Clinical trial NCT04672252
Conditions: Pain, Postoperative
Sponsor: NYU Langone Health
Start date: 2020-12-01; Completion date: 2022-12-16
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to evaluate the effects of administering CBD to control post-operative pain in patients undergoing shoulder arthroscopy. Secondly, the purpose will be to evaluate the effectiveness of CBD in comparison with opioid therapy for post-operative pain.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: CBD Oral Disintegrating Tablet (ODT) intervention 2: Placebo ODT
Intervention descriptions: intervention 1: Cohort 1: CBD ODTs to be administered with routine post-operative pain management regimen intervention 2: Cohort 2 will not receive CBD; but a visually indistinguishable placebo ODT instead.

The resident physician, physician assistant, anesthesiologist, surgeon and study team members will remain blinded. Additionally, all patients will receive a traditional upper extremity interscalene block as per routine.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title: 
The Use of Cannabidiol (CBD) in Pain Reduction and Opioid Use After 
Shoulder Arthroscopy; A Double-Blind, Randomized Control Study   
NCT Number: 
NCT04672252 
Study Number: 
19-01293 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
July 5, 2022 
 


The use of cannabidiol (CBD) in pain reduction and opioid use after shoulder arthroscopy. A Double-
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The use of cannabidiol (CBD) in pain reduction and opioid use 
after shoulder arthroscopy. A Double-Blind, Randomized 
Control Study 
 
 
 
 
Funding Sponsor: 
Department of Orthopaedic Surgery 
301 E. 17th Street 
New York, NY 10003 
Principal Investigator and 
Regulatory Sponsor: 
Michael J. Alaia, MD 
Division of Sports Medicine 
New York University Hospital for Joint Diseases 
New York, NY 10003 
Office: (646) 501-7223 
 
 
Participating sites:  
 
Jacksonville Orthopaedic Institute  
1325 San Marco Blvd., Suite 200 
Jacksonville, FL 32207 
 
 
IND Number: 
147249 
Version Date: 
6/28/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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I. PURPOSE OF THE STUDY AND BACKGROUND 
Purpose 
To evaluate the effects of administering CBD to control post-operative pain in patients 
undergoing shoulder arthroscopy. Secondly, the purpose will be to evaluate the effectiveness of 
CBD in comparison with opioid therapy for post-operative pain. 
 
Rationale 
Shoulder arthroscopy is one of the commonly performed orthopaedic procedures to treat a variety 
of conditions, with over 500,000 procedures performed every year. Additionally, new techniques 
are allowing for more pathologies to be treated arthroscopically. However, post-operative pain is 
a common complaint, and due to the increasing rise in opioid addiction among orthopaedic 
patients, management strategies have become increasingly important. As a result of the increasing 
volume of shoulder arthroscopy performed as an outpatient, alternative pain management solutions 
to opioid therapy have become of increased importance.  
 
The Endocannabinoid System (ECS) is a neuromodulatory system that has recently emerged as a 
promising new therapeutic target with many potential applications. The ECS is comprised of the 
CB1 and CB2 cannabinoid receptors, endogenous cannabinoid ligands known as 
Endocannabinoids, and the enzymes responsible for the synthesis and degradation of cannabinoids. 
The ECS is involved in regulating the inflammatory response to injury, as well as modulating pain 
and thus is a pharmacological target in pain management.  
 
Cannabidiol (CBD) has become a subject of growing interest since Congress passed the 2018 Farm 
Bill, which legalized Industrial Hemp (Cannabis Sativa plants containing <0.3% THC content) 
and its derivative cannabinoids, including CBD.  CBD is a non-psychotropic cannabinoid that has 
been reported to exhibit a range of therapeutic properties. It is well tolerated in humans with a low 
risk of side effects, and has not been shown to interact with, nor potentiate the effects of opioid 
analgesics. This makes it an attractive target for managing post-operative pain.  
 
However, CBD suffers from poor oral bioavailability (6-11%) due to extensive first pass 
metabolism via CYP3A4. To mitigate this issue, CBD will be administered in a proprietary Orally 
Disintegrating Tablet (ODT) provided by Concours Pharmaceuticals®. This formulation allows for 
transmucosal absorption of CBD via the buccal mucosa in the oral cavity. This delivery method 
reduces the effective dose of CBD needed to achieve relevant plasma concentrations. 
 
