A Randomized, Double-Blind Placebo Controlled Parallel Group Study of Safety and Efficacy of FSD201 in Patients With Chronic Widespread Musculoskeletal Nociplastic Pain Associated With Idiopathic Mast Cell Activation Syndrome (Disorder)
Phase: PHASE2
Conditions: Mast Cell Activation Syndrome, Mast Cell Activation Disorder Idiopathic
Sponsor: Quantum Biopharma

Study Protocol for FSD201-010 
 
Trial Title: A Randomized, Double-Blind Placebo Controlled Parallel Group Study of Safety 
and Efficacy of FSD201 in Patients with Chronic Widespread Musculoskeletal Nociplastic 
Pain Associated with Idiopathic Mast Cell Activation Syndrome (Disorder) 
 
NCT number: NCT05652907 
 
Document Date: 13Feb2023 

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Clinical Study Protocol 
 
A Randomized, Double-Blind Placebo Controlled Parallel Group Study 
of Safety and Efficacy of FSD201 in Patients with Chronic Widespread 
Musculoskeletal Nociplastic Pain Associated with Idiopathic Mast Cell 
Activation Syndrome (Disorder) 
 
 
Protocol FSD201-010 
 
Short Title: Safety and Efficacy of FSD201 for the treatment of chronic pain 
associated with idiopathic MCAS (MCAD)  
 
 
 
 
 
 
 
 
 
Name of Investigational Product: 
 
FSD201 
 
Indication: 
Musculoskeletal Nociplastic Pain Associated with 
Idiopathic Mast Cell Activation Syndrome (Disorder) 
(MCAS/MCAD) 
 
 
Study Sponsor: 
FSD Pharma  
53 Loveton Circle, Suite 104 
Sparks, MD 21152, USA 
 
Clinical Trials Management 
 
 
Sarah Garisto 
Company/Clinical Trials  
 
 
Ozmosis Research Inc.  
Specialist: 
 
 
 
 
700 University Avenue 
 
 
 
 
 
 
Suite 217-2N, Toronto, ON M5G 1Z5 
 
 
 
 
 
 
Main Line: 416-634-8300 
 
 
 
 
 
 
Fax: 416-634-8333 
 
Document Status:  
 
 
 
Final 
 
Country: 
 
 
 
 
USA 
 
Version, Date:   
 
 
 
Version 2.3, 13Feb2023 
 
This document is the confidential property of FSD Pharma, Inc.  
and may not be disclosed or used without the prior written consent of FSD Pharma, Inc. 
 
 
 

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Protocol Approval Signature 
Protocol Title: 
A Randomized, Double-Blind Placebo Controlled Study of Safety 
and Efficacy of FSD201 in Patients with Chronic Widespread 
Musculoskeletal Nociplastic Pain Associated with Idiopathic Mast 
Cell Activation Syndrome (Disorder) (MCAS/MCAD) 
Protocol Number: 
FSD201-010  
Country: 
 
 
 
 
USA 
Version, Date:   
 
 
Version 2.3, 13Feb2023 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonization (ICH) guidelines for current Good 
Clinical Practice (GCP), and applicable regulatory requirements. 
Sponsor Signatory 
Dr Andrzej Chruscinski 
Vice President-Clinical and Scientific Affairs, 
Lucid Psycheceuticals Inc.  
(Subsidiary of FSD Pharma, Inc.) 
Signature 
Date (DD-MMM-YYYY) 
 
 

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Investigator Signature Page 
Protocol Title: 
A Randomized, Double-Blind Placebo Controlled Parallel Group Study of Safety 
and Efficacy of FSD201 in Patients with Chronic Widespread Musculoskeletal 
Nociplastic Pain Associated with Idiopathic Mast Cell Activation Syndrome/ 
Disorder (MCAS/MCAD) 
Protocol Number: 
FSD201-010 
Confidentiality and Current Good Clinical Practice (GCP)/E6(R2)/Compliance Statement 
• 
I, the undersigned, have reviewed this protocol (and any amendments), including appendices, and 
I will conduct the study as described in compliance with this protocol (and any amendments), GCP, 
and relevant International Council for Harmonisation guidelines. 
• 
I am thoroughly familiar with the appropriate use of the study drug, as described in this protocol 
and any other information provided by FSD Pharma, Inc. including, but not limited to, the current 
investigator’s brochure. 
• 
Once the protocol has been approved by the research ethics board (REB)/institutional review board 
(IRB)/independent ethics committee (IEC), I will not modify this protocol without obtaining prior 
approval of FSD Pharma, Inc. and of the REB/IRB/IEC. I will submit the protocol amendments 
and/or any informed consent form (ICF) modifications to FSD Pharma, Inc. and the REB/IRB/IEC, 
and approval will be obtained before any amendments are implemented. 
• 
I ensure that all persons or party assisting me with the study are adequately qualified and informed 
about the FSD Pharma, Inc. study drug and of their delegated study-related duties and functions as 
described in the protocol. 
• 
I ensure that source documents and study records that include all pertinent observations on each of 
the site’s patients will be attributable, legible, contemporaneous, original, accurate, and complete.  
• 
I understand that all information obtained during the conduct of the study regarding the patients’ 
state of health will be regarded as confidential. No patients’ names will be disclosed. All patients 
will be identified by assigned numbers on all case report forms, laboratory samples, or source 
documents forwarded to the sponsor. Clinical information may be reviewed by the sponsor or its 
agents or regulatory agencies. Agreement must be obtained from the patient before disclosure of 
patient information to a third party. 
• 
Information developed in this clinical study may be disclosed by FSD Pharma, Inc. to other clinical 
investigators, regulatory agencies, or other health authority or government agencies as required. 
Printed Name  
Investigator Signature 
Title  
Date (DD-MMM-YYYY) 
Institution 
 
 
 

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1. Table of Contents 
Table of Contents 
Clinical Study Protocol ........................................................................................................... 1 
1. 
Table of Contents ...............................................................................................................4 
2. 
Synopsis ............................................................................................................................6 
Secondary Objectives ........................................................................................................................................... 6 
Primary endpoint .................................................................................................................................................. 6 
Key Secondary endpoints ..................................................................................................................................... 7 
Other Secondary Endpoints .................................................................................................................................. 7 
Exploratory endpoints .......................................................................................................................................... 8 
Safety endpoints ................................................................................................................................................... 8 
Randomization Criteria ...................................................................................................................................... 10 
3. 
Abbreviations and Definitions .......................................................................................... 13 
4. 
Background Information .................................................................................................. 15 
4.1. 
Introduction ......................................................................................................................................... 15 
4.2. 
FSD201 ................................................................................................................................................. 17 
4.3. 
Safety and Pharmacokinetic (PK) data from FSD201 Phase I SAD/MAD Study in Healthy Individuals 18 
4.4. 
Study Governance ................................................................................................................................ 21 
4.5. 
Description of the study population .................................................................................................... 21 
5. 
Study Objectives .............................................................................................................. 21 
5.1. 
Main Objectives ................................................................................................................................... 21 
5.2. 
Secondary Objectives ........................................................................................................................... 21 
5.3. 
Study Endpoints ................................................................................................................................... 22 
6. 
Study Design .................................................................................................................... 23 
6.1. 
Description of Study Design ................................................................................................................. 23 
6.2. 
Patient Recruitment ............................................................................................................................. 23 
6.3. 
Overall Program Design and Plan ........................................................................................................ 25 
6.4. 
Study Procedures and Evaluations....................................................................................................... 26 
7. 
Description of Procedures ................................................................................................ 27 
7.1. 
Subject Enrollment Procedures ........................................................................................................... 27 
8. 
Treatment Plan ................................................................................................................ 34 
8.1. 
Product, Dose and Mode of Administration Dose ............................................................................... 34 
8.2. 
Description of Compound, Packaging, Labeling, Storage .................................................................... 34 
9. 
Materials ......................................................................................................................... 36 
10. 
Selection and Withdrawal of Subjects ............................................................................... 36 
10.1. 
Inclusion Criteria .................................................................................................................................. 36 
10.2. 
Randomization Criteria ........................................................................................................................ 38 
10.3. 
Exclusion Criteria ................................................................................................................................. 38 
10.4. 
Subject Withdrawal or Replacement ................................................................................................... 39 
10.5. 
Planned Sample Size ............................................................................................................................ 39 
11. 
Efficacy ............................................................................................................................ 41 
12. 
Safety .............................................................................................................................. 41 

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12.1. 
Biomarkers ........................................................................................................................................... 41 
12.2. 
Exploratory FSD201 plasma concentration .......................................................................................... 41 
12.3. 
Definitions of Adverse Events .............................................................................................................. 41 
12.4. 
Severity of Adverse Events .................................................................................................................. 42 
12.5. 
Adverse Events Outcomes ................................................................................................................... 42 
12.6. 
Serious Adverse Events ........................................................................................................................ 43 
12.7. 
Abnormal Laboratory Values ............................................................................................................... 43 
12.8. 
Pregnancy ............................................................................................................................................ 43 
13. 
Reporting Procedures and Requirements .......................................................................... 44 
13.1. 
Reporting of Serious Adverse Events ................................................................................................... 44 
13.2. 
Procedures for Expedited Reporting.................................................................................................... 45 
14. 
Statistical Methods and Planned Analyses ........................................................................ 45 
14.1. 
Efficacy Analysis ................................................................................................................................... 46 
14.2. 
Exploratory Analysis ............................................................................................................................. 46 
14.3. 
Safety Analysis ..................................................................................................................................... 46 
14.4. 
Methods for Handling Missing Data .................................................................................................... 47 
15. 
Investigational Obligations ............................................................................................... 47 
15.1. 
General considerations ........................................................................................................................ 47 
15.2. 
Ethical Guidelines for the Conduct of the Study .................................................................................. 47 
15.3. 
Written Informed Consent ................................................................................................................... 47 
15.4. 
Confidentiality ..................................................................................................................................... 48 
16. 
Study Management .......................................................................................................... 48 
16.1. 
Approval and Consent ......................................................................................................................... 48 
16.2. 
Investigator Selection .......................................................................................................................... 50 
16.3. 
Protocol Amendment and Protocol Deviation ..................................................................................... 50 
16.4. 
Administrative Requirements .............................................................................................................. 51 
17. 
References ....................................................................................................................... 54 
18. 
Appendixes (Scales) ......................................................................................................... 58 
 
Figures: 
Figure 1 Study Schematic of FSD201 Phase I Clinical Trial. ...................................................... 18 
Figure 2 Mean Plasma Pharmacokinetic Concentrations for FSD201 in the SAD Study (Part A)
....................................................................................................................................................... 19 
Figure 3 Mean Plasma Pharmacokinetic Concentrations for FSD201 in the MAD Study (Part B, 
Day 1 through Day 7) ..................................................................................................... 20 
Figure 4 Arithmetic Mean Plasma Concentration vs Time Profiles of FSD-201 for single dose of 
1200 mg in fed and fasted individuals ............................................................................ 20 
Figure 5 Schematic of Clinical Activities from Visit 1 (Screening) until Visit 11 (Follow-up) .. 25 
 
 
 

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Tables: 
Table 1 Schedule of Events........................................................................................................... 26 
Table 2 Lab Requirements ............................................................................................................ 31 
Table 3 Individual Stopping Criteria ............................................................................................ 34 
Table 4 Probabilities of Go, Pause or Stop Given the True Treatment Difference ...................... 40 
 
 
 
2. Synopsis 
 
STUDY TITLE 
A Randomized, Double-Blind Placebo Controlled Parallel Group Study of 
Safety and Efficacy of FSD201 in Patients with Chronic Widespread 
Musculoskeletal Nociplastic Pain Associated with Idiopathic Mast Cell 
Activation Syndrome/ Disorder (MCAS/MCAD) 
PROTOCOL 
NUMBER 
FSD201-010 
VERSION NUMBER 
2.3, 13Feb2023 
COUNTRY 
USA 
NUMBER OF STUDY 
SITES 
Canada 01, USA 02, Total Worldwide: 03 
STUDY 
OBJECTIVES:  
Main Objectives 
● To evaluate the analgesic efficacy of FSD201 compared to 
placebo in subjects with chronic widespread musculoskeletal 
nociplastic pain associated with Idiopathic Mast Cell Activation 
Syndrome/ Disorder (MCAS/MCAD) 
 
Secondary Objectives 
● To evaluate the efficacy of FSD201 as compared to placebo on 
pain-related 
function, 
sleep 
interference, 
and 
global 
improvement 
● To assess safety and tolerability of FSD201 in subjects with 
chronic widespread musculoskeletal nociplastic pain 
● To evaluate the change in serum tryptase, IL-6 and IL-1beta 
serum biomarker levels 
STUDY ENDPOINTS: Primary endpoint 
Targeted treatment effect of 30% decrease from baseline to Day 28 
in the average daily pain intensity score measured by an 11-point 
numerical pain rating scale (NPRS). Averages will be calculated as 
follows: 
Baseline: calculated weekly average from Day -7 to Day -1 
Day 28: calculated weekly average from Day 23 to Day 28 
 

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Key Secondary endpoints 
Key secondary efficacy endpoints will include changes from 
baseline to Day 56 as measured by: 
● Percentage of subjects achieving ≥30% reduction in NPRS score 
at the end of treatment with FSD201 
● Change in Patient Global Impression of Change (PGIC) after 56 
days treatment 
● Change or reduction in patient average daily NPRS after 56 days 
of treatment1 
● Change 
in 
Patient-Reported 
Outcomes 
Measurement 
Information System (PROMIS) Sleep Disturbance- Short Form 
(SF) 8a after 56 days treatment 
● Change in the PROMIS Pain Interference- SF 8a score after 56 
days treatment 
● Change in the PROMIS General Life Satisfaction- SF 5a after 56 
days treatment 
● Change in the PROMIS Fatigue- SF 8a after 56 days treatment 
● To determine whether FSD201 treatment reduces serum mast 
cell tryptase, IL-6 and IL-1beta during treatment 
 
