Impact of CardiolRx on Myocardial Recovery in Patients With Acute Myocarditis (ARCHER)

Impact of CardiolRx on Myocardial Recovery in Acute Myocarditis. A Double-blind, Placebo-controlled Trial

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. CardiolRx is pharmaceutically produced Cannabidiol and is free of tetrahydrocannabinol (THC<5 ppm). 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 (cannabidiol [CBD] solution), 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.

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

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

Eligible patients will be randomized to receive CardiolRx or placebo. Intervention will be administered orally (via syringe) with food twice daily.

Major event defined as cardiac transplant, left-ventricular assist device (LVAD), hospitalization for Heart failure (HF)

Any change in CMR parameters from baseline to 12 weeks post randomization: LVEF (%), ECV (%), GLS (%), LGE (%)

Any change in CMR parameters from baseline to 12 weeks post randomization: LVEDV (ml/m2), LVESV (ml/m2), LAESV (ml/m2).

New York Heart Association classification (NYHA) ranked in order of best to worse outcome from Class I (best) to Class IV (worst). Record any change from baseline in percentage of patients in NYHA class IV/III/II class over the course of 12 weeks.

Any changes from baseline KCCQ compared to after 12 weeks of treatment Where "No limits" is the best outcome and "Severely limited" is the worst outcome.

Patients with myocarditis present with abnormal (very high) values in inflammatory and biomarkers. The investigators are trying to determine if CardiolRx normalizes them faster than placebo.

Changes in inflammatory and biomarkers NT-proBNP (pg/ml), TNF-alpha (pg/ml), IL-1 beta (pg/ml) and IL-6 (pg/ml)

Patients with myocarditis present with abnormal (very high) values in inflammatory and biomarkers. The investigators are trying to determine if CardiolRx normalizes them faster than placebo.

Patients with myocarditis present with abnormal (very high) values in inflammatory and biomarkers. The investigators are trying to determine if CardiolRx normalizes them faster than placebo.

Patients with myocarditis present with abnormal (very high) values in inflammatory and biomarkers. The investigators are trying to determine if CardiolRx normalizes them faster than placebo.

Inclusion Criteria: Males and females 18 years of age or older Diagnosed with acute myocarditis including: Clinical criteria (symptoms of chest pain, arrhythmia or shortness of breath, or history of viral-like illness), preferably followed by elevated troponin PLUS CMR diagnosis (Lake Louise Criteria) within 10 days prior to randomization OR Endomyocardial biopsy (EMB) showing either cellular inflammation and/or immunohistochemistry consistent with inflammation. Male subjects with partners of childbearing potential who have had a vasectomy or are willing to use double barrier contraception methods during the conduct of the study and for 2 months after the last dose of study drug. Women of childbearing potential willing to use an acceptable method of contraception starting with study drug administration and for a minimum of 2 months after study completion. Otherwise, women must be post- menopausal. Exclusion Criteria: Coronary artery disease (CAD) defined as a stenosis greater than 50% in a major epicardial coronary artery Severe valvular heart disease Inability to safely undergo CMR including administration of gadolinium Estimated glomerular filtration rate (eGFR) < 30 ml/min Elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 times the upper limit of normal (ULN) or ALT or AST >3x ULN plus bilirubin >2x ULN. Sepsis, defined as documented bacteremia at the time of presentation or other documented active infection. Severe left ventricular (LV) dysfunction requiring inotropic support, left ventricular assist device (LVAD) or other circulatory assist devices, or urgent need for transplantation Documented biopsy evidence of giant cell or eosinophilic myocarditis Prior history of sustained ventricular arrhythmia Acute coronary syndrome within 30 days Percutaneous coronary intervention within 30 days History of QT interval prolongation or QTc interval > 500 msec Treated with strong inducers CYP3A4 or CYP2C19, as listed in Appendix 17.8 Treated with digoxin and/or type 1 or 3 antiarrhythmics Current participation in any research study involving investigational drugs or devices Inability or unwillingness to give informed consent Ongoing drug or alcohol abuse Women who are pregnant or breastfeeding Current diagnosis of cancer, with the exception of non-melanoma skin cancer Any factor, which would make it unlikely that the patient can comply with the study procedures On any cannabinoid during the past month Body weight > 170 kg Showing suicidal tendency as per the C-SSRS, administered at screening

Lee WS, Erdelyi K, Matyas C, Mukhopadhyay P, Varga ZV, Liaudet L, Hasku G, Cihakova D, Mechoulam R, Pacher P. Cannabidiol Limits T Cell-Mediated Chronic Autoimmune Myocarditis: Implications to Autoimmune Disorders and Organ Transplantation. Mol Med. 2016 Sep;22:136-146. doi: 10.2119/molmed.2016.00007. Epub 2016 Jan 8.