Given the potential risks treating postoperative pain with prolonged opioid use, we are proposing 
a study to evaluate the effects of CBD as an adjunct to opioid analgesics. Therefore, the purpose 
of the proposed study is to evaluate the analgesic effects of CBD administered via this ODT to 
patients that have undergone shoulder arthroscopy, with the goals of reducing post-operative pain 
and lessening the need for prolonged opioid therapy. Our hypothesis is that CBD will reduce 
postoperative pain, opioid use and associated side effects like nausea. 
 
Study Design 
This will be a multi-center, double-blinded randomized controlled study. The study is comparing 
postoperative pain, patient satisfaction, and opioid use in two cohorts: patients undergoing 


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shoulder arthroscopy who receive post-operative CBD and a placebo group. Patients will be 
asked on postoperative Day 1, 2, 7, and 14 to rate their pain according to the VAS scale. 
Additionally, opioid consumption, CBD consumption, as well as patient satisfaction will be 
measured. Patients will be asked in the post-trial period to fill out a questionnaire pertaining to 1-
year outcomes. The questionnaire will be in the form of a single online survey including ASES 
score, VAS score, KJOC Shoulder score, and SANE score. 
 
Rationale for multi-center study: 
The second site is essential for this project, for both recruitment and logistical purposes. While 
NYULOH does have high-volume, a large proportion of these patients will be ineligible due to 
the exclusion criteria and will not want to participate given that this is a randomized, controlled, 
double blinded study. Additionally, the second site PI was absolutely instrumental in the 
conceptualization and the design of this study, as well as securing the necessary funding for it 
happen. This study would not be feasible without their collaboration. Additionally, the second 
site PI has an academic appointment here at NYU Langone, and is instrumental in the education 
of the trainees here at our institution 
 
Primary Objective 
The primary objective of the study is to determine if there are any differences in post-operative 
pain between patients receiving CBD after shoulder arthroscopy compared to patients who do 
not receive it. 
 
Secondary Objective 
Secondary objective of the study is to determine if there are any differences in patient 
satisfaction, the incidence of opioid induced nausea, and the numbers of opioids and 
CBD/placebo ODTs consumed by the two patient cohorts. 
 
II. CHARACTERISTICS OF THE RESEARCH POPULATION 
Number of Subjects 
We will aim to enroll a total of 100 subjects (50 per cohort) as determined by the priori sample 
size calculator.  
 
Gender of Subjects  
Men and women will be included in this study. 
 
Age of Subjects 
Subjects included study will be aged 18-75 years, inclusive. 
 
Racial and Ethnic Origin 
There are no enrollment restrictions based on race or ethnic origin. 
 
Inclusion Criteria 
Patients will be screened for eligibility using the following criteria. All study subjects must meet 
the following inclusion criteria: 


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• Patients undergoing an arthroscopic shoulder procedure (rotator cuff repair, 
decompression, labrum repair) 
• Patients ages 18-75, inclusive 
• Female patients must be currently practicing effective forms of two types of birth control, 
which are defined as those, alone or in combination, that result in a low failure rate (less 
than 1% per year) when used consistently and correctly 
• Male patients must be using an effective form of contraception   
 
Exclusion Criteria 
Patients meeting the following criteria will be excluded from participation in this study: 
• Legally incompetent or mentally impaired (e.g., minors, Alzheimer’s subjects, dementia, 
etc.) 
• Younger than 18 years of age 
• Older than 75 years of age 
• Any patient considered a vulnerable subject: pregnant women or fetuses, children, 
cognitively impaired adults, prisoners 
• History of cannabis abuse or dependence  
• History of coagulation abnormalities and thromboembolic disease or current abnormal 
coagulation test values  
• History of stroke or acute coronary syndromes within 3 months before surgery 
• Abnormal coagulation profile 
• Renal failure (serum creatinine > 250 μmol/L [2.83 mg/dL]) or liver cirrhosis  
• Patients with a history of hypersensitivity to Percocet 
• Patients that have been on pre-operative opioid management for any reason 
• Patients meeting the DSM-V for major psychiatric illness, such as bipolar disorder 
• Patients diagnosed with major depression, psychosis, or substance abuse disorder 
• Patients with current or a history of suicidal ideation 
• Breastfeeding females 
• Patients with clinically significant illness, including cardiovascular disorders 
• Clinically significant lab abnormalities 
• Abnormal LFTs 
• Patients with major neurological disorders, such as dementia, Parkinson’s disease, 
cognitive impairment, epilepsy, history of traumatic brain/head injury, or seizures 
• Patients with moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C). 
• Patients taking moderate or strong inhibitors of CYP3A4 and CYP2C19 (listed below) 
concomitantly 
• Patients taking strong CYP3A4 and CYP2C19 inducers (listed below) concomitantly 
• Patients taking substrates of UTG1A9, UTGB17, CYP2A1, CYP2B6, CYP2C8, CYP2C9 
and CYP2C19 (listed below) concomitantly 
 
CYP3A4 Strong 
Inhibitors  
Clarithromycin, Telithromycin, Nefazodone, Itraconazole, Ketoconazole, 
Atazanavir, Darunavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, Saquinavir, 
Tipranavir. 


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CYP3A4 Moderate 
inhibitors 
Amiodarone, Erythromycin, Fluconazole, Miconazole, Diltiazem, Verapamil, 
Delavirdine, Amprenavir, Fosamprenavir, Conivaptan 
CYP2C19 Strong 
Inhibitors 
Fluconazole 
CYP2C19 Moderate 
Inhibitors 
Amiodarone, Fluvoxamine, Miconazole, Oxandrolone, 
CYP3A4 Inducers 
Carbamazepine, Dexamethasone, Ethosuximide, Glucocorticoids, Griseofulvin, 
Phenytoin, Primidone, Progesterone, Rifabutin, Rifampin, Nafcillin, Nelfinavir, 
Nevirapine, Oxcarbazene, Phenobarbital, Phenylbutazone, St Johns Wort, 
Sulfadimidine, Sulfinpyrazone, Troglitazone 
CYP2C19 Inducers 
Carbamazepine, Enzalutamide, Rifampin  
UTG1A9 Substrates 
Regorafenib, Acetaminophen, Canagliflozin, Propacetamol, Sorafenib, 
Indomethacin, Entacapone, Etodolac, Irinotecan, Propofol, Mycophenolic acid, 
Sulfamethoxazole, Valproic acid, Haloperidol, Zileuton, Flurbiprofen, Ibuprofen, 
Lumiracoxib, Valdecoxib, Buprenorphine, Nateglinide, Seratrodast, Gavestinel, 
Ketobemidone, Ambrisentan, Troglitazone, Mycophenolate mofetil, Ezogabine, 
Tapentadol, Dabigatran etexilate, Oxazepam, Dapagliflozin, Topiroxostat, 
Enasidenib, Dolutegravir, Ertugliflozin, Artenimol, Fostamatinib, Glasdegib, 
Diclofenac, Labetalol, Ataluren, Naproxen, Vadimezan, Dexibuprofen, 
Gemfibrozil, Fenofibrate, Darolutamide, Phenytoin, Formoterol 
UTGB17 Substrates 
Formoterol, Losartan, Diclofenac, Etodolac, Flurbiprofen, Ibuprofen, Naproxen, 
Suprofen, Mitiglinide, Zaltoprofen, Ambrisentan, Troglitazone, Morphine, 
Indomethacin, Mycophenolate mofetil, Ezetimibe, Mycophenolic acid, Vadimezan, 
Epirubicin, Tapentadol, Pitavastatin, Silodosin, Zidovudine, Lovastatin, 
Simvastatin, Oxazepam, Carbamazepine, Codeine, Fluvastatin, Valproic acid, 
Dapagliflozin, Enasidenib, Nalmefene, Acemetacin, Ertugliflozin, Artenimol, 
Labetalol, Tamoxifen, Carvedilol, Ketorolac, Dabigatran etexilate, Dexibuprofen, 
Gemfibrozil, Anastrozole, Loxoprofen, Cenobamate 
CYP1A2 Substrates 
Acetominaphen, Amitriptyline, Clomipramine, Clozapine, Cyclobenzaprine, 
Doxepin, Duloxetine, estradiol, Fluvoxamine, Halperidol, Imipramine n-deme, 
mexiletine, nabumentone, Napqi, Naproxen, Olanzapine, Ondansetron, Phenacetin, 
Perfenidone, Propranolol, Riluzole, Ropivacaine, Rucaparib, Tacrine, 
Theophylline, Tizanidine, Triamterene, Verapamil, Warfarin, Zileuton 
CYP2B6 Substrates 
Artemisinin, Buproprion, Cyclophosphamide, Efavirenz, Ifosphamide, Ketamine, 
Meperidine, Methadone, Nevirapine, Propafol, Selegine, Sorafenib, Tramadol, 
Velpatasvir 
CYP2C8 Substrates 
Amodiaquine, Cerivastatin, Paclitaxel, Repaglinide, Selexipag, Sorafenib, 
Torsemide 
CYP2C9 Substrates 
Amitriptyline, Capecitabine, Celecoxib, Clopidogrel, Diclofenac, Doxepin, 
Fluoxetine, Fluoxetine, Fluvastatin, Glibenclamide, Glimepiride, Glipizide, 
Glyburide, Ibuprofen, Irbesartan, Lesinurad, Lornoxicam, Meloxicam, Nateglinide, 
Phenytoin-4-oh2, Piroxicam, Rosiglitazone, S-naproxen-nor, S-warfarin1, 
Suprofen, Tamoxifen, Tolbutamide, Tolbutamide1, Torsemide, Valproic Acid, 
Venlafaxine, Voriconazole, Zakirlukast 
CYP2C19 Substrates 
Amitriptyline, Atomoxetine, Brivaracetam, Carisoprodol, Chloramphenicol, 
Citaprolam, Clomipramine, Clopidogrel, Cyclophosphamide, Diazepam-nor, 
Doxepin, Escritolapram, Esomeprazole, Flibanserin, Hexobarbital, Imipramine-n-
deme, Indomethacin, Labetalol, Lansoprazole, Moclobemide, Nelfinavir, 
Nilutamide, Omeprazole, Pantoprazole, Phenobarbitone, Phenytoin(o), Primidone, 
Progesterone, Proguanil, Propranolol, r-Methobarbital, r-Warfarin, s-Mephytoin, 
Suvorexant, Teniposide, Venlafaxine, Vorconizole 
 


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Vulnerable Subjects 
We do not intend to enroll vulnerable subjects. 
 
Subject withdrawal criteria.   
Patients are free to withdraw of their own volition at any time from the study before or after 
surgery. 
 
A subject may be withdrawn from the study at any time if the Investigator determines that an 
illness, injury, complication or adverse event requires immediate study removal, whether or not 
considered by the Investigator to be related to the study drug.  
 
Subjects found to have elevated liver transaminase and/or bilirubin levels on Day 2, or Day 7 
will be removed from the study.    
 
III. METHODS AND PROCEDURES 
Methods and Procedures  
Patients indicated and scheduled for a shoulder arthroscopy will be identified from faculty surgeon 
case logs at the NYU Langone Health, Langone Orthopedic Hospital Sports Medicine Division.   
After informed consent is obtained, a chart review of patients’ medications and past medical 
histories will be performed based on their electronic medical records to identify any current pain 
medications or exclusion criteria. In order to maintain the blind, another surgeon not involved in 
the procedure will randomize the patient to one of two cohorts using REDCap. Both surgeons are 
members of the study team. The randomization will be block randomization, via a computer 
generator on RedCap. 
- 
Cohort 1: CBD ODTs to be administered with routine post-operative pain management 
regimen 
- 
Cohort 2: Will not receive CBD; but a visually indistinguishable placebo ODT instead.   
The resident physician, physician assistant, anesthesiologist, surgeon and study team members 
will remain blinded. Additionally, all patients will receive a traditional upper extremity 
interscalene block as per routine.  
 
Immediate post-operative management will not be affected by this study. All patients will 
receive a standardized regimen of Percocet for pain management, which is standard of care post-
operative treatment. Patients will receive a standard dose of 5/325mg and be discharged with 30 
tabs and will be instructed to take 1-2 tablets, as needed, every 4-6 hours.  
 
Additionally, patients will be randomized into one of two cohorts. The first cohort will receive a 
25mg CBD ODT, every 4-6 hours as needed, with instructions to take two CBD ODTs if they 
weigh more than 80 kg (total maximum of 50mg per dose every 4-6 hours as needed). Cohort 2 
will receive the same instructions, but with the placebo ODT instead. The dose of 25mg for 
subjects weighing >/= 80kg and 50mg for subjects weighing more than 80kg was selected based 
on recommendations from the FDA. 
 


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All subjects will be required to refrain from use of THC, or other cannabis-related products for 
the duration of the study. 
 
Information to be recorded pre-operatively includes age, sex, height, weight, BMI, and American 
Society of Anesthesiology (ASA) classification. As well as baseline levels of complete blood 
count (CBC), chemistry profile, liver enzymes, gamma glutamate transferase (GGT), 
electrocardiogram, urine analysis, 12-panel urine drug test, and a urine pregnancy test. 
 
Intra-operative information will also be recorded, including operative time, procedure, number of 
anchors, and complications. Patients will subsequently be stratified in different subgroups based 
on the procedure performed.  
 