Key secondary efficacy endpoints will include changes from 
baseline to Day 28 and Day 56 as measured by: 
 
● Percentage of subjects achieving ≥30% reduction in NPRS score1 
● Change or reduction in patient average daily DSIS after 28 and 
56 days of treatment1 
● Change in Patient Global Impression of Change (PGIC)  
 
 
Note: 
1DSIS and NPRS averages will be calculated as follows: 
Baseline: calculated weekly average from Day -7 to Day -1 
Day 28: calculated weekly average from Day 23 to Day 28 
Day 56: calculated weekly average from Day 49 to Day 55 for the 
NPRS and Day 50 to Day 56 for the DSIS 
 
 
Other Secondary Endpoints 
● Change in pain intensity on the NPRS from baseline to each week 
of treatment 

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● Percentage of subjects achieving ≥50% reduction in NPRS at 
Day 562 
● Change from baseline to Day 56 in PROMIS General Life 
Satisfaction -SF 5a 
● The total amount of rescue medication used 
 
Note: 
2DSIS averages will be calculated as follows: 
Baseline: calculated weekly average from Day -7 to Day -1 
Day 56: calculated weekly average from Day 49 to Day 55  
 
Exploratory endpoints 
● Changes in CRP, IL-2, IL-4, IL-8, IL-10, IL-12 (p70), IL-13, 
TNF-α and IFN-γ from baseline to Day 14, Day  28 and Day 56; 
 
● Estimation of Plasma levels of PEA as measured at baseline, day 
14, Day 28 and Day 56 
 
● Change or reduction in patient weekly PI-NRS after 28 and 56 
days of treatment 
 
Safety endpoints 
● Incidence and severity of treatment-emergent adverse events 
(TEAEs) throughout the dosing period;  
● Incidence and severity of treatment-emergent changes in 
laboratory values at Day 56;  
● Change from baseline in vital signs at each visit.  
STUDY 
POPULATION: 
 
Number of Subjects:  
 
Number of Groups: 
 
Age/sex:  
Musculoskeletal Nociplastic Pain Associated with Idiopathic Mast 
Cell Activation Syndrome (Disorder) (MCAS/MCAD) 
 
60 
 
2 (FSD201, placebo) 
 
≥18 and ≤75, male and female 
Selection of Patients 
Adults ≥18 years with chronic musculoskeletal nociplastic pain in 
three or more body regions secondary, more likely to Idiopathic 
MCAS are selected and randomized to receive either FSD201, 600 
mg b.i.d. or placebo. 60 study subjects. 
 
1. The subject is ≥ 18 and ≤ 75 years of age at the time of signing 
ICF; 

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2. Clinical diagnosis of idiopathic MCAS (in the presence or 
absence of a generalized hypermobility spectrum disorder (G-
HSD) or Ehlers-Danlos Syndrome (EDS)) as per the global 
consensus diagnostic criteria (consensus-2 criteria (Afrin et al., 
2021)); 
a) Medical history shows a constellation of clinical 
complaints attributable to pathologically increased mast 
cell (MC) activity (MC mediator release syndrome) 
            b)  Medical history of symptomatic response to inhibitors of 
     MC activation or MC mediator production or action 
3.  Adults with widespread chronic nociplastic pain (in three or 
more body regions); 
4. Chronic pains of intensity ≥4.0 but ≤9.0 on a Numeric Pain 
Rating Scale, symptom duration of >6 months 
5. Subject signed a Research Ethics Board (REB) or Institutional 
Review Board (IRB) approved written informed consent and 
privacy 
language 
(Health 
Insurance 
Portability 
and 
Accountability Act (HIPAA)) and (PIPEDA) authorization 
before performing any study-related procedures 
6. The subject is considered reliable and capable of adhering to the 
protocol (i.e., able to understand and complete forms and 
questionnaires, visit schedule, or medication intake according to 
the judgment of the investigator)      
7. Subject agrees to use only acetaminophen (e.g., Tylenol) (up to 
1000 mg per dose and not to exceed 3000 mg/day) or 
diphenhydramine (e.g. Benadryl) (up to 300 mg/day) as rescue 
medication for chronic widespread musculoskeletal nociplastic 
pains throughout the trial 
8. The subject is willing to maintain current activity and exercise 
levels throughout the study 
9. During the study, the subject agrees not to initiate or change any 
non-pharmacologic interventions (including chiropractic care, 
physical therapy, psychotherapy, and massage therapy). Any 
ongoing non-pharmacologic intervention must be stable for at 
least 4 weeks before screening and should be continued for the 
duration of the study 
10. Female subjects of childbearing potential must have a negative 
serum pregnancy test at the Screening Visit and a negative urine 
pregnancy test at Randomization Visit 
11. Female subjects of childbearing potential must use an acceptable 
method of birth control.  Acceptable birth control includes total 

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abstinence from heterosexual intercourse, a vasectomized 
partner, intrauterine device, or double barrier method including 
condoms sponge, diaphragm, contraceptives (oral, parenteral, or 
transdermal), or vaginal ring with spermicidal jellies or cream. 
Subjects considered not of childbearing potential must be 
surgically sterile (total hysterectomy, bilateral salpingo-
oophorectomy, or tubal ligation) or be more than one year post-
menopausal, defined as a complete cessation of menstruation for 
at least one year. Male subjects who are sexually active must use 
an acceptable method of birth control. Acceptable birth control 
includes total abstinence from heterosexual intercourse, or use of 
a double barrier method including condoms sponge, diaphragm, 
contraceptives (oral, parenteral, or transdermal), or vaginal ring 
with spermicidal jellies or cream used by partner. Periodic 
abstinence and withdrawal are not acceptable methods of 
contraception  
12. The subject is in good health as judged by the investigator, based 
on medical history, physical examination, serum chemistry, 
hematology, and urine analysis 
13. At the screening visit, the body mass index (BMI) is between 18 
and 39 kg/m2 
14. The subject is sufficiently fluent in English language to answer 
the questionnaires in clinic and on the App 
 
 
Randomization Criteria 
1. The subject is compliant with daily App entries during the 
baseline period, as defined by the completion of a minimum of 5 
of 7 daily NPRS scores  
2. The average daily pain intensity scores on the NPRS are ≥ 4.0 
and ≤ 9.0 over the last seven days before the Randomization Visit  
 
Exclusion Criteria: 
 
1. 
The subject has pain that cannot be clearly differentiated 
from or that could interfere with the assessment of chronic 
musculoskeletal nociplastic pain secondary likely to 
idiopathic MCAS (e.g., post-herpetic neuralgia, traumatic 
injury, prior surgery, complex regional pain syndrome) 
2. 
Adults with chronic cancer pain 

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3. 
Adults with inflammatory connective tissue disorder or 
rheumatological disorder-related pain (e.g., rheumatoid 
arthritis) 
4. 
Adults with focal musculoskeletal pain 
5. 
Adults with skin diseases (e.g., chronic urticaria, pemphigus, 
lupus, rosacea etc.) 
6. 
Adults 
with 
endocrinological 
disorders 
(e.g., 
acute 
hypothyroidism, acute adrenal insufficiency etc.) 
7. 
Adults with systemic gastrointestinal conditions (e.g., 
Inflammatory bowel disease) 
8. 
Significant psychological comorbidities: PHQ-9 score >20; 
and GAD-7 score >15 (indication of severe anxiety that could 
interfere with accurate logging of pain ratings) 
9. 
Current or recent (within 12 months of screening) history of 
a substance use disorder including cannabinoid or alcohol use 
disorder as defined by the Diagnostic and Statistical Manual 
of Mental Disorders (5th edition; DSM-5) 
10. 
Subject has neurologic disorder unrelated to chronic 
widespread musculoskeletal nociplastic pains (e.g., phantom 
limb from amputation, vitamin B12 deficiency, chronic 
inflammatory demyelinating polyneuropathy), circulatory 
disorder (e.g., peripheral artery disease), a skin condition in 
the area of neuropathy that could alter sensation (e.g., plantar 
ulcer), or other painful conditions (e.g., arthritis) that, in the 
judgment of the investigator, could interfere with reporting 
of pain due to chronic widespread musculoskeletal 
nociplastic pains 
 
11. 
Current severe or uncontrolled major depressive disorder or 
anxiety disorders. Mild to moderate major depression or 
anxiety disorders are permitted provided that the investigator 
assesses the patient as clinically stable and appropriate for 
entry into the study. Stable doses of the selective serotonin 
reuptake inhibitors (SSRIs) are allowed for the treatment of 
depression if the dose is stable for 60 days before Screening 
Visit 
12. 
Subject has a history of suicide attempt or suicidal behaviour 
within the last 12 months or has suicidal ideation within the 
previous 12 months or who is at significant risk to commit 
suicide, as judged by the Investigator at Screening or during 
the treatment period 

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13. 
The subject is currently using protocol-specified prohibited 
medications  
14. 
Positive urine drug screen for illegal or non-prescribed drugs 
at the Screening Visit or during the treatment period. 
15. 
Pregnant or lactating females or females planning to become 
pregnant during the study or within 28 days following the last 
dose of study medication.  
16. 
Male patients planning a partner pregnancy or sperm 
donation during the study or within three months following 
the last dose of study medication. 
17. 
Patients with active malignancy or history of malignancy, 
except for basal cell or squamous cell carcinoma and actinic 
keratosis. Basal cell carcinoma and small squamous cell 
carcinoma of the skin which have been excised according to 
guidelines within the last 5 years or in situ cervical carcinoma 
that has been fully treated and shows no evidence of 
recurrence are allowed. 
18. 
Positive human immunodeficiency virus (HIV), hepatitis B 
or hepatitis C laboratory result.   
19. 
Any clinically significant unstable medical abnormality or 
acute 
or 
chronic 
disease 
of 
the 
cardiovascular, 
gastrointestinal, respiratory, hepatic, or renal systems.  
Subject with aspartate transferase or alanine transferase > 2.5 
times the upper limit of normal (ULN) or alkaline 
phosphatase > 3.0 times ULN.  
20. 
Any clinically significant deviation from normal in physical 
examination, vital signs, or clinical laboratory tests, as 
determined by the investigator. 
21. 
Known history of seizure disorder, epilepsy, convulsions, or 
increased intracranial pressure anytime during the subject's 
life except for pediatric febrile seizures. 
22. 
Subject has received an investigational therapy of any kind 
within 28 days or 5 half-lives, whichever is longer, before 
Screening Visit. 
23. 
Subject has had known hypersensitivity or intolerance to the 
use 
of 
PEA, 
diphenhydramine 
(e.g. 
Benadryl) 
or 
acetaminophen (e.g. Tylenol) and/or their associated 
formulation components 
24. 
The subject is a member of the site staff or relative of a staff 
member 

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26. 
Individuals with high baseline serum tryptase levels  
(defined as above the normal range of 2.2 to 13.2 
µg/L) suggestive of Primary or Secondary MCAS 
 
INVESTIGATIONAL 
PRODUCT: 
 
Route of 
administration: 
 
Dosage:  
 
Duration of dosing: 
FSD201 
 
 
Oral 
 
 
600 mg BID  
 
56 days 
COMPARATOR 
INVESTIGATIONAL: 
Placebo 
 
ANTICIPATED 
STUDY DURATION: 
Study accrual: 8 months 
Study duration: 10 months  
 
3.  Abbreviations and Definitions 
 
ALT 
Alanine transaminase 
App 
Study electronic Application for tracking patient responses 
AST 
Aspartate transaminase 
b.i.d. 
Two times a day; b.i.d. stands for "bis in die" (in Latin, two times a day) 
BUN 
Blood Urea Nitrogen 
CB2 
Cannabinoid Receptor 2 
CRP 
C- reactive protein 
CTA 
Clinical Trial Application 
CTM 
 Clinical Trial Management Company 
CTS 
Clinical Trial Specialist 
ECG 
Electrocardiogram 
eCRF(s) 
Electronic Case Report Form(s) 
EDS 
Ehlers-Danlos Syndrome 
EoT 
End of Trial 
GCP 
Good Clinical Practice 
GGT 
γ-glutamyl transpeptidase 
G-HSD 
Generalized Hypermobility Spectrum Disorder 
HIPAA 
Health Insurance Portability and Accountability Act (USA) 
IB 
Investigational Brochure 
ICF 
Informed Consent Form 
IFN-γ 
Interferon-γ 

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IL-1beta 
Interleukin 1 Beta 
IL-6 
Interleukin 6 
IMP 
Investigational Medicinal Product (a medicinal product that is being tested or 
used as a reference, including as a placebo) 
IND 
Investigational New Drug Application 
IRB/IEC 
Institutional review board/ Independent Ethics committee 
MAD 
Multiple Ascending Dose 
MC 
Mast Cell 
MCAD 
Mast Cell Activation Disorder 
MCAS 
Mast Cell Activation Syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities - is a medical terminology used to 
classify adverse event information associated with the use of 
biopharmaceuticals and other medical products (updated twice a year) 
MMRM 
Mixed Model for Repeated Measure 
NPRS 
11-point Numerical Pain Rating Scale (24-hour recall) 
NSAID 
Nonsteroidal anti-inflammatory drug 
PEA 
Palmitoylethanolamide 
PFT 
Pulmonary Function Test 
PGIC 
Patient Global Impression of Change 
PI 
Principal Investigator 
PI-NRS 
Pain Intensity Numerical Rating Scale (7-day recall) 
PIPEDA 
Personal Information Protection and Electronic Documents Act (Canada) 
PK 
Pharmacokinetic 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
RTSM 
Randomization and Trial Supply Management 
SAD 
Single Ascending Dose 
SM 
Systemic mastocytosis 
SpO2(%) 
Oxygen Saturation  
TEAE(s) 
Treatment-Emergent Adverse Event(s) 
um-PEA 
Ultramicronized Palmitoylethanolamide 
VEGF 
Vascular Endothelial Growth Factor 
 
 
 
 
 

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4. Background Information 
 
4.1.  Introduction 
Chronic pain affects one in five adults in North America and contributes to higher healthcare costs 
and lost productivity in the region. In addition, chronic pain has been linked to impaired mobility, 
activity of daily living challenges, opioid dependence, anxiety, depression, poor perceived health 
and reduced quality of life. Chronic pain is a pathological response associated with the prolonged 
disease state—one in four Canadians aged 15 or older (estimated 7.63 million) live with chronic 
pain. In Canada, chronic pain has significant impacts on physical and mental health, family and 
community life, society, and the economy, with the total direct and indirect cost of $38.3 to 
$40.4 billion in 2019 (Campbell et al., 2020) and in and in the USA, an estimated 50 million 
Americans, or just over 20 percent, have some form of chronic pain (Zelaya et al., 2020). 
 
Mast cells are cellular regulators of physiologic and pathologic pain responses and facilitate 
neuroimmune cross-talk for pain modulation. Systemic activation of mast cells in Mast Cell 
Activation Syndrome (MCAS) results in the release of neuroinflammatory mediators, causing 
widespread pain in multiple body sites. Criteria for the diagnosis of MCAS have been recently 
published (Afrin et al., 2021). In this document, consensus-2 criteria for MCAS include one major 
and 6 minor criteria. For the diagnosis of MCAS, patients must have the major criterion 
(Constellation of clinical complaints attributable to pathologically increased MC activity) and at 
least one of the minor criteria. MCAS is an immunological condition in which mast cells 
excessively release chemical mediators (tryptase, histamine along with others), resulting in a wider 
range of pain and chronic symptoms, including anaphylaxis or near-anaphylaxis episodes (Valent 
et al., 2012). Hence, tryptase levels are associated with mast cell activation and serve as a marker 
of mast cell activity. Pro-inflammatory and pro-nociceptive cytokines like TNF-α, IL-6, IL1beta 
and VEGF are also involved with the activation of mast cells (Sev’er, et al., 2009). MCAS, being  
complex and heterogeneous in clinical presentation is  classified into three major types: Primary  
MCAS, Secondary MCAS, and Idiopathic MCAS (Akin et al., 2010, Afrin et al., 2021). Chronic 
widespread musculoskeletal nociplastic pain, arising from neurogenic inflammation, is likely 
associated with ‘idiopathic MCAS.’ Nociplastic pain is an idiopathic pain that is mechanistically 
different from nociceptive pain, which is caused by ongoing inflammation and tissue damage 
(Fitzcharles et al., 2021). Nociplastic pain is defined as “pain that arises from altered nociception 
despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral 
nociceptors or evidence for disease or lesion of the somatosensory system causing the pain” 
(Kosek et al., 2021 ). 
 
Two types of outcome assessments will be used as measures of patient's health status: 1) Clinical 
Outcome Assessment (COA) are those that depend on someone's judgment, such as the patient, a 
clinician, or a caregiver, and 2) Biomarker assessments in which a defined characteristic is 
measured as an indicator of normal biological processes, pathogenic processes, or responses to an 

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exposure or intervention, including therapeutic intervention. Biomarkers are designed to have 
measurement properties that are minimally subject to human influence. Biomarkers can in 
principle be used to measure treatment effects when they can be demonstrated to predict some 
meaningful clinical outcome but do not measure that clinical outcome directly. Biomarkers can, 
however, be useful in the development of therapeutics as measures of important attributes of the 
biological effect of the treatment, such as target engagement, which can be useful for development 
purposes even when falling short of being able to substitute for a COA as an outcome measure. In 
studies of pain treatments, the primary outcome assessment is almost always a COA because the 
goal of treatment is clinical benefit. A 30% decrease in pain as assessed by COA has previously 
been reported to represent a clinically significant value (Younger et al., 2009). Because the use of 
biomarkers has increased the success of therapeutic development across a range of indications, 
there is a growing interest in the use of biomarkers in clinical trials of pain, particularly early trials. 
(Katz, 2021). 
 
In most patients with cutaneous mastocytosis (defined by the absence of dense compact mast cell 
(MC) infiltrates in tryptase-stained bone marrow sections), normal or near-normal serum tryptase 
levels (median 10 ng/ml, range 2-23 ng/ml) were measured. By contrast, in the vast majority of 
patients with systemic mastocytosis (SM), elevated serum tryptase levels (median 67 ng/ml) were 
found. In addition, there was a significant correlation between the grade of infiltration of the BM 
by neoplastic mastic cells and tryptase levels in patients with SM (r = 0.8). Moreover, tryptase 
levels differed significantly among the groups of patients with different types of SM. In summary, 
serum tryptase is a reliable biomarker that can be used to estimate the burden of MC in patients 
with mastocytosis and to distinguish between categories of disease (Sperr et al., 2002). An 
additional publication (Akin, 2014) utilizes as elevated baseline tryptase level as a criterion to 
classify primary disorders of mast cell activation. Another study highlights the long-term effects 
of IL-6 on human mast cells, which are associated with expression of SOCS3 through methylation 
of SOCS3 promoter and suppression of the spontaneous production of soluble sIL-6R. 
Interestingly, the inverse relationship between serum levels of sIL-6R and IL-6 observed in 
mastocytosis has been reported for colorectal cancer, neuroblastoma, and juvenile arthritis. 
Therefore, suppression of` sIL-6 production by IL-6 may occur in other types of cells as well as 
mast cells and may thus reduce formation of the trans-activating IL-6/sIL-6R pro-inflammatory 
complexes. These findings have relevance in mast cell driven diseases associated with elevated 
levels of IL-6 including mastocytosis where treatment directed at lowering IL-6 levels could have 
a therapeutic benefit (Desai et al., 2016). 
 
Human cytokine interleukin-37 (IL-37), a unique IL-1Beta family member, has strong protective 
and anti-inflammatory properties, influencing cellular metabolism. The effect of IL-37 on 
inflammation in mastocytosis are well studied and suggest that the hematopoietic expression of 
IL-37 can reduce the inflammatory state in this disease. IL-37 limits excessive inflammation, 
which suggests that IL-1 Beta may be beneficial to the metabolic and inflammatory process and is 

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a candidate as a potential new therapeutic agent (Conti et al., 2019). These studies above explain 
the rationale behind the importance of biomarkers in this study of FSD 201. 
 
Palmitoylethanolamide (PEA) is an endogenous lipid that blocks histamine release and mast cell 
degranulation. Preliminary reports have provided evidence that PEA downregulates hyperactive 
mast cells in a dose-dependent manner (Mazzari et al., 1996; Rankin and Fowler, 2020). PEA's 
modulation of mast cell responses can serve as a novel target for treating and managing debilitating 
pain conditions (Passavanti et al., 2019). Many clinical trials assessing the safety and efficacy of 
ultramicronized PEA (um-PEA) on chronic pain have been published in the last decade. Overall, 
um-PEA at doses up to 2700 mg/day administered to patients with various chronic pain syndromes, 
such as burning mouth syndrome, migraine with aura, fibromyalgia, low back pain, or chronic 
pelvic pain, induced a significant decrease in pain intensity, compared to control groups (Paterniti 
et al., 2013; Schifilliti et al., 2014; Marcucci et al., 2016; Paladini et al., 2016; Germini et al., 2017; 
Passavanti et al., 2017; Ottaviani et al., 2019; Stochino Loi et al., 2019; Papetti et al., 2020). 
Several studies showed that the quality of life and psychological well-being of patients were also 
improved. Um-PEA also showed efficacy in slowing the decline in pulmonary function in patients 
with amyotrophic lateral sclerosis (ALS). In addition, clinical studies have demonstrated that um-
PEA is generally very well tolerated. Overall, more than 3500 patients have received either 
ultramicronized or micronized PEA in clinical studies, and no adverse events were reported in 
most studies at doses as high as 2700 mg/day. Only a few cases of diarrhea and pre-existing chronic 
venous insufficiency were reported in one trial. Another trial reported one case of drowsiness and 
another of palpitations (Paladini et al., 2016). 
 
4.2.  FSD201 
 
FSD Pharma Inc. is developing FSD201, an agent that primarily targets medical conditions where 
inflammation and pain are the major concerns and offers promising hope for the treatment of such 
conditions. PEA is an endogenous biologically active lipid belonging to the class of N-
acylethanolamines (NAEs) and exerts anti-inflammatory, analgesic, and neuroprotective 
properties for the maintenance of homeostasis. PEA is synthesized in the body in response to 
external stressors and tissue injury. The pleiotropic effects of PEA involve several mechanisms, 
including activation of the peroxisome proliferator‐activated receptor α (PPARα), the 
downregulation of mast cell activation of type 1 vanilloid transient receptors (TRPV1) channel, 
and prevention of NFkB nuclear translocation among others. PEA  also inhibits the release of 
synthesised mast cell mediators, including histamine and TNF-α.  
  

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4.3.  Safety and Pharmacokinetic (PK) data from FSD201 Phase I SAD/MAD Study in 
Healthy Individuals 
To evaluate the safety and tolerability of FSD201, a single-center, Phase 1, randomized, double-
blind, placebo-controlled, sequential SAD/MAD study with a food-effect arm was conducted.  
48 healthy male or female adult light smokers or non-smoker subjects were included in this study. 
The primary objective of the study was to evaluate the safety and tolerability of FSD201 
following oral administration of single ascending doses (SAD) ranging from 600 mg to 2400 mg 
and multiple ascending doses (MAD) ranging from 600 mg to 1200 mg administered twice a day 
(b.i.d.) for seven consecutive days, in healthy subjects. The study's secondary objectives were to 
characterize the pharmacokinetic (PK) profile of FSD201 following single and multiple oral doses 
in healthy subjects and evaluate the effect of food on the absorption of FSD201. The study 
schematic is shown in Figure 1. 
 
 
Figure 1 Study Schematic of FSD201 Phase I Clinical Trial.  
 
Absorption of FSD201 increased in a less than dose-proportional manner over the dose range of 
600 to 2400 mg following oral administration of single doses of FSD201 in healthy subjects. 
Administration of FSD201 under fed conditions resulted in a significant increase in PEA 
absorption rate – for a dose of 1200 mg of FSD201 in a fed state (Figure 4), it was seen that the 

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peak plasma concentration was seen to be about 250 ng/mL in about 2 hours as compared to 
50 ng/mL in about 45 minutes in fasting state. However, it did not appear to affect the time to 
reach the peak of concentration of PEA in the high-fat diet, as shown in Figure 4. Peak plasma 
levels and total exposure during a dosing interval increased in a dose-proportional manner across 
the dose range 600 to 1200 mg following repeated oral doses. However, the Cmin ss appeared to 
increase less than in a dose-proportional manner, as shown in Figure 2.  
There appears to be no significant accumulation of FSD201 following repeated doses with 600 
and 1200 mg. Following multiple dosing, steady-state was achieved within seven days at the 
600 mg dose level and within four days at the 1200 mg b.i.d. dose level, as shown in Figure 3. 
 
 
Figure 2 Mean Plasma Pharmacokinetic Concentrations for FSD201 in the SAD Study (Part A) 
 
 
 
 
 
 
SAD 

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MAD 
Figure 3 Mean Plasma Pharmacokinetic Concentrations for FSD201 in the MAD Study (Part B, Day 1 through Day 7) 
Fasted vs Fed 
Figure 4 Arithmetic Mean Plasma Concentration vs Time Profiles of FSD-201 for single dose of 1200 mg in fed and fasted 
individuals 

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Overall, FSD201 following an oral administration of a single dose, ranging from 600 mg to 
2400 mg, and multiple doses ranging from 600 mg to 1200 mg b.i.d., were safe and well-tolerated 
in normal healthy subjects. No serious adverse events (SAEs) were reported for these studies. The 
safety results seen in this Phase I trial were consistent with published information. There were no 
Treatment-Emergent Adverse Events (TEAEs) related to clinical laboratory results, ECGs, and 
physical examination in both the SAD and MAD recipients. No clinically relevant differences were 
observed between the treatment groups with respect to mean values and changes from baseline for 
clinical laboratory results, vital signs, and ECG results.  
 
In the SAD study, one vital sign abnormality (hypotension) was experienced by one subject in 
Cohort 2 [1200 mg], observed during the scheduled measurements, considered a TEAE. This 
TEAE was considered mild and represented a transient lowering of systolic blood pressure of less 
than 10 mmHg. Overall, no safety issues were observed for clinical laboratory, vital signs, ECGs, 
or physical examination results.  
 
4.4. Study Governance  
This study is a prospective, randomized, double-blind, placebo-controlled sponsor-initiated trial. 
The study's design is set to accept individuals who meet the criteria for chronic widespread 
musculoskeletal nociplastic pain (arising from neurogenic inflammation) secondary to likely 
“Idiopathic MCAS.” The study will be conducted at three centres: one in Canada and two in the 
USA. The study will be conducted under an IND (US FDA) and CTA (Health Canada). 
Participants will be randomized on Day 0 in a ratio of 2:1 to receive 600 mg FSD201 or placebo 
orally twice daily for 56 days. 
 
