Phase I study to evaluate the safety of mRNA-0184 in participants with heart failure
| ISRCTN | ISRCTN79552451 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN79552451 |
| EudraCT/CTIS number | 2022-000784-46 |
| IRAS number | 1005671 |
| Secondary identifying numbers | mRNA-0184-P101, IRAS 1005671, CPMS 50852 |
- Submission date
- 28/05/2022
- Registration date
- 21/10/2022
- Last edited
- 01/11/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Circulatory System
Plain English Summary
Background and study aims
Chronic heart failure (HF) is a condition commonly caused by an abnormality or damage to the heart muscle. Approximately 920,000 people in the UK have been diagnosed with HF. The goals of treatment are to improve the patient’s quality of life and reduce mortality. mRNA-0184 is an investigational drug that is being studied to determine its ability to increase your body’s ability to make a protein like a naturally occurring hormone called relaxin, which promotes the widening of blood vessels and the formation of new blood vessels. The aim of this study is to evaluate the safety and tolerability of single and multiple doses of mRNA-0184 in participants with chronic HF.
Who can participate?
Patients aged 18 years and over with HF
What does the study involve?
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. Participants in the SAD groups will receive one dose of mRNA-0184 and are expected to be in the study for up to 31 weeks. Participants enrolled in the MAD groups will be assigned by chance in a 3:1 ratio to receive up to 4 doses of either mRNA-0184 or placebo (an inactive substance that looks like the study drug). Treatment will be administered at dosing intervals of once every 2, 3 or 4 weeks, depending on data from the SAD groups. The duration for participants in these groups is up to 46 weeks depending on the dosing interval. All participants will be closely monitored during the study drug infusion and for a period after completion of the infusion. Study procedures include physical examinations, blood and urine samples, questionnaires, ECGs, ultrasounds of the heart and kidneys and monitoring of blood pressure and heart rate/rhythm.
What are the possible benefits and risks of participating?
As part of being in this study, the participant’s condition will be closely monitored by doctors who specialise in heart health (cardiologists). The study drug is intended to increase the body’s ability to make a protein similar to a naturally occurring hormone called relaxin. Researchers believe that increasing the amount of relaxin in the body will reduce symptoms of heart failure. Participants could see an improvement in their heart failure symptoms; however, there is no guarantee there will be any benefits from their taking part in this clinical study. In addition, this study may improve both their understanding and the healthcare field’s understanding of heart failure and how it responds to the study drug. Participating in this study may help people with heart failure in the future.
This is a Phase I first-in-human study where the study drug has not been tested in humans previously and therefore there is little information on the possible risks and adverse reactions associated with the IV administration of mRNA 0184. There may be side effects and discomforts from the study drug that are not yet known. The study doctor will discuss all information regarding possible side effects of the study drug with participants.
There is a small chance that the participant will experience an infusion-related reaction/allergic reaction to mRNA-0184. Infusion-related reactions (IRRs)/allergic reactions may range from mild, such as skin rash or hives, to severe such as breathing difficulties or shock. A severe reaction would require immediate medical treatment and could result in permanent disability or death. Participants in the Single Ascending Dose (SAD) cohort will be closely monitored in the hospital for at least 24 hours after receiving the study drug, and participants in the Multiple Ascending Dose (MAD) cohort will be monitored for at least 6 hours after the first infusion of study drug and for at least 4 hours after the study drug infusion on subsequent doses, to ensure the participants' safety. To prevent or reduce the severity of any IRRs, participants will receive several medications (acetaminophen/paracetamol, H1-receptor blocker and H2-receptor blocker) about 60 minutes before infusion of the study drug. The study team administering the study drug have experience in administering IV infusions and are trained to know what to do in the event of a serious reaction. Participants will be told about any new findings that develop during the course of the study, which may affect their decision to stay in the study.
