Impact of CardiolRxTM on Recurrent Pericarditis An Open Label Pilot Study (MAvERIC-Pilot Study)
Phase: PHASE2
Conditions: Recurrent Pericarditis
Sponsor: Cardiol Therapeutics Inc.

 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
 
1 
 
 
Clinical Study Protocol 
 
Study Title: 
Impact of CardiolRxTM on Recurrent Pericarditis 
An open label Pilot Study 
Sponsor: 
Cardiol Therapeutics Inc. 
2265 Upper Middle Road East 
Suite 602 
Oakville, ON, L6H 0G5, Canada 
 
Protocol Prepared by: 
Cardiol Therapeutics Inc. 
 
Document Type: 
 
Protocol Number: 
 
Clinical Study Protocol 
 
Cardiol 100-004  
Study Type: 
Pilot Study 
Release Date: 
June 03, 2022, v. 1.2 (Administrative changes) 
 
Amendment 1, July 09, 2022 
Amendment 2, January 18, 2023 
 
 
 
 
 
 
 
 
 
 
STATEMENT OF CONFIDENTIALITY: 
The information in this document contains scientific and commercial information that is 
privileged or confidential and may not be disclosed unless such disclosure is required 
by federal law or regulations.  In any event, persons to whom the information is 
disclosed must be informed that the information is privileged or confidential and may not 
be disclosed by them.  These restrictions on disclosure will apply equally to all future 
information supplied to you, which is indicated as privileged or confidential. 
 
 

Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023
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Signature Page for Sponsor
Protocol No. Cardiol 100-004 
Impact of CardiolRxTM on Recurrent Pericarditis
An open label Pilot Study
Lead Author:
_____________________________________________
__________________
Andrea B. Parker, MSc., PhD        
 
 
 
 
Date
Senior Director, Clinical Operations
Reviewed and Approved by:
___________________________________________ 
__________________
Allan Klein, MD 
 
 
 
 
 
 
 
Date 
Study Chair  
___________________________________________ 
__________________
Andrew Hamer, MD  
 
 
 
 
 
 
Date 
Chief Medical Officer 
 
___________________________________________ 
__________________
Bernard Lim, MIET CEng (UK) 
 
 
 
 
 
Date 
Chief Operating Officer 
 
___________________________________________ 
__________________
Anne Tomalin, BA, BSc, RAPS       
 
 
 
 
Date
Director of Regulatory Affairs
	

________________________________
D
	

___________________________________
arker, MSc., PhD     
or Clinical Operations
	

________________________________
r, MD
Officer
_______________________________
BA, BSc, RAPS      
ulatory Affairs
	

	

_______________________________
IET CEng (UK)
g Officer

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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Signature Page for Investigator 
 
  
 
Title: 
Impact of CardiolRxTM on Recurrent Pericarditis 
 
 
Product: 
 
CardiolRxTM 
Protocol No.: 
 
 
Cardiol 100-004 
Protocol  
Release Date: 
 
June 03, 2022 v. 1.2 (Administrative changes) 
Amendment 1, July 09, 2022 
Amendment 2, January 18, 2022 
 
I have read this protocol and the Investigator Brochure and agree to conduct this trial in 
accordance with all stipulations of the protocol and in accordance with the Declaration 
of Helsinki. 
 
 
 
 
 
 
 
 
 
 
 
Investigator Name 
Signature  
  
Date 
Please print 
 
 
 
 
Please Print 
 
 
 
 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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TABLE OF CONTENTS 
 
1 
STUDY SYNOPSIS ....................................................................................................................................... 7 
2 
LIST OF ABBREVIATIONS ........................................................................................................................... 11 
3 
BACKGROUND.......................................................................................................................................... 15 
3.1 
DESCRIPTION OF RECURRENT PERICARDITIS ........................................................................................................ 15 
3.2 
PREVALENCE ................................................................................................................................................. 16 
3.3 
CLINICAL COURSE .......................................................................................................................................... 17 
3.4 
CURRENT TREATMENT OPTIONS ....................................................................................................................... 17 
3.5 
RATIONALE ................................................................................................................................................... 18 
4 
STUDY OBJECTIVES ................................................................................................................................... 23 
4.1 
EFFICACY ..................................................................................................................................................... 23 
4.1.1 
Primary Objective ................................................................................................................................. 23 
4.1.2 
Primary Efficacy Endpoint .................................................................................................................... 23 
4.1.3 
Additional Efficacy Parameters of Interest .......................................................................................... 23 
4.2 
SAFETY ........................................................................................................................................................ 23 
4.2.1 
Safety Objective ................................................................................................................................... 23 
4.2.2 
Safety Parameters ................................................................................................................................ 23 
5 
STUDY POPULATION ................................................................................................................................ 24 
5.1 
ENROLMENT AND STUDY CENTERS .................................................................................................................... 24 
5.2 
INCLUSION CRITERIA ....................................................................................................................................... 24 
5.3 
EXCLUSION CRITERIA ...................................................................................................................................... 25 
6 
STUDY DESIGN ......................................................................................................................................... 26 
6.1 
SUMMARY OF STUDY DESIGN ........................................................................................................................... 26 
6.2 
EXTENSION PERIOD ........................................................................................................................................ 26 
6.3 
FOLLOW-UP PROCEDURES ............................................................................................................................... 26 
6.4 
STUDY MEDICATION ....................................................................................................................................... 27 
6.5 
PREMATURE INTERRUPTION OR WITHDRAWAL FROM STUDY TREATMENT ................................................................. 27 
6.5.1 
Permanent Suspension of Study Treatment ......................................................................................... 27 
6.5.2 
Temporary Suspension of Treatment ................................................................................................... 28 
6.5.3 
Withdrawal of Consent ........................................................................................................................ 28 
6.6 
CONCOMITANT TREATMENTS ........................................................................................................................... 28 
6.7 
MANAGEMENT OF PERICARDITIS RECURRENCE DURING THE EXTENSION PERIOD ........................................................ 29 
6.8 
CORONAVIRUS 2019 (COVID-19) MEASURES ................................................................................................... 29 
7 
STUDY PLAN ............................................................................................................................................. 31 
8 
INVESTIGATIONAL PRODUCTS, DOSE AND DURATION OF TREATMENT ..................................................... 32 
8.1 
INVESTIGATIONAL PRODUCT ............................................................................................................................ 32 
8.2 
ADMINISTRATION, DOSAGE AND DURATION OF TREATMENT .................................................................................. 32 
8.3 
STUDY TREATMENT RETURN AND RECONCILIATION .............................................................................................. 32 
8.4 
SUPPLY, PACKAGING, LABELLING AND STORAGE .................................................................................................. 32 
8.4.1 
Supply and Packaging .......................................................................................................................... 32 
8.4.2 
Labelling and Storage .......................................................................................................................... 32 
9 
CONDUCT OF THE STUDY .......................................................................................................................... 33 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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9.1 
SCHEDULING OF STUDY PROCEDURES ................................................................................................................ 33 
9.2 
CLINICAL PROCEDURES AND SAFETY EVALUATIONS ............................................................................................... 37 
9.2.1 
Informed Consent ................................................................................................................................. 37 
9.2.2 
Demography ........................................................................................................................................ 37 
9.2.3 
Standard 12-lead Electrocardiogram (ECG) ......................................................................................... 37 
9.2.4 
Medical History .................................................................................................................................... 38 
9.2.5 
Clinical Assessment .............................................................................................................................. 38 
9.2.6 
Vital Signs, Body Height and Weight ................................................................................................... 38 
9.2.7 
Collection of NRS Scores ....................................................................................................................... 38 
9.2.8 
Concomitant Treatment ....................................................................................................................... 38 
9.2.9 
Laboratory Tests .................................................................................................................................. 39 
Laboratory tests include CRP, CBC, AST/ALT, alkaline phosphatase, bilirubin, creatinine/eGFR, INR, 
pregnancy test (female patients of childbearing potential only). Please see Appendix 17.2 for the exact 
schedule of all laboratory tests. Visit 4 (Week 3) can only be virtual if the laboratory assessments can be 
performed by a local laboratory. ................................................................................................................................. 39 
9.2.10 
C-SSRS .............................................................................................................................................. 39 
9.2.11 
Management of AEs ........................................................................................................................ 39 
9.2.11.1 
AE Reporting ............................................................................................................................................ 39 
9.2.11.2 
Pregnancy ................................................................................................................................................ 41 
9.2.11.3 
Drug-Induced Liver Injury (DILI) ............................................................................................................ 41 
9.2.11.4 
Overdose .................................................................................................................................................. 42 
9.2.11.5 
Drug-Drug Interactions ........................................................................................................................... 42 
9.2.12 
Drug Accountability ......................................................................................................................... 42 
10 
CRITERIA FOR EVALUATION OF STUDY RESULTS ........................................................................................ 43 
10.1 
CRITERIA FOR EVALUATION OF EFFICACY ............................................................................................................ 43 
10.1.1 
Primary Efficacy Outcome ............................................................................................................... 43 
10.1.2 
Additional Efficacy Parameters of Interest ...................................................................................... 43 
10.2 
CRITERIA FOR EVALUATION OF SAFETY ............................................................................................................... 43 
10.3 
DESCRIPTION OF PATIENT GROUPS FOR ANALYSES ............................................................................................... 43 
10.3.1 
Population for Efficacy and Safety Analyses ................................................................................... 43 
11 
STATISTICAL METHODS ............................................................................................................................ 44 
11.1 
SAMPLE SIZE ESTIMATION ............................................................................................................................... 44 
11.2 
OUTCOME ANALYSES ..................................................................................................................................... 44 
11.3 
SAFETY ANALYSES .......................................................................................................................................... 44 
11.4 
MISSING VALUES ........................................................................................................................................... 44 
11.5 
STOPPING GUIDELINES .................................................................................................................................... 44 
12 
ORGANISATIONAL STRUCTURE ................................................................................................................. 45 
12.1 
SPONSOR ..................................................................................................................................................... 45 
12.2 
CONTRACT RESEARCH ORGANIZATION (CRO) ..................................................................................................... 45 
13 
DATA COLLECTION AND MONITORING ..................................................................................................... 46 
13.1 
CASE REPORT FORMS (CRFS) .......................................................................................................................... 46 
13.2 
DATA COLLECTION AND CLEANING .................................................................................................................... 46 
13.2.1 
Data Collection ................................................................................................................................ 46 
13.2.2 
Data validation ................................................................................................................................ 46 
13.3 
MONITORING ............................................................................................................................................... 46 
13.3.1 
Virtual and/or On-site Monitoring .................................................................................................. 46 
13.3.2 
In-house Monitoring ........................................................................................................................ 46 
13.3.3 
Audit/Inspection .............................................................................................................................. 47 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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14 
INVESTIGATOR RESPONSIBILITIES AND OBLIGATIONS ............................................................................... 48 
14.1 
DECLARATION OF HELSINKI .............................................................................................................................. 48 
14.2 
LOCAL IRB/REB ........................................................................................................................................... 48 
14.3 
INFORMED CONSENT AND PATIENT PROTECTION ................................................................................................. 48 
14.3.1 
Patient Informed Consent ............................................................................................................... 48 
14.3.2 
Patient Data Protection .................................................................................................................. 49 
14.4 
STUDY PROTOCOL ADHERENCE AND MODIFICATIONS ........................................................................................... 49 
14.4.1 
Protocol Adherence ......................................................................................................................... 49 
14.4.2 
Changes to Protocol and Related Procedures ................................................................................. 49 
14.5 
INVESTIGATIONAL PRODUCT CONTROL ............................................................................................................... 49 
14.6 
DATA COLLECTION AND DOCUMENTATION ......................................................................................................... 50 
14.7 
REPORTING OF AES AND SAES ......................................................................................................................... 50 
14.8 
RECORDS RETENTION ..................................................................................................................................... 50 
14.9 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT RECORDS ........................................................................... 51 
14.10 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................................................................................. 51 
15 
STUDY TIMELINES .................................................................................................................................... 52 
16 
REFERENCES ............................................................................................................................................. 53 
17 
APPENDICES ............................................................................................................................................. 61 
17.1 
DECLARATION OF HELSINKI .............................................................................................................................. 61 
17.2 
SCHEDULE OF STUDY PROCEDURES .................................................................................................................... 65 
17.3 
NUMERICAL RATING SCALE (NRS) .................................................................................................................... 66 
17.4 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – BASELINE/SCREENING VERSION ....................... 67 
17.5 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – SINCE LAST VISIT VERSION ............................... 73 
17.6 
DRUGS THAT CAN PROLONG QTC INTERVALS ....................................................................................................... 79 
17.7 
DRUGS THAT ARE STRONG INDUCERS OF CYP3A4 AND CYP2C19 ......................................................................... 82 
17.7.1 
CYP3A4 Inducers .............................................................................................................................. 82 
17.7.2 
CYP2C19 Inducers ............................................................................................................................ 82 
17.8 
CANNABIDIOL AND DRUG-DRUG INTERACTIONS .................................................................................................. 83 
 
 
 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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1 STUDY SYNOPSIS 
Protocol Title 
Impact of CardiolRxTM on Recurrent Pericarditis 
An open label Pilot Study 
Diagnosis 
Recurrent Pericarditis 
Rationale 
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.. 
Inclusion Criteria 
The following inclusion criteria must be met to enroll a patient into this 
study: 
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; 
a. C-Reactive Protein** (CRP) level ≥1.0 mg/dL within prior 
7 days OR 
b. 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 for treatment of 
pericarditis (in any combination) 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: 
a. Pericarditic chest pain 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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b. Pericardial rub 
c. New widespread ST-segment elevation or PR-segment 
depression according to electrocardiogram (ECG) findings 
d. Pericardial effusion (new or worsening) 
 
** Conversion: 1 mg/dL CRP = 10 mg/L hs-CRP 
Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the 
study: 
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 arrhythmias 
6. History of QT interval prolongation  
7. QTc interval > 500 msec (please refer to Section 9.2.3 for bundle 
branch block, bifascicular block and paced rhythm correction) 
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: 
a. Rilonacept 
b. Anakinra 
c. Canakinumab 
d. Methotrexate 
e. Azathioprine 
f. Cyclosporine 
g. Intravenous immune globulin (IVIG) 
Primary Efficacy 
Objective 
The primary objective is to evaluate the effect of treatment with 
CardiolRxTM on recurrent pericarditis. 
Primary Efficacy 
Endpoint 
The primary efficacy endpoint is the change in patient-reported pericarditis 
pain using an 11-point NRS from baseline to 8 weeks. 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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Additional Efficacy 
Endpoints of Interest 
- 
Pain score using 11-point NRS after 26 weeks of treatment  
- 
Percentage of patients with normalized CRP levels at 8 weeks (for 
patients with CRP ≥1.0 mg/dL at baseline) 
- 
Percentage of patients with pericarditis recurrence during the 
extension period (EP) 
- 
Percentage of patients with normalized CRP levels at 26 weeks 
(for patients with CRP ≥1.0 mg/dL at baseline) 
- 
Time to CRP normalization for patients with CRP ≥1.0 mg/dL at 
baseline 
- 
CRP change from baseline at 26 weeks (%)  
Safety Objective 
The primary safety objective is to demonstrate that administration of 
CardiolRxTM in the proposed doses in this patient population is safe. 
Safety Parameters 
Safety parameters include the number of adverse events (AEs) and 
serious adverse events (SAEs), changes in C-SSRS as well as changes 
in laboratory parameters, including liver function parameters and INR as 
well as ECG intervals and rhythm during the 26-week study period. 
Number of 
Patients/Sites: 
Approximately 25 patients will be enrolled in multiple centers. 
Scheduled Duration of 
Study: 
Estimated 4 months site setup, 12 months recruitment, 26 weeks of 
follow-up, approximately 2 months data cleaning and database lock, 2 
months for analysis and report, for a total of approximately 26 months. 
Design & Methodology 
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 as well as any (S)AEs after 
informed consent has been obtained. 
Study treatment will be initiated in eligible patients in the evening of Day 1, 
after all baseline assessments are completed.  
Oral administration (accompanied by food) is as follows: 
• 
Initial starting dose (Day 1 p.m. dose to Day 3 a.m. dose):  
5 mg/kg of body weight CardiolRxTM b.i.d.  
• 
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 study (a.m. dose on Week 26):  
10 mg/kg of body weight CardiolRxTM b.i.d. 
• 
The morning and evening doses should be taken minimally 6 
hours and maximally 18 hours between each intake. 
If the next higher dose after each study drug increase is not tolerated, the 
dose will be reduced to the previous tolerated dose.  

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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Unless contraindicated in the opinion of the investigator, after 8 weeks of 
study treatment, patients will enter an 18-week EP, in which they continue 
study treatment while their concomitant medications to treat pericarditis 
will be weaned. 
Follow-up Procedures 
At every assessment before study drug dose increase the patient will be 
re-evaluated. This includes a twelve-lead ECG at approximately 5 hours 
post-morning dose (Tmax) to surveil for deleterious effects on ECG 
intervals (particularly the QTc interval) and rhythm.  
Drug titration to 7.5 and 10 mg/kg b.i.d. will be dependent on investigator 
or designate interrogation of the ECGs and the absence of clinically 
significant abnormalities on those ECGs. 
Concurrent medication changes and (S)AEs will be recorded at all visits. 
Vital signs, blood chemistry including liver function tests, hematology as 
well as INR assessments will be carried out at selected visits (see detailed 
schedule in Appendix 17.2).  
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. 
Concomitant 
Treatments 
Patients must be on Standard of care (SOC) treatments with NSAIDs, 
colchicine, or corticosteroids (in any combination) prior to Day 1. These 
SOC treatments will be weaned during the 18 weeks EP, as described in 
Section 6.6.  
Patients will not be allowed to be on immunosuppressive therapy with 
rilonacept, anakinra, canakinumab, methotrexate, azathioprine, 
cyclosporine, mycophenolate and/or IVIG and cannot take any 
cannabinoids during the study period or strong inducers of CYP3A4 and 
CYP2C19 (see Appendix 17.7). Drugs that are known to prolong QT 
intervals must not be started during the trial. (Appendix 17.6) 
Statistical Analysis 
Approach 
Given the small sample size and the design of the study (no placebo 
comparison), no inferential statistical analyses are planned.  
Depending on their distribution, continuous variables will be expressed as 
mean ± standard deviation (SD) or as median (Interquartile range [IQR]). 
Categorical variables will be expressed in counts with percentages. 
For all continuous variables, including the NRS pain score, the change 
from baseline will be presented as summary statistics.  
For categorical variables, summary statistics will be calculated. 
 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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2 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
5-HT1A  
5-Hydroxy Tryptamine (Serotonin) Receptor 1A   
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
a.m. 
Morning 
ASC 
Apoptosis-associated speck-like protein containing a caspase 
recruitment domain 
AST 
Aspartate Aminotransferase 
ATP 
Aadenosine triphosphate 
BBB 
Bundle Branch Block 
b.i.d. 
Twice a Day 
BNP 
Brain Natriuretic Peptide 
CB1/CB2 
Cannabinoid receptors 1/2 
CBC 
Complete Blood Count 
CBD 
Cannabidiol 
CMR 
Cardiac Magnetic Resonance Imaging 
CRF  
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV 
Cardiovascular 
DDI 
Drug-Drug Interaction 
DILI 
Drug-Induced Liver Injury 
DOX 
Doxorubicin 
EAM 
Experimental Autoimmune Myocarditis 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eDCF 
Electronic Data Clarification Form 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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Abbreviation 
Definition 
EDV 
End Diastolic Volume 
eGFR 
Estimated Glomerular Filtration Rate 
EP 
Extension period 
ESC 
European Society of Cardiology 
ESR 
Erythrocyte sedimentation rate 
eTMF 
Electronic trial master file 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practices 
GI 
Gastrointestinal 
GPR 
G-Protein-coupled Receptor 
hGMSCs 
Human gingival mesenchymal stem cells  
HFC 
High-fat, high-cholesterol  
HR 
Heart Rate 
Hs-CRP 
High-sensitivity C-reactive protein 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH  
International Conference on Harmonization 
IFN-gamma 
Interferon-gamma 
IL-1 α 
Interleukin 1-alpha 
IL-1 β 
Interleukin 1-beta 
IL-6 
Interleukin 6 
INR 
International Normalized Ratio 
IRB/REB 
Institutional Review Board/Research Ethics Board 
IQR 
Interquartile range 
IVIG 
Intravenous immune globulin 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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Abbreviation 
Definition 
LBBB 
Left Bundle Branch Block 
LPS 
Lipopolysaccharide 
LVAD 
Left ventricular assist device 
MCP1 
Monocyte Chemoattractant Protein-1 
MCT 
Medium-chain triglyceride 
NF-κB 
Nuclear factor kappa light chain enhancer of activated B cells 
NLRP 
Nod-Like Receptor Protein 
NLR 
NOD-like receptor 
NOD 
Nucleotide-binding and oligomerization  
NRS 
Numerical Rating Scale 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
p.m. 
Afternoon 
PPAR-gamma 
Peroxisome Proliferator-Activated Receptor Gamma 
RBBB 
Right Bundle Branch Block 
ROS 
Reactive oxygen species 
SAE 
Serious Adverse Event 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SD 
Standard Deviation 
SOC  
Standard of Care 
TB 
Tuberculosis 
THC  
Tetrahydrocannabinol 
Tmax 
Time to Maximum Concentration 
TNF- α 
Tumor Necrosis Factor Alpha 
NRF2 
Nuclear factor erythroid 2-related factor 2 
TRP 
Transient Receptor Potential 
ULN 
Upper Limit of Normal 
UVA 
Ultraviolet rays A  

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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Abbreviation 
Definition 
UVB 
Ultraviolet rays B 
WBC 
White Blood Count 
 
 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
15 
3 BACKGROUND 
3.1 Description of Recurrent Pericarditis 
Recurrent pericarditis is a disease characterized by a remitting-relapsing inflammation 
(or symptoms that fluctuate in severity) of the pericardium, a thin tissue sac surrounding 
the heart.(A. L. Klein, Imazio, et al. 2021)   
Pericarditis often causes chest pain, which can be sharp.  This chest pain worsens 
when patients take a deep breath.  Etiologies of pericarditis include infectious causes 
(viral, bacterial, fungal and parasitic) and non-infectious causes (idiopathic, 
autoimmune, neoplastic, metabolic, traumatic, post-surgical and drug-related)(Massimo 
Imazio et al. 2010; Zayas et al. 1995).  In 80% of cases in developed countries, the 
cause of pericarditis is either post-viral or “idiopathic” in that it cannot be attributed to a 
specific condition.(Mauro et al. 2021) 
Diagnosis of pericarditis is based on the presence of typical chest pain (improved by 
sitting up and leaning forward) along with fever, pericardial friction rub, 
electrocardiographic changes, pericardial effusion, or elevated levels of inflammation 
markers [white blood cell count (WBC), CRP, or erythrocyte sedimentation rate (ESR)]. 
The ESC Guidelines for the Diagnosis and Management of Pericardial Diseases define 
an acute pericarditis episode as the presence of at least 2 of the 4 following criteria: 
pericarditic chest pain, pericardial rubs, new widespread ST-segment elevation or PR-
segment depression based on ECG findings, and pericardial effusion (new or 
worsening).  Elevations of certain markers of inflammation (i.e., CRP, ESR and WBC) or 
evidence of pericardial inflammation by an imaging technique, e.g., CMR are used as 
supportive findings.(Adler et al. 2015)  
For most patients, pericarditis manifests as a single episode that lasts a few days to 
several weeks, and symptoms are resolved through conventional treatments such as 
NSAIDs with or without colchicine. 
There are, however, some patients who do not experience long-term symptom 
resolution after an acute pericarditis episode. Up to 30% of patients experience 
recurrent pericarditis within 18 months when a subsequent episode occurs following a 
symptom-free period of at least 4 weeks. Beyond the first recurrence, the clinical picture 
of recurrent pericarditis varies broadly, with some patients responding well to 
conventional therapy and having no further recurrence. By contrast, 25% to 50% of 
patients who have experienced a first recurrence will experience additional recurrences, 
and among patients who have experienced ≥2 recurrences, 20% to 40% are expected 
to have subsequent episodes.(A. Klein et al. 2021)  
 
The etiology of recurrent pericarditis is presumed to be an immune-mediated 
phenomenon related to an incomplete treatment of the disease rather than to a 
recurrent viral infection. (Chiabrando et al. 2020) This is supported by the time to event, 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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the evidence of non-organ-specific antibodies, and the good response to corticosteroid 
therapy. Factors associated with an increased risk of recurrences are female sex, 
previous corticosteroid use, and frequent prior recurrences. 
 
Although its pathogenesis is not completely understood, it has been hypothesized that 
pericarditis represents a stereotypical response to an acute injury of the mesothelial 
cells of the pericardium.(Buckley et al. 2018; Brucato et al. 2016) The trigger, an 
“irritant,” such as a virus or cellular debris following a viral infection, may activate the 
NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) 
inflammasome, a macromolecular intracellular complex evolved to sense stress or injury 
and then trigger a local or systemic inflammatory response through the release of 
proinflammatory cytokines, such as interleukin (IL)-1β. The NLRP3 inflammasome is 
formed by the oligomerization of: 1) a sensor, namely NLRP3, which is a member of the 
NOD-like receptor (NLR) proteins; 2) a scaffold protein, apoptosis-associated speck-like 
protein containing a caspase recruitment domain (ASC); and 3) an effector, caspase-1, 
whose activation is strictly required for the activity of the inflammasome as it cleaves 
pro–IL-1β to the active IL-1β. IL-1α is another isoform of the IL-1 family that is released 
during cellular injury, functioning as an alarmin, and triggering the same inflammatory 
signaling as IL-1β.(Mauro et al. 2021)  
 
A recent study (Mauro et al. 2021) described the presence of NLRP3 inflammasome 
expression in human pericardial specimens from patients with pericarditis. It also 
demonstrated that the phenotype of acute pericarditis—thickening of the pericardium, 
presence of an effusion, and inflammation associated with NLRP3 expression—can be 
reproduced in a mouse model with the instillation within the pericardial space of 
zymosan A, an activator of the NLRP3 inflammasome. Furthermore, drugs known to 
inhibit the NLRP3 inflammasome pathway (i.e., colchicine, NLRP3inh 16673-34-0, 
anakinra, and the rilonacept) were found to reduce all or most of the above-mentioned 
inflammatory effects. 
3.2 Prevalence 
Exact epidemiological data for acute pericarditis are lacking. The incidence was 
reported as 27.7 cases per 100,000 person-years in an urban area in Northern Italy, 
with concomitant myocarditis in about 15% of cases.(Massimo Imazio and Gaita 2017) 
Acute pericarditis is diagnosed in 0.2% of all cardiovascular (CV) in-hospital admissions 
and is responsible for 5% of emergency room admissions for chest pain in North 
America and Western Europe. (Spodick 2003; Massimo Imazio et al. 2010; 2004; Kytö, 
Sipilä, and Rautava 2014) Up to 30% of patients with an acute pericarditis experience a 
recurrence after an initial symptom-free period of 4 to 6 weeks.(Massimo Imazio et al. 
2013) 
 
The estimated prevalence of recurrent pericarditis in the US and Europe is 70,000 to 
160,000 patients including approximately 8,000 to 21,000 patients who are refractory or 
intolerant to current therapies or who require long-term administration of corticosteroids 

 
 
 
 
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17 
to control their disease.(Lazaros et al. 2016; Massimo Imazio et al. 2010; Khandaker et 
al. 2010; M. Imazio et al. 2008)  
 
A recent retrospective US database analysis included newly diagnosed patients with 
recurrent pericarditis with ≥24 months of continuous history following their first 
pericarditis episode found that recurrent pericarditis of idiopathic or post-viral etiology 
has a US prevalence of about 37,000 cases, of which approximately half are expected 
to develop a complication or require a procedure within 2 years of diagnosis.(A. Klein et 
al. 2021) 
3.3 Clinical Course 
Within the population of recurrent pericarditis, some patients, including those with 
multiple recurrences or other serious complications, are at higher risk for adverse 
outcomes. Cremer et al (Cremer et al. 2016) have proposed a set of real–world clinical 
stages of pericarditis: acute, first recurrence, multiple recurrences, colchicine-resistant 
or steroid-dependent, and constrictive. While each stage is clearly defined clinically, the 
epidemiology of patients who experience multiple recurrences and/or recurrence plus 
complications is not well understood. Multiple recurrences and/or complications occur in 
up to one-third of patients with acute pericarditis, leading to increased morbidity, 
prolonged disease duration, impaired physical and mental health-related quality of life, 
and clinical complications. Complications related to pericarditis include serious and 
potentially life-threatening issues such as cardiac tamponade, constrictive pericarditis, 
or pericardial effusion. Patients who experience multiple recurrences and/or have 
serious complications or comorbidities may utilize substantial healthcare resources 
without necessarily experiencing clinical improvement.  
3.4 Current Treatment Options 
Currently, there are no US treatment guidelines for pericarditis or recurrent pericarditis; 
standard therapy consists of NSAIDs or aspirin with or without colchicine. 
Corticosteroids and other off-label immunosuppressants are used in patients with 
continued recurrence and inadequate response to conventional therapy.(Lotrionte et al. 
2010) European guidelines indicate that corticosteroids should generally be avoided, as 
their use has been associated with increased risk of recurrence, particularly if the dose 
is tapered rapidly. In the most severe cases, pericardiectomy may be performed, 
although it does not always prevent recurrence. Among the patients with recurrent 
pericarditis with multiple recurrences and/or complications, disease burden is 
substantial and treatment options are currently inadequate.(Adler et al. 2015) 
 
The potential of IL-1 inhibition was evaluated in a trial of the recombinant IL-1-receptor 
antagonist anakinra in a small number of patients with colchicine-resistant idiopathic 
recurrent pericarditis who had previously had pericarditis recurrence after the 
withdrawal of glucocorticoids; many of the patients continued using colchicine during 
that trial.(Brucato et al. 2016) A subsequent phase 2 trial of rilonacept, an IL-1α and IL-
1β cytokine trap (A. L. Klein, Lin, et al. 2021), provided early evidence of resolution of 

 
 
 
 
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pericardial inflammation. The phase 3 trial RHAPSODY was then conducted to test the 
primary hypothesis that rilonacept would lead to a lower risk of pericarditis recurrence 
than placebo. The trial found that among the patients with recurrent pericarditis, 
rilonacept led to rapid resolution of recurrent pericarditis episodes and to a significantly 
lower risk of pericarditis recurrence than placebo after withdrawal of background 
therapy.(A. L. Klein, Imazio, et al. 2021) The only approved therapy for the treatment of 
recurrent pericarditis is rilonacept. 
 
The clinical benefit seen with IL-1 inhibitors is hypothesized to be indirect evidence of 
the involvement of the NLRP3 inflammasome signaling in the pathophysiology of 
pericarditis.(Mauro et al. 2021) 
3.5 Rationale 
It is proposed that CardiolRxTM (a pure CBD oral solution), that is known to have anti-
inflammatory properties, can treat the underlying inflammatory process and thereby 
favorably modify recurrent pericarditis. 
 
CBD interacts with a range of cellular receptors, which could potentially account for the 
anti-inflammatory activities of CBD. Published evidence indicates that CBD is active at 
peroxisome proliferator-activated receptor gamma (PPAR-gamma) receptors.(De 
Filippis et al. 2011; Giuseppe Esposito et al. 2011; Saoirse Elizabeth O’Sullivan 2016) 
5-Hydroxy Tryptamine (Serotonin) Receptor 1A  (5-HT1A) (Mishima et al. 2005; Pazos 
et al. 2013; Resstel et al. 2009), Adenosine A1 and A2 receptors (Ribeiro et al. 2012; 
Carrier, Auchampach, and Hillard 2006), transient receptor potential (TRP) channels, 
including TRPV1, TRPV2, TRPM8, TRPA1 (Hegde, Nagarkatti, and Nagarkatti 2011; 
Laragione et al. 2015; Muller, Morales, and Reggio 2019), and the G-protein-coupled 
receptors GPR55, GPR18, GPR6 and GPR3 (Brown 2007; Laun and Song 2017; 
Morales and Reggio 2017), although probably not at the canonical endocannabinoid 
receptors CB1 (Reggio et al. 1995; Mukhopadhyay et al. 2011; McPartland et al. 2017) 
and CB2 (Mukhopadhyay et al. 2011; McPartland et al. 2017). 
 
Effects of Cannabidiol on the inflammasome: 
 
While the exact molecular mechanisms by which cannabidiol modulates inflammasome 
signaling has not been investigated completely, the current evidence supports their 
importance as promising therapy to regulate inflammasome signaling.(Suryavanshi, 
Kovalchuk, and Kovalchuk 2020) 
 
The first report on the direct effect of CBD on the inflammasome came in 2016 from a 
group of Italian researchers.(Libro et al. 2016) They treated human gingival 
mesenchymal stem cells (hGMSCs) for 24 h with CBD (5 mM) and performed gene 
expression analysis and immunocytochemistry. They discovered that CBD-treated 
hGMSCs suppressed NLRP3, caspase-1, and IL-18 at the gene and protein levels and 
inhibited NF-κB. As NF-κB is involved in the priming of the NLRP3 inflammasome, the 

 
 
 
 
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CBD treatment– induced inactive state of the NLRP3 inflammasome in hGMSCs 
suggested that CBD-treated gingival stem cells were more immunocompetent, avoiding 
the risk of inflammatory reactions and promoting survival. Mice fed with a high-fat, high 
cholesterol (HFC) diet for 8 weeks showed significantly higher expressions of NLRP3 
inflammasome pathway proteins (NLRP3, ASC, IL-1β, and caspase-1) in the liver; these 
proteins were significantly attenuated by simultaneous treatment with CBD (5 mg/kg/day 
for 8 weeks). Similarly, the phosphorylation of NF-κB was significantly reduced in the 
liver of CBD-treated HFC mice compared to the non-treated group, corroborating the 
role of NF-κB in priming the NLRP3 inflammasome. To further confirm the role of the 
inflammasome in liver inflammation, the authors studied the effect of CBD on an LPS + 
ATP treated mouse macrophage cell line, confirming with in vivo data that the 
expressions of NLRP3, ASC, IL-1β, NF-κB, and caspase-1 were lower in CBD-treated 
cells. (Huang et al. 2019) Mouse microglial cells treated with LPS to simulate 
neuroinflammatory conditions exhibited a robust activation of pro-inflammatory cytokine 
repertoire, and CBD (1–10 mM) was able to suppress the secretion of IL-1β and inhibit 
the NF-κB signaling pathway.(Dos-Santos-Pereira et al. 2019). 
 
In an in vitro skin inflammation model, human keratinocytes were treated with ultraviolet 
rays A and B (UVA and UVB) and treated with CBD (1 mM) for 24 h. CBD inhibited 
protein-protein interaction between nuclear factor erythroid 2-related factor 2 (Nrf2) and 
NF-κB in UVA- and UVB-treated skin cells. CBD increased NRF2 expression, leading to 
decreased reactive oxygen species (ROS), which in turn may have partially suppressed 
NLRP3 inflammasome activation by reducing NF-κB levels.(Jastrząb, Gęgotek, and 
Skrzydlewska 2019). Beta Amyloid induced neurotoxicity (G Esposito et al. 2007) and 
the severity of inflammatory colitis (Borrelli et al. 2009) were significantly suppressed by 
CBD treatment in mice partly due to inhibiting the expression and release of IL-1β. 
 
A significant reduction of IL-1β by CBD treatment in a murine viral model of multiple 
sclerosis was also shown, suggesting its role in combating inflammation in multiple 
sclerosis. (Mecha et al. 2013) Recently, CBD was shown to inhibit NLRP3 
inflammasome by reducing K+ efflux by binding to the P2X7 receptor in human 
monocytes.(Liu et al. 2020) Remarkably, the fact that only CBD (non-psychoactive), not 
tetrahydrocannabinol (THC) (psychoactive), was found to inhibit NFκB signaling 
(Rimmerman et al. 2011), coupled with the direct proven inhibitory action of CBD on 
inflammasomes (Huang et al. 2019) and downstream proteins, indicates the 
incomparable potential of CBD as an inflammasome-inhibitory drug target. 
 
Evidence of an effect of CBD on inflammatory markers in humans is limited.  A recent 
randomized controlled trial studied the effects of 12 weeks of 800 mg/day of pure CBD 
on inflammatory markers in 48 individuals with cocaine use disorder. It was seen that, 
compared to participants receiving placebo (n = 24), those participants treated with CBD 
(n = 24) had significantly lower levels of IL-6 (p = 0.017), vascular endothelial growth 
factor (VEGF; p = 0.032), intermediate monocytes CD14+CD16+ (p = 0.024), and 
natural killer CD56negCD16hi (p = 0.000).(Morissette et al. 2021) An earlier clinical 
study in patients with type 2 diabetes assessed CBD effects on three inflammatory 

 
 
 
 
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markers: IL-6, CRP, and tumor necrosis factor-α (TNF-α). The authors found no 
significant difference between the CBD (n = 13) and placebo (n = 14) groups on these 
markers with 100 mg CBD twice daily for 13 weeks; however, this dose is low compared 
to other human studies (Bergamaschi et al. 2011; Leweke et al. 2012; Morissette et al. 
2021) that use higher doses of CBD (600 – 800 mg/day), which may explain lack of 
therapeutic effects seen with CBD in this study.(Jadoon, Tan, and O’Sullivan 2017) 
 
Effects of CBD on models of CV inflammation including pericarditis: 
 
CBD improves endothelial function, and endothelial dysfunction is an important 
therapeutic target in a number of CV diseases including heart failure. CBD reduces 
inflammatory activation of the endothelial lining of blood vessels (Rajesh et al. 2007) 
thus improving endothelial vaso-relaxation (Stanley et al. 2015; Saoirse E. O’Sullivan et 
al. 2009) and blood flow. CBD has also been shown to attenuate a number of measures 
of potential importance in the treatment of heart failure, including cardiac dysfunction, 
oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in models 
of diabetes (Rajesh et al. 2010), a common co-morbidity in CV disease patients.  CBD 
has also been shown to be protective against doxorubicin (DOX)-induced cardiotoxicity, 
including reducing pro-inflammatory responses in the heart.(Fouad et al. 2013; Hao et 
al. 2015)  
 
A murine model of experimental autoimmune myocarditis (EAM) induced by 
immunization with the myocarditogenic cardiac myosin peptide (αMHC334–352) resulted in 
T cell infiltration into the myocardium, T cell–mediated inflammation, cardiomyocyte cell 
death, fibrosis and myocardial dysfunction.  In this model, chronic treatment with CBD 
(10 mg/kg, ip for 46 days) reduced the infiltration of the myocardium by inflammatory 
cells, decreased myocardial inflammation as reflected by lowered levels of inflammatory 
cytokines and chemokines (IL-6, IL-1β, IFN-gamma, MCP1), reduced markers of 
oxidative stress and reduced myocardial fibrosis.(Lee et al. 2016)  
 
The effect of CBD was also investigated on the cardiomyocyte cell line H9c2. H9c2 cells 
respond to angiotensin II by increasing in size, reflecting the myocardial hypertrophy 
seen in heart failure.  The surface area of cultured cardiomyocytes is significantly 
increased by angiotensin II, and this increase is significantly decreased by CBD.  
Similarly, the expression of both BNP and collagen by H9c2 cells is significantly 
increased by angiotensin II and, again, this increase is prevented by CBD (Cardiol 
Therapeutics, unpublished data).  In conclusion, CBD reduces the deleterious effect of 
angiotensin II on cardiomyocytes, including abrogating increases in cardiomyocyte size 
and the expression of remodeling markers. 
 
In addition, the animal model of heart failure in male C57BL/6 mice, based on the 
published method of Cordero-Reyes has been used to assess CBD 
effectiveness.(Cordero‐Reyes et al. 2016) This is a model of cardiac inflammation with 
associated depression of myocardial function. The results show that CBD reduced 

 
 
 
 
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inflammation and fibrosis induced by angiotensin-II in this model of heart failure.  
Measurements of myocyte area showed that CBD administered by sub-cutaneous 
injection resulted in a significant reduction at doses of both 1 and 10 mg/kg. 
Measurements of BNP, which is released from cardiomyocytes in response to 
excessive stretching and is elevated in heart failure, showed that CBD reduced 
expression of BNP in heart failure hearts.(Lozano et al. 2020)  In conclusion, CBD 
administered by subcutaneous injection reduced a number of markers reflecting heart 
failure in this model system. 
 
Cardiol Therapeutics is currently conducting a trial in patients with acute myocarditis 
(IND 145215). A trial in patients with COVID-19 at high CV risk (IND 152096) has been 
discontinued due to a lack of eligible hospitalized COVID-19 patients. 
 
The efficacy of cannabidiol has been tested in a mouse model of acute pericarditis that 
was developed to investigate whether the pathophysiology of acute pericarditis is linked 
to a virus or another irritant activating the NLRP3 inflammasome, leading to IL-1β 
release, COX-2 activation, and prostaglandins production. (Mauro et al. 2021) The 
model uses zymosan A, a product of the yeast wall that activates NLRP3, injected 
directly into the pericardial space. Pericardial inflammation is measured by 
echocardiography (pericardial effusion) and at pathology (pericardial thickening, 
expression of the NLRP3 inflammasome component ASC). Results have demonstrated 
that cannabidiol treatment significantly reduces the pericardial effusion and pericardial 
thickening induced by zymosan A in this model. 
 
Additional in vitro models using activated murine macrophages have demonstrated 
cannabidiol’s ability to significantly inhibit release of the inflammatory cytokines IL-1β 
and IL-6, and significantly inhibit transcription of NLRP3 and pro-IL-1β. Together, these 
results suggest cannabidiol plays a role in attenuating multiple inflammatory pathways, 
including inhibiting activation of the NLRP3 inflammasome. These results have been 
presented at and the American Heart Association Scientific Sessions 2022. (Martinez-
Naya 2022). This model has been used previously to demonstrate the efficacy of 
colchicine, IL-1 blockers anakinra and rilonacept, and NLRP3 inhibitors in reducing 
pericardial effusion and thickening. Cannabidiol has now also been shown to 
significantly reduce pericardial effusion and thickening in this mouse model of acute 
pericarditis, suggesting cannabidiol may represent a novel strategy for treating 
pericarditis, its complications, and preventing its recurrence. 
 
Unmet need: 
 
The recent US Database Study (A. Klein et al. 2021) found the most-commonly 
prescribed treatments for a first episode were colchicine alone (12%), or with NSAIDs 
(14%). Second, third, fourth, and fifth episodes were most-commonly treated with 
colchicine alone, corticosteroids alone, or another drug (not colchicine, corticosteroid, or 
NSAID; included intravenous immunoglobulin, azathioprine, methotrexate, and 
cyclosporine). The percentage of patients receiving something other than 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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corticosteroids, NSAIDs, or colchicine, alone or in combination, rose from 4% in the first 
episode up to 17% in the fourth episode and 15% in the fifth episode. This data was 
collected prior to the publication of the RHAPSODY trial and subsequent approval of 
rilonacept by the FDA for treatment of recurrent pericarditis and reduction in risk of 
recurrence.(A. L. Klein, Imazio, et al. 2021) 
 
The low level of utilization of colchicine is likely due to a multitude of factors. Colchicine 
has a narrow therapeutic window with risk of fatal overdose, significant drug 
interactions, and neuromuscular toxicity. In addition, approximately 10% to 15% of 
patients experience significant gastrointestinal (GI) side effects with colchicine, including 
GI intolerance or severe diarrhea, requiring treatment discontinuation.(Cremer et al. 
2016) Colchicine resistance likely leads to its use being abandoned in many patients. 
 
The ESC guidelines stipulate that corticosteroids should be prescribed for the 
management of pericarditis episodes only in cases of incomplete response, intolerance, 
or contraindications to NSAIDs and colchicine because of their unfavorable long-term 
benefit-risk profile.  Corticosteroid use is associated with side effects, including weight 
gain, diabetes, osteoporosis, avascular bone necrosis, and increased risk for 
infections.(Massimo Imazio et al. 2008)  For the management of pericarditis, 
corticosteroids are usually administered at low to moderate doses and can provide rapid 
control of symptoms.  However, they often require many months of tapering after the 
normalization of CRP levels.  In addition, there is a high rate of pericarditis relapse 
when corticosteroid use is tapered or stopped (Maisch et al. 2004; Lotrionte et al. 2010), 
particularly in the absence of concurrent colchicine treatment. 
 
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 can be particularly challenging to manage. While rilonacept is now 
available to some of these patients, its uptake has been low and there is the need for a 
safe, well tolerated, oral, accessible medication to add to the therapeutic options for 
these patients. 
 
Rationale for pilot study: 
 
This pilot study is to assess the tolerance and safety of CardiolRxTM during the 
resolution of pericarditis symptoms, evaluate improvement in objective measures of 
disease, and during the extension period assess the feasibility of weaning concomitant 
background therapy including corticosteroids while taking CardiolRxTM. The results of 
this trial will inform the feasibility of designing a randomized double blind withdrawal trial 
to assess the effects of CardiolRxTM vs placebo in the treatment and prevention of 
recurrent pericarditis. 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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4 STUDY OBJECTIVES 
4.1 Efficacy 
4.1.1 Primary Objective 
The primary objective is to evaluate the effect of treatment with CardiolRxTM on 
recurrent pericarditis. 
4.1.2 Primary Efficacy Endpoint 
The primary efficacy endpoint is patient-reported pericarditis pain using an 11-point 
NRS pain score, validated across multiple conditions with acute and chronic pain 
(Dworkin et al. 2005; Mannion et al. 2007; Hawker et al. 2011) from baseline (highest 
pain score within the past 7 days of Day 1) to Week 8 (highest pain score during the 
past 7 days of Week 8). 
4.1.3 Additional Efficacy Parameters of Interest 
- 
Pain score using 11-point NRS from baseline (highest pain score within the past 
7 days of Day 1) to Week 26 (highest pain score during the past 7 days of Week 
26)  
- 
Percentage of patients with normalized CRP levels at 8 weeks (for patients with 
CRP ≥ 1.0 mg/dL at baseline) 
- 
Percentage of patients with pericarditis recurrence during the EP 
- 
Percentage of patients with normalized CRP levels at 26 weeks (for patients with 
CRP ≥1.0 mg/dL at baseline) 
- 
Time to CRP normalization for patients with CRP ≥1.0 mg/dL at baseline 
- 
CRP change from baseline at 26 weeks (%)  
 
4.2 Safety 
4.2.1 Safety Objective 
The primary safety objective is to demonstrate that administration of CardiolRxTM in the 
proposed doses in this patient population is safe. 
4.2.2 Safety Parameters 
Safety parameters include the number of AEs and SAEs, changes in C-SSRS as well 
as changes in laboratory parameters, including liver function parameters and INR as 
well as ECG intervals and rhythm during the 26-week study period. 

 
 
 
 
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24 
5 STUDY POPULATION 
5.1 Enrolment and Study Centers 
Approximately 25 patients will be enrolled in multiple centers. 
5.2 Inclusion Criteria 
The following inclusion criteria must be met to enroll a patient into this study: 
 
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 NRS within prior 7 days 
4. One of; 
a. CRP** level ≥1.0 mg/dL within prior 7 days OR 
b. Evidence of pericardial inflammation assessed by delayed pericardial 
hyperenhancement on CMR 
5. Currently receiving NSAIDs and/or colchicine and/or corticosteroids for treatment 
of pericarditis (in any combination) 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 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.   
 
* Diagnosis of pericarditis according to the 2015 ESC Guidelines for the Diagnosis and 
Management of Pericardial Diseases (Adler et al. 2015): 
 
At least two of: 
a. Pericarditic chest pain 
b. Pericardial rub 
c. New widespread ST-segment elevation or PR-segment depression according 
to ECG findings 
d. Pericardial effusion (new or worsening) 
 
** Conversion: 1 mg/dL CRP = 10 mg/L hs-CRP 
 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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5.3 Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study: 
 
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 
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 arrhythmias 
6. History of QT interval prolongation 
7. QTc interval > 500 msec (please refer to Section 9.2.3 for bundle branch block, 
bifascicular block and paced rhythm correction) 
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 C-SSRS, administered at screening 
16. On digoxin and/or type 1 or 3 antiarrhythmics 
17. On immunosuppressive therapy with any of the following: 
a. Rilonacept 
b. Anakinra 
c. Canakinumab 
d. Methotrexate 
e. Azathioprine 
f. Cyclosporine 
g. IVIG 
 
 
 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
26 
6 STUDY DESIGN 
6.1 Summary of Study Design 
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, 
pain score NRS, 12-lead ECG; C-SSRS as well as hematology and blood chemistry and 
a pregnancy test for women with child-bearing potential. If CRP was measured within 7 
days of Day 1, this value will be used as the baseline value. If there is no CRP 
measurement available within 7 days of Day 1, CRP needs to be measured at baseline. 
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 (accompanied by food) is as follows: 
• Initial starting dose (Day 1 p.m. dose to Day 3 a.m. dose):  
5 mg/kg of body weight CardiolRxTM b.i.d.  
• 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 (a.m. dose at week 26):  
10.0 mg/kg of body weight CardiolRxTM b.i.d. 
• The morning and evening doses should be taken minimally 6 hours and 
maximally 18 hours between each intake. 
 
If the next higher dose after each study drug increase is not tolerated, the dose will be 
reduced to the previous tolerated dose.  
6.2 Extension Period 
Unless contraindicated in the opinion of the investigator, after 8 weeks of study 
treatment, patients will enter an 18-week extension period (EP) in which they continue 
study treatment while their concomitant medications to treat pericarditis will be weaned, 
as described in Section 6.6.  
6.3 Follow-up Procedures 
At every assessment before study drug 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.  

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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Drug titration will be dependent on investigator or designate interrogation of the ECGs 
and the absence of abnormalities on those ECGs. 
Vital signs, blood chemistry including liver function tests, hematology as well as INR 
assessments will be carried out at selected visits. Concurrent medications and (S)AEs 
will be recorded at all 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, i.e. 
at Visit 5.  
 
6.4 Study Medication 
CardiolRxTM (cannabidiol) solution contains cannabidiol at a concentration of 100 
mg/mL.   Inactive ingredients include medium-chain triglyceride (MCT) oil and Vitamin 
E. 
   
6.5 Premature Interruption or Withdrawal from Study Treatment 
Before a decision is taken on premature discontinuation of study treatment, the medical 
monitor should be contacted. 
6.5.1 Permanent Suspension of Study Treatment 
Permanent suspension of study treatment must occur in the following cases: 
o If, in the view of the investigator, the patient experiences a severe allergic 
reaction that cannot be explained by the administration of any other medication. 
o Development of liver function abnormality, as described in Section 9.2.11.3. 
o Development of an AE or any medical condition, which, in the opinion of the 
investigator, necessitates permanent suspension of study treatment. 
o If the patient did not tolerate the starting dose of 5 mg/kg of body weight b.i.d. 
o Withdrawal of consent. 
 
Patients have the right to discontinue study treatment for any reason. However, unless 
they withdraw consent and are no longer willing to participate, they should be followed 
for the remainder of the trial and all AEs should be reported, regardless of whether or 
not the event occurs under the care of another physician or institution. 

 
 
 
 
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6.5.2 Temporary Suspension of Treatment 
Temporary suspension of study treatment (up to 7 days) can occur in case of a 
development of an (S)AE or a medical condition, which, in the opinion of the 
investigator, necessitates temporary interruption of study treatment. 
 
After temporary interruption of study treatment, all efforts should be made to re-institute 
study treatment using the last tolerated dose as soon as the clinical condition of the 
patient has stabilized. 
6.5.3 Withdrawal of Consent 
Patients may decide to fully or partially withdraw their consent to participate in the study. 
At that point, it should be established, whether the withdrawal is related to study 
treatment, further assessments, or any further involvement in the study. If the 
withdrawal is primarily related to study treatment or specific assessments, patients 
should be encouraged to continue follow-up and to attend all other subsequent study 
assessments. Reports of AEs and SAEs should be collected until completion of the 
study for all withdrawals, unless the patient objects to such follow-up. 
6.6 Concomitant Treatments 
Patients must be on SOC treatments for pericarditis with either NSAIDs, colchicine, or 
corticosteroids (in any combination) for at least 72 hours prior to Day 1. Unless 
contraindicated, these SOC treatments will be weaned during the 18 weeks EP as 
follows: 
NSAIDs will be weaned within 2 weeks after the EP entry and corticosteroids within 6 
weeks of EP entry (by 5 mg prednisone or equivalent every week).  
For patients not taking corticosteroids, colchicine will be weaned between 2 and 4 
weeks of EP entry, and for those on corticosteroids, colchicine weaning will be between 
6 and 8 weeks of EP entry.  Should it become evident that weaning of colchicine leads 
to high levels of pericarditis recurrence, the study leadership and the sponsor may 
decide colchicine weaning will no longer be performed during the EP. 
 
Patients will not be allowed to be on immunosuppressive therapy with rilonacept, 
anakinra, canakinumab, methotrexate, azathioprine, cyclosporine, mycophenolate 
and/or IVIG and cannot take any cannabinoids during the study period nor strong 
inducers of CYP3A4 and CYP2C19 (see Section 17.7). 
 
Use of digoxin and/or type 1 or 3 antiarrhythmics is an exclusion criterion for the trial. 
No drugs that are known to prolong QTc intervals should be started during the study 
(Appendix 17.6). 
  
Also, because CardiolRx™ is known to inhibit the metabolism of certain other drugs, 
new symptoms or findings may represent toxicity from a concomitant medication that 

 
 
 
 
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29 
had previously been well tolerated. Please refer to Section 6.3 of the Investigator 
Brochure (IB) and to Appendix 17.8. 
 
6.7 Management of Pericarditis Recurrence During the Extension 
Period 
Pericarditis recurrence during the extension period is defined as the recurrence of 
typical pericarditis pain associated with supportive objective evidence of pericarditis in 
the opinion of the investigator. At any timepoint during the EP, patients who experience 
suspected recurrence of their pericarditis will have been instructed to inform their site 
Investigator as soon as possible. Patients who experience a suspected recurrence of 
pericarditis symptoms will be requested to report to the study site/clinic for a scheduled 
or unscheduled visit, during which clinical assessments will be performed to gather all 
the necessary diagnostic data to confirm or rule out the presence of pericarditis 
recurrence. The Investigator will evaluate all assessments performed for a diagnostic 
workup, whether at the study site or at locations outside. 
 
Following communication with the study medical monitor, patients who report at least 1 
day with pericarditis pain measurement ≥4 on the 11-point NRS AND have a CRP value 
≥1 mg/dL (either on the same day or separated by no more than 7 days) during the EP 
of the trial will receive rescue therapy at the discretion of the investigator, i.e., if not 
already taking; analgesics first, then NSAIDs, and then colchicine. Immunosuppressive 
therapy such as corticosteroids or rilonacept may be added for pericarditis recurrence at 
the discretion of the investigator. 
 
6.8 Coronavirus 2019 (COVID-19) Measures 
The study will be initiated while the COVID-19 pandemic is ongoing. Testing for SARS-
CoV-2 is not required for this study and Investigators should follow local guidance. 
Should a study participant become infected with SARS-CoV-2 / contract or become 
suspected to have contracted COVID-19, standards for testing and management should 
be followed according to local and site-specific guidelines. 
 
SARS-CoV-2 infection (if asymptomatic), COVID-19 (including pneumonia related to 
COVID-19), and COVID-19-related symptoms, will be reported as adverse events. 
 
Treatments used for COVID-19 as well as vaccines are allowed without restriction 
during the study. They will be reported in the eCRF in the same way as any other 
concomitant medications described in Section 6.6 of the protocol. 
 
The study design minimizes the physical contacts and therefore the associated risks of 
infection by the SARS-CoV-2. The scheduled study follow-up contacts will be performed 
as virtual visits and resupply of study treatment may be performed via shipment to 

 
 
 
 
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patient’s home, when locally allowed and if feasible. The only mandatory hospital visits 
are those where laboratory tests for safety are required per protocol.  

 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
 
31 
7 STUDY PLAN 
 
 
 
 

 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
 
32 
8 INVESTIGATIONAL PRODUCTS, DOSE AND DURATION 
OF TREATMENT 
8.1 Investigational Product 
CardiolRxTM is synthetically produced. It contains cannabidiol oil in a concentration of 
100 mg/mL and is free of THC (<5 ppm). 
8.2 Administration, Dosage and Duration of Treatment 
Study drug will be administered orally (via syringe) with food according to the following 
treatment schedule: 
• Initial starting dose (Day 1 p.m. dose to Day 3 a.m. dose):  
5 mg/kg of body weight CardiolRxTM b.i.d.  
• 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 study (a.m. dose at Week 26):  
10.0 mg/kg of body weight CardiolRxTM b.i.d. 
• The morning and evening doses should be taken minimally 6 hours and 
maximally 18 hours between each intake. 
 
If the next higher dose is not tolerated, the patient should return to the last tolerated 
dose. The highest tolerated dose should be administered until the end of the study (26 
weeks post start of study medication). 
8.3 Study Treatment Return and Reconciliation 
A detailed treatment dispensing log will be kept at each site, which will be checked at 
each monitoring visit. After completion of the study, including final drug accountability, 
all unused study materials must be destroyed on site. 
8.4 Supply, Packaging, Labelling and Storage 
8.4.1 Supply and Packaging 
The study drug will be provided in 30 mL bottles. New bottles will be supplied for each 
assessment period.  
8.4.2 Labelling and Storage 
All investigational drugs will be labeled in English and Spanish according to local 
regulations for investigational drugs.  
 
All clinical drug supplies are to be stored in a secure, limited-access area as follows:  
- 
Room temperature 59ºF - 86ºF or refrigerated 36ºF - 47ºF 
- 
The study supplies need to be protected from light (to be kept in closed cartons 
or boxes). 
- 
The study supplies need to be stored in an upright position to prevent leakage. 

 
 
 
 
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9 CONDUCT OF THE STUDY 
9.1 Scheduling of Study Procedures 
Patients diagnosed with recurrent pericarditis will be invited to participate in the study. 
Informed consent must be obtained PRIOR to performing any study-related procedure. 
There is no time limit between obtaining informed consent and assigning study 
treatment to the patient. Some of the scheduled follow-up visits may be performed 
remotely if it’s not possible to conduct an in-patient visit. The following must be in place 
to enable a remote visit to take place: 
 
• The patient is able to obtain an ECG recording, which can immediately be 
transmitted to the study site 
• The patient agrees to go to a local laboratory to have the blood tests 
planned by protocol performed  
 
Visit 1 (Screening and baseline assessments – within 72 hours of Day 1) 
The following evaluations will be performed a baseline: 
- 
Written informed consent 
- 
Demographics 
- 
Medical History/Current conditions, including prior CV events and interventions 
- 
Clinical assessment  
- 
Vital signs, including heart rate (HR), blood pressure, body height and weight  
- 
Collect highest NRS pain score within the past 7 days of DAY 1 
- 
12-lead ECG 
- 
C-SSRS 
- 
Collection of concurrent medication and medication history for the previous 1 
month 
- 
Local laboratory assessments, including CRP*, CBC, AST/ALT, alkaline 
phosphatase, bilirubin, creatinine/eGFR, INR, pregnancy test (in women with 
childbearing potential) 
- 
AE and SAE recording after informed consent has been obtained 
- 
Assign study treatment to the patient 
 
* only if no measurement within 7 days of Day 1 is available 
 
Start of study medication in the evening of Day 1.  
 
Visit 2 (Day 3 + 2 days) – This visit may be performed as a virtual visit if an in-person 
visit is not possible as long as the ECG recording can be obtained 
The following evaluations will be performed on Day 3 after start of study medication: 
- 
Vital signs, including HR and blood pressure (if visit in person) 
- 
Review/collection of daily diary NRS pain scores, if not submitted electronically to 
Patient Portal if the patient has completed the questionnaire on paper 

 
 
 
 
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34 
- 
12-lead ECG 5 hours post morning dose (time window 3.5 – 6 hours); QTc 
intervals on ECG to be reviewed by site investigator, or designate, who decides if 
patient can continue study medication. If the visit is done remotely, the patient 
will record the ECG on a portable device at home or will have the ECG recording 
performed at a local clinic. The tracings must immediately be transmitted to the 
site for review. 
- 
Study drug dose increase to 7.5 mg/kg of body weight b.i.d. if patient tolerating 
starting dose of 5 mg/kg of body weight b.i.d. (If patient did not tolerate the 
starting dose of 5 mg/kg of body weight b.i.d., the patient will stop the study 
medication but will continue in the study and follow all assessments until Visit 5 
to be included in the safety analyses)  
- 
Study drug accountability 
- 
Recording of changes in concomitant medications 
- 
AE and SAE recording 
 
Visit 3 (Day 10 ± 2 days) – This visit may be performed as a virtual visit if an in-person 
visit is not possible as long as the ECG recording can be obtained 
 
The following evaluations will be performed on Day 10 after start of study medication: 
- 
Vital signs, including HR and blood pressure (if visit in person) 
- 
Review/collection of daily diary NRS pain scores, if not submitted electronically to 
Patient Portal if the patient has completed the questionnaire on paper 
- 
Collect highest NRS pain score within the past 7 days 
- 
12-lead ECG 5 hours post morning dose (time window 3.5 – 6 hours); QTc 
intervals on ECG to be reviewed by site investigator, or designate, who decides if 
patient can continue study medication. If the visit is done remotely, the patient 
will record the ECG on a portable device at home or will have the ECG recording 
performed at a local clinic. The tracings must immediately be transmitted to the 
site for review. 
- 
Study drug dose increase to 10 mg/kg of body weight b.i.d. if patient tolerating 
7.5 mg/kg of body weight b.i.d. If patient did not tolerate 7.5 mg/kg of body weight 
b.i.d., patient can return to 5 mg/kg of body weight b.i.d. 
- 
Study drug accountability 
- 
Recording of changes in concomitant medications 
- 
AE and SAE recording 
 
Visit 4 (Week 3 ± 3 days) – This visit may be performed as a virtual visit if an in-person 
visit is not possible as long as the ECG recording can be obtained and the laboratory 
assessments can be done by a local laboratory. 
  
The following evaluations will be performed at 2 weeks after start of study medication: 
- 
Clinical assessment (if visit in person) 
- 
Vital signs, including HR and blood pressure (if visit in person) 
- 
Review/collection of daily diary NRS pain scores, if not submitted electronically to 
Patient Portal if the patient has completed the questionnaire on paper 

 
 
 
 
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35 
- 
Collect highest NRS pain score within the past 7 days 
- 
12-lead ECG 5 hours post morning dose (time window 3.5 – 6 hours); QTc 
intervals on ECG to be reviewed by site investigator, or designate, who decides if 
patient can continue study medication. If the visit is done remotely, the patient 
will record the ECG on a portable device at home or will have the ECG recording 
performed at a local clinic. The tracings must immediately be transmitted to the 
site for review. 
- 
Study drug dose adjustment (if patient did not tolerate 10 mg/kg of body weight 
b.i.d., patient can return to 7.5 mg/kg of body weight b.i.d. 
- 
Study drug accountability 
- 
Recording of changes in concomitant medications 
- 
AE and SAE recording 
- 
Local laboratory assessments, including CRP, CBC, AST/ALT, alkaline 
phosphatase, bilirubin, creatinine/eGFR, INR (if visit not in person, patient needs 
to go to a local laboratory for blood collection and assessments) 
 
Visit 5 (Week 8 ± 4 days) – final study visits for patients not continuing in the EP  
The following evaluations will be performed at 8 weeks after start of study medication: 
- 
Clinical assessment 
- 
Vital signs, including HR, blood pressure and body weight 
- 
Review/collection of daily diary NRS pain scores, if not submitted electronically to 
Patient Portal if the patient has completed the questionnaire on paper 
- 
Collect highest NRS pain score within the past 7 days 
- 
12-lead ECG 5 hours post morning dose (time window 3.5 – 6 hours); QTc 
intervals on ECG to be reviewed by site investigator, or designate, who decides if 
patient can continue study medication 
- 
C-SSRS 
- 
Study drug accountability 
- 
Recording of changes in concomitant medications 
- 
Start weaning background therapy over the next 8 weeks for patients continuing 
in the EP 
- 
AE and SAE recording 
- 
Local laboratory assessments, including CRP, CBC, AST/ALT, alkaline 
phosphatase, bilirubin, creatinine/eGFR, INR 
 
Visit 6 (Week 12 ± 4 days) – Virtual visit 
The following evaluations will be performed virtually at 12 weeks after start of study 
medication: 
- 
Review/collection of daily diary NRS pain scores, if not submitted electronically to 
Patient Portal 
- 
Collect highest NRS pain score within the past 7 days 
- 
Study drug accountability 
- 
Recording of changes in concomitant medications 
- 
AE and SAE recording 
 

 
 
 
 
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36 
Visit 7 (Week 16 ± 4 days) 
The following evaluations will be performed at 16 weeks after start of study medication: 
- 
Clinical assessment 
- 
Vital signs, including HR and blood pressure 
- 
Review/collection of daily diary NRS pain scores, if not submitted electronically to 
Patient Portal if the patient has completed the questionnaire on paper 
- 
Collect highest NRS pain score within the past 7 days 
- 
12-lead ECG 5 hours post morning dose (time window 3.5 – 6 hours); QTc 
intervals on ECG to be reviewed by site investigator, or designate, who decides if 
patient can continue study medication 
- 
Study drug accountability 
- 
Recording of changes in concomitant medications 
- 
AE and SAE recording 
- 
Local laboratory assessments, including CRP, CBC, AST/ALT, alkaline 
phosphatase, bilirubin, creatinine/eGFR, INR 
 
Visit 8 (Week 20 ± 5 days) – Virtual visit 
The following evaluations will be performed virtually at 20 weeks after start of study 
medication: 
- 
Review/collection of daily diary NRS pain scores, if not submitted electronically to 
Patient Portal if the patient has completed the questionnaire on paper 
- 
Collect highest NRS pain score within the past 7 days 
- 
Study drug accountability 
- 
Recording of changes in concomitant medications 
- 
AE and SAE recording 
 
Visit 9 (Week 26 ± 5 days) 
The following evaluations will be performed at 26 weeks after start of study medication: 
- 
Clinical assessment 
- 
Vital signs, including HR, blood pressure and body weight 
- 
Review/collection of daily diary NRS pain scores, if not submitted electronically to 
Patient Portal if the patient has completed the questionnaire on paper 
- 
Collect highest NRS pain score within the past 7 days 
- 
12-lead ECG 5 hours post morning dose (time window 3.5 – 6 hours) 
- 
C-SSRS 
- 
Study drug accountability 
- 
Recording of changes in concomitant medications 
- 
AE and SAE recording 
- 
Local laboratory assessments, including CRP, CBC, AST/ALT, alkaline 
phosphatase, bilirubin, creatinine/eGFR, INR 
 
If a visit is missed and/or an ECG cannot be performed, the patient should stay on 
the current study drug dose until the next assessment. 
 

 
 
 
 
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37 
9.2 Clinical Procedures and Safety Evaluations 
9.2.1 
Informed Consent 
Patients who comply with the eligibility criteria will be approached and informed of the 
possibility of study participation. The benefits and risks of participating in the study will 
be explained to the patient. The patient will be provided with an opportunity to read the 
detailed information about the study in an informed consent form (ICF) and ask any 
questions he/she may have. Prior to conducting any study-related procedures, the 
patient must provide consent to participate by signing the Institutional Review 
Board/Research Ethics Board (IRB/REB) approved ICF.  
9.2.2 
Demography 
This includes collection of age, sex and race. 
9.2.3 
Standard 12-lead Electrocardiogram (ECG) 
A 12-lead ECG will be performed at baseline, and at all in-person follow-up visits. Visits 
2 (Day 3), 3 (Day 10) and 4 (Week 3) can only be virtual if an ECG can be performed 
and transmitted to the site for review.  
The ECG after start of study medication will be recorded approximately 5 hours (time 
window 3.5 – 6 hours) post-morning dose (Tmax) to surveil for deleterious effects on 
ECG intervals (particularly the QTc interval) and rhythm. Continuation on study drug will 
be assessed by the investigator or designate dependent on interrogation of the ECG, 
most importantly the QT interval.  
 
The QT interval can be obtained from the automated measurements of the ECG 
recorder unless the data quality is poor. In this case, the QT interval is measured from 
the beginning of the QRS complex to the end of the T wave and averaged over three 
cardiac cycles. The average QT interval should be corrected for heart rate variability 
using Bazett’s formula (QTC = QT / √ RR) or Fridericia’s formula (QTC = QT / RR 1/3) to 
create the QTc interval. Each patient should have the QTc measured using the same 
method on all designated days in the study.  
 
The presence of a bundle branch block (BBB) represents a particular challenge in 
properly measuring the QTc interval. Following international recommendations, QT 
interval should be measured in leads showing the longest QT interval, which is usually 
in right precordial leads. In presence of a BBB, these leads are strongest affected by 
conduction delay and therefore hamper adequate measurement. A new formula for 
evaluation of the QT interval in patients with left bundle branch block (LBBB) was 
introduced in 2014: 
 
QTmean = QTBBB – 50% QRSBBB (Bogossian et al. 2014)  
 

 
 
 
 
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This formula has proved to be a reliable tool in clinical practice for QTc interval evaluation 
in patients with LBBB, right bundle branch block (RBBB) or bifascicular block. (Bogossian 
et al. 2020; Erkapic et al. 2020) 
 
Similarly, ventricular paced rhythm with an increased QRS duration can impact the QT 
interval. In patients with ventricular paced rhythm, 50ms should be subtracted from the 
Bazett’s formula or Fridericia’s formula.(Chakravarty et al. 2015) 
 
If the QTc interval increases to 500 msec or more – or increases 60 msec or more from 
the baseline recording on any one measurement, this must be reported as an SAE and 
the study medication must be discontinued. 
 
Other new clinically relevant ECG changes also need to be reported as an AE or SAE. 
9.2.4 
Medical History 
Data will be collected from patients at baseline consisting of medical history, including 
previous cardiac investigations, previous cardiac history, and medications taken in the 
past month. 
9.2.5 
Clinical Assessment 
A routine clinical assessment is required at baseline, and at all in-person visits. Any 
abnormality must be recorded. 
9.2.6 
Vital Signs, Body Height and Weight 
Vital signs including blood pressure, HR and body weight will be recorded at baseline 
(Visit 1), and at all in-person visits. Body height will be recorded at baseline (Visit 1). 
9.2.7 
Collection of NRS Scores 
Patients will be asked to enter their pain scores into a diary on a daily basis using the 
11-point NRS. Patients will have the choice to complete the NRS scale either on paper 
or in an electronic patient reported outcomes platform – i.e., eSOCDAT Patient Portal. 
Access to the eSOCDAT Patient Portal is restricted to authorized users only. State-of-
the-art procedures are in place to prevent unauthorized access and data corruption, 
namely, firewalls, up-to-date virus scanning in addition to the encryption of data stored 
in the database and transmitted via the Internet. Patients will be provided with a unique 
username and password to access the eSOCDAT Portal. 
 
In addition, the highest NRS pain score within the past 7 days will be recorded at 
baseline (patient recall) and at each visit after randomization from the Patient Portal 
entries/diaries or, if not available, from patient recall. 
9.2.8 
Concomitant Treatment 
Guidelines for concomitant treatment are given in Section 6.6 of this protocol. 
 

 
 
 
 
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All changes in concomitant medications during the study must be recorded, as must 
those started within one week of study entry and continued thereafter. 
9.2.9 
Laboratory Tests 
Laboratory tests include CRP, CBC, AST/ALT, alkaline phosphatase, bilirubin, 
creatinine/eGFR, INR, pregnancy test (female patients of childbearing potential only). 
Please see Appendix 17.2 for the exact schedule of all laboratory tests. Visit 4 (Week 3) 
can only be virtual if the laboratory assessments can be performed by a local laboratory. 
 
9.2.10 
C-SSRS 
The C-SSRS is a questionnaire designed for the assessment of suicidal ideation and 
behavior in adolescents and adults. 
To monitor for the emergence of suicidal ideation and behavior, patients will undergo 
C-SSRS evaluations at baseline, at Week 8 and at Week 26. 
The questionnaire must be administered by an investigator or other individual that is 
suitably qualified by education or training. See Appendix 17.4 for a sample 
C-SSRS - Baseline/Screening version assessment and Appendix 17.5 for a sample 
post-dose C-SSRS assessment. 
If a patient becomes suicidal during the study, an investigator or medically qualified 
sub-investigator should provide the appropriate treatment to the patient. 
9.2.11 
Management of AEs 
9.2.11.1 
 AE Reporting 
An AE is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient or clinical investigation patient administered 
an investigational (medicinal) product and that does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of investigational product, whether or not 
considered related to the investigational product. 
 
AEs can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a patient. (In order to prevent reporting bias, patients 
should not be questioned regarding the specific occurrence of one or more AEs.) 
 
Any AE that results in any of the following outcomes will be considered an SAE:   
1. Death 

 
 
 
 
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2. Life-threatening situation (patient was at risk of death at the time of the event.  This 
does not refer to an event that might have caused death if it was of greater 
intensity.) 
3. New in-patient hospitalization or prolongation of existing index hospitalization 
4. Persistent or significant disability or incapacity 
5. Congenital anomaly or birth defect 
6. QTc interval increases to > 500 msec or >60 msec from baseline. 
7. Important medical events that may not result in death, be life-threatening, or require 
hospitalization but may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the above outcomes (based upon appropriate medical 
judgment), e.g., allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
in-patient hospitalization, or the development of drug dependency or drug abuse. 
Potential Drug-Induced Liver Injury (DILI) is also considered an important medical 
event.  (See Section 9.2.11.3 for the definition of potential DILI.) 
All SAEs experienced by a patient after informed consent has been obtained must be 
reported to SOCAR Research (SOCAR) within 24 hours of the site’s awareness of the 
event.  
 
The term “severe” is often used to describe the intensity (severity) of a specific event 
(as in mild, moderate, or severe pain); the event itself, however, may be of relatively 
minor medical significance (such as severe headache).  By contrast, the term “serious” 
is used to describe an event based on an event outcome or actions usually associated 
with events that pose a threat to a patient’s life or functioning.  Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations. 
 
For all collected SAEs, the clinician who examines and evaluates the patient will 
determine the event’s causality based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories 
below: 
 
Definitely Related: There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out.  
 
Probably Related: There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely.  
 
Possibly Related: There is some evidence to suggest a causal relationship.  However, 
the influence of other factors may have contributed to the event. 
  

 
 
 
 
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41 
Unlikely: A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable and in which 
other drugs or chemicals or underlying disease provides plausible explanations. 
  
Not Related: The SAE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology.  
 
Pre-existing conditions should be recorded upon patient enrolment (including start date 
of the condition, and severity - mild, moderate, severe). After the patient signs the 
informed consent form, any worsening of these conditions would be recorded.   
 
Any new conditions would be recorded including date of onset, date of resolution, 
severity (mild, moderate, severe, or serious as defined above) and possible relationship 
to study drug or procedure. As part of the source notes, follow up clinical assessments, 
laboratory tests, ECGs and diagnostic imaging related to AE should be documented. 
9.2.11.2 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a 
study patient is pregnant or may have been pregnant at the time of investigational 
product exposure, including during at least 6 half-lives after product administration, the 
investigational product will be permanently discontinued, and the pregnancy will be 
reported to SOCAR within 24 hours of the site’s awareness of the event. 
Protocol-required procedures for study discontinuation and follow-up must be performed 
on the patient unless contraindicated by pregnancy. Other appropriate pregnancy 
follow-up procedures should be considered if indicated. 
9.2.11.3 
Drug-Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event. All occurrences of potential 
DILIs, meeting the defined criteria below, must be reported as SAEs. 
Potential DILI is defined as:  
1. ALT or AST elevation > 8 x ULN 
OR 
2. ALT or AST elevation > 5 x ULN for more than 2 weeks 
                                                         OR 
3. ALT or AST elevation > 3 x ULN and bilirubin >2 x ULN or INR > 1.5. 
If a patient meets one of the above criteria, the study drug needs to be discontinued and 
the investigator is to arrange for the patient to return to the investigational site as soon 
as possible (within 24 hours of notice of abnormal results) for repeat assessment of 
ALT, AST, bilirubin and alkaline phosphatase, detailed history, and clinical assessment. 
Patients are to be followed in this way until all abnormalities have normalized (in the 

 
 
 
 
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42 
investigator’s opinion) or returned to the baseline state. If the patient cannot return to 
the investigational site, repeat assessments could be performed at a local laboratory 
(and the results are then to be sent to SOCAR by the investigator). 
Elevations in ALT or AST > 3 × ULN or bilirubin > 2 × ULN alone, i.e., when not 
concomitant, are not grounds for withdrawal but are to be followed up, as above, within 
72 hours of notice of abnormal results.  
9.2.11.4 
Overdose 
All occurrences of overdose must be reported as SAEs. An overdose is defined as the 
accidental or intentional administration of any dose of a product that is considered both 
excessive and medically important.  
9.2.11.5 
Drug-Drug Interactions 
CardiolRxTM is known to be metabolized largely through the cytochrome P450 enzyme 
system in the liver. A number of the drugs commonly used in the management of heart 
failure and other CV or concomitant conditions are also capable of being inducers or 
inhibitors of these enzymes. The patients should specifically be monitored for (S)AEs 
that might reflect Drug-Drug Interactions (DDIs). See Section 6.3 of the IB for more 
detailed discussion. 
 
Drugs that are known to prolong QTc intervals must not be started during the study 
(Appendix 17.6). 
 
In addition, to aid investigators in screening concomitant medications for risk of DDIs, a 
table of medications that serve as substrate for certain enzyme isoforms inhibited by 
CardiolRx™ has been prepared (Appendix 17.8). 
9.2.12 
Drug Accountability 
Drug accountability will be performed at all visits after randomization and start of study 
medication, including virtual visits. 
 
 

 
 
 
 
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10 CRITERIA FOR EVALUATION OF STUDY RESULTS 
10.1 Criteria for Evaluation of Efficacy 
10.1.1 
Primary Efficacy Outcome 
The primary efficacy endpoint of this Pilot study is the change in patient-reported 
pericarditis pain using an 11-point NRS from baseline (highest score within the past 
seven days of Day 1) to Week 8 (highest score recorded within the past seven days). 
10.1.2 
Additional Efficacy Parameters of Interest 
Additional efficacy parameters of interest are listed in Section 4.1.3. 
 
10.2 Criteria for Evaluation of Safety 
The safety parameters are listed in Section 4.2.2. 
10.3 Description of Patient Groups for Analyses 
10.3.1 
Population for Efficacy and Safety Analyses 
All patients who were enrolled and took at least one dose of study medication will be 
included in the safety analyses. 
 
Patients who do not tolerate the initial dose of 5 mg/kg of body weight b.i.d. will stay in 
the study for safety evaluations but will be replaced for the assessment of efficacy. 
 

 
 
 
 
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44 
11 STATISTICAL METHODS 
11.1 Sample Size Estimation 
No formal sample size was calculated for this Pilot study. Approximately 25 patients will 
be included in this study. Patients who do not tolerate the initial dose of 5 mg/kg of body 
weight b.i.d. will stay in the study for safety evaluations but will be replaced for the 
assessment of efficacy. 
 