Pain severity scores at rest will be assessed by use of a visual analog scale (VAS; 0 = no pain, 10 
= worst pain imaginable) at 6, 24, and 48 hours as well as 7 days and 14 days after surgery. 
Patients will record their satisfaction with their management, on a 0-10 scale, 24 hours, 2 days 
and 7 days, and 14 days after surgery. 
 
Additionally, any nausea experienced by the patients will be recorded by use of a VAS (0 = no 
nausea, 10 = worst nausea imaginable) at 2 days, 7 days and 14 days after surgery.  
 
Percocet consumption will be recorded at 24 hours, 2 days and 7 days, and 14 days after surgery. 
Additionally, subjects will be asked to record the dates and times of CBD consumption. 
 
Liver function tests, consisting of the standard hepatic panel, and including serum transaminase 
and bilirubin levels will be administered for study purposes on Day 7 and Day 14 after surgery.  
 
Incidence of CBD-related side effects will be noted. Time to discharge from the post-anesthesia 
care unit (PACU) and time to discharge from the hospital will be recorded. Patients will be in the 
study a duration of 14 days and will be asked to fill out one online survey at the 1-year mark to 
determine the long-term effects that may be associated with using CBD.  
 
In order to maintain the blinding, all data, including pain severity scores, side effects, opioid and 
CBD consumption, will be collected by the resident physician or physician assistant However, if 
needed, in the event of an emergency or SAE, the unblinded surgeon responsible for 
randomization will be able to confirm whether a subject has been assigned to receive CBD or 
placebo.  
 
Study Time Points 
Day 0 - Day of Surgery 
 
 
 
Baseline suicidality assessment (C-SSRS), Record Pain (6hrs and 24 hrs), 
Record clinical data during surgery and post op including time to discharge 
from PACU and time to discharge from the hospital, monitor for AEs 
 
Day 1 
 
Record Pain, Opioid consumption, CBD consumption, Satisfaction, monitor
for AEs 
 


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Day 2 
 
Record Pain, Opioid consumption, CBD consumption, Satisfaction, Nausea,
monitor for AEs 
 
Day 7 - Standard of Care Visit 1 
Record Pain, Opioid consumption, CBD consumption, Satisfaction, Nausea 
 
Liver Function Tests - Non-standard of care, C-SSRS, Drug accountability, 
monitor for AEs 
 
Day 14 - Standard of Care Visit 
2 
Record Pain, Opioid consumption, CBD consumption, Satisfaction, Nausea,
monitor for AEs 
Month 12 – Post-Trial Survey 
Liver Function Tests - Non-standard of care, C-SSRS, Drug accountability 
and review of completed subject diary, monitor for AEs 
 
Record Pain; Complete ASES, KJOC Shoulder, and SANE assessment 
 
 
Data Analysis and Statistical Plan 
Our power analysis was based on the literature of post-operative pain control following shoulder 
arthroscopy. Under the assumption of a VAS of 3 and 1.8 for the control and CBD respectively, 
with a SD of 2: Group sample sizes of 45 in each group would achieve 80% power to reject the 
null hypothesis of equal means when the population mean difference between Control and CBD 
is μ1 - μ2 = 3.0 - 1.8 = 1.2 with a standard deviation for both groups of 2.0 at a significance level 
(alpha) of 0.05 using a two-sided two-sample equal-variance t-test. Thus, to allow for a 5% drop-
out at 14-day follow-up, 100 patients would be required to enroll. 
For descriptive statistics, categorical values will be described by percentages, and continuous 
variables will be described by means with standard deviations. To compare primary and 
secondary outcomes, a T-Test will be performed, with a p-value of 0.05 set to determine 
statistical significance. Testing will be performed to determine whether sample distribution is 
normal; if not, non-parametric testing will be performed. 
 
Analysis of the Primary Efficacy Endpoint(s) 
To compare primary outcomes (VAS score), a T-Test test will be performed, with a p-value of 
0.05 set to determine statistical significance. Testing will be performed to determine whether 
sample distribution is normal; if not, non-parametric testing will be performed. Patients who do 
not complete at least 80% of follow-up visits will be considered lost to follow-up and will not be 
included in the analysis. 
 
Analysis of the Secondary Endpoint(s) 
To compare secondary outcomes (opioid use, satisfaction), complication rates), a T-Test will be 
performed, with a p-value of 0.05 set to determine statistical significance. For categorical 
variables, a Fisher’s exact test will be performed. Testing will be performed to determine 
whether sample distribution is normal; if not, non-parametric testing will be performed. Patients 
who do not complete at least 80% of follow-up visits will be considered lost to follow-up and 
will not be included in the analysis. 
 
 


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Data and Safety Monitoring Plan 
Data monitoring will be done by Dr. Alaia, the principal investigator will oversee the conduct of 
the study. He will review enrollment, accumulated study data, including pain VAS scores, 
Percocet consumption VAS scores, liver function test results, adverse events, protocol 
deviations, study compliance and data accuracy quarterly.   
 
He will monitor whether or not: 
1. Collection and storage of patient data was performed in a sensitive and secure manner, 
as defined in the informed consent form and protocol, ensuring information is stored 
on REDCap. 
2. All study activities were conducted with primary emphasis on patient care and 
wellbeing, ensuring the patients are not in discomfort and have an abnormally high 
VAS following the surgery. 
3. If there were any adverse events, and if so were addressed appropriately and per 
protocol  
4. The risk/benefit to patients has remained the same throughout the course of the study. 
 
The study will be stopped if there are unexpected severe adverse events in more than one patient. 
Adverse Events (AEs) will be defined as negative reactions to the CBD treatment. We will 
submit summaries of data and safety monitoring to the IRB annually.  De-identified primary and 
secondary outcome data will be shared by the participating site PI quarterly, and they will notify 
the host site PI (MJA) upon each enrolled patient.  
 
The participating site PI will be responsible for verifying data accuracy and compliance at their 
site, and notifying the host site PI (MJA) of any protocol deviations. The plan for data safety 
monitoring in the second site will be for the PI there to perform a similar quarterly review of 
safety (including any adverse response to CBD, LFTs, and C-SSRS), and provide both 
the raw cumulative data and a summary of the adverse events and outcomes of the safety 
monitoring to Dr. Alaia. Additionally, there will be a quarterly teleconference between the site 
PIs to discuss and the affiliate site will be monitored by the IRB at their hospital as well, with 
NYU being the lead institution. 
 
Data Storage and Confidentiality 
Data recorded from this study will be organized in REDCap. Participant medical information will 
only be available to the principal investigator and research staff as necessary for data analysis. All 
patient health information will be de-identified and assigned a code. Information linking 
participants’ names, social security numbers and medical record numbers will be stored in a secure 
location separate from the medical information. No data will be shared to anyone outside of the 
study team.  
 
Adverse Event Reporting 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as 
adverse events.  Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality: 


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• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that 
is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance. They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
 
 
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. 
Definition of Unanticipated Problems (UP) 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency  (i.e. not described in study-related 
documents such as the IRB-approved protocol or consent form, the investigators brochure, 
etc) 
• Related or possibly related to participation in the research (i.e. 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) 


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• Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
The clinician’s assessment of an AE's relationship to study agent (drug, biologic, device) is part 
of the documentation process, but it is not a factor in determining what is or is not reported in 
the study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. All AEs must have their relationship to study agent assessed. In a clinical trial, the 
study product must always be suspect. To help assess, the following guidelines are used. 
 
• Related – The AE is known to occur with the study agent, there is a reasonable possibility that the 
study agent caused the AE, or there is a temporal relationship between the study agent and event. 
Reasonable possibility means that there is evidence to suggest a causal relationship between the 
study agent and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study agent 
caused the event, there is no temporal relationship between the study agent and event onset, or 
an alternate etiology has been established. 
 
 
For all collected AEs, the clinician who examines and evaluates the participant will determine 
the AE’s causality based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below. 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to drug administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the drug 
(dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary. 
• 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 drug, is unlikely to be attributed to concurrent disease 
or other drugs or chemicals, and follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition. 
• 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 drug administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the trial medication) 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 drug 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. 
 
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, or upon review by a 


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study monitor. All AEs including local and systemic reactions not meeting the criteria for SAEs 
will be captured on the appropriate RF. 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 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. UPs will be recorded in 
the data collection system throughout the study. 
 
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. 
 
The PI will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation. At each study visit, the investigator will inquire about the occurrence of AE/SAEs 
since the last visit. Events will be followed for outcome information until resolution or 
stabilization.  
 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the investigator should instruct each subject to report any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be related to 
participation in this study.  The investigator should notify the PI of any death or adverse event 
occurring at any time after a subject has discontinued or terminated study participation that may 
reasonably be related to this study.  The PI should also be notified if the investigator should 
become aware of the development of cancer or of a congenital anomaly in a subsequently 
conceived offspring of a subject that has participated in this study.  
 
