Study to Evaluate the Efficacy of Immunosuppression in Myocarditis or Inflammatory Cardiomyopathy.

NCT04654988 | Recruiting Phase 4 DMC

• 2 other identifiers: PREDAZA/WUM/10-09-20202020-003877-23
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Myocarditis can result in numerous complications, but there is paucity of data regarding optimal therapy, short- and long-term effects of possibly effective immunosuppressive therapy. The IMPROVE-MC study will provide high-quality scientific data about efficacy and safety of immunosuppressive therapy, non-invasive (MRI, biomarkers) and invasive diagnostics tests (endomyocardial biopsy), and prognosis in myocarditis. The objective of this multicenter, prospective, randomized, double-blind placebo-controlled trial is to assess the efficacy and safety of 12 - month treatment with prednisone and azathioprine comparing to placebo on top of guideline-recommended medical therapy in patients with biopsy-proven virus negative myocarditis or inflammatory cardiomyopathy and reduced ejection fraction (LVEF ≤ 45%). The study will also assess persistence of the treatment effects after 12 months.

Conditions

Myocarditis; Heart Failure; Endomyocardial Biopsy; Cardiomyopathies, Secondary; Immunosuppression

Keywords

myocarditis, cardiomyopathy, immunosuppression, biopsy

Outcome Measures

Primary Outcomes (1)

• LVEF at 12 - months.

  Left ventricle ejection fraction (LVEF) at 12 - months.

  12- months

Secondary Outcomes (48)

• Proportion of patients who responded to immunosuppressive therapy.

  12-months

• LVEF at 12 months in subgroups of patients with baseline LVEF ≤30% and >30%

  12 months

• Change in the LV end-systolic and end-diastolic dimensions as well as the LV end-systolic and end-diastolic volumes over time.

  12-months

• Change from baseline in NYHA class over time.

  12-months

• Occurrence of adjudicated heart failure decompensation (hospitalization or ambulatory visit).

  12-months

Study Arms (2)

Immunosuppression

EXPERIMENTAL

Prednisone: 1 mg/kg daily for 4 weeks followed by gradually tapered dose for 5 months and Azathioprine: 2 mg/kg daily for 12 months

Drug: Prednisone; Drug: Azathioprine

Placebo

PLACEBO COMPARATOR

placebo matching prednisone: 1 mg/kg daily for 4 weeks followed by gradually tapered dose for 5 months and placebo matching azathioprine: 2 mg/kg daily for 12 months

Drug: Placebo Prednisone; Drug: Placebo Azathioprine

Interventions

Prednisone DRUG

Prednisone: 1 mg/kg daily for 4 weeks followed by gradually tapered dose for 5 months

Immunosuppression

Azathioprine DRUG

Azathioprine: 2 mg/kg daily for 12 months

Immunosuppression

Placebo Prednisone DRUG

Placebo Prednisone

Placebo

Placebo Azathioprine DRUG

Placebo Azathioprine

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent to participate in the IMPROVE-MC study (including two EMBs and two cardiac CMRs) prior to any evaluation or procedure related to the study.
• Patient with clinically suspected myocarditis or inflammatory cardiomyopathy (according to the criteria of the ESC Working Group on Myocardial \& Pericardial Diseases 2013 and ESC Heart Failure Guidelines 2021); OR/ AND, Patients with already diagnosed active myocarditis (lymphocytic or eosinophilic) or inflammatory cardiomyopathy who will undergo diagnostic right ventricular (or/and left ventricular) EMB during the screening; OR / AND, Patients with already diagnosed active myocarditis (lymphocytic or eosinophilic) or inflammatory cardiomyopathy confirmed by right ventricular (or/and left ventricular) EMB that was performed according to the IMPROVE-MC study protocol within 3 months from screening.
• Men or women aged 18-65. Women of childbearing age must have a negative pregnancy test result. Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception (with a failure rate of \< 1% per year) for the duration of the study (from the time they sign consent) and for 8 weeks after the last dose of study treatment to prevent pregnancy. Patients agreeing to total sexual abstinence can also be included, assuming it is their usual lifestyle. Women are considered postmenopausal and without the potential to have a child if they have 12 months of natural (spontaneous) amenorrhea with an appropriate clinical picture (e.g. appropriate age, history of vasomotor symptoms) or have undergone bilateral surgical ovariectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of ovariectomy alone, only if the reproductive status of the woman has been confirmed by assessing hormone levels.
• No significant improvement in clinical condition or worsening course of the disease despite the standard treatment in the investigator's opinion, in the last ≥ 3 months prior to the screening period.
• LVEF 10 - 45% measured by echocardiogram taken during the screening period
• No significant LVEF improvement in the last ≥3 months prior to the screening period in the investigator's opinion.
• LVEF should be measured under stable conditions as assessed by the investigator.
• LVEF should be verified in the CORE-LAB.
• Histological and immunohistochemical evidence of active myocarditis (lymphocytic or eosinophilic) OR inflammatory cardiomyopathy during the screening period (EMB during the screening or within last 3 months).
• Absence of cardiotropic viruses in cardiac tissue at PCR analysis during the screening period (EMB during the screening or within last 3 months).