4.5.  Description of the study population  
Adults (≥18 years and ≤ 75 years.) with chronic widespread musculoskeletal nociplastic pain (in 
three or more body regions) likely related to ‘idiopathic MCAS’ are selected and randomized to 
receive either FSD201 600 mg b.i.d. or placebo. 
 
5. Study Objectives 
 
5.1.  Main Objectives 
● To evaluate the analgesic efficacy of FSD201 compared to placebo in subjects with chronic 
widespread musculoskeletal nociplastic pain; 
 
5.2.  Secondary Objectives 
● To evaluate the efficacy of FSD201 as compared to placebo on pain-related function, sleep 
interference, and global improvement; 

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● To assess safety and tolerability of FSD201 in subjects with chronic widespread 
musculoskeletal nociplastic pain;  
● To evaluate the change in serum tryptase, IL-6 and IL-1beta serum biomarker levels. 
 
5.3.  Study Endpoints 
5.3.1. Primary endpoint 
Targeted treatment effect of 30% decrease from baseline to Day 28 in the average daily pain 
intensity score measured by an 11-point numerical pain rating scale (NPRS). Averages will be 
calculated as follows: 
Baseline: calculated weekly average from Day -7 to Day -1 
Day 28: calculated weekly average from Day 22 to Day 28 
 
5.3.2. Key Secondary endpoints 
Key secondary efficacy endpoints will include changes from baseline to Day 56 as measured by: 
 
● Percentage of subjects achieving ≥30% reduction in NPRS score at the end of treatment with 
FSD2011 
● Change in Patient Global Impression of Change (PGIC) after 56 days treatment 
● Change or reduction in patient average daily NPRS after 56 days of treatment1; 
● Change in Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep 
Disturbance- Short Form (SF) 8a after 56 days treatment 
● Change in the PROMIS Pain Interference- SF 8a score after 56 days treatment 
● Change in the PROMIS General Life Satisfaction- SF 5a after 56 days treatment 
● Change in the PROMIS Fatigue- SF 8a after 56 days treatment 
● To determine whether FSD201 treatment reduces serum mast cell tryptase, IL-6 and IL-1beta 
during treatment. 
 
Key secondary efficacy endpoints will include changes from baseline to Day 28 and Day 56 as 
measured by: 
● Percentage of subjects achieving ≥30% reduction in NPRS score1 
● Change in Daily Sleep Interference Scale (DSIS) after 28 and 56 days of treatment1 
● Change in Patient Global Impression of Change (PGIC).  
 
Note: 
 
1DSIS and NPRS averages will be calculated as follows: 
Baseline: calculated weekly average from Day -7 to Day -1 
Day 28: calculated weekly average from Day 22 to Day 28 
Day 56: calculated weekly average from Day 49 to Day 55 for the NPRS and Day 50 to Day 56 
for the DSIS 
 

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5.3.3. Other Secondary Endpoints 
● Change in pain intensity on the NPRS from baseline to each week of treatment 
● Percentage of subjects achieving ≥50% reduction in NPRS at Day 562 
● The total amount of rescue medication used. 
 
Note: 
2DSIS averages will be calculated as follows: 
Baseline: calculated weekly average from Day -7 to Day -1 
Day 56: calculated weekly average from Day 49 to Day 55  
 
5.3.4. Exploratory endpoints 
● Changes in CRP, IL-2, IL-4, IL-8, IL-10, IL-12 (p70), IL-13, TNF-α and IFN-γ from baseline 
to Day 14, Day 28 and Day 56.  
● FSD201 plasma exposure will be performed by analyzing plasma samples. 
● Change or reduction in patient weekly PI-NRS after 28 and 56 days of treatment. 
 
5.3.5. Safety endpoints 
● Incidence and severity of treatment-emergent adverse events (TEAEs) throughout the dosing 
period  
● Incidence and severity of treatment-emergent changes in laboratory values at Day 56  
● Change from baseline in vital signs at each in-patient visit.  
 
6.  Study Design 
 
6.1. Description of Study Design 
This study is a randomized, double-blind, parallel-group, placebo-controlled study to evaluate the 
efficacy and safety of FSD201 in adult subjects with musculoskeletal nociplastic pain associated 
with MCAS.  
 
The study design consists of up to 17 days screening period, a 56-day treatment period, and a 7-
day follow-up period.  Each subject will participate in the trial for up to 80 days.  
 
6.2. Patient Recruitment 
Subjects will be recruited by physician databases.  
All subjects will provide written informed consent for the study at the beginning of the Screening 
Visit, prior to performance of any of the study procedures and collection of study data.  
 
The subject’s eligibility for randomization will be determined at Visit 2 according to the 
inclusion and exclusion criteria set forth in Section 10.1. 

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A unique identification number will be given to study subjects to keep their information 
anonymous. Subject numbers will be assigned in sequential order (i.e., the first subject’s 
identification number will be 001, etc.). This number will be used in all CRFs.  
 
Demographic Data and Medical History 
The subject’s demographic information and medical history will be recorded at the Screening 
Visit and documented on the appropriate CRF. This will include:  
• Demographic information: sex, age, race and ethnicity 
• Medical history for the past 10 years prior to screening and other relevant history will 
be collected, including other types of pain (e.g., arthritis); surgeries; diabetes; cancer; 
cardiovascular events; and gastrointestinal problems 
• Data on MCAS will be captured separately, in detail, including date of onset, and 
attempted treatments 
 
After providing written informed consent, potential study subjects will be screened for study 
eligibility during the maximum 17 days screening and baseline period.  During this time, subjects 
will complete daily entries to collect daily pain and sleep disturbance scores, and document rescue 
medication use (acetaminophen or diphenhydramine). Entries will be collected by means of a 
Study electronic Application (App) developed for this trial. The app can be installed on the 
patient’s own device (assisted by the study coordinator), or the patient will be provided with a 
device (phone or tablet) to record these entries daily.    
 
The values recorded on the last seven days before the randomization/Visit 2 will be used to 
determine the baseline scores. Subjects who completed entries in the App on at least 5 out of 7 
days before randomization /Visit 2 and have an average pain intensity between 4.0 and 9.0 that 
meets the study-specified threshold and who continue to meet all other study eligibility criteria 
will be enrolled in the study. 
 
Patients who meet the eligibility criteria will be randomized on Visit 2 in a ratio of 2:1 to receive 
600 mg FSD201 or a placebo orally twice daily for 56 days. Subjects will take their first dose of 
the investigational either FSD201 or placebo in the clinic. An assessment for allergy or 
hypersensitivity reaction will be conducted immediately after the first dose; signs and symptoms 
to be evaluated include flushing, skin rash, urticaria, fever, dyspnea, bronchospasm, edema, 
angioedema, hypotension, and anaphylaxis. 
 
Subjects will continue completing daily App entries throughout the 56 day treatment period 
including their 11-point pain scale over the last 24 hours, their sleep disturbance score, their rescue 
medication and their Investigational Compliance. 

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Subjects will return to the site at Day 14, Day 28 and Day 56/ Early termination visit. A phone call 
will be made to each subject seven (7) days after the last intake of the investigational product. 
 
Subjects will be monitored for adverse events (AEs) from the date of first dose until the last follow-
up visit (AEs noted between signing of Informed Consent Form (ICF) and first dose should be 
recorded as Medical History). Any SAEs occurring within 7 days after the last investigational 
medicinal product (IMP) intake will be collected. Efficacy and safety will be assessed as outlined 
in the schedule of events (Table 1). 
 
6.3.  Overall Program Design and Plan  
A timeline of study activities is shown in Figure 5.  
 
 
 
 
 
 Figure 5 Schematic of Clinical Activities from Visit 1 (Screening) until Visit 11 (Follow-up) 

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6.4. Study Procedures and Evaluations 
Visit Number
1
2
3
4
5
6
7
8
9
10
11
ET
Study Day
Day -17 to 
Day -8
Day -7 to 
Day -1
Day 0
Day 7 Day 14 Day 21 Day 28
Day 35 Day 42 Day 49 Day 56
Day 63
N/A
Type of Visit
On Site
N/A
On Site
Phone
On Site
Phone
On Site
Phone
Phone
Phone
On Site
Phone
On Site
Written informed consent 
X
Demographic data
X
Medical and medication history
X
X
MCAS/MCAD History
X
Physical examination (1)
X
X
X
X
X
X
Body Mass Index (BMI)
X
Weight and Vital signs [BP, pulse, RR] (2)
X
X
X
X
X
X
Safety Laboratory Testing (3)
X
X
X
X
X
X
HIV, Hepatitis testing
X
Pregnancy test (4)
X
X
X
X
X
X
Urine drug screen
X
X
X
X
X
X
Blood test (biomarkers) (5)
X
X
X
X
X
X
FSD201 Plasma exposure
X
X
X
X
X
Review of Inclusion / Exclusion criteria
X
X
X
X
X
X
Sleep Disturbance SF (PROMIS)
X
X
X
X
X
Pain Interference (PROMIS)
X
X
X
X
X
General Life Satisfaction (PROMIS)
X
X
X
X
X
Fatigue (PROMIS)
X
X
X
X
X
Anxiety (PROMIS)
X
X
X
X
X
Pain Intensity Numerical Rating Scale           
(PI-NRS)
X
X
X
X
X
X
Pain Catastrophizing Scale (PCS)
X
X
X
X
X
Health Questionnaire (PHQ-9) 
X
Anxiety Disorder (GAD–7) 
X
Patient Global Impression of Change (PGIC)
X
X
Randomization
X
Allergy Assessment
X
Adverse event recording 
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
Connect to patient App/provide device
X
11-point NPRS
X
X
X
X
X
X
X
X
X
X
X
X
DSIS Sleep scale
X
X
X
X
X
X
X
X
X
X
X
X
Rescue medication intake recording
X
X
X
X
X
X
X
X
X
X
X
X
Review of patient results in App
X
X
X
X
X
Investigational product dispensing
X
X
X
Investigational product return and 
accountability
X
X
X
X
(2) Vital signs measurements [T, HR, BP, SO2, RR]
(3) Safety Laboratory Testing (Hematoloty, Biochemistry, Urine analysis)
(4) Serum pregnancy will be performed at Visit 1 screening; Urine pregnancy to be performed at all other visits
(5) Biomarkers: At Visit 1, only Serum Tryptase performed; all biomarkers performed at other visits
(6) To be performed within 14 (±2) days of discontinuation or withdrawal
(1) A detailed physical examination to be performed at Visit 1 and a focused exam to be performed at all other visits
 
 
Table 1 Schedule of Events 

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A schedule of events is shown in Table 1. Visits 3-11 may occur ±2 days from the days listed in 
the table, except for Visit 4, which may occur from Day 12 to Day 15. 
 
7. Description of Procedures 
 
7.1. Subject Enrollment Procedures  
Subjects will be recruited by various methods, including advertising, physician referral, 
brochures posted in health-care facilities, and subject databases.  
Prior to screening a patient, each institution must have submitted all necessary regulatory 
documentation to Ozmosis Research Inc. Access to the electronic case report forms (eCRFs) will 
only be granted once this has been received. All sites should contact Ozmosis Research Inc. at 
the information provided on the cover page to verify study availability. 
All subjects will provide written informed consent for the study at the beginning of the Screening 
Visit, prior to performance of any of the study procedures and collection of study data. Subjects 
will be assigned a unique subject number when the signing the informed consent. 
 
A subject’s eligibility for randomization will be determined at Visit 2 according to the inclusion 
and exclusion criteria set forth in Section 10.1. Failure to meet specific inclusion or exclusion 
criteria will be reviewed on a case-by-case basis, and enrollment waivers will be completed as 
necessary. The sponsor must agree to any waivers prior to patient being randomized. 
 
Upon enrollment into the study, an RTSM system will be used to assign patient to a treatment 
arm, according to the randomized treatment list. The system will assign a wallet number to the 
patient based upon treatment arm. Patients will be assigned the first wallet at Visit 2, a second 
wallet at Visit 4, and 2 additional wallets at Visit 6 (all in the same treatment arm) 
 
Protocol treatment should begin within 17 working day of patient registration.  
Note: it is the responsibility of the investigator in charge to satisfy themselves that the patient is 
indeed eligible before requesting registration.  
 
7.1.1. Demographic Data and Medical History 
The subject’s demographic information and medical history will be recorded at the Screening 
Visit and documented on the appropriate CRF. This will include:  
• Demographic information: sex, age, race and ethnicity 
• Medical history for the past 10 years prior to screening and other relevant history will 
be collected, including other types of pain (e.g., arthritis); surgeries; diabetes; cancer; 
cardiovascular events; and gastrointestinal problems 
• History of chronic widespread musculoskeletal nociplastic pain 

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7.1.2. Prior Medications 
Prior and Concomitant Medications: Medications taken for the past 3 months preceding 
screening will be recorded at the Screening Visit (Visit 1). Prior medications include analgesics 
of all types, anti-inflammatory drugs, antidepressants, and anticonvulsants. Patient will be 
allowed to continue their current pain medication regimen as long as they are not taking a 
prohibited medication listed in Section 8.2.2. In addition, they should not start any other 
analgesics while in the study. 
7.1.3. Treatment Assignment/Randomization and Blinding 
At the Screening Visit (Visit 1), subjects who meet all entry criteria, including minimum pain 
score will be trained on completing the App entries and will enter the Baseline Period if the 
results of the laboratory tests confirm their eligibility. During this period, subjects will capture 
their 0-10 NPRS scores daily using the App. At Visit 2, App entries will be reviewed and those 
subjects who have an average daily pain intensity score ≥ 4.0 and ≤ 9.0 on the 0-10 NRS over the 
1-week Baseline Period will be randomized to either FSD201 or placebo treatment in a double-
blind manner; subjects will be required to have completed at least 5 of the daily diaries during 
the Baseline Period.  
 
