Conditions: Radiculopathy
Keywords: Cannabidiol
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 14
Healthy volunteers: no

Brief summary:
This double-blind, placebo-controlled, exploratory trial is designed to compare effects of oral CBD 600mg to placebo (PCB) in 20 outpatients with chronic spinal radiculopathies (without co-occurring Opioid Use Disorder), maintained on stable opioid analgesics for a minimum of 1 month. The trial duration will be approximately 2 weeks (from the point of randomization) of daily CBD 600mg vs placebo. Safety and tolerability of CBD will be assessed throughout the trial. The secondary efficacy outcome is change in pain outcomes from baseline to end of the treatment period at 2-weeks post-randomization/initiation of treatment with a Mixed Model for Repeated Measures (MMRM) statistical analysis performed to assess between group treatment effects of CBD relative to placebo.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Cannabidiol intervention 2: Placebo
Intervention descriptions: intervention 1: 600 mg oral daily use (each capsule of active drug contains 50 mg of CBD) intervention 2: identical capsules containing placebo (taken daily by mouth)

Protocol document:
Prot_SAP_001.pdf: 
Official Title:
A Phase I/II, Randomized, Double-blind, Placebo-controlled, Single-
center Study of the Effects of Cannabidiol (CBD) on Opioid Plasma 
Levels in Participants With Chronic Radiculopathic Pain Syndromes 
Maintained on Chronic Opioid Therapy (COT)  
NCT Number: 
NCT04760613 
Study Number:
21-00230 
Document Type:
Study Protocol and Statistical Analysis Plan
Date of the 
Document: 
 
December 23, 2022 


Page i
CONFIDENTIAL 
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authorized in writing by the study sponsor 
Tool Revision History: 
 
Version Number 
Version Date 
Summary of Revisions Made 
1.0 
05/20/2021 
Original Version 
2.0 
7/27/2021 
1) Clarification about Certificate of Confidentiality from NIDA 
automatically generated (p. 13) 
2) Storage of study drugs location clarification. Use of NYU-
HHC CTSI investigational pharmacy (p. 29) 
3) Correction of study drug dispensation/accountability log and 
study drug participant self-administration log (p 29) 
4) Correction of visit T5 to T6 (p. 30) 
5) Updated/Corrected Schedule of assessments ( p. 31) 
6) Clarification of SCID-5 version and use (p. 33) 
7) Clinical Opioid Withdrawal Scale replaced with Subjective 
Opiate Withdrawal Scale for ease of administration (p. 34) 
8) Baseline erroneously listed twice in QoL section (p. 35) 
9) T4 visit corrected to include pharmacokinetic assessment (p. 
38) 
10) T9 visit corrected to include collection of urine for drug test 
and pregnancy test (p. 41) 
11) Medical monitor now listed as PI Stephen Ross (p. 49) 
12) Specification of DSMB members (p. 51) 
13) Correction of participant reimbursement at T6 visit (p. 61) 
14) Updated/Corrected Schedule of assessments (p. 74)
3.0 
11/11/2021 
1) Removal of John Rotrosen MD as co-I 
4.0 
11/16/2021 
1) Addition of CBD trough levels (p. 15-16, 34, 37-39) 
2) Corrections of time assessments for pharmacokinetic 
analysis (p. 3, 15-16, 35) 
3) Correction to hyperlinks (p. 18, 42) 
4) Correction of blood specimen storage temperature (p. 36) 
5) Addition of Visit Number to blood specimen labels (p. 36) 
6) Correction to blood specimen shipment frequency (p. 36) 
7) Added name of specimen tracking log (p. 36) 
8) Corrections to Schedule of Assessments (p. 31, 74) 
9) Spelling, punctuation, and formatting corrections 
5.0 
1/6/2022 
1) Fixed Table of Contents pages (p. iv-vii)
2) Added Epic/DataCore to Recruitment Strategies (p. 19) 
3) Added Medication Self-Administration Log to Screening and 
Baseline Visits (p. 74) 
4) Added COVID-19 as possible reason for participant 
termination/withdrawal (p. 20) 
5) Added PI discretion for Field Sobriety Tests regarding 
disability (p. 43) 
4) Spelling, punctuation, and formatting corrections 
6.0 
2/28/2022 
1) Fixed year for last modification date
2) Changed “trough” language to “plasma” (p. 2, 14-16, 32, 34, 
36-40, 53-54) 
3) Specified opioid & CBD blood draw timing (p. 15-16, 36-37)


Page ii
CONFIDENTIAL 
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authorized in writing by the study sponsor 
Version 
Number 
Version 
Date
Summary of Revisions Made
7.0 
6/3/2022 
Primary Changes to Study Design 
1) Primary Efficacy Outcome now assessing pain (p. 1, 14-16, 31, 71) 
2) Opioid sparing is now an exploratory outcome (p. 2, 14-16, 51) 
3) Removed MEDD, Communication with Provider, and Motivation to Change Opioid Use 
from Inclusion Criteria (p. 16) 
4) Reduced opioid maintenance dose from 3 months to 1 (p. 1, 16) 
5) Reduced study duration from 6 months to 2 weeks (13 visits reduced to 8, no follow-up 
period)  
6) Added one 5-hr PK assessment during T3 (p. 34, 37, 38) 
7) 40 participants reduced to 20 participants (p. 1, 3, 15, 20, 52) 
8) Compensation increased from $240 to $400 (~$18/hr) (p. 58) 
9) Removed COMM, SOWS, Motivation to Change Opioid Use, & Quality of Life 
measures (p. 14-16, 31, 36, 38, 51, 52, 71) 
Changes to Schedule of Assessments (p. 31, 71) 
1) Removed visits T5-T9
2) Removed COMM, SOWS, Motivation to Change Opioid Use, Quality of Life  
3) Changed Primary Efficacy Outcome to Pain  
4) Moved LFTs to 1-week & 2-week  
5) Added Birth Control Documentation to 1-day & 1-week  
6) Added MEDD to 1-day & 2-day 
7) Added Opioid Craving VAS to 1-day, 2-day, 1-week 
8) Added Pain & Mental Health measures to 1-day, 2-day, 1-week 
9) Moved Blinding Integrity to 2-week 
10) Added Compensation to 1-day, 2-day, 2-week 
Other Revisions 
1) Fixed titles (p. iii, 1, 46) 
2) Changed PI address to new location (p. iii, 4) 
3) Fixed Table of Contents pages (p. v-vii) 
4) Adjusted study length and assessment dates (p. 1, 2, 3, 11, 12, 14-16, 20, 28, 29, 33-
39, 49-51, 58) 
5) Capitalized and added hyperlink to email (p. 4) 
6) Moved Secondary Analyses to Exploratory Analyses/Outcomes and reordered (p. 2, 
14-17, 49-53)  
7) Removed mediational analyses (p. 53) 
8) Added Depression & Opioid Craving to Exploratory Analyses (p. 2, 14-16, 49-52) 
9) Removed Opioid-Related ADRBs (p. 2, 14-16, 35, 49-52) 
10) Removed Opiate Withdrawal (p. 15, 16, 34, 52) 
11) Removed Opioid Tapering Strategy (p. 17) 
12) Moved Opioid Outcomes after Mental Health (p. 34) 
13) Removed ELISA assays from PK assessment (p. 34) 
14) Removed Bellevue Lab area (p. 11, 29, 30, 39) 
15) Specified pregnancy alternatives (p. 13) 
16) Added details about recruitment through physicians (p. 19) 
17) Added ResearchMatch to recruitment strategies (p. 20-21) 
18) Fixed Anxiety, Depression, and Sleep scales (p. 16, 34) 
19) Added provision of naloxone kit (p. 17) 
20) Removed erroneous assessment of abuse potential for CBD (p. 51) 
21) Added Birth Control to Medical Screening (p. 32) 
22) Adjusted DSMP participant numbers (p. 51) 


Page iii
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Version 
Number
Version 
Date
Summary of Revisions Made
8.0 
7/11/2022 
NIDA/NIH-Requested Revisions to DSMP 
1) Changed “proof-of-concept” to “exploratory” (p. 1, 15) 
2) Changed pain from primary efficacy to secondary (p. 1, 3, 16, 33, 51-53, 73) 
3) Add acceptable forms of birth control (p. 13) 
4) Add sentence about COT-induced hyperalgesia to Description of Study (p. 15) 
and Pain assessment description (p. 16)  
5) Add sentence specifying that Primary Outcome is safety and PK effects (p. 
16) 
6) Add “stable dose of” to opioid maintenance inclusion criteria 
7) Change “serious” to “clinically significant” for exclusionary laboratory 
abnormalities (p. 17) 
8) Add exclusion criteria for positive urine toxicology at screening (p. 17) 
9) Add exclusion criteria for alcohol level greater than 0 at screening (p. 17) 
10) Make suicidality exclusion more stringent: any history of attempts (p. 17) 
11) Add alcohol testing to Screening (p. 33, 37, 73) 
12) Make SAE reporting more stringent: all SAEs regardless of relationship to 
study participation (p. 46, 48) 
13) Add DSMB reporting requirement for all SAEs within 72hrs (p. 46, 47) 
14) Add description of anticipated AEs of concern to Study Halting Rules (p. 47) 
15) Fix erroneous grant number (p. 47) 
16) Prior NIDA/NIH approval for changes to DSMP changed to “all significant 
changes to the protocol must be approved by NIDA Program Officer prior to 
implementation” (p. 48, 49) 
17) Added annual DSM report to “Responsibility for Data and Safety Monitoring” 
(p. 49) 
18) Specify numerical value for Hypothesis 1b (p. 14, 51) 
 
Other Revisions 
1) Fix Brief Summary to include placebo comparison again (p. 1) 
2) Add Weill Medical College of Cornell University as a referral source (p. 18) 
3) Removed erroneous word “below” (p. 34) 
4) Added parenthetical explanations to Hypotheses 1a & 2 for consistency (p. 
51) 
5) Adjusted Schedule of Assessments to include breathalyzer (p. 33, 73) 
6) Formatting and punctuation changes 
9.0
9/30/2022
Clarification regarding pregnancy testing and birth control documentation (p. 13): 
1) Specified that it is unnecessary for participants incapable of bearing or 
fathering a child
2) Adjusted inclusion criteria to reflect that it only applies to men capable of 
fathering a child (p. 17)
10.0 
10/26/2022 
1) Fixed error in compensation structure (swapped T2/T3) (p. 60) 
11.0 
11/22/22 
1) Indicated when the 5hr blood draw would take place on the S.O.A. (p. 33)
2) Expanded Screening window to account for additional screening visits (p. 33)  
3) Added bullet for scheduling additional Screening Visits (p. 38) 
12.0 
12/13/22 
1) Swapped out DSMB Member (p. 51) 
 
 
 


Page iv
CONFIDENTIAL 
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authorized in writing by the study sponsor 
 
A phase I/II, randomized, double-blind, placebo-controlled, single-center study of the 
effects of Cannabidiol (CBD) on opioid plasma levels in participants with chronic 
radiculopathic pain syndromes maintained on chronic opioid therapy (COT) 
 
Principal Investigator:
Stephen Ross, MD
Department of Psychiatry
NYULH 
1 Park Ave, 8th Floor
New York, NY, 10016 
Email: Stephen.Ross@nyulangone.org
Telephone: 212-263-6289
NYULMC Study Number:
i21-00230     
Funding Sponsor:
Primary Sponsor:  
NATIONAL INSTITUTE ON DRUG ABUSE (NIDA/NIH)  
Grants Management Specialist: Jennifer L Schermerhorn 
Email: schermerhornj@mail.nih.gov Phone: 301-827-6704  
Program Official: Aidan Hampson  
Email: aidan.hampson@nih.gov Phone: 301-827-5925 
 
Supplemental funding:  
ANANDA Scientific 
 
IND/IDE Number:
152957
Regulatory 
Sponsor/Holder of the 
IND: 
Stephen Ross, MD
Department of Psychiatry 
NYULH 
1 Park Ave, 8th Floor 
New York, NY, 10016 
Email: Stephen.Ross@nyulangone.org
Study Product:
Cannabidiol (CBD)
Study Product Provider:  
ANANDA Scientific 
ClinicalTrials.gov 
Number:
NCT04760613 
Initial Version:  
May 20, 2021  
 
 
 
 
 
 
 


Page v
CONFIDENTIAL 
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authorized in writing by the study sponsor 
Statement of Compliance 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection 
of Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as applicable, any other 
applicable US government research regulations, and institutional research policies and 
procedures. The International Conference on Harmonization (“ICH”) Guideline for Good Clinical 
Practice (“GCP”) (sometimes referred to as “ICH-GCP” or “E6”) will be applied only to the extent 
that it is compatible with FDA and DHHS regulations. The Principal Investigator will assure that 
no deviation from, or changes to the protocol will take place without prior agreement from the 
sponsor and 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. 


Study number: s21-00230
Page vi
Version: 12/13/2022 
 
 
 
CONFIDENTIAL 
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authorized in writing by the study sponsor 
Table of Contents
 
STATEMENT OF COMPLIANCE.................................................................................................................V
LIST OF ABBREVIATIONS......................................................................................................................... IX
PROTOCOL SUMMARY .............................................................................................................................. 1
SCHEMATIC OF STUDY DESIGN............................................................................................................... 3
1 
KEY ROLES ......................................................................................................................................... 4
2 
INTRODUCTION, BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ....................... 5
2.1
BACKGROUND INFORMATION AND RELEVANT LITERATURE................................................................5
2.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL AGENT .............................................................. 7
2.2.1 
Preclinical Data 8 
2.2.2 
Clinical Data to Date
8
2.2.3 
Dose Rationale 
8 
2.3
RATIONALE....................................................................................................................................9
2.4
POTENTIAL RISKS & BENEFITS........................................................................................................9
2.4.1 
Known Potential Risks & Risk Mitigation Strategies 
9
2.4.2 
Known Potential Benefits 15 
3 
OBJECTIVES AND PURPOSE ......................................................................................................... 15
3.1 
PRIMARY OBJECTIVE .................................................................................................................... 15
3.2 
EXPLORATORY OBJECTIVES/AIMS................................................................................................. 15
4 
STUDY DESIGN AND ENDPOINTS ................................................................................................. 15
4.1 
DESCRIPTION OF STUDY DESIGN .................................................................................................. 15
4.2 
STUDY ENDPOINTS....................................................................................................................... 16
4.2.1 
Primary Study Endpoints 16 
4.2.2 
Secondary Study Endpoints 
16 
5 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................................. 17
5.1 
INCLUSION CRITERIA .................................................................................................................... 17
5.2 
EXCLUSION CRITERIA ................................................................................................................... 17
5.3 
VULNERABLE SUBJECTS............................................................................................................... 18
5.4.1 
Collaboration with Treating Physicians [TPs] for Recruitment Purposes 19 
5.4.2 
Use of DataCore/EPIC/ResearchMatch Information for Recruitment Purposes
20 
5.5 
DURATION OF STUDY PARTICIPATION............................................................................................ 21
5.6
TOTAL NUMBER OF PARTICIPANTS AND SITES................................................................................21
5.7 
PARTICIPANT WITHDRAWAL OR TERMINATION................................................................................ 21
5.7.1 
Reasons for Withdrawal or Termination 
21 
5.7.2 
Handling of Participant Withdrawals or Termination 
21 
6 
STUDY AGENT (STUDY DRUG) AND/OR PROCEDURAL INTERVENTION................................ 22
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION.............................................................................. 22
Nomenclature 
22
Description of Liquid Nanodomains Oral Formulations 22 
PHARMACOKINETICS OF THE ANANDA FORMULATIONS IN RAT...................................................................... 23
CLINICAL PHARMACOKINETICS OF ORALLY ADMINISTERED CBD .................................................................. 25
Absorption 
26
Elimination 
26
The Postulated Effect of the Formulation A1002N5S on GI Absorption of CBD 
28 
6.1.1 
Acquisition 
28
6.1.2 
Formulation, Appearance, Packaging, and Labeling 
28 
Drug Substance and Excipients 
28 
PLACEBO CAPSULES ................................................................................................................................. 28
6.1.3 
Product Storage and Stability 
29 


Study number: s21-00230
Page vii
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authorized in writing by the study sponsor 
Chemical and Physical Stability of the Liquid Nanodomains Formulation A1002N5S 
29 
6.1.4 
Preparation 
29
6.1.5 
Dosing and Administration 29 
6.1.6 
Route of Administration
29 
6.1.7
Starting Dose and Dose Escalation Schedule30
6.1.8
Dose Adjustments/Modifications/Delays
30
6.1.9
Duration of Therapy
30
6.2 
STUDY AGENT AND OPIOID PHARMACOTHERAPY ACCOUNTABILITY AND ADHERENCE PROCEDURES . 30
6.3
STUDY BEHAVIORAL OR SOCIAL INTERVENTION(S) .........................................................................31
6.3.1 
Administration of Intervention 
31 
6.3.2
Procedures for Training Interventionalists and Monitoring Intervention Fidelity
31
6.3.3
Assessment of Subject Compliance with Study Intervention
32
6.4 
STUDY PROCEDURAL INTERVENTION DESCRIPTION TABLE 1: STUDY ENDPOINTS/ASSESSMENTS..... 32
6.4.2 
Procedures for Training of Clinicians on Procedural Intervention
34 
6.4.3 
Assessment of Participant Compliance with Study Procedural Intervention 
34 
7
STUDY PROCEDURES AND SCHEDULE .......................................................................................34
7.1 
 STUDY PROCEDURES/EVALUATIONS ............................................................................................ 34
7.1.1 
Study Specific Procedures 34 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ................................................................................... 37
7.2.1 
Clinical Laboratory Evaluations 
37 
7.2.2 
Other Assays or Procedures
37 
7.2.3 
Specimen Preparation, Handling, and Storage 
37 
7.2.4 
Specimen Shipment 
37 
7.3 
STUDY SCHEDULE........................................................................................................................ 37
7.3.1 
Screening 
37
7.3.2 
Enrollment/Baseline 
38 
7.3.3 
Intermediate Visits 
38 
7.3.5 
Withdrawal/Early Termination Visit 40 
7.3.6 
Unscheduled Visit 
41 
7.5.1 
Precautionary Medications, Treatments, and Procedures 
41 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES................................................... 41
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES ............................................................. 41
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE ........................................................ 42
8 
ASSESSMENT OF SAFETY ............................................................................................................. 42
8.1.1 
Definition of Adverse Events (AE)
42 
8.1.2 
Definition of Serious Adverse Events (SAE) 42 
8.1.3 
Definition of Unanticipated Problems (UP) 
43 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ....................................................................................... 43
8.2.1 
Severity of Event 43
8.2.2 
Relationship to Study Agent 
43 
8.2.3 
Expectedness
44
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP.................................... 44
8.4 
REPORTING PROCEDURES – NOTIFYING THE IRB, FDA, DSMB ..................................................... 45
8.4.1 
ADVERSE EVENT REPORTING ....................................................................................................... 45
8.4.2 
Serious Adverse Event Reporting 
46 
8.4.3 
Unanticipated Problem Reporting 
47 
8.4.4 
Reporting of Pregnancy 
48 
8.6 
 REPORTING PROCEDURES – NOTIFYING THE FDA ........................................................................ 48
See section 8.4.2 Serious Adverse Event Reporting
48 
8.7
 
REPORTING PROCEDURES – PARTICIPATING INVESTIGATORS......................................................... 48
8.8 
STUDY HALTING RULES................................................................................................................ 48
8.9 
SAFETY OVERSIGHT: DSMP ......................................................................................................... 48
Plans for Interim Analysis of efficacy data: see section 10.4.7
Planned Interim Analysis 50 
9 
CLINICAL MONITORING .................................................................................................................. 51
10
STATISTICAL CONSIDERATIONS .................................................................................................. 52
10.1
STATISTICAL AND ANALYTICAL PLANS (SAP) ................................................................................. 52


Study number: s21-00230
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authorized in writing by the study sponsor 
10.2
STATISTICAL HYPOTHESES...........................................................................................................52
10.3
ANALYSIS DATASETS....................................................................................................................52
10.4
DESCRIPTION OF STATISTICAL METHODS ...................................................................................... 52
10.4.1
GENERAL APPROACH...................................................................................................................52
10.4.2
Analysis of the Primary Endpoint(s) 53 
10.4.3
Analysis of the Secondary Endpoint(s)
53
10.4.4
Safety Analyses
53
10.4.5
Adherence and Retention Analyses 54
10.4.6
Baseline Descriptive Statistics
54
10.4.7
Planned Interim Analysis 54 
10.4.8
Additional Sub-Group Analyses 
54 
10.4.9
Multiple Comparison/Multiplicity
54 
10.4.10 Tabulation of Individual Response Data 
54 
10.4.11 Exploratory Analyses
54 
10.5
SAMPLE SIZE/POWER CALCULATION.............................................................................................55
10.6
MEASURES TO MINIMIZE BIAS: BLINDING INTEGRITY ASSESSMENTS................................................ 55
10.6.1
Enrollment/Randomization/Masking Procedures 
55 
10.6.2
Evaluation of Success of Blinding 
55 
10.6.3
Breaking the Study Blind/Participant Code 
55 
11
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................. 55
12
QUALITY ASSURANCE AND QUALITY CONTROL ....................................................................... 56
13
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................. 56
13.1
ETHICAL STANDARD ..................................................................................................................... 56
13.2
INSTITUTIONAL REVIEW BOARD..................................................................................................... 56
13.3
INFORMED CONSENT PROCESS .................................................................................................... 56
13.3.1
Consent and Other Informational Documents Provided to Participants 
56 
13.3.2
Consent Procedures and Documentation 
57 
13.4
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................................... 57
13.4.1
Research Use of Stored Human Samples, Specimens, or Data 58 
13.5
FUTURE USE OF STORED DATA .................................................................................................... 59
14
DATA HANDLING AND RECORD KEEPING ................................................................................... 59
14.2
STUDY RECORDS RETENTION ....................................................................................................... 59
14.3
PROTOCOL DEVIATIONS ............................................................................................................... 59
14.4
PUBLICATION AND DATA SHARING POLICY..................................................................................... 60
15
STUDY FINANCES ............................................................................................................................ 60
15.1
FUNDING SOURCE ........................................................................................................................ 60
15.2
COSTS TO THE PARTICIPANT ......................................................................................................... 60
15.3
PARTICIPANT REIMBURSEMENTS OR PAYMENTS ............................................................................61
16
STUDY ADMINISTRATION ............................................................................................................... 61
16.1
STUDY LEADERSHIP ..................................................................................................................... 61
17
CONFLICT OF INTEREST POLICY .................................................................................................. 61
19
ATTACHMENTS ................................................................................................................................ 72
20
SCHEDULE OF EVENTS .................................................................................................................. 73
 
 
 
 
 
 


Study number: s21-00230
Page ix
Version: 12/13/2022 
 
 
 
CONFIDENTIAL 
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authorized in writing by the study sponsor 
List of Abbreviations
AE
Adverse Event/Adverse Experience
CBD
Cannabidiol
CNCP
Chronic Non-Cancer Pain
CRF
Case Report Form
DCC
Data Coordinating Center
DHHS
Department of Health and Human Services
DSMB
Data and Safety Monitoring Board
FFR
Federal Financial Report
FWA
Federalwide Assurance
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
ICF
Informed Consent Form 
ICH
International Conference on Harmonization 
IRB
Institutional Review Board
ISM 
Independent Safety Monitor
MOP
Manual of Procedures
N
Number (typically refers to participants)
NIH
National Institutes of Health
OHRP 
Office for Human Research Protections
OHSR 
Office of Human Subjects Research
OUD 
Opioid Use Disorder 
PI 
Principal Investigator
QC 
Quality Control
SAE
Serious Adverse Event/Serious Adverse Experience
SOP
Standard Operating Procedure
US 
United States


Study number: s21-00230
Page 1 
Version: 12/13/2022 
 
 
 
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authorized in writing by the study sponsor 
Interventional Template Version: 05 JAN 2017 
 
Protocol Summary
Title 
A phase I/II, randomized, double-blind, placebo-controlled, single-
center study of the effects of Cannabidiol (CBD) on opioid plasma 
levels in participants with chronic radiculopathic pain syndromes 
maintained on chronic opioid therapy (COT)
Short Title
CBD for chronic radiculopathy on chronic opioid therapy (COT)
Brief Summary 
This double-blind, placebo-controlled, exploratory trial is designed to 
compare the effects of oral CBD 600mg to placebo (PCB) in 20 
outpatients with chronic spinal radiculopathies (without co-occurring 
Opioid Use Disorder), maintained on stable opioid analgesics for a 
minimum of 1 month. The trial duration will be approximately 2 
weeks (from the point of randomization) of daily CBD 600mg vs 
placebo. Safety and tolerability of CBD will be assessed throughout 
the trial. The secondary efficacy outcome is change in pain outcomes 
from baseline to end of the treatment period at 2-weeks post-
randomization/initiation of treatment with a Mixed Model for Repeated 
Measures (MMRM) statistical analysis performed to assess between 
group treatment effects of CBD relative to placebo.
Phase 
Clinical Study Phase I/II
Objectives 
To collect preliminary safety, tolerability, and pharmacokinetic data for 
the use of CBD in patients with chronic non-cancer spinal 
radiculopathies maintained on COT.  
 
