Chronic heart failure Circulatory System Heart failure
Conditions
Interventions
The study has a Single Ascending Dose (SAD) and a Multiple Ascending Dose (MAD) stage. Each stage will be split into several groups based on the dose of mRNA-0184 that will be given.
each cohort in the SAD stage includes a minimum of three sentinel participants who will each receive a single IV infusion of mRNA-0184. Each sentinel participant will be monitored for safety for a min
Sponsors
Moderna France
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age =18 years at the time of informed consent 2. Documented diagnosis of HF based on medical records 3. Left ventricular ejection fraction (LVEF) =35% and <50% at Screening, or documented within the 3 months before Screening, measured by TTE or cardiac magnetic resonance imaging (MRI) 4. New York Heart Association (NYHA) HF Class I or II 5. On a stable regimen of cardiovascular medication(s) for a duration of at least 4 weeks before Screening 6. Heart rate =50 bpm at Screening 7. Systolic blood pressure =110 mmHg and =160 mmHg at Screening 8. Sexually active female participants of childbearing potential and sexually active male participants of reproductive potential agree to use a highly effective method of contraception during the study and for 6 months after the last administration of IP
Exclusion criteria
Exclusion criteria: 1. Hospitalized for cardiovascular causes within 3 months before Screening 2. Decompensated HF, acute myocarditis, hypertrophic and/or restrictive/constrictive cardiomyopathy, or moderate or severe valvular heart disease (as classified by echocardiography) at Screening or within the 3 months before Screening. Moderate tricuspid regurgitation is not exclusionary 3. Symptoms of angina pectoris at Screening 4. Severe obstructive or restrictive pulmonary pathology, including chronic obstructive pulmonary disease Gold Stage III or IV current use of oxygen therapy, or pulmonary hypertension 5. History of sustained ventricular tachycardia or atrial fibrillation/atrial flutter with a ventricular response =110 bpm at the time of Screening 6. Severe renal impairment defined as one or both of the following: 6.1. Estimated glomerular filtration rate (eGFR) 450 ms at Screening 8. Laboratory abnormality within an exclusionary threshold at Screening 9. For female participants, positive pregnancy test at Screening or Baseline or currently breastfeeding 10. Hypersensitivity to acetaminophen/paracetamol or H1-receptor or H2-receptor blockers 11. History of hypersensitivity to any components of the IP 12. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive hepatitis B surface antigen [HBsAg] result), hepatitis C virus (HCV), or HIV (positive HIV-1/HIV-2 antibodies). Participants with a past or resolved hepatitis virus B (HBV) infection(defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acids (RNA) 13. Participant has received a COVID-19 vaccination (irrespective of type of vaccine) or is anticipated to require a second dose of a two-dose COVID-19 vaccine series within 7 days of the planned date of IP administration 14. For SAD cohort participants to be rolled over into the MAD stage, have experienced a DLT in a SAD cohort 15. Participation in another clinical study of another IP within 30 days before Screening or within 5 effective elimination half-lives of the IP, whichever is longer 16. Has a positive urine drug screen for any of the following nonprescription drugs of abuse at Screening: alcohol, opiates, cocaine, phencyclidine, amphetamines, methamphetamines, barbiturates, benzodiazepines, or methadone. Positive drug screens for benzodiazepines or opiates will not be exclusionary if prescribed concomitant medications can justify the result 17. Any other clinically significant medical condition that, in the Investigator’s opinion, could interfere with the interpretation of study results or limit the participant’s participation in the study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Incidence and severity of TEAEs, SAEs, and TEAEs leading to treatment discontinuation. This is measured at 26 weeks for the SAD stage, 8 weeks for the MAD stage Q2W, 12 weeks for the MAD stage Q3W and 16 weeks for the MAD stage Q4W. 2. Vital signs, weight, physical examination findings, ECG results, and laboratory findings (including hematology, serum chemistry, urinalysis, and coagulation parameters). This is measured at 26 weeks for the SAD stage, 8 weeks for the MAD stage Q2W, 12 weeks for the MAD stage Q3W and 16 weeks for the MAD stage Q4W. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. PK of mRNA-0184 assessed as serum concentrations of Rel2-vlk mRNA and plasma concentrations of SM-86/OL-56. Parameters will include, but are not limited to, Cmax, Tmax, AUClast, AUC0-t, AUC0-8, t½, CL/F, and Vz/F 2. PD of mRNA-0184 assessed as serum concentrations of Rel2-vlk protein. Parameters will include, but are not limited to, Emax, TEmax, AUEC, AUEC0-t, AUEC0-8, and t½ 3. Quantification of transthoracic echocardiography (TTE) PD markers. This will include, but not be limited to: stroke volume (SV), CO, cardiac index (CI), ejection fraction (EF), systemic vascular resistance (SVR), measures of left ventricular filling pressures and diastolic function, left ventricular strain, and pulmonary artery pressure. 4. Anti-PEG antibodies measured using ELISA ligand binding assay 5. Anti–Rel2-vlk protein antibodies measured using assay that has not been validated yet These are measured at 26 weeks for the SAD stage, 8 weeks for the MAD stage Q2W, 12 weeks for the MAD stage Q3W and 16 weeks for the MAD stage Q4W. | — |
Countries
England, Scotland, United Kingdom
Contacts
Public ContactChim Lang
Outcome results
None listed