Colchicine Versus Placebo in Acute Myocarditis Patients

Acute Myocarditis Clinical Trial

— ARGO  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05855746
• Other study ID #: APHP211429
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: June 22, 2024
• Est. completion date: June 22, 2028

Study information

• Verified date: May 2024
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Thomas BOCHATON
• Phone: +33472357549
• Email: thomas.bochaton[@]chu-lyon.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Myocarditis is an inflammatory disease of the heart, mostly caused by viruses. Patients with acute myocarditis are exposed to several complications: recurrence, ventricular arrhythmias (from 5 to 30%), heart failure (5-10%), death or heart transplantation (< 4%). To date, there is no specific treatment for myocarditis. Patient management only focuses upon empirical optimal care of arrhythmia and heart failure.

There is a strong rationale for using colchicine in acute myocarditis:

• the IL1 (Interleukin1) pathway plays a detrimental role in acute myocarditis. NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome assembly, and subsequent IL-1beta production, are profoundly inhibited by colchicine.

• colchicine has been shown to improve cardiac outcomes in inflammatory cardiac disorders, including pericarditis, coronary artery disease, and post pericardiotomy syndrome.

• In murine model of CVB3-induced myocarditis (coxsackievirus B3), colchicine improved myocarditis through reduction of NLRP3 activity.

• Small case series with improvement of left ejection fraction in myocarditis following low-dose colchicine in addition to conventional heart failure therapy have been reported.

With its pleiotropic anti-inflammatory effect in the pro-inflammatory cascade, reducing the myocardial damage and cell death induced during myocarditis, colchicine has the potential to reduce the risk of heart failure and ventricular arrhythmias. Finally, colchicine is a drug widely available, at low cost, and has a long and well-known safety record.

Description:

This study is a prospective, randomized, multicenter, double blind, controlled versus placebo, phase III study in which two groups of participants are compared: a group treated with the experimental treatment Colchicine (in addition to standard of care therapy) compared to a control group that receive the corresponding placebo (in addition to standard of care therapy).

The inclusion visit takes place during the hospitalization stay. The study is presented to all patients presenting with acute myocarditis symptoms and inclusion criteria, hospitalized in participating centers.

Once eligible participants have been informed and signed their informed consent, they are randomized (1:1) by a centralized web system (IWRS) in the experimental group (Colchicine) or the control group (Placebo).

Participants receive then a numbered box with three months' treatment of Colchicine or placebo. The treatment must start at least within 72h after randomization. Another dispensing is performed during the three months' follow-up visit.

All randomized participants are followed during six months after the end of the treatment.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 300
• Est. completion date: June 22, 2028
• Est. primary completion date: December 22, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Symptom onset of 21 days or less,

• Chest pain and/or Heart failure symptoms and/or palpitations

• Troponins superior to 99 percentile of reference value,

• Myocarditis diagnostic confirmation (by Contrast-Enhanced Cardiac Magnetic Resonance (CMR), according to the Lake Louise criteria with the presence of myocardial damage),

• No evidence for ischemic heart disease on coronary angiography or coronary computed tomography angiography for patients with age superior to 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 one month after,

• Man accepting effective contraception for the duration of treatment and one month after,

• Participant 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 discontinued for more than 24 hours can be enrolled)

• Giant cell myocarditis or eosinophilic myocarditis

• Acute coronary syndrome or known coronary stenosis superior to 50%

• Toxic cardiomyopathy

• Active chronic inflammatory disease, chronic active infection, evolving cancer

• A recent severe sepsis (7 days) or all recent acute illness

• Hypersensitivity to Investgational Medical Product's active substances (colchicine) or to any of the excipients (including lactose, sucrose, microcrystalline cellulose, colloidal silica, magnesium stearate, colourants : E127, Dual Red 40 )

• Any known contra-indication to CMR or associated contract products (claustrophobia, pace maker, defibrillator, history of hypersensitivity to gadoteric acid or to gadolinium contrast agents or to meglumine),

• Chronic treatment with corticosteroids or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) or immunosuppressant.

