Cannabidiol in Patients With COVID-19 and Cardiovascular Disease or Risk Factors

Study to Evaluate the Efficacy and Safety of CardiolRx™ in Patients With COVID-19 and Cardiovascular Disease or Risk Factors A Double-blind, Placebo-controlled Trial

Non-critical patients, hospitalized within the previous 24 hours who tested positive for COVID-19 and have a prior history of cardiovascular disease (CVD) and/or significant risk factors for CVD will be treated for 28 days.

Multi-center, double-blind, randomized, placebo-controlled, parallel group design. 1:1 randomization.

Screening (Day 0-1): Patients hospitalized for COVID-19 within the past 24 hours will be screened. If patient consent can be obtained, baseline assessments will be carried out: Physical examination (including vital signs), ECG including QTc interval assessment, echocardiogram to measure left-ventricular ejection fraction (LVEF), chest X-ray, local laboratory (including CBC, AST/ALT, alkaline phosphatase, bilirubin, creatinine/eGFR, INR, pregnancy test (in women with child-bearing potential only), lymphocyte count and LDH. A C-SSRS will also be completed. Frozen plasma will be retained for central analysis of CardiolRx™ levels, hs-troponin, NT-proBNP, D-dimer as well as inflammatory markers (hs-CRP, ferritin, TNF-alpha, IL-1 beta, IL-6, IL-10).

If all eligibility criteria are met, the patient will be randomized to either CardiolRx™ or placebo.

Study treatment will be initiated immediately after all baseline assessments have been completed and the patient is randomized (Day1). Oral administration is as follows:

• Day 1 and Day 2: Initial dose: 2.5 mg/kg of body weight b.i.d. with food: CardiolRx™ or placebo
• Day 3 and Day 4: Increased to 5 mg/kg of body weight b.i.d. with food: CardiolRx™ or placebo
• Day 5 to Day 28: Increased to 7.5 mg/kg of body weight b.i.d. with food: CardiolRx™ or placebo For the first 7 days and on Day 10, an ECG will be recorded 4 hours post morning dose with QTc intervals measured. If the QTc interval is >500 msec or an increase of > 60 msec from baseline is observed, the study medication must be stopped immediately.

If the next higher dose is not tolerated for other reasons, the dose will be reduced to the previous tolerated dose. The highest tolerated dose will be administered until Day 28.

If the patient is discharged before Day 10, the assessments up to Day 10 will be carried out as home visits. After Day 10, all remaining scheduled assessments will be carried out during out-patient visits (or home visits, if out-patient visits are not feasible).

In addition to prolongation of the QTc intervals, careful observation is required to detect other Adverse Drug Reactions (ADRs) and Drug-Drug Interactions (DDIs). Because CardiolRx™, may inhibit the metabolism of other drugs, new symptoms may represent toxicity from a concomitant medication that had previously been well tolerated.

A nasopharyngeal swab will also be done every day until Day 7 and on Day 14 to test for presence of the SARS-CoV-2 virus.

After Day 7, assessments will be carried out on a weekly basis except for as noted above on Day 10.

Frozen plasma will be retained for central analysis of CardiolRx™ levels, hs-troponin, NT-proBNP, D-dimer, inflammatory markers (hs-CRP, ferritin, TNF-alpha, IL-1 beta, IL-6, IL-10) and additional parameters of interest every two days until Day 7 as well as on day 28.

The assessments on Day 28 include the following: Physical examination (including vital signs), ECG (recorded 4 hours post morning dose for measurement of QTc interval), echocardiogram to measure LVEF, chest X-ray, local laboratory assessments, including CBC, AST/ALT, alkaline phosphatase, bilirubin, creatinine/eGFR, INR, lymphocyte count and LDH. In addition, a C-SSRS will be completed and the patient will be asked to answer a PICQ.

Further follow-up visits are scheduled for Day 45 and Day 60 post randomization. These include a clinical assessment (including vital signs) as well as the completion of the PICQ (PICQ on Day 60 only). Any changes in concomitant medications and (S)AEs will also be recorded.

Inclusion Criteria:

1. Males and females 18 years of age or older 2. Hospitalized for COVID-19 with the most recent test positive*; not receiving or likely to receive invasive mechanical ventilation within the next 24 hours 3. Prior history of at least one of: i) CVD [cardiovascular (CV), cerebrovascular or peripheral vascular diagnoses], ii) Age > 64, iii) Diabetes (DM), iv) Hypertension (HTN), v) Abnormal serum lipids, vi) Obesity (BMI > or equal 30 or waist circumference >102 cm [40"] for men and >88 cm [35"] for women), vii) Current smoker

* Must be PCR test.

Exclusion Criteria:

1. Patients who have received vasopressors, extracorporeal membrane oxygenation and mechanical ventilation within last 30 days
2. Background of cardiac transplant surgery
3. Implanted defibrillator (ICD) in the last three months
4. Implanted left-ventricular assist device (LVAD)
5. Acute coronary syndrome (ACS) within 30 days
6. Percutaneous coronary intervention (PCI) within 30 days
7. Receiving any immuno-suppressive agent other than dexamethasone
8. History of QTc interval prolongation
9. QTc interval > 500 msec
10. Treated with strong inducers of CYP3A4 or CYP2C19
11. Chronic renal failure, determined as eGFR < 30 ml/min
12. 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
13. Bacterial sepsis, defined as documented bacteremia at the time of presentation or other active bacterial infection
14. Current participation in any research study involving investigational drugs or devices with the exception of dexamethasone, remdesivir, baricitinib plus remdesivir, convalescent plasma or monoclonal antibodies against the SARS-CoV-2 virus or any other therapy approved under emergency use in the region for treatment of COVID-19
15. Inability or unwillingness to give informed consent
16. Ongoing drug, alcohol or cannabis abuse
17. Women who are pregnant or breastfeeding
18. Any factor, which would make it unlikely that the patient can comply with the study procedures
19. Hemoglobin <8.5 gm/dL
20. Leukocyte count < 3000/ mm3
21. Platelets < 100,000 / mm3
22. Current diagnosis of cancer, with the exception of non-melanoma skin cancer
23. Showing suicidal tendency as per the Columbia-Suicide Severity Rating Scale (C-SSRS) administered at screening
24. Any cannabinoid intake in the past month
25. Body weight > 170 kg