitesi Hastanesi

Bornova, İzmir, 35100, Turkey (Türkiye)

Location

Kocaeli Üniversitesi

İzmit, Kocaeli, 41380, Turkey (Türkiye)

Location

Afyon Kocatepe Üniversitesi Tıp Fakültesi

Afyonkarahisar, 03030, Turkey (Türkiye)

Location

Ankara Etlik City Hospital

Ankara, 06170, Turkey (Türkiye)

Location

Trakya University Medical Faculty Hospital

Edirne, 22030, Turkey (Türkiye)

Location

T.C. Sağlık Bakanlığı İzmir Tepecik Eğitim ve Araştırma Hast

Izmir, 35120, Turkey (Türkiye)

Location

Dokuz Eylul Universitesi Hastanesi

Izmir, 35330, Turkey (Türkiye)

Location

Mersin University

Mersin, 33343, Turkey (Türkiye)

Location

Wycombe General Hospital

High Wycombe, Buckinghamshire, HP11 2TT, United Kingdom

Location

Raigmore Hospital

Inverness, Highland, IV2 3JH, United Kingdom

Location

Northwick Park Hospital

Harrow, London, City of, HA1 3UJ, United Kingdom

Location

Glasgow Royal Infirmary

Glasgow, Scotland, G31 2ER, United Kingdom

Location

West Middlesex University Hospital

Isleworth, TW7 6AF, United Kingdom

Location

Aintree University Hospital NHS Foundation Trust

Liverpool, L9 7AL, United Kingdom

Location

Wythenshawe Hospital

Manchester, M23 9LT, United Kingdom

Location

Royal Berkshire Hospital

Reading, RG1 5AN, United Kingdom

Location

Related Publications (1)

• Borlaug BA, Testani JM, Petrie MC, Wang Z, Cunningham J, Adams KF Jr, Amir O, Belohlavek J, Bocchi E, Freitas A Jr, Hominal M, Kadokami T, Merkely B, Miller CA, Nunez J, Verma S, Yilmaz MB, Oru E, Sam F. Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial. Nat Med. 2025 Nov;31(11):3853-3861. doi: 10.1038/s41591-025-03939-6. Epub 2025 Aug 31.

  PMID: 40887551 DERIVED

Related Links

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

MeSH Terms

Conditions

Heart Failure

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Chief Medical Officer
• Organization: Eli Lilly and Company

ClinicalTrials.gov@lilly.com

08005455979

Study Officials

• Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

  Eli Lilly and Company

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 20, 2022
• First Posted: October 24, 2022
• Study Start: February 3, 2023
• Primary Completion: January 22, 2025
• Study Completion: January 22, 2025
• Last Updated: February 5, 2026
• Results First Posted: February 5, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and European Union (EU), whichever is later. Data will be indefinitely available for requesting.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.

Locations

PL (14); US (22); BR (15); IL (4); HU (6); CZ (3); ES (12); CA (9); JP (19); TU (10); GB (8); AR (15)