11.2 Outcome Analyses 
Given the small sample size and the design of the study (no placebo comparison), no 
inferential statistical analyses are planned.  
 
Depending on their distribution, continuous variables will be expressed as mean ± 
standard deviation (SD) or as median (interquartile range [IQR]). Categorical variables 
will be expressed in counts with percentages. 
 
For all continuous variables, including the NRS pain scores, the change from baseline 
will be presented as summary statistics.  
 
For categorical variables, summary statistics will be calculated. 
 
11.3 Safety Analyses 
The same approaches as in Section 11.2 will be taken. 
 
11.4 Missing Values 
All attempts will be made to minimize missing follow-up data. No imputations for missing 
data are planned.  
 
11.5 Stopping Guidelines 
If, after at least 12 patients have been enrolled, more than 50% of patients are suffering 
from pericarditis recurrences, the study will be stopped. 
 
 

 
 
 
 
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45 
12 ORGANISATIONAL STRUCTURE 
12.1 Sponsor 
Cardiol Therapeutics Inc., 2265 Upper Middle Road, Suite 602, Oakville, Ontario, L6H 
0G5 Canada will be the Sponsor of this study. 
12.2 Contract Research Organization (CRO) 
OZMOSIS Inc will be responsible for site management and site monitoring which 
includes site initiation, site training, remote/in-person site visits and close out visits. 
SOCAR will be responsible for overall study management, including build of the eCRFs, 
data management, oversight of the electronic trial master file (eTMF) and statistical 
analysis. TMC Pharma is responsible for pharmaco-vigilance.  
 

 
 
 
 
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13 DATA COLLECTION AND MONITORING 
13.1 Case Report Forms (CRFs) 
Electronic data capture will be used for this trial, meaning that all study data will be 
entered in electronic case report forms (eCRF) at the investigational site. Data collection 
will be completed by authorized study site personnel designated by the Investigator. 
Appropriate training and security measures will be completed with the Investigator and 
all authorized study site personnel prior to the study being initiated and any data being 
entered into the system for any study patients.   
 
13.2 Data Collection and Cleaning 
13.2.1 
Data Collection 
Records for all patients from whom an Informed Consent is obtained will be stored on a 
secure eCRF that will be maintained at the Data Management Centre. All eCRF 
corrections are to be made by an investigator or other authorized study site personnel. 
The investigator/co-investigator must confirm by his/her electronic signature in a specific 
section of the eCRF that he/she has reviewed the data, and that the data is complete 
and accurate. 
13.2.2 
Data validation 
Data validation procedures will be described in detail in the Data Management Plan.  
13.3 Monitoring 
13.3.1 
Virtual and/or On-site Monitoring 
Ozmosis is responsible for monitoring according to applicable Good Clinical Practice 
(GCP) standards and International Conference on Harmonization (ICH) guidelines to 
ensure the completeness, correctness, and consistency of the data and to assess 
whether the study is executed according to this protocol. Specific items to be checked 
are listed in the Investigator’s Study File. 
 
To verify that the CRFs are completed accurately and in accordance with source 
documents, source data verification will be performed. The CRFs and related source 
documents will be reviewed in detail by the on-site monitor during each visit. Checks for 
completeness and correctness of the data will be done by comparing CRF entries with 
information in the patients’ local medical records. 
13.3.2 
In-house Monitoring 
In-house data review and cleaning will be performed by SOCAR. In case of missing, 
erroneous or incomplete data, further information will be requested by SOCAR via 
electronic Data Clarification Forms (eDCFs). These are sent directly to the investigator 
and copied to the on-site monitor. 

 
 
 
 
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47 
13.3.3 
Audit/Inspection 
The Sponsor, SOCAR and/or a competent authority may perform audits/inspections. 
The auditor/inspector must have access to all study and source documentation, facilities 
and equipment used in this study. The Steering Committee will supervise audit 
procedures and is entitled to initiate audits on its own. 

 
 
 
 
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48 
14 INVESTIGATOR RESPONSIBILITIES AND OBLIGATIONS 
14.1 Declaration of Helsinki 
The study will be carried out in accordance with the provisions of the Declaration of 
Helsinki (last revised version, see Appendix 17.1) and with applicable local GCP 
standards. 
14.2 Local IRB/REB 
According to local laws and regulations, the study protocol and the Patient ICF must be 
approved by a local IRB/REB for each participating center. 
 
It is the responsibility of the investigator to submit the protocol for institutional review. A 
copy of the letter of approval from the local IRB/REB, with a content in accordance with 
local regulations, must have been received by SOCAR prior to shipment of study drugs 
to the investigational site. Major changes to the protocol, as well as a change of a 
principal investigator, must be approved by the local IRB/REB and documentation of 
this approval must be provided. Records of the local IRB/REB review and approval of all 
documents pertaining to this study must be kept on file by the investigator in the 
Investigator’s Study File.  
 
Apart from the investigational procedures specified in the protocol, investigators are not 
allowed to perform ancillary studies without written approval from the Steering 
Committee and the local IRB/REB. 
14.3 Informed Consent and Patient Protection 
14.3.1 
Patient Informed Consent 
It is an obligation of the investigator to obtain informed consent from the patient by 
means of a dated and signed ICF before any study-related procedure is performed. The 
ICF must be written in English and the local language(s) in accordance with local laws 
and regulations. 
  
‘Informed consent’ also implies individual discussion with the patient about the nature of 
study treatment and examinations to be conducted in a language that is easy to 
comprehend. The patient should fully understand that his/her refusal to participate in the 
study will not affect the quality of medical care. In addition, the patient must be informed 
that, without disclosing his/ her name, relevant medical data will be disclosed to 
CRO(s), that his/her medical records will be inspected during on-site monitoring and 
may be inspected again by auditors and/or regulatory authorities. 
 
Should a protocol amendment be made, the ICF may be revised to reflect the changes 
in the protocol. It is the responsibility of the investigator to ensure that an amended ICF 
is reviewed and approved by the local IRB/REB, and that it is signed by all patients 

 
 
 
 
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49 
subsequently entered in the study and those currently in the study, if affected by the 
amendment. 
14.3.2 
Patient Data Protection 
The patients should be informed in writing that his/her medical data relevant to this 
study will be stored and analyzed while maintaining confidentiality in accordance with 
local data protection laws. All data transferred to the CRF, and any process derived 
from the CRF will be handled anonymously. This will ensure that the identity of the 
individual will be protected. 
 
The patient should also be informed in writing about the possibility of audits by 
authorized representatives of the Sponsor, SOCAR or a designee and/or regulatory 
agencies in which case a review of those parts of the hospital records relevant to the 
study may be required. 
14.4 Study Protocol Adherence and Modifications 
14.4.1 
Protocol Adherence 
The protocol must be read thoroughly, and the instructions must be followed exactly. 
The same applies to instructions given in the eCRF and to any additional instructions 
issued by SOCAR. Whenever a deviation occurs in the interest of the patient’s well-
being, the on-site monitor must be informed, and a course of action must be agreed 
upon. All deviations will be kept in the protocol deviation log. 
14.4.2 
Changes to Protocol and Related Procedures 
Changes to the protocol should only be made in the form of protocol amendments. If 
substantial changes to the design of the study are made, local IRBs/ERBs should be 
notified and, if required, approve the change before inclusion of new patients. 
 
SOCAR is responsible for the distribution of a protocol amendment to investigators. 
Investigators are responsible for the distribution of an amendment to all staff involved in 
the study and to the local IRB/ERB. 
14.5 Investigational Product Control 
It is the investigator’s responsibility to ensure that study drugs are stored in a secure 
area (locked, limited personnel access), and dispensed appropriately. 
 
The investigator is responsible for maintaining accurate records of the dispensing of the 
study medication in a study drug accountability log.  
 
All study drug supplies are for this protocol only and not for any other use. After 
completion of the study, including final study drug accountability, all unused study 
materials must be destroyed on site. 

 
 
 
 
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14.6 Data Collection and Documentation 
For every patient, the hospital or clinic file must clearly indicate that the patient has 
given informed consent and participates in the study. For all study assessments, the 
hospital or clinic file should include clinic visit and interim contact dates, records of vital 
signs, medical history, clinical assessment findings, procedures performed and their 
findings, laboratory results, concomitant treatment, any AEs encountered and other 
notes as appropriate. This constitutes ‘source data’. All entries on the eCRFs must be 
backed up by source data unless specified otherwise. Source data must be made 
available for perusal by the on-site monitor during a monitoring visit. In order to allow 
detection of inaccuracies in transcribing data from original records into the eCRF, all 
original laboratory reports must be kept available for review in the patient hospital or 
clinic file. 
 
The CRFs must be kept in order and up to date so that they always reflect the latest 
observations on the patients enrolled in the study. 
 
Each patient’s study file should have attached to it the original signed ICF. When the 
study is completed, the ICF should be kept on file with a copy of the completed eCRF in 
the study file provided, or a note should be made indicating where the study records can 
be located. All records should be kept in accordance with applicable national laws and 
regulations. 
14.7 Reporting of AEs and SAEs 
It is a regulatory obligation of the investigator and her/his staff to record and report any 
serious clinical event or adverse experience that occurs while a patient is participating in 
this study. Detailed instructions for AE and SAE reporting are given in Section 9.2.11.1 
of this protocol. The instructions given in this section must be observed closely. Non-
compliance is a serious protocol violation and may lead to the closure of the center 
involved. 
 
If required by local regulations, the investigator must also inform the local IRB/ERB 
about SAEs. 
14.8 Records Retention 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into two different separate categories (1) investigator’s 
study file, and (2) patient clinical source documents. 
 
The investigator’s study file will contain the protocol/amendments, case report and 
query forms, IRB/ERB and governmental approval (if required) with correspondence, 
sample informed consent, drug records, staff curriculum vitae and authorization forms 
and other appropriate documents/correspondence, etc. 
 

 
 
 
 
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51 
The patient’s clinical source documents (usually defined by the project in advance to 
record key efficacy/safety parameters independent of the CRFs) would include patient 
hospital/clinic records, physician’s and nurse’s notes, appointment book, original 
laboratory reports, ECG and special assessment reports, signed ICF(s), consultant 
letters, and patient screening and enrolment logs. The investigator must keep these two 
categories of documents on file after completion or discontinuation of the study 
according to local requirements. 
 
Should the investigator wish to assign the study records to another party or move them 
to another location, SOCAR must be notified in advance. 
 
Where source documents are required for the continued care of the patient, appropriate 
copies should be made. 
14.9 Confidentiality of Trial Documents and Patient Records 
The investigator must assure that patient anonymity will be maintained and that their 
identities shall be protected from unauthorized parties. On eCRFs or other documents 
submitted to SOCAR and/or to the Sponsor, patients should not be identified by their 
names, but by an identification code. The investigator should keep a patient enrolment 
log relating codes to the names of patients. The investigator should maintain documents 
that are not for submission to SOCAR and/or the Sponsor in strict confidence. 
14.10 Direct Access to Source Data/Documents 
The investigator shall supply the Clinical Research Associate (CRA), SOCAR, the 
Sponsor and/or regulatory agencies on request with any required background data from 
the study documentation or clinic records.  This is particularly important when errors in 
data entry are suspected.  In case of special problems and/or governmental queries or 
requests for audit inspections, it is also necessary to have access to the complete study 
records, provided that patient confidentiality is protected. 

 
 
 
 
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15 STUDY TIMELINES 
Eligible patients will be enrolled and will be followed for 26 weeks. We estimate the 
following: 4 months for site setup, a recruitment period of 12 months, time for data 
collection, cleaning and database lock 2 months, analysis and reporting 2 months, 
resulting in a total study time of approximately 26 months. 

 
 
 
 
