Conditions: Odontalgia Toothache
Keywords: Cannabidiol (CBD) Opioid Dose Dental Pain Epidiolex CBD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 64
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaulate CBD as a therapeutic approach for dental pain. Eligible subjects presented with emergency dental pain will be give a single dose of Epidiolex (FDA-approved CBD) or placebo and will be monitored for 3 hours for pain symptoms and psychologic effects.

Detailed description:
CBD is a non-psychoactive, non-addictive compound of cannabis that has shown analgesic and anti-inflammatory properties. Epidiolex is the only FDA-approved oral CBD solution and will be the drug of choice in this study.

Arms:
arm 1: After drug administration, subjects will be monitored for 3 hours, and pain intensity and safety data will be collected at various time points. Ibuprofen 600mg (or acetaminophen/codeine 650/60mg, if a contraindication for ibuprofen exists) will be provided in the 3-hour observation period as rescue medication if needed. Subjects will be encouraged to wait at least 60min after administration of the drug study before consuming the rescue medication. It will be given at the patient's request. If rescue medication was required, the study drug will still be dosed as per protocol, and time-to -rescue analysis will be performed. Then, the recommended root canal therapy will be performed the same or the next day. arm 2: The 20mg/kg dose is the maximum recommended daily dose from the manufacturer. After drug administration, subjects will be monitored for 3 hours, and pain intensity and safety data will be collected at various time points. Ibuprofen 600mg (or acetaminophen/codeine 650/60mg, if a contraindication for ibuprofen exists) will be provided in the 3-hour observation period as rescue medication if needed. Subjects will be encouraged to wait at least 60min after administration of the drug study before consuming the rescue medication. It will be given at the patient's request. If rescue medication was required, the study drug will still be dosed as per protocol, and time-to -rescue analysis will be performed. Then, the recommended root canal therapy will be performed the same or the next day. arm 3: Placebo drug will be a solution with the same taste, texture and color as the drug. After drug administration, subjects will be monitored for 3 hours, and pain intensity and safety data will be collected at various time points. Ibuprofen 600mg (or acetaminophen/codeine 650/60mg, if a contraindication for ibuprofen exists) will be provided in the 3-hour observation period as rescue medication if needed. Subjects will be encouraged to wait at least 60min after administration of the drug study before consuming the rescue medication. It will be given at the patient's request. If rescue medication was required, the study drug will still be dosed as per protocol, and time-to -rescue analysis will be performed. Then, the recommended root canal therapy will be performed the same or the next day.

Interventions: intervention 1: Epidiolex 100 mg/mL Oral Solution intervention 2: Placebo
Intervention descriptions: intervention 1: Cannabidiol (CBD): is the primary non-psychoactive and non-addictive compound in cannabis, has already shown potential in treating pain such as arthritis, neuropathic, cancer and chronic pain intervention 2: Placebo drug will be a solution with the same taste, texture and color as the drug.

Protocol document:
Prot_SAP_000.pdf: 
20-305H, Chrepa, Form CT, 04-19-21, AMD.docx 
 
1 
V November 19, 2018  
 
COVER PAGE  
 
 
 
 
 
Official Study Title: Cannabidiol (CBD) for the Management of Emergency Dental 
Pain 
 
NCT number: NCT04642404 
 
IRB Approval Date: 04/19/2021 
 
 
Unique Protocol ID: HSC20200305H 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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                            2 
 
Form CT 
UTHSA Clinical Trial Description 
This form is not mandatory.  Other documents are acceptable if equivalent information is provided. 
UTHSCSA Tracking Number 
(internal use only) 
HSC20200305H 
1. Original Version 
Date 
2020-07-07 V1.1 
 
 
1.1. Revision Date(s)  
add rows as needed 
 
 
TITLE:  Cannabidiol (CBD) for the management of emergency dental pain 
 
2. Background 
Briefly discuss the important literature relevant to the trial and that provides background for the trial.  Include the importance of the trial and any relevant 
treatment issues or controversies. 
Dental pain can be devastating and often hard to treat effectively and safely. Endodontic pain is being routinely managed with root 
canal treatment often combined with pharmacologic agents, nonetheless post-operative pain often occurs, especially in cases with 
pre-operative pain (1, 2). Current analgesic regimens in endodontics mainly include non-steroidal anti-inflammatory drugs (NSAIDS) 
and acetaminophen often combined with opioids (3-5). These drugs, besides their large variability in effectiveness, are also 
associated with moderate to severe side-effects that range from gastrointestinal bleeding disorders to liver/kidney damage, 
cardiovascular effects and even death (6-8). CBD, which is the primary non-psychoactive and non-addictive compound in cannabis, 
is currently FDA-approved for the treatment of epileptic seizures, and has already shown potential in treating pain such as arthritis, 
neuropathic, cancer and chronic pain (9-12). The rational leading to this project is that the use of CBD, a cannabinoid with no 
psychoactive and addictive effects and mild-to-moderate side effects, may provide a better alternative to these analgesics for 
dental pain (13, 14). Further, we propose to study in our clinical model the already FDA-approved CBD formulation (Epidiolex, GW 
Pharmaceuticals) off-label, thus ensuring that the drug, if successful, could be more readily available for our dental patients. 
Notably, the alternative CBD formulation will aim to reduce the rate of opioid prescriptions for dental pain and provide a significant 
relief to the opioid epidemic. Reported CBD-related AEs after long term use include gastrointestinal effects, sleep disorders and 
elevated liver transaminases (15, 16). Events after short-term use, which is typically the schedule for dental pain, are not reported 
(14, 16). Collectively, it is important to note that we do not propose to replace opioids with another drug that can develop psychotic 
disorders and addiction, nor does our proposed used of CBD present with significant known AEs as often seen with NSAIDS and 
acetaminophen. 
 
Preliminary data. We isolated 
TG neurons from C57BL/6 
female mice and cultured 
them for 5 days. This assay 
takes advantage of a reporter 
dye (Fura-2) that increases 
fluorescence by an influx of 
calcium into the cell, thus 
providing a measure of 
neuronal activation. Briefly, 
TG neurons were incubated 
with Fura-2AM, then 
pretreated with CBD (1-
1000uM) or vehicle for 5 min. 
A major subclass of 
nociceptive (“pain detecting”) 
neurons were then 
stimulated with capsaicin 
(15nM for 40s) and 
intracellular calcium levels [Ca+2]I were recorded using a FlexStation 3 (Molecular Devices). The net changes in [Ca+2]I were 
calculated by subtracting the baseline [Ca+2]i (mean value collected for 60s prior to addition of CBD) from the Max [Ca+2]i value 
achieved after exposure to the drugs. Preliminary data show that CBD 100uM and 1000uM significantly inhibited capsaicin-
induced [Ca+2]I accumulation. These preliminary data support our central hypothesis that CBD produces analgesia via peripheral 
inhibition of TG nociceptive neurons. 
0.341
0.229
0.295
0.166
0.081
0.000
0.050
0.100
0.150
0.200
0.250
0.300
0.350
0.400
Veh
CBD 1µM
CBD 10µM
CBD 100µM
CBD 1000µM
Delta(MAX-Baseline)
Cap. 15nM
Delta


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                            3 
 
 
3. Objectives and Endpoints     All data points collected in the study should support an objective or have a regulatory purpose.   
Complete the table – add rows as needed.   
3.1. Objective(s)  
Clearly and concisely define the primary and 
secondary outcomes.  
3.2. Endpoint 
Clearly define the endpoints.  
(endpoints are the basis for concluding that 
the objective has been met). 
3.3. Justification for Endpoint 
Briefly explain why the endpoint(s) were chosen. 
1. Primary outcome measure: 
a.VAS pain intensity 
differences from baseline 
among the groups at each time 
point and maximum pain 
relief. 
 
b.Bite Force measurement 
using the Bite Fork at baseline, 
1.5 h, 3h and 7d. 
 
 
 
 
 
2. Secondary outcome measure: 
Measure psychoactive effects, 
mood changes at 0, 1.5h and 
3h points, and somnolence at 
3h and 1- week time point. 
1. Patients will report their pain level 
using a 100mm Visual Analogue 
Scale (VAS) at 0, 15min, 30min, 
45min, 1h, 1.5h, 2 and 3 hour and 
1week post-administration visit time 
of study drug Epidiolex or Placebo. 
 
