Virginia Commonwealth University

This is a phase 2/3 seamless design study with one interim efficacy analysis. At stage 1 (assuming possible 10% dropout rate in run-in period and screening), around 25 patients will be enrolled. At least 20 patients will be randomized to receive either RPH-104 treatment or placebo.

During the interim analysis, the enrollment won’t be paused. Based on interim analysis results the study could be continued or closed. In the case of study continuation, the final estimated sample size is at least 72 patients to be randomized in the withdrawal period (including 20 or more patients randomized in the Stage 1 of the study). Assuming possible 10% dropout in run-in period and 45% dropout in screening period, approximately enrollment of 80 subjects are planned and around 146 subjects will be screened in this study.

The study will consists of five following periods:

1. Screening period (up to 4 weeks). The patients’ eligibility for the study will be evaluated based on the eligibility criteria.
2. Run-in (RI) single-blind treatment period (16 weeks) will include single- blind treatment with RPH-104 at a dose 160 mg subcutaneous (SC) on Day 0, and 80 mg on Day 7, Day 14 and thereafter once in two weeks (Q2W) for all patients.

   The RI period includes:

   • 2-weeks Stabilization period, during which blinded RPH-104 is administered on top of standard of care (SOC) pericarditis therapy, and the ongoing pericarditis episode is treated.
   • 10- week Weaning period, during which patients are gradually tapered and stopped background SOC pericarditis therapy, while treatment with blinded RPH-104 continues. corticosteroids (CS) and analgesics (opioid and non-opioid) dose will be tapered starting at RI week 2 and will be stopped by Week 12. NSAIDs and colchicine will be tapered starting at RI Week 6 and will be stopped by Week 12. Opioid analgesics can be continued after Week 12 at stable doses through the end of the OL period if cannot be discontinued without withdrawal symptoms.
   • 4-week Monotherapy period: patients who stopped of background SOC pericarditis therapy will continue to receive blinded RPH-104.

   Patients who discontinue SOC therapy and achieve clinical response at Week 16 are eligible for randomization in the randomized withdrawal (RW) period.

3. Randomized withdrawal (RW) period (24 weeks) includes double-blind treatment with RPH-104 80 mg or placebo Q2W depending on the randomization group.
4. Open-label treatment period (OL) (12 weeks). After completion of the RW period, all subjects that did not discontinue study drug will be transferred to Open-Label (OL) period and will receive open-label RPH-104 80 mg once in two weeks.
5. Safety follow-up period includes monitoring of safety for 8 weeks after the last dosing of the study drug for patients who decided not to participate in open label extension long-term safety study (CL04018108).

The total maximal duration of the study for an individual subject will be approximately 64 weeks.

Acute myocarditis (AM) is a common condition characterized by histological evidence of inflammatory infiltrates associated with myocyte necrosis of non-ischemic origin. Clinical presentation spans from indolent form to cardiogenic shock also called fulminant myocarditis (FM). Patients can be stratified on the basis of their clinical presentation: patients with left ventricular (LV) ejection fraction (EF)<50% at first echocardiogram, and those with sustained ventricular arrhythmias, called complicated AM, have a worse prognosis compared with uncomplicated cases with preserved left ventricular ejection fraction (LVEF) and without arrhythmias. Among complicated AM, FM patients are those ones at the highest risk, presenting with severely impaired LVEF (generally <40%), and with need for inotropes and/or temporary mechanical circulatory supports (t-MCS).The pathogenesis of AM is felt to be due to an immune-mediated response against the myocardium.

As such, the overall objective is to evaluate the efficacy of pulsed IV corticosteroids therapy for the treatment of AM. It is proposed to test the efficacy of pulsed IV methylprednisolone in a single blind randomized controlled trial versus standard therapy on top of maximal support. The rationale for using pulsed corticosteroid therapy in the acute setting (within 3 weeks from cardiac symptoms’ onset) to reduce myocardial inflammatory infiltrates favoring recovery appears strong. Nevertheless, no trial has tested this hypothesis in the very acute phase of AM, despite the high mortality rate of this condition and the fact that AM mainly affects young patients.