To obtain a preliminary assessment of efficacy of CBD in reducing 
pain catastrophizing.
Methodology 
Randomized, double-blind, placebo-controlled, parallel design 
Endpoint 
AEs, plasma concentrations of opioids and CBD, and outcomes of 
pain, anxiety, depression, sleep, opioid craving, and opioid sparing. 
Study Duration 
2 years 
Participant Duration 
2 weeks 
Duration of IP 
administration 
2 weeks 
Population 
20 men and women (aged 
with chronic spinal radiculopathies 
maintained on COT in the New York area
Study Sites 
NYULH  
Number of 
participants 
30 participants expected to be enrolled; 20 participants to receive CBD 
or placebo over 2-week treatment period 
Description of Study 
Agent/Procedure 
Oral CBD 600mg administered daily over a 2-week treatment period 
Reference Therapy 
Inactive placebo 
Key Procedures 
Study questionnaires
Blood draws 
EKG 


Study number: s21-00230
Page 2 
Version: 12/13/2022 
 
 
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authorized in writing by the study sponsor 
Statistical Analysis
For Hypothesis 1a (safety and tolerability), the frequency of AEs will 
be analyzed and tabulated for each treatment group, and compared 
using chi-squared tests. The incidence of AEs will be summarized by 
system organ class, preferred term, the likelihood of its relationship to 
the treatment, and the severity for each treatment group.  
 
For Hypothesis 1b (plasma opioid concentrations), the respective 
outcomes will be analyzed with an MMRM to assess differences in 
change from baseline. The primary contrast is change from baseline to 
1-day and 1-week post-randomization/initiation of pharmacologic 
treatment with secondary analyses contrasting changes from baseline 
to 2-weeks post-randomization.    
 
For Hypothesis 2 (pain), Hypothesis 3 (anxiety), Hypothesis 4
(depression), Hypothesis 5 (sleep), Hypothesis 6 (opioid craving), 
Hypothesis 7 (opioid sparing), the respective outcomes will be 
analyzed with an MMRM to assess differences in change from 
baseline. The primary contrast is change from baseline to end of the 
treatment period at 1-week post-randomization/initiation of treatment 
with secondary analyses contrasting changes from baseline to end of 
the treatment period at 2-weeks post-randomization. 
 


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Schematic of Study Design
Recruit N = 30: Obtain informed consent. Screen potential subjects by 
inclusion and exclusion criteria, obtain history, document.
Randomize = 20
Arm 1: CBD    
N = 15
Subjects
Arm 2: PCB   
N = 5
Subjects
Perform baseline assessments
Administer initial study intervention with oral CBD vs PCB 
and continue daily for next 2-weeks  
See Section 6.4, Schedule of Events Table for assessments from T0
T4
Safety, pharmacokinetic, and efficacy assessments
Opioid plasma concentrations at baseline, and Opioid and CBD plasma 
concentrations at 1-day, 2-day,
1-week, and 2-weeks after starting medication interventions
End of pharmacologic intervention
Final assessments of study end points:  
safety & efficacy
Secondary Efficacy Outcome (pain)
Section 6.4, Schedule of Events Table
Week 0:
T0
Prior to 
Randomization
1-day to 
2-weeks:
T1-T4
Target 
Week 2: 
T4


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1 
Key Roles
Stephen Ross, MD – Principal Investigator 
New York University School of Medicine 
Department of Psychiatry 
1 Park Ave, 8th Floor, NY, NY, 10016
(212) 263-6289 
Stephen.Ross@nyulangone.org 
Esther Blessing, MD PhD – Sub-Investigator 
New York University School of Medicine 
Department of Psychiatry 
1 Park Ave, 8th Floor, NY, NY, 10016
(646) 754-4855 
Esther.Blessing@nyulangone.org
Lisa Doan, MD – Sub-Investigator 
New York University School of Medicine 
Department of Anesthesiology, Perioperative Care, and Pain Medicine 
240 E 38th St, 14th floor, NY, NY, 10016 
(212) 201-1004 
Lisa.Doan@nyulangone.org
Martin Cheatle, PhD – Sub-Investigator 
Perelman School of Medicine, University of Pennsylvania 
Department of Psychiatry 
3535 Market Street, Room 541 
Philadelphia, PA 19104 
(215) 746-7365 
cheatle@pennmedicine.upenn.edu
Yongzhao Shao, PhD – Sub-Investigator 
New York University School of Medicine 
Department of Population Health and Environmental Medicine 
180 Madison Ave, Room 4-55, NY, NY, 10016 
(646) 501-3645 
Yongzhao.Shao@nyulangone.org 
Jing Wang, MD PhD – Other Significant Contributor 
New York University School of Medicine 
Department of Anesthesiology, Perioperative Care, and Pain Medicine 
Department of Neuroscience and Physiology 
301 E 17th St, NY, NY, 10003 
(212) 598-6321 
Jing.Wang@nyulangone.org
 


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2
Introduction, Background Information and Scientific Rationale
2.1 
 Background Information and Relevant Literature 
 
Need for novel, safe, non-addictive, non-opioid medications for patients with chronic 
non-cancer radiculopathy maintained on chronic opioid therapy (COT) 
Chronic pain (pain lasting 3 or more months) (1) is a highly prevalent public health 
problem (2) (3), and constitutes the greatest economic burden of any medical condition (4). The 
most effective treatment strategy for chronic pain is an integrated approach of multimodal 
strategies across a variety of medical disciplines (i.e., pain medicine, anesthesia, physical 
medicine/rehabilitation, psychology/psychiatry) that incorporate a broad spectrum of treatments 
such as: physical therapy/rehabilitation, psychological (i.e., cognitive-behavioral therapy, 
mindfulness-based interventions), interventional (i.e., nerve blocks, neurostimulators, joint 
injections), pharmacologic (non-opioid and opioid), and other (i.e., acupuncture, massage, 
chiropractic) modalities (5, 6). However, such integrated/interdisciplinary pain treatment 
programs are rarely accessible (i.e., lack of insurance reimbursement, paucity of existing 
programs) to patients with chronic non-cancer pain (CNCP) and a vast number of efficacious 
non-opioid therapies are poorly reimbursed or unavailable in underserved and rural 
communities.  By default COT was inappropriately prescribed as first line treatment (7). While 
there is an established evidence base to support the use of opioids for acute pain, cancer-
related pain, and in end-of-life/palliative care (7), the data supporting COT for CNCP is very 
limited with few RCTs, limited sample sizes, and trial durations rarely over 3 months (1) (8-12). 
Further, only 30-50% of patients with CNCP respond to opioid analgesics (13) and the average 
reduction in pain in this population is only approximately 30% (14). Compounding this lack of 
evidence, there is abundant evidence of harms associated with COT in CNCP conditions 
including fractures, cardiac complications, immuno-suppression, endocrine abnormalities (i.e., 
opioid induced androgen deficiency), motor vehicle accidents, cognitive impairment, sleep 
disturbance, worsening of pain (due to opioid-induced hyperalgesia), opioid diversion, opioid 
abuse and development of opioid use disorders, opioid-induced respiratory suppression and 
overdose fatalities (8); and these adverse effects increase with dose and treatment duration (8), 
(15), (16). Estimates of the prevalence of opioid use disorders (OUDs) in CNCP range from 5% 
in a meta-analysis (17) to 20-35% (18), (19), (20), (21). All of this notwithstanding, COT 
prescribing for CNCP increased markedly between 1990 and 2010, and is one of the root 
causes of the current opioid epidemic (22).  
Of the CNCP conditions, radicular pain disorders (particularly low back pain) have 
particularly high rates of opioid prescribing (23), and higher opioid doses predict poorer 
functional outcomes in this cohort of chronic pain patients (11). Radiculopathy describes a 
range of symptoms produced by compression of a nerve root in the spinal canal that can occur 
at varying areas along the spine (e.g., cervical, thoracic, lumbar). Radiculopathies are typically 
caused by changes in the tissues surrounding nerve roots including spinal vertebrae, tendons 
and intervertebral discs. Radicular pain can be caused by herniation of the nucleus pulposus 
(intervertebral disk), vertebral degenerative changes, bone spurs, and spinal stenosis. This 
leads to inflammation at the nerve roots and/or irritation of the dorsal root ganglion (24). 
Symptoms of radiculopathies frequently include: pain, numbness, weakness, and tingling 
(paresthesia). Lumbar radiculopathy occurs in the lower back, is the most common form of 
radiculopathy, and is often referred to as sciatica because the nerve roots of the sciatic nerve 
are often involved.      
Our goal is to develop an intervention to reduce opioid use in patients with radicular 
CNCP syndromes receiving moderate to high-dose COT to safer doses while at the same time 
maintaining or improving pain management. We will exclude patients with co-occurring OUD. 
However, patients with chronic radiculopathies on moderate to high-dose COT are at elevated 
risk to misuse or abuse opioids, develop an OUD along a spectrum of aberrant drug-related 
behaviors (ADRBs) (i.e., use of opioid for reason other than pain, mood or anxiety management, 


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sleep induction, euphoria (15, 25), and to develop other complications from opioid use including 
overdose death. Although a variety of non-opioid pharmacologic treatments (i.e., NSAIDs, 
acetaminophen, anticonvulsants, anti-depressants, topicals, corticosteroids) are used to 
manage radicular CNCP conditions, their efficacy is limited, and none are known to be effective 
at both decreasing opioid use and pain in this patient population (26), (27). Further, although 
there are effective pharmacologic interventions to treat opioid withdrawal and achieve 
abstinence in patients with OUDs (28), there has been relatively little research on interventions 
to reduce COT in CNCP without co-occurring OUD, with only 5 RCTs [acupuncture, 
mindfulness, and CBT interventions (i.e., motivational interviewing)] in the published literature 
(29-33), and none of pharmacologic interventions. A meta-analysis of the 5 RCTs found mixed 
results for reductions in opioid use and pain and concluded that currently ‘there is no evidence 
for the efficacy… of methods for reducing prescribed opioid use in chronic pain’ (34).  
 
Cannabidiol as a candidate drug for reducing the risk of developing an OUD in patients 
with radicular CNCP on COT: Opioid Sparing 
Over the past decade, a rapidly growing body of pre-clinical research has suggested that 
Cannabidiol (CBD) is a highly promising candidate to treat substance use disorders (SUDs), 
including OUDs (35), (36), (37), (38), (39). In pre-clinical studies, high dose CBD decreases 
rewarding effects of morphine via actions at 5-HT1a receptors) (40). CBD alone may decrease 
opioid withdrawal in animals (41), although the data are inconsistent (42), and CBD may 
potentiate THC’s effects in diminishing opioid-withdrawal (43), (44). Further, in an experimental 
rat model, CBD was associated with a reduction in cue-induced heroin seeking and 
reinstatement, with long-lasting effects over 2 weeks, associated with normalization of heroin-
seeking-induced changes in GluR1-containing AMPA receptors and CB1 receptor expression in 
the nucleus accumbens (45). In rodents CBD mitigates heightened negative affect, impulsivity 
and disturbed reward behaviors associated with addiction (46).  
In man, CBD may produce sustained anti-opioid craving effects. A small double-blind 
controlled trial in abstinent heroin dependent individuals showed 3 days of oral CBD (versus 
placebo) reduced cue-induced craving with effects lasting up to one week (47) (48). Further, a 
study in healthy subjects reported CBD did not potentiate subjective or physiological effects of 
fentanyl (49). Overall, animal and preliminary human studies suggest CBD has potential for 
preventing or treating OUDs by possibly reducing opioid reward and withdrawal, limiting 
reinstatement, mitigating behavioral imbalances known to perpetuate drug-seeking, and acting 
upon brain circuitry implicated in addiction with long lasting effects that suggest the potential for 
disease modification. It is possible that CBD could be used to prevent the progression to an 
OUD in patients with radicular CNCP on COT by affecting a reduction or elimination in dose of 
COT (i.e., decrease opioid withdrawal or craving). These promising anti-addictive effects of CBD 
may stem from its actions on the endocannabinoid system, which is recognized to play an 
important role in the pathophysiology and treatment of addiction (50). Although CBD has a low 
affinity for CB1 and CB2 receptors, it acts at these receptors respectively as an inverse agonist 
and as an antagonist (51); at the same time it indirectly facilitates endocannabinoid 
neurotransmission by inhibiting hydrolysis of the endocannabinoid anandamide by fatty acid 
amide hydrolase (FAAH) and reducing anandamide uptake by the anandamide membrane 
transporter (AMT) (52). In addition to its impact on the endocannabinoid system, CBD produces 
allosteric modulation of ligand-
(53) and acts as an 
agonist at the serotonin 1A (5-HT1A) receptor (54).  
 
CBD as a candidate drug for reducing chronic pain  
Preclinical evidence supports the use of CBD as an anti-nociceptive treatment for 
radicular CNCP syndromes. In animal studies, CBD reduces pain behaviors and inflammation in 
chronic inflammatory pain models (55), (56), (57), (58) and displays anti-nociceptive effects in 
neuropathic pain models (56), (57), (59). Studies of CBD in humans for pain are limited. 


