A Study of the Efficacy and Safety of Danicamtiv in Participants With Symptomatic Genetic and Familial Dilated Cardiomyopathy

Official title

A Phase 2b/3, Adaptive, Randomized, Double-blind, Placebo-controlled, Multicenter Study to Assess the Efficacy and Safety of Danicamtiv in Participants With Symptomatic Genetic and Familial Dilated Cardiomyopathy

Overview

The Sponsor is studying an investigational medication called danicamtiv to determine if it can help people with genetic and familial dilated cardiomyopathy (DCM). Investigational means that the safety and effectiveness of danicamtiv have not been established. Currently, there are no approved drugs that are designed specifically to treat genetic or familial DCM. The purpose of this study is to evaluate how well danicamtiv works compared to a placebo (sugar pill that looks like danicamtiv pill but does not contain any danicamtiv) and see how safe it is for people with genetic and familial DCM. In DCM, the heart muscle weakens and enlarges, making it harder for the heart to pump blood; this can happen for different reasons. Some people have DCM because of a change in a gene (called genetic DCM). Others may have DCM that runs in their family, even if no specific gene change is found (called familial DCM). The main goals of the study are: * To assess the effect of danicamtiv on cardiac function using echocardiogram. * To evaluate the impact of danicamtiv on exercise capacity * To evaluate the safety and tolerability of danicamtiv Participants will: * Take danicamtiv or placebo every day for approximately 6 months * Visit the clinic about 12 times for initial evaluation, checkups, tests and follow up

Interventions

• Drug danicamtiv
  Danicamtiv will be administrated twice daily for up to 26 weeks
• Drug Placebo
  Placebo will be administrated twice daily for up to 26 weeks

Primary outcome measures

• Part 1: Change from Baseline (Day 1) to Week 26 in left atrial function index in Cohort 1 [Time frame: 26 weeks]
• Part 2: Change from Baseline (Day 1) to Week 26 in peak VO2 in Cohort 1 [Time frame: 26 weeks]

Secondary outcome measures (12)

• Part 1: Change from Baseline (Day 1) to Week 26 in peak VO2 [Time frame: 26 weeks]
• Part 1: Association between response in left ventricular global longitudinal strain and/or left atrial function index after 2 weeks of active treatment with placebo-adjusted Week 26 response in peak VO2 [Time frame: 26 weeks]
• Part 1: Change from Baseline (Day 1) to Week 26 in left atrial function index in overall population [Time frame: 26 weeks]
• Part 1 and 2: Change from Baseline (Day 1) to Week 26 in left ventricular ejection fraction [Time frame: 26 weeks]
• Part 1 and 2: Change from Baseline (Day 1) to Week 26 in ventilatory efficiency [Time frame: 26 weeks]
• Part 1 and 2: Change from Baseline (Day 1) to Week 26 in Kansas City Cardiomyopathy Questionnare (KCCQ-23) Clinical Summary Score [Time frame: 26 weeks]
• Part 1: Proportion of participants from Baseline (Day 1) to Week 26 who achieve at least a one-class improvement in New York Heart Association (NYHA) class [Time frame: 26 weeks]
• Part 2: Change from Baseline (Day 1) to Week 26 in left atrial function index [Time frame: 26 weeks]
• Part 2: Change from Baseline (Day 1) to Week 26 in peak VO2 in the responder subgroup [Time frame: 26 weeks]
• Part 2: Change from Baseline (Day 1) to Week 26 in peak VO2 in overall population [Time frame: 26 weeks]
• Part 1 and 2: Change from Baseline (Day 1) to Week 26 in left ventricular global longitudinal strain [Time frame: 26 weeks]
• Part 1 and 2: Percent change from Baseline (Day 1) to Week 26 in NT-proBNP concentrations [Time frame: 26 weeks]

Eligibility criteria

Inclusion criteria

• Has a diagnosis of DCM due to probable disease-causing variants of MYH7, TTN, or other identified genetic DCM variants, or with familial DCM
• Has New York Heart Association (NYHA) Class II-IV at Screening with stable symptoms for ≥1 month.
• Has at least mild left ventricular enlargement (LVE) and has adequate acoustic windows to enable accurate TTEs according to the Echocardiography Core Laboratory.
• Has a LVEF of ≤45%.
• Is on stable doses of maximally tolerated standard-of-care heart failure (HF) therapies reflecting current guidelines for at least 4 weeks prior to the first visit.
• Has DCM not attributed to substance abuse, amyloidosis, sarcoidosis, or any other secondary form of cardiomyopathy per the Investigator.
• Can perform an upright cardiopulmonary exercise training (CPET) with a peak oxygen uptake (pV̇O2) of 80% or less of predicted for a healthy individual and respiratory exchange ratio (RER) of ≥1.05