There may be a possibility that the study drug could damage an unborn child or nursing infant. Therefore, patients that are pregnant, planning to become pregnant or breastfeeding must not enter this study. From screening, throughout the duration of the study and for 6 months after the last infusion of the study drug, women of childbearing potential and sexually active males must use an adequate method of contraception. This will be fully explained in the participant information sheet.
Participants will need to schedule time out of their normal routine to attend extra clinic visits. As the study drug infusions can take up to 4 hours to administer and close monitoring of the patient is needed for 24 hours after infusion of the study drug in the SAD cohort and for 6 hours after infusion of the study drug in the MAD cohort, the participant may need to stay in the hospital for extended periods of time or overnight. Participants will also need to take a blood pressure measurement at least once a day for up to 17 weeks depending on whether they are in the SAD or MAD cohort. Participants will also be asked to wear an ambulatory blood pressure monitor (ABPM) and a Holter monitor for at least 24 hours up to 6 times during the study. Due to the amount of time the participant will need to spend in clinic visits and the burden of daily blood pressure monitoring and wearing monitoring equipment, participants will receive specified patient stipends as compensation for their time. Reasonable travel expenses for study clinic visits will also be reimbursed.
Taking blood may cause some discomfort, bruising and, very rarely, infection where the needle goes into the skin. The patient may also experience dizziness, nausea, or fainting during blood collections. Ambulatory blood pressure monitoring (ABPM) is virtually free of risk, except for a small chance of skin irritation where the cuff is applied. Some other discomforts that have been reported are that the device is noisy, that wearing the device can cause some inconvenience to normal daily routine, and disturbances to sleep. The ECG is a safe procedure with no known risks. Some people may be allergic or sensitive to the sticky patches used to attach the electrodes. This can cause skin irritation, itching and redness. Removing the sticky patches can feel like having an adhesive bandage taken off. The Holter monitor is virtually free of risk, except for a small chance of skin irritation at the site of electrode placement similar to the ECG.
Where is the study run from?
Moderna (France)
When is the study starting and how long is it expected to run for?
May 2022 to July 2024
Who is funding the study?
Moderna (France)
Who is the main contact?
Prof. Chim Lang
c.c.lang@dundee.ac.uk
Contact information
Scientific
Ninewells Hospital & Medical School
Dundee
DD1 9SY
United Kingdom
| Phone | +44 (0)1382 383 283 |
|---|---|
| c.c.lang@dundee.ac.uk |
Public
Ninewells Hospital & Medical School
Dundee
DD1 9SY
United Kingdom
| Phone | +44 (0)1382 383 283 |
|---|---|
| c.c.lang@dundee.ac.uk |
Principal Investigator
Ninewells Hospital & Medical School
Dundee
DD1 9SY
United Kingdom
| Phone | +44 (0)1382 383 283 |
|---|---|
| c.c.lang@dundee.ac.uk |
Study information
| Study design | Open-label single ascending dose to single-blind randomized placebo-controlled multiple ascending dose trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | A Phase I, adaptive, open-label, single ascending dose to single-blind, placebo-controlled, multiple ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of mRNA-0184 in participants with chronic heart failure |
| Study hypothesis | 1. Evaluate the safety and tolerability of single and multiple doses at escalating dose levels of intravenously (IV) administered mRNA-0184 2. Characterize the pharmacokinetic (PK) profile of mRNA encoding relaxin-2-variable light chain kappa (Rel2-vlk mRNA) and of SM-86/OL-56 following single and multiple dose administration at escalating dose levels of mRNA-0184 3. Characterize the pharmacodynamic (PD) response of single and multiple dose administration at escalating dose levels of mRNA-0184 4. Assess the presence and development of anti-polyethylene glycol (anti-PEG) antibodies and anti–Rel2-vlk protein antibodies |
| Ethics approval(s) | Approved 07/10/2022, South Central – Oxford A REC (Temple Quay House, 2 The Square, Bristol Research Ethics Committee Centre, BS1 6PN, UK; +44 207 104 8206; oxforda.rec@hra.nhs.uk), ref: 22/SC/0208 |
| Condition | Chronic heart failure |
| Intervention | 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. In the SAD stage, participants will be given a single dose of mRNA-0184 and will be followed for safety for 26 weeks after dosing. The SAD stage includes five dose cohorts with the option of two additional cohorts, for a maximum of seven cohorts. The initial dose will be 0.025 mg/kg and the dose in subsequent cohorts will not exceed the proposed maximum dose of 1.0 mg/kg. Dosing will follow a “3+3” design; 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 minimum of 7 days before the next sentinel participant is dosed. Participants will be closely monitored for safety in the clinic for at least 24 hours after completion of the infusion. If one of the participants in a given cohort meets dose-limiting toxicity criteria within 7 days after the dose, an additional three participants may be enrolled in that cohort to further characterise the safety and tolerability of that dose. If a second dose-limiting toxicity occurs within the cohort, the Safety Monitoring Committee will review and make a recommendation on how the study should proceed. The last participant in a SAD cohort will be monitored for safety for a minimum of 7 days before dosing participants in the next SAD dose level or before dosing participants in a MAD cohort at the same or lower dose level(s). In the MAD stage, participants will receive up to four planned doses of mRNA-0184 or placebo via IV infusion and will be followed for safety for 26 weeks after the end of treatment visit. There will be a maximum of seven MAD cohorts. Within each cohort, eight participants will be randomised in a 3:1 ratio to mRNA-0184 or placebo. The dose levels will not exceed the highest dose cleared in any SAD cohort. The dosing regimen will be at prespecified intervals of once every 2, 3, or 4 weeks, with treatment occurring over 8 weeks, 12 weeks and 16 weeks, respectively. The selection of dosing interval will be determined based on data from the SAD stage. A sentinel dosing strategy will not be employed in the MAD cohorts. Participants will be closely monitored in the clinic for at least 6 hours after completion of the infusion for Dose 1 and observed for at least 4 hours in clinic after completion of the infusion on subsequent doses. Participants previously enrolled in a SAD cohort will be permitted to enroll into a MAD cohort after a washout period of at least 5 effective half-lives of the Rel2-vlk protein (as calculated from clinical data collected in the SAD cohort) or 45 days (if Rel2-vlk protein t1/2 cannot be estimated). |
| Intervention type | Biological/Vaccine |
| Pharmaceutical study type(s) | |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | mRNA-0184 |
| Primary outcome measure | 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 outcome measures | 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-∞, 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-∞, 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. |
| Overall study start date | 26/05/2022 |
| Overall study end date | 04/07/2024 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 98 |
| Participant 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 |
| Participant 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) <30 ml/min/1.73 m², calculated using the Simplified Modification of Diet in Renal Disease equation 6.2. Current or planned dialysis or ultrafiltration 7. Prolonged QTcF >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 |
| Recruitment start date | 26/09/2022 |
| Recruitment end date | 15/08/2023 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
Study participating centres
Dundee
DD1 9SY
United Kingdom
Derriford
Plymouth
PL6 8DH
United Kingdom
London
NW3 2QG
United Kingdom
Sponsor information
Industry
25 Rue du 4 Septembre
Paris
75002
France
| Phone | +33 (0)630 434 080 |
|---|---|
| Marie.Caby-Tosi@modernatx.com |
Funders
Funder type
Industry
Private sector organisation / For-profit companies (industry)
- Alternative name(s)
- Moderna Therapeutics, Moderna, Inc., Moderna, Inc
- Location
- United States of America
Results and Publications
| Intention to publish date | 04/07/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | 1. Peer-reviewed scientific journals 2. Submission to regulatory authorities |
| IPD sharing plan | The data-sharing plans for the current study are unknown and will be made available at a later date. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
01/11/2022: Internal review.
01/11/2022: The ethics approval was added.
21/10/2022: ISRCTN received notification of combined HRA/MHRA approval for this trial on 21/10/2022
30/05/2022: Trial's existence confirmed by the HRA.