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Sativex®, an extract of cannabis consisting of equal parts of THC and CBD, has been studied in 
humans for neuropathic and cancer pain, with more promising results for neuropathic pain (60), 
(61), (62). In contrast, the effects of CBD alone on pain in humans are not well elucidated. A 
case series reported that daily oral CBD use (up to 150mg for 3 weeks) was well tolerated and 
reduced pain scores in seven kidney transplant patients with uncontrolled chronic pain (63). 
Another case series of oral CBD (up to 150mg/day over 3 months) in twelve females with pain 
associated with dysautonomic syndrome following HPV vaccination, reported that CBD was 
safely administered and associated with significant reductions in pain (64). CBD appears to 
mediate its anti-nociceptive effects by affecting multiple targets along descending inhibitory 
nociceptive pathways including vanilloid TRPV1 receptors (65), 5-HT1A receptors (54), (66), 
glycine receptors (57), as well as indirect facilitation of endocannabinoid transmission via FAAH 
inhibition and AMT reuptake inhibition (52), (67).  
 
Opioid sparing with CBD in patients with radicular CNCP on COT  
In addition to the known anti-nociceptive effects of opioids and cannabinoids alone, the 
combination of opioids and cannabinoids can have synergistic effects in animal models of acute 
and chronic pain (68), (69), (70), (71), (72). In humans, additive or synergistic analgesic effects 
of opioids and cannabinoids have been observed in the electrical stimulation test (73) and for 
alleviating negative affect associated with thermal stimuli (74). Further, there is population-level 
evidence for a negative correlation between the availability of state medical marijuana programs 
and opioid use/overdose suggesting that patients with CNCP may be replacing opioids with 
cannabis for pain management (75), (76, 77); however, other data suggests that medical 
marijuana users may be more likely to report medical use of opioid analgesics in the past 12 
months (78) and a recent study suggests that the association between medical cannabis laws 
and opioid overdose mortality has reversed over time (79). More research is necessary to 
determine the exact relationship between opioid and cannabinoid treatments in CNCP, but it is 
worth exploring if CBD could be used to decrease or eliminate the need for COT in patients with 
radicular CNCP (thereby reducing the risk of serious adverse events including overdose death 
and possibly preventing the transition to an OUD), while at the same time effectively managing 
pain.  
  
Potential mediators of CBD effects on opioid use in radicular CNCP on COT: pain, 
anxiety, insomnia, depression, opioid withdrawal, opioid craving    
Pain and OUD are intimately related. Opioids are often helpful for acute pain but their anti-
nociceptive properties often diminish over time (or can worsen pain through opioid-induced 
hyperalgesia) and opioid-withdrawal can increase pain perception in a vicious cycle leading to 
increased opioid use and development of OUD (80). While opioids can acutely diminish anxiety, 
depression, and insomnia (which are very common conditions in patients with CNCP), opioid 
withdrawal worsens all of these symptoms and can trigger relapse in patients with a SUD (81). 
Also, anxiety and sleep disturbances typically worsen pain with sleep disturbances associated 
with reduced pain tolerance and leading to the release IL-6 pro-inflammatory cytokine (82). CBD 
may be effective in treating pain, anxiety, depression and insomnia in humans (83-85). So, in 
addition to CBD’s potential direct effects of decreasing opioid use by blunting intoxication, 
craving, withdrawal, it may indirectly decrease opioid use or withdrawal symptoms by 
diminishing pain, anxiety, depression, and insomnia. 
2.2 Name and Description of the Investigational Agent
CBD is a phytocannabinoid abundant in cannabis and has shown therapeutic effects across 
various medical, psychiatric, and addictive disorders (86). Unlike tetrahydrocannabinol (THC), 
CBD has no known addictive liability (87), lacks psychotogenic, intoxicating or rewarding effects, 
and has been safe and well-tolerated in humans up to high doses (88), (89). CBD possesses 
neuroprotective, anti-inflammatory, antioxidant, anticonvulsant, and analgesic properties (56), 


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(55). CBD is available as an FDA-approved medication (Epidiolex®) for the treatment of seizures 
associated with Lennox-Gastaut syndrome and Dravet syndrome (90). It is manufactured by GW 
Pharmaceuticals and is a schedule IV drug.   
Existing data suggest CBD is safe to administer to humans. However, clinical data are limited, 
and its use in the treatment of patients with chronic radiculopathies maintained on COT is 
experimental. The data and safety monitoring plan in this trial is designed to ensure that the 
risks of medications and study-related procedures are minimized for patients. CBD remains a 
schedule 1 drug (even though CBD in the form of Epidiolex® is a schedule IV drug), a class 
defined as drugs with no known medicinal value and high potential for abuse. Despite this 
scheduling, CBD is not addictive (rather appears to have anti-addictive properties) and the 
recent 2018 Farm Bill in the US removed hemp from the controlled substances act (CSA) and 
therefore hemp-derived CBD is not a drug that falls under the CSA scheduling system.  Even 
though CBD in the form of Epidiolex® is FDA-approved for the treatment of seizures associated 
with Lennox-Gastaut syndrome and Dravet syndrome, its use for the treatment of chronic 
radiculopathies maintained on COT is experimental and therefore, this study will be performed 
under an Investigational New Drug Application (IND # 152957). Refer to ANANDA Scientific 
Investigator's Brochure A1002N5S CBD in Liquid Nanodomains Oral Formulations for 
comprehensive drug information. 
2.2.1 Preclinical Data 
See section 2.1 above.  
2.2.2 Clinical Data to Date 
See section 2.1 above.  
2.2.3 Dose Rationale  
There is no known data on optimal dosing of CBD in attempting to reduce maintenance opioid 
analgesic doses in CNCP, and oral CBD dosing is complicated by limited bioavailability, at 
approximately 6% (91). However, in a small pilot trial in abstinent heroin dependent 
participants that suggested sustained anti-craving effects of CBD, doses of 400mg and 
800mg were safely administered (48). In a study in healthy participants, CBD (400mg and 
800mg) was co-administered with intravenous fentanyl without reports of serious adverse 
events (49). Further, CBD has safely been administered to patients with chronic pain 
syndromes at oral dosing up to 150mg daily for up to 3 months (63), (64). Case reports 
suggesting anti-addictive effects of CBD in cannabis use disorder have used doses of CBD 
up to 600mg daily orally (39, 92), and in a study of the acute effects of co-administration of 
CBD and alcohol, CBD was administered at a dose of 200mg (93). Consistent anxiolytic 
effects of CBD have been observed with oral dosing in the range of 400-600 mg/day (94) and 
CBD has been safely given to patients with schizophrenia up to 1280 mg per day (95). In a 
currently approved NIAAA funded clinical trial at NYULMC (Effects of cannabidiol in alcohol 
use disorder; NCT 03252756), CBD will be administered to patients with alcohol use disorder 
at 600mg and 1200mg daily oral doses. In this trial of patients with CNCP on COT, we 
propose to use an oral daily dose of 600mg per day of CBD and to contrast the effects with 
placebo. Based on previous human studies, the proposed dose of 600 mg daily is expected to 
be well tolerated in humans and to yield steady state levels within a safe and potentially 
therapeutic range. CBD does not appear to be psychoactive in this dose range (94) and 
although it has historically been classified as a schedule I drug (recent FDA re-scheduling to 
IV for Epidiolex®), it has no known addictive liability (87), unlike THC (the main psychoactive 
and addictive component of the cannabis plant). 
 
 


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2.3
Rationale
There is growing evidence implicating the endogenous cannabinoid system in mediating neural 
processes involved in opioid use/addiction and pain. Preclinical and preliminary studies in 
humans suggest that cannabidiol (CBD) may be helpful in reducing opioid use and decreasing 
pain in patients with radicular CNCP syndromes, but no studies have yet been conducted of the 
effects of CBD in humans with radicular CNCP maintained on COT. This would be the first 
clinical trial exploring the effects of CBD in patients with radicular CNCP syndromes (without 
OUD but at risk for developing an OUD), maintained on COT, and to assess its safety and 
pharmacokinetics when co-administered with opioid analgesics and potential efficacy in 
reducing maintenance opioid dose, while potentially decreasing pain. This investigation is 
significant from a public health perspective because given the limited efficacy to high risk 
profile of COT in CNCP, there is an urgent need to develop novel, safe, and non-addictive, non-
opioid pharmacotherapies that can both reduce the dose of maintenance prescription opioids 
and pain in patients with CNCP syndromes.   
 
2.4 
 Potential Risks & Benefits 
2.4.1 Known Potential Risks & Risk Mitigation Strategies 
2.4.1.1 Risks of experimental medication  
 
Oral CBD has been administered in clinical trials to both healthy volunteers and patients with 
various medical conditions, as single or multiple doses ranging from 10 mg to 6000 mg (49, 89, 
95-111). In most of the studies CBD was well tolerated and no severe or serious adverse events 
(AE) were reported. Hence, CBD is generally considered to have a favorable safety profile. It is 
noteworthy, however, that since clinical trials are conducted under widely varying conditions, the 
observed AE rates are difficult to compare and may not necessarily reflect those observed in 
practice. CBD safety has been further affirmed by the World Health Organization in a 
comprehensive monograph on this matter (112). Any adverse effects are therein considered 
more a result of drug-drug interactions between CBD and patients’ existing medications than 
anything else. This premise is likewise stated in a review of CBD for treating epilepsy (90).  
 
In a study published recently involving healthy volunteers, oral CBD doses of up to 6000 mg 
(single administration) and up to 1500 mg/d (multiple dose) were associated with only mild or 
moderate AEs, and none resulted in the early termination of participation (97). The most common 
AEs in all the trial arms were diarrhea, nausea, headache, and somnolence. Diarrhea and 
headache were more common in subjects taking CBD compared with placebo. The recommended 
dose of the FDA-approved Epidiolex® (mostly to children) ranges from 5 mg/kg/day to 5 mg/kg 
twice daily (10 mg/kg/day). Occasionally 20 mg/kg/day have also been administered. Since the 
drug has only been approved recently, no post-marketing safety data is available, and the 
following information is based on controlled and uncontrolled clinical trials experience. The most 
common adverse reactions that occurred in Epidiolex®-treated patients (incidence at least 10% 
and greater than placebo) were somnolence; decreased appetite; diarrhea; transaminase 
elevations; fatigue, malaise and asthenia; rash; insomnia, sleep disorder poor quality sleep, and 
infections (113, 114). Overall transaminase elevations were observed in 14% of CBD-treated 
patients versus 3% in those receiving placebo.  
 
In a human safety and PK study (see section 6.1 Study Agent(s) and Control Description  
Human safety and PK study with A1002 formulation) conducted on the formulation of A1002N5S 
and a second, similar formulation, a total of 12 AE’s occurred after the start of dosing.  None were 
serious, all were considered mild, and none were considered related to the study drugs.  The 
most frequent AE was headache (6/12, 50.0%) reported by 5 (out of the 15) subjects. 
 


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We do not anticipate any serious adverse events related to CBD administration in this trial. 
Subjects’ participation in the trial will be subject to discontinuation in the event of serious 
medication side effects, or if continued participation was deemed unsafe by study personnel. 
Patients who are discontinued from the trial will have a final evaluation within one week, and will 
be given appropriate treatment referrals.   
 
2.4.1.2 Risks of potential drug-drug interactions: Metabolism, P450 system and opioids 
A detailed review on human metabolites of CBD—their formation, biological activity and relevance 
in therapy—has been recently published (115). CBD undergoes extensive hydroxylation by 
CYP450 mixed function oxidases at multiple sites, primarily the liver and gut. Seven recombinant 
human CYP enzymes were identified as capable of metabolizing CBD: CYP1A1, CYP1A2, 
CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 (116, 117). CYP2C19 is particularly 
dominant in formation of the active metabolite 7-hydroxy-cannabidiol (7-OHCBD) which is then 
further metabolized by CYP3A4 to its inactive metabolite 7-carboxy-cannabidiol (7-COOH-CBD). 
The enzymatic processes responsible for the formation of the metabolites also involve several 
UDP-glucuronosyltransferase (UGT) isoforms, including UGT1A9, UGT2B7 and UGT2B17 and 
sulfotransferases (91, 115-117). It should also be mentioned that inter-individual differences in 
the expression and function of CYP450 enzymes may considerably affect the pharmacokinetics 
of CBD and its metabolites, and this could be relevant in the therapeutic action and any possible 
adverse effects of CBD-containing preparations. There is limited evidence for effects of CYP450-
metabolized drugs on the bioavailability or clearance of CBD except for CYP3A inhibitor 
ketoconazole and CYP3A inducer rifampicin. ketoconazole has been shown to double AUC of 
oral CBD and THC, while CYP3A inducer rifampicin reduced AUC by 2-fold (98). In the same 
study pretreatment with CYP2C19 inhibitor omeprazole did not affect CBD bioavailability, 
suggesting that bioavailability of CBD may not be compromised in patients with limited CYP2C19 
metabolic capacity.  
 
In summary, in vitro studies suggest that CBD is a potent inhibitor of CYP2C19 and CYP3A4 and 
a weaker CYP2D6 inhibitor (118-120). However, these in vitro studies found CBD IC50s in the 2-
ibition. Inhibitory constants 
(Ki)s were not calculated in these studies and so the observed values depended on the substrate 
concentration used to characterize the inhibition. In the Epidiolex registration trials CBD at doses 
ranging from 10-20 mg/kg/day were shown not affect the conversion of concomitantly 
administered clobazam to its active metabolite nor-clobazam (a CYP3A -mediated reaction) (121) 
but did affect clearance of nor-clobazam (a CYP2C19 mediated reaction).  This result provides 
evidence that CBD is a significant inhibitor of CYP2C19, but does not support a substantial effect 
of CBD as an inhibitor of CYP3A at the 20mg/kg doses used. A case study of 13 y.o. girl 
demonstrated increased circulating methadone levels (CYP3A is central to methadone 
metabolism) (122), but the mother of the child had been administering 250mg of CBD 6 times a 
day for 14 days and the child had metastatic liver disease (123). No clinical evidence of CBD 
interaction with CYP2D6-metabolized drugs currently exists, but CBD has been shown to be a 
moderate-potent CYP2D6 inhibitor in vitro (120). Interactions with tacrolimus have been reported 
(124) although the patient was receiving 2000-2900 mg CBD/day. More information on 
interactions with many drugs commonly used for other indications is warranted when considering 
dose adjustment of either CBD or the concomitant medications. There are also potential concerns 
about interactions with drugs with a narrow therapeutic index with significant metabolism through 
the CYP2C9 isoenzyme family. In a case report of a 27 y.o. man on warfarin (significantly 
metabolized by CYP2C9) and smoking recreational cannabis (includes CBD and THC), there was 
a reported increase in International Normalized Ratio (INR) to 4.6 without any clinical sequelae 
(125). 
 


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There is no currently published data regarding the interaction between CBD and ethanol or 
grapefruit, although a study with ketoconazole, which like grapefruit juice can inhibit intestinal 
CYP3A4, induced a doubling of CBD bioavailability (98). In the same study CYP3A inducer 
rifampicin reduced CBD AUC by 2-fold and pretreatment with CYP2C19 inhibitor omeprazole did 
not affect CBD bioavailability. 
 
Regarding potential drug-drug interactions with opioids and safety considerations, given that 
several prescription opioids are significantly metabolized by 2C19 (126, 127), it is theoretically 
possible that CBD could increase plasma and CNS concentrations of a participant’s opioid 
medication if this drug is significantly metabolized by these CYP enzymes, and this could have 
important safety considerations such as opioid intoxication and overdose. We are aware of one 
trial where oral CBD (up to a dose of 800mg) was co-administered with an opioid (intravenous 
fentanyl) with no reports of serious adverse events; however, because plasma fentanyl 
concentrations were not detectable in this study, it is difficult to gauge the significance of the 
outcomes (48). By excluding participants taking opioids that are significantly metabolized by 
2C19, we do not anticipate any significant or clinically relevant CBD-opioid interactions (i.e., 
signs of opioid intoxication, respiratory suppression, opioid overdose). 
 
However, we will take extra precautions to mitigate the risk of CBD-opioid interactions that could 
potentially cause increased plasma and CNS opioid concentrations. Given that the terminal 
elimination half-life of oral CBD is approximately 24 hours (128), one can assume it would take 
approximately 1 week for the initial dosing of CBD to achieve a steady-state plasma level and 
that this would represent the period of greatest risk of opioid toxicity. Therefore, we will take the 
following extra precautions after initiating treatment with CBD:  
 
 
On the first day of CBD vs placebo administration (T1), and at 2-days (T2), 1-week 
(T3), and 2-week (T4) after initiating CBD vs placebo treatment, participants will be 
administered the first daily morning dose of medication (CBD 300mg- six 50mg 
capsules, or placebo) for that treatment period, after a light meal, and will be 
evaluated for at least 3 hours at a supervised clinical laboratory setting within the 
NYU-HHC Clinical & Translational Science Institute (NYU-HHC CTSI) at Bellevue 
Hospital before discharge home. After administration of study drug or placebo until 
discharge for all visits, participants will be continuously monitored by the study 
physician or CTSI nursing staff. Participants will be monitored with safety 
assessments with particular attention directed to detect any signs of opioid 
intoxication or overdose (i.e., physical examination signs, vital sign monitoring 
including respiration and oxygenation). Vital signs (blood pressure, pulse) will be 
obtained at a minimum of every 30 minutes by study staff or with increased 
frequency (including continuous monitoring) if clinically necessary. The use of 
continuous pulse oximetry monitoring will occur post administration of study drug or 
placebo until discharge from the clinic to assess oxygenation status. The study 
physician will assess for clinical signs and symptoms suggestive of opioid 
intoxication or overdose (i.e., miosis, respiratory suppression, decreased 
oxygenation, sedation/lethargy), and will take appropriate medical steps to assure 
patient safety (i.e., Narcan administration, oxygen administration, inpatient 
hospitalization, breaking the blind, discontinuing study medication). The Richmond 
Agitation-Sedation Scale (RASS) (see section 7.1.1 Study Specific Procedures for 
details) will be used to assess clinician-rated somnolence or sedation. Participants 
will not be permitted to leave the study site until they are able to pass a standard field 
sobriety test (one-leg stand, finger-finger test, Romberg’s test, walk-and-turn task, 
and counting backwards) (129). If there are no AEs during this time period or lasting 
intoxicating effects of the study drug (e.g., participants are able to pass field sobriety 


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tests several hours after study drug administration), participants will be dispensed 
the proper quantity of study drug (CBD or placebo) to self-administer daily at home 
until the next scheduled study visit. 
 
We will advise participants of possible CBD-opioid interactions, and ask them to 
report exacerbation or decrease of the effects of opioids during treatment, should this 
occur. This will be reported as routine outcome data, or in the case the interaction 
results in adverse symptoms, it will be reported as an adverse effect. We will closely 
monitor for subjective adverse effects throughout the study, especially for signs and 
symptoms that may indicate increased opioid concentrations. If necessary, at any 
point for safety reasons, we will break the blind if there is the possibility of serious 
adverse CBD-opioid interactions and take appropriate steps to assure safety of 
the participant. Participants will also be counseled about how to recognize adverse 
events, and will be provided with a contact number to reach study personnel in 
between these weekly interviews.  
 
Regarding the potential effects of CBD on interactions with drugs with significant CYP 3A4 
interactions, there are potential concerns of drug-drug interactions especially with CYP3A4 
inhibitor ketoconazole and CYP3A4 inducer rifampicin. As such we will exclude medications 
primarily or significantly metabolized by CYP3A4 (i.e., ketoconazole, rifampicin) but will not 
exclude opioids (i.e., hydrocodone, oxycodone) that are partially metabolized through 3A4 
(126). In addition, given that CBD is a weak inhibitor of CYP2D6, we will not exclude 
medications (including opioids) that are metabolized partially by 2D6 (i.e., hydrocodone, 
oxycodone) (126). We will exclude drugs with a narrow therapeutic window and significant 
metabolism through the CYP2C9 isoenzyme family with potential for clinically significant drug-
drug interactions (i.e., warfarin). Given that grapefruit juice is a significant inhibitor of CYP 3A4, 
we will instruct participants to avoid consuming grapefruit or grapefruit juice during the duration 
of the study. 
2.4.1.3 Risk of hepatocellular injury and adverse CBD-valproate interactions 
CBD (in the form of Epidiolex™) has been reported to be associated with dose-related elevations 
in liver transaminases (ALT and/or AST). Increased levels of ALT were more pronounced than 
AST, suggesting that the liver was the source of this occurrence. There also was a clear dose 
association: 8% elevations overall in the 10 mg/kg group and 16% in the 20 mg/kg group (113, 
114). Elevated liver enzymes do not necessarily signal a serious liver problem. There do not 
appear to be reports of CBD-treated patients who have experienced liver failure, and CBD may 
actually have therapeutic utility in treating liver conditions associated with alcohol, inflammation 
use, oxidative stress and steatosis (130). Identified risk factors for transaminase elevation 
included concomitant treatment with valproic acid (a medication used to treat seizure disorders, 
mood conditions and migraine headaches), elevated baseline liver function tests, and higher 
doses of cannabidiol. Most events of transaminase elevation occurred within 30 to 90 days after 
initiation of CBD treatment although rare cases were observed up to 200 days after initiation of 
treatment, particularly in patients also taking valproic acid. These abnormalities generally resolved 
with discontinuation of cannabidiol or dose decreases in cannabidiol or valproic acid, yet elevated 
levels also resolved spontaneously without changing the dose of CBD (113).   
Given that CBD can cause dose-related elevations in liver transaminases, potential participants 
with elevated baseline transaminase levels 
2 times the upper limit of normal (ULN) will be 
excluded from trial participation. Further, in addition to obtaining baseline liver function tests 
(LFTs), after initiating study medication or placebo, subsequent LFTs will be obtained at 1-week 
and 2-weeks (final study visit). If participants develop clinical signs and symptoms suggestive of 
significant hepatic injury (i.e., nausea, vomiting, right upper quadrant pain, anorexia, fatigue, 


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jaundice, dark urine), they will be immediately evaluated medically with an assessment of LFTs 
and appropriate medical steps will be taken to assure patient safety (i.e., breaking the blind, 
discontinuing study medication, hospitalization). Any subject who has LFTs 
2 x ULN will be 
discontinued from study participation and will be referred for appropriate follow-up. Given the 
known adverse drug-drug interaction between CBD and valproate (in terms of hepatic function), 
we will exclude potential participants who are on valproate.   
 
2.4.1.4 Risk in sexual reproduction  
Risks of CBD in pregnancy, lactation, and sperm are unknown. Therefore, pregnancy and 
lactation are exclusion criteria, and participants capable of bearing or fathering a child will be 
required to document birth control use and be offered pregnancy testing throughout the study. 
All participants will be informed of the potential risks.  
 
If the participant is biologically male, they will not be offered pregnancy testing. If they are 
capable of fathering a child, they must document birth control use throughout the study. If they 
are incapable of fathering a child (e.g., vasectomy), they will not need to document birth control 
use. 
 
If the participant is biologically female or intersex and not of childbearing potential (e.g., bilateral 
oophorectomy, menopause with >1yr since last menstruation), they will not be offered 
pregnancy testing and will not need to document birth control use. If the participant is of 
childbearing potential, they will be required to document birth control use and will be offered 
pregnancy testing throughout the study, even if their sexual preferences and/or behaviors will 
not lead to pregnancy.  
 
If the participant is pregnant, they will be asked to discontinue participation in this study and will 
be referred to their primary care physician. If a participant becomes pregnant while in this study, 
they will immediately contact their study physician and will be counseled as to possible 
alternatives to study participation.  
 
