E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Inflammatory cardiovascular involvement due to COVID-19, defined by Cardiovascular magnetic resonance imaging |
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E.1.1.1 | Medical condition in easily understood language |
COVID-19 disease with cardiovascular inflammatory involvement |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10084268 |
E.1.2 | Term | COVID-19 |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10007650 |
E.1.2 | Term | Cardiovascular disorder NOS |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to determine the efficacy of a combined immunosuppressive and antiremodelling therapy in COVID-19 related inflammatory cardiovascular involvement by CMR to reduce inflammatory myocardial injury compared to placebo.
The primary safety objective is to demonstrate that a combined immunosuppressive and antiremodelling therapy in proposed doses in this patient population is safe. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to determine the efficacy of a combined immunosuppressive and antiremodelling therapy in COVID-19 related inflammatory cardiovascular involvement by CMR to reduce inflammatory myocardial injury compared to placebo by improvement in other clinical parameters. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Participants ≥ 18 years • Participants with documented recent COVID19 infection (> 4 weeks) • Post-acute sequelae of SARS-CoV-2 infection (PASC) Syndrome, defined by persistence or new symptoms, not present prior to the infection. • Cardiovascular magnetic resonance imaging (CMR) evidence of inflammatory cardiac involvement at baseline (BL) by any of the following criteria: o Increased native T1≥ 1130 ms at 3.0 Tesla (or 1030 ms at 1.5 Tesla) and/or; o Increased native T2 ≥39.5 ms at 3.0 Tesla (or 49.5 at 1.5 Tesla) and/or o present non-ischaemic myopericardial Late gadolinium enhancement (LGE) and/or; o Left ventricular ejection fraction (LVEF) ≥45 - ≤50%. • Willingness to comply with the study procedures and study protocol.
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E.4 | Principal exclusion criteria |
• Severe course of acute COVID illness requiring hospitalisation • Known allergy to or intolerance of the study medications • Symptomatic hypotension (systolic blood pressure less than 90 mm Hg), not reversible with oral hydration • Any previous or current use of ACE inhibitors, AR Blockers • Any previous oral prednisolone, or any other immunosuppressive or biological treatment (within 10 weeks) • History or CMR evidence of preexisting heart disease, including: a. Known cardiac impairment with LVEF ≤44% b. Congestive heart failure (NYHA III-IV) c. Active heart failure treatment d. Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease e. Persistent or permanent atrial fibrillation or significant heart rhythm abnormalities. f. Congenital or clinically relevant valvular heart disease (moderate or severe) g. Specific cardiomyopathy (hypertrophic, hypertensive heart disease, amyloidosis, previous myocarditis, non-ischaemic dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, non-compaction cardiomyopathy, etc). h. Known significant concomitant diseases that are likely to interfere with the evaluation of the participant's safety and of the study outcome (e.g. diabetes, lung or hepatic disease, epilepsy, psychiatric disorders, renal disease with a current estimated GFR <30 mL/min/1.73 m² using MDRD formula, chronic systemic infection or immunocompromise) i. Exceeding scanner bore and table-holding capacity: Weight >125 kg, BMI > 35 kg/m2 • Contraindications to contrast-enhanced CMR imaging, e.g. a. MR-unsafe implantable device b. known allergy to gadolinium-based contrast agent (GBCA) • For female participants: a. Pregnant or lactating women b. Women of childbearing potential not willing to use effective contraception (as defined in18.2.13) • Known alcohol, drug, or chemical abuse • Participants currently participating in an investigational study or for whom participation is planned. • Unable to provide written informed consent
Patients with CMR evidence of structural heart disease or incidental heart rhythm abnormalities will be advised to see their own doctor for further investigations.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study is absolute LVEF change to baseline at W16, measured by CMR, compared between the verum and placebo group by absolute treatment difference |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary endpoints include the following continuous endpoints, where “changes” refer to the difference between baseline and W16 (BL, absolute and in %): • Mean Late gadolinium enhancement (LGE) extent (%) and change thereof compared to BL • CPET (achieved Work Rate, VO2max, VCO2 max, RER, AT, slope) and change thereof compared to BL • Mean T1 and T2 values (ms) and change thereof compared to BL • Mean LV and RV volumes (ml/m2) and LV mass (g/m2) as well as derived parameters and change thereof compared to BL • Mean Myocardial strain (%) and change thereof compared to BL • Mean Pulse wave velocity (m/s) and change thereof compared to BL • Aortic wall thickness (LGE, mm); and change thereof compared to BL • Average Symptom Score and change thereof compared to BL • Compliance: Frequency of prescribed medication consumed, participants diary and drug adherence, total cumulative steroid dose; • Tolerance: number of participants who required dose reduction or treatment cessation due to side effects, especially due to o Hypotension o Unblinding due to emergency safety issues • Number of Responders by achieving: o partial response: a normal CMR result is defined as normal T1 and T2, normal gender-age predicted LVEF, non-dilated LV o total response: in addition to the above absence of LGE • Proportion of participants with HF or MACE after 1 • 1-year Event-free survival
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The global end of the study is defined as the last visit of the last patient randomized.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |