CardiolRx in Recurrent Pericarditis Following IL-1 Blocker Cessation

Multi-center, randomized, double-blind, placebo-controlled, phase-3 Trial. Patients with a history of recurrent pericarditis who are being treated with an IL-1 blocker for at least 12 months, scheduled to be discontinued, will be approached for potential trial participation.

Double-blind treatment will be initiated 10 - 14 days prior to the last scheduled dose of the IL-1 blocker and continued for 24 weeks.

The objective is to assess whether patients who discontinue therapy with an IL-1 blocker for recurrent pericarditis remain free of pericarditis recurrence while receiving CardiolRx.

Double-blind, randomised, placebo-controlled Phase-3 trial. The primary objective is to assess whether patients with IL-1 blocker-dependent recurrent pericarditis can discontinue IL-1 blocker therapy and remain free of recurrence while receiving CardiolRx.

After informed consent is obtained, patients will be screened for eligibility. Baseline assessments will be performed during screening within 7 days of Day 1 (Visit 1) and include the following: Physical examination, vital signs, highest NRS pain score within the past 7 days of Day 1, 12-lead ECG; hematology (CBC with differential) and blood chemistry (including complete metabolic panel: sodium, potassium, calcium, glucose, ALT/AST, bilirubin, alkaline phosphatase, blood urea nitrogen (BUN), creatinine/eGFR), C-SSRS and a pregnancy test for women of childbearing potential.

Eligible patients will be randomized on Day 1 to either CardiolRx or matching placebo. Double-blind trial therapy will be initiated in the evening of Day 1, 10 - 14 days prior to the last scheduled dose of the IL-1 blocker and after all baseline assessments are completed. Trial therapy will be administered for 24 weeks.

Final efficacy assessments will take place 24 weeks after starting trial therapy and include a physical exam, vital signs, pain score NRS, a 12-lead ECG, as well as laboratory assessments (including a pregnancy test in women of childbearing potential) and a C-SSRS.

A safety follow-up visit will be scheduled 4 weeks after the last trial therapy administration.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female 18 years of age or older
2. A history of recurrent pericarditis\* with stable disease and currently being treated with an IL-1 blocker, scheduled to be discontinued. Stable disease is defined as:

   * treatment with an IL-1 blocker for at least 12 months;
   * free of pericarditis recurrence for at least 6 months and this recurrence, if present, must have occurred in the setting of an interruption or tapering of an IL-1 blocker; and
   * treatment with an unchanged dose and regimen of on an IL-1 blocker for at least 3 months prior to randomization.
3. Pericarditis pain more or equal than 2 on the 11-point Numerical Rating Scale (NRS) for at least the prior 7 days
4. C-Reactive Protein (CRP\*\*) \< 1.0 mg/dL within the 7 days of screening prior to Day 1 (Visit 1)
5. Male patients with partners of childbearing potential who have had a vasectomy or who are willing to use double barrier contraception methods during the conduct of the trial and for 2 months after the last dose of trial therapy
6. Women of childbearing potential willing to use an acceptable method of contraception starting with trial drug administration and for a minimum of 2 months after trial completion. Otherwise, women must be postmenopausal (at least 1 year absence of vaginal bleeding or spotting and confirmed by follicle stimulating hormone \[FSH\] ≥40 mIU/mL \[or ≥ 40 IU/L\] if less than 2 years postmenopausal) or be surgically sterile.

Exclusion Criteria:

1. Pericarditis recurrence(s) during IL-1 blocker treatment without interruption or tapering of the IL-1 blocker
2. 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); systemic autoimmune disease (e.g., systemic lupus erythematosus)
3. Primary diagnosis of myocarditis (diagnosis of myopericarditis is accepted)
4. Estimated glomerular filtration rate (eGFR) \< 30 mL/min at baseline
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 baseline or other untreated or uncontrolled bacterial infection\*
7. Prior history of sustained ventricular arrhythmia(s)
8. History of diagnosed long QT syndrome
9. QTc interval \> 500 msec at baseline
10. Showing suicidal tendency, as defined by answering "yes" to question 4 or 5 of the Columbia Suicide Severity Rating Scale (C-SSRS), administered at baseline
11. Currently participating in any research trial involving investigational drugs or devices
12. Inability or unwillingness to give informed consent
13. Ongoing drug or alcohol abuse in the opinion of the investigator
14. On any cannabinoid during the past month and unwilling to stay abstinent from all cannabis products for the duration of the trial
15. Pregnant or breastfeeding
16. Current diagnosis of cancer, with the exception of non-melanoma skin cancer
17. Any factor, which would make it unlikely that the patient can comply with the trial procedures
18. Moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment
19. Has received systemic immunomodulatory agents prior to randomization:

    1. Methotrexate (within 2 weeks)
    2. Azathioprine (within 24 weeks)
    3. Cyclosporine (within 24 weeks)
    4. Intravenous immune globulin (IVIG) (within 8 weeks)
    5. Corticosteroids (within 4 weeks).