2. Patients will report their pain level 
that is elicited by biting down on the 
Bite Fork at 0, 1.5h, 3h and 1week 
post-administration visit time of 
study drug Epidiolex or Placebo. 
2.Patients will report feelings of drug 
high, alterations in internal 
perception and alterations in 
external perception, along with 
alertness, contentment and 
calmness by completing the 
following questionnaires: 
a. Bowdle questionnaire 
b. Bond & Lader Mood Scale 
c. Epworth Sleepiness Scale 
1.The VAS has been shown to be sensitive to 
changes in a patient’s pain experience, is 
easily understood and easy to use. It has been 
successfully used in various health fields in 
children and adults. 
 
 
2.The bite force measurement provided 
additional pain information being able to 
isolate one particular tooth (the problem 
tooth) being studies. 
 
 
 
 
2. The three listed questionnaires are 
commonly used for psychedelic assessment 
and safety assessment of cannabinoids use, 
with a longstanding administration in 
previous published studies in medical journals 
such as “Pain”, “CNS Drugs”, and “Journal of 
Psychopharmacology”. Such effects are not 
commonly associated with CBD use because 
of the inherent nature of the absence of THC 
based on current literature. Nevertheless, 
patients that report such adverse events at 
the end of the observation period will be 
asked to have a family member to accompany 
them home. 
 
4. Rationale 
Briefly state the reason for conducting the clinical trial.  
CBD is currently being tested in ~155 clinical trials for various disorders, with 16 of those trials assessing pain outcomes including 
one new study assessing analgesic efficacy of CBD after tooth extractions (www.clinicaltrials.gov, accessed March 2020). By an 
unusual regulatory circumstance, synthetic CBD is a Schedule I drug, whereas hemp-derived CBD is a Schedule V drug. 
Accordingly, we propose to use the FDA-approved cannabis-derived CBD (Epidiolex, Greenwich Biosciences, CA). Epidiolex is the 
first, and thus far only, FDA-approved Schedule V CBD oral solution designated for rare forms of epileptic seizures. The objective 
here is to test Epidiolex off-label for the treatment of emergency tooth pain in a human clinical trial. We hypothesize that 
Epidiolex will provide substantial pain relief for the patients presenting with emergency odontalgia in our clinical research facility.   
 
 
5. Study Design 
5.1. Number of Groups/Arms 
3 
Group name(s) 
1. CBD 10mg/kg single dose (given one time only )Epidiolex 
100mg/ml oral solution 
2. CBD 20mg/kg single dose (given one time only) Epidiolex 
100mg/ml oral solution 
3. Placebo oral solution single dose (given one time only)  
5.2. Overall Design 
Select all applicable   


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☒ 
Randomization 
☐ 
Cluster Randomized 
☐ 
Group-Sequential 
☐ 
Adaptive Design 
☐ 
Parallel Design 
☐ 
Placebo-Controlled 
☐ 
Superiority 
☐ 
Equivalence 
☐ 
Non-inferiority 
Device 
☐ 
Pilot 
☐ 
Pivotal 
☐ 
Post-Approval 
Drug/Biologic 
☐ 
Phase 1 
☐ 
Phase 1/2 
☒ 
Phase 2 
☐ 
Phase 2/3 
☐ 
Phase 3 
☐ 
Phase 4 
☐ 
Dose escalation 
If yes, details → 
 
☒ 
Dose ranging 
If yes, details → 
10mg/kg single dose (given one time only) Epidiolex 100mg/ml oral solution  
                                            vs.   
20mg/kg single dose (given one time only) Epidiolex 100mg/ml oral solution 
☐ 
Sub-studies 
If yes, details → 
 
5.3. Other Design Details: 
Double-arm phase II randomized placebo-controlled trial with quadruple masking (Participant, Care Provider, Investigator, 
Outcomes Assessor) 
 
6.  Study Population 
 
6.1.  Study Population(s) 
Label/Name 
 
 
 
 
To add more populations – select a row, copy & 
paste 
6.2.  Identify the criteria for inclusion 
The criteria that every potential participant must satisfy, 
to qualify for study entry.  
 
