Impact of CardiolRx on Myocardial Recovery in Patients With Acute Myocarditis

Acute Myocarditis Clinical Trial

— ARCHER  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05180240
• Other study ID #: Cardiol 100-002
• Status: Recruiting
• Phase: Phase 2
• Start date: June 22, 2022
• Est. completion date: December 2024

Study information

• Verified date: February 2024
• Source: Cardiol Therapeutics Inc.
• Contact: Andrea B Parker, MSc, PhD
• Phone: +1 289.910.0862
• Email: andrea.parker[@]cardiolrx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: December 2024
• Est. primary completion date: November 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Myocarditis
• Myocarditis

Intervention

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

Locations

Country	Name	City	State
Brazil	Hospital Felicio Rocho - Fundação Felice Rosso	Belo Horizonte
Brazil	Nupec-Orizonti	Belo Horizonte	Minas Gerais
Brazil	Hospital Angelina Caron	Campina Grande Do Sul
Brazil	PUC trials	Curitiba	PR
Brazil	Complexo Hospitalar de Niterói	Niterói	Rio De Janeiro
Brazil	Hospital de Clínicas de Porto Alegre (HCPA)	Porto Alegre	RS
Brazil	Hospital Moinhos de Vento	Porto Alegre	RS
Brazil	Hospital São Lucas	Porto Alegre
Brazil	Hospital Pró-Cardíaco	Rio de Janeiro
Brazil	Instituto D´Or de Pesquisa e Ensino	Rio de Janeiro
Brazil	Hospital Regional de São José	São José
Brazil	Hospital Nove de Julho	São Paulo	SP
Brazil	Instituto do Coração - InCor	São Paulo
Brazil	Irmandade da Santa Casa de Misericórdia de São Paulo	São Paulo
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	McGill University Health Centre	Montréal	Quebec
France	Hopital Louis Pradel Hospices Civils de Lyon	Bron
France	CHU de Montpellier	Montpellier
France	Centre Hospitalier Universitaire de Nîmes	Nîmes
France	Hopital Bichat Claude Bernard	Paris
France	Hôpital européen Georges-Pompidou	Paris
France	Hôpital Lariboisière - Département de Cardiologie	Paris
France	Institut de Cardiologie hopital Pitié Salpêtrière	Paris
France	Centre Hospitalier Universitaire de Poitiers	Poitiers
France	Hôpital Foch	Suresnes
France	Chu Rangueil	Toulouse
Israel	Barzilai Medical Center	Ashkelon
Israel	Shaare Zedek Medical Center	Jerusalem
Israel	Beilinson Hospital, Rabin medical Center	Petah Tikva
Israel	Tel Aviv Sourasky Medical Center (Ichilov)	Tel Aviv
Israel	Shamir Medical Center (Assaf Harofeh)	Zrifin
United States	Massachusetts General Hospital site	Boston	Massachusetts
United States	Cleveland Clinic	Cleveland	Ohio
United States	Palm Springs Community Health Centre	Miami Lakes	Florida
United States	Minneapolis Heart Institute Foundation	Minneapolis	Minnesota
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Virginia Commonwealth University	Richmond	Virginia
United States	MedStar Heart and Vascular Institute	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Cardiol Therapeutics Inc.

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  France,  Israel, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percentage of patients recovered	defined as LVEF = 0.55 at 12 weeks of treatment	From baseline to 12 weeks of treatment
Other	Survival, free from major event	Major event defined as cardiac transplant, left-ventricular assist device (LVAD), hospitalization for Heart failure (HF)	12 weeks post randomization
Other	Change in CMR parameters (%)	Any change in CMR parameters from baseline to 12 weeks post randomization: LVEF (%), ECV (%), GLS (%), LGE (%)	From baseline to 12 weeks of treatment
Other	Change in CMR parameters (mL/m2)	Any change in CMR parameters from baseline to 12 weeks post randomization: LVEDV (ml/m2), LVESV (ml/m2), LAESV (ml/m2).	From baseline to 12 weeks of treatment
Other	Change in CMR parameters (g/m2)	Any change in CMR parameters from baseline to 12 weeks post randomization: LV mass (g/m2)	From baseline to 12 weeks of treatment
Other	New York Heart Association classification (NYHA)	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.	From baseline to 12 weeks of treatment
Other	Kansas City Cardiomyopathy Questionnaire (KCCQ)	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.	From baseline to 12 weeks of treatment
Other	Time to resolution of clinical symptoms	chest pain, arrhythmias, shortness of breath	From baseline to 12 weeks of treatment
Other	Changes in inflammatory and biomarker hs-troponin (nh/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.	From baseline to 12 weeks of treatment
Other	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.	From baseline to 12 weeks of treatment
Other	Changes in inflammatory and biomarkers hs-CRP (mg/l), and ferritin (mg/l)	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.	From baseline to 12 weeks of treatment
Other	Changes in inflammatory and biomarker IL-10 (ng/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.	From baseline to 12 weeks of treatment
Other	Normalization of prognostically important ECG changes	Time to normalization of normalization of PR interval	From baseline to 12 weeks of treatment
Other	Normalization of prognostically important ECG changes	Time to normalization of normalization of QRS duration	From baseline to 12 weeks of treatment
Other	Normalization of prognostically important ECG changes	Time to normalization of normalization of ST/T wave changes	From baseline to 12 weeks of treatment
Primary	extracellular volume (ECV)	primary	12 weeks post randomization
Primary	Global longitudinal Strain (GLS)	primary	12 weeks post randomization
Secondary	Left-ventricular ejection fraction (LVEF)	secondary endpoint	12 weeks post randomization