Any participant capable of bearing or fathering a child must be willing to practice appropriate 
and reliable birth control. Acceptable forms of birth control for all trial participants are as follows: 
 
Hormonal methods like birth control capsules, patches, vaginal rings, or implants 
 
Barrier methods such as condoms or a diaphragm used with spermicide (i.e., foam, 
cream or gel that kills sperm) 
 
Intrauterine device (IUD) 
 
Vasectomy  
 
Sexual abstinence (from intercourse from which pregnancy may occur) 
 
Monogamous relationship with a vasectomized partner 
 
Monogamous relationship with a partner of non-childbearing potential 
 
Same-sex relationship 
 
2.4.1.5 Risks to confidentiality and privacy  
There is a risk for the identity of a participant to be disclosed to non-study personnel, resulting in 
a loss of privacy and a potential risk to reputation. This risk is estimated to be extremely low due 
to the various protections listed below, which include obtaining a certificate of confidentiality. In 
addition, information from this study may be submitted to the U.S. Food and Drug Administration 
(FDA) and NIH/NIDA. Records which identify subjects and the consent form signed by subjects 
may be inspected by the FDA, NIH/NIDA, and the NYU Medical Center Institutional Review Board. 
Because of the need to release information to these parties, absolute confidentiality cannot be 
guaranteed. The results of this research project may be presented at meetings or in publications. 
However, the identity of individual subjects will not be disclosed in those presentations. In this 


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study participants will be asked about drug use and other possibly illegal activities. The 
researchers will keep information as confidential as possible, but complete confidentiality cannot 
be guaranteed. On rare occasions, research records may be subpoenaed by a court. Exceptions 
to the protection of a participant’s confidentiality would occur if it were learned that the participant 
was a danger to him/herself or to others, that a child had been abused or neglected, or that an 
elder or dependent had been abused. Should this happen, the appropriate authorities would be 
notified, as required by law.  
Confidentiality of research material will be ensured by storing the research materials in locked 
cabinets. Permission for access must be granted by the PI. Material will be available only to 
project staff, and only as needed. All project staff will be thoroughly trained in issues relating to 
confidentiality. Participants will be identified in case report forms (CRFs) by initials and an 
identification code. Data will be entered into TrialMaster®, a 21 CFR 11 compliant system at 
NYULH, a program designed specifically to protect patient privacy and confidentiality. Published 
reports will be based on group data; no individual data will be reported. As a further protection to 
confidentiality, and because this trial is funded by NIH/NIDA, a certificate of confidentiality has 
been automatically generated by NIH/NIDA (https://grants.nih.gov/policy/humansubjects/coc/how-
to-apply.htm). With this Certificate, the investigators cannot be forced (for example by court order 
or subpoena) to disclose research information that may identify individual patients in any Federal, 
State, or local civil, criminal, administrative, legislative, or other proceedings. Disclosure will be 
necessary, however, upon request of NIH/NIDA for audit or program evaluation purposes. 
NIH/NIDA ensures confidentiality of requested data. Participants will be notified in the informed 
consent that the Certificate of Confidentiality does not prevent them or a member of their family 
from voluntarily releasing information about themselves and their involvement in the research. If 
an insurer, employer or other person obtains their written consent to receive research information, 
then the researcher may not use the Certificate to withhold that information. Participants will also 
be informed that the Certificate of Confidentiality does not prevent the researchers from disclosing 
voluntarily, without their consent, information that would identify them as a participant of the 
research project under the following circumstances: the present danger of child abuse, suicide, 
and/or homicide. 
2.4.1.6 Risks of blood draws  
For most people, needle punctures for blood draws do not cause any serious problems. However, 
they may cause bleeding, bruising, discomfort, infections and/or pain at the needle site, or 
dizziness. 
 
2.4.1.7 Risks of assessment procedures  
There are no known psychological risks associated with the questionnaires used in the study, all 
of which have been used extensively in clinical populations. It is possible that discussion of 
substance use and psychiatric symptoms may cause emotional discomfort in some participants. 
One of the investigators of the project will be available to meet with any participant who 
becomes distressed about any aspect of the protocol and wishes to discuss this. Further, with 
respect to minimizing the discomfort that may result from the interview, research coordinators or 
research data associates are selected based on their personal attributes and interpersonal skills 
as well as their substantive knowledge.  They are further trained and periodically observed to 
ensure that they are respectful and sensitive to the needs and feelings of the subjects in all 
contacts.  Furthermore, they are trained to recognize signs of significant stress or enervation 
and are instructed that they should gently terminate the interview, perhaps to re-approach the 
subject at another time, whenever distress is observed. 


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2.4.2
Known Potential Benefits
Subjects may or may not experience clinical benefit from this study. Pre-clinical and clinical data 
suggest a possibility that the study drug (CBD) could produce anxiolytic, anti-addictive, and anti-
pain effects. Components of study participation that are likely to be of benefit to participants 
include free psychiatric and medical evaluations, and the support and attention of participating 
in a clinical trial. 
 
Objectives and Purpose 
3.1 
Primary Objective 
Aim 1 (Safety): To collect preliminary safety, tolerability, and pharmacokinetic data for the use 
of CBD in patients with radicular CNCP syndromes maintained on COT. Hypothesis 1a: 
Compared to placebo, CBD will be well tolerated by participants with no treatment-related 
serious adverse events (SAEs) or persisting CBD-related AEs. Hypothesis 1b (plasma opioid 
concentrations): Compared to placebo, CBD will not increase plasma opioid concentrations 
(relative to baseline) by greater than or equal to 150% at any of the assessment time-points 
post-randomization (1-day, 2-day, 1-week, and 2-weeks). 
3.2 
Secondary Objective 
Aim 2 (Efficacy): To obtain a preliminary assessment of efficacy of CBD vs placebo in reducing 
pain. Secondary Outcome (Pain): Hypothesis 2: Relative to baseline, CBD will be associated 
with a greater reduction in pain measures (pain catastrophizing and pain intensity/pain-related 
interference) compared to placebo at week 2.  
3.3 
Exploratory Objectives/Aims 
3.3.1 Exploratory Objectives. The objective is to obtain a preliminary assessment of efficacy 
of CBD vs placebo in reducing anxiety, depression, insomnia, opioid craving, and opioid use. 
Exploratory Aim 1: Compared to placebo, CBD will be associated with a greater reduction in 
anxiety relative to baseline.  
Exploratory Aim 2: Compared to placebo, CBD will be associated with a greater reduction in 
depression relative to baseline.  
Exploratory Aim 3: Compared to placebo, CBD will be associated with a greater reduction in 
insomnia relative to baseline. 
Exploratory Aim 4: Compared to placebo, CBD will be associated with a greater reduction in 
opioid craving relative to baseline.  
Exploratory Aim 5: Compared to placebo, CBD will be associated with a greater reduction in 
opioid use relative to baseline.  
Results will serve as proof of concept, inform us about the safety and potential efficacy of this 
approach, and guide the design of a larger clinical trial.   
4 
 
Study Design and Endpoints 
4.1 
Description of Study Design 
The proposed study is a phase I/II, double-blind, randomized, exploratory study designed to 
assess feasibility, safety, pharmacokinetics, and to contrast effects of CBD treatment to those of 
placebo on pain outcomes in patients with chronic non-cancer spinal radicular pain syndromes 
maintained on COT. We will specifically evaluate the safety of a 2-week, daily CBD treatment 
regimen in a chronic pain (radiculopathies) population maintained on COT, assess the impact of 
CBD on pharmacologic and psychological domains in patients with chronic radiculopathies 
maintained on COT, and to generate preliminary data on the impact of CBD on pain 
catastrophizing and interference, anxiety, depression, sleep quality, opioid craving, and opioid 


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sparing in this patient population. Many patients with chronic radicular pain syndromes who are 
maintained on COT may have COT-induced hyperalgesia, and it is possible, therefore, that a 
reduction of COT dose might produce a reduction in chronic pain. Following screening and 
baseline assessments, 20 participants will be randomized in a 3:1 ratio to receive either 600mg 
CBD/day (PO) or placebo for 2 weeks. Safety and tolerability of CBD will be assessed 
throughout the trial. Opioid analgesic maintenance dose will be assessed at baseline and 
longitudinally. Opioid analgesic plasma concentrations will be collected at the same time 
relative to when participants take their daily opioid analgesic medications at baseline (prior to 
initiating pharmacologic treatment) and all subsequent visits: 1-day, 2-day, 1-week, and 2-
weeks. CBD plasma concentrations will be obtained at study visits following initiation of study 
drug administration (1-day, 2-day, 1-week, and 2-weeks) and will occur at the following time 
assessment points at these visits: trough (pre-dose), 1-hour post drug administration, and 3-
hours post drug administration, with an additional sample collected 5-hours post drug 
administration at T3 visit (1-week).  
4.2 
Study Endpoints 
4.2.1 Primary Study Endpoints 
Primary Outcome 
Establishment of the safety and pharmacokinetic effects of 300mg CBD BID on plasma levels of 
the following opioid analgesics in pain patients on a daily regimen: morphine, hydrocodone, 
oxycodone.  
 
Safety 
Safety will be assessed by collection of adverse events at all visits after treatment is initiated. 
Liver function tests (LFTs) will be obtained at screening, 1-week, and 2-weeks after initiating 
study medication or placebo to assess liver function during treatment with study medication. 
Any subject who has LFTs 
2 x ULN will be discontinued from study participation and will be 
referred for appropriate follow-up. Risk of suicidality will be assessed using the Columbia-
Suicide Severity Rating Scale (C-SSRS) (131). Extensive safety monitoring (see Safety 
Oversight section below for details) will occur at the CTSI for all study visits, to assess for any 
clinical signs of opioid intoxication/overdose.  
Pharmacokinetics: Plasma Opioid and CBD concentrations 
Opioid analgesic plasma concentrations will be collected at the same time relative to when 
participants take their daily opioid analgesic medications at baseline (prior to initiating 
pharmacologic treatment) and at all subsequent visits: 1-day, 2-day, 1-week, and 2-weeks. 
CBD plasma concentrations will be obtained at study visits (1-day, 2-day, 1-week, and 2-
weeks) following initiation of study drug administration. Samples will be collected at the 
following time assessment points at these visits: trough (pre-dose), 1-hour post drug-
administration, and 3-hours post drug administration, with an additional sample taken 5-hours 
post drug-administration during the T3 visit.  
Primary efficacy endpoint: None 
 
4.2.2 Secondary Study Endpoints: Effects of CBD vs placebo on pain outcomes:  
Pain: Participants in this trial with chronic radicular pain syndromes who are maintained on COT 
may have COT-induced hyperalgesia, and therefore, we expect a reduction of COT dose might 
produce a reduction in chronic pain. Pain will be assessed by measuring pain catastrophizing 
[with the Pain Catastrophizing scale (PCS)] (132)  and pain intensity/pain-related interference 
[with the Brief Pain Inventory (BPI)] (133) assessed at baseline, 1-day, 2-day, 1-week, and 2-


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weeks. The secondary efficacy outcome will be assessment of change in pain from the 
baseline visit to 2-weeks post-initiation of treatment. 
4.2.3 Exploratory Endpoints 
Anxiety: Anxiety will be assessed with the PROMIS® (134) (Patient-Reported Outcomes 
Measurement Information System) anxiety scale (long form) assessed at baseline and the 
following post-randomization time-points: 1-day, 2-day, 1-week, and 2-weeks. 
 
Depression: Anxiety will be assessed with the PROMIS® (134) (Patient-Reported Outcomes 
Measurement Information System) depression scale (short form) assessed at baseline and the 
following time-points: 1-day, scale (135), at baseline and the following time-points: 1-day, 2-
day, 1-week, and 2-weeks.  
Opioid Craving will be measured with the Visual Analog Scale (VAS) (136) assessed at 
baseline and the following time-points: 1-day, 2-day, 1-week, and 2-weeks. 
 
Sleep disturbances will be measured with the PROMIS® Sleep-Related Impairment (SRI) short 
form (135), at baseline and the following post-randomization time-points: 1-day, 2-day, 1-week, 
and 2-weeks.   
Opioid maintenance dose will be measured in morphine equivalent daily doses (MEDD) 
assessed at screening, baseline, 1-day, 1-week, and 2-weeks.  
 
5 
Study Enrollment and Withdrawal 
5.1 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
 
 
 
Diagnosis of radicular CNCP (i.e., lumbar, cervical, thoracic)  
 
Maintained on stable dose of opioid therapy for a minimum of 1 month 
o Note: Only opioid pharmacotherapies using immediate or sustained release 
versions of morphine, hydrocodone, oxycodone will be allowed 
 
Able to provide voluntary informed consent  
 
If a person of reproductive potential, are willing to use approved form of contraception 
from screening for duration of the trial  
5.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
trial: 
 
Exclusionary medical conditions (e.g., unstable cardiac, hepatic, renal, neurologic 
illness) or any medical illness that in the opinion of the study physician poses a 
potential medical danger to the participant 
 
Exclusionary laboratory abnormalities (clinically significant abnormalities of complete 
blood count or chemistries, significantly impaired liver function2) 
 
Current substance use disorder (including Opioid Use Disorder) other than nicotine or 
caffeine 
 
At screening, a positive urine toxicology test for: amphetamines (AMP), barbiturates 
(BAR), buprenorphine (BUP), benzodiazepines (BZO), cocaine (COC), 3,4-


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methylenedioxymethamphetamine (MDMA), methamphetamine (MET), methadone 
(MTD), phencyclidine (PCP), and tetrahydrocannabinol (THC) 
 
At screening, an alcohol level greater than 0 on a breathalyzer  
 
Severe psychiatric conditions including past or current DSM5 diagnosis of 
schizophrenia, schizoaffective disorder, bipolar disorder 
 
Current significant suicidality (assessed using the C-SSRS), any suicidal behavior in the 
past 12 months, or any history of suicide attempts 
 
Current use of recreational or medical cannabis or any product containing CBD  
 
Pregnancy or lactation 
 
Current use of concomitant medications metabolized primarily by CYP2C19 isoenzymes 
 
Current use of concomitant medications significantly or primarily metabolized by 
CYP3A4 with the potential for adverse drug-drug interactions with CBD (i.e., 
ketoconazole, rifampicin)  
o Note: Participants will be instructed to avoid grapefruit juice during the duration of 
the study 
 
Current use of concomitant medications with a narrow therapeutic window significantly 
or primarily metabolized by CYP2C9 with the potential for adverse drug-drug interactions 
with CBD (i.e., warfarin)  
 
Current use of concomitant medications known to have adverse drug-drug interactions 
with CBD (i.e., valproate) or the potential to cause significant drug-drug interactions (i.e., 
clobazam). 
 