Currently, no specific medications in the acute phase of lymphocytic AM are recommended beyond supportive therapy with inotropes and t-MCS. One Cochrane review on corticosteroids showed that almost all studies focused on inflammatory cardiomyopathies with 6 months of symptoms of heart failure (HF), and despite an improvement of cardiac function observed in low quality and small size studies, there was no improvement in the survival. In the past, only one study assessed the efficacy of immunosuppression in AM, the Myocarditis Treatment Trial (MTT) that reported no benefit from immunosuppression. Neutral results in the MTT could be ascribed to a delay in the initiation of this potentially effective treatment. Thus, 55% of patients started immunosuppressive therapy after 1 month from the onset of myocarditis, when the left ventricle (LV) was already dilated, as highlighted by a mean LV end-diastolic diameter (EDD) of 64 mm. It is expected that patients with FM have normal LV dimension during the acute phase despite severe LV systolic dysfunction. Based on a study from PI group, it was observed that FM patients recover most of the LVEF in the first 2 weeks after admission, with a median absolute increase of 30%. This finding further suggests that an immunosuppressive treatment should be started as soon as possible to demonstrate effectiveness. As little has changed in the medical treatment of this condition in the last 30 years, identification of effective drugs is needed.

Patients admitted to hospital for suspected AM complicated by acute HF/cardiogenic shock and LV systolic dysfunction will be screened for randomization.

Patients will be randomized in the two arms in a 1:1 ratio (Pulsed methylprednisolone therapy vs Placebo). Randomization will be performed with stratification by country.

The primary objective is to demonstrate a reduction in the rate of the primary composite endpoint on patients treated with pulsed methylprednisolone therapy vs. standard therapy and maximal supportive care.

Endpoints will be analyzed according to the following principles:

• Intention-to-treat (ITT) population
• Per Protocol (PP) population:
• “Safety population”
• A sensitivity analysis will also be performed on the previously defined populations after excluding patients (1) with histological diagnosis of giant cell myocarditis (GCM) or (2) who did not reach the final diagnosis of acute myocarditis based on CMRI or histology.

Sample size calculation: we plan to recruit a total of 360 patients, and we expect that about 20% of these patients or local physicians will refuse randomization. This would leave a total of 288 randomized patients (144 per arm).

Considering as relevant a reduction in the probability to reach the primary endpoint at 6 months from 25% in the standard therapy on top of maximal supportive care arm to 12% in the pulsed corticosteroid therapy arm (absolute risk reduction of 13% in absolute corresponding to a hazard ratio (HR) pulsed corticosteroid therapy vs. standard therapy of 0.44), the planned sample size will allow achieving a power of 0.80 with a one-sided log-rank test and an overall type I error of 0.025. The 25% figure considered for the standard therapy derives from a retrospective analysis of the patient’s cohort spanning over 20 years. The calculation includes an interim analysis planned at 50% recruitment (O&#39;Brien-Fleming method). This interim analysis is accounted for in the sample size calculation with an alpha level of 0.001525 (final analysis 0.023475 alpha level) and is planned on the primary endpoint to assess a possible early treatment effect. No specific stopping rules are planned, given the multiplicity of aspects involved, but the report on safety will be reviewed by the Data and Safety Monitoring Committee (DSMC) will advise on possible aspects of the trial that need reconsideration.

Sample size adaptation: We will consider, based on the DSMC advise an adaptive approach to sample size in two regards:

1. At the interim analysis, if the baseline incidence is lower than the expected 25%, the sample size calculation may be re-evaluated keeping the same HR of 0.44. For instance, if the observed incidence is 20%, maintaining the same HR of 0.44 (corresponding to an incidence of 9% in the pulsed corticosteroid therapy group, i.e. 11% in absolute risk reduction) the effective sample size needed to achieve 80% power should be increased to 360 patients. If the baseline incidence is higher than 25%, the planned actual sample size will achieve a power greater than 80% to detect a HR of 0.44 and no action will be taken.
2. Based on the conditional power method, and on the DSMC advise, we may reconsider if a less promising result than HR=0.4444 is worth pursuing, given the current observed estimate. This case would require an increase in sample size that will be discussed in terms of relevance and feasibility. For example, if at the planned interim analysis, the estimated absolute risk reduction is at least 10% (HR=0.56) with 25% baseline, and the conditional power of meeting this 10% target (instead of the planned 13%) would be at least 60%, the sample size may be increased to reach the 80% desired power. In this case, the final effective sample size should be increased to 254 patients per arm to preserve an 80% power of demonstrating the less marked difference. The flexibility allowed in the sample size estimate will be considered based on the evaluation of the interim report by the DSMC and no data will be disclosed on interim treatment estimates to the study coordinator and steering committee.

The overall duration of the study from first patient first visit to last patient last visit will be 39 months. The follow-up will be up to 6 months and with additional 3 months to lock the database. Enrollment will last 30 months.