Randomization  
Eligible patients who consent to participate in the trial will be randomized through the RTSM 
using a randomization list in a 2:1 manner with FSD201 or placebo.  
 
Blinding 
The investigators, site staff, monitor and sponsor will be blinded to the study assignment.  
 
Unblinding 
The study investigators, statistical team, and sponsor will be blinded to the trial randomization 
code. The Principal Investigator may decide to unblind a subject’s treatment code in the case of a 
medical emergency or in the event of a serious medical condition, for which the knowledge of the 
treatment is essential for the clinical management of the subject’s condition. The investigator 
should promptly document and explain to the Sponsor any premature unblinding (e.g. accidental 
unblinding, unblinding due to a serious adverse event, etc.) of the study participant. Women who 
become pregnant during the study period and male subjects whose partner becomes pregnant will 
be withdrawn from the study and unblinded due to unknown risks to the fetus. A subject’s 
treatment may also be unblinded in the event of a suspected unexpected serious adverse event 
(SUSAR) in order to determine reportability of the event to regulatory authorities.  Whenever 
possible, the Sponsor will be notified prior to breaking the blind. 
 
When study participant unblinding is required, the investigator will use the RTSM system to 
determine treatment arm. Only the PI will have this function available. Unblinding will be 
documented in the Investigator site file (ISF) and the CRF. Unblinding the treatment assignment 
for the study will occur after database lock when all trial subjects have completed their end-of-
treatment or study discontinuation visit.  

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Treatment 
Investigational product (FSD201 or placebo) will be dispensed at Visit 2 (one wallet containing 
15 days treatment), Visit 4 (one wallet containing 15 days treatment), and Visit 6 (2 wallets for a 
total of 28 days treatment). Outside of the visits, subjects are to orally self-administer the 
investigational product b.i.d. at home during the Treatment Period. The last dose of 
investigational product is to be taken in the morning of Visit 10. The investigational product is to 
be taken with a glass of water, within 30 minutes of a meal/food. 
 
Subjects who forget to take their dose at the usual required time should take it immediately upon 
noting that it was missed. If a dose is missed altogether, the subject should record this in the 
daily dose compliance tracker (App) and continue with the normal scheduled dose on the 
following dose. 
 
Adherence to Treatment: Following App review the Investigator or Investigator’s designee 
will determine adherence to treatment. Subjects will be asked to bring their medication at Visit 4 
and Visit 6 for an investigational product count. Subjects who missed >20% of the doses will be 
considered non-compliant. Non-compliant subjects will be counselled to adhere to the 
medication regimen and will be used for a sub-analysis study.  
 
Safety Measures 
General Physical Examination: A general physical assessment of the major body systems will 
be performed at the Screening Visit (Visit 1). An abbreviated physical exam focusing on the 
previously identified abnormalities or any patient reported symptoms will be performed at Visit 
2, Visit 4, Visit 6, Visit 10 and the Early Termination Visit(if applicable). 
 
Pregnancy Test (if applicable): At the Screening Visit, a serum pregnancy test will be 
performed. At Visit 2, Visit 4, Visit 6, Visit 10, and Early Termination a urine pregnancy test 
will be conducted at the clinic. 
 
Vital Signs: Sitting blood pressure, heart rate, body temperature, oxygen saturation using Pulse 
oximetry and breathing rate will be measured at each visit after the subject has been sitting 
quietly for at least 5 minutes. Data will be recorded in the appropriate CRF. 
 
Clinical Laboratory (Non fasting): Clinical laboratory testing will be performed at the 
Screening Visit (to determine and confirm eligibility) Visit 2, Visit 4, Visit 6, Visit 10 (End of 
Treatment) and in the event of Early Termination as shown in Table 2. Blood (~15 mL) and 
urine samples will be collected. The clinical laboratory analyses will include: 
• Biochemistry: LFTs (serum ALT, AST, alkaline phosphatase, γ-glutamyl 
transpeptidase (GGT), albumin, bilirubin), CK, Cr (eGFR), blood urea nitrogen 
(BUN), HbA1c, lipid assessment, sodium, potassium, chloride, bicarbonate, and 
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• Viral testing: HBV (antibody and antigen), HCV (antibody), HIV (antibody) 
• Hematology: CBC with differential, PT/ INR, PTT  
• Urinalysis: total urinalysis (chemical), drug test, Albumin/Cr ratio, urine pregnancy 
test including a microscopic examination 
• Biomarkers: CRP, tryptase, cytokine panel (IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, 
IL-12 (p70), IL-13, TNF-α and IFN-γ) (only serum tryptase performed at Visit 1, all 
biomarkers performed at subsequent visits) 

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Visit 1
Visit 2
Visit 4
Visit 6
Visit 10
Screening
Day 0
Day 14
Day 28
Day 56
Hematology
CBC with differential
X
X
X
X
X
X
PT/ INR
X
X
X
X
X
X
PTT
X
X
X
X
X
X
Biochemistry
HCV and HBV testing
X
HIV testing
X
Sodium
X
X
X
X
X
X
Potassium
X
X
X
X
X
X
Chloride
X
X
X
X
X
X
Bicarbonate
X
X
X
X
X
X
LFT (ALT, AST, GGT, ALP, albumin, 
bilirubin)
X
X
X
X
X
X
CK
X
X
X
X
X
X
Albumin/ Creatinine ratio
X
X
X
X
X
X
Creatinine (eGFR)
X
X
X
X
X
X
Blood urea nitrogen (BUN)
X
X
X
X
X
X
Glucose
X
X
X
X
X
X
HbA1C
X
X
X
X
X
X
Lipid assessment 
X
X
X
X
X
X
beta-HCG (serum pregnancy)
X
Biomarkers
CRP
X
X
X
X
X
Serum Tryptase
X
X
X
X
X
X
Cytokine Panel*
X
X
X
X
X
FSD201 Exposure
FSD201 Plasma Level
X
X
X
X
X
Urine Analysis
Drug Test
X
X
X
X
X
X
Urine Pregnancy Test
X
X
X
X
X
Urinanalysis (chemical)
X
X
X
X
X
X
Early 
Termination
 
Table 2 Lab Requirements 
* IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 (p70), IL-13, TNF-α -and IFN gamma. 
 
A central lab will be used for analysis in this study. Data will be recorded in the appropriate 
CRF. Laboratory data may be repeated at the discretion of the Investigator. 

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Adverse Events (AE): At Visit 2, subjects will be instructed to call the study center in the event 
of any AEs that may require medical attention, regardless of possible relatedness to the study 
medication. At each visit and during the telephone calls, the study staff will prompt the subject to 
report all AEs that have occurred since the last visit. See Section 12 for more details on how AEs 
are defined, reported, and managed. 
 
7.1.4. Pain Assessments 
Numerical Pain Rating Scale (NPRS): This self-administered questionnaire will be conducted 
using the Study electronic App. This 11-point scale (from 0-10) will ask the patient to assess their 
pain level over the past 24 hours. This scale will be assessed once each day during screening, 
baseline and treatment. 
 
Pain Intensity Numerical Rating Scale (PI-NRS): This self-administered questionnaire will be 
conducted in the clinic. This 11-point scale (from 0-10) will ask the patient to assess their pain 
level over the past 7 days. This scale will be assessed at visit 1, 2, 4, 6 and 10, or early termination 
if applicable. 
 
Pain Interference – Short Form 8a (PROMIS): This form is a self-administered questionnaire 
where subjects will be asked to measure the effect of pain on their social, cognitive, emotional, 
physical, and recreational activities at visit 2, 4, 6 and 10, or early termination if applicable. 
 
Pain Catastrophizing Scale (PCS): Subjects will be asked about their feelings while experiencing 
or thinking about pain – they don’t necessarily have to be in pain while completing this 
questionnaire. This will be performed at visit 2, 4, 6 and 10, or early termination if applicable. 
  
7.1.5. Sleep Scores 
Sleep Disturbance – Short Form 8a (PROMIS): This form is a self-administered questionnaire 
where subjects will be asked to rate the attributes of their sleep over the past week. A total score 
is obtained by adding the results of each question (8 in total) to get a score out of 40. This will be 
assessed in clinic at Visits 2, 4, 6 and 10.   
 
Daily Sleep Interference Scale (DSIS): This self-administered questionnaire is used to quantify 
sleep interference due to pain. This scale should be completed by patients once a day (upon 
awakening) to accurately capture variability in sleep interference due to pain. This questionnaire 
will be conducted using the Study electronic App. This scale will be assessed once each day during 
screening, baseline and treatment. 
 
7.1.6. Questionnaires 
Patient Global Impression of Change (PGIC): This self-administered questionnaire assesses the global 
status of the subject by asking the subject if s/he feels that his/her condition has improved, has not 
changed, or has worsened since the beginning of the study. The PGIC questionnaire will be 
administered at Visit 10 (End of Treatment) and in the event of Early Termination. 

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Fatigue – Short Form 8a (PROMIS): A self administered questionnaire that assesses the 
consequences of pain on a person’s ability to enjoy their life. It will be administered at visit 2, 4, 
6 and 10, or early termination if applicable. 
General Life Satisfaction – Short Form 5a (PROMIS): A self-administered questionnaire that 
assesses the overall life satisfaction of the subject. This questionnaire will be administered at visit 
2, 4, 6 and 10, or early termination if applicable. 
Anxiety - Short Form 8a (PROMIS): A self-administered questionnaire that assesses the subjects 
overall change in mood symptoms (depression, anxiety, and anger) since the beginning of the 
study. This questionnaire will be administered at visit 2, 4, 6 and 10, or early termination if 
applicable. 
Generalized Anxiety Disorder (GAD–7):  A self-administrated test to assess generalized anxiety 
disorder. The normative data enable users to discern whether an individual’s anxiety score is 
normal, or mildly, moderately, or severely elevated.  This questionnaire will be administered at 
Visit 1 (screening) to exclude patients with scores score >15. 
Patient’s Health Questionnaire (PHQ-9): A self administered questionnaire that diagnoses and 
measures severity of depression in a subject. This questionnaire will be administered at Visit 1 
(screening) to exclude patients with scores score >20. 
 
7.1.7. Withdrawal/Discontinuation Procedures 
A subject may be discontinued from the study at the discretion of the Investigator for medical 
reasons, or if the subject wishes to withdraw. Subjects who do not meet the additional criteria 
for entering the Treatment Period at Visit 2 will be discontinued from the study and 
considered screen fails. Women who become pregnant during the study and males whose 
partners become pregnant during the study will immediately be discontinued from the study. 
Refer to Section 12.8 for Pregnancy report criteria. Subjects may, at the Investigator’s discretion, 
also be discontinued at any time due to non-adherence to treatment regimen (e.g., <80% of the 
doses taken, failed urine drug test) and missed visits. If a subject does not return for a scheduled 
visit, every effort will be made to contact the subject, and document the subject outcome, if 
possible.  
 
Based on previous studies of PEA and the FSD201 Phase 1 trial, the most likely AEs would be 
related to gastrointestinal intolerance and/or diarrhea. Based on this, laboratory changes consistent 
with severe diarrhea including a decrease in kidney function (eGFR < 60 mL/min/1.73m2) or 
hyperkalemia/hypokalemia (serum potassium < 3.0 mmol/L or serum potassium > 5.5mmol/L) 
will cause the patient to be discontinued from treatment. In addition, patients who experience a 
single SAE probably related to the study drug will also be discontinued (whether or not this SAE 
is related to gastrointestinal intolerance/diarrhea). Individual stopping criteria are summarized in  
Table 3.  
 

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Table 3 Individual Stopping Criteria 
All subjects who withdraw or are discontinued by the Investigator (for any reason) will have an 
Early Termination Visit performed within 14 (±2) days of discontinuation or withdrawal. If 
subjects have ongoing AEs at the time of discontinuation, the site should follow up with the 
patient until all AEs are resolved or closed. 
The study will be stopped if there are four individuals with SAEs probably related to the study 
drug in the FSD201 treatment group. This represents 10% of the expected 40 patients in the FSD 
treatment group.  
 
8. Treatment Plan 
 
8.1. Product, Dose and Mode of Administration Dose  
FSD201 is provided as a 600 mg tablet. Participants will be provided with a wallet containing 3 
blister cards (sufficient for 15 days of dosing). Subjects should take one (1) tablet twice daily after 
food approximately 12 hours apart. The subjects will receive a total of 4 wallets over the course of 
the study, dispensed at Visits 2, 4 and 6. 
 
8.1.1. Investigational Therapy 
All randomized subjects will receive the study drug from Day 0 to Day 56 (Visit 2 to Visit 10). 
Subjects will take one tablet in the morning and one tablet in the evening (i.e., approximately every 
12 hours, approximately at the same time every day, and at least 8 hours apart) according to their 
randomized treatment arm assignment as described below: 
 
Arm A: FSD201 600 mg tablet b.i.d. for oral administration after food. 
Arm B: One placebo tablet (i.e., matching 600 mg FSD201 tablets) b.i.d. for oral administration 
after food. 
 
The first dose of the study drug will be taken at the site.  
 
