Heart FailurePhase 2NCT05592275
A Study of LY3540378 in Participants With Worsening Chronic Heart Failure With Preserved Ejection Fraction (HFpEF)
A Phase 2 study testing LY3540378 in people with Heart Failure and Heart Failure With Preserved Ejection Fraction, run by Eli Lilly and Company at 137 sites in 12 countries.
Trial 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 Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure, Heart Failure With Preserved Ejection Fraction
- What is being tested?
- LY3540378
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 332 participants
- Where
- 137 sitesin 12 countries
- Study dates
- 3 Feb 2023to 22 Jan 2025
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 19Show fewer
- 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 600 pg/mL [atrial fibrillation or atrial flutter] OR BNP (>100 [sinus rhythm] or 200 pg/mL [atrial fibrillation or atrial flutter]) at screening.
- eGFR of >20 mL/min/1.73 m² at V1 (screening; determined by local laboratory), derived from serum creatinine values, age, and sex based on the CKD-EPI equation.
Who cannot join
- 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.
- Have a chronic pulmonary/lung disease (COPD), (pulmonary arterial hypertension, etc) as defined by chronic oxygen dependence. Night-time oxygen is not exclusionary.
- Uncorrected thyroid disease.
Trial locations and contacts
137 sites in 12 countries.
137 sites in 12 countries
United States22 sites
Abington Memorial Hospital
Abington, Pennsylvania, 19001
PharmaTex Research
Amarillo, Texas, 79109
Excel Medical Clinical Trials
Boca Raton, Florida, 33434
Boston Medical Center
Boston, Massachusetts, 02118
University of North Carolina Medical Center
Chapel Hill, North Carolina, 27514
Valley Clinical Trials, Inc.
Covina, California, 91723
Baylor Scott & White Health-Advanced Heart and Lung Disease
Dallas, Texas, 75246
UT Southwestern Medical Center
Dallas, Texas, 75390
Henry Ford Hospital
Detroit, Michigan, 48202
University of Texas Medical Branch
Galveston, Texas, 77555-0553
West Houston Area Clinical Trial Consultants
Houston, Texas, 77094
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, 53792
Texas Institute of Cardiology, PA
McKinney, Texas, 75071
Infinite Clinical Research
Miami, Florida, 33133
University Medical Center New Orleans
New Orleans, Louisiana, 70112
Valley Clinical Trials, Inc.
Northridge, California, 91325
University of California Irvine Medical Center
Orange, California, 92868
Pasadena Clinical Research
Pasadena, California, 91105
South Florida Research Solutions - North Flamingo Road
Pembroke Pines, Florida, 33028
Mayo Clinic in Rochester, Minnesota
Rochester, Minnesota, 55905
Velocity Clinical Research, Coastal Heart Medical Group
Santa Ana, California, 92704
Pima Heart
Tucson, Arizona, 85719
Japan19 sites
Saiseikai Futsukaichi Hospital
Chikushino-shi, Fukuoka, 818-8516
Harasanshin Hospital
Fukuoka, 812-0033
Minamino Cardiovascular Hospital
Hachiōji, Tokyo, 192-0918
Nakamura Cardiovascular Clinic
Itoshima, Fukuoka, 819-1104
Kasugai Municipal Hospital
Kasugai, Aichi-ken, 486-8510
Yamanashi Prefectural Central Hospital
Kofu, Yamanashi, 400-8506
Rakuwakai Otowa Hospital
Kyoto, 607-8062
Gunma University Hospital
Maebashi, Gunma, 371-8511
Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital
Nagoya, Aichi-ken, 466-8650
National Hospital Organization Okayama Medical Center
Okayama, 701-1154
Ome Medical Center
Ōme, Tokyo, 198-0042
Sakurabashi Watanabe Advanced Healthcare Hospital
Osaka, 530-0005
Yodogawa Christian Hospital
Osaka, 533-0024
National Hospital Organization - Osaka National Hospital - Institute For Clinical Research
Osaka, 540-0006
National Hospital Organization Takasaki General Medical Centar
Takasaki, Gunma, 370-0829
Toyama Prefectural Central Hospital
Toyama, 930-0975
Yokohama City University Medical Center
Yokohama, Kanagawa, 232-0024
Yokohama Minami Kyosai Hospital
