Evaluation of Mycophenolate Mofetil and Prednisolone in Virus-Negative Inflammatory Cardiomyopathy: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of the TRINITY trial is to evaluate the **clinical benefit** of immunosuppressive treatment with mycophenolate mofetil (MMF) and prednisolone compared to placebo in patients with chronic virus-negative inflammatory cardiomyopathy. This is assessed by measuring the absolute increase in left ventricular ejection fraction (LVEF) at 12 months follow-up, using both metric and binary co-primary endpoints as determined by MRI core lab. This objective is clinically relevant as it aims to determine the efficacy of the treatment in improving cardiac function in patients who have persistent deterioration despite optimal medical treatment for heart failure.

Secondary objectives include assessing the clinical benefit concerning left ventricular function and diameters, quality of life, physical capacity, cardiac autonomic function, transplant-free survival, hospitalization rate, biomarkers, and adverse events at 6 and 12 months follow-up. These objectives provide a comprehensive evaluation of the treatment's impact on various aspects of patient health and disease progression.

The clinical trial involves participants diagnosed with **virus-negative inflammatory dilated or nondilated left ventricular cardiomyopathy** who exhibit persistent deterioration of cardiac function despite optimal medical treatment for heart failure. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a persistent reduction of left ventricular ejection fraction (LVEF) of less than 50% as determined by routine echocardiographic evaluation. The trial population was selected based on specific inclusion criteria, including the absence of established cardiotropic virus infection and immunohistochemical evidence of lymphocytic myocarditis. The sponsor has not provided information regarding the total number of participants. The study also considers lifestyle factors such as the use of highly effective contraceptive measures in women of childbearing potential. The trial includes a vulnerable population, ensuring that all participants have provided written informed consent.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of immunosuppressive treatment in patients with chronic virus-negative inflammatory cardiomyopathy. The trial aims to assess the clinical benefit of treatment with mycophenolate mofetil and **prednisolone** compared to placebo, focusing on the absolute increase in left ventricular ejection fraction (LVEF) over a 12-month follow-up period. The study will involve multiple visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as age, medical history, and specific echocardiographic and immunohistochemical findings. Participants will be required to have a persistent reduction in LVEF and absence of established cardiotropic virus infection, among other criteria.

The trial will span an estimated duration from January 2023 to March 2029, with participant involvement expected to last up to 12 months. The sequence of study visits includes baseline assessments, regular follow-up visits at 6 and 12 months, and an end-of-study visit. These visits will involve various assessments, including MRI and echocardiographic evaluations to measure changes in cardiac function and structure, as well as assessments of exercise capacity and quality of life. The primary endpoints are the absolute increase in LVEF and the proportion of patients achieving a significant increase in LVEF at 12 months. Secondary endpoints include composite clinical outcomes and changes in cardiac parameters over time.

Participants may be withdrawn from the study if they experience severe adverse events, fail to comply with study procedures, or if the investigator deems it necessary for safety reasons. The trial is not categorized as low intervention and is classified as a Phase II/III study. The investigational products, including prednisolone and mycophenolate mofetil, are administered orally, with placebo tablets designed to be identical in appearance to maintain blinding. The study is conducted under strict ethical guidelines, with informed consent obtained from all participants prior to inclusion.

The clinical trial involves the administration of **Prednisolone** in various formulations. **Prednisolone 1 mg JENAPHARM** is provided in tablet form, with each capsule containing two 1 mg tablets. The route of administration is oral, and the maximum daily dose is 1 mg/kg. The treatment period is up to 6 months. The tablets are over-encapsulated to ensure blinding, and participant compliance is monitored through regular assessments.

**Prednisolon 5 mg JENAPHARM** is also administered orally in tablet form, with a maximum daily dose of 1 mg/kg. The tablets are over-encapsulated, and the treatment duration is 6 months. Compliance is monitored similarly to the 1 mg formulation.

**Prednisolon 10 mg GALEN® Tabletten** and **Prednisolon 20 mg GALEN® Tabletten** are administered orally, with each tablet over-encapsulated to maintain blinding. The maximum daily dose for both is 1 mg/kg, and the treatment period is 6 months. Compliance is ensured through regular follow-ups.

The trial also includes **Mowel 500 mg Filmtabletten**, containing **Mycophenolate Mofetil**. These film-coated tablets are administered orally, with a maximum daily dose of 2 g and a total dose of 350 g over the treatment period of 6 months. The tablets are packaged specifically for the study, and compliance is monitored through scheduled assessments.

Placebo treatments are used to maintain the double-blind nature of the trial. The placebo tablets for both **Prednisolone** and **Mycophenolate Mofetil** are identical in appearance to the active drug tablets, ensuring that neither the participants nor the investigators can distinguish between the active and placebo treatments. Compliance with placebo administration is monitored in the same manner as the active treatments.

The efficacy of the clinical trial will be assessed through a series of predefined endpoints, focusing on the evaluation of immunosuppressive treatment in patients with chronic virus-negative inflammatory cardiomyopathy. The primary efficacy endpoints include two co-primary measures: the absolute increase in left ventricular ejection fraction (**LVEF**) at 12 months follow-up, and the proportion of patients achieving an absolute increase in LVEF of at least 10% at the same timepoint. These endpoints will be assessed by blinded investigators using magnetic resonance imaging (MRI) at a core lab.

Secondary efficacy endpoints encompass a range of clinical and imaging outcomes. These include a composite clinical outcome of cardiac death, heart transplantation, left ventricular assist device (LVAD) implantation, or heart failure events within 12 months from randomization. Additional secondary endpoints involve changes in LVEF, left ventricular dimensions, volumes, mass, and sphericity, as well as global longitudinal strain, all measured at 6 and 12 months follow-up using both MRI and echocardiography. Other secondary measures include changes in cardiopulmonary exercise capacity, New York Heart Association (NYHA) functional class, patient-reported quality of life via the Kansas City Cardiomyopathy Questionnaire (KCCQ), and cardiac autonomic function. The time-averaged proportional change in NT-proBNP levels will also be evaluated.

The efficacy assessments will be conducted at specified intervals, with key measurements taken at baseline, 6 months, and 12 months follow-up. The use of validated imaging techniques and patient-reported outcome measures ensures the reliability and accuracy of the data collected. The analysis will be performed in a blinded manner to maintain the integrity of the trial results.