8.2. Description of Compound, Packaging, Labeling, Storage  
FSD201: Each white-colored oval Oral tablet formulation contains 600 mg of FSD201 drug 
substance (ultramicronized N-(2-hydroxyethyl)hexadecanamide). The excipients used in tablet 
formulation include Microcrystalline Cellulose, Croscarmellose Sodium, Povidone, Magnesium 
Stearate, Silicon Dioxide and Polysorbate 80 (vegetal origin).  
Stopping Criteria 
Value for Stopping 
Kidney Function (eGFR) 
<60 mL/min/1.73m2 
Potassium 
<3.0 mmol/L or >5.5mmol/L 
Development of an SAE probably related to 
the study drug 
1 SAE 

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Placebo: Oral tablet formulation containing Microcrystalline cellulose, Dicalcium Phosphate, 
Croscarmellose Sodium, Magnesium Stearate and Silicon Dioxide. The placebo tablet will be 
identical in appearance to the study drug.  
 
Primary and Secondary Packaging: Tablets are provided in blister cards of 10 tablets per card, 
3 cards per wallet, sufficient for 15 days of dosing. 
 
Labelling: The blister cards will not be labelled individually. The wallet of three blister cards will 
be labelled according to applicable regulations. 
 
Storage: The blister cards should be stored in the wallet bearing the study label. The 
investigational product should be stored at room temperature (15-25℃) out of reach of children. 
 
8.2.1. Rescue Medication 
Acetaminophen (maximum daily dose 3,000 mg) or diphenhydramine (maximum daily dose 300 
mg) is allowed, starting at the screening visit.  
 
8.2.2. Concomitant and Prohibited Medication 
Medications taken for pain associated with chronic widespread musculoskeletal nociplastic pains 
(arising from neurogenic inflammation) secondary or likely “idiopathic MCAS” during the 17 days 
before the Screening Visit will be recorded in the case report form.  
 
Concomitant use of the following medications or therapies could influence the evaluation of the 
study drug's efficacy and safety and are prohibited throughout the study: 
 
• Antidepressants (except for selective serotonin reuptake inhibitors) 
• Ketamine 
• Opioid agonists 
• Mast cell stabilizers (e.g., cromolyn sodium, ketotifen, hydroxyurea) 
• Mast cell inhibitors (e.g., montelukast, zafirlukast, zileuton, petosan) 
• Chemotherapeutic agents (e.g., imatinib, masitinib, dasatinib, nilotinib) 
• Intravenous immune globulin (IVIG) 
• NSAIDs 
• Cannabinoids 
• Herbal remedies/supplements containing palmitoylethanolamide 
 
Procedures that may have efficacy in reducing chronic musculoskeletal nociplastic pain are 
prohibited unless stable for 4 weeks before the Screening Visit, for example, nerve block, 

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iontophoresis, laser therapy, acupuncture, spinal cord stimulation therapy, transcutaneous 
electrical nerve stimulation. Stable procedures should be continued for the duration of the study. 
 
The following medications are permitted if they have been at a stable dose (defined as no change 
to the regimen and the subject reports taking the medication as prescribed) for at least 4 weeks 
before the Screening Visit, and the dose will remain unchanged during the study: 
 
● Sedatives (e.g., zopiclone, zolpidem, benzodiazepines except lorazepam, temazepam, 
oxazepam, midazolam); 
● Aspirin (low dose, ≤325 mg once daily, for cardio prophylaxis) 
● Histamine blockers 
● Naltrexone (opioid antagonist) 
● Gabapentinoids and other anticonvulsants 
● Muscle relaxants 
● Local anesthetics 
● Topical pain mediations 
 
Stable doses of the selective serotonin reuptake inhibitors (SSRIs) are allowed to treat depression 
if the dose is stable for 60 days before Screening Visit. 
 
8.2.3. Treatment Duration 
Each subject will participate in the study for a maximum of 80 days, including a screening period 
of up to 17 days, a 56 day double-blind treatment period, and a 1-week post-treatment follow-up 
period. 
 
After their last study drug intake (Day 56), a safety follow-up assessment 7 days (7 ± 2 days) will 
occur. Follow-up on SAEs and AEs will continue until resolution of the event or until a stable 
condition is reached. Any SAEs occurring within 7 days after the last IMP (Investigational 
Medicinal Product) intake will be collected. 
 
9. Materials 
 
The Sponsor will provide at no cost the investigational medicinal product to be used. In addition, 
the App will be provided at no cost. Patients can choose to have the App installed on their own 
device, or a device can be provided by the site at no cost. 
 
10. Selection and Withdrawal of Subjects  
 
10.1. Inclusion Criteria 
1. The subject is ≥ 18 and ≤ 75 years of age at the time of signing ICF 

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2. Clinical diagnosis of idiopathic MCAS (in the presence or absence of a generalized 
hypermobility spectrum disorder (G-HSD) or Ehlers-Danlos Syndrome (EDS)) as per the 
global consensus diagnostic criteria (consensus-2 criteria (Afrin et al., 2021); 
a) Medical history shows a constellation of clinical complaints attributable to 
pathologically increased mast cell (MC) activity (MC mediator release syndrome) 
b) Medical history of symptomatic response to inhibitors of MC activation or MC 
mediator production or action 
3. Adults with widespread chronic nociplastic pain (in three or more body regions) 
4. Chronic pains of intensity ≥4.0 but ≤9.0 on a Numeric Pain Rating Scale, symptom duration 
of >6 months 
5. Subject signed a Research Ethics Board (REB) or Institutional Review Board (IRB) approved 
written informed consent and privacy language (Health Insurance Portability and 
Accountability Act (HIPAA) and Personal Information Protection and Electronic Documents 
Act (PIPEDA) authorization before performing any study-related procedures 
6. The subject is considered reliable and capable of adhering to the protocol (e.g. able to 
understand and complete forms and questionnaires, visit schedule, or medication intake 
according to the judgment of the investigator      
7. Subject agrees to use only acetaminophen (up to 1000 mg per dose and not to exceed 3000 
mg/day) or diphenhydramine (up to 300 mg/day) as rescue medication for chronic widespread 
musculoskeletal nociplastic pains throughout the trial 
8. The subject is willing to maintain current activity and exercise levels throughout the study 
9. During the study, the subject agrees not to initiate or change any non-pharmacologic 
interventions (including chiropractic care, physical therapy, psychotherapy, and massage 
therapy). Any ongoing non-pharmacologic intervention must be stable for at least 4 weeks 
before screening and should be continued for the duration of the study 
10. Female subjects of childbearing potential must have a negative serum pregnancy test at the 
Screening Visit and a negative urine pregnancy test at Randomization Visit 
11. Female subjects of childbearing potential must use an acceptable method of birth control.  
Acceptable birth control includes total abstinence from heterosexual intercourse, a 
vasectomized partner, intrauterine device, or double barrier method including condoms, 
sponge, diaphragm, contraceptives (oral, parenteral, or transdermal), or vaginal ring with 
spermicidal jellies or cream. Subjects considered not of childbearing potential must be 
surgically sterile (total hysterectomy, bilateral salpingo-oophorectomy, or tubal ligation) or be 
more than one year post-menopausal, defined as a complete cessation of menstruation for at 
least one year. Male subjects who are sexually active must use an acceptable method of birth 
control. Acceptable birth control includes total abstinence from heterosexual intercourse, or 
use of a double barrier method including condoms sponge, diaphragm, contraceptives (oral, 
parenteral, or transdermal), or vaginal ring with spermicidal jellies or cream used by partner. 
Periodic abstinence and withdrawal are not acceptable methods of contraception.  
12. The subject is in good health as judged by the investigator, based on medical history, physical 
examination, serum chemistry, hematology, and urine analysis 

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13. At the screening visit, the body mass index (BMI) is between 18 and 39 kg/m2 
14. The subject is sufficiently fluent in English language to answer the questionnaires in clinic and 
on the App. 
 
10.2. Randomization Criteria 
1. The subject is compliant with daily App entries during the baseline period, as defined by the 
completion of a minimum of 5 of 7 daily NPRS scores  
2. The average daily pain intensity scores on the NPRS are ≥ 4.0 and ≤ 9.0 over the last seven 
days before the Randomization Visit  
 
10.3. Exclusion Criteria 
1. The subject has pain that cannot be clearly differentiated from or that could interfere with the 
assessment of chronic musculoskeletal nociplastic pain secondary likely to idiopathic MCAS 
(e.g.post-herpetic neuralgia, traumatic injury, prior surgery, complex regional pain syndrome) 
2. Adults with chronic cancer pain 
3. Adults with inflammatory connective tissue disorder or rheumatological disorder-related pain, 
e.g. rheumatoid arthritis 
4. Adults with focal musculoskeletal pain 
5. Adults with skin diseases (e.g., chronic urticaria, pemphigus, lupus, rosacea etc.) 
6. Adults with endocrinological disorders (e.g., acute hypothyroidism, acute adrenal 
insufficiency etc.) 
7. Adults with systemic gastrointestinal conditions (e.g., Inflammatory bowel disease) 
8. Significant psychological comorbidities: PHQ-9 score >20; and GAD-7 score >15 (indication 
of severe anxiety that could interfere with accurate logging of pain ratings) 
9. Current or recent (within 12 months of screening) history of a substance use disorder including 
cannabinoid or alcohol use disorder as defined by the Diagnostic and Statistical Manual of 
Mental Disorders (5th edition; DSM-5) 
10. Subject has neurologic disorder unrelated to chronic widespread musculoskeletal nociplastic 
pains (e.g., phantom limb from amputation, vitamin B12 deficiency, chronic inflammatory 
demyelinating polyneuropathy), circulatory disorder (e.g., peripheral artery disease), a skin 
condition in the area of neuropathy that could alter sensation (e.g., plantar ulcer), or other 
painful conditions (e.g., arthritis) that, in the judgment of the investigator, could interfere with 
reporting of pain due to chronic widespread musculoskeletal nociplastic pains 
11. Current severe or uncontrolled major depressive disorder or anxiety disorders. Mild to 
moderate major depression or anxiety disorders are permitted provided that the investigator 
assesses the patient as clinically stable and appropriate for entry into the study. Stable doses of 
SSRIs are allowed for the treatment of depression if the dose is stable for 60 days before 
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12. Subject has a history of suicide attempt or suicidal behaviour within the last 12 months or has 
suicidal ideation within the previous 12 months or who is at significant risk to commit suicide, 
as judged by the Investigator at Screening or during the treatment period 
13. The subject is currently using protocol-specified prohibited medications.  
14. Positive urine drug screen for illegal or non-prescribed drugs at the Screening Visit or during 
the treatment period 
15. Pregnant or lactating females or females planning to become pregnant during the study or 
within 28 days following the last dose of study medication  
16. Male patients planning a partner pregnancy or sperm donation during the study or within three 
months following the last dose of study medication 
17. Patients with active malignancy or history of malignancy, except for basal cell or squamous 
cell carcinoma and actinic keratosis. Basal cell carcinoma and small squamous cell carcinoma 
of the skin which have been excised according to guidelines within the last 5 years or in situ 
cervical carcinoma that has been fully treated and shows no evidence of recurrence are allowed 
18. Positive human immunodeficiency virus (HIV), hepatitis B or hepatitis C laboratory result   
19. Any clinically significant unstable medical abnormality or acute or chronic disease of the 
cardiovascular, gastrointestinal, respiratory, hepatic, or renal systems.  Subject with aspartate 
transferase or alanine transferase > 2.5 times the upper limit of normal (ULN) or alkaline 
phosphatase > 3.0 times ULN  
20. Any clinically significant deviation from normal in physical examination, vital signs, or 
clinical laboratory tests, as determined by the investigator 
21. Known history of seizure disorder, epilepsy, convulsions, or increased intracranial pressure 
anytime during the subject's life except for pediatric febrile seizures 
22. Subject has received an investigational therapy of any kind within 28 days or 5 half-lives, 
whichever is longer, before Screening Visit 
23. Subject has had known hypersensitivity or intolerance to the use of PEA, diphenhydramine 
(e.g. Benadryl) or acetaminophen (e.g. Tylenol) and/or their associated formulation 
components 
24. The subject is a member of the site staff or relative of a staff member 
25. Individuals with high baseline serum tryptase levels suggestive of Primary or Secondary 
MCAS (defined as above the normal range of 2.2 to 13.2 µg/L) 
 
10.4. Subject Withdrawal or Replacement  
A subject can withdrawal at any time for any reason. Subjects will be withdrawn if they are unable 
to receive a dose.  
 
10.5. Planned Sample Size 
The planned sample size for this study is based on making a Go/No-Go evaluation, focussing on 
the percentage of patients achieving the reduction in NPRS score, that is, using the binary 
responder endpoint. A decision criterion is applied with possible decision outcomes being ‘Go’ 

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(suggests FSD201 warrants further development), ‘Stop’ (or no-Go, suggests further development 
of the FSD201 should stop), and ‘Pause’ (inconclusive, additional investigation should be 
performed before a decision is made). This decision framework was published by Lalonde et al., 
(2007)  and Frewer et al., (2016). Note that these decision criteria will not be definitive as the final 
decision to continue development will be based on more than just the responder endpoint. 
 
For this decision framework, a lower reference value (LRV) and a target value (TV) are defined 
for the treatment effect (i.e., difference in the drug response rate between FSD201 and placebo) as 
follows: 
 
• LRV: The minimum treatment effect below which there is no desire to continue development the 
compound. 
• TV: The targeted treatment effect above which the compound is expected to replace the current 
standard of care in terms of efficacy 
 
The Go/No-Go calculations are based on the TV of a 30% difference between FSD201 and 
placebo, and the minimum difference to be considered for further development being 10% (LRV).  
Furthermore, the calculations have been made such that there is at most 30% probability of a false-
go, i.e., there is at least 70% desired confidence that the treatment effect is better than a 10% 
improvement (LRV), given that a Go decision is made. Similarly, there is a maximum of 10% 
false-stop risk, i.e., a maximum probability that the treatment effect is better than a 30% 
improvement (TV), given a Stop decision is made. Finally, it is assumed that the placebo response 
rate is 20%. 
 
