ARGO Colchicine versus Placebo in Acute Myocarditis Patients to Reduce Late Gadolinium Enhancement Mass on Cardiac Magnetic Resonance and the risk of Clinical Outcomes: The ARGO trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

4 Oct 2024 → ongoing

Decision date (initial)

2024-10-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

DGOS

External identifiers

EU CT number

2024-514610-13-00

EudraCT number

2022-002563-29

ClinicalTrials.gov

NCT05855746

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

The main objective of this study will be to assess the efficacy of colchicine versus placebo on a co-primary endpoint including inflammatory myocardial damage on CMR or composite clinical outcomes at 6 months.

Secondary objectives 10

1. 1. To evaluate the safety of colchicine in acute myocarditis during 6 months
2. 2. To evaluate the efficacy of colchicine on secondary efficacy endpoints, including a/ Composite clinical outcome assessed on the rate of heart failure or acute myocarditis recurrence; or clinically relevant chest pain (defined as leading to an unplanned/urgent consultation or hospitalization or requiring an additional treatment); or sustained ventricular arrhythmias; or left ventricular assistance; or heart transplantation; or cardiovascular death at 1 year
3. b/ Each component of the composite clinical endpoint at 6 months and 1 year(Rate of heart failure or acute myocarditis recurrence Rate of clinically relevant chest pain (defined as leading to an unplanned/urgent consultation or hospitalization or requiring an additional treatment) Rate of sustained ventricular arrhythmias Rate of left ventricular assistance Rate of heart transplantation Rate of cardiovascular death
4. c/ LVEF, LV end-diastolic and end-systolic volumes, by CMR at 6 months determined centrally by the Corelab
5. d/ The relative variation in LVEF determined by a follow-up transthoracic echocardiography at 6 months,
6. e/ Relative variation in LGE and edema between baseline and 6 months determined by centrally by the Corelab
7. f/ Cardiac magnetic resonance criteria: value of native T1 and T2 mapping (ms), % of extracellular volume at 6 months.
8. g/ Serum biomarkers during the hospitalization period (eg: admission, 24h, 48h (after admission), inclusion or discharge) and at 6 months: Troponin (I or T according to investigator), NT-pro BNP, CRP, CK
9. h/ Specific Inflammatory markers for participating centers of biocollection: IL-6, ST2 and IL-1β at inclusion; 24h and 48h post-inclusion if possible; and at 6 months (after randomization)
10. i/ Ventricular premature complex (VPC) burden at 3 months

Conditions and MedDRA coding

patients suffering from acute myocarditis confirmed on Cardiac magnetic resonance imaging.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. - Age ≥ 18 years and < 65 years old,
2. - Symptom onset ≤ 28 days,
3. - Myocarditis initially presenting with chest pain and/or heart failure symptoms and/or palpitations
4. - Troponins > 99 percentile of reference value at any time between admission and inclusion,
5. - Myocarditis diagnostic confirmed by CMR according to the Lake Louise criteria (2009 or later),
6. - 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)
7. - Woman of child-bearing age with an effective contraception method according to the investigator for the duration of treatment and 1 month after
8. - Man accepting effective contraception for the duration of treatment and 1 month after
9. - Patients with affiliation to the French Health Care System “sécurité sociale”
10. - Written informed consent of the patient obtained.

Exclusion criteria 21

1. - Cardiogenic shock requiring inotropes or vasopressors (patients with inotropes or vasopressors discontinued for >24h can be enrolled)
2. - Sarcoidosis
3. - Severe liver (Child Pugh C) or known renal dysfunction (known GFR < 30 ml/min according Cockroft),
4. - 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)
5. - Major digestive disorders (chronic diarrhea, inflammatory disease of the digestive tract as uncontrolled ulcerative colitis or active Crohn disease)
6. - Immunosuppression, spinal cord aplasia
7. - Hemopathy
8. - Hypereosinophilia > 0.5 G/L between admission and inclusion
9. - 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
10. - Administration of any investigational drug or participation in another interventional trial, within 30 days before randomization.
11. - 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],
12. - Giant cell myocarditis or eosinophilic myocarditis
13. - Patients under legal protection: under guardianship (trusteeship or curatorship),
14. - Acute coronary syndrome or known coronary stenosis > 50%
15. - Toxic cardiomyopathy
16. - Active chronic inflammatory disease, chronic active infection, evolving cancer
17. - A recent severe sepsis (7 days)
18. - 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)
19. - 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)
20. - Chronic treatment with corticosteroids or NSAIDs or high-dose aspirin or immunosuppressant.
21. 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),

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. - Extent of late gadolinium enhancement (% of left ventricle mass) evaluated on CMR at 6 months. OR - Composite clinical outcome at 6 months, defined as the occurrence of heart Failure or acute myocarditis recurrence; or a clinically relevant chest pain (defined as leading to an unplanned/urgent consultation or hospitalization or requiring an additional treatment); or a sustained ventricular arrhythmia; left ventricular assistance; or heart transplantation; or cardiovascular death during the s

Secondary endpoints 15

1. Rate of Serious Adverse Events related to colchicine at 6 months, rate of permanent discontinuation on 6 months, rate of diarrhea, rate of nausea and/or vomiting and rate of myelotoxicity on 6 months, renal function during hospitalization and at 6 months.
2. Efficacy of colchicine between the two groups : a- Composite clinical outcome at 1 year b- Each component of the composite clinical endpoint at 6 months and 1 year
3. Rate of heart failure or recurrence of acute myocarditis
4. Rates of clinically relevant chest pain (defined as requiring unscheduled/urgent consultation or hospitalisation or additional treatment)
5. Rate of sustained ventricular arrhythmias
6. Rate of left ventricular assistance
7. Rate of heart transplantation
8. Cardiovascular mortality rate
9. LVEF (Left Ventricular Ejection Fraction), GEDV (TeleDiastolic Volume) and TSV (TeleSystolic Volume) volumes determined on a 6-month cardiac MRI using Corelab centralised reading.
10. Relative change in LVEF, LVOT and STV volumes, determined by follow-up transthoracic echocardiography at 6 months,
11. The relative change in late gadolinium enhancement and oedema determined on a 6-month follow-up cardiac MRI scan using Corelab centralised reading.
12. Cardiac magnetic resonance criteria at 6 months: value of native T1 and T2 mapping (ms), percentage of extracellular volume.
13. g/ Serum biomarkers during the hospitalization period (eg: admission, 24h, 48h (after admission), inclusion or discharge) and at 6 months: Troponin (I or T according to investigator), NT-pro BNP, CRP, CK
14. For centres participating in the bio-collection: specific inflammatory markers IL-6, ST2 and IL-1β at inclusion; 24 and 48 hours after inclusion if possible; and at 6 months (after randomisation
15. Burden of VSE (Ventricular ExtraSystoles) measured at 3 months on Holter ECG

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Ivestigatror

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Ivestigatror

Locations

1 EU/EEA country · 29 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications