A Randomized Controlled Trial of Topical Cannabidiol for the Treatment of Thumb Basal Joint Arthritis
Phase: PHASE2
Conditions: CBD, Hand Osteoarthritis
Sponsor: University of Virginia

Title: A Randomized Controlled Trial of Topical Cannabidiol for the
Treatment of Thumb Basal Joint Arthritis
NCT Number: NCT04611347
Document Date: 27-April-2020

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1 
 
A Randomized Controlled Trial of Topical Cannabidiol for the 
Treatment of Thumb Basal Joint Arthritis 
 
 
Protocol Number: 03 
 
National Clinical Trial (NCT) Identified Number:  TBD 
IND number: 146012 
Principal Investigator: Brent DeGeorge MD, PhD 
IND Sponsor: Brent DeGeorge MD, PhD 
Version Date:  27 APRIL 2020 
 
 
 
Confidentiality Statement 
The information contained in this document is the property of the University of Virginia School of 
Medicine.  Distributing, copying, or disclosing information contained in this document requires prior 
authorization from the Primary Investigator, except that this document may be disclosed to the 
appropriate institutional review boards, and representatives of the U.S. Food and Drug 
Administration or other regulatory agencies as required by law.   

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Key Roles and Study Governance 
 
Sponsor/ PI 
Brent DeGeorge MD, PhD 
Department of Plastic Surgery 
University of Virginia 
415 Ray C. Hunt Dr. 
Charlottesville, VA 22903 
434-760-3297 
bd6u@virginia.edu 
 
 
Clinical Research 
Coordinator 
 
John Heineman MD, MPH 
Department of Plastic Surgery 
University of Virginia 
jth4y@virginia.edu 
 
 
 
 

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STATEMENT OF COMPLIANCE ................................................................................... 5 
ABBREVIATIONS .......................................................................................................... 6 
1 
PROTOCOL SUMMARY ......................................................................................... 7 
1.1 
SYNOPSIS .......................................................................................................... 7 
1.2 
SCHEMA ............................................................................................................ 9 
2 
INTRODUCTION ....................................................................................................10 
2.1 
STUDY RATIONALE ............................................................................................10 
2.2 
BACKGROUND ...................................................................................................10 
3 
RISK/BENEFIT ASSESSMENT .............................................................................11 
4 
OBJECTIVES AND ENDPOINTS ..........................................................................11 
5 
STUDY DESIGN ....................................................................................................12 
5.1 
OVERALL DESIGN ..............................................................................................12 
5.2 
JUSTIFICATION FOR DOSE ..................................................................................13 
5.3 
END OF STUDY DEFINITION ................................................................................13 
6 
STUDY POPULATION ...........................................................................................13 
6.1 
INCLUSION CRITERIA .........................................................................................13 
6.2 
EXCLUSION CRITERIA ........................................................................................14 
6.3 
SCREEN FAILURES ............................................................................................15 
6.4 
LIFESTYLE CONSIDERATIONS .............................................................................15 
7 
STUDY INTERVENTION ........................................................................................15 
7.1 
DESCRIPTION OF STUDY INTERVENTION(S) .........................................................15 
7.2 
DOSING AND ADMINISTRATION ...........................................................................16 
7.3 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ........................................16 
7.4 
STUDY INTERVENTION COMPLIANCE ...................................................................17 
7.5 
REGISTRATION, RANDOMIZATION AND BLINDING..................................................17 
7.6 
CONCOMITANT THERAPY ...................................................................................18 
8 
STUDY CLOSURE, STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL ............................................18 
8.1 
STUDY DISCONTINUATION AND CLOSURE ...........................................................18 
8.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ...................................................19 
8.3 
PROCEDURES FOR DISCONTINUATION OF STUDY INTERVENTION ..........................19 
8.4 
LOST TO FOLLOW-UP ........................................................................................19 
9 
STUDY ASSESSMENTS AND PROCEDURES .....................................................20 
9.1 
CLINICAL ASSESSMENTS ...................................................................................20 
9.2 
SAFETY ASSESSMENTS .....................................................................................20 
10 
DATA AND SAFETY MONITORING PLAN ........................................................21 
10.1 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ............................................21 
10.2 
UNANTICIPATED PROBLEMS ...............................................................................25 
11 
STATISTICAL CONSIDERATIONS ...................................................................26 
11.1 
STATISTICAL HYPOTHESES ................................................................................26 
11.2 
SAMPLE SIZE DETERMINATION ...........................................................................26 

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12 
REGULATORY AND OPERATIONAL CONSIDERATIONS ..............................26 
12.1 
REGULATORY AND ETHICAL CONSIDERATIONS ....................................................26 
12.2 
DATA HANDLING AND RECORD KEEPING .............................................................28 
13 
REFERENCES ...................................................................................................30 
14 
APPENDICES ....................................................................................................31 
14.1 
SCHEDULE OF ACTIVITIES (SOA) ........................................................................31 
14.2 
PROTOCOL AMENDMENT HISTORY .....................................................................33 
14.3 
DAILY SIN MONITORING DIARY ...........................................................................35 
14.4 
LIST OF ATTACHMENTS ......................................................................................36 
 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable United States (US) 
Code of Federal Regulations (CFR). The Principal Investigator will assure that no 
deviation from, or changes to the protocol will take place without documented approval 
from the Institutional Review Board (IRB), except where necessary to eliminate an 
immediate hazard(s) to the trial participants. All personnel involved in the conduct of this 
study have completed Human Subjects Protection training. 
The protocol, informed consent form(s), recruitment materials, and all participant 
materials will be submitted to the IRB for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  All 
changes to the consent form will be IRB approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form. 
 
 
 
 
Sponsor-Investigator 
 
______________________  
_______________________  
_________ 
Name (print)  
 
 
Signature 
 
 
 
Date 

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ABBREVIATIONS 
 
 
 
 
AE 
Adverse Event 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CBD 
Cannabidiol 
CFR 
Code of Federal Regulations 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HIPAA 
Health Insurance Portability and Accountability Act  
HRQoL 
Health Related Quality of Life 
HSR 
Health Science Research 
ICH 
International Conference on Harmonisation  
IND 
Investigational New Drug Application 
IP 
Interphalangeal 
IRB 
Institutional Review Board 
MP 
Metacarpal phalangeal 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NRS 
Numeric Rating Scale 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SOA 
Schedule of Activities 
SOC 
Standard of Care 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
UVA 
University of Virginia 
VPR 
Vice President for Research 

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1 
 
PROTOCOL SUMMARY 
1.1 
Synopsis  
Title: 
A Randomized Controlled Trial of Topical Cannabidiol for the Treatment 
of Thumb Basal Joint Arthritis. 
Study 
Description:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Objectives & 
Endpoints: 
 
To investigate the therapeutic potential of cannabidiol (CBD) as a 
topical treatment for thumb basal joint arthritis.  Rationale: CBD is 
commonly being used as an over-the-counter treatment for arthritis-
related pain, however no clinical trial has been performed to establish 
efficacy.  Hypothesis: CBD is more effective than placebo for relieving 
pain and improving patient-reported outcomes for thumb basal joint 
arthritis.   
Study Design: The study design with be a double-blind, randomized 
controlled trial with crossover. Treatment will be blinded to the subjects 
and investigators. Patients will be randomly assigned 2 weeks of the 
CBD or control and then crossover to the other condition for 2 additional 
weeks. Patients will apply a novel cream containing CBD at the thumb 
base joint twice daily for 1 hour. Subjects will be advised to observe for 
physiologic changes, skin changes, or other adverse effects.  
 
 
Objectives 
Endpoints 
Primary 
 
To determine the therapeutic 
potential of CDB as a topical 
treatment for thumb basal 
joint arthritis. 
Hand Functional Assessment:  
Change from baseline hand 
functional assessment including 
grip, appositional, and oppositional 
pinch strength (kg); Kapandji score; 
and metacarpal phalangeal (MP) 
and interphalangeal (IP) range of 
motion. 
Patient Reported Outcome 
Measures: Change from baseline in 
the PROMIS-29 (Patient-Reported 
Outcomes Measurement Information 
System) and PROMIS upper 
extremity tests. The PROMIS-29 is a 
free publicly available generic health 
related quality of life (HRQoL) 
measure consisting of indices of 
pain, pain interference, depression, 
anxiety, global function, and social 
interactions. The PROMIS upper 
extremity test utilizes item-response 
theory and Computer Adaptive Test 
to efficiently and precisely report 
patient symptoms and perceived 
function.  
 
Secondary 
 

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To determine the safety of 
treatment CBD. 
Safety will be determined by 
evaluating: 
• 
The frequency and severity 
of adverse events from the 
beginning of treatment 
through the end of study 
participation. 
• 
Changes in skin appearance 
from baseline using 
standardized skin 
assessment tool.  (patient 
will be removed from study 
with a score >/= 2) 
• 
Clinically significant change 
in CBC (baseline and follow-
up) 
• 
Clinically significant change 
in basic metabolic panel 
(i.e., BUN, creatinine, CO2, 
Cl, K, Na, and glucose) 
(baseline and weekly follow-
up) 
• 
Clinically significant change 
in hepatic function testing 
(i.e., serum transaminases 
[ALT/AST], total bilirubin, 
and alkaline phosphatase) 
(baseline and weekly follow-
up) 
• 
Clinically significant change 
in vital sign assessments 
(i.e., heart rate and blood 
pressure) (baseline and 
weekly follow-up) 
• 
Suicidal behavior and 
thoughts as a specific 
question using the 
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
(baseline and weekly follow-
up) 
 
 
 
 
 
Study 
Population: 
40 subjects with presenting with thumb basal joint arthritis over the age 
of 18 will be recruited from the UVA Hand Center. 
 
 
Description of 
Sites/Facilities 
This will be a single-site study conducted at the UVA Hand Center at the 
University of Virginia. 

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Enrolling 
Participants: 
Description of 
Study 
Intervention: 
The study design will be a double-blind randomized control trial with 
crossover. Treatment will be blinded to the subjects and investigators. 
Patients will be randomly assigned two (2) weeks of the case (CBD) or 
control cream and then crossover to the other cream for two (2) 
additional weeks. Patients will apply the topical cream at their thumb 
basal joint twice daily for 1 hour. The subjects will be advised to observe 
for physiologic changes, skin changes, or other adverse effects. If mild 
to serious adverse events are noticed, the creams will be removed 
immediately and appropriate care and observation will be taken. Each 
condition will last for 2 weeks and then subjects will be contacted by the 
study coordinator to facilitate crossover into the other condition. To 
capture any delayed-onset adverse events, including those related to 
skin changes that might develop after the drug is discontinued, subjects 
will attend a follow-up visit seven (7) days following the last dose of 
investigational cream. 
 
Study 
Duration: 
This study will last one year from the beginning of subject recruitment to 
data analysis. 
Participant 
Duration: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects will be enrolled in this study for approximately six (6) weeks 
from Screening until the final Study Visit.  
1.2 
Schema 

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2  
INTRODUCTION 
2.1 
Study Rationale  
Arthritis of the thumb basal joint is common, leading to debilitating pain, weakness, and 
instability that severely limits function (1).  Cannabidiol (CBD) is a non-psychoactive 
hemp derivative with demonstrated efficacy for reducing cancer-related pain; however, 
its role in the treatment of arthritis-related pain has yet to be established.   
2.2 
Background  
Numerous studies have shown the safety and efficacy of topical CBD for the treatment 
of osteoarthritis in dogs (2) and rats (3). Topical administration has been shown to have 
increased regional bioavailability and attenuates inflammation and pain without 
significant side-effects. The dose of maximum absorption and efficacy seen in rats was 
shown to be 6.2 mg/day (3). To date, no studies have been performed to evaluate the 
safety and efficacy of topical CBD for the treatment of basal thumb arthritis in human 
subjects.  

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Nitecka-Buchta et al. performed a double-blind randomized controlled trial of topical 
CBD for 60 total patients with myofascial pain. Topical application of 67 mg CBD – 
including other minor cannabinoids – was applied to masseter muscles twice daily for 14 
days in the case group.  Visual Analog Scores (VAS) were reduced from 5.6 on Day 0 to 
1.7 on Day 14 (70.2% reduction) in the case group, versus 5.1 on Day 0 and 4.6 on Day 
14 (9.8% reduction) in the control group (p = 0.00). (4)   
 Xu et al. performed a randomized controlled trial with cross-over for topical CBD treatment 
of 29 patients with symptomatic lower extremity neuropathy. Topical application of 250 mg 
of pure CBD (case arm) was applied up to four (4) times daily for four (4) weeks, and then 
patients switched to emu oil (control arm) with the same application for 4 weeks followed 
by cross-over.  They showed a statistically significant reduction in Neuropathic Pain Scale 
scores for intense (5.11 to 4.02) (p=0.009) and sharp (4.01 to 3.09) (p<0.001) pain 
between case and control arms. (5)   
 No side effects or adverse events were noted in either clinical trial. 
We have designed a randomized, controlled crossover design clinical trial to assess the 
safety and efficacy of topical CBD versus placebo for the treatment of thumb basal joint 
arthritis. 
3 RISK/BENEFIT ASSESSMENT   
 
 Known Potential Risks  
No major side effects were noted from previous topical studies. Minor side effects from 
topical and oral CBD studies include nausea, diarrhea, fatigue, change in appetite, and 
weight gain/loss (3). Exogenous CBD may affect the metabolism of Coumadin and other 
drugs based on the P450 metabolism. Another theoretical risk is contact dermatitis. 
 Assessment of Potential Risks and Benefits  
 
 A potential benefit of this treatment is the potential pain relief and gain of hand function 
if the CBD is effective at improving symptoms.  
 
In addition – if the study shows that the administration of CBD cream will alleviate 
arthritic symptoms, this would be a cheap and easy treatment that could be used for 
many patients by delaying or potentially avoiding surgical intervention and improving 
their quality of life. 
 
There has yet to be a randomized controlled trial demonstrating benefit of topical CBD 
products in this patients with osteoarthritis. The risks involved as detailed above are 
mitigated by safety monitoring and are outweighed by the ability to add to the current 
research in Cannabidiol products, which are currently understudied. 
 
 
4 OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
To determine therapeutic 
potential of CDB as a topical 
Hand Functional Assessment:  Change from baseline in 
hand functional assessment including grip, appositional, 

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treatment for thumb basal 
joint arthritis. 
and oppositional pinch strength (kg); Kapandji score; and 
MP and IP range of motion. 
 
Patient Reported Outcome Measures: Change from 
baseline in the PROMIS-29 (Patient-Reported Outcomes 
Measurement Information System) and PROMIS upper 
extremity tests. The PROMIS-29 is a free publicly 
available generic health related quality of life (HRQoL) 
measure consisting of indices of pain, pain interference, 
depression, anxiety, global function, and social 
interactions. The PROMIS upper extremity test utilizes 
item-response theory and Computer Adaptive Test to 
efficiently and precisely report patient symptoms and 
perceived function.  
 
Secondary 
 
To determine the safety of 
treatment CBD. 
Safety will be determined by evaluating: 
• 
The frequency and severity of adverse events 
from the beginning of treatment through the end of 
study participation. 
• 
Changes in skin appearance from baseline using 
standardized skin assessment tool  (patient will be 
removed from study with a score >/= 2) 
• 
Clinically significant change in CBC (baseline and 
weekly follow-up) 
• 
Clinically significant change in basic metabolic 
panel (i.e., BUN, creatinine, CO2, Cl, K, Na, and 
glucose) (baseline and weekly follow-up) 
• 
Clinically significant change in hepatic function 
testing (i.e., serum transaminases [ALT/AST], total 
bilirubin, and alkaline phosphatase) (baseline and 
weekly follow-up) 
• 
Clinically significant change in vital sign 
assessments (i.e., heart rate and blood pressure)  
• 
Suicidal behavior and thoughts as a specific 
       question using the Columbia-Suicide Severity  
       Rating Scale (C-SSRS) at baseline and follow-up. 
 
 
 
 
 
 
 
5 STUDY DESIGN  
 
5.1 
Overall Design 
 
The study design will be a double-blind randomized controlled trial with crossover. 
Treatment will be blinded to the subjects and investigators. Patients will be randomly 

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assigned two (2) weeks of the case or control topical cream and then crossover to the 
other cream for two (2) more weeks. Patients will apply the cream at their thumb basal 
joint twice daily for one (1) hour. The subjects will be advised to observe for physiologic 
changes, skin changes, or other adverse effects. If mild to severe drug-related adverse 
events are noticed, the creams will be removed immediately and appropriate care and 
observation will be taken. Each condition will last for two (2) weeks and then subjects 
will be contacted by the study coordinator to facilitate crossover into the other condition.  
This study will last one year from the beginning of subject recruitment to data analysis. 
Subjects will be enrolled in this study for approximately six (6) weeks from Screening 
until the final Study Visit.  
 
5.2 
Justification for Dose 
Nitecka-Buchta et al. performed a double-blind randomized controlled trial of topical 
CBD for 60 total patients with myofascial pain. Topical application of 67 mg CBD – 
including other minor cannabinoids – was applied to masseter muscles twice daily for 14 
days in the case group.  Visual Analog Scores (VAS) were reduced from 5.6 on Day 0 to 
1.7 on Day 14 (70.2% reduction) in the case group, versus 5.1 on Day 0 and 4.6 on Day 
14 (9.8% reduction) in the control group (p = 0.00). (4)   
 Xu et al. performed a randomized controlled trial with cross-over for topical CBD treatment 
of 29 patients with symptomatic lower extremity neuropathy. Topical application of 250 mg 
of pure CBD (case arm) was applied up to four (4) times daily for four (4) weeks, and then 
patients switched to emu oil (control arm) with the same application for 4 weeks followed 
by cross-over.  They showed a statistically significant reduction in Neuropathic Pain Scale 
scores for intense (5.11 to 4.02) (p=0.009) and sharp (4.01 to 3.09) (p<0.001) pain 
between case and control arms. (5)   
 No side effects or adverse events were noted in either clinical trial. 
 
5.3 
End of Study Definition 
Primary completion date is the date that the final participant was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure 
with different completion dates, this term refers to the date on which data collection is 
completed for all of the primary outcomes defined as the final date for the collection of 
data for the primary endpoint. 
 
Study completion date is the date the final participant was examined or received an 
intervention for purposes of final collection of data for the primary and secondary 
outcome measures and adverse events (for example, last participant’s last visit), 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. 
 
6 STUDY POPULATION 
 
6.1 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 

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1. Provision of signed and dated informed consent form. 
2. Stated willingness to comply with all study procedures and availability for the 
duration of the study.  
3. Male or female, aged 18 years or older. 
4. Females of childbearing potential must have a negative urine and blood 
pregnancy test at Screening and a negative urine pregnancy test before study 
drug is administered. Females must abstain from sex or use a highly effective 
method of contraception during the period from Screening to administration of 
study drug and for 30 days after the last dose of study medication. Standard 
acceptable methods include abstinence or the use of a highly effective method of 
contraception, including; hormonal contraception, diaphragm, cervical cap, 
vaginal sponge, condom with spermicide, vasectomy, intrauterine device. If 
females are of non-child bearing potential, they must be post-menopausal 
defined as: age > 55 with no menses within the past 12 months, or history of 
hysterectomy, or history of bilateral oophorectomy, or bilateral tubal ligation.  
5. Males must consent to use a medically acceptable method of contraception 
throughout the entire study period and for 90 days after their last study drug 
application. They must agree to not donate sperm for 90 days after their last 
study drug application.  
6. Presence of radiographically confirmed diagnosis of thumb basal joint arthritis. 
 
 
6.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in 
this study: 
1. Subject does not speak English. 
2. Subject is blind. 
3. Severe cardiac, pulmonary, liver and /or renal disease. 
4. Coumadin use at time of screening. 
5. History of mental illness. 
6. Subjects who are incarcerated. 
7. History of drug or substance abuse. 
8. Pre-existing CBD or hemp based product usage. 
9. Subject has had a corticosteroid injection ≤ 3 months prior. 
10. Subject has had prior surgery for osteoarthritis treatment. 
11. Females who are pregnant, nursing or planning a pregnancy; females of 
childbearing potential who are unwilling or unable to use an acceptable method 
of contraception as outlined in this protocol from Screening to the first dose of 
study medication and for 30 days after the last dose of study medication. 
Standard acceptable methods include abstinence or the use of a highly effective 
method of contraception, including; hormonal contraception, diaphragm, cervical 
cap, vaginal sponge, condom with spermicide, vasectomy, intrauterine device.  
12. Any skin disease or condition, including eczema, psoriasis, melanoma, acne or 
contact dermatitis, scarring, imperfections, lesions, tattoos or discoloration that 
may affect treatment application, application site assessments, or affect 
absorption of the study drug.  
13. Subjects with ALT/AST >3 times the upper limit of normal at screening.  
14. Subjects with history of or active depression or suicide ideation based on 
Columbia-Suicide Severity Rating Scale (C-SSRS).  

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15. Subjects taking prescription or non-prescription medication which are substrates 
of CYP3A4 (Itraconazole, Ketoconazole, Azamulin, Troleandomycin, Verapamil, 
John’s wart, Phenobarbital), CYP2C19 (Nootkatone, Ticlopidine, Rifampin, 
Omeprazole), CYP2C8 (Montelukast, Quercetin, Phenelzine, Rifampin, 
Clopidogrel) , CYP2C9 (Sulfaphenazole, Tienilic acid, Carbamazepine, 
Apalutamide, Fluconazole, Celecoxib), CYP1A2 (alpha-Naphthoflavone, 
Furafylline, Phenytoin, Rifampin, Ritonavir, smoking, Teriflunomide, 
Ciproflaoxacin, oral contraceptives, Alloprinol) and CYP2B6 (Sertraline, 
Phencyclidine, Thiotepa, Ticlopidine, Carbamazepine, Efavirenez, Rifampin, 
Bupropion) within 14 days of the study procedure.  
 
 
6.3 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently randomly assigned to the study intervention or entered in the 
study. A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure participants to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements (for NIH studies) and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any serious adverse event (SAE). 
6.4 
Lifestyle Considerations 
Females must abstain from sex or use a highly effective method of contraception during 
the period from Screening to administration of study drug and for 30 days after the last 
dose of study medication. Standard acceptable methods include abstinence or the use 
of a highly effective method of contraception, including; hormonal contraception, 
diaphragm, cervical cap, vaginal sponge, condom with spermicide, vasectomy, 
intrauterine device. If females are of non-child bearing potential, they must be post-
menopausal defined as: age > 55 with no menses within the past 12 months, or history 
of hysterectomy, or history of bilateral oophorectomy, or bilateral tubal ligation.  
 
Males must consent to use a medically acceptable method of contraception throughout 
the entire study period and for 90 days after their last study drug application. They must 
agree to not donate sperm for 90 days after their last study drug application.  
 
Subjects will be advised not to drive or operate machinery until they have gained 
sufficient experience on study drug.  
 
 
 
7 STUDY INTERVENTION 
 
7.1 
Description of Study Intervention(s)  
 

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Product with 
description, all 
names, dosage 
form 
Potency 
Investigational 
or Standard of 
Care (SOC) 
Packaging/Appearance 
Manufacturer 
Storage 
Conditions 
Case – 99.99% 
pure cannabidiol 
(CBD) with 
100% Pure 
USDA Organic 
Shea Butter 
6.2 
mg/mL 
Investigational  
Placed within 10mL 
syringe labeled with 
approved institutional 
labeling for research 
use only.  
Eco-X, Inc, 
Grand 
Junction, CO 
(CBD) 
 
Mary Taylor 
Naturals, LLC, 
Fort Myers, FL 
(Shea Butter) 
Room 
Temperature 
Control – 100% 
Pure USDA 
Organic Shea 
Butter 
N/A 
Investigational 
Placed within 10mL 
syringe labeled with 
approved institutional 
labeling for research 
use only. 
Mary Taylor 
Naturals, LLC, 
Fort Myers, FL 
Room 
Temperature 
 
7.2 
Dosing and Administration 
Subjects will be randomized to receive a total of 28mL of either 6.2 mg/mL of CBD with 
Shae butter or Shae butter alone placed within three (3) 10mL syringes. Subjects will be 
advised to apply 1 mL of the cream overlying their thumb basal joint dorsally twice daily, 
approximately every 12 hours.  In the CBD condition, the cream will be formulated to 
deliver approximately 12.4 mg of purified CBD per day, whereas in the control condition 
the Shea butter will be utilized alone. The purified CBD is colorless and odorless to 
facilitate blinding. 
The CBD with Shae Butter or Shae butter alone will be provided to subjects in 10 mL 
syringes without a needle, with a rubber topper. Subjects will be instructed to store the 
cream at room temperature. Subjects may dispense the cream from the syringe into a 
gloved hand. Gloves will be provided to the subject along with the investigational 
product. The cream will need to be applied to the base of the thumb until completely 
absorbed. Subjects should avoid water to the area for at least one hour. 
 
7.3 
Preparation/Handling/Storage/Accountability 
 
 Acquisition and Accountability 
The investigational drugs (CBD with Shea butter and Shea butter control) will be stored 
in a secure area within the UVA Hand Center. Study drug accountability will be 
maintained by the research team. The investigational drugs will be distributed to the 
subjects by the study team and are returned to the study team at the next visit. Any 
remaining investigational drugs will be destroyed in accord with institutional policies. 
 
 Formulation, Appearance, Packaging, and Labeling 
 

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Hemp Isolate (CBD) will be used from Eco-X, Inc. (2536 Rimrock Avenue, Suite 400 Box 
324, Grand Junction, CO 81505). The product is rated for personal care products 
formulations and the product was tested by Desert Valley Testing.  
 
In the Michael Timko, PhD Laboratory at the University of Virginia, the CBD will be 
mixed to the final desired concentration with USDA Organic Shae butter (Mary Taylor 
Naturals, LLC, 2126 Alicia Street, Fort Myers, FL 33901). The control group will receive 
USDA Organic Shae butter only.  
 
Instructions on how to apply and remove the creams will be provided and explained to 
subjects. Investigational product will be labeled appropriately for the product to be 
administered for home use. Minimum labeling requirements include space for subject 
identification (name or other ID), product name/strength/beyond use date, basic 
instructions for use, emergency contact information and protocol number. The subjects 
will be instructed to store the cream at room temperature, and to keep the product out of 
reach of children. 
 
Notes: This study is using a plant derived cannabinoid (phytocannabinoid) preparations 
containing CBD. Phytocannabinoid preparations unlike chemically-synthesized 
cannabinoids, also contain low levels of non-cannabinoid constituents of the Cannabis 
plant that belong to miscellaneous groups of natural products (primarily terpenoids and 
flavonoids). The low levels of these adjuvants in the purified material may contribute to 
the analgesic, as well as the anti-inflammatory effects of Cannabis extracts, but for all 
intents and purpose are below levels that would be considered therapeutically relevant. 
Plant derived CBD is identical chemically to endocannabinoids (present endogenously in 
human or animal tissues) and synthetic CBD. The majority of all CBD containing 
products on the commercial market are prepared with phytocannabinoid preparations of 
varied purity.  
 
 Product Storage and Stability 
The case and control creams are stored by the research team at the UVA Hand Center 
at room temperature and protected from light. The creams will be used in the study 
within six (6) months from formulation. After formulation and packaging in the Timko 
Laboratory, no further preparation such as thawing, diluting, mixing, and/or reconstitution 
will be required.  
7.4 
Study Intervention Compliance 
Subjects will be instructed to return all tubes containing the control or CBD Cream to the 
study team at each visit.  
 
7.5 
Registration, Randomization and Blinding 
Registration will occur following verification of eligibility by the treating physician. 
Participants who are consented and accrued to the study should be registered in 
OnCore in accordance with the Clinical Trial Management System Policy via the UVa 
OnCore Resources link in Oncore. General guidelines are available in the OnCore User 
Manual and Data Entry Guide.  

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Treatment allocation will be discussed with participants during the process of informed 
consent, and informed consent must be documented prior to randomization.  The study 
participants will be randomized to either the treatment group or placebo group (1:1 ratio) 
once consent is signed and inclusion/exclusion criteria are satisfied.    All investigators 
and subjects will be blinded. The study coordinator will have the master randomization 
list.  
 Emergency Unblinding Procedures 
Randomization codes and corresponding treatment assignment will be made available to 
the Primary Investigator (PI) for emergency use when applicable. If it is not reasonable 
to inform the PI in advance of unblinding, the study staff must promptly document in the 
subject’s source record and should subsequently contact the PI to explain any 
premature unblinding of treatment assignment [such as accidental unblinding or 
unblinding due to a serious adverse event (SAE)]. The PI will document within study 
correspondence the rationale, circumstances, and the person or persons being informed 
about the unblinding. 
 
7.6 
Concomitant Therapy 
For this protocol, a prescription medication is defined as a medication that can be 
prescribed only by a properly authorized/licensed clinician. Medications to be reported in 
the Case Report Form (CRF) are concomitant prescription medications, over-the-counter 
medications and supplements.  
8 STUDY CLOSURE, STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL 
8.1 
Study Discontinuation and Closure 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the investigator, 
the Investigational New Drug (IND) sponsor and regulatory authorities.  If the study is 
prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform 
the Institutional Review Board (IRB) and will provide the reason(s) for the termination or 
suspension.  Study participants will be contacted, as applicable, and be informed of 
changes to study visit schedule. 
  
Circumstances that would warrant termination or suspension include, but are not limited 
to 
 
• 
Determination of unexpected, significant, or unacceptable risk to participants  
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
• 
Change in funding status 
 

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Study may resume once concerns about safety, protocol compliance, and data quality 
are addressed by the IRB, and Food and Drug Administration (FDA). 
 
Participants receiving study treatment at the time of study discontinuation should 
complete procedures described in section 8.3. 
 
8.2 
Participant Discontinuation/Withdrawal  
Participants are free to withdraw from participation in the study at any time upon request. 
A participant’s study treatment would be discontinued for the following reasons: 
 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical 
condition or situation occurs such that continued participation in the study would 
not be in the best interest of the participant  
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation 
• 
Participant decision to withdraw from study treatment and/or the study. 
The reason for participant discontinuation or withdrawal from study treatment will be 
recorded. Participants who sign the informed consent form and are randomized but do 
not receive the study intervention may be replaced.  Participants who sign the informed 
consent form, and are randomized and receive the study intervention, and subsequently 
withdraw, or are withdrawn or discontinued from the study, will not be replaced. 
Participants that withdraw from the study (not only from study treatment, but all study 
follow-up) will not be contacted for any further study visits. 
8.3 
Procedures for Discontinuation of Study Intervention 
Discontinuation from study treatment means that the subject is withdrawn from the 
study. In the event of study discontinuation, the participant will not be contacted for any 
further study visits. 
8.4 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for one 
scheduled visit and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit 
within 24 hours and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain if the participant wishes to and/or should 
continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant. 
• 
These contact attempts should be documented in the study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 

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9 STUDY ASSESSMENTS AND PROCEDURES 
9.1 
Clinical Assessments  
Hand Functional Assessment:  Hand functional assessment will include grip, 
appositional, and oppositional pinch strength (kg); Kapandji score; and MP and IP range 
of motion. Assessments will be performed at Baseline and study Days 7, 14, 21, and 28. 
Patient Reported Outcome Measures: The PROMIS-29 and PROMIS upper extremity 
tests will be collected. The PROMIS-29 is a free publicly available generic HRQoL 
measure consisting of indices of pain, pain interference, depression, anxiety, global 
function, and social interactions (Attachment 1, Appendix 14.4)  Subjects will complete 
the measure at Baseline and study Days 7, 14, 21, and 28. The PROMIS upper 
extremity test utilizes item-response theory and Computer Adaptive Test to efficiently 
and precisely report patient symptoms and perceived function. Subjects will complete 
the measure in clinic using an iPad. The  PROMIS upper extremity assessment is 
provided in Attachment 2 (Appendix 14.4). Subjects will complete the PROMIS 
assessment at Baseline and study Days 7, 14, 21, and 28.  
 
9.2 
Safety Assessments 
Medical History: Relevant medical history, including history of mental illness, drug or 
substance abuse, history of hemp-based product usage and other pertinent history will be 
recorded in the case report form. 
 
Laboratory Testing: At baseline and Study Day 35, blood draws will be performed on 
all subjects at the UVA Medical Laboratory. The following tests will be ordered and 
monitored for clinical abnormalities: 
• 
CBC  
• 
Basic metabolic panel (i.e., BUN, creatinine, CO2, Cl, K, Na, and glucose)  
• 
Hepatic function testing (i.e., serum transaminases [ALT/AST], total bilirubin, 
and alkaline phosphatase)  
 
• 
Pregnancy Testing (if applicable) (Screening) 
 
• 
Urine Pregnancy Test (if applicable) (Screening and Day 0 before dosing) 
Daily Skin Monitoring: Subjects will be asked to observe the testing site for physiologic 
changes, skin changes or other adverse events daily. Subjects will be provided with a 
daily diary to record and monitor any observed changes. The daily diary is provided in 
Appendix 14.3. They will be instructed to notify the investigator of any sudden changes 
in skin appearance or increase in their arthritic symptoms that are more than minimally 
tolerated.  
Physician Skin Monitoring: At baseline and at every subsequent visit, the investigator 
will assess the CBD cream site for adverse events. A score will be given corresponding to 
the assessment tool below: 

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• 
NOTE: Changes in skin appearance will be evaluated using the standardized 
skin assessment tool above.  A patient will be removed from study with a score 
>/= 2. 
 
Clinical Evaluations: Subjects will be monitored weekly for the following: 
• 
Vital sign assessments (i.e., heart rate and blood pressure)  
• 
Suicidal behavior and thoughts as a specific question using the Columbia-
Suicide Severity Rating Scale (C-SSRS). The full questionnaire is provided in 
Attachment 3 (Appendix 14.4).  
o Monitor for somnolence and sedation and advise patients not to drive or 
operate machinery until they have gained sufficient experience on study 
drug Subjects will be asked if they feel more, less, or no change in their 
level of fatigue during the time they were administering study drug. 
Adverse Event Monitoring: Information regarding occurrence of adverse events will be 
captured throughout the study. Duration (start and stop dates and times), severity/grade, 
outcome, treatment and relation to study intervention will be recorded. 
 
10 DATA AND SAFETY MONITORING PLAN  
10.1 Adverse Events and Serious Adverse Events 
 Definition of Adverse Events (AE) 
An adverse event will be considered any undesirable sign, symptom, medical, or 
psychological condition even if the event is not considered to be related to the 
investigational drug/intervention. Medical condition/diseases present before starting the 
investigational drug/intervention will be considered adverse events only if they worsen 
after starting study treatment/intervention.  An adverse event is also any undesirable and 
unintended effect of research occurring in human subjects as a result of the collection of 
identifiable private information under the research.  Adverse events also include any 
problems associated with the use of an investigational drug that adversely affects the 
rights, safety or welfare of subjects. 
 Definition of Serious Adverse Events (SAE) 

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An adverse event (AE) is considered a serious adverse reaction (SAE) if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes:  
• 
death,  
• 
a life-threatening adverse event,  
• 
inpatient hospitalization or prolongation of existing hospitalization,  
• 
a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or  
• 
a congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 Classification of an Adverse Event 
10.1.3.1 Severity of Event 
For AEs not included in the protocol defined grading system, the following guidelines will 
be used to describe severity.  
• 
Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually potentially 
life-threatening or incapacitating.  Of note, the term “severe” does not necessarily 
equate to “serious”. 
10.1.3.2 Relationship to Study Intervention 
All AEs must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories 
below. In a clinical trial, the study product must always be suspect.  
• 
Definitely Related – There is clear evidence to suggest a causal relationship, 
and other possible contributing factors can be ruled out. The clinical event, 
including an abnormal laboratory test result, occurs in a plausible time 
relationship to study intervention administration and cannot be explained by 
concurrent disease or other drugs or chemicals.  
 
• 
Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal 
laboratory test result, occurs within a reasonable time after administration of the 
study intervention, is unlikely to be attributed to concurrent disease or other 

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drugs or chemicals, and follows a clinically reasonable response on withdrawal 
(dechallenge).  
 
• 
Possibly Related – There is some evidence to suggest a causal relationship 
(e.g., the event occurred within a reasonable time after administration of the trial 
medication). However, other factors may have contributed to the event (e.g., the 
participant’s clinical condition, other concomitant events). Although an AE may 
rate only as “possibly related” soon after discovery, it can be flagged as requiring 
more information and later be upgraded to “probably related” or “definitely 
related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test 
result, whose temporal relationship to study intervention administration makes a 
causal relationship improbable (e.g., the event did not occur within a reasonable 
time after administration of the study intervention) and in which other drugs or 
chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
 
• 
Not Related – The AE is completely independent of study intervention 
administration, and/or evidence exists that the event is definitely related to 
another etiology. There must be an alternative, definitive etiology documented by 
the clinician. 
10.1.3.3 Expectedness 
The PI will be responsible for determining whether an AE is expected or unexpected.  An 
AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study intervention.  
 Time Period and Frequency for Event Assessment and Follow-Up 
 
The occurrence of an AE or SAE may come to the attention of study personnel during 
study visits and interviews of a study participant presenting for medical care. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate case report form (CRF). Information to be collected includes 
event description, time of onset, clinician’s assessment of severity, relationship to study 
product (assessed only by those with the training and authority to make a diagnosis), 
and time of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution. 
 
Any medical condition (including a laboratory abnormality) that is present at the time that 
the participant is screened will be considered as baseline and not reported as an AE. 
However, if the study participant’s condition deteriorates at any time during the study, it 
will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as 
intermittent require documentation of onset and duration of each episode. 

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 Adverse Event Reporting 
AEs must be recorded into the case report forms per the following guidelines (Table 1). 
Table 1 
Type of Event 
To whom will 
it be reported: 
Time Frame for 
Reporting 
How reported? 
Any internal event 
resulting in death that is 
deemed DEFINITELY 
related to (caused by) 
study participation 
An internal event is one that 
occurs in a subject enrolled 
in a UVa protocol 
IRB-HSR 
Within 24 hours 
IRB Online and phone call 
 
www.irb.virginia.edu/ 
 
Internal, Serious, 
Unexpected adverse event  
 
 
IRB-HSR 
Within 7 calendar 
days from the time 
the study team 
received 
knowledge of the 
event. 
 
Timeline includes 
submission of 
signed hardcopy 
of AE form. 
IRB Online 
 
www.irb.virginia.edu/ 
 
Unanticipated Problems 
that are not adverse events 
or protocol deviations  
This might include a Data 
Breach.   
IRB-HSR 
 
 
Within 7 calendar 
days from the time 
the study team 
received 
knowledge of the 
event.  
Unanticipated Problem 
report form.  
Unanticipated 
Problem Report Form 
 
 
Protocol 
Deviations/Noncompliance 
The IRB-HSR only requires 
that MAJOR deviations be 
reported, unless otherwise 
required by your sponsor, if 
applicable. 
 
  
IRB-HSR 
 
 
Within 7 calendar 
days from the time 
the study team 
received 
knowledge of the 
event.  
 
Protocol Deviation, 
Noncompliance and 
Protocol Exception 
Reporting Form 
Protocol Deviation 
Protocol Exception 
Reporting Form 
  
 
 
Data Breach  
The UVa 
Corporate 
Compliance 
and Privacy 
Office 
 
 
 
ITC:  if breach 
involves  
electronic data  
As soon as 
possible and no 
later than 24 
hours from the 
time the incident 
is identified. 
 
As soon as 
possible and no 
later than 24 
hours from the 
UVa Corporate 
Compliance and Privacy 
Office- Phone 924-9741 
 
 
 
 
ITC:  Information 
Security Incident 
Reporting procedure,  

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Police if breach 
includes items 
that are stolen: 
 
Stolen on UVA 
Grounds 
 
OR  
 
Stolen off UVa 
Grounds- 
contact police 
department of 
jurisdiction of 
last known 
location of PHI 
time the incident 
is identified. 
 
IMMEDIATELY.  
 
 
https://security.virginia.edu
/report-information-
security-incident 
 
 
 
 
 
 
 
 
UVa Police-Phone- (434) 
924-7166 
UVA PI HELD IND 
Life-threatening and/or 
fatal unexpected 
events related or 
possibly related to the 
use of the 
investigational agent. 
FDA 
Within 7 
calendar days 
of the study 
team learning 
of the event 
Form FDA 3500A (MedWatch) or 
narrative 
Serious, unexpected 
and related or possibly 
related adverse events 
FDA 
Within 15 
calendar days 
after the study 
team receives 
knowledge of 
the event 
Form FDA 3500A (MedWatch) or 
narrative 
All adverse events 
FDA 
Annually 
IND annual report 
 
 
10.2 Unanticipated Problems 
 Definition of Unanticipated Problems (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems 
(UPs) (may include a data breach) involving risks to participants or others to include, in 
general, any incident, experience, or outcome that meets all of the following criteria: 
 

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• 
Unexpected in terms of nature, severity, or frequency given the research 
procedures that are described in the protocol-related documents, such as the 
Institutional Review Board (IRB)-approved research protocol and informed 
consent document; and (b) the characteristics of the participant population being 
studied; 
• 
Related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
11 STATISTICAL CONSIDERATIONS  
 
11.1 Statistical Hypotheses 
Outcomes between the two groups will be compared and in a within-subject analysis will 
be performed given the crossover design.  A descriptive analysis of the variables will be 
performed by calculating mean and standard deviation (SD), as appropriate, and 
absolute and percentage frequency. Differences between pre- and post-treatment 
scores (delta scores) will be assessed with the Wilcoxon signed-rank test. Correlations 
between delta scores and the variables considered [age, gender, body mass index 
(BMI), radiographic features] will be evaluated with the Spearman, Mann-Whitney, and 
Kruskal-Wallis tests. The significance threshold will be set at 0.05. 
 
11.2 Sample Size Determination 
Based on a 95% confidence interval to show a 50% reduction effect (as shown in the 
literature) and receive 80% power with a population variance of 0.25, sample size 
analysis resulted in a sample size of at least 16.  The UVA Hand Center performed 421 
operative procedures in 2018 for the management of thumb basal joint arthritis among 
our 6 fellowship trained hand surgeons, and consequently has a volume sufficient to 
accrue 40 patients during the study period. 
 Randomization 
The study participants will be randomized to either the treatment group or placebo group 
(1:1 ratio) once consent is signed and inclusion/exclusion criteria are satisfied.  
Randomization will be not be stratified.  All investigators and subjects will be blinded.  
 
11.2.2 Safety Analyses 
 
All adverse events will be recorded and categorized according to severity, relationship to 
study treatment.  Any subject who receives the study drug will be considered Intent to 
Treat (ITT) for safety assessments. All AEs will be assessed for their relationship to the 
treatment.  
 
12 REGULATORY AND OPERATIONAL CONSIDERATIONS 
12.1 Regulatory and Ethical Considerations 

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 Informed Consent Document and Process 
 
Once a potential subject is identified, they will be interviewed in a quiet and private place 
and may have family or friends with them if they choose.  If there is concern that the 
potential subject may not be able to read the potential subject will be asked to read the 
first sentence of the consent form to determine if they are capable of reading. Depending 
on the response they will either be offered the opportunity to read the consent form or 
have the consent form read to them.  Once the consent has been read the person 
obtaining consent will summarize the consent form verbally, asking open ended 
questions to determine if the potential subject understands what is being covered in the 
consent form.   Questions might include:   
• 
Would you summarize for me what you believe will be done to you if you 
are in this study?  
• 
Would you benefit from this study? 
• 
What do you feel are the risks of being in this study? 
 
Potential subjects will be given an opportunity to ask questions.  Their level of 
understanding will dictate how much time will be spent covering each item.  Once all of 
their questions have been answered, if they decide to participate, they will be asked to 
sign the consent form.  The person obtaining consent will sign the form and subjects will 
be given a copy of the signed consent form. Study procedures will then begin.  The 
informed consent process for each individual subject will be documented in the subject’s 
medical record. 
 Confidentiality and Privacy  
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators and their staff. The study protocol, documentation, data, and all other 
information generated will be held in strict confidence. Consents will be maintained in a 
confidential manner in accordance with the code of federal regulations and HIPAA. No 
information concerning the study or the data will be released to any unauthorized third 
party without prior written approval.  
All research activities will be conducted in as private a setting as possible. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept 
in a secure location for as long a period as dictated by the reviewing IRB, and 
institutional policies. 
 Safety Oversight and Monitoring 
 
Any study under the purview of the University of Virginia HSR-IRB is subject to review. 
Studies are chosen for post-approval monitoring either a) at random or b) requested by a 
study team member or any member of the IRB-HSR.   
 
The purpose of post-approval monitoring audits is to ensure that documentation of 
clinical research studies is of the highest quality, verify protocol adherence, and ensure 
that all Federal and local rules concerning clinical research are being fulfilled.  Post-
approval monitoring is done by staff within the office of the Vice President for Research 

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(VPR) in accordance with their Standard Operating Procedures. The conduct of an on-
site review may include but is not limited to: 
• 
requests for progress reports from investigators, 
• 
examinations of research records, including signed informed consent documents, 
protocol modifications, and unexpected, serious, and/or related adverse 
experience reports, 
• 
contacts with research subjects, or 
• 
observation of the consent process and/or research procedures. Examples of 
when observation of the consent process could occur are: 
• 
Full board IRB determines during review of a project that a conflict of 
interest exists such that the informed consent process should be 
observed by a neutral party; 
• 
IRB is made aware of a complaint or concern with regard to the informed 
consent process; or 
• 
IRB determines as a result of the monitoring process that the consent 
process is insufficient and education/training is required for conduct of 
consent. 
 Quality Assurance and Quality Control 
 
Each clinical site will perform internal quality management of study conduct, data and 
biological specimen collection, documentation and completion according to institutional 
policies.  
 
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing and inspection 
by local and regulatory authorities. 
 
12.2 Data Handling and Record Keeping  
 Data Collection and Management Responsibilities  
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site investigator. The investigator is responsible for ensuring the 
accuracy, completeness, legibility, and timeliness of the data reported.  
 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.   
 
Hardcopies of the study records will be provided for use as source document worksheets 
for recording data for each participant enrolled in the study.  Data recorded in the case 
report form (CRF) derived from source documents should be consistent with the data 
recorded on the source documents.  
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into Microsoft Excel for data analysis. 
Clinical data will be entered directly from the source documents. 
 Study Records Retention  

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Record retention will be in accord with 21 CFR 312.62 and HIPAA regulations. 
An Environmental Assessment is not required because the action requested qualifies for 
a categorical exclusion per 21 CFR 25.31(e). To the applicant’s knowledge, no 
extraordinary circumstances exist per 21 CFR 25.15(d)  
 
 
 
 
 
 

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13 REFERENCES  
1. Wolf et al. Sick Leave After Surgery for Thumb Carpometacarpal Osteoarthritis: A 
Population-Based Study. Journal of Hand Surgery. 2018. 43(5):439-447.  
2. Gamble et al. Pharmacokinetics, safety, and clinical efficacy of cannabidiol treatment in 
osteoarthritic dogs. Frontiers in Veterinary Science. 2018. 5(165): 1-9. 
 3. Iffland and Grotenherhermen. An update on safety and side effects of cannabidiol: A 
review of clinical data and relevant animal studies. Cannabis Cannabdinoid Res. 2017. 
2(1): 139-154. 
4. Nitecka-Buchta A, Nowak-Wachol A, Wachol K, Walczynska-Dragon K, Olczyk P, 
Batoryna O, Kempa W, Baron S. Myorelaxant Effect of Transdermal Cannabidiol 
Application in Patients with TMD: A Randomized, Double-Blind Trial. J Clin Med, 2019 
Nov 6, 8(11).2)  
5. Xu DH, Cullen BD, Tang M, Fang Y. The Effectiveness of Topical Cannabidiol Oil in 
Symptomatic Relief of Peripheral Neuropathy of the Lower Extremities. Curr Pharm 
BIotechnol. 2019 Dec 1(3)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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14 APPENDICES 
14.1 Schedule of Activities (SoA) 
Visit 
Visit 1 
(Screening 
and 
Baseline) 
 
Visit 2 
(Baseline) 
Visit 3 
Visit 
4 
Visit 5 
Visit 
6 
Visit 7 
Study Day 
 
-71 
0 
7 (+/- 1) 
14 
(+/- 
1) 
21 (+/- 
1) 
28 
(+/- 1) 
35 (+/- 
1) 
Informed 
Consent 
 
 
X 
 
 
 
 
 
 
Review 
study 
eligibility 
X 
 
 
 
 
 
 
Blood Draw2 
X3 
 
 
 
 
 
X 
Urine 
Pregnancy 
Test (if 
applicable) 
X 
X 
 
 
 
 
 
Hand 
Functional 
Assessment 
 
X 
X 
X 
X 
X 
 
Patient 
Reported 
Outcome 
Measures 
 
X 
X 
X 
X 
X 
 
Physician 
Skin 
Monitoring 
 
X 
X 
X 
X 
X 
X 
Columbia-
Suicide 
Severity 
Rating 
Scale 
X 
X 
X 
X 
X 
X 
X 
 
 
1 Screening may take place within one week of baseline visit to allow for results of 
bloodwork and pregnancy testing. 
2 Blood pregnancy test to be ordered during screening visit only. 
3 Baseline blood testing (Hemoglobin and Platelet count, Creatinine, AST/ALT) will be 
obtained at the screening blood draw. 

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Monitor for 
somnolence 
and 
sedation  
 
 
X 
X 
X 
X 
X 
Study 
Medication 
Dispensed 
 
X 
 
X 
 
 
 
Diary 
dispensed 
 
 
X 
 
X 
 
 
 
Diary 
Review 
 
 
X 
X 
X 
X 
X 
Study 
Medication 
Collected 
 
 
X 
X 
X 
X 
 
Assessment 
of Adverse 
Events 
 
X 
X 
X 
X 
X 
X 
 
 
 

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14.2 Protocol Amendment History 
 
Version 
Date 
Description of Change  
Brief Rationale 
02 
11/23/19 
Addition of PI address and 
CRC contact information 
Protocol clarification 
02 
11/23/19 
Addition of relevant 
abbreviations 
Protocol clarification 
02 
11/23/19 
Clarification and addition of 
secondary safety endpoints 
FDA Clinical Hold 
response 
02 
11/23/19 
Addition of one-week follow-up 
visit 
FDA Clinical Hold 
response 
02 
11/23/19 
Corrected literature references 
Protocol clarification 
02 
11/23/19 
Duration of subject 
participation changed to up to 
seven (7) weeks 
FDA Clinical Hold 
response 
02 
11/23/19 
Clarified study schema 
FDA Clinical Hold 
response 
02 
11/23/19 
Added “There has yet to be a 
randomized controlled trial 
demonstrating benefit of 
topical CBD products in this 
patient population. The risks 
involved as detailed above are 
mitigated by safety monitoring 
and are outweighed by the 
ability to add to the current 
research in Cannabidiol 
products, which are currently 
understudied.” 
 
Added risk/benefit 
analysis. 
02 
11/23/19 
Added inclusion/exclusion 
criteria. 
FDA Clinical Hold 
response 
02 
11/23/19 
Clarified product packaging 
information. 
Protocol clarification 
02 
11/23/19 
Added Physician Skin 
Monitoring Scale 
FDA response 
02 
11/23/19 
Clarified clinical blood labs 
drawn 
FDA Clinical Hold 
Response 
02 
11/23/19 
Relevant changes made to 
Schedule of Activities 
FDA Clinical Hold 
Response 
03 
04/27/20 
Addition of relevant 
abbreviations 
Protocol clarification 
03 
04/27/20 
Dosage increase from once to 
BID 
Literature review 
03 
04/27/20 
Added change from baseline to 
endpoints 
Protocol clarification 
03 
04/27/20 
Added additional information 
and references to Background 
section 
Literature review 

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03 
04/27/20 
Removed “oil” throughout 
Protocol clarification 
03 
04/27/20 
Additional information provided 
in Section 5.2 Justification for 
Dose 
Information added to 
support dosage increase 
03 
04/27/20 
Added “Subject is blind” to 
Section 6.2 Exclusion Criteria 
Protocol clarification 
03 
04/27/20 
Added medication examples 
for Exclusion criteria #15. 
Protocol clarification 
03 
04/27/20 
Addition of Section 6.4 Lifestyle 
Considerations 
Protocol clarification 
03 
04/27/20 
Section 7.2 Dosing and 
Administration – changed 
dosing to BID. Investigational 
product is given in three 10mL 
syringes. 
Information changed to 
support dosage increase 
03 
04/27/20 
Provided list of attachments 
Protocol clarification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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14.3 Daily Sin Monitoring Diary 
 
 
 
 
 
 
Signature: 
__________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
Day X 
Time of onset 
Time of symptom 
improvement 
Time of symptom 
resolution 
Itching 
 
 
 
Redness 
 
 
 
Red 
bumps/hives 
 
 
 
Swelling 
 
 
 
Diarrhea 
 
 
 
Nausea 
 
 
 
Change in 
appetite 
 
 
 
Fatigue 
 
 
 
Other 
concerning 
signs/symptoms 
 
 
 

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14.4 List of Attachments 
1. PROMIS-29 
2. PROMIS Upper Extremity Assessment 
3. Columbia-Suicide Severity Rating Scale