Yokohama, Kanagawa, 236-0037
Kanagawa Cardiovascular and Respiratory Center
Yokohama, Kanagawa, 236-0051
Argentina15 sites
Investigaciones Medicas Imoba Srl
Balvanera, Buenos Aires F.D., C1056ABH
Sanatorio Anchorena Recoleta
Buenos Aires, Buenos Aires F.D., 1425
Mautalen Salud e Investigación
Buenos Aires, Buenos Aires F.D., C1128AAF
Centro Medico Dra. Laura Maffei- Investigacion Clinica Aplicada
Buenos Aires, Buenos Aires F.D., C1425AGC
CEMEDIC
Buenos Aires, 1407
Fundación Respirar
Buenos Aires, C1426ABP
Centro de Investigaciones Metabólicas (CINME)
Ciudad Autónoma de Buenos Aires, Buenos Aires, C1056ABI
Instituto Médico Río Cuarto
Río Cuarto, Córdoba Province, 5800
Hospital Provincial del Centenario
Rosario, Santa Fe Province, 2002
Instituto de Investigaciones Clinicas Rosario
Rosario, Santa Fe Province, S2000CVD
Investigaciones Clínicas Tucumán
San Miguel de Tucumán, Tucumán Province, 4000
Centro de Investigaciones Clinicas del Litoral
Santa Fe, 3000
Clínica de Nefrología, Urología y Enfermedades Cardiovasculares
Santa Fe, 3000
Sanatorio San Martin
Venado Tuerto, Santa Fe Province, 2600
Instituto de Investigaciones Clinicas Zarate
Zárate, Buenos Aires, B2800DGH
Brazil15 sites
Centro de Pesquisa Clinica do Coracao
Acaraju, Sergipe, 49055-530
Centro de Pesquisa Sao Lucas
Campinas, São Paulo, 13034-685
Instituto de Pesquisa clinica de Campinas
Campinas, São Paulo, 13060-080
PUC Trials- Nucleo de Pesquisa clinica da Escola de Medicina da PUCPR
Curitiba, Paraná, 80230-130
Universidade Federal de Goias
Goiânia, Goiás, 74605-020
Instituto Do Coracao De Marilia
Marília, São Paulo, 17515-000
CAPED Centro Avancado Pesquisa e Diagnostica
Ribeirão Preto, São Paulo, 14026-900
Centro de Pesquisa Silvestre Santé
Rio Branco, Acre, 69915-030
Hospital São Lucas de Copacabana
Rio de Janeiro, 22061-080
Instituto D'Or Pesquisa e Ensino
Rio de Janeiro, 22281-100
Pesquisare Saude
Santo André, São Paulo, 09080-110
Hospital Santa Paula
São Paulo, São Paulo, 04556-100
Incor - Instituto do Coracao
São Paulo, São Paulo, 05403-900
Instituto de Molestias Cardiovasculares de Tatui
Tatuí, São Paulo, 18270-170
Integral Pesquisa e Ensino
Votuporanga, São Paulo, 15501-405
Poland14 sites
Uniwersytecki Szpital Kliniczny w Białymstoku
Bialystok, Podlaskie Voivodeship, 15-540
KLIMED Marek Klimkiewicz
Bialystok, Podlaskie Voivodeship, 15-704
NZOZ Centrum Medyczne KERmed
Bydgoszcz, Kuyavian-Pomeranian Voivodeship, 85-231
INTERCOR
Bydgoszcz, Kuyavian-Pomeranian Voivodeship, 85-605
Private Practice - Dr. Ewa Mirek Bryniarska
Krakow, Lesser Poland Voivodeship, 30-082
SPZOZ Uniwersytecki Szpital Kliniczny Im. Wojskowej Akademii Medycznej UM W Łodzi Centralny Szpital Wetera -T
Lodz, Łódź Voivodeship, 90-549
Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi
Lodz, Łódź Voivodeship, 93-513
1 Wojskowy Szpital Kliniczny w Lublinie
Lublin, Lublin Voivodeship, 20-043
CenterMed Lublin NZOZ
Lublin, Lublin Voivodeship, 20-044
MEDICOME Centrum Badań Klinicznych Oświęcimskie
Oświęcim, Lesser Poland Voivodeship, 32-660
IRMED Osrodek Badan Klinicznych
Piotrkow Trybunalski, Łódź Voivodeship, 97-300
Provita Profamilia
Piotrkow Trybunalski, Łódź Voivodeship, 97-300
Wojewodzki Szpital im. Sw. Ojca Pio w Przemyslu
Przemyśl, Podkarpackie Voivodeship, 37-700
Balsam Medica
Warsaw, Masovian Voivodeship, 01-249
Spain12 sites
Hospital Germans Trias i Pujol
Badalona, Barcelona [Barcelona], 08916
Hospital Universitario Reina Sofia
Córdoba, Andalusia, 14004
Hospital de Denia Marina Salud
Denia, Alicante, 03700
Hospital Clínico Universitario Virgen de la Arrixaca
El Palmar, Murcia, Murcia, Región de, 30120
Hospital Universitari de Bellvitge
L'Hospitalet de Llobregat, Catalunya [Cataluña], 08907
Hospital Universitario Ramón y Cajal
Madrid, Madrid, Comunidad de, 28034
Hospital Universitario 12 de Octubre
Madrid, 28041
Hospital Universitario Virgen de la Victoria
Málaga, Málaga, 29010
CHUS - Hospital Clinico Universitario
