Efficacy of Colchicine Versus Placebo in Reducing Late Gadolinium Enhancement in Acute Myocarditis: A Randomized Controlled Trial
- Trial ID
- 2024-514610-13-00
- Protocol
- APHP211429
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **efficacy** of colchicine versus placebo on a co-primary endpoint, which includes inflammatory myocardial damage as observed on cardiac magnetic resonance (CMR) or composite clinical outcomes at 6 months. This is clinically relevant as it aims to determine whether colchicine can effectively reduce myocardial inflammation and improve clinical outcomes in patients with acute myocarditis, a condition characterized by inflammation of the heart muscle that can lead to severe complications.
Secondary objectives include:
- Evaluating the **safety** of colchicine in acute myocarditis over a 6-month period.
- Assessing the efficacy of colchicine on secondary endpoints, such as the rate of heart failure, recurrence of acute myocarditis, clinically relevant chest pain, sustained ventricular arrhythmias, need for left ventricular assistance, heart transplantation, and cardiovascular death at 1 year.
- Analyzing each component of the composite clinical endpoint at 6 months and 1 year.
- Measuring left ventricular ejection fraction (LVEF), end-diastolic and end-systolic volumes via CMR at 6 months.
- Determining the relative variation in LVEF, end-diastolic volume, and end-systolic volume between baseline and 6 months using transthoracic echocardiography (TTE).
- Evaluating the relative variation in late gadolinium enhancement (LGE) and edema between baseline and 6 months as determined centrally by the Corelab.
- Assessing cardiac magnetic resonance criteria, including native T1 and T2 mapping values and the percentage of extracellular volume at 6 months.
- Monitoring serum biomarkers such as Troponin, NT-pro BNP, CRP, and CK at admission, 24h, 48h, and 6 months.
- Investigating specific inflammatory markers, including IL-6, ST2, and IL-1β, at inclusion, 24h, 48h, and 6 months for participating centers of biocollection.
- Evaluating ventricular premature complex (VPC) burden at 3 months.
Participants
The clinical trial involves **patients suffering from acute myocarditis** confirmed on cardiac magnetic resonance imaging. The study population includes both male and female participants aged 18 to 64 years. Participants are required to have a confirmed diagnosis of myocarditis according to the Lake Louise criteria and must not have evidence of ischemic heart disease. The trial population was selected based on specific inclusion criteria, such as symptom onset within 21 days, elevated troponin levels, and the absence of ischemic heart disease in patients over 40 with cardiovascular risk factors. Participants must be affiliated with the French Health Care System and adhere to effective contraception methods during and after the treatment period. The sponsor has not provided information regarding the total number of participants. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, ensuring comprehensive representation within the study parameters.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **colchicine** compared to a placebo in patients with acute myocarditis, confirmed via cardiac magnetic resonance imaging (CMR). This study is structured as a randomized, double-blind, controlled trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias. The trial is expected to span a duration of approximately four years, with recruitment anticipated to commence in July 2024 and conclude by July 2028.
Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility criteria are assessed. Key inclusion criteria include age between 18 and 65 years, symptom onset within 21 days, and confirmation of myocarditis by CMR according to the Lake Louise criteria. Exclusion criteria are not specified in the provided data. Following the inclusion visit, participants will be randomized to receive either **colchicine** or a placebo, administered orally in tablet form. The maximum treatment period is six months, with a daily dose of 1 mg and a total dose not exceeding 180 mg.
Throughout the study, participants will attend follow-up visits to monitor the primary and secondary endpoints. The primary endpoints include the extent of late gadolinium enhancement on CMR and composite clinical outcomes at six months. Secondary endpoints encompass the rate of serious adverse events, efficacy of **colchicine** at one year, and various cardiac and clinical parameters. The end-of-study visit will occur at six months post-randomization, where final assessments will be conducted.
Participant involvement is expected to last for six months, with conditions for early termination including the occurrence of serious adverse events or non-compliance with the study protocol. The trial aims to provide valuable insights into the potential benefits of **colchicine** in reducing myocardial damage and improving clinical outcomes in patients with acute myocarditis.
Treatment
The clinical trial involves the administration of **Colchicine Opocalcium**, a pharmaceutical product formulated as a **tablet**. Each tablet contains 1 mg of the active substance **colchicine**, which is of chemical origin. The tablets are designed to be **scored**, allowing for potential dose adjustments if necessary. The route of administration is **oral**, with a maximum daily dose of 1 mg. The total maximum dose over the course of the treatment is 180 mg, with the treatment period extending up to 6 months. The product is manufactured by Laboratoires Mayoly Spindler and is authorized for use in France. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.
The study also includes a **placebo** group, where participants will receive a placebo designed to mimic the appearance of the colchicine tablet. The placebo is labeled as **Placebo de Colchicine 1 mg**. It does not contain any active substance and is used to provide a comparator for evaluating the efficacy of colchicine in the trial. The placebo administration follows the same oral route and dosing schedule as the active treatment to maintain blinding and ensure the integrity of the study results.