2:1 randomisation 
A total sample size of 60 patients (40 on FSD201 and 20 on placebo) has been chosen to balance 
the needs to minimize the probability of ‘Pause’ whilst maintaining reasonable recruitment cost 
and time. Table 4 shows the probabilities of making a Go, Pause or Stop decision. 
 
True Treatment Effect 
Go 
Pause 
Stop 
TV (30%) 
85.2% 
4.3% 
10.4% 
LRV (10%) 
25.7% 
7.5% 
66.8% 
Sum of the probabilities may not be 100% due to rounding for display 
Table 4 Probabilities of Go, Pause or Stop Given the True Treatment Difference 
 

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11. Efficacy 
 
Subjects will report daily average Numerical Pain Rating Scale (NPRS), their Daily Sleep 
Interference Scale (DSIS), their rescue medication and Investigational Compliance each day using 
the App.  
 
The questionnaires on efficacy to be performed during the clinic visits include: 
 
Patients Health Questionnaire (PHQ-9), Generalized Anxiety Disorder (GAD–7), Patient Global 
Impression of Change (PGIC), Anxiety – Short Form 8a (PROMIS), Sleep Disturbance – Short 
Form 8a (PROMIS), Pain Interference – Short Form 8a (PROMIS), Fatigue – Short Form 8a 
(PROMIS), General Life Satisfaction – Short Form 5a (PROMIS), Pain Catastrophizing Scale 
(PCS). Refer to the Study Procedures and Evaluations to determine which questionnaires are 
performed at each visit. 
 
12. Safety 
 
The safety and tolerability of FSD201 will be evaluated based on an assessment of treatment-
emergent adverse events (TEAEs), clinical laboratory evaluations and physical examinations. 
 
12.1. Biomarkers 
Blood samples for analysis of inflammatory cytokines will be collected at Visit 2, Visit 4, Visit 6 
and Visit 10. Blood sample collection will be captured in the source and recorded into the 
Electronic Case Report Form (eCRF). 
 
12.2. Exploratory FSD201 plasma concentration 
Blood samples for analysis of FSD201 will be collected on Visit 2, Visit 4, Visit 6 and Visit 10. 
Blood sample collection and processing times will be captured in the source and recorded into the 
eCRF, along with time of last test article intake (by patient recall). Blood samples should be 
processed according to the provided procedure as soon after collection as possible. 
 
12.3. Definitions of Adverse Events  
Per International Council for Harmonization (ICH) E2A: An adverse event (AE) is any untoward 
medical occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have to have a causal relationship with this treatment. An 
AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not it is considered to be related to the medicinal product.  
 

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Medical interventions such as surgeries, diagnostic procedures, and therapeutic procedures are not 
AEs, but the action taken to treat the medical condition. They should be recorded as treatment of 
the AEs.  
 
Use the following categories for assigning the certainty of the relatedness: 
• Not Related: A causal relationship between the study drug and the AE can be easily 
ruled out (e.g., based on the temporal sequence, absence of a reasonable 
pathophysiological mechanism, or direct evidence of actual cause).  
• Unlikely Related: A clinical event, including a laboratory test abnormality, with a 
temporal relationship to drug administration which makes a causal relationship 
improbable, and for which other drugs, chemicals, or underlying disease provide 
plausible explanations.  
• Possibly Related: A clinical event, including a laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which could also be 
explained by concurrent disease or other drugs or chemicals. Information on drug 
withdrawal may be lacking or unclear.  
• Probably Related: A clinical event, including a laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and which follows a clinically reasonable 
response on withdrawal. Rechallenge information is not required to fulfill this definition. 
• Definitely Related: A clinical event, including a laboratory test abnormality, which is a 
known effect of the drug, follows an obvious sequence of time from the drug’s 
administration, and ceases with discontinuation of the drug. Rechallenge information is 
not required to fulfill this definition. 
 
12.4. Severity of Adverse Events 
Each AE will be assessed for its severity or for its intensity as experienced by the subject and 
according to the most recent MedDRA Version.  
• Grade 1 – Mild 
• Grade 2 – Moderate 
• Grade 3 – Severe 
• Grade 4 – Life Threatening 
• Grade 5 – Death 
 
12.5. Adverse Events Outcomes 
The Investigator will categorize the outcome of AEs according to the definitions below: 
• Resolved: The subject recovered from the AE.  
• Not Resolved/Ongoing: At the time of the last assessment, the event is ongoing, with 
an undetermined outcome. Note: Ongoing AEs are not considered resolved as a result 
of death. No AE stop date will be recorded with an AE that is ongoing. 

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• Chronic/Stable: At the time of the last assessment, the event is ongoing and 
stabilized, with no change to the event outcome anticipated.  
• Death: The AE directly caused death. 
• Unknown: There is an inability to access the subject or the subject’s records to 
determine the outcome (i.e., subject withdraws consent or is lost to follow-up). 
 
12.6. Serious Adverse Events  
An SAE or reaction is any untoward medical occurrence that at any dose: 
● Requires inpatient hospitalization or prolongation of existing hospitalization 
● Results in persistent or significant disability or incapacity  
● Is a congenital anomaly or congenital disability  
● Is a significant medical event (e.g., intensive treatment in an emergency room or for allergic 
bronchospasm; blood dyscrasias, or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse; malignancy) 
● Is life-threatening 
● Results in death 
 
12.7. Abnormal Laboratory Values  
Any abnormality in a laboratory value that is new in onset, or which has worsened in severity or 
frequency from the baseline condition and meets 1 of the following criteria will be recorded on the 
AE pages of the eCRF:  
 
● Is judged by the investigator as clinically significant 
● Leads to discontinuation of the investigational product  
● Requires therapeutic intervention or diagnostic tests  
● Has accompanying or inducing symptoms or signs 
 
12.8. Pregnancy 
The Sponsor should report all pregnancies and pregnancies in the partners of subjects to the 
REB/IRB and Regulatory Authorities per institutional and/or regulatory guidelines.  
 
Women who become pregnant during the study will be immediately discontinued from the study; 
if the woman was taking a double-blind treatment, the blind will be broken to determine whether 
the woman was taking placebo or FSD201; in the latter case, the woman will be regularly 
followed during the pregnancy until the child is born. Male participants whose partners become 
pregnant during the study will be immediately discontinued from the study; if the man was 
taking a double-blind treatment, the blind will be broken to determine whether he was taking 
placebo or FSD201. 
 

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Subjects should be instructed to immediately notify the investigator of any pregnancies and the 
investigator should counsel the subject, discussing any risks of continuing the pregnancy and any 
possible effects on the fetus.  
 
A Pregnancy Reporting Form should be completed by the investigator and submitted to Ozmosis 
Research Inc. either by email (ozmsafety@ozmosisresearch.ca) or via fax (416-637-8333) within 
24 hours after learning of the pregnancy. Pregnancy should not be recorded on the Adverse Event 
eCRF but the date of pregnancy will be recorded in the database on the Pregnancy Report form 
CRF.  
 
13. Reporting Procedures and Requirements  
 
Any Adverse Events (AEs) occurring before the start of treatment (i.e., before the first dose of the 
investigational product) will be recorded in the medical history. The AE reporting period for this 
study begins when the subject received the first dose of study drug on trial and ends at the last 
follow-up visit. All AEs must be recorded in the eCRFs. The sign, symptoms, or diseases present 
before starting the treatment period are only considered AEs if they worsen after starting the 
treatment period.  
 
13.1. Reporting of Serious Adverse Events  
All serious adverse events (SAE) defined per ICH guidelines must be recorded on case report 
forms. In addition, all serious adverse events must be reported, whether or not considered causally 
related to treatment using the SAE form to Ozmosis Research Inc. within 24 hours of becoming 
aware of the event. The SAE must be completely described in the case report form. The reporting 
period for SAEs is the period immediately following the time of first dose through the last follow-
up visit. The investigator and/or Sponsor are responsible for informing the Ethics Committee 
and/or the Regulatory Authority of the SAE as per local requirements. 
 
Serious Adverse Event Reporting Instructions  
 
All serious adverse events must be reported as follows:  
 
Within 24 hours: 
Report initial information (on trial specific SAE report form) by fax or e-
mail to:  
 
 
Ozmosis Research Inc.  
 
 
Email: ozmsafety@ozmosisresearch.ca 
 
 
Fax: 416-864-8333 
 
The initial information should always contain:  
- 
Name of Reporter/Investigator 

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- 
Subject identification  
- 
SAE Term  
- 
Study drug dose and start/stop dates  
 
On the next working day: Fax or e-mail completed trial-specific Serious Adverse Event form. 
  
All SAEs must be followed until resolved, become chronic, or stable unless the subject is lost to 
follow up. Resolution status of such an event should be documented on the CRF. 
 
13.2. Procedures for Expedited Reporting  
Responsibility for Reporting Serious Adverse Events to Regulatory Authorities  
 
Ozmosis Research Inc. will provide expedited reports SAEs to Intrinsik for submission to Health 
Canada and FDA according to applicable guidelines and regulations, i.e. events which are BOTH 
serious AND unexpected, AND which are thought to be related to protocol treatment (or for which 
a casual relationship with protocol treatment cannot be ruled out).  
 
Reporting Serious Adverse Events to Local Ethics Boards 
 
Ozmosis Research Inc. will notify all Investigators of all Serious Adverse Events that are 
reportable to regulatory authorities from this trial or from other clinical trials as reported to the 
Sponsor. This includes all serious events that are unexpected and related to protocol treatment. 
Investigators must notify their Research Ethics Board (REB) / Institutional Review Board (IRB) 
and file the report with their Investigator Site File. Documentation that serious adverse events 
(SAEs) have been reported to REB/IRB must be kept on file at Ozmosis Research Inc.  
 
Documentation can be any of the following:  
• Letter from REB/IRB acknowledging receipt  
• Stamp from the REB/IRB, signed and dated by REB/IRB chair, acknowledging 
receipt  
• Letter demonstrating the SAE was sent to the board  
 
All expedited serious adverse events occurring within a centre should also be reported to local 
REB/IRB.  
 
14. Statistical Methods and Planned Analyses 
 
The intent-to-treat (ITT) population will consist of all randomized subjects. The safety population 
will include all randomized subjects who receive at least one dose of the study drug. The per-
protocol population will consist of all subjects in the ITT population who have no major protocol 
deviations that would have a significant effect on the efficacy of the study treatment. The ITT 

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population will be the primary population for all efficacy analyses.  All safety data will be 
summarized based on the safety population. The per-protocol population will be used as the 
population for sensitivity analyses of the primary and key secondary efficacy endpoints. 
 
All efficacy and safety will be summarized descriptively. 
 
14.1. Efficacy Analysis 
As the primary analysis, the change from baseline in the weekly average of the daily pain intensity 
measured by NPRS will be analyzed using the mixed model for repeated measure (MMRM) with 
the treatment as a factor, visit, the interaction between treatment and visit, and baseline as a 
covariate. The analysis of covariance (ANCOVA) will also be used as an additional analysis. The 
change in the weekly average of the daily sleep score on Daily Sleep Interference Score (DSIS) 
and the change in the NPRS score will be analyzed using the same methods for primary endpoint 
analysis. The percentage of subjects achieving ≥30% and ≥50% reduction in NPRS score at Day 
28 and Day 56 will be analyzed using Fisher's exact test and the logistic regression model. The 
change in Patient Global Impression of Change (PGIC) and other continuous efficacy endpoints 
will be analyzed using ANCOVA. 
 
No multiplicity adjustment will be used in this study. The missing data imputation methods and 
sensitivity analyses for primary and key secondary efficacy endpoints will be included in Statistical 
Analysis Plan (SAP). 
 
14.2. Exploratory Analysis 
The change in CRP, serum tryptase, and plasma cytokines will be summarized descriptively by 
treatment group in the ITT (Intention-To-Treat) population. A further exploratory endpoint of 
FSD201 plasma exposure will be performed by analyzing plasma samples. 
 
14.3. Safety Analysis    
The safety analysis population includes subjects who received at least 1 dose of study 
medication. Safety endpoints include adverse events, vital signs, and clinical laboratory data. 
Safety endpoints will be listed and/or summarized descriptively by treatment group.  
 
All adverse events (AEs) will be coded using the most recent MedDRA Version. The incidence of 
TEAEs, SAEs, and AEs leading to treatment discontinuation will be summarized by system organ 
class and preferred term. Summaries in terms of severity and relationship to study drug will also 
be provided. SAEs will be summarized separately in a similar manner. Subject listings of AEs 
causing discontinuation of study medication and SAEs will be produced. 
 
Clinical laboratory data and vital signs will be summarized, including absolute values and changes 
from baseline values and numbers of subjects with clinically significant values. The incidence and 

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severity of treatment-emergent changes in laboratory values will be summarized separately; 
Summary tables will be provided for physical examination by treatment group and visit where 
appropriate. Vital signs analysis will include the mean, standard deviation, minimum, maximum, 
and quartiles at baseline and at the end of treatment, and the change from baseline to the end of 
treatment. Concomitant medications will be analyzed descriptively. 
 
