Single-blinded randomized investigator-initiated controlled trial to assess the efficacy of colchicine to treat patients with cardiomyopathy with myocarditis (chronic inflammatory cardiomyopathy) – Trial and Registry to study the role of genotype environment interaction in Chronic myocarditis and inflammatory cardiomyopathies with ventricular pro-arrhythmic and heart failure phenotypes (PNRR-MAD-2022-12376225)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

ASST Grande Ospedale Metropolitano Niguarda

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Decision date (initial)

2024-10-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Italian Ministry of Health, NextGenerationEU (PNRR-MAD-2022- 12376225)

External identifiers

EU CT number

2024-517945-14-00

EudraCT number

2022-003912-99

ClinicalTrials.gov

NCT06158698

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

The primary objective is to assess the efficacy of colchicine compared to placebo after 6 months of treatment. It is expected that among patients on optimal medical therapy (OMT) plus colchicine a larger proportion of patients will reach the primary endpoint with respect to the placebo arm.

Secondary objectives 1

1. The primary objective of the REGISTRY at the end of a minimum follow-up of 6 months is to assess whether MCGV status (+ or -) can independently affect the outcome (as defined below) of patients with Infl-CMP. The co-primary aim of the REGISTRY is the identification of baseline variables that are independently associated with the outcome

Conditions and MedDRA coding

Inflammatory cardiomyopathy

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 3

1. Patients of 18 years or older
2. Evidence of myocardial inflammation on CMRI (using 2018 Lake Louis criteria) or FDG-PET performed in the 3 months before randomization to be included in the trial OR in the last 12 months before for the registry
3. Presence of any of the following characteristics and if symptoms are present lasting for more than 1 month: a. Mono-morphic or polymorphic PVC burden of ≥500 in 24 hours, or NSVTs (defined as ≥3 consecutive beats at a rate >100 beats per minute lasting <30 seconds) or evidence of sustained ventricular tachycardias (SVT) b. Reduced LVEF on echocardiogram (<50%) or on CMRI (<60%) c. Increased N-terminal pro-B-type natriuretic peptide (NT- proBNP) concentration of 1000 pg/mL or more, or a B-type natriuretic peptide (BNP) concentration of 200 pg/mL or more d. Persistence of increased high-sensitivity troponin levels above the upper reference limit (URL) after at least 2 months from the first assessment and at least a mono-morphic or polymorphic PVC burden of ≥1000 in 24 hours

