Patients with recurrent pericarditis who are refractory or intolerant to current therapeutic management options or who require long-term administration of corticosteroids to control their disease are particularly challenging to manage. The pathogenesis of pericarditis involves the activation of the inflammasome. CardiolRxTM (a pure cannabidiol [CBD] solution) is known to have anti-inflammatory properties, including modulation of inflammasome signaling. This pilot study is to assess the tolerance and safety of CardiolRxTM during the resolution of pericarditis symptoms, assess improvement in objective measures of disease, and during the extension period, assess the feasibility of weaning concomitant background therapy including corticosteroids while taking CardiolRxTM.

Multi-center, open label Pilot Study. Patients who present with recurrent pericarditis will be screened and informed consent obtained.

Baseline assessments include the following: Clinical assessment, including vital signs, highest NRS pain score within the past 7 days of Day 1, 12-lead ECG; C-SSRS as well as hematology and blood chemistry and a pregnancy test for women with child-bearing potential.

Concomitant medications are recorded and any (S)AEs after informed consent has been obtained.

Study treatment will be initiated in the evening of Day 1, after all baseline assessments are completed.

Oral administration is as follows:

• Initial starting dose (Day 1 p.m. dose to Day 3 a.m. dose):

  5 mg/kg of body weight CardiolRxTM

• Day 3 p.m. dose to Day 10 a.m. dose: 7.5 mg/kg of body weight CardiolRxTM b.i.d.

• Day 10 p.m. dose to end of treatment period: 10.0 mg/kg of body weight CardiolRxTM b.i.d.

If the next higher dose after each study drug increase is not tolerated, the dose will be reduced to the previous tolerated dose.

Unless contraindicated in the opinion of the investigator, after 8 weeks of treatment, patients will enter an 18-week extension period (EP), in which they continue study treatment while their concomitant medications will be weaned.

Follow-up Procedures Every visit (before the next dose increase) the patient will be re-evaluated. This includes ECG monitoring at approximately 5 hours post-morning dose (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 (S)AEs will be recorded at all visits. Blood chemistry including liver function tests, hematology as well as INR assessments will be carried out at selected visits.

Final efficacy assessments will take place after 26 weeks of study treatment and include a clinical assessment, vital signs, pain score NRS, a 12-lead ECG, the C-SSRS, as well as laboratory assessments.

For patients who do not enter the EP, Final assessments will be done after 8 weeks.

Inclusion Criteria:

1. Male or female 18 years of age or older

2. Diagnosis of at least two episodes of recurrent pericarditis*,

3. At least 1 day with pericarditis pain ≥4 on the 11-point Numerical Rating Scale (NRS) within prior 7 days

4. One of;

   1. C-Reactive Protein** (CRP) level ≥1.0 mg/dL within prior 7 days OR
   2. Evidence of pericardial inflammation assessed by delayed pericardial hyperenhancement on cardiac magnetic resonance imaging (CMR)

5. Currently receiving non-steroidal anti-inflammatory drugs (NSAIDs) and/or colchicine and/or corticosteroids (in any combination) for treatment of pericarditis in stable doses

6. Male patients 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.

7. 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 postmenopausal (at least 1 y absence of vaginal bleeding or spotting and confirmed by follicle stimulating hormone [FSH] ≥40 mIU/mL [or ≥ 40 IU/L] if less than 2 y postmenopausal) or be surgically sterile.

   • Diagnosis of pericarditis according to the 2015 European Society of Cardiology (ESC) Guidelines for the Diagnosis and Management of Pericardial Diseases (Adler et al. 2015):

At least two of:

1. Pericarditic chest pain

2. Pericardial rub

3. New widespread ST-segment elevation or PR-segment depression according to electrocardiogram (ECG) findings

4. Pericardial effusion (new or worsening)

   • Conversion: 1 mg/dL CRP = 10 mg/L hs-CRP

Exclusion Criteria:

1. Diagnosis of pericarditis that is secondary to specific prohibited etiologies, including tuberculosis (TB); neoplastic, purulent, or radiation etiologies; post-thoracic blunt trauma (e.g., motor vehicle accident); myocarditis

2. Estimated glomerular filtration rate (eGFR) <30 mL/min at screening

3. 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

4. Sepsis, defined as documented bacteremia at the time of screening or other documented active infection

5. Prior history of sustained ventricular arrhythmia

6. History of QT interval prolongation

7. QTc interval > 500 msec

8. Current participation in any research study involving investigational drugs or device

9. Inability or unwillingness to give informed consent

10. Ongoing drug or alcohol abuse

11. On any cannabinoid during the past month

12. Women who are pregnant or breastfeeding

13. Current diagnosis of cancer, with the exception of non-melanoma skin cancer

14. Any factor, which would make it unlikely that the patient can comply with the study procedures

15. Showing suicidal tendency as per the Columbia Suicide Severity Rating Scale (C-SSRS), administered at screening

16. On digoxin and/or type 1 or 3 antiarrhythmics

17. On immunosuppressive therapy with any of the following:

    1. Rilonacept
    2. Anakinra
    3. Canakinumab
    4. Methotrexate
    5. Azathioprine
    6. Cyclosporine
    7. Intravenous immune globulin (IVIG)

Adverse events were collected from the signed ICF until the last study visit for each patient, up to 26 weeks.

AE description does not differ from the clinical trials.gov AE definition.

AEs were collected on an ongoing basis throughout the study.

In terms of limitations, this study was an open label, single-arm study so there was no control group. The number of patients included was also small but considered a sufficient sample size to demonstrate both the efficacy and safety objectives of this pilot study.