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53 
16 REFERENCES 
1. 
Adler, Yehuda, Philippe Charron, Massimo Imazio, Luigi Badano, Gonzalo 
Barón-Esquivias, Jan Bogaert, Antonio Brucato, et al. 2015. “2015 ESC 
Guidelines for the Diagnosis and Management of Pericardial Diseases.” 
European Heart Journal 36 (42): 2921–64. 
https://doi.org/10.1093/eurheartj/ehv318. 
2. 
Bergamaschi, Mateus M, Regina Helena Costa Queiroz, Marcos Hortes 
Nisihara Chagas, Danielle Chaves Gomes de Oliveira, Bruno Spinosa De 
Martinis, Flávio Kapczinski, João Quevedo, et al. 2011. “Cannabidiol 
Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-
Naïve Social Phobia Patients.” Neuropsychopharmacology 36 (6): 1219–26. 
https://doi.org/10.1038/npp.2011.6. 
3. 
Bogossian, Harilaos, Gerrit Frommeyer, Ilias Ninios, Fuad Hasan, Quy Suu 
Nguyen, Zana Karosiene, Dejan Mijic, et al. 2014. “New Formula for 
Evaluation of the QT Interval in Patients with Left Bundle Branch Block.” 
Heart Rhythm 11 (12): 2273–77. https://doi.org/10.1016/j.hrthm.2014.08.026. 
4. 
Bogossian, Harilaos, Dominik Linz, Jordi Heijman, Nana-Yaw Bimpong-Buta, 
Dirk Bandorski, Gerrit Frommeyer, Damir Erkapic, Melchior Seyfarth, Markus 
Zarse, and Harry J. Crijns. 2020. “QTc Evaluation in Patients with Bundle 
Branch Block.” International Journal of Cardiology. Heart & Vasculature 30 
(October): 100636. https://doi.org/10.1016/j.ijcha.2020.100636. 
5. 
Borrelli, Francesca, Gabriella Aviello, Barbara Romano, Pierangelo Orlando, 
Raffaele Capasso, Francesco Maiello, Federico Guadagno, et al. 2009. 
“Cannabidiol, a Safe and Non-Psychotropic Ingredient of the Marijuana Plant 
Cannabis Sativa, Is Protective in a Murine Model of Colitis.” Journal of 
Molecular Medicine 87 (11): 1111–21. https://doi.org/10.1007/s00109-009-
0512-x. 
6. 
Brown, A J. 2007. “Novel Cannabinoid Receptors.” British Journal of 
Pharmacology 152 (5): 567–75. https://doi.org/10.1038/sj.bjp.0707481. 
7. 
Brucato, Antonio, Massimo Imazio, Marco Gattorno, George Lazaros, Silvia 
Maestroni, Mara Carraro, Martina Finetti, et al. 2016. “Effect of Anakinra on 
Recurrent Pericarditis Among Patients With Colchicine Resistance and 
Corticosteroid Dependence: The AIRTRIP Randomized Clinical Trial.” JAMA 
316 (18): 1906. https://doi.org/10.1001/jama.2016.15826. 
8. 
Buckley, Leo F., Michele M. Viscusi, Benjamin W. Van Tassell, and Antonio 
Abbate. 2018. “Interleukin-1 Blockade for the Treatment of Pericarditis.” 
European Heart Journal. Cardiovascular Pharmacotherapy 4 (1): 46–53. 
https://doi.org/10.1093/ehjcvp/pvx018. 
9. 
Carrier, Erica J., John A. Auchampach, and Cecilia J. Hillard. 2006. 
“Inhibition of an Equilibrative Nucleoside Transporter by Cannabidiol: A 
Mechanism of Cannabinoid Immunosuppression.” Proceedings of the 
National Academy of Sciences 103 (20): 7895–7900. 
https://doi.org/10.1073/pnas.0511232103. 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
54 
10. Chakravarty, Saneka, Jeffrey Kluger, Lovely Chhabra, Bhavadharini Ramu, 
and Craig Coleman. 2015. “Corrected QT in Ventricular Paced Rhythms: 
What Is the Validation for Commonly Practiced Assumptions?” Cardiology 
130 (4): 207–10. https://doi.org/10.1159/000370026. 
11. Chiabrando, Juan Guido, Aldo Bonaventura, Alessandra Vecchié, George F. 
Wohlford, Adolfo G. Mauro, Jennifer H. Jordan, John D. Grizzard, et al. 2020. 
“Management of Acute and Recurrent Pericarditis.” Journal of the American 
College of Cardiology 75 (1): 76–92. 
https://doi.org/10.1016/j.jacc.2019.11.021. 
12. Cordero‐Reyes, Andrea M., Keith A. Youker, Alejandro R. Trevino, Rene 
Celis, Dale J. Hamilton, Jose H. Flores‐Arredondo, Carlos M. Orrego, Arvind 
Bhimaraj, Jerry D. Estep, and Guillermo Torre‐Amione. 2016. “Full 
Expression of Cardiomyopathy Is Partly Dependent on B‐Cells: A Pathway 
That Involves Cytokine Activation, Immunoglobulin Deposition, and Activation 
of Apoptosis.” Journal of the American Heart Association: Cardiovascular and 
Cerebrovascular Disease 5 (1). https://doi.org/10.1161/JAHA.115.002484. 
13. Cremer, Paul C., Arnav Kumar, Apostolos Kontzias, Carmela D. Tan, E. 
Rene Rodriguez, Massimo Imazio, and Allan L. Klein. 2016. “Complicated 
Pericarditis: Understanding Risk Factors and Pathophysiology 
to Inform Imaging and Treatment.” Journal of the American College of 
Cardiology 68 (21): 2311–28. https://doi.org/10.1016/j.jacc.2016.07.785. 
14. De Filippis, Daniele, Giuseppe Esposito, Carla Cirillo, Mariateresa Cipriano, 
Benedicte Y. De Winter, Caterina Scuderi, Giovanni Sarnelli, et al. 2011. 
“Cannabidiol Reduces Intestinal Inflammation through the Control of 
Neuroimmune Axis.” PLoS ONE 6 (12). 
https://doi.org/10.1371/journal.pone.0028159. 
15. Dos-Santos-Pereira, Mauricio, Franscisco S. Guimarães, Elaine Del-Bel, Rita 
Raisman-Vozari, and Patrick P. Michel. 2019. “Cannabidiol Prevents LPS-
Induced Microglial Inflammation by Inhibiting ROS/NF-ΚB-Dependent 
Signaling and Glucose Consumption.” Glia, October. 
https://doi.org/10.1002/glia.23738. 
16. Dworkin, Robert H., Dennis C. Turk, John T. Farrar, Jennifer A. 
Haythornthwaite, Mark P. Jensen, Nathaniel P. Katz, Robert D. Kerns, et al. 
2005. “Core Outcome Measures for Chronic Pain Clinical Trials: IMMPACT 
Recommendations.” Pain 113 (1–2): 9–19. 
https://doi.org/10.1016/j.pain.2004.09.012. 
17. Erkapic, Damir, Gerrit Frommeyer, Niklas Brettner, Korkut Sözener, Harry J. 
G. M. Crijns, Melchior Seyfarth, Christian W. Hamm, and Harilaos Bogossian. 
2020. “QTc Interval Evaluation in Patients with Right Bundle Branch Block or 
Bifascicular Blocks.” Clinical Cardiology 43 (9): 957–62. 
https://doi.org/10.1002/clc.23389. 
18. Esposito, G, C Scuderi, C Savani, L Steardo, D De Filippis, P Cottone, T 
Iuvone, V Cuomo, and L Steardo. 2007. “Cannabidiol in Vivo Blunts β-
Amyloid Induced Neuroinflammation by Suppressing IL-1β and INOS 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
55 
Expression.” British Journal of Pharmacology 151 (8): 1272–79. 
https://doi.org/10.1038/sj.bjp.0707337. 
19. Esposito, Giuseppe, Caterina Scuderi, Marta Valenza, Giuseppina Ines 
Togna, Valentina Latina, Daniele De Filippis, Mariateresa Cipriano, Maria 
Rosaria Carratù, Teresa Iuvone, and Luca Steardo. 2011. “Cannabidiol 
Reduces Aβ-Induced Neuroinflammation and Promotes Hippocampal 
Neurogenesis through PPARγ Involvement.” PLoS ONE 6 (12). 
https://doi.org/10.1371/journal.pone.0028668. 
20. Fouad, Amr A., Waleed H. Albuali, Abdulruhman S. Al-Mulhim, and Iyad 
Jresat. 2013. “Cardioprotective Effect of Cannabidiol in Rats Exposed to 
Doxorubicin Toxicity.” Environmental Toxicology and Pharmacology 36 (2): 
347–57. https://doi.org/10.1016/j.etap.2013.04.018. 
21. Hao, Enkui, Partha Mukhopadhyay, Zongxian Cao, Katalin Erdélyi, Eileen 
Holovac, Lucas Liaudet, Wen-Shin Lee, György Haskó, Raphael Mechoulam, 
and Pál Pacher. 2015. “Cannabidiol Protects against Doxorubicin-Induced 
Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis.” 
Molecular Medicine 21 (1): 38–45. 
https://doi.org/10.2119/molmed.2014.00261. 
22. Hawker, Gillian A., Samra Mian, Tetyana Kendzerska, and Melissa French. 
2011. “Measures of Adult Pain: Visual Analog Scale for Pain (VAS Pain), 
Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire 
(MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain 
Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and 
Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP).” Arthritis 
Care & Research 63 Suppl 11 (November): S240-252. 
https://doi.org/10.1002/acr.20543. 
23. Hegde, Venkatesh L., Prakash S. Nagarkatti, and Mitzi Nagarkatti. 2011. 
“Role of Myeloid-Derived Suppressor Cells in Amelioration of Experimental 
Autoimmune Hepatitis Following Activation of TRPV1 Receptors by 
Cannabidiol.” PLoS ONE 6 (4). https://doi.org/10.1371/journal.pone.0018281. 
24. Huang, Yuanling, Ting Wan, Nengzhi Pang, Yujia Zhou, Xuye Jiang, 
Bangyan Li, Yingying Gu, et al. 2019. “Cannabidiol Protects Livers against 
Nonalcoholic Steatohepatitis Induced by High-Fat High Cholesterol Diet via 
Regulating NF-ΚB and NLRP3 Inflammasome Pathway.” Journal of Cellular 
Physiology 234 (11): 21224–34. https://doi.org/10.1002/jcp.28728. 
25. Imazio, M., E. Cecchi, B. Demichelis, A. Chinaglia, S. Ierna, D. Demarie, A. 
Ghisio, F. Pomari, R. Belli, and R. Trinchero. 2008. “Myopericarditis versus 
Viral or Idiopathic Acute Pericarditis.” Heart (British Cardiac Society) 94 (4): 
498–501. https://doi.org/10.1136/hrt.2006.104067. 
26. Imazio, Massimo, Antonio Brucato, Roberto Cemin, Stefania Ferrua, Stefano 
Maggiolini, Federico Beqaraj, Daniela Demarie, et al. 2013. “A Randomized 
Trial of Colchicine for Acute Pericarditis.” New England Journal of Medicine 
369 (16): 1522–28. https://doi.org/10.1056/NEJMoa1208536. 
27. Imazio, Massimo, Antonio Brucato, Davide Cumetti, Giovanni Brambilla, 
Brunella Demichelis, Silvia Ferro, Silvia Maestroni, et al. 2008. 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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“Corticosteroids for Recurrent Pericarditis: High versus Low Doses: A 
Nonrandomized Observation.” Circulation 118 (6): 667–71. 
https://doi.org/10.1161/CIRCULATIONAHA.107.761064. 
28. Imazio, Massimo, Brunella Demichelis, Iris Parrini, Marco Giuggia, Enrico 
Cecchi, Gianni Gaschino, Daniela Demarie, Aldo Ghisio, and Rita Trinchero. 
2004. “Day-Hospital Treatment of Acute Pericarditis: A Management 
Program for Outpatient Therapy.” Journal of the American College of 
Cardiology 43 (6): 1042–46. https://doi.org/10.1016/j.jacc.2003.09.055. 
29. Imazio, Massimo, and Fiorenzo Gaita. 2017. “Acute and Recurrent 
Pericarditis.” Cardiology Clinics 35 (4): 505–13. 
https://doi.org/10.1016/j.ccl.2017.07.004. 
30. Imazio, Massimo, David H. Spodick, Antonio Brucato, Rita Trinchero, and 
Yehuda Adler. 2010. “Controversial Issues in the Management of Pericardial 
Diseases.” Circulation 121 (7): 916–28. 
https://doi.org/10.1161/CIRCULATIONAHA.108.844753. 
31. Jadoon, Khalid A., Garry D. Tan, and Saoirse E. O’Sullivan. 2017. “A Single 
Dose of Cannabidiol Reduces Blood Pressure in Healthy Volunteers in a 
Randomized Crossover Study.” JCI Insight 2 (12): 93760. 
https://doi.org/10.1172/jci.insight.93760. 
32. Jastrząb, Anna, Agnieszka Gęgotek, and Elżbieta Skrzydlewska. 2019. 
“Cannabidiol Regulates the Expression of Keratinocyte Proteins Involved in 
the Inflammation Process through Transcriptional Regulation.” Cells 8 (8): 
E827. https://doi.org/10.3390/cells8080827. 
33. Khandaker, Masud H., Raul E. Espinosa, Rick A. Nishimura, Lawrence J. 
Sinak, Sharonne N. Hayes, Rowlens M. Melduni, and Jae K. Oh. 2010. 
“Pericardial Disease: Diagnosis and Management.” Mayo Clinic Proceedings 
85 (6): 572–93. https://doi.org/10.4065/mcp.2010.0046. 
34. Klein, Allan, Paul Cremer, Apostolos Kontzias, Muhammad Furqan, Ryan 
Tubman, Mike Roy, Michelle Z. Lim‐Watson, and Matthew Magestro. 2021. 
“US Database Study of Clinical Burden and Unmet Need in Recurrent 
Pericarditis.” Journal of the American Heart Association: Cardiovascular and 
Cerebrovascular Disease 10 (15): e018950. 
https://doi.org/10.1161/JAHA.120.018950. 
35. Klein, Allan L., Massimo Imazio, Paul Cremer, Antonio Brucato, Antonio 
Abbate, Fang Fang, Antonella Insalaco, et al. 2021. “Phase 3 Trial of 
Interleukin-1 Trap Rilonacept in Recurrent Pericarditis.” New England Journal 
of Medicine 384 (1): 31–41. https://doi.org/10.1056/NEJMoa2027892. 
36. Klein, Allan L, David Lin, Paul C Cremer, Saifullah Nasir, Sushil Allen Luis, 
Antonio Abbate, Andrew Ertel, et al. 2021. “Efficacy and Safety of Rilonacept 
for Recurrent Pericarditis: Results from a Phase II Clinical Trial.” Heart 107 
(6): 488–96. https://doi.org/10.1136/heartjnl-2020-317928. 
37. Kytö, Ville, Jussi Sipilä, and Päivi Rautava. 2014. “Clinical Profile and 
Influences on Outcomes in Patients Hospitalized for Acute Pericarditis.” 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
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Circulation 130 (18): 1601–6. 
https://doi.org/10.1161/CIRCULATIONAHA.114.010376. 
38. Laragione, Teresina, Kai F. Cheng, Mark R. Tanner, Mingzhu He, Christine 
Beeton, Yousef Al-Abed, and Pércio S. Gulko. 2015. “THE CATION 
CHANNEL TRPV2 IS A NEW SUPPRESSOR OF ARTHRITIS SEVERITY, 
JOINT DAMAGE AND SYNOVIAL FIBROBLAST INVASION.” Clinical 
Immunology (Orlando, Fla.) 158 (2): 183–92. 
https://doi.org/10.1016/j.clim.2015.04.001. 
39. Laun, Alyssa S., and Zhao-Hui Song. 2017. “GPR3 and GPR6, Novel 
Molecular Targets for Cannabidiol.” Biochemical and Biophysical Research 
Communications 490 (1): 17–21. https://doi.org/10.1016/j.bbrc.2017.05.165. 
40. Lazaros, George, Massimo Imazio, Antonio Brucato, Dimitrios Vassilopoulos, 
Panagiotis Vasileiou, Marco Gattorno, Dimitrios Tousoulis, and Alberto 
Martini. 2016. “Anakinra: An Emerging Option for Refractory Idiopathic 
Recurrent Pericarditis: A Systematic Review of Published Evidence.” Journal 
of Cardiovascular Medicine (Hagerstown, Md.) 17 (4): 256–62. 
https://doi.org/10.2459/JCM.0000000000000266. 
41. Lee, Wen-Shin, Katalin Erdelyi, Csaba Matyas, Partha Mukhopadhyay, 
Zoltan V Varga, Lucas Liaudet, György Haskó, Daniela Čiháková, Raphael 
Mechoulam, and Pal Pacher. 2016. “Cannabidiol Limits T Cell-Mediated 
Chronic Autoimmune Myocarditis: Implications to Autoimmune Disorders and 
Organ Transplantation.” Molecular Medicine 22 (1): 136–46. 
https://doi.org/10.2119/molmed.2016.00007. 
42. Leweke, F M, D Piomelli, F Pahlisch, D Muhl, C W Gerth, C Hoyer, J 
Klosterkötter, M Hellmich, and D Koethe. 2012. “Cannabidiol Enhances 
Anandamide Signaling and Alleviates Psychotic Symptoms of 
Schizophrenia.” Translational Psychiatry 2 (3): e94. 
https://doi.org/10.1038/tp.2012.15. 
43. Libro, Rosaliana, Francesca Diomede, Domenico Scionti, Adriano Piattelli, 
Gianpaolo Grassi, Federica Pollastro, Placido Bramanti, Emanuela Mazzon, 
and Oriana Trubiani. 2016. “Cannabidiol Modulates the Expression of 
Alzheimer’s Disease-Related Genes in Mesenchymal Stem Cells.” 
International Journal of Molecular Sciences 18 (1). 
https://doi.org/10.3390/ijms18010026. 
44. Liu, Chang, Hang Ma, Angela L. Slitt, and Navindra P. Seeram. 2020. 
“Inhibitory Effect of Cannabidiol on the Activation of NLRP3 Inflammasome Is 
Associated with Its Modulation of the P2X7 Receptor in Human Monocytes.” 
Journal of Natural Products 83 (6): 2025–29. 
https://doi.org/10.1021/acs.jnatprod.0c00138. 
45. Lotrionte, Marzia, Giuseppe Biondi-Zoccai, Massimo Imazio, Davide 
Castagno, Claudio Moretti, Antonio Abbate, Pierfrancesco Agostoni, et al. 
2010. “International Collaborative Systematic Review of Controlled Clinical 
Trials on Pharmacologic Treatments for Acute Pericarditis and Its 
Recurrences.” American Heart Journal 160 (4): 662–70. 
https://doi.org/10.1016/j.ahj.2010.06.015. 

 
 
 
 
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46. Lozano, Omar, Gerardo García-Rivas, Martín Ramos, Eduardo Vázquez-
Garza, Héctor Chapoy-Villanueva, Néstor Rubio, Víctor Treviño, James 
Bolton, and Guillermo Torre-Amione. 2020. “CARDIOPROTECTIVE EFFECT 
OF CANNABIDIOL IN A NON ISCHEMIC MODEL OF HEART FAILURE.” 
Journal of the American College of Cardiology 75 (11): 705. 
https://doi.org/10.1016/S0735-1097(20)31332-2. 
47. Maisch, Bernhard, Günther Hufnagel, Susanne Kölsch, Rainer Funck, 
Annette Richter, Heinz Rupp, Matthias Herzum, and Sabine Pankuweit. 
2004. “Treatment of Inflammatory Dilated Cardiomyopathy and 
(Peri)Myocarditis with Immunosuppression and i.v. Immunoglobulins.” Herz 
29 (6): 624–36. https://doi.org/10.1007/s00059-004-2628-7. 
48. Mannion, Anne F., Federico Balagué, Ferran Pellisé, and Christine 
Cedraschi. 2007. “Pain Measurement in Patients with Low Back Pain.” 
Nature Clinical Practice. Rheumatology 3 (11): 610–18. 
https://doi.org/10.1038/ncprheum0646. 
49. Martinez-Naya, Nadia. 2022. “Protective Effects of Cannabidiol in a Mouse 
Model of Acute Pericarditis.” Presented at the American Heart Association 
Scientific Sessions, Chicago, IL, November 5. 
50. Mauro, Adolfo G., Aldo Bonaventura, Alessandra Vecchié, Eleonora 
Mezzaroma, Salvatore Carbone, Pratyush Narayan, Nicola Potere, et al. 
2021. “The Role of NLRP3 Inflammasome in Pericarditis.” JACC: Basic to 
Translational Science 6 (2): 137–50. 
https://doi.org/10.1016/j.jacbts.2020.11.016. 
51. McPartland, John M., Christa MacDonald, Michelle Young, Phillip S. Grant, 
Daniel P. Furkert, and Michelle Glass. 2017. “Affinity and Efficacy Studies of 
Tetrahydrocannabinolic Acid A at Cannabinoid Receptor Types One and 
Two.” Cannabis and Cannabinoid Research 2 (1): 87–95. 
https://doi.org/10.1089/can.2016.0032. 
52. Mecha, M., A. Feliú, P. M. Iñigo, L. Mestre, F. J. Carrillo-Salinas, and C. 
Guaza. 2013. “Cannabidiol Provides Long-Lasting Protection against the 
Deleterious Effects of Inflammation in a Viral Model of Multiple Sclerosis: A 
Role for A2A Receptors.” Neurobiology of Disease 59 (November): 141–50. 
https://doi.org/10.1016/j.nbd.2013.06.016. 
53. Mishima, Kenichi, Kazuhide Hayakawa, Kohji Abe, Tomoaki Ikeda, Nobuaki 
Egashira, Katsunori Iwasaki, and Michihiro Fujiwara. 2005. “Cannabidiol 
Prevents Cerebral Infarction Via a Serotonergic 5-Hydroxytryptamine 1A 
Receptor–Dependent Mechanism.” Stroke 36 (5): 1071–76. 
https://doi.org/10.1161/01.STR.0000163083.59201.34. 
54. Morales, Paula, and Patricia H. Reggio. 2017. “An Update on Non-CB1, Non-
CB2 Cannabinoid Related G-Protein-Coupled Receptors.” Cannabis and 
Cannabinoid Research 2 (1): 265–73. https://doi.org/10.1089/can.2017.0036. 
55. Morissette, Florence, Violaine Mongeau-Pérusse, Elie Rizkallah, Paméla 
Thébault, Stéphanie Lepage, Suzanne Brissette, Julie Bruneau, et al. 2021. 
“Exploring Cannabidiol Effects on Inflammatory Markers in Individuals with 
Cocaine Use Disorder: A Randomized Controlled Trial.” 

 
 
 
 
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Neuropsychopharmacology: Official Publication of the American College of 
Neuropsychopharmacology 46 (12): 2101–11. 
https://doi.org/10.1038/s41386-021-01098-z. 
56. Mukhopadhyay, Partha, Mohanraj Rajesh, Béla Horváth, Sándor Bátkai, Ogyi 
Park, Galin Tanashian, Rachel Y Gao, et al. 2011. “Cannabidiol Protects 
against Hepatic Ischemia/Reperfusion Injury by Attenuating Inflammatory 
Signaling and Response, Oxidative/Nitrative Stress, and Cell Death.” Free 
Radical Biology & Medicine 50 (10): 1368–81. 
https://doi.org/10.1016/j.freeradbiomed.2011.02.021. 
57. Muller, Chanté, Paula Morales, and Patricia H. Reggio. 2019. “Cannabinoid 
Ligands Targeting TRP Channels.” Frontiers in Molecular Neuroscience 11 
(January). https://doi.org/10.3389/fnmol.2018.00487. 
58. O’Sullivan, Saoirse E., Yan Sun, Andrew J. Bennett, Michael D. Randall, and 
David A. Kendall. 2009. “Time-Dependent Vascular Actions of Cannabidiol in 
the Rat Aorta.” European Journal of Pharmacology 612 (1–3): 61–68. 
https://doi.org/10.1016/j.ejphar.2009.03.010. 
59. O’Sullivan, Saoirse Elizabeth. 2016. “An Update on PPAR Activation by 
Cannabinoids.” British Journal of Pharmacology 173 (12): 1899–1910. 
https://doi.org/10.1111/bph.13497. 
60. Pazos, M. Ruth, Nagat Mohammed, Hector Lafuente, Martin Santos, Eva 
Martínez-Pinilla, Estefania Moreno, Elsa Valdizan, et al. 2013. “Mechanisms 
of Cannabidiol Neuroprotection in Hypoxic–Ischemic Newborn Pigs: Role of 
5HT1A and CB2 Receptors.” Neuropharmacology 71 (August): 282–91. 
https://doi.org/10.1016/j.neuropharm.2013.03.027. 
61. Rajesh, Mohanraj, Partha Mukhopadhyay, Sándor Bátkai, György Haskó, 
Lucas Liaudet, Viktor R. Drel, Irina G. Obrosova, and Pál Pacher. 2007. 
“Cannabidiol Attenuates High Glucose-Induced Endothelial Cell Inflammatory 
Response and Barrier Disruption.” American Journal of Physiology. Heart 
and Circulatory Physiology 293 (1): H610–19. 
https://doi.org/10.1152/ajpheart.00236.2007. 
62. Rajesh, Mohanraj, Partha Mukhopadhyay, Sándor Bátkai, Vivek Patel, Keita 
Saito, Shingo Matsumoto, Yoshihiro Kashiwaya, et al. 2010. “Cannabidiol 
Attenuates Cardiac Dysfunction, Oxidative Stress, Fibrosis, and Inflammatory 
and Cell Death Signaling Pathways in Diabetic Cardiomyopathy.” Journal of 
the American College of Cardiology 56 (25): 2115–25. 
https://doi.org/10.1016/j.jacc.2010.07.033. 
63. Reggio, P.H., R.D. Bramblett, H. Yuknavich, H.H. Seltzman, D.N. Fleming, 
S.R. Fernando, L.A. Stevenson, and R.G. Pertwee. 1995. “The Design, 
Synthesis and Testing of Desoxy-CBD: Further Evidence for a Region of 
Steric Interference at the Cannabinoid Receptor.” Life Sciences 56 (23–24): 
2025–32. https://doi.org/10.1016/0024-3205(95)00185-9. 
64. Resstel, Leonardo BM, Rodrigo F Tavares, Sabrina FS Lisboa, Sâmia RL 
Joca, Fernando MA Corrêa, and Francisco S Guimarães. 2009. “5-HT1A 
Receptors Are Involved in the Cannabidiol-Induced Attenuation of 
Behavioural and Cardiovascular Responses to Acute Restraint Stress in 

 
 
 
 
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Rats.” British Journal of Pharmacology 156 (1): 181–88. 
https://doi.org/10.1111/j.1476-5381.2008.00046.x. 
65. Ribeiro, Alison, Viviane Ferraz-de-Paula, Milena L. Pinheiro, Luana B. 
Vitoretti, Domenica P. Mariano-Souza, Wanderley M. Quinteiro-Filho, 
Adriana T. Akamine, et al. 2012. “Cannabidiol, a Non-Psychotropic Plant-
Derived Cannabinoid, Decreases Inflammation in a Murine Model of Acute 
Lung Injury: Role for the Adenosine A2A Receptor.” European Journal of 
Pharmacology 678 (1): 78–85. https://doi.org/10.1016/j.ejphar.2011.12.043. 
66. Rimmerman, Neta, Ana Juknat, Ewa Kozela, Rivka Levy, Heather B. 
Bradshaw, and Zvi Vogel. 2011. “The Non-Psychoactive Plant Cannabinoid, 
Cannabidiol Affects Cholesterol Metabolism-Related Genes in Microglial 
Cells.” Cellular and Molecular Neurobiology 31 (6): 921–30. 
https://doi.org/10.1007/s10571-011-9692-3. 
67. Spodick, David H. 2003. “Acute Cardiac Tamponade.” The New England 
Journal of Medicine 349 (7): 684–90. https://doi.org/10.1056/NEJMra022643. 
68. Stanley, Christopher P., William H. Hind, Cristina Tufarelli, and Saoirse E. 
O’Sullivan. 2015. “Cannabidiol Causes Endothelium-Dependent 
Vasorelaxation of Human Mesenteric Arteries via CB1 Activation.” 
Cardiovascular Research 107 (4): 568–78. 
https://doi.org/10.1093/cvr/cvv179. 
69. Suryavanshi, Santosh V., Igor Kovalchuk, and Olga Kovalchuk. 2020. 
“Cannabinoids as Key Regulators of Inflammasome Signaling: A Current 
Perspective.” Frontiers in Immunology 11: 613613. 
https://doi.org/10.3389/fimmu.2020.613613. 
70. Zayas, Ricardo, Manuel Anguita, Francisco Torres, Diego Gime´nez, 
Francisco Bergillos, Marti´n Ruiz, Mar Ciudad, Arsenio Gallardo, and 
Federico Valle´s. 1995. “Incidence of Specific Etiology and Role of Methods 
for Specific Etiologic Diagnosis of Primary Acute Pericarditis.” American 
Journal of Cardiology 75 (5): 378–82. https://doi.org/10.1016/S0002-
9149(99)80558-X. 
 