Information about any breach of confidentiality will be documented in the electronic data 
collection system and/or on the paper CRFs, as appropriate. It will be the responsibility of the 
Principal Investigator to report any Serious Adverse Event (SAE) that occurs during the course 
of the prospective data collection to the Institutional Review Board (IRB) within the timeframe 
specified by NYU SoM. 
 
Notifying the FDA 
 
The PI (sponsor-investigator) is required to report certain study events in an expedited fashion to 
the FDA.  These written notifications of adverse events are referred to as IND safety reports.  
 
The following describes the IND safety reporting requirements by timeline for reporting and 
associated type of event: 


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• Within 7 calendar days (via telephone or facsimile report) 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening 
 
• Within 15 calendar days (via written report) 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to 
fit the criteria for reporting (reporting within 15 calendar days from when event was 
deemed reportable). 
Any finding from tests in laboratory animals that:  
– suggest a significant risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity. 
 
The following describes the IDE safety reporting requirements by timeline for reporting and 
associated type of event: 
 
• Within 10 working days (via telephone or facsimile report) 
Any study event that is: 
– associated with the use of the study device, and 
– unanticipated,  
regardless of the seriousness of the event. 
 
• Within 5 working days (via written report) 
– Protocol deviation to protect the life of the subject in emergency 
– Withdrawal of IRB approval 
– Lack of informed consent 
 
 
Additional reporting requirements 
The sponsor-investigator is also required to identify in IND safety reports all previous reports 
concerning similar adverse events and to analyze the significance of the current event in light of 
the previous reports. 
 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A (MEDWATCH Form) or in a narrative 
format meeting FDA requirements. The contact information for submitting IND safety reports is 
noted below: Rigoberto Roca, 


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Division of Anesthesiology, Addiction Medicine, and Pain Medicine (DAAP) 
5901-B Ammendale Road, Beltsville, MD 20705-1266 
Phone: (301) 796-2280 
Fax: (301) 796-9723 
 
 
Notifying participating sites: The study PI will notify the participating sites within 24 hours. 
 
IV. RISK/BENEFIT ASSESSMENT 
Risk 
This study involves risk of medication side effects as well as a breach of confidentiality. Oral 
CBD can cause the following side effects: 
• Fatigue 
• Diarrhea 
• Changes in appetite/weight 
 
Rare side effects include: 
• Unusual tiredness or weakness 
• Hepatic toxicity 
• Testicular toxicity was observed in a preclinical study where mice were given CBD, although 
this has not been observed in clinical studies. 
 
Protection against Risks  
Patients will be screened for any contraindication to CBD or Percocet use, including Cannabis 
dependence. Patients will receive baseline assessments for history and physical, including 
psychiatric exam, complete blood count (CBC), chemistry profile, liver enzymes, gamma 
glutamate transferase (GGT), electrocardiogram, urine analysis, 12-panel urine drug test, and urine 
pregnancy test.  
 
Planned safety monitoring during the duration of the study will include monitoring for liver 
function, laboratory abnormalities and suicidality assessments throughout the study and for follow-
up visits. Liver function tests, including serum transaminase and bilirubin, will be obtained on Day 
2, Day 7, and Day 14. Elevated liver transaminase and bilirubin levels will be grounds for 
immediate removal from the study.  C-SSRS will be assessed at baseline, Day 7, and Day 14 by 
the surgeon. Although CBD does not increase risk of suicidal ideation and behavior, this is being 
done in accordance with FDA recommendation for clinical trials involving drugs with CNS 
activity.  If subjects are found to pose a risk to themselves, standard institutional procedures will 
be followed to refer subjects for appropriate care, including emergency care if needed. 
 
 
The maximum CBD dose given to any subject will be less than 2mg/kg/day, well below levels 
associated with any hepatic risk (Iffland & Grotenherman, 2017).  
  


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CBD was not deemed to increase the severity of Percocet's opioid toxicities, as they act on different 
pathways. There is a potential for CBD to work in the same C450 cytochrome pathway as the 
acetaminophen, and thus no additional acetaminophen is to be prescribed outside of this, which is 
well below the maximum prescribing threshold of 4g per day. 
 
The patients will stay in the recovery unit until cleared for discharge by an anesthesiologist. They 
will be prohibited from driving or operating a motor vehicle for 2 hours following their first dose 
of the study drug.  
 
Patients will be educated on the importance of keeping the study drug in a safe place at all times 
and ensure it is not accessible to anyone other than themselves.  
 
Additionally, all patients will be de-identified and given a code. Information linking the patient 
codes to the participants’ names and medical record numbers will be stored in a secure location 
separate from the medical information.  Access to the information linking the linkage codes with 
participant identifiers shall be restricted.   
 