Exclusion criteria 18

1. Proven history of myocardial infarction with evidence of ischemic scar on echocardiogram or CMRI
2. Significant flow-limiting coronary artery disease (stenosis above 50%) on invasive coronary angiography or computed tomography (CT) coronary angiography
3. Cardiomyopathy attributed to toxins such as alcohol and illicit drugs, or to specific causes (i.e. amyloidosis or hypertrophic cardiomyopathy)
4. Known systemic autoimmune disorder (the exception will be for patients with systemic autoimmune disease or isolated cardiac sarcoidosis with a family history of cardiomyopathy, myocarditis, or arrhythmias, where overlap between an autoimmune event and a genetic background can occur). These patients will undergo genetic tests. Patients with autoimmune systemic disorders and isolated cardiac sarcoidosis with positive genetic tests for MCVG will be included in the registry.
5. Previous history of cardiac surgery for instance correction of congenital heart disease or a valve repair/replacement
6. Known chronic infective disease, such as HIV infection or tuberculosis
7. Participants involved in another clinical trial
8. Any other significant disease or disorder which (expected life expectancy <12 months), in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial or the participant's ability to participate in the trial
9. Women with childbearing potential
10. Current symptomatic atrial arrhythmias (including persistent atrial fibrillation) associated with LV dysfunction
11. Advance heart failure (NYHA III or need for inotropes including levosimendan), or recurrent VA despite previous catheter ablation
12. Known systemic autoimmune disorder or other conditions at the time of randomization where immunosuppression is assumed useful (i.e. cardiac sarcoidosis)
13. Patients already on chronic immunosuppressive therapies (including colchicine) or in whom immunosuppressive therapy is deemed necessary
14. Contraindication to colchicine, including allergies to this medication and its excipients (i.e., lactose and sucrose)
15. Impaired renal function (eGFR<30 ml/min/1.73m2)
16. Known history of hepatic cirrhosis or transaminase levels at baseline > x3-fold the URL
17. Patients with peripheral eosinophilia (eosinophil count >10% of the leukocytes) or known hypereosinophilic syndrome at the time of randomization.
18. Severe gastrointestinal insufficiency (for instance, malabsorption syndrome, severe chronic diarrhea)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. Proportion of patients that are alive and free of any worsening (clinical, arrhythmic burden and imaging outcome) and that shows at least one of the signs of improvements (IMAGING or ARRHYTMIC improvements) at 6 months from randomization
2. Clinical worsening is defined as the occurrence of at least one of the following events: 1. cardiac death, 2. hospitalization for worsening HF or arrhythmic events, and 3. Occurrence of sustained ventricular tachycardia (SVT)
3. Worsening arrhythmic burden is defined as the occurrence of at least one of the following events: 1. a PVC burden increase of 50% on ECG ambulatory monitoring OR 2. an increase in the number of non-sustained ventricular tachycardia (NSVT) of 30% compared with baseline OR 3. Any SVT recorded in the follow-up.
4. Worsening imaging outcomes is defined as the occurrence of at least one of the following events: 1. a reduction in LVEF >10% on a 6-month follow-up echocardiogram or CMRI, 2. the appearance of new areas of edema on CMRI or FDG-PET associated with an increase in the edema in the inflammatory lesion identified on baseline CMRI or FDGPET.
5. IMPROVEMENT OF IMAGING OUTCOME is defined as the occurrence of at least one of the following events: 1. Reduction of edema on CMRI or FDG uptake without the appearance of new areas of edema on CMRI/FDG-PET and high sensitivity troponin in the normal range 2. The disappearance of edema on CMRI or NO FDG uptake on PET (if present on the baseline)
6. IMPROVEMENT OF ARRHYTHMIC OUTCOME is defined as the occurrence of PVC burden reduction of 70% on the ECG ambulatory monitoring without evidence of NSVT or SVT at 6 months compared with the baseline ambulatory monitoring

Secondary endpoints 9

1. Absolute change at 6 months from randomization of the left ventricular (LV) ejection fraction (EF) on echocardiogram. Patients not performing the CMRI due to death, heart transplantation (HTx) will be counted as -10 point in the LVEF
2. Absolute change at 6 months from randomization of the LVEF on CMRI when available. Patients not performing the CMRI due to death, heart transplantation (HTx), LV assist device (LVAD) implantation or device implantation after randomization (i.e. pacemaker [PM] or implantable cardioverter defibrillator [ICD]) will be counted as -10 point in the LVEF
3. Proportion of patients with LVEF<55% AND/OR LV dilation on 6-month CMRI (CMRI clips will be centrally reviewed) or not performing the CMRI due to death, HTx, LVAD implantation or device implantation after randomization (i.e. PM or ICD)
4. Composite endpoint defined as the time from randomization to the first event occurring within 6 months: all-cause death or HTx or long-term LVAD implantation, or first rehospitalization due to HF or VA, or advanced atrioventricular (AV) block
5. Mortality: time from randomization to all-cause death within 6 months
6. Time from randomization to hospitalization for HF/VA or advanced AV block within 6 months
7. Composite endpoint of presence of NSVT OR increased burden of PVCs (>5% ) on 24-hour ECG ambulatory monitoring, performed at 6- months
8. Changes in quality of life and health assessment at 6 months follow up compared with baseline using 2 different questionnaires: the EuroQoL 5-dimension, 5-level questionnaire (EoQ-5D) and Kansas City Cardiomyopathy Questionnaire (KCCQ – clinical summary scale and overall summary scale)
9. Need to initiate an immunosuppressive drug (i.e. corticosteroids)

Investigational products

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

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

ASST Grande Ospedale Metropolitano Niguarda

Sponsor organisation

ASST Grande Ospedale Metropolitano Niguarda

Address

Piazza Dell'ospedale Maggiore 3

City

Milan

Postcode

20162

Country

Italy

Scientific contact point

Organisation

ASST Grande Ospedale Metropolitano Niguarda

Contact name

Enrico Ammirati

Public contact point

Organisation

ASST Grande Ospedale Metropolitano Niguarda

Contact name

Enrico Ammirati

Locations

1 EU/EEA country · 12 investigational sites

By country

Investigational sites

Results and documents

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

Documents 43 files

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

Application history

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