 
 
 
 
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17 APPENDICES 
17.1 Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI  
for  
Medical Research Involving Human Subjects  
Adopted by the 18
th WMA General Assembly  
Helsinki, Finland, June 1964  
and amended by the  
29
th WMA General Assembly, Tokyo, Japan, October 1975  
35
th WMA General Assembly, Venice, Italy, October 1983  
41
st WMA General Assembly, Hong Kong, September 1989  
48
th WMA General Assembly, Somerset West, Republic of South Africa, October 1996  
and the  
52
nd WMA General Assembly, Edinburgh, Scotland, October 2000  
and the  
Washington DC 2002 clarification on Paragraph 29  
 
A. INTRODUCTION  
1. The World Medical Association has developed the Declaration of Helsinki as a 
statement of ethical principles to provide guidance to physicians and other 
participants in medical research involving human subjects. Medical research 
involving human subjects includes research on identifiable human material or 
identifiable data.  
2. It is the duty of the physician to promote and safeguard the health of the people. 
The physician's knowledge and conscience are dedicated to the fulfillment of this 
duty.  
3. The Declaration of Geneva of the World Medical Association binds the physician 
with the words, "The health of my patient will be my first consideration," and the 
International Code of Medical Ethics declares that, "A physician shall act only in 
the patients interest when providing medical care which might have the effect of 
weakening the physical and mental condition of the patient."  
4. Medical progress is based on research, which ultimately must rest in part on 
experimentation involving human subjects.  
5. In medical research on human subjects, considerations related to the well-being of 
the human subject should take precedence over the interests of science and 
society.  
6. The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the 
aetiology and pathogenesis of disease. Even the best-proven prophylactic, 
diagnostic, and therapeutic methods must continuously be challenged through 
research for their effectiveness, efficiency, accessibility and quality.  
7. In current medical practice and in medical research, most prophylactic, diagnostic 
and therapeutic procedures involve risks and burdens.  
8. Medical research is subject to ethical standards that promote respect for all human 

 
 
 
 
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62 
beings and protect their health and rights. Some research populations are 
vulnerable and need special protection. The particular needs of the economically 
and medically disadvantaged must be recognized. Special attention is also 
required for those who cannot give or refuse consent for themselves, for those who 
may be subject to giving consent under duress, for those who will not benefit 
personally from the research and for those for whom the research is combined with 
care.  
9. Research Investigators should be aware of the ethical, legal and regulatory 
requirements for research on human subjects in their own countries as well as 
applicable international requirements. No national ethical, legal or regulatory 
requirement should be allowed to reduce or eliminate any of the protections for 
human subjects set forth in this Declaration.  
 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH  
10. It is the duty of the physician in medical research to protect the life, health, privacy, 
and dignity of the human subject  
11. Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, 
other relevant sources of information, and on adequate laboratory and, where 
appropriate, animal experimentation.  
12. Appropriate caution must be exercised in the conduct of research, which may affect 
the environment, and the welfare of animals used for research must be respected.  
13. The design and performance of each experimental procedure involving human 
subjects should be clearly formulated in an experimental protocol. This protocol 
should be submitted for consideration, comment, guidance, and where 
appropriate, approval to a specially appointed ethical review committee, which 
must be independent of the investigator. This independent committee should be in 
conformity with the laws and regulations of the country in which the research 
experiment is performed. The committee has the right to monitor ongoing trials. 
The researcher has the obligation to provide monitoring information to the 
committee, especially any serious adverse events. The researcher should also 
submit to the committee, for review, information regarding funding, institutional 
affiliations, other potential conflicts of interest and incentives for subjects.  
14. The research protocol should always contain a statement of the ethical 
considerations involved and should indicate that there is compliance with the 
principles enunciated in this Declaration.  
15. Medical research involving human subjects should be conducted only by 
scientifically qualified persons and under the supervision of a clinically competent 
medical person. The responsibility for the human subject must always rest with a 
medically qualified person and never rest on the subject of the research, even 
though the subject has given consent.  
16. Every medical research project involving human subjects should be preceded by 
careful assessment of predictable risks and burdens in comparison with 
foreseeable benefits to the subject or to others. This does not preclude the 
participation of healthy volunteers in medical research. The design of all studies 
should be publicly available.  
17. Physicians should abstain from engaging in research projects involving human 
subjects unless they are confident that the risks involved have been adequately 
assessed and can be satisfactorily managed. Physicians should cease any 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
63 
investigation if the risks are found to outweigh the potential benefits or if there is 
conclusive proof of positive and beneficial results.  
18. Medical research involving human subject should only be conducted if the 
importance of the objective outweighs the inherent risks and burdens to the 
subject. This is especially important when the human subjects are healthy 
volunteers.  
19. Medical research is only justified if there is a reasonable likelihood that the 
populations in which the research is carried out stand to benefit from the results of 
the research.  
20. The subjects must be volunteers and informed participants in the research project.  
21. The right of research subjects to safeguard their integrity must always be 
respected. Every precaution should be taken to respect the privacy of the subject, 
the confidently of the patient's information and to minimize the impact of the study 
on the subject’s physical and mental integrity and on the personality of the subject.  
22. In any research on human beings, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and 
potential risks of the study and the discomfort it may entail. The subject should be 
informed of the right to abstain from participation in the study or to withdraw 
consent to participate at any time without reprisal. After ensuring that the subject 
has understood the information, the physician should then obtain the subjects 
freely- given informed consent preferably in writing. If the consent cannot be 
obtained in writing, the non-written consent must be formally documented and 
witnessed.  
23. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician 
or may consent under duress. In that case the informed consent should be 
obtained by a well-informed physician who is not engaged in the investigation and 
who is completely independent of the relationship.  
24. For a research subject who is legally incompetent physically or mentally incapable 
of giving consent or is a legally incompetent minor, the investigator must obtain 
informed consent from the legally authorized representative in accordance with 
applicable law. These groups should not be included in research unless the 
research is necessary to promote the health of the population represented and this 
research cannot instead be performed on legally competent persons.  
25. When a subject deemed legally incompetent, such as a minor child, is able to give 
assent to decisions about participation in research, the investigator must obtain 
that assent in addition to the consent of the legally authorized representative.  
26. Research on individuals from whom it is not possible to obtain consent, including 
proxy or advance consent, should be done only if the physical/mental condition 
that prevents obtaining informed consent is a necessary characteristic of the 
research population. The specific reasons for involving research subjects with a 
condition that renders them unable to give informed consent should be stated in 
the experimental protocol for consideration and approval of the review committee. 
The protocol should state that consent to remain in the research should be 
obtained as soon as possible from the individual or a legally authorized surrogate.  
27. Both authors and publishers have ethical obligations. In publication of the results 
of research, the investigators are obliged to preserve the accuracy of the results. 
Negative as well as positive results should be published or otherwise publicly 

 
 
 
 
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64 
available, Sources of funding, institutional affiliations and any possible conflicts of 
interest should be declared in the publication. Reports of experimentation not in 
accordance with the principles laid down in this Declaration should not be accepted 
for publication.  
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE  
28. The physician may combine medical research with medical care, only to the extent 
that the research is justified by its potential prophylactic, diagnostic or therapeutic 
value. When medical research is combined with medical care, additional 
standards apply to protect the patients who are research subjects.  
29. The benefits, risks, burdens and effectiveness of a new method should be tested 
against those of the best current prophylactic, diagnostic, and therapeutic 
methods. 'This does not exclude the use of placebo, or no treatment, in studies 
where no proven prophylactic, diagnostic or therapeutic method exists.  
30. At the conclusion of the study, every patient entered into the study should be 
assured of access to the best-proven prophylactic, diagnostic and therapeutic 
methods identified by the study.  
31. The physician should fully inform the patient which aspects of the care are related 
to the research. The refusal of a patient to participate in a study must never 
interfere with the patient-physician relationship.  
32. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic 
methods, do not exist or have been ineffective, the physician, with informed 
consent from the patient, must be free to use unproven or new prophylactic, 
diagnostic and therapeutic measures if in the physician's judgment it offers hope 
of saving life, re-establishing health or alleviating suffering. Where possible, these 
measures should be made the object of research, designed to evaluate their safety 
and efficacy. In all cases, new information should be recorded and, where 
appropriate, published. The other relevant guidelines of this Declaration should be 
followed.  
 
FOOTNOTE: NOTE OF CLARIFICATION ON PARAGRAPH 29 of the WMA DECLARATION OF HELSINKI  
The WMA hereby reaffirms its position that extreme care must be taken in making use of a placebo-controlled trial and 
that in general this methodology should only be used in the absence of existing proven therapy. However, a placebo-
controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:  
- 
Where for compelling and scientifically sound methodological reasons its use is necessary to determine the 
efficacy or safety of a prophylactic, diagnostic or therapeutic method; or  
- 
Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the 
patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.  
All other provisions of the Declaration of Helsinki must be adhered to, especially the need for appropriate ethical and 
scientific review.  
 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
65 
 
17.2 Schedule of Study Procedures 
 
 
1  Vital signs include heart rate and blood pressure; body weight at baseline, at all in-person visits; height at baseline 
2 Except for Visit 1, all ECGs to be recorded 3.5 – 6 hours post morning dose of study Rx  
3  Start of study drug in the evening of Day 1 after completion of baseline assessments 
4  Study drug adjustment up to Visit 4 (Week 3); drug accountability at all visits, including virtual visits 
5  Adverse Event recording starts after informed consent is obtained 
6  All local laboratory assessments at baseline to be performed before start of study Rx 
7  Pregnancy test in women with childbearing potential 
8 For patients not able to participate in the EP, Visit 5 (Week 8) is the end of study visit 
9 EP starting after Visit 5 until Visit 9 
10 If CRP was measured within 7 days of Day 1, this value will be used as the baseline value. If there is no CRP measurement available within 7 
days of Day 1, CRP needs to be measured at baseline. 
11Highest NRS pain score within the past 7 days of Day 1 from patient recall; after randomization from the Patient Portal entries/diary entries or, if 
not available, from patient recall 
12 Visits 2 (Day 3), 3 (Day 10), and 4 (Week 3) can be performed virtually, via video link, if an ECG can be performed with direct transmission to site 
for review by investigator or designate and local laboratory assessments at Visit 4 can be arranged 
 
 
 
 
 
VISIT 
1 
2 
3 
 
4 
 
5 
6 
7 
8 
9 
DAYS 
Within 72 
hours of 
Day 1 
3 
10 
 
 
 
 
 
 
 
 
WEEKS 
 
 
 
 
3 
 
88,9 
12 
16 
20 
26 
 
 
Virtual 
visit if 
feasible 
and not 
possible 
in person 
Virtual 
visit if 
feasible 
and not 
possible 
in person 
 
Virtual 
visit if 
feasible 
and not 
possible 
in person 
 
 
Virtual 
visit 
 
 
Virtual 
visit 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Clinical assessment 
X 
 
 
 
 
 
X 
 
X 
 
X 
Vital signs1 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Highest NRS pain score within the past 7 
days recorded11 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Review/Collection of NRS Pain Scores 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
12-lead ECG2 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
C-SSRS 
X 
 
 
 
 
 
X 
 
 
 
X 
Study medication3 
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
Start of EP (weaning of concomitant Rx) 
 
 
 
 
 
 
X 
 
 
 
 
Study Rx adjustment and accountability4 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Concomitant medication recording 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
AE and SAE recording5 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Laboratory 
DAYS 
WEEKS 
Local Laboratory 
16 
3 
10 
 
3 
 
8 
12 
16 
20 
26 
CRP10 
X 
 
 
 
X 
 
X 
 
X 
 
X 
CBC 
X 
 
 
 
X 
 
X 
 
X 
 
X 
ALT/AST 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Alkaline Phosphatase 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Bilirubin 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Creatinine/ eGFR 
X 
 
 
 
X 
 
X 
 
X 
 
X 
INR 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Pregnancy Test7 
X 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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17.3 Numerical Rating Scale (NRS) 
 
Patients will be asked to select the score that best describes their average level of 
pericarditis pain over the previous 24 hours using this 11-point NRS, where zero (0) 
indicates ‘no pain’ and ten (10) indicates ‘pain as bad as it could be’. 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
On this scale of 0 – 10, zero (0) indicates ‘no pain’ and ten (10) indicates 
‘pain as bad as it could be’, please rate your pericarditis pain on average 
over the last 24 hours. Please tick or circle only one number.  
 
Patients will have the choice to complete the NRS scale either on paper or in an 
electronic patient reported outcomes platform – i.e. eSOCDAT Patient Portal. Access to 
the eSOCDAT Patient Portal is restricted to authorized users only. State-of-the-art 
procedures are in place to prevent unauthorized access and data corruption, namely, 
firewalls, up-to-date virus scanning in addition to the encryption of data stored in the 
database and transmitted via the Internet. Patients will be provided with a unique user 
name and password to access the eSOCDAT Portal. 
 
 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
67 
 
 
17.4 COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – 
BASELINE/SCREENING VERSION 
COLUMBIA-SUICIDE SEVERITY  
RATING SCALE  
(C-SSRS) 
Baseline/Screening Version 
Version 1/14/09 
 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; 
Fisher, P.; Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J. 
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its 
administration. The questions contained in the Columbia-Suicide Severity Rating Scale 
are suggested probes. Ultimately, the determination of the presence of suicidal ideation 
or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The 
Columbia Suicide History Form, developed by John Mann, MD and Maria Oquendo, 
MD, Conte Center for the Neuroscience of Mental Disorders (CCNMD), New York State 
Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of 
research instruments. In M.B. First [Ed.] Standardized Evaluation in Clinical Practice, 
pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric 
Institute, 1051 Riverside Drive, New York, New York, 10032; inquiries and training 
requirements contact posnerk@nyspi.columbia.edu 
 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
 
 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
68 
PART 1 OF 5 
 
SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the answer to 
question 2 is “yes”, ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is “yes”, complete 
“Intensity of Ideation” section below. 
Lifetime: Time 
He/She Felt  
Most Suicidal 
Past __ 
Months 
1.  Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not 
wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
 
 Yes 
No 
 
 
 
2.  Non-Specific Active Suicidal Thoughts 
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing 
myself”) without thoughts of ways to kill oneself/associated methods, intent, or plan during the assessment 
period. 
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
 
 Yes 
No 
 
 
 
 
 Section below not applicable 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment 
period. This is different than a specific plan with time, place or method details worked out (e.g., thought of 
method to kill self but not a specific plan). Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it… and I would 
never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
 
 Yes 
No 
 
 
 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, 
as opposed to “I have the thoughts but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them? 
 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
 
 Yes 
No 
 
 
 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to 
carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to 
carry out this plan? 
 
If yes, describe: 
 
 Yes 
No 
 
 
 
 
 Yes 
No 
 
 
 
 
 
 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
69 
 
PART 2 OF 5 
 
 Section below not applicable 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from 
above, with 1 being the least severe and 5 being the most severe). Ask about time he/she was feeling 
the most suicidal. 
Most Severe 
Most 
Severe 
Lifetime - 
Most Severe Ideation:    __________  
 
 
 
Type # (1-5) 
Description of Ideation 
Past X Months - 
Most Severe Ideation:    __________  
 
 
 
Type # (1-5) 
Description of Ideation 
Frequency 
How many times have you had these thoughts? 
____ 
____ 
 
(1) Less than once a week 
(2) Once a week 
(3) 2-5 times in week 
(4) Daily or almost daily 
(5) Many times each day 
Duration 
When you have the thoughts how long do they last? 
 
 
(1) Fleeting - few seconds or minutes 
(2) Less than 1 hour/some of the time 
(3) 1-4 hours/a lot of time 
(4) 4-8 hours/most of day 
(5) More than 8 hours/persistent or 
continuous 
____ 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
 
 
(1) Easily able to control thoughts 
(2) Can control thoughts with little difficulty 
(3) Can control thoughts with some difficulty 
(4) Can control thoughts with a lot of 
difficulty 
(5) Unable to control thoughts 
(0) Does not attempt to control thoughts 
____ 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from 
wanting to die or acting on thoughts of committing suicide? 
 
 
(1) Deterrents definitely stopped you from attempting 
suicide 
(2) Deterrents probably stopped you 
(3) Uncertain that deterrents stopped you 
(4) Deterrents most likely did not stop you 
(5) Deterrents definitely did not stop you 
(0) Does not apply 
____ 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to 
end the pain or stop the way you were feeling (in other words you couldn’t go on living with this 
pain or how you were feeling) or was it to get attention, revenge or a reaction from others? Or 
both? 
 