Exclusion criteria

• Has heart failure with reduced ejection (HFrEF) caused primarily by ischemic heart disease, chronic valvulopathy, or another condition, as determined by the Investigator.
• Recent (<90 days) clinically significant cardiac events, including acute coronary syndrome, hemodynamically significant epicardial coronary disease (per Investigator), coronary revascularization (percutaneous coronary intervention \[PCI\] or coronary artery bypass graft \[CABG\]), or hospitalization for heart failure/intravenous (IV) diuretic use.
• Presence of disqualifying cardiac rhythms that might interfere with reliable echocardiographic measurements of left ventricle (LV) function, as determined by the Investigator including: (a) inadequately rate-controlled atrial fibrillation, (b) ectopic beats (atrial, junctional or ventricular) of sufficient frequency (e.g. > 10% of total beats) that the participant's cardiac rhythm is irregular potentially interfering with reliable echocardiographic measurements of LV function.
• Unstable or untreated severe ventricular arrythmia (eg, ventricular tachycardia or ventricular fibrillation).
• History of malignancy of any type within 5 years prior to Screening
• Severe renal insufficiency (defined at the time of Screening as current estimated glomerular filtration rate \[eGFR\] <15 mL/min/1.73m2 by simplified Modification of Diet in Renal Disease equation \[sMDRD\]).
• History or evidence of any other clinically significant disorder, condition, or disease that, in the opinion of the Investigator or Sponsor, would pose a risk to participant safety or interfere with the study evaluation
• History of heart transplantation or anticipated heart transplantation in the next 6 months.
• Ongoing or anticipated advanced cardiac interventions, including chronic IV inotropic therapy, planned cardiac resynchronization therapy (CRT) or major surgery, or current/anticipated ventricular assist device placement within 6 months
• Clinically significant laboratory abnormalities at Screening

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 28 centers

• University of Alabama Birmingham — Birmingham
• Cedars Sinai — Los Angeles
• University of California, Los Angeles (UCLA) - David Geffen School of Medicine — Los Angeles
• University of California, San Diego (UCSD) - Medical Center — San Diego
• UCSF — San Francisco
• Stanford University Medical Center — Stanford
• MedStar Washington Hospital Center — Washington D.C.
• Mayo Clinic - Jacksonville — Jacksonville
• … and 20 more centers

Italy · 10 centers

• Azienda Ospedaliera Universitaria Consorziale - Policlinico Bari — Bari
• Azienda Ospedaliero-Universitaria Careggi — Florence
• IRCCS Ospedale San Raffaele — Milan
• Centro Cardiologico Monzino — Milan
• ASST Grande Ospedale Metropolitano Niguarda — Milan
• Azienda Ospedale - Università Padova — Padova
• Fondazione IRCCS Policlinico San Matteo — Pavia
• Ospedale Policlinico Casilino — Roma
• … and 2 more centers

Spain · 8 centers

• Hospital Universitario Vall d'Hebron — Horta-Guinardó
• Hospital Universitario Puerta de Hierro — Majadahonda
• Hospital Universitario de A Coruña — A Coruña
• Hospital Universitari de Bellvitge — Barcelona
• Hospital Universitario Virgen de la Victoria — Málaga
• Hospital Clinico Universitario Virgen de la Arrixaca — Murcia
• Hospital Universitario Son Llatzer — Palma de Mallorca
• Hospital Universitario Virgen del Rocio — Seville

United Kingdom · 8 centers

• University Hospitals Bristol NHS Foundation Trust — Bristol
• NHS Greater Glasgow and Clyde — Glasgow
• Glenfield Hospital — Leicester
• St. Bartholomew's Hospital — London
• St George's Hospital — London
• Royal Brompton Hospital — London
• Hammersmith Hospital, Imperial College of London — London
• Cardiovascular Clinical Research Facility (CCRF) — Oxford

Belgium · 5 centers

• AZORG - Campus Moorselbaan — Aalst
• Universite Libre de Bruxelles (ULB) - Hopital Erasme — Brussels
• Universitair Ziekenhuis Antwerpen (UZA) — Edegem
• Jessa Ziekenhuis — Hasselt
• UZ Leuven — Leuven

France · 5 centers

• CHRU de Tours - Hopital Trousseau — Chambray-lès-Tours
• CHU de Lille - Institut Coeur Poumon — Lille
• AP-HP Hopital Pitie-Salpetriere — Paris
• AP-HP Hopital Europeen Georges Pompidou — Paris
• CHU Rennes - Hopital Pontchaillou — Rennes

Poland · 4 centers

• Uniwersyteckie Centrum Kliniczne, Gdansk — Gdansk
• Krakowski Szpital Specjalistyczny im. sw. Jana Pawla II — Krakow
• Samodzielny Publiczny Zaklad Opieki Zdrowotnej Centralny Szpital Kliniczny Uniwersytetu Me — Lodz
• Narodowy Instytut Kardiologii Stefana kardynala Wyszynskiego - Panstwowy Instytut Badawczy — Warsaw

Denmark · 3 centers

• Aarhus University Hospital — Aarhus
• Rigshospitalet — Copenhagen
• Odense University Hospital - Odense — Odense

Netherlands · 3 centers

• Amsterdam UMC - Locatie AMC — Amsterdam
• Maastricht University Medical Center — Maastricht
• Erasmus MC — Rotterdam

Hungary · 2 centers

• Semmelweis Egyetem - Varosmajori Sziv es Ergyogyaszati Klinika — Budapest
• Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont — Szeged

Sweden · 2 centers

• Sodersjukhuset AB — Stockholm
• Danderyds sjukhus — Stockholm

Identifiers

NCT: NCT07210723 · DAN-301

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