You may not qualify if:

• Presence of contraindications to immunosuppressive therapy with steroids and/ or azathioprine (including hypersensitivity to azathioprine/ 6-mercaptopurine or prednisone, mainly untreated systemic infection, uncontrolled diabetes, poorly controlled endocrine diseases, osteoporosis, active gastric or duodenal ulcer, uncontrolled hypertension, leukocytopenia (leukocyte counts \<4 x 109/l), neutropenia (neutrophils \<1.5 x 109/l), thrombocytopenia (platelet levels \<130 x 109/l), anemia (hemoglobin levels \<11 g/dl).
• Positive clinical screening for active infections, including HIV, HBV, HCV. Assessment of tuberculosis infection should be considered before screening, according to the local epidemiologic status and according to investigator's opinion. After careful evaluation of the activity of the infection (or cure of the infection), the patient may continue participation in the study according to investigator's opinion.
• Another specific cause of heart failure (including severe congenital, valvular, hypertensive, and/or coronary artery disease) that could justify the severity of cardiac dysfunction.
• Cardiomyopathy based on infiltrative diseases (e.g. amyloidosis), storage diseases (e.g. haemochromatosis, Fabry disease), muscular dystrophies, genetic hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy or known pericardial constriction.
• NYHA class I and IV.
• Subjects with body mass index \>40 kg/m2 or body weight \<50 kg.
• Pregnancy, lactation or women who plan to become pregnant during the trial. Lack of consent to the use of effective forms of contraception.
• Any documented or suspected active malignant neoplasm or history of malignant neoplasm within the 5 years prior to the screening period.
• History of cytostatic therapy or radiotherapy.
• Liver disease defined as any of the following: AST or ALT or ALP above 3x ULN; bilirubin \>1.5 mg/dL.
• Impaired renal function, defined as eGFR \<45 mL / min / 1.73 m2 (CKD-EPI) measured under stable condition or requiring dialysis. Conditionally, according to the investigator's decision, patients with eGFR 40-45 ml / min / 1.73 m2 may be included.
• The need or refusal to stop taking any drug considered to interfere with the safe course of the study (e.g., allopurinol).
• Currently implanted or planned VAD, CRT or heart transplant.
• Patients with pacemaker or ICD requiring a high percentage of ventricular pacing (\>30%) which could influence the result of LVEF measurement in the investigator's opinion.
• Gastrointestinal surgery or gastrointestinal disorder that could interfere with trial drug(s) absorption in the investigator's opinion.

Sponsors & Collaborators

• Medical University of Warsaw: lead

Study Sites (1)

First Department of Cardiology, Medical University of Warsaw

Warsaw, 02-097, Poland

RECRUITING

MeSH Terms

Conditions

Myocarditis; Heart Failure; Cardiomyopathies

Interventions

Prednisone; Azathioprine

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Thionucleosides; Sulfur Compounds; Organic Chemicals; Mercaptopurine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Marcin Grabowski, Professor

  Medical University of Warsaw

  STUDY CHAIR

• Krzysztof Ozierański, MD, PhD

  Medical University of Warsaw

  PRINCIPAL INVESTIGATOR

• Agata Tymińska, MD, PhD

  Medical University of Warsaw

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Krzysztof Ozierański, MD, PhD

CONTACT

22 5991958; krzysztof.ozieranski@wum.edu.pl

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 3, 2020
• First Posted: December 4, 2020
• Study Start: December 1, 2022
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): March 30, 2028
• Last Updated: March 28, 2024

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: after the study completion
• Access Criteria: On demand

Locations

PL (1)