All individuals in this study population must meet 
all of the inclusion criteria in order to be eligible to 
participate in the study  
6.3.  Identify the criteria for exclusion 
The characteristics that make an individual ineligible 
for study participation.   
 
All individuals in this study population meeting 
any of the exclusion criteria at baseline will be 
excluded from study participation. 
Adults 18-75 years old with 
moderate-severe odontogenic 
pain 
-Healthy adults 18-75 years old, ASA I or II. 
-Permanent tooth with moderate to severe 
odontogenic pain, i.e. ≥30 on a 100mm VAS, 
as reported verbally by the patient. 
-Clinical pulpal diagnosis of irreversible 
pulpitis or pulpal necrosis, and periapical 
diagnosis of symptomatic apical periodontitis. 
-Test negative for recent cannabis use and/or 
other drugs of abuse including alcohol (urine 
tests collected at screening visit. Results will 
be available on site within 3-5 minutes). 
-Participant able to understand the forms 
(English or Spanish) and provide informed 
written consent 
-ASA Class III or IV, patients with hepatic 
impairment, pregnant or lactating women 
(pregnancy test is performed at the 
screening visit). 
-Patients on drugs metabolized by enzymes 
that also metabolize CBD (e.g. clobazam, 
diazepam, topiramate, warfarin), or other 
drugs known to interact with Epidiolex (as 
assessed by PI at time of screening). 
-Self-reported prior experience inhaling 
cannabis (either via smoking or 
vaporization). 
-Use of opioids in the month prior to 
screening/treatment visit, and/or NSAIDS 
or acetaminophen 6 hours prior to 
treatment. 
-Unwilling to participate 
6.4.  
Will screen failures be allowed to 
re-screen at a later date? 
 ☒ 
No 
☐ 
Yes            If yes, describe criteria below ↓ 
Since the patients present with emergency pain and their pain will need to be addressed in a 
timely manner with appropriate treatment, there won’t be any re-screening.  
 
7.  Study Intervention(s) being tested or evaluated 
This can include prevention, diagnostic or therapeutic interventions (e.g., drug or device) or educational, health services or basic science interventions (e.g., 
educational program, health care delivery model, or examining basic physiology)  


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This is a therapeutic intervention study where the FDA approved study drug used off-label in two different doses according to 
randomization will be assessed against a Placebo of similar taste and appearance.  
Group 1:  CBD 10mg/kg single dose (given one time only )Epidiolex 100mg/ml oral solution 
Group 2:  CBD 20mg/kg single dose (given one time only) Epidiolex 100mg/ml oral solution 
Group 3:  Placebo oral solution single dose (given one time only) 
 The objective here is to test Epidiolex off-label for the treatment of emergency tooth pain in a human clinical trial. We 
hypothesize that Epidiolex will provide substantial pain relief for the patients presenting with emergency odontalgia in our clinical 
research facility.  
 
Patients who present to the UT dental clinics will be provided a standard of care dental exam assessing the oral problem that 
brought them to the clinic.  A non-research, routine oral exam will be provided.  If the patient has expressed pain as part of their 
dental problem, they will be approached by study staff to explain the study and inquire if the patient would be interested in 
entering the study.  If interested, informed consent will be obtained and documented.  Medical history, demographics, vitals, pain 
questionnaire, Bite Force measurement,and study oral exam will be completed.  Height & weight of the patient will be obtained 
for calculation of study medication to be given.  Screening labs (urine pregnancy test for women of child-bearing age and urine 
toxicology) will be completed for research purposes to confirm inclusion/exclusion criteria.  Subjects who meet all eligibility 
criteria will proceed to randomization.  Eligible subjects will be randomized in a 1:1 ratio to one of the three study intervention 
arms:  Epidiolex 10mg/kg, Epidiolex 20mg/kg or Placebo. Rescue pain medication of Ibuprofen 600mg or Acetaminophen 500mg 
will be administered if needed. Pain, Psychoactive and sleep questionnaires will be completed following study intervention 
administration at the timepoints outlined in the schedule of events.  A follow-up research visit will occur one-week post-drug 
administration where a research sleep questionnaire will be completed and oral exam data collected (pain assessment, reported 
issues post-treatment, any rescue medication used). 
 
The following coding system will be used to ensure that participant identities remain confidential and to protect against 
disclosure. Each participant will be assigned a unique Study ID# and all study data collected will be coded with this number.  The 
Study ID# will be linked to participants’ names on the Participant Log which will be kept in a secure location separate from the 
coded study data and will be accessible only to members of the research team. Data collected for this study will be coded with a 
Study ID# and securely stored in the offices of the research team. Certain personal identifiers required to conduct the study but 
not for statistical analysis (name and phone numbers) will be kept separate from research data collected and not entered into 
REDCap. Certain personal identifiers such as date of birth and gender that are needed for statistical analyses will be entered into 
REDCap. REDCap is password-protected and HIPAA-compliant. Data entered into REDCap is stored on a secure UT Health server. 
All electronic data will be protected using password-protected computers.  Government or university staff may review this study 
to make sure it is being conducted safely and legally.   
 
The PI will be informed by study staff of any subject who experience an adverse event, whether during the study visits or during 
the one-week post-procedure time.  The PI will proceed with unblinding of the subject’s group.  Depending on the nature and 
severity of the adverse event, the patient will be instructed to contact their physician or visit the urgent care clinic. 
  
 
8.  Protocol-Directed procedures, items, services or tests 
List all procedures directed by the study plan - including items or services provided as part of routine or conventional care and those needed to diagnosis or treat 
research related complications.    
Important Note – The protocol directed procedures listed must match those in the Schedule of Activities (attachment) 
8.1. Drugs (trade and generic, dosage, route of administration)     
1.  Epidiolex (cannabidiol) 100mg/ml oral solution given in a one time only single dose of either Group 1:10mg/kg  OR Group 2: 
20mg/kg (Research) 
2.  Placebo oral solution developed in a similar taste and appearance as the Epidiolex (Research) 
3. Rescue Medication (Ibuprofen 600mg or acetaminophen/codeine 650/60mg if contraindication to Ibuprofen); as needed post-
study intervention per provider discretion (Research) 
 
8.2. Devices 
 
 
8.3. Biologics 
 
 


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                            6 
 
8.4. Laboratory Tests  
Urine pregnancy test (Research) 
Urine toxicology (drug screen; Research) 
 
8.5. Imaging Procedures  
 
 
8.6. Other Research Procedures (e.g., other safety and efficacy assessments.) 
Medical History and Demographics (Routine care) 
Oral Examination w/ vitals (Routine care) 
Pain, Psychoactive and Sleep scale Questionnaires (Research) 
Randomization to one of three study groups: Group 1) Epidiolex 10mg/kg; Group 2) Epidiolex 20mg/kg; Group 3) Placebo 
(Research) 
Planned dental treatment (Routine care) 
 
8.7  Attach a Schedule of Activities (SOA) Excel File  [Download the Template here: Schedule of Activities] 
Check to indicate that the  
SOA Excel File is attached  → 
☒ 
 
 
9. 
Preparation/Handling/ Storage/Accountability of Investigational Drug, Biologic, or Device 
N/A  - This study does not include any investigational products (e.g. drugs, devices or biologics) 
N/A  - An Investigator Brochure is attached 
N/A  - A Drug/Device Manual is attached 
☐ 
☐ 
☐ 
9.1.  Acquisition and accountability 
State how the study intervention and control product will be provided to the investigator. Describe plans about how and by whom the study intervention will be 
distributed, including participation of a drug repository or pharmacy, and plans for disposal of expired or return of unused product. 
Local Walgreens Pharmacy will provide the drug and placebo at requested intervals during the study to study team who will 
oversee drug accountability, storage and administration.  The study medication in both concentrations and the placebo will be 
provided by the pharmacy in a multi-use vials, ready to be drawn from according to the patient height/weight once a patient is 
randomized. Approved study staff will safely discard any remaining medication in the bottle when expired in accordance with the 
university drug disposal policy. When study recruitment has been completed, all remaining study drug will be discarded in the 
same manner. 
9.2. Formulation, Appearance, Packaging, and Labeling 
Describe the formulation, appearance, packaging, and labeling of the study intervention and control product, as supplied.  Information in this section can usually 
be obtained from the IB or the package insert, or device labeling. This section should include the name of the manufacturer of the study intervention and control 
product. 
Epidiolex is manufactured by GW Pharmaceuticals. EPIDIOLEX is a strawberry flavored clear, colorless to yellow solution supplied 
in a 105 mL amber glass bottle with a child-resistant closure containing 100 mL of oral solution (NDC 70127-100-01). Each mL 
contains 100 mg of cannabidiol. EPIDIOLEX is packaged in a carton with two 5 mL calibrated oral dosing syringes and a bottle 
adapter (NDC 70127-100-10). The pharmacy will provide the Epidiolex in a multi-dose vial to be drawn upon when the patient is 
randomized. Placebo will appear in a similar form. 
9.3.  Product Storage and Stability 
Describe storage and stability requirements (e.g., protection from light, temperature, humidity) for the study intervention and control product.  For studies in which 
multi-dose vials are utilized, provide additional information regarding stability and expiration time after initial use (e.g., the seal is broken). 
Store EPIDIOLEX in an upright position at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 
86°F). [See USP Controlled Room Temperature]. Do not freeze. Keep the cap tightly closed. Use within 12 weeks of first opening 
the bottle, then discard any remainder. 
9.4.  Preparation 
Describe the preparation of the study intervention and control product, including any preparation required by study staff and/or study participants.  Include 
thawing, diluting, mixing, and reconstitution/preparation instructions in this section. For devices, include any relevant assembly or use instructions. 
Following randomization, study staff will retrieve the study drug or placebo bottle and prepare the amount based on patient’s 
randomization group and weight/height. Study staff will prepare the dose in a 10ml calibrated syringe and wrap it with non-
transparent tape so patient and clinician are blinded to the amount/type of medication used.  Placebo will be prepared in the 
same manner, thus blinding the clinician study staff to study product used. 
 
 


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                            7 
 
 
10.  Study Intervention Additional Details 
10.1.  Measures to Minimize Bias: Randomization and Blinding 
This section should contain a description of randomization and blinding procedures (if applicable to the study design).  It should include a description or a table that 
describes how study participants will be assigned to study groups, without being so specific that blinding or randomization might be compromised.  Plans for the 
maintenance of trial randomization codes and appropriate blinding for the study should be discussed. The timing and procedures for planned and unplanned 
breaking of randomization codes should be included.  Include a statement regarding when unblinding may occur and who may unblind. Provide the criteria for 
breaking the study blind or participant code.  Discuss the circumstances in which the blind would be broken for an individual or for all participants (e.g., for serious 
adverse evets (SAEs)). Indicate to whom the intentional and unintentional breaking of the blind should be reported. 
REDCap will be utilized to create the randomization for treatment arm for all participants.  Limited data will be entered into the 
REDCap software which will create a unique Study ID# for each participant.  Randomization will also occur in REDCap per 
individual unique Study ID# created by the software. 
Unblinding of a subject who has experienced an adverse event will be conducted by the PI by review of the online system of that 
particular subject’s study e-chart and will occur within 24 hours of the AE notification.  The PI will document and assess the 
unblinded information and appropriately report the AE, additionally make the appropriate treatment recommendations for the 
patient to ensure safety.  In the case of serial adverse events of a similar type, or with a serious adverse event, the PI will unblind 
all participants and report to the IRB as required. 
We will collect subject names and phone numbers to be recorded in the Participant Log in order to track when patients are 
scheduled for their regular clinic visits as research data collection will be linked to these regularly scheduled visits.   
10.2.  Study Intervention Compliance 
Define how adherence to the protocol (e.g., administration of study intervention, use of device,) will be assessed, and verified (if applicable, e.g., plasma assays, 
electronic monitoring devices, daily diaries). 
Participants will be monitored continuously throughout the 3 hours study intervention timeline by either a licensed dentist or 
licensed registered nurse.  Administration of the Epidiolex study drug or Placebo will be achieved by a licensed dentist.  All study 
personnel will be fully calibrated as to the study requirements/standards prior to initiation of the study.  Each participant will be 
assigned a pre-numbered study packet containing all study required case report forms, including the questionnaires with 
assigned administration times clearly noted at the top of the document.  A study ‘Time Out’ will occur to review that all study 
documentation has been completed and the appropriate randomization has occurred prior to escorting the participant to the 
operatory for the dental procedure. 
10.3.  Permitted Concomitant Therapy 
This section should be consistent with the medication restrictions in the inclusion/exclusion criteria previously listed.  Describe how allowed concomitant therapy 
might affect the outcome (e.g., drug-drug interaction, direct effects on the study endpoints). 
Ibuprofen 600mg and acetaminophen/codeine 650/60mg if a contraindication for 600mg ibuprofen exists, will be allowed in the 
trial. 
These medications will be given at patient’s request as a rescue medication during the observation period. We do not expect any 
drug-to drug interaction with these medications. 
 
These analgesics will reduce the pain levels. To that end we will perform a time-to-rescue analysis. The subjects will complete the 
study. 
10.4.   
 
Rescue Medicine 
List all medications, treatments, and/or procedures that may be provided during the study for “rescue therapy” and relevant instructions. 
☐ 
N/A, no rescue medicine 
Ibuprofen 600mg (or acetaminophen/codeine 650/60mg, if 600mg contraindication for ibuprofen exists) will be provided in the 
3-hour observation period as a rescue medication, if needed. 
 
 
 
11.  Study Intervention Discontinuation  
11.1.  Discontinuation of Study Intervention 
Describe the criteria for discontinuing the study intervention (e.g., halting rules), including any monitoring test(s) and associated clinical decision point(s). Include 
reasons for temporary discontinuation of the study intervention (e.g., type and quantity of adverse events), clearly stating the length of time, if applicable, and 
describe the data to be collected at the time of study intervention discontinuation and approaches for restarting administration of or re-challenging with study 
intervention.   
Participant safety monitoring, source documentation review and decision to discontinue study intervention will be under the 
oversight of the PI. Subjects will be monitored at each study visit/study follow up for any potential AE’s or SAE’s. To further 


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                            8 
 
minimize risk to subjects and subsequent study discontinuation, the following medications will be screened for and restricted 
during the study intervention:  
  
Patients on drugs metabolized by enzymes that also metabolize CBD (e.g. clobazam, diazepam, topiramate, warfarin).   Epidiolex is 
metabolized by CYP3A4 and CYP2C19 and has the potential to inhibit CYP2C8, CYP2C9, and CYP2C19 at clinically relevant 
concentrations, therefore we chose to avoid potential drug interactions. 
 
Info copied from drug prescription: Effect of Other Drugs on EPIDIOLEX  
Moderate or Strong Inhibitors of CYP3A4 or CYP2C19  
EPIDIOLEX is metabolized by CYP3A4 and CYP2C19. Therefore, coadministration with a moderate or strong inhibitor of CYP3A4 or 
CYP2C19 will increase cannabidiol plasma concentrations, which may result in a greater risk of adverse reactions. 
Strong CYP3A4 or CYP2C19 Inducers  
Coadministration with a strong CYP3A4 or CYP2C19 inducer will decrease cannabidiol plasma concentrations, which may lower 
the efficacy of EPIDIOLEX. 
 
Effect of EPIDIOLEX on Other Drugs  
UGT1A9, UGT2B7, CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP2C19 Substrates  
1. In vitro data predict drug-drug interactions with CYP1A2 substrates (e.g., theophylline, caffeine), CYP2B6 substrates (e.g., 
bupropion, efavirenz), uridine 5' diphospho-glucuronosyltransferase 1A9 (UGT1A9) (e.g., diflunisal, propofol, fenofibrate), and 
UGT2B7 (e.g., gemfibrozil, lamotrigine, morphine, lorazepam) when coadministered with EPIDIOLEX. Coadministration of 
EPIDIOLEX is also predicted to cause clinically significant interactions with CYP2C8 and CYP2C9 (e.g., phenytoin) substrates. 
 
2. Self-reported prior experience inhaling cannabis (either via smoking or vaporization).  Cannabis trials often present with high 
placebo effect. Cannabis naïve subjects are thus proposed to minimize this effect as well the possibility of tachyphylaxis. 
 
3. Use of opioids in the month prior to screening/treatment visit, and/or NSAIDS or acetaminophen 6 hours prior to treatment. 
Any analgesic can potentially mask the effects of the study drug and increase placebo effect. 
 
Continued Study Monitoring and Halting Rules: 
 
Study drug is administered one time only at study hour zero with monitoring for the next three hours.  Once the assigned study 
drug is given, the subject will continue in the 3-hour study observation period, even if they request the rescue medication.  Only if 
they specifically request to formally withdraw from the study will they proceed to the dental treatment early, however subjects 
will be asked to complete the 3rd hour pain and Psychoactive Assessment Questionnaires at the time of consuming the rescue 
medication.  Each patient is different in regards to their pain endurance level, so subjects will be instructed to request rescue 
medication when their pain becomes uncomfortable. Subjects will be encouraged to wait at least 60 minutes after the one time 
administration of the study drug before consuming any rescue medication.  Subjects will additionally be asked to attend the one-
week follow-up visit and complete the VAS and Sleepiness Scale Assessment.   
 
In the case that a serious event appears within the same arm more than three times, we will discontinue the arm of the study.  
The PI will unblind the cases for close monitoring of the adverse event.   
 
11.2.  Continued Follow-up Discontinuation of Study Intervention 
Describe efforts that will be made to continue follow-up of participants who discontinue the study intervention, but remain in the study for follow-up, especially for 
safety and efficacy study endpoints (if applicable).  Reasonable efforts must be made to undertake protocol-specified safety follow-up procedures to capture 
adverse events (AE), serious adverse events (SAE), and unanticipated problems involving risks to subjects or others (UPIRSOs). 
We will have a follow-up study visit 1 week after intervention to assess safety and ask them to complete a survey in redcap to 
report adverse events or unanticipated problems. The PI will proceed with unblinding of the subject’s group depending on the 
nature and severity of the adverse event. The patient will be instructed to contact their physician or visit the urgent care clinic to 
address any medical event. 
 
 
 
12.  Statistical Considerations 
12.1. Statistical Hypotheses   


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State the formal and testable null and alternative hypotheses for primary and key secondary endpoints, specifying the type of comparison (e.g., superiority, 
equivalence or non-inferiority, dose response) and time period for which each endpoint will be analyzed. 
We hypothesize that Epidiolex will provide substantial pain relief for the patients presenting with emergency odontalgia in our 
clinical research facility.   
12.2.  Sample Size Determination 
Include number of participants to recruit, screen, and enroll to have adequate power to test the key hypotheses for the study.  Provide all information needed to 
validate your calculations and judge the feasibility of enrolling and following the necessary number of participants. 
This is a pilot clinical trial to determine the necessary effect size for an appropriately powered definitive clinical trial that will be 
pursued in a subsequent R01 (or UG3/UH3) application submitted to the NIH. We plan to enroll a convenience sample of 
N=22/group. We note that prior definitive studies in this pain model have detected NSAIDs such as ibuprofen with a similar 
sample size (17, 18). 
12.3.  Populations for Analyses 
Clearly identify and describe the analysis datasets (e.g., which participants will be included in each). 
All participants in all three groups will be included in the analyses. The 3 groups will be compared to each other. While we expect 
that randomization will lead to balanced groups, we will specifically assess for age and sex balance and perform sensitivity 
analyses, if indicated. Further, we will employ generalized estimating equation models accounting for correlation between pain 
measures at various timepoints to assess the timepoint when maximum analgesia is observed. 
12.4.  Statistical Analyses    
Include analysis of primary efficacy endpoints, secondary endpoints, safety analyses, and any planned interim analyses 
This analysis will provide critical information for subsequent sample size calculations and endpoint determination in the 
subsequent main study. Mixed model analyses will be used for both primary and secondary outcomes. AEs among the groups will 
be analyzed with X2 tests. The time-to-rescue medication will be summarized using Kaplan-Meier curves and compared between 
groups using stratified log-rank tests. Level of significance will be set at a=0.05. JMP software and GraphPad will be used for the 
analyses and the graphs. 
 
 
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