Known allergy to CBD or any ingredient of the study compound 
 
Currently enrolled in a clinical trial assessing the effects of an anti-pain intervention 
 
1Per the July 2020 FDA drug safety communication (https://www.fda.gov/drugs/drug-safety-and-
availability/fda-recommends-health-care-professionals-discuss-naloxone-all-patients-when-
prescribing-opioid-pain), the study team will communicate with all clinicians prescribing opioids 
to subjects enrolled in study that they provide a naloxone prescription for each participant. If a 
participant does not have access to naloxone, study staff will provide them with a naloxone kit. 
2Significantly impaired liver function is defined as: Liver Fun
of normal (ULN).   
5.3 
Vulnerable Subjects 
No vulnerable populations will be included in this clinical trial.  
 
5.4 
Strategies for Recruitment and Retention 
Drs. Doan (co-I) and Wang, anesthesiologists with expertise in pain and with access to patients 
with radiculopathic CNCP on COT in the NYULH system, and Dr. Ross will initiate contact with 
potential participants through a multimodal approach including contacts with treating clinicians in 
pain clinics throughout the NYULH but in particular at the following clinics where Drs. Doan and 
Wang treat patients with CNCP syndromes:   
 
Center for the Study and Treatment of Pain 
Department of Anesthesiology, Perioperative Care and Pain Medicine 
240 E 38th St, 14th floor 
NY, NY 10016 
Yearly total visits: 3416 
New patients per year: 1766 
 
Center for the Study and Treatment of Pain – Preston Robert Tisch Center for Men’s Health 


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Department of Anesthesiology, Perioperative Care and Pain Medicine
555 Madison Ave 
NY, NY 10022 
Yearly total visits: 666 
Center for the Study and Treatment of Pain – NYU Langone Seaport Orthopedics 
Department of Anesthesiology, Perioperative Care and Pain Medicine 
233 Broadway, Suite 640 
NY, NY 10279 
Yearly total visits: 1100
 
Other potential sites for recruitment within the NYULMC system will include patients at 
pain clinics at: Bellevue Hospital, the Manhattan VA, and Lutheran Hospital. Active recruitment 
will also take place through direct advertising (i.e., newspaper, radio) and social media sources 
(i.e., Facebook, Twitter). Note that the recruitment materials will be submitted via modification 
following initial IRB approval and prior to use.    
To optimize recruitment, we have a large number of potentially eligible patients across 
recruitment sites at NYULMC and in the local NYC area, and recruitment will be led by co-
investigators in the NYULMC Anesthesia Department (Dr. Wang, Dr. Doan), who are experts 
in pain medicine and have access to patients within the NYULMC system with radicular 
CNCP syndromes. If recruitment within the NYULMC system does not yield enough 
participants, we will reach out to other institutions with treating clinicians in pain clinics 
throughout the Metropolitan area (e.g., Weill Medical College of Cornell University). 
If recruitment lags, strategies would include examining recruitment strategies and 
modifying or increasing them as necessary. Regarding retention, we will include procedures to 
optimize retention rates including weekly reimbursements, medical management, and tracking 
forms. If follow-up rates fall below 85%, we will re-evaluate and optimize these procedures 
accordingly. If this is a frequent occurrence, we would examine screening procedures, increase 
contact with participants, and consider altering the reimbursement schedule to enhance 
retention.  
5.4.1 Collaboration with Treating Physicians [TPs] for Recruitment Purposes 
This study will utilize a multimodal approach for recruitment, including collaboration with treating 
clinicians in pain clinics throughout the NYULH system and/or Metropolitan area. A member of 
the study team will initiate contact with potential participants through the following methods:
 
Treating physicians will independently discuss the study with potentially eligible 
participants  
o 
If the patient is interested, the TP will contact a study team member with the 
patient’s contact information or MRN (to obtain contact information) 
o 
Study team member will contact the patient to request a pre-screening telephone 
interview to determine eligibility for a screening visit 
 
Treating physicians will discuss the study with potentially eligible participants with help 
from the study team  
o Physicians will provide their schedule to the study team through EPIC 
o Study team will review the TP’s upcoming patient visits and provide them with a 
list of potentially eligible patients 
o TP will discuss the study with potentially eligible patients or study team will obtain 
the TP’s permission to directly contact potentially eligible patients on behalf of TP 
by [letter, phone, MyChart, email, and/or going to the facilities] to ask if they’re 
interested in participating. These recruitment materials are uploaded in RNAV. 
 
Any recruitment information (as well as any contact with potential or enrolled 
participants) sent by email will utilize [Send Safe] email methodology.   


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Should the potential participants agree, the study team will provide the participants with 
information regarding the next steps for study participation.
5.4.2 Use of DataCore/EPIC/ResearchMatch Information for Recruitment Purposes
This study will utilize DataCore/EPIC and ResearchMatch to identify potentially eligible study 
participants. The following process will be utilized regarding the use of EPIC/ResearchMatch for 
recruitment: 
 
The data will be gathered by requesting a report of potentially eligible participants 
through DataCore or ResearchMatch 
 
The data will be used for several purposes including: 
o Identifying potentially eligible participants who may meet core study entry criteria 
such as diagnosis of chronic radicular pain syndromes (i.e., 
cervical/thoracic/lumbar radiculopathy) and currently on opioid 
pharmacotherapies (i.e., morphine, oxycodone, or hydrocodone derivatives) 
o Contacting participants who are potentially eligible based on the 
DataCore/ResearchMatch queries to request a pre-screening telephone interview 
to determine eligibility for a screening visit 
 
The following study team members will have access to the EPIC/ResearchMatch search 
results: 
o PI 
o Research Coordinator 
o Research Project Manager 
o Research Data Associate 
o Co-investigators (i.e., involved in the recruitment process) 
 
The following data points will be used for the DataCore/ResearchMatch search: 
o 
 
o Diagnosis of chronic radicular pain syndromes (i.e., lumbar, cervical, thoracic) 
o List of current medications, including currently on an opioid pharmacotherapy 
allowed as part of study participation (i.e., morphine, oxycodone, or hydrocodone 
derivatives) or exclusionary medications (i.e., ketoconazole, rifampicin, warfarin, 
valproate, clobazam) 
o List of current known allergies  
Data will be discarded immediately after the recruitment targets have been met
The study team will search EPIC every 2 months throughout the study until recruitment 
targets have been met 
 
After eligible, potential participants have been identified, their treating physicians (TPs) 
will be notified of this. 
 
The study team will obtain the TP’s permission to directly contact potential participants 
on behalf of TP by [letter, phone, MyChart, and/or email] to ask if they’re interested in 
participating. These recruitment materials are uploaded in RNAV. 
 
Any recruitment information (as well as any contact with potential or enrolled 
participants) sent by email will utilize [Send Safe] email methodology.   
 
Should the potential participants agree, the study team will provide the participants with 
information regarding the next steps for study participation.   
 
If a potential participant requests information regarding opting out of further recruitment 
for all research, they will be directed to contact the study coordinator or have them 
contact research-contact-optout@nyumc.org or 1-855-777-7858.  


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5.5
Duration of Study Participation
The total duration of participant involvement, including screening and treatment visits, will be 
approximately 6 weeks. The total approximate time of contact during these 6 weeks is estimated 
at 24 hrs. 
5.6 
Total Number of Participants and Sites  
Recruitment will end when approximately 30 participants are enrolled. It is expected that 
approximately 30 participants will be enrolled in order to produce 20 participants that can be 
evaluated to adequately assess study endpoints.  
 
5.7 
Participant Withdrawal or Termination 
5.7.1 Reasons for Withdrawal or Termination 
Participants are free to withdraw from participation in the study at any time upon request. An 
investigator may terminate participation in the study 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 
 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 
The participant fails to adhere to protocol requirements 
 
COVID-19 status significantly interferes with continued participation in the study 
5.7.2 Handling of Participant Withdrawals or Termination 
Every effort will be made to undertake the protocol-specified safety follow-up procedures to 
capture AEs, SAEs, and Unanticipated Problems. The investigator will attempt to obtain at a 
minimum survival data on all participants lost to follow-up. If a participant is lost to follow-up, 
they study team will attempt to contact the participant 3 times by telephone and twice by email. 
If the participant fails to respond, locators identified by the participant at screening will be 
contacted in the method specified by the participant. If participants withdraw, are terminated, or 
are lost to follow-up prior to the end of the 2-week treatment phase (prior to T4), they will be 
replaced to allow for 20 participants to complete the 2-week treatment phase (through T4). 
 
5.8 
Premature Termination or Suspension of Study 
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 Dr. Ross, NIH/NIDA, or 
the FDA. If the study is prematurely terminated or suspended, the PI will promptly inform the 
IRB and will provide the reason(s) for the termination or suspension. 
 
Circumstances that may 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 with protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 
Study may resume once concerns about safety, protocol compliance, data quality are 
addressed and satisfy the sponsor, IRB and/or FDA. 
 


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6 
 
Study Agent (Study drug) and/or Procedural Intervention 
6.1 
Study Agent(s) and Control Description  
Nomenclature 
Chemical name:       Cannabidiol 
IUPAC name: 
 2-(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl-5-pentylbenzene-
1,3-diol 
Structure 
The chemical structure of CBD is shown below: 
 
 
  
 
 
 
 
 
 
 
Figure 1 
Chemical structure of C 
Molecular formula: C21H30O2
Molecular weight:  314.469 g/mol 
The active ingredient in the Ananda investigational new drug (A1002N5S) is cannabidiol (CBD), 
extracted from hemp, at a 5% strength, produced and purified by Mile High Labs International 
Description of Liquid Nanodomains Oral Formulations 
The novel formulation is based on the principle that a water-free mixture of some concentrated 
inactive ingredients (excipients) self-assemble spontaneously into liquid nanodomains that 
contain the active component CBD. CBD in such nanodomains is fully water soluble. In contrast, 
CBD alone is insoluble. Since the nanodomains are very small (10- 50 nm diameter) and thus 
have a very high surface-area-to-volume ratio, they have a high loading capacity of CBD at their 
interface.  
Ananda Scientific Inc., in conjunction with LDS Technologies (Jerusalem, Israel), is currently 
developing a new, pharmaceutical-grade, highly pure form of CBD, extracted from hemp with 
improved bioavailability which is eventually intended for marketing approval by regulatory 
authorities in the United States and elsewhere as a pharmaceutical drug. 
In a single-dose (50mg oral CBD), three-way pilot cross-over study in heathy normal volunteers, 
the A1002N5S formulation was shown to reduce Tmax from about 2 hours to 1 hour (see clinical 
information section below) and increase absorption by about 40% over a CBD in oil reference 
compound.  
Pre-clinical Information 
Pharmacokinetics 
The oral bioavailability of CBD is apparently very low, in some reports less than 10%. Absorption 
is slow and erratic, resulting in maximal plasma concentrations usually after more than 1 hour, 


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increasing with food and various lipid formulations. CBD is readily distributed throughout the body 
including brain tissue (i.e., crosses the blood-brain barrier). Plasma and brain concentrations are 
dose-dependent in animals. Like delta-9-tetrahydrocannabinol (THC), CBD may preferentially 
accumulate in adipose tissues due to its high lipophilicity. There are data showing that CBD 
undergoes extensive first pass metabolism. The resulting metabolites, most of which are 
physiologically inactive, are excreted in feces and urine. Based on animal and human studies, 
elimination of CBD from plasma is usually bi-phasic with an initial half-life ranging from 
approximately 1 to 3 hours and the terminal elimination half-life is in the order of 24 hours or 
longer (97, 113, 137). 
Toxicology
The pre-clinical toxicology information presented in this section is derived from the Epidiolex® (an 
FDA-approved version of CBD for the treatment of Dravet’s and Lennox Gestaut syndrome) non-
clinical reviews, submitted by GW Pharmaceuticals to the FDA in October 2017 and approved in 
June 2018 (114). In a 26-week (gavage) Wistar rat study, no dose-limiting toxicity was observed. 
Slight (1.2-1.4-fold) increases in alanine transaminase (ALT) and alkaline phosphatase (ALP) 
were observed at the 50 mg/kg QD mid-dose (MD) and 150 mg/kg QD high-dose (HD). No effects 
were observed on sperm parameters; interstitial cell hyperplasia in ovary was observed at the MD 
and HD. In a 39-week Beagle dog study there were no deaths and the only clinical ramification 
was soft/liquid/mucoid feces. Decreases in absolute body weight (compared to control) were 
observed in all dogs. As in rats, the primary target organ was liver, with hepatocellular hypertrophy 
detected at all doses including 10 mg/kg low-dose (LD), accompanied by increases in ALT (slight) 
and ALP (up to 8-fold). A full battery of oral reproductive and developmental studies was 
conducted using purified CBD. Fertility and early embryonic development, embryo-fetal 
development (EFD), and pre- and postnatal development studies in Wistar rats were conducted 
using dose of 0, 75, 150, and 250 mg/kg. Toxicity expected at a high dose in these studies was 
not observed in females. In an EFD study in New Zealand White rabbit (0, 50, 80, and 125 mg/kg), 
adverse fetal effects (reduced body weight and increased variations) were observed at the HD, 
associated with maternal toxicity (body weight loss). There was no evidence of mutagenicity in a 
standard battery of genetic toxicology studies. The carcinogenic potential of CBD was assessed 
in a dietary carcinogenicity study in mice. No drug-related neoplastic findings were reported in 
two 13-week dose-ranging studies. 
Pharmacokinetics of the Ananda Formulations in Rat  
The PK profile of the Ananda formulations in rat was studied at Science in Action Ltd., (Israel). 
Blood samples were assayed for CBD concentrations at Analyst Research Laboratories (Israel) 
and the PK parameters were calculated from the data. 
 
Sprague Dawley male rats (average weight 250g) received a single dose of 8 mg/kg (i.e., an 
average of 2.0 mg/animal) via gavage feeding. The CBD concentration in all formulations was 4.0 
mg/mL. Blood samples for CBD plasma concentrations were collected at 0.25, 0.5, 2.0, 4.0, 8.0 
and 12 hrs after dosing. 6 different formulations were evaluated and compared to a Control 
formulation (CBD in olive oil) at the same concentration. There were 5 animals in each group. Of 
the 6 formulations 2 were selected, due to their unique PK parameters, as candidates for a 
preliminary human PK study: A1002  
 


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Figure 1 displays the time-concentration curves of two selected formulations, compared to the 
Control, CBD in olive oil, preparation. Table 1 outlines the average concentrations and the ratio 
between the new formulation and the Control formulation at each time point.  
Figure 1  
CBD Plasma concentration-over-time Curves 
Table 1 
Average CBD Plasma Concentrations per Time Point and IP/Control Ratio 
*Ave: average, [SD]: Standard deviation  
**Ratio: IP/Control 
 
The PK parameters (Tmax, Cmax and AUC0-12) are displayed in Figure 2 and summarized in Table 
2. The tested formulation shows advantages in either Cmax, AUC0-12 and/or Tmax values compared 
to the 'Control' formulation. 
 
Formulation A1002 was selected for the preliminary human PK trial because its bioavailability 
parameters (Cmax and AUC0-12) were markedly superior to the Control formulation. Tmax, however, 
was the same (2 hrs). This is significant when comparing the A1002 formulation with the known 
published data of the commercialized and FDA approved Epidiolex® product in which the Tmax
was measured between 4 to 5 hours post oral administration. 
Formulation
Time (Hr) 
0.25
0.5
2.0
4.0 
8.0 
12.0 
A1002 (N=5) 
Ave (ng/mL)  
[SD]*
28.10 
[0.76] 
137.34 
[5.49] 
213.77 
[16.82] 
54.65 
[4.42] 
18.66 
[3.58) 
5.40 
[0.58] 
Ratio** 
3.86
2.90
1.62 
1.69 
3.13 
2.08 
Control 
Ave  (ng/mL  
[SD]*
7.28 
[0.83]
47.43 
[3.40]
131.68 
[4.76]
32.29 
[1.90]
5.97 
[0.91]
2.60 
[0.09]


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Figure 2 PK parameters for A1002 formulation
Table 3 
CBD PK parameters and ratio of IP vs. Control 
Formulation
Tmax (hr) 
Cmax (ng/mL) 
AUC0-12 (ng*h/mL)
A1002N5S 
Ave*   
[SD]   
2.0
0.0
213.77 
16.82
750.65 
41.65 
Ratio**
1.00 
1.62 
1.88
Control  
Ave*   
[SD]   
2.0
0.0
131.68 
4.76 
399.70 
11.46 
*Ave: average, [SD]: Standard deviation  
**Ratio: IP/Control 
Overall Summary of pre-clinical Studies 
The pharmacokinetic (PK) profile of the A1002N5S formulation was studied in rats. Sprague 
Dawley male rats (average weight 250 gr) received a single dose of 8 mg/kg (i.e., an average of 
2.0 mg/animal) via gavage feeding. The CBD concentration of the formulation was 4.0 mg/mL. 
Blood samples for CBD plasma concentrations were collected at designated time points until 12 
hrs after dosing. Six different formulations were evaluated and compared to a Control formulation 
(CBD in olive oil) at the same concentration. Of the 6 formulations 2 were selected, due to their 
unique PK parameters, as candidates for a preliminary human PK study; Formulation A1002N5S 
was selected because its bioavailability parameters (Cmax and AUC0-12) were markedly superior to 
the Control formulation (62% and 88% higher, respectively). Tmax, however, was the same (2 hrs).  
This is significant when comparing A1002N5S to the known published data of the commercialized 
and FDA approved Epidiolex® product in which the Tmax was measured between 4 to 5 hours post 
oral administration. 
 
Clinical Pharmacokinetics of Orally Administered CBD 
A systematic search of all articles reporting pharmacokinetic data of CBD in humans has been 
recently published (137). This review highlights the paucity in data and some discrepancy in the 
pharmacokinetics of cannabidiol, despite its widespread use in humans. The following sections 


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summarize the relevant available PK data for oral administration, including data from the Ananda 
safety and PK study conducted in Israel.  
 
Absorption 
Poor GI absorption and extensive hepatic first pass metabolism create significant barriers to oral 
bioavailability of CBD (which is usually low and erratic). Based on a review of available data, 
CBD’s low bioavailability can be ascribed to incomplete gastrointestinal absorption coupled with 
extensive hepatic pre-systemic metabolism.  Because CBD behaves as a high hepatic clearance 
compound, drug–drug interactions affecting its metabolism are likely to have a prominent impact 
on its systemic exposure after oral administration. There is a potential for developing improved 
CBD formulations with greater oral bioavailability and reduced susceptibility to food effects (138). 
 
Distribution  
CBD is a highly lipophilic compound and is readily taken up by adipose tissues and highly 
perfused organs such as the brain, heart, lung, and liver (91). Therefore, CBD has a large 
apparent volume of distribution; mean apparent volume of distribution (V/F [L]) was reported as 
2,520 L following IV administration, and following single acute doses through oromucosal spray 
administration, the apparent volume of distribution was reported as 26,298, 31,994, and 28,312 
L. In the Epidiolex® submission data (114), the estimated volume of distribution in healthy 
volunteers ranged from 20,963 L to 42,849 L. High plasma protein binding was observed for CBD 
and its metabolites (>94%). 
 
Metabolism and drug-drug interactions (see section 2.4.1.2 Risks of potential drug-drug 
interactions: Metabolism, P450 system and opioids) 
Elimination 
Excretion: Fecal excretion is the major route of elimination of CBD and its metabolites [41]. 
Following a single oral dose of 14C-CBD at 5 mg/kg, radioactivity was excreted predominantly via 
the fecal route (84%), and smaller proportions of administered radioactivity recovered in the urine 
(8%). The total recovery after 168 hours was 94% (114).  
 
Half-life: The reported half-life (t½) values of CBD appear to be inconsistent and depend on route 
of administration, formulation and probably other factors such as length of use, assay sensitivity, 
etc. The true elimination half-life of CBD may be difficult to calculate, as the equilibrium ratio 
plasma/fatty tissue is reached only slowly, resulting in very low plasma concentrations that are 
difficult to analyze.  
Based on animal and human studies, elimination of oral cannabinoids from plasma is usually bi-
phasic with an initial half-life ranging from approximately 1 to 3 hours, and the terminal elimination 
half-lives are in the order of 24 hours or longer (97, 114). 
 
Human safety and PK study with A1002 formulation 
  
The A1002 formulation (similar formulation to the A1002N5S Softgel Capsules) has been 
evaluated in a single-dose, three-way crossover study to assess the safety and pharmacokinetics 
of CBD in healthy volunteers.  The study was conducted at Hadassah Clinical Research Center 
in Jerusalem, Israel (study AN-P-19-01).  The test article was 5% synthetic CBD in the same 
excipient formulation as A1002N5S Softgel Capsules but diluted into water for oral ingestion 
rather than administered as a softgel capsule.    
 
The trial, entitled A Single-Dose Three-Way Crossover Pilot Study to Assess the Safety and 
Pharmacokinetics of Cannabidiol (CBD) Following Oral Administration of Either a Novel Liquid 


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Nanodomains Formulation or a Reference CBD in Oil Preparation, to Healthy Volunteers, was 
conducted by Hadassah Clinical Research Center in Jerusalem, Israel (study AN-P-19-01).  
In this study, fifteen subjects were dosed at 50 mg of CBD and then monitored for safety and 
pharmacokinetics using the A1002N5S excipient nanodomain formulation with a CBD in olive oil 
as a reference.  The CBD used for this study was synthetically produced.  The subjects were 
dosed with a 1 mL formulation that was diluted with water to a 2% concentration and then taken 
orally.  The study design was a single-dose, crossover study with a 7-day washout period between 
doses.  All dosing was conducted in a fasted state (10 hr min).  A summary of the PK data from 
this study is noted in Table 4.
Table 4     Oral Bioavailability Parameters from Healthy Volunteer Studies for the A1002 
Formulation
The comparison of the PK profile for the A1002 formulation compared to the CBD in olive 
oil reference is shown as Figure 6.  
Figure 6
PK profile of Two Nanodomain Formulations Compared to Reference
Compound
Dose 
(mg)
Statistical
Variable 
Tmax (hrs)1
Cmax
(ng/mL)2
AUC0-24
(ng*h/mL)2
AUC0-inf
(ng*h/mL)2
T1/2
(hrs) 
A1002
50
Mean (SD)
SEM 
Median (range)
0.97 (0.50)
0.133
1.00 (0.50-
2.00)
14.58 (4.79)
1.279
14.55 
(7.30-
24.36)
37.14 (16.26)
4.345
37.00 
(18.80-
80.54)
38.62 
(16.62)
4.441
38.45 
(19.72-
82.99)
3.33 
(0.96)
0.255
3.75 
(1.99-
4.54)
CBD in Oil 
(control)
50
Mean (SD)
SEM 
Median (range)
1.72 (0.83)
0.221
1.75 (0.50-
4.00)
13.05 (10.83)
2.893
9.79 
(4.57-
47.27)
36.00 (26.26)
7.018
26.48 (12.49 – 
116.10)
37.49 
(26.48)
7.076
27.92 
(13.57-
117.99)
3.27 
(0.91)
0.243
3.22 
(2.26-
4.35)


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The Postulated Effect of the Formulation A1002N5S on GI Absorption of CBD  
The structures within the formulation are self-assembled, thermodynamically stable, almost 
monodispersed and very small in size (10-50 nm). The formulation is based on non-ionic 
emulsifying agents (surfactants) that render CBD less susceptible to degradation or 
decomposition by the gastric fluid. Due to their small size, the droplets are spread over a 
significantly large surface area of the gut mucosa. The formulations contain phospholipids that 
enhance the mucosal enterocyte’s membrane recognition of the droplets.  The small micelle size 
of the nanoemulsion also promotes penetration of the mucus-rich “unstirred water layer” close to 
the intestinal wall, deeper between the intestinal villi. 
 
The sesame oil nanodomains may enhance adherence to the surface membranes of mucosal 
enterocytes and so facilitate absorption. The CBD nanodomain in the sesame oil passes through 
the enterocytes into the mesenteric blood supply.  
 
The improved contact with the surface of the GI mucosa due to the sesame oil facilitates the 
absorption of CBD and significantly shortens the time to maximum permeation of the drug (Tmax). 
The improved surface area to volume facilitated by the surfactants results in enhanced 
bioavailability of CBD.  
6.1.1 Acquisition  
The investigational product, cGMP CBD, will be obtained from ANANDA Scientific with drug 
product shipped from the manufacturer located in the United States. A1002N5S Softgel Capsules 
will be manufactured by Baxco Pharmaceutical Inc., (California, USA) under cGMP conditions 
and shipped to NYULH.   
6.1.2 Formulation, Appearance, Packaging, and Labeling 
Drug Substance and Excipients 
A1002N5S Softgel Capsules will be administered as a 1 mL softgel capsule containing 50mg of 
pure CBD. The softgel capsule formulation will be supplied in white HDPE with child-resistant 
HDPE bottle caps. The clinical trial material will be packaged and labelled in compliance with the 
Good Manufacturing Practice for drugs used in clinical trials.  
 
The formulation that was selected for the clinical trial contains CBD extracted from hemp (50 mg 
per capsule) and excipients as listed below:  
Formulation 
A1002N5S  
- Emulsifying agents: Cremophor