• Sarcoidosis

• Severe liver (Child Pugh C) or known renal dysfunction (known Glomerular Filtration Rate (GFR) less or equal to 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

• 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 more than 0.5 G/L

• 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,

• Participant 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,

• Participant under legal protection: under guardianship (trusteeship or curatorship)

Related Conditions & MeSH terms

• Acute Myocarditis
• Myocarditis

Intervention

Drug:
• Colchicine Pill
Participant receive, in addition to standard of care therapy, six months of colchicine (at a dose of 0.5 mg twice daily, morning and evening) beginning maximum 72 hours post-randomization. The standard of care is defined according to the European consensus paper as follow: All participants without contraindication receive a betablockers, and heart failure ESC (European Society of Cardiology) guidelines directed medical therapies if LVEF < 50% (Left Ventricular Ejection Fraction), including ACE (Angiotensin-Converting Enzyme) inhibitors, diuretics if indicated. The choice of the dosage and the drug is left at the investigator decision. During the six months of the treatment administration, in case of severe adverse reaction (such as nausea and/or diarrhea during five days), a dose reduction could be considered by the investigator: half of the study protocol dose could be accepted (0.5 mg per day in the morning). In case of remaining adverse reactions, the study drug should be stopped.
• Placebo
Participant receive, in addition to standard of care therapy, six months of placebo (at a dose of 0.5 mg twice daily, morning and evening) beginning maximum 72 hours post-randomization. The standard of care is defined according to the European consensus paper as follow: All participants without contraindication receive a betablockers, and heart failure ESC (European Society of Cardiology) guidelines directed medical therapies if LVEF < 50% (Left Ventricular Ejection Fraction), including ACE (Angiotensin-Converting Enzyme) inhibitors, diuretics if indicated. The choice of the dosage and the drug is left at the investigator decision.

Locations

Country	Name	City	State
France	Unité de Soins Intensifs Cardiologiques - Hôpital Cardiovasculaire Louis Pradel	Bron
France	Institut de Cardiologie - APHP Pitié Salpêtrière	Paris

Sponsors (3)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	Fonds de Dotation ACTION, Hospices Civils de Lyon

Country where clinical trial is conducted

France, 

References & Publications (5)

Ammirati E, Cipriani M, Moro C, Raineri C, Pini D, Sormani P, Mantovani R, Varrenti M, Pedrotti P, Conca C, Mafrici A, Grosu A, Briguglia D, Guglielmetto S, Perego GB, Colombo S, Caico SI, Giannattasio C, Maestroni A, Carubelli V, Metra M, Lombardi C, Campodonico J, Agostoni P, Peretto G, Scelsi L, Turco A, Di Tano G, Campana C, Belloni A, Morandi F, Mortara A, Ciro A, Senni M, Gavazzi A, Frigerio M, Oliva F, Camici PG; Registro Lombardo delle Miocarditi. Clinical Presentation and Outcome in a Contemporary Cohort of Patients With Acute Myocarditis: Multicenter Lombardy Registry. Circulation. 2018 Sep 11;138(11):1088-1099. doi: 10.1161/CIRCULATIONAHA.118.035319. — View Citation

Imazio M, Brucato A, Cemin R, Ferrua S, Maggiolini S, Beqaraj F, Demarie D, Forno D, Ferro S, Maestroni S, Belli R, Trinchero R, Spodick DH, Adler Y; ICAP Investigators. A randomized trial of colchicine for acute pericarditis. N Engl J Med. 2013 Oct 17;369(16):1522-8. doi: 10.1056/NEJMoa1208536. Epub 2013 Aug 31. — View Citation

Kyto V, Sipila J, Rautava P. Rate and patient features associated with recurrence of acute myocarditis. Eur J Intern Med. 2014 Dec;25(10):946-50. doi: 10.1016/j.ejim.2014.11.001. Epub 2014 Nov 7. — View Citation

Peretto G, Sala S, Rizzo S, Palmisano A, Esposito A, De Cobelli F, Campochiaro C, De Luca G, Foppoli L, Dagna L, Thiene G, Basso C, Della Bella P. Ventricular Arrhythmias in Myocarditis: Characterization and Relationships With Myocardial Inflammation. J Am Coll Cardiol. 2020 Mar 10;75(9):1046-1057. doi: 10.1016/j.jacc.2020.01.036. — View Citation