In parallel, there will be a prospective registry of patients that are eligible for the trial, but they are not randomized.

A second registry, called MYOCARDITIS REGISTRY will prospectively recruit all patients with acute myocarditis demonstrated by CMRI or EMB who are not eligible for randomization (not all centers will take part in this registry).

The study is supported by a grant from Italian Ministry of Health (GR-2019-12368506) and Lombardy Region.

Exemption from the investigational new drug (IND) regulations by FDA on August 2nd, 2021 (PIND: 15727)

EudraCT identifier: 2021-000938-34

Multi-center, double-blind, placebo-controlled, parallel group design. Patients with myocarditis will be screened and, if eligible, randomized within 10 days of the diagnostic CMR to CardiolRx or placebo.

The treatment period is 12 weeks; a last follow-up visit is scheduled one week after the last treatment, 13 weeks after randomization. Study assessments include Cardiac Magnetic Resonance imaging (CMR), ECG monitoring, the Kansas City Cardiomyopathy Questionnaire (KCCQ), the Columbia-Suicide Severity Rating Scale (C-SSRS) as well as physical exams and laboratory tests.

The primary and secondary outcome parameters are measured by CMR. Additional outcomes include clinical endpoints and changes in inflammatory and biomarkers.

Rationale:

Myocarditis is an acute inflammatory condition of the myocardium. Presentation of the disease may be fulminant and necessitate cardiac support, or even result in sudden cardiac death; milder cases are usually self-limiting but may progress to dilated cardiomyopathy with eventual end-stage heart failure. Other than treatments for associated heart failure there are no specific indicated treatments for myocarditis. CardiolRxTM, which is known to have anti-inflammatory properties, is being investigated to treat the underlying inflammatory process and thereby favorably modify acute myocarditis. The primary endpoints of the trial are cardiac magnetic resonance measures of left ventricular systolic function (ejection fraction and longitudinal strain) and myocardial edema (extra cellular volume) which have been shown to predict long term prognosis of patients with acute myocarditis.

Multi-center, double-blind, randomized, placebo-controlled, parallel group design. 1:1 randomization; treatment will be stratified within sites.

Patients diagnosed with acute myocarditis by a biopsy or a CMR will be screened within 10 days of the diagnostic CMR. Informed consent will be obtained at this point. For patients who have been diagnosed using an EMB, a CMR needs to be performed as well, which will be included in the informed consent form (ICF).Eligible patients will then be randomized within 10 days from the CMR assessment.

Baseline assessments include the following: Clinical assessment, including vital signs, ECG, 24-hr Holter, chest x-ray; Hematology and blood chemistry, NYHA classification, C SSRS and KCCQ. Frozen plasma will be retained for central analysis of hs-troponin, NT-proBNP and inflammatory markers.

Study treatment needs to be taken with food and will be initiated in the evening of Day 1, after all baseline assessments have been completed and the patient has been randomized.

Oral administration is as follows:

• • Week 1 (p.m. dose of Day 1 to a.m. dose of Day 7): 2.5 mg/kg of body weight b.i.d. CardiolRxTM or placebo
  • Week 2 (p.m. dose of Day 7 to a.m. dose of Day 14): 5 mg/kg of body weight b.i.d. CardiolRxTM or placebo
  • Week 3 (p.m. dose of Day 14 to a.m. dose of Day 21): 7.5 mg/kg of body weight b.i.d. CardiolRxTM or placebo
  • Week 4 to end of treatment period (p.m. dose of Day 21 to a.m. dose of last day of treatment period at week 12): 10 mg/kg of body weight b.i.d. CardiolRxTM or placebo

If the next higher dose after each study drug increase is not tolerated, the dose will be reduced to the previous tolerated dose.

Every week (before the next dose increase) the patient will be re-evaluated. This includes ECG monitoring at approximately 5 hours post-morning dose (time of Tmax) to surveil for deleterious effects on ECG intervals (particularly the QTc interval) and rhythm. Drug titration will be dependent on investigator or designate interrogation of the ECGs and the absence of new, clinically significant abnormalities on those ECGs.

Vital signs, concurrent medication and Adverse Events (AEs), including Serious Adverse Events (SAEs) will be recorded, blood chemistry including liver function tests, hematology as well as INR assessments will be carried out.

Final efficacy assessments (including a second CMR) will take place after 12 weeks of study treatment. A final safety assessment will take place after 13 weeks, 1 week after completion of study treatment.