 
(1) Completely to get attention, revenge or a reaction 
from others 
(2) Mostly to get attention, revenge or a reaction from 
others 
(3) Equally to get attention, revenge or a reaction from 
others and to end/stop the pain 
(4) Mostly to end or stop the pain (you 
couldn’t go on living with the pain or 
how you were feeling) 
(5) Completely to end or stop the pain 
(you couldn’t go on living with the pain 
or how you were feeling) 
(0) Does not apply 
____ 
____ 
 
 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
70 
PART 3 OF 5 
 
 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Lifetime 
Past __ 
Years 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in 
part thought of as method to kill oneself. Intent does not have to be 100%. If there is any intent/desire to 
die associated with the act, then it can be considered an actual suicide attempt. There does not have 
to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in 
mouth but gun is broken so no injury results, this is considered an attempt. 
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the 
behavior or circumstances. For example, a highly lethal act that is clearly not an accident so no other 
intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). Also, 
if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you_____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve 
stress, feel better, get sympathy, or get something else to happen)? (Self-Injurious Behavior without 
suicidal intent) 
If yes, describe: 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 Yes 
No 
 
 
 
 Yes 
No 
 
 
 
Total # of 
Attempts 
______ 
Total # of 
Attempts 
______ 
 Yes 
No 
 
 
 
 Yes 
No 
 
 
 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
71 
PART 4 OF 5 
 
 Section below not applicable 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Lifetime 
Past __ 
Years 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act 
(if not for that, actual attempt would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes 
an attempt rather than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken 
away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, even if 
the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from 
ledge. Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or 
something stopped you before you actually did anything? 
If yes, describe: 
 
 Yes 
No 
 
 
 
 Yes 
No 
 
 
 
Total # of 
interrupted 
______ 
Total # of 
interrupted 
______ 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before they 
actually have engaged in any self-destructive behavior. Examples are similar to interrupted attempts, 
except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped 
yourself before you actually did anything? 
If yes, describe: 
 
 Yes 
No 
 
 
 
 Yes 
No 
 
 
 
Total # of 
aborted 
______ 
Total # of 
aborted 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a 
verbalization or thought, such as assembling a specific method (e.g., buying pills, purchasing a gun) or 
preparing for one’s death by suicide (e.g., giving things away, writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as 
collecting pills, getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
 
 Yes 
No 
 
 
 
 
 
Following must be answered 
 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
 Yes 
No 
 
 
 
 Yes 
No 
 
 
 
 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
72 
PART 5 OF 5 
 
 Section below not applicable 
Answer for Actual Attempts Only 
Most Recent 
Attempt  
Date: 
Most Lethal 
Attempt  
Date: 
Initial/First 
Attempt  
Date: 
Actual Lethality/Medical Damage: 
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, 
somewhat responsive; second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care 
required (e.g., comatose with reflexes intact; third-degree burns less than 20% of body; 
extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., 
comatose without reflexes; third-degree burns over 20% of body; extensive blood loss with 
unstable vital signs; major damage to a vital area). 
5.  Death 
Enter Code 
______ 
Enter Code 
______ 
Enter Code 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having 
no actual medical damage, had potential for very serious lethality: put gun in mouth and 
pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with 
oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
______ 
Enter Code 
______ 
Enter Code 
______ 
 
 
 
 

 
 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
73 
17.5 COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – 
SINCE LAST VISIT VERSION 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; 
Fisher, P.; Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its 
administration. The questions contained in the Columbia-Suicide Severity Rating Scale 
are suggested probes. Ultimately, the determination of the presence of suicidal ideation 
or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The 
Columbia Suicide History Form,  developed by John Mann, MD and Maria Oquendo, 
MD, Conte Center for the Neuroscience of Mental Disorders (CCNMD), New York State 
Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of 
research instruments. In M.B. First [Ed.] Standardized Evaluation in Clinical Practice, 
pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric 
Institute, 1051 Riverside Drive, New York, New York, 10032; inquiries and training 
requirements contact posnerk@nyspi.columbia.edu 
 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
74 
 
 
PART 1 OF 5 
 
SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the 
answer to question 2 is “yes”, ask questions 3, 4 and 5. If the answer to question 1 and/or 2 
is “yes”, complete “Intensity of Ideation” section below. 
Since Last 
Visit 
1.  Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
2.  Non-Specific Active Suicidal Thoughts 
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) 
without thoughts of ways to kill oneself/associated methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
 
 Section below not applicable 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is 
different than a specific plan with time, place or method details worked out (e.g., thought of method to kill self but 
not a specific plan). Includes person who would say, “I thought about taking an overdose but I never made a 
specific plan as to when, where or how I would actually do it…..and I would never go through with it”. 
Have you been thinking about how you might do this? 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as 
opposed to “I have the thoughts but I definitely will not do anything about them”. 
Have you had these thoughts and had some intention of acting on them? 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it 
out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out 
this plan? 
If yes, describe: 
 
 
 Yes 
No 
 
 
 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
75 
PART 2 OF 5 
 
 Section below not applicable 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from 
above, with 1 being the least severe and 5 being the most severe). 
Most 
Severe 
Most Severe Ideation: 
 _______  
 
 
 
Type # (1-5) 
Description of Ideation 
Frequency 
How many times have you had these thoughts? 
____ 
 
(1) Less than once a 
week 
(2) Once a 
week 
(3) 2-5 times in 
week 
(4) Daily or almost 
daily 
(5) Many times 
each day 
Duration 
When you have the thoughts how long do they last? 
 
(1) Fleeting - few seconds or minutes 
(2) Less than 1 hour/some of the time 
(3) 1-4 hours/a lot of time 
(4) 4-8 hours/most of day 
(5) More than 8 hours/persistent or 
continuous 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
 
(1) Easily able to control thoughts 
(2) Can control thoughts with little difficulty 
(3) Can control thoughts with some difficulty 
(4) Can control thoughts with a lot of 
difficulty 
(5) Unable to control thoughts 
(0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped 
you from wanting to die or acting on thoughts of committing suicide? 
 
(1) Deterrents definitely stopped you from attempting suicide 
(2) Deterrents probably stopped you 
(3) Uncertain that deterrents stopped you 
(4) Deterrents most likely did not stop you 
(5) Deterrents definitely did not stop you 
(0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself? 
Was it to end the pain or stop the way you were feeling (in other words you couldn’t go 
on living with this pain or how you were feeling) or was it to get attention, revenge or a 
reaction from others? Or both? 
 
(1) Completely to get attention, revenge or a reaction from 
others 
(2) Mostly to get attention, revenge or a reaction from others 
(3) Equally to get attention, revenge or a reaction from others 
and to end/stop the pain 
(4) Mostly to end or stop the pain (you 
couldn’t go on living with the pain or 
how you were feeling) 
(5) Completely to end or stop the pain (you 
couldn’t go on living with the pain or 
how you were feeling) 
(0) Does not apply 
____ 
 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
76 
PART 3 OF 5 
 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since 
Last 
Visit 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part 
thought of as method to kill oneself. Intent does not have to be 100%. If there is any intent/desire to die 
associated with the act, then it can be considered an actual suicide attempt. There does not have to be 
any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is 
broken so no injury results, this is considered an attempt. 
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or 
circumstances. For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be 
inferred (e.g., gunshot to head, jumping from window of a high floor/story). Also, if someone denies intent to die, 
but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you_____? 
Or Did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like 
to relieve stress, feel better, get sympathy, or get something else to happen)? (Self-Injurious 
Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
 Yes 
No 
 
 
 
Total # of 
Attempts 
______ 
 Yes 
No 
 
 
 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
77 
PART 4 OF 5 
 
 Section below not applicable 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not 
for that, actual attempt would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an 
attempt rather than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by 
someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, even if the gun fails to 
fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person 
has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or 
something stopped you before you actually did anything? 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
Total # of 
interrupted 
______ 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually 
have engaged in any self-destructive behavior. Examples are similar to interrupted attempts, except that the 
individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you 
stopped yourself before you actually did anything? 
If yes, describe: 
 
 Yes 
No 
 
 
 
Total # of 
aborted 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a 
verbalization or thought, such as assembling a specific method (e.g., buying pills, purchasing a gun) or preparing 
for one’s death by suicide (e.g., giving things away, writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself 
(such as collecting pills, getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
 Yes 
No 
 
 
 
 
 
Following must be answered 
 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
 Yes 
No 
 
 
 
Suicide: 
 
 Yes 
No 
 
 
 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
78 
PART 5 OF 5 
 
 Section below not applicable 
Answer for Actual Attempts Only 
Most Lethal 
Attempt  
Date: 
Actual Lethality/Medical Damage: 
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; 
second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose 
with reflexes intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major 
fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; 
third-degree burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital 
area). 
5.  Death 
Enter Code 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical 
damage, had potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no 
medical damage; laying on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
______ 
 
 
 
 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
79 
17.6 Drugs that can prolong QTc intervals 
 
 
 
 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
80 
 
 
 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
81 
 
 
 
 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
82 
 
17.7 Drugs That Are Strong Inducers of CYP3A4 and CYP2C19 
17.7.1 
CYP3A4 Inducers 
• Anticonvulsants Phenytoin and Carbamazepine 
• Testosterone receptor inhibitors Apalutamide and Enzulutamide 
• Adrenal cortex hormone inhibitor Mitotane 
• Antibiotic Rifampin 
• St John’s Wort 
• Possibly Phenobarbital 
17.7.2 
CYP2C19 Inducers 
• Rifampin 
 
 
 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
83 
17.8 Cannabidiol and Drug-Drug Interactions 
 
Notes: 
1. Cannabidiol is a strong inhibitor of a number of CYP and UGT isoforms. Medications that 
depend on one (or more) of these enzyme isoforms for metabolism (that is, medications 
serve as a substrate for the enzyme) may then have slowed metabolism, thereby 
resulting in increased blood levels of the drug. For some drugs (particularly those with a 
narrow therapeutic index), this may result in toxicity.  
2. The drugs listed are those that serve as a substrate for one or more of CYP2C8, 
CYP2C9, CYP2C19, CYP1A2, CYP2B6, UGT1A9 and UGT2B7. 
3. Please note that certain drugs that are substrates for these enzymes are also strong 
inducers of CYP3A4 and therefore are exclusion criteria for this study, as depicted in 
Appendix 17.7. 
4. Drugs listed in the table are arranged as follows: cardiovascular drugs, diabetes care 
drugs and then other commonly used drugs (in alphabetical order). The CYP or UGT 
isoform for which the drugs serve as a substrate are listed in the final column.  
5. Many drugs serve as a substrate for more than one CYP or UGT isoform. They have 
only been recorded once in the table. 
6. This patient population maybe taking a wide spectrum of medication. If a medication of 
interest is not included in this list, please refer to a respected website such as DrugBank 
(www.drugbank.ca) to determine likelihood of drug-drug interaction. 
 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
84 
Drug Class 
Drug Name 
Signs/Monitoring/Mitigation 
Strategies 
Enzyme 
 
Cardiovascular 
Drugs 
 
 
 
Diuretic 
Torasemide 
May cause hypotension, 
hypokalemia, increased 
creatinine - Monitor body 
weight and renal function. 
Adjust dose accordingly 
CYP2C8 
 
Triamterene 
May cause hyperkalemia, 
hyponatremia, nausea and 
vomiting, diarrhea, kidney 
stones – monitor potassium, 
adjust dose or change to 
other diuretic 
CYP1A2 
Statin 
 
Cerivistatin 
Atorvastatin 
Fluvastatin 
Imvastatin 
Pitavastatin 
Lovastatin 
May cause muscle 
breakdown, muscle pain, 
Monitor cholesterol level and 
review adverse effect profile - 
Adjust dose or substitute 
another agent 
CYP2C8 
 
Rosuvastatin 
As above. Rarely causes 
memory loss/confusion 
CYP2C9 
 
Simvastatin 
May cause muscle damage – 
adjust dose or substitute 
other medication 
CYP2C19 
Other Cholesterol 
lowering agents  
Ezetimibe 
Usually used in combination 
with a statin. May cause joint 
pain, muscle breakdown, 
diarrhea, increased upper 
respiratory tract infections – 
UGT1A9 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
85 
monitor cholesterol, adjust 
dose or use another agent 
 
Gemfibrozil  
May cause angioedema, 
muscle breakdown, liver 
damage – monitor 
cholesterol, liver enzymes. 
Adjust dose or use another 
agent 
UGT1A9 
Anticoagulant 
Warfarin 
Monitor INR - Adjust dose if 
needed 
CYP2C8 
 
Apixiban 
An oral anticoagulant 
(NOAC) which is Xa inhibitor. 
Can cause bleeding – if 
bleeding not controlled, 
reverse with anti-Xa agent 
CYP2C8 
 
Dabigitran 
May cause bleeding, allergic 
reactions, gastritis – monitor 
clotting and adjust dose 
UGT1A9 
Anti-platelet  
Clopidogrel 
Bruising, bleeding – adjust 
dose 
CYP2C9 
 
Cilostazol 
May cause headache, 
dizziness or diarrhea – adjust 
dose or change medication 
CYP2C19 
Calcium Channel 
Blocker 
Verapamil 
Diltiazem 
Nicardipine 
May cause headache, 
bradycardia, edema, 
constipation, worsening HF - 
Reduce dose as needed 
CYP2C8 
 
Nifedipine 
May cause edema, cough, 
hypotension – adjust dose or 
use another agent 
CYP1A2 
Angiotensin 
receptor blocker 
Irbesartan 
May cause hypotension, 
muscle pains, angioedema – 
reduce dose/change 
medication 
CYP2C8 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
86 
 
Candesarten 
Valsarten 
Losarten 
Can cause 
hypotension/volume 
depletion – adjust dose 
CYP2C9 
Anti-anginal 
Perhexiline 
Perhexiline is a pFOX 
inhibitor used in some 
countries for severe angina. 
It has complex metabolism 
and difficult to use  
CYP2B6 
Beta Blockers 
Carvedilol 
Bradycardia, tiredness, 
bronchospasm – reduce 
dose or suspend 
CYP2C9 
 
Timolol 
Propranolol 
Timolol may be used for 
glaucoma. Can cause 
tiredness, SOB, worsening of 
asthma – adjust dose or 
change to another 
medication 
CYP2C19 
 
Betaxolol 
May cause bradycardia, 
nausea, constipation, 
unpleasant dreams and 
increase severity of asthma – 
adjust dose or change to 
other agent. 
CYP1A2 
Anti-hypertensives 
Doxazosin 
Hypotension, drowsiness, 
priapism -  adjust dose 
CYP2C9 
 
Clonidine 
( Alpha-2 agonist) 
 
May cause dry mouth, 
dizziness, drowsiness, 
arrhythmia, and even 
confusion – Adjust dose or 
change to another agent 
CYP1A2 
 
Labetalol 
( Alpha & Beta 
adrenergic blocker) 
Primarily used to treat 
hypertension. May cause 
hypotension, fatigue, 
dizziness, bronchospasm – 
monitor BP, adjust dose or 
change to other medication 
UGT1A9 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
87 
Peripheral Arterial 
Disease 
Pentoxyphylline 
May cause tachycardia, 
headache, dizziness, gastric 
upset – adjust dose or use 
another agent 
CYP1A2 
Pulmonary anti-
hypertensive  
Bosentan 
Hypotension, headache, 
transaminase elevation, 
edema, anemia, pulmonary 
veno-occlusive disease – 
requires close monitoring of 
co-administered drugs for DD 
interactions. 
CYP2C9 
 
Ambrisentan 
Used to treat primary 
pulmonary hypertension. It is 
teratogenic if taken during 
pregnancy. Has limited 
usage 
UGT1A9 
PD5 Inhibitor 
Sildenafil 
Hypotension, tachycardia - 
Avoid nitrates, adjust dose or 
change to another agent 
 
CYP2C9 
Drugs for 
Diabetes Care 
 
 
 
Hypoglycemic 
Rosiglitizone 
Tolbutamide 
Troglitazone 
Gliquidone 
Monitor blood sugar - Adjust 
dose if needed. 
Hypersensitivity may occur 
with Tolbutamide 
CYP2C8 
 
Glyburide 
Hypoglycemia, gastric 
discomfort, nausea/vomiting 
– monitor blood sugar and 
adjust dose as needed 
CYP2C9 
 
Gliclazide 
Hypoglycemia, abdominal 
pain, transaminase elevation 
– monitor blood glucose and 
adjust dose. 
CYP2C9 
 
Dapagliflozin 
Improves glycemic control in 
Type 2 DM and improves HF 
CYP1A2 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
88 
management. May cause 
hypoglycemia, hypotension, 
rapid weight loss, 
dehydration, worsen urinary 
tract infections – monitor 
blood sugar, adjust dose 
 
Empagliflozin 
May cause dehydration, 
hypotension, hypoglycemia 
and increased urinary tract 
infection – monitor glucose  
and body weight and adjust 
dose 
UGT1A9 
Other Commonly 
Used Drugs 
 
 
 
Anti-asthmatic 
Formoterol 
A long-acting B-2 agonist 
used for the control of 
asthma. May cause 
increased bronchospasm – 
monitor wheezing, adjust 
dose or change to short-
acting product 
UGT2B7 
 
Theophylline 
May cause nausea, diarrhea, 
tachycardia, insomnia – 
reduce dose or change to 
other drug. Has lots of DD 
interactions 
CYP1A2 
Anti-convulsant 
Trimethidione 
Assess for excessive 
adverse effects such as 
drowsiness, swelling of  
gums – Adjust dose or 
substitute other agent 
CYP2C8 
 
Valproic Acid 
Nausea and vomiting, 
drowsiness, dry mouth, 
transaminase elevations – 
monitor liver enzymes – 
adjust dose or change 
medication  
CYP2C9 
 
 
 
CYP2C9 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
89 
Anti-diarrheal 
Loperamide 
May cause dehydration, 
weakness, faintness, rapid 
heart rhythm – discontinue if 
possible 
CYP2C8 
Antihistamine 
Loratadine 
Can cause sleepiness, dry 
mouth, allergic reactions - 
Assess need for this 
medication during current 
illness 
CYP2C19 
Anti-depressant 
Amitriptyline 
May cause blurred vision, 
postural hypotension, dry 
mouth, constipation, urinary 
retention, suicidal thoughts - 
Reduce dose if appropriate. 
CYP2C19 
 
Imipramine 
Nortriptyline 
Can cause dry mouth, 
drowsiness, hypotension, 
urinary retention and ECG 
changes – adjust dose or 
change med 
CYP2C19 
 
Fluoxetine 
Paroxetine 
May cause sleep disorder, 
sexual dysfunction, mania, 
suicidal behaviour – adjust 
dose or change med 
CYP2C19 
Anti-inflammatory 
(Non-steroidal) 
Diclofenac 
Ibuprofen 
Naproxen 
Celecoxib 
Ketorolac 
Meloxicam 
If taking long term, there may 
be abdominal discomfort, 
pain, nausea and increased 
risk of bleeding and renal 
damage - Should be 
discontinued if concern of 
toxicity. 
CYP2C8 
 
Valdecoxib 
May cause GI bleeding – 
Discontinue if not required 
CYP2C9 
Anti-inflammatory 
(Other) 
Chloroquine 
Hydroxychloroquine 
QT prolongation, nausea, 
vomiting, diarrhea, muscle 
twitching, Tinnitus/deafness – 
assess QT, adjust dose or 
discontinue drug 
CYP2C8 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
90 
 
Phenylbutazone 
Used mostly in animals 
recently. Can cause gastric 
irritation and bleeding and 
increase action of warfarin 
anti-coagulants – change to 
other anti-inflammatory 
CYP2C9 
 
Indomethacin 
Can cause edema, increased 
potassium, sodium, 
creatinine and hypertension – 
adjust dose or change 
medication 
CYP2C19 
Antipsychotic 
Clozapine 
May cause low WBC, 
drowsiness, increased 
salivation, hypotension, 
blurred vision, seizures and 
cardiac inflammation 
(myocarditis) – monitor WBC, 
ECG – reduce dose or chose 
another agent 
CYP2C8 
 
Haloperidol 
QT prolongation, tardive 
dyskinesia – adjust dose or 
use different medication 
CYP2C9 
Anti-viral 
Remdesivir 
May cause hypersensitivity 
reactions and increases in 
transaminases – slow 
infusion 
CYP2C8 
Anti-fibrotic 
Pirfenidone 
May cause nausea, GERD, 
skin rash, increased 
transaminases, dizziness, 
fatigue, weight loss – adjust 
dose or d/c. 
CYP1A2 
Analgesic 
acetaminophen 
May cause liver damage if 
blood levels are too high for 
too long – reduce dose or 
use another analgesic 
CYP1A2 
Anxiolytic 
Diazepam 
May cause drowsiness, poor 
coordination, suicidal 
CYP2C8 

 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
Recurrent Pericarditis Protocol, Amendment 2, January 18, 2023 
91 
 
thoughts – reduce 
dose/change medication 
Sedatives/hypnotics Zopiclone 
 
Can cause depression, 
confusion, nightmares and 
even hallucinations - Dose 
should be adjusted or d/c if 
possible 
CYP2C8 
Hormone 
Estradiol 
May increase risk of venous 
thrombosis, heart attack, 
stroke – adjust dose or d/c 
CYP2C8 
 
Progesterone 
Reduce dose 
CYP2C9 
Estrogen receptor 
modulator 
Tamoxifen 
Slight increase in risk of PE, 
stroke, uterine cancer. 
Causes hot flashes, weight 
loss – adjust dose or d/c 
CYP2C9 
Proton Pump 
Inhibitor 
Pantoprazole 
Allergic reactions, c difficile 
infection – adjust dose or 
change medication 
CYP2C19 
 
Omeprazole 
Nausea & vomiting, 
abdominal pain, c difficile 
infection – reduce 
dose/change medication 
CYP2C8 
H2 antagonist 
Ranitidine 
May cause headaches, 
bradycardia, liver damage, 
increase c difficile infection – 
adjust dose or change to 
other agent 
CYP1A2 
Serotonin 2C 
receptor Antagonist 
Lorcaserin  
Weight loss agent. Removed 
form USA market in 2020  
due to increased cancer risk 
CYP2B6