Acute Myocarditis
Conditions
Keywords
Pharmaceutically produced CBC, THC < 5ppm
Brief summary
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.
Detailed description
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.
Interventions
DRUGCardiolRx
Eligible patients will be randomized to receive CardiolRx or placebo. Intervention will be administered orally (via syringe) with food twice daily.
Sponsors
Cardiol Therapeutics Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Placebo will match active study drug in color, odor, taste and appearance to assure proper blinding.
Intervention model description
Multi-center, double-blind, randomized, placebo-controlled, parallel group design. 1:1 randomization
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Males and females 18 years of age or older 2. Diagnosed with acute myocarditis including: 1. Clinical criteria (symptoms of chest pain, arrhythmia or shortness of breath, or history of viral-like illness), preferably followed by elevated troponin PLUS 2. CMR diagnosis (Lake Louise Criteria) within 10 days prior to randomization OR 3. Endomyocardial biopsy (EMB) showing either cellular inflammation and/or immunohistochemistry consistent with inflammation. 3. 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. 4. 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
1. Coronary artery disease (CAD) defined as a stenosis greater than 50% in a major epicardial coronary artery 2. Severe valvular heart disease 3. Inability to safely undergo CMR including administration of gadolinium 4. Estimated glomerular filtration rate (eGFR) \< 30 ml/min 5. 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. 6. Sepsis, defined as documented bacteremia at the time of presentation or other documented active infection. 7. Severe left ventricular (LV) dysfunction requiring inotropic support, left ventricular assist device (LVAD) or other circulatory assist devices, or urgent need for transplantation 8. Documented biopsy evidence of giant cell or eosinophilic myocarditis 9. Prior history of sustained ventricular arrhythmia 10. Acute coronary syndrome within 30 days 11. Percutaneous coronary intervention within 30 days 12. History of QT interval prolongation or QTc interval \> 500 msec 13. Treated with strong inducers CYP3A4 or CYP2C19, as listed in Appendix 17.8 14. Treated with digoxin and/or type 1 or 3 antiarrhythmics 15. Current participation in any research study involving investigational drugs or devices 16. Inability or unwillingness to give informed consent 17. Ongoing drug or alcohol abuse 18. Women who are pregnant or breastfeeding 19. Current diagnosis of cancer, with the exception of non-melanoma skin cancer 20. Any factor, which would make it unlikely that the patient can comply with the study procedures 21. On any cannabinoid during the past month 22. Body weight \> 170 kg 23. Showing suicidal tendency as per the C-SSRS, administered at screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Extracellular Volume (ECV) | 12 weeks post randomization | Change of ECV from baseline at 12 weeks, measured by cardiac Cardiac MRI. ECV is measuring the degree of edema and fibrosis. The unit of measure was percentage. It was the percentage of myocardial tissue that is extracellular space (i.e. fraction of the myocardium occupied by extracellular matrix and interstitial fluid). |
| Global Longitudinal Strain (GLS) | 12 weeks post randomization | The outcome was the change in GLS from baseline at 12 weeks, measured by cardiac Cardiac MRI. GLS is a predictor of cardiac function. The unit of measure is percentage. It is the percent change in myocardial length relative to its original (end-diastolic) length along the long axis. Longitudinal strain during systole is usually negative, because the ventricle shortens; normal peak GLS in healthy adults is around -20% (i.e., 20% shortening relative to original length) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Left-ventricular Ejection Fraction (LVEF) From Baseline at 12 Weeks | 12 weeks post randomization | Left-ventricular ejection fraction (LVEF) as measured by Cardiac MRI at 12 weeks. LVEF is a measure of cardiac function. The unit of measure is percentage. It is the percent of end-diastolic blood volume in the left ventricle that is ejected with each systolic contraction. Mathematically, LVEF = (stroke volume/end-diastolic volume) x 100. |
Countries
Brazil, Canada, France, Israel, United States
Contacts
STUDY_CHAIRDennis McNamara, MD
University of Pittsburgh
Participant flow
Recruitment details
166 patients signed informed consent between July 28, 2022, and October 31,2024, in 29 centers in Brazil; France; Israel and the United States. There were 57 screening failures and 109 patients were randomized to either CardiolRx™ (N=56) or Placebo (N=53). All randomized patients started the IMP and completed the study as planned - no patient withdrew prematurely from follow-up. In total, 11 patients discontinued the IMP before the Week 12 visit, 6 on CardiolRx and 5 on placebo.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 39.6 years STANDARD_DEVIATION 15.47 |
| Extracellular volume (ECV) | 29.74 % STANDARD_DEVIATION 4.47 |
| Global longitudinal strain (GLS) | -15.34 % STANDARD_DEVIATION 4.06 |
| Left-ventricular ejection fraction (LVEF) | 59.35 % STANDARD_DEVIATION 10.79 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants |
| Race (NIH/OMB) White | 79 Participants |
| Region of Enrollment Brazil | 50 participants |
| Region of Enrollment France | 27 participants |
| Region of Enrollment Israel | 14 participants |
| Region of Enrollment United States | 4 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 56 | 0 / 53 |
| other Total, other adverse events | 42 / 56 | 35 / 53 |
| serious Total, serious adverse events | 6 / 56 | 3 / 53 |
Outcome results
None listed