Potential Benefits to the Subjects  
Patients may experience less pain post-operatively, and may require less narcotics use, which has 
a steeper side-effect profile. However, these benefits cannot be guaranteed. 
 
Additionally, it is the hope of the research team that results of this study will benefit future 
patients and their physicians by providing more information regarding the use of CBD after 
surgery.  This will allow for a more open and informed dialogue, and possibly a change standard 
of care treatment.  
 
Drug Shipment, Storage, Dispensing, Accountability, and Destruction: The CBD and 
matching placebo ODTs will be shipped to the NYU Langone Health Research Pharmacy in 
bottles labeled CBD or Placebo 25mg ODT with the subject #, date of dispensing and # of 
ODTs. Subjects will be dispensed enough 25mg ODTs for a maximum dose of every 4-6 hours 
for 14 days (subjects weighing over 80kg will be dispensed twice the amount of ODTs to 
account for 2 ODTs per dose (a total of 50mg CBD or placebo per dose). Subjects will be 
reminded that they should take the CBD or placebo ODT orally, every 4-6 hours, as needed for 
14 days. The dates and times the ODT is taken are to be recorded in the subject’s diary. 
Subjects will need to bring the drug with them (including empty and unused bottles) to the site 
for their Day 7 and Day 14 visits for accountability. Any remaining drug will be collected at Day 
14 and destroyed per NYULH Research Pharmacy SOP. 
 
 
V. INVESTIGATOR’S QUALIFICATIONS AND EXPERIENCE 
The CV, medical license, and human subjects’ tutorial completion report are attached for all 
investigators who are participating in this study.  All research personnel have medical research 
experience and are qualified to participate in this quality study. Most importantly, staff have been 
properly educated and certified with CITI training to conduct research in a matter that will 
maintain full patient confidentiality. The research coordinator for this study is trained in GCP 


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principles and practices and will be responsible for compliance with GCP guidelines for all study 
investigators and research assistants. 
 
VI. SUBJECT IDENTIFICATION, RECRUITMENT AND CONSENT/ASSENT 
Method of Subject Identification and Recruitment 
Appropriate patients, who meet all of the inclusion criteria and none of the exclusion criteria, who 
require a shoulder arthroscopy, will be identified from the clinical offices of the investigator 
surgeons.  
 
Process of Consent 
Written consent will be obtained from subjects who are eligible candidates for shoulder 
arthroscopy based upon their medical condition (as determined by their physician). The consent 
process will take place during the office visit when it is determined necessary to perform the 
procedure—at which time the investigator has determined subject’s voluntary participation has 
been upheld. Subjects will be informed about the study and the intended purpose. They will be 
given the opportunity to ask questions and receive thorough explanations. They will be made aware 
of the possible risks and anticipated benefits. They will also be informed of alternative procedures. 
Subjects will then be given another opportunity to ask questions and agree or disagree to consent. 
 
Subject Capacity 
All subjects enrolled in this study will have capacity to provide informed consent. 
 
Consent Forms 
Written consent will be obtained from the patient. 
 
Documentation of Consent 
Signed consent forms will be kept in a binder and stored in a locked file cabinet.   
 
Costs to the Subject 
Subjects will not incur any additional financial costs as a participant in this study. 
 
Payment for Participation  
Subjects will be paid $100 for participating in this study. 
 
VII. References 
 
1. Lu HC, Mackie K. An Introduction to the Endogenous Cannabinoid System. Biol Psychiatry. 
2016;79(7):516–525. doi:10.1016/j.biopsych.2015.07.028 
2. Guindon J, Hohmann AG. The endocannabinoid system and pain. CNS Neurol Disord Drug 
Targets. 2009;8(6):403–421.  
3.  Bergamaschi MM, Queiroz RH, Zuardi AW, et al. Safety and side effects of cannabidiol, a 
Cannabis sativa constituent. Curr Drug Saf. 2011;6:237–249  
4.  Iffland K, Grotenhermen F (2017) An update on safety and side effects of cannabidiol: a review 
of clinical data and relevant animal studies, Cannabis and Cannabinoid Research 2:1, 139–
154, DOI: 10.1089/can.2016.0034. 


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5.  Zhornitsky 
S, 
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6. Parker LA, Rock EM, Limebeer CL. Regulation of nausea and vomiting by cannabinoids. Br J 
Pharmacol. 2011; 163(7):1411-1422. doi:10.1111/j.1476-5381.2010.01176.x