Efficacy
The efficacy of colchicine in the treatment of acute myocarditis will be assessed through a co-primary endpoint. This includes evaluating the extent of inflammatory myocardial damage using cardiac magnetic resonance (CMR) imaging and monitoring composite clinical outcomes at 6 months. The primary endpoints are defined as the extent of late gadolinium enhancement, expressed as a percentage of left ventricle mass, and the occurrence of clinical events such as heart failure, recurrence of acute myocarditis, clinically relevant chest pain, sustained ventricular arrhythmia, need for left ventricular assistance, heart transplantation, or cardiovascular death.
Secondary endpoints will include the rate of serious adverse events related to colchicine, permanent discontinuation rates, and the incidence of side effects such as diarrhea, nausea, vomiting, and **myelotoxicity** over a 6-month period. Additional secondary measures will assess renal function, the efficacy of colchicine between treatment groups, and various cardiac parameters such as Left Ventricular Ejection Fraction (LVEF), TeleDiastolic Volume (GEDV), and TeleSystolic Volume (TSV) using CMR and echocardiography. Serum biomarkers, including Troponin, NT-pro BNP, CRP, and CK, will be measured at admission, 24 and 48 hours post-admission, and at 6 months. For centers participating in the bio-collection, specific inflammatory markers such as IL-6, ST2, and IL-1β will be assessed at inclusion, 24 and 48 hours post-inclusion, and at 6 months.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18 years and < 65 years old,
- Symptom onset ≤ 28 days,
- Myocarditis initially presenting with chest pain and/or heart failure symptoms and/or palpitations
- Troponins > 99 percentile of reference value at any time between admission and inclusion,
- Myocarditis diagnostic confirmed by CMR according to the Lake Louise criteria (2009 or later),
- No evidence for ischemic heart disease as assessed by coronary angiography or coronary computed tomography angiography for patients with age > 40-year-old with one or more cardiovascular risk factor (hypertension, smoking, hypercholesterolemia, diabetes, personal or family history of coronary artery disease)
- Woman of child-bearing age with an effective contraception method according to the investigator for the duration of treatment and 1 month after
- Man accepting effective contraception for the duration of treatment and 1 month after
- Patients with affiliation to the French Health Care System “sécurité sociale”
- Written informed consent of the patient obtained.
Exclusion Criteria
- Cardiogenic shock requiring inotropes or vasopressors (patients with inotropes or vasopressors discontinued for >24h can be enrolled)
- Sarcoidosis
- Severe liver (Child Pugh C) or known renal dysfunction (known GFR < 30 ml/min according Cockroft),
- Cytopenia: hemoglobin less than 100 grams/L, white blood cell count less than 3.0 G/L, platelet count less than 100 G/L between admission and inclusion (within 7 days)
- Major digestive disorders (chronic diarrhea, inflammatory disease of the digestive tract as uncontrolled ulcerative colitis or active Crohn disease)
- Immunosuppression, spinal cord aplasia
- Hemopathy
- Hypereosinophilia > 0.5 G/L between admission and inclusion
- Pregnant or nursing women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive local laboratory test
- Administration of any investigational drug or participation in another interventional trial, within 30 days before randomization.
- Patient under treatment having an interaction with colchicine [macrolides (telithromycin, azithromycin, clarithromycin, dirithromycin, erythromycin, josamycin, midecamycin, roxithromycin), pristinamycin, cyclosporine, verapamil, all protease inhibitors, telaprevir, CYP3A4 powerful inhibitors, azole antifungals, vitamin K antagonists],
- Giant cell myocarditis or eosinophilic myocarditis
- Patients under legal protection: under guardianship (trusteeship or curatorship),
- Acute coronary syndrome or known coronary stenosis > 50%
- Toxic cardiomyopathy
- Active chronic inflammatory disease, chronic active infection, evolving cancer
- A recent severe sepsis (7 days)
- Hypersensitivity to IMP’s active substances (colchicine) or to any of the excipients (including lactose, sucrose, microcrystalline cellulose, colloidal silica, magnesium stearate colorants: E127, Dual Red 40)
- Any known contra-indication to CMR or associated contract products (claustrophobia, intra-ocular metal foreign bodies, clips such as cerebral, carotid, or aortic aneurysm, cochlear implants, any implant held in by magnet,history of hypersensitivity to gadoteric acid or to gadolinium contrast agents or to meglumine)
- Chronic treatment with corticosteroids or NSAIDs or high-dose aspirin or immunosuppressant.
- Patients with an implantable cardioverter-defibrillator (ICD) or pacemaker (PM) are also excluded due to the risk of imaging artifacts, which may compromise the reliable quantification of late gadolinium enhancement (LGE),
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 16 Jul 2024 | 300 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PLACEBO DE COLCHICINE 1 mg | Placebo | N/A | — | — | — | N/A |
COLCHICINE OPOCALCIUM 1 mg, comprimé sécable | Test | COMPRIMÉ SÉCABLE | ORAL USE | 1 | 6 | PRD2447366 |