Tschope C, Cooper LT, Torre-Amione G, Van Linthout S. Management of Myocarditis-Related Cardiomyopathy in Adults. Circ Res. 2019 May 24;124(11):1568-1583. doi: 10.1161/CIRCRESAHA.118.313578. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Extent of Late Gadolinium Enhancement (LGE) evaluated on Cardiac Magnetic Resonance (CMR)	Extent of LGE (pourcentage of left ventricle mass) is evaluated (centralized reading by the Corelab) on CMR performed at six months and compared to baseline CMR (performed at the hospital admision or inclusion).; The inclusion visit takes place during the initial hospitalization.	Six months post-inclusion
Primary	Composite Clinical primary outcome	Composite Clinical primary outcome is assessed during the study period at six months on: the rate of rehospitalization for heart Failure or acute myocarditis recurrence; or the rate of clinically relevant recurrent chest pain (defined as leading to an unplanned/urgent consultation or hospitalization); or the rate of sustained ventricular arrhythmias; or the rate of left ventricular assistance; or the rate of heart transplantation; or the rate of cardiovascular death	Six months post-inclusion
Secondary	Safety of colchicine	Safety of colchicine is defined as : Rate of Serious Adverse Events related to colchicine; Rate of permanent treatment discontinuation; Rate of diarrhea; Rate of nausea and/or vomiting; Rate of myelotoxicity (evaluated on Complete Blood Count); Renal function evaluated by creatinine level and creatinine clearance (MDRD)	Six months post-inclusion
Secondary	Composite clinical secondary outcome	Composite Clinical secondary outcome is assessed during the study period at one year on: Rate of rehospitalization for heart failure or acute myocarditis recurrence; Rate of clinically relevant recurrent chest pain (defined as leading to an unplanned/urgent consultation or hospitalization); Rate of sustained ventricular arrhythmias; Rate of left ventricular assistance or heart transplantation; Rate of cardiovascular death	one year post-inclusion
Secondary	Left ventricular volume on Cardiac Magnetic Resonance (CMR)	Left Ventricular Ejection Fraction (LVEF), left ventricular end-diastolic and left ventricular end-systolic volumes are evaluated (centralized reading by the Corelab) on CMR performed at six months and compared to baseline CMR (performed at the hospital admision or inclusion).	Six months post-inclusion
Secondary	Left ventricular volume on transthoracic echocardiography (TTE)	Relative variation in Left ventricular ejection fraction (LVEF), end-diastolic volume and end-systolic volume between baseline and 6-months as determined by TTE.	6 months post-inclusion
Secondary	Relative variation in Extent of late gadolinium enhancement (LGE) and edema	Relative variation in LGE and edema between baseline and six months determined centrally by the Corelab on the CMR	Six months post-inclusion
Secondary	Tissue properties evaluated on Cardiac Magnetic Resonance (CMR)	Cardiac magnetic resonance criteria: value of native T1 and T2 mapping (ms), pourcentage of extracellular volume	Six months post-inclusion
Secondary	Serum biomarkers	Serum biomarkers at hospital admission, 24h and 48h (after admission) and at six months: Troponin (I or T according to investigator), N-terminal pro-brain natriuretic peptide (NT-pro BNP), C-Reactiv Protein (CRP) and Creatin Kinase (CK)	Six months post-inclusion
Secondary	Specific Inflammatory markers	A biocollection, only for participating centers, is performed for specific Inflammatory markers : interleukin 6 (IL-6), interleukin 1 beta (IL-1bß) and ST2 (or soluble interleukin 1 receptor-like 1). Patients undergo two blood samples of 4 mL at inclusion ; 24 hours and 48 hours after the inclusion visit, if the patient is still in hospital.	Inclusion visit and 24 hours and 48 hours post-inclusion visit
Secondary	Ventricular premature complex (VPC) evaluated on Holter ElectroCardiogramm (ECG)	VPC burden on Holter ECG performed during the hopsital consultation at three months	three months post-inclusion