14.4. Methods for Handling Missing Data  
Reasonable efforts will be made to obtain complete data for all subjects; however, missing 
observations may occur due to subjects lost to follow-up or non-adherence to required 
assessments. The reasons for missing data will be evaluated. In addition, the distribution of 
prognostic factors between subjects with data and those without data will be examined to 
evaluate any potential sources of bias. In the absence of any apparent systematic loss, data will 
be analyzed assuming that these observations are missing at random. 
For efficacy endpoints, missing data will be adjusted in the analysis by using the method of last 
observation carried forward (LOCF). A sensitivity analysis will be carried out using the baseline 
observation carried forward (BOCF).  
 
15. Investigational Obligations  
 
15.1. General considerations  
The end date for the study overall will be defined as the date of last contact or final contact attempt 
for the last subject completing or withdrawing from the study. If the Sponsor were to suspend or 
terminate the study prematurely for any reason, prompt notification would be given to 
investigators, REBs, IRBs, and regulatory authorities in accordance with regulatory requirements.  
 
The Sponsor should be notified promptly if the study is terminated by the investigator or the 
REB/IRB at the applicable study site. A particular study site may be terminated from this study at 
the discretion of the investigator, Sponsor, or REB/IRB (e.g., for nonenrolment of subjects or 
noncompliance with the protocol).  
 
15.2. Ethical Guidelines for the Conduct of the Study  
The investigator is responsible for ensuring that the study is conducted in accordance with the 
clinical protocol and is in full compliance with FDA regulatory requirements; the basic principles 
outlined in 21 CFR Parts 50, 54, 56 & 312, the ICH-Guidelines for Good Clinical Practice as 
published in the Federal Register on May 9, 1997, and the Declaration of Helsinki (ICH 1996;  
FDA Regulation 2021). 
 
15.3. Written Informed Consent  
A written informed consent form will be provided to each subject describing this information. The 
investigator will inform the subject of the nature, risks, and purpose of the study. This form must 

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be reviewed and approved by the Sponsor and the REB/IRB before its use in the study. Each 
volunteer must sign and date this form prior to their participation in the study. A signed original 
consent form for each subject will be kept on file at the clinical site. A copy will also be given to 
the subject signing the form.  
 
15.4. Confidentiality 
The Principal Investigator at each site and designees, employees and agents involved with this 
study will comply with relevant provincial/state and federal laws relating to the confidentiality, 
privacy and security of the subject's health information. They will only create, maintain, use or 
disclose any data that is generated by this study or other information disclosed to the Principal 
Investigator or their employees or agents during the course of the study to the Sponsor, REB/IRB, 
Health Canada, FDA or other authorized recipients as appropriate for the execution, analysis, 
review and reporting of this study. Such information shall not be used for any other purposes and 
will remain confidential. 
 
16. Study Management 
 
16.1. Approval and Consent 
16.1.1. Regulatory Guidelines 
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and all relevant regulations as set forth in Parts 50, 56, 312, Subpart D, of Title 21 of the 
United States Code of Federal Regulations (CFR), in compliance with International Council for 
Harmonisation and GCP guidelines and according to the appropriate regulatory requirements in 
the countries where the study was conducted. 
 
16.1.2. Research Ethics Board or Institutional Review Board/Independent Ethics 
Committee 
Conduct of the study must be approved by an appropriately constituted REB or IRB/IEC. Approval 
is required for the study protocol, protocol amendments (if applicable), IB, informed consent form 
(ICFs), recruitment material and patient information sheets, and other patient-facing material. 
 
16.1.3. Informed Consent 
For each subject (or the patient’s Legally Authorized Representative (LAR)), informed consent 
will be obtained before any protocol-related activities. As part of this procedure, the principal 
investigator (PI) or designee must explain the nature of the study, its purpose, procedures, expected 
duration, alternative therapy available, and the benefits and risks involved in study participation. 
The subject (or the subject’s LAR) should be informed that he/she may withdraw from the study 
at any time, and the subject will receive all information that is required by local regulations and 
guidelines for International Council for Harmonisation. The PI will provide the sponsor or its 
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16.1.4. Data Handling 
Clinical data will be entered by site personnel on eCRFs for transmission to the sponsor. Data on 
eCRFs transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site. All study forms and records transmitted to the sponsor 
must only include coded identifiers such that directly identifying personal information is not 
transmitted. The primary method of data transmittal is via the secure, internet-based electronic 
data capture (EDC) system maintained by eClinical Services. Access to the EDC system is 
available only to authorized users via the study’s internet website, where a user unique assigned 
username and password are required for access. 
Any changes made to data after collection will be made through the use of data clarification forms 
or queries in the EDC system. When all missing and/or incorrect data have been resolved, eCRFs 
will be considered complete. 
 
16.1.5. Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. The investigator will provide direct 
access to source documents and/or source data in the facilitation of study-related monitoring, 
audits, review by REBs or IRB/IECs, and regulatory inspections. 
 
The investigator/institution should maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the site’s subjects. Source data should be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data 
should be traceable, not obscure the original entry, and be explained if necessary. 
 
16.1.6. Record Retention 
Study records and source documents must be preserved for at least 25 years after the completion 
or discontinuation of/withdrawal from the study, at least 2 years after the drug being studied has 
received its last approval for sale, or at least 2 years after the drug development has stopped, and 
in accordance with the applicable local privacy laws, whichever is the longer period. 
 
The investigator agrees to comply with all applicable federal, state, and local laws and regulations 
relating to the privacy of patient health information, including, but not limited to, the Standards 
for Individually Identifiable Health Information, 45 CFR, Parts 160 and 164 (the Health Insurance 
Portability Accountability Act of 1996 Privacy Regulation). The investigator shall ensure that 
study subjects authorize the use and disclosure of protected health information in accordance with 
Health Insurance Portability Accountability Act (HIPAA) Privacy Regulation and in a form 
satisfactory to the sponsor. 
 

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16.1.7. Monitoring 
The study will be monitored to ensure that it is conducted and documented properly according to 
the protocol, GCP, and all applicable regulatory requirements. Ozmosis Research Inc. will 
organize remote/on-site monitoring of this study to be conducted as per the Monitoring Plan.  
 
As this trial is conducted under both a CTA with Health Canada and an IND with the United States’ 
Food and Drug Administration, your site may be subject to an inspection by the Health Products 
and Food Branch Inspectorate or FDA. Other audits may be conducted by the study sponsor, 
Ozmosis Research Inc. 
 
16.1.8. Quality Control and Quality Assurance 
The sponsor or its designee will perform the quality assurance and quality control activities of this 
study; however, responsibility for the accuracy, completeness, security, and reliability of the study 
data presented to the sponsor lies with the investigator generating the data. 
 
The sponsor may arrange audits as part of the implementation of quality assurance to ensure that 
the study is being conducted in compliance with the protocol, standard operating procedures, GCP, 
and all applicable regulatory requirements. Audits will be independent of and separate from the 
routine monitoring and quality control functions. Quality assurance procedures will be performed 
at study sites and during data management to assure that safety and efficacy data are adequate and 
well documented. 
 
16.2. Investigator Selection 
The Investigator must be of good standing as an Investigator and knowledgeable in relevant 
areas of clinical research to ensure adherence to the requirements of the protocol, including the 
protection of human subjects. Other site personnel must have appropriate research experience 
and infrastructure to ensure adherence to the protocol and enrollment of sufficient numbers of 
evaluable subjects. The curriculum vitae of the Investigator will be maintained in the Sponsor 
files as documentation of previous medical training, and federal databases will be searched to 
ensure that the Investigator and/or the site are not prohibited from engaging in federally 
sponsored clinical research. The Principal Investigator will sign the signature page of this 
protocol, agreeing to comply with all applicable government regulations and the requirements of 
this study. 
 
16.3. Protocol Amendment and Protocol Deviation 
16.3.1. Protocol Amendment 
Amendments to the protocol that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no effect on 
the safety of patients or the conduct of the study will be classed as administrative amendments and 
will be submitted to the REB or IRB/IEC for information only. The sponsor will ensure that 
acknowledgment is received and filed. Amendments that are classed as substantial amendments 

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must be submitted to the appropriate regulatory authorities and the REB or IRB/IECs for approval 
and will not be implemented at sites until such approvals are received other than in the case of an 
urgent safety measure. 
 
16.3.2. Protocol Deviations 
Should a protocol deviation occur, the sponsor/Ozmosis Research must be informed as soon as 
possible. Protocol deviations and/or violations and the reasons they occurred will be included in 
the CSR. Reporting of protocol deviations to the REB or IRB/IEC and in accordance with 
applicable regulatory authority mandates is the investigator’s responsibility. All REB or IRB/IEC 
correspondence is to be forwarded to Ozmosis Research Inc.  
 
16.4. Administrative Requirements 
16.4.1. Drug Accountability 
The study drug may only be used for subjects enrolled in this study under the supervision of the 
Investigator and under the terms of the clinical protocol. The Investigator may not provide study 
drug to any person not authorized to use it. Where allowed, the Investigator may choose to assign 
drug accountability responsibilities to a pharmacist or other appropriate individual. The 
Investigator, or delegate, will also ensure that the drugs are maintained under secure storage and 
that the drug accountability record is maintained. This may include: 
 
• Product code 
• Lot number 
• Receipt dates 
• Dates and quantities dispensed, including subject number 
• Return date to the clinical site (if any) 
• Return date to the Sponsor (if any) 
• Any drugs that have not been used will be returned to the Sponsor.  
 
The Sponsor will supply the Investigator with an adequate amount of the investigational drug for 
completion of the study. All unused or expired study drug will be returned to the Sponsor or the 
Sponsor’s designee or, if authorized, disposed of at the study site per the site’s Standard 
Operating Procedures and documented. Study drug is expected to be dispensed to the subject at 
the study site.  
 
Unblinding envelopes will also be provided with the drug product shipments, and should be kept 
in a controlled, restricted cabinet. These envelopes must be kept sealed and only used if the PI 
determines unblinding to be necessary. Accountability on these envelopes will be performed at 
the end of the clinical trial. 
 

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16.4.2. Communication with the Sponsor 
Although the Investigator and his/her staff may have contact with other key individuals at the 
Sponsor throughout the course of the study, all communications regarding conduct of the study 
must be channeled through the Sponsor’s clinical affairs personnel or their designees. 
 
16.4.3. Required Documentation 
An Investigator may not screen or enroll subjects until authorized to do so by the Sponsor. At a 
minimum, the following documentation must be received by the Sponsor prior to study 
commencement:  
 
• Curriculum vitae for the Principal Investigator and Sub-investigators  
• Signed Investigator Agreement  
• Signed Confidentiality Statement for Investigator and Sub-investigators 
• Signed “Protocol Agreement Page” (page 2 of this protocol)  
• IRB/REB’s written approval of both the protocol and the ICF  
• Signed Financial Disclosure Statement, if applicable  
• Signed Qualified Investigator Undertaking form, if applicable  
• IRB Assurance of Compliance Form or equivalent 
 
16.4.4. Termination of Study 
The Sponsor reserves the right to suspend enrollment or terminate the study at any time as set 
forth in the Clinical Study Agreement. Written notice will be submitted to the Investigator in 
advance of such termination. 
 
The Sponsor may suspend enrollment or terminate the study at a specific site for reasons 
including, but not limited to, inadequate data collection, low subject enrollment rate, 
achievement of the total enrollment, or noncompliance with the protocol or other clinical 
research requirements. 
 
The REB or IRB/EC will be informed promptly and provided with a detailed written explanation 
for the termination or suspension.  
 
As directed by the Sponsor, all study materials must be collected and all eCRFs completed to the 
greatest extent possible. 
 
16.4.5. Ethical Considerations 
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 

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Subpart D, of Title 21 of the CFR; EU 536/2014, Annex 1, D, 17 (a); and in compliance with GCP 
guidelines. 
 
REB or IRB/IECs will review and approve this protocol and the ICF. All patients (or the patient’s 
LAR) are required to give informed consent before participation in the study. 
 
16.4.6. Financing and Insurance 
Before the study commences, the sponsor (or its designee) and the investigator (or the institution, 
as applicable) will agree on costs necessary to perform the study. This agreement will be 
documented in a financial agreement that will be signed by the investigator (or the institution 
signatory) and the sponsor (or its designee). 
 
The investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice. The sponsor will provide no-exclusion insurance coverage for the clinical 
study as required by national regulations. 
 
16.4.7. Publication Policy/Disclosure of Data 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters) generated by the investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will be 
agreed between the institution and the sponsor or their designee. With respect to such rights, the 
sponsor or its designee will solely own all rights and interests in any materials, data, and 
intellectual property rights developed by investigators and others performing the clinical study 
described in this protocol, subject to the terms of any such agreement. In order to facilitate such 
ownership, investigators will be required to assign all such inventions either to their institution or 
directly to the sponsor or its designee, as will be set forth in the clinical study agreement. 
 
 
 
 

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17. References 
 
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18. Appendixes (Scales) 
 
18.1 
Anxiety – Short Form 8a (PROMIS) 
18.2 
Body Mass Index (BMI) 
18.3 
Daily Sleep Interference Scale (DSIS) 
18.4 
Fatigue – Short Form 8a (PROMIS) 
18.5 
Generalized Anxiety Disorder (GAD–7)  
18.6 
General Life Satisfaction – Short Form 5a (PROMIS) 
18.7 
11-point Numerical Pain Rating Scale (NPRS): 24-hour recall  
18.8 
Pain Catastrophizing Scale (PCS) 
18.9 
Pain Intensity Numerical Rating Scale (PI-NRS): 7-day recall  
18.10 
Pain Interference – Short Form 8a (PROMIS) 
18.11 
Patient Global Impression of Change (PGIC) 
18.12 
Patients Health Questionnaire (PHQ–9)  
18.13 
Sleep Disturbance – Short Form 8a (PROMIS) 
 
 
 
 

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