Santiago de Compostela, A Coruña [La Coruña], 15706
Hospital Universitario Virgen de Valme
Seville, Andalusia, 41014
Hospital San Juan de la Cruz
Úbeda, Jaén, 23400
Hospital Clinico de Valencia
Valencia, Valenciana, Comunitat, 46010
Turkey (Türkiye)10 sites
Afyon Kocatepe Üniversitesi Tıp Fakültesi
Afyonkarahisar, 03030
Ankara Etlik City Hospital
Ankara, 06170
Ege Universitesi Hastanesi
Bornova, İzmir, 35100
Trakya University Medical Faculty Hospital
Edirne, 22030
Eskisehir Osmangazi University
Eskişehir, Eskişehir, 26480
T.C. Sağlık Bakanlığı İzmir Tepecik Eğitim ve Araştırma Hast
Izmir, 35120
Dokuz Eylul Universitesi Hastanesi
Izmir, 35330
Kocaeli Üniversitesi
İzmit, Kocaeli, 41380
Mersin University
Mersin, 33343
Bursa Yüksek İhtisas Eğitim Ve Araştırma Hastanesi
Yıldırım, Bursa, 16310
Canada9 sites
Private Practice - Dr. Saul Vizel
Cambridge, Ontario, N1R 7R1
PACE Cardiology
Newmarket, Ontario, L3Y 2P6
North York Diagnostic and Cardiac Centre
North York, Ontario, M6B 3H7
Oakville Trafalgar Memorial Hospital
Oakville, Ontario, L6M 1M1
Heart Health Institute - Scarborough Office
Scarborough Village, Ontario, M1B 4Z8
Centre Hospitalier Universite de Sherbrooke - Hôtel-Dieu Hospital
Sherbrooke, Quebec, J1G 2E8
SMH Cardiology Clinical Trials
Surrey, British Columbia, V3V 0C6
Medicus MFC Research Clinic
Toronto, Ontario, M4P 1E4
CPS Research
Waterloo, Ontario, N2T 0C1
United Kingdom8 sites
Glasgow Royal Infirmary
Glasgow, Scotland, G31 2ER
Northwick Park Hospital
Harrow, London, City of, HA1 3UJ
Wycombe General Hospital
High Wycombe, Buckinghamshire, HP11 2TT
Raigmore Hospital
Inverness, Highland, IV2 3JH
West Middlesex University Hospital
Isleworth, TW7 6AF
Aintree University Hospital NHS Foundation Trust
Liverpool, L9 7AL
Wythenshawe Hospital
Manchester, M23 9LT
Royal Berkshire Hospital
Reading, RG1 5AN
Hungary6 sites
Dél-Pesti Centrumkórház
Budapest, 1097
Semmelweis University
Budapest, 1122
Kistarcsai Flor Ferenc Korhaz
Kistarcsa, Pest County, 2143
Medifarma 98 Kft
Nyíregyháza, Nyíregyháza, 4400
Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ
Szeged, Csongrád megye, 6720
Belvárosi Egészségház
Zalaegerszeg, Zala County, 8900
Israel4 sites
Rambam Health Care Campus
Haifa, Northern District, 3109601
Hadassah Medical Center
Jerusalem, Jerusalem, 9112001
Sourasky Medical Center
Tel Aviv, Tell Abīb, 6423906
Yitzhak Shamir Medical Center
Ẕerifin, Central District, 609300
Czechia3 sites
Fakultní nemocnice Brno Bohunice
Brno, Brno-město, 62500
Fakultni Nemocnice u sv. Anny v Brne
Brno, South Moravian, 60200
Vseobecna fakultni nemocnice v Praze
Prague, 12808
About this study
Official title: 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)
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
- Being tested
- LY3540378, Placebo
- Medical subject headings
- Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LY3540378Drug
Administered SC
PlaceboDrug
Administered SC
| Study group | Role | What they receive |
|---|---|---|
| 25 mg LY3540378 | Experimental | Participants received 25 mg LY3540378 administered once weekly as subcutaneous (SC) injection for 26 weeks. Receives: Drug: LY3540378 |
| 50 mg LY3540378 | Experimental | Participants received 50 mg LY3540378 administered once weekly as SC injection for 26 weeks. Receives: Drug: LY3540378 |
| 100 mg LY3540378 | Experimental | Participants received 100 mg LY3540378 administered once weekly as SC injection for 26 weeks. Receives: Drug: LY3540378 |
| Placebo | Placebo comparator | Participants received placebo administered once weekly as SC injection for 26 weeks. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline, Week 26
Secondary outcomes (13)
Change From Baseline in Left Atrial Reservoir Strain (LARS) at Week 12
Results are estimated using LS mean from the MMRM model: Change from baseline = Baseline + Strata + Gender + Treatment + Time + Treatment*Time + Baseline*Treatment.
Measured: Baseline, Week 12
Change From Baseline in Log-transformed N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) at Week 12
Results are estimated using LS mean from the MMRM model: Change from baseline = Baseline + Strata + Gender + Treatment + Time + Treatment*Time + Baseline*Treatment.
Measured: Baseline, Week 12
Change From Baseline in Log-transformed N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) at Week 26
Results are estimated using LS mean from the MMRM model: Change from baseline = Baseline + Strata + Gender + Treatment + Time + Treatment*Time + Baseline*Treatment.
Measured: Baseline, Week 26
Change From Baseline in Left Atrial End-Diastolic Volume Index (LAEDVI) at Week 12
Results are estimated using LS mean from the MMRM model: Change from baseline = Baseline + Strata + Gender + Treatment + Time + Treatment*Time + Baseline*Treatment.
Measured: Baseline, Week 12
Change From Baseline in Left Atrial End-Diastolic Volume Index (LAEDVI) at Week 26
Results are estimated using LS mean from the MMRM model: Change from baseline = Baseline + Strata + Gender + Treatment + Time + Treatment*Time + Baseline*Treatment.
Measured: Baseline, Week 26
Change From Baseline Left Atrial End-Systolic Volume Index (LAESVI) at Week 12
Results are estimated using LS mean from the MMRM model: Change from baseline = Baseline + Strata + Gender + Treatment + Time + Treatment*Time + Baseline*Treatment.
Measured: Baseline, Week 12
Change From Baseline Left Atrial End-Systolic Volume Index (LAESVI) at Week 26
Results are estimated using LS mean from the MMRM model: Change from baseline = Baseline + Strata + Gender + Treatment + Time + Treatment*Time + Baseline*Treatment.
Measured: Baseline, Week 26
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 12
Results are estimated using LS mean from the MMRM model: Change from baseline = Baseline + Strata + Gender + Treatment + Time + Treatment*Time + Baseline*Treatment.
The unit of measure for this outcome is millilitres per minute per 1.73 square metres (mL/min/1.73 m²)
Measured: Baseline, Week 12
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 26
Results are estimated using LS mean from the MMRM model: Change from baseline = Baseline + Strata + Gender + Treatment + Time + Treatment*Time + Baseline*Treatment.
Measured: Baseline, Week 26
Change From Baseline in Log-transformed Serum Creatinine at Week 12
Results are estimated using LS mean from the MMRM model: Change from baseline = Baseline + Strata + Gender + Treatment + Time + Treatment*Time + Baseline*Treatment.
Measured: Baseline, Week 12
Change From Baseline in Log-transformed Serum Creatinine at Week 26
Results are estimated using LS mean from the MMRM model: Change from baseline = Baseline + Strata + Gender + Treatment + Time + Treatment*Time + Baseline*Treatment.
Measured: Baseline, Week 26
Change From Baseline in Log-transformed Cystatin-C at Week 12
Results are estimated using LS mean from the MMRM model: Change from baseline = Baseline + Strata + Gender + Treatment + Time + Treatment*Time + Baseline*Treatment.
Measured: Baseline, Week 12
Change From Baseline in Log-transformed Cystatin-C at Week 26
Results are estimated using LS mean from the MMRM model: Change from baseline = Baseline + Strata + Gender + Treatment + Time + Treatment*Time + Baseline*Treatment.
Measured: Baseline, Week 26
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Oct 2022
- Study start3 Feb 2023
- Primary completion22 Jan 2025
- Study completion22 Jan 2025
Why it stopped: An interim was conducted and after review of available data, including efficacy evaluation of heart failure events, Lilly is terminating the study due to low likelihood of study success for this HFpEF patient population.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- More trials run by Eli Lilly and CompanyThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 332 participants (actual)
Sponsor and investigators
- Lead sponsor
- Eli Lilly and Company
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- 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), Study director, Eli Lilly and Company
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05592275
- Sponsor's protocol ID
- 18473
- Other IDs
- J3E-MC-EZDB, 2023-505902-40-00, 2023
- Status last verified
- Jan 2026
- First submitted
- 20 Oct 2022
- Last updated
- 5 Feb 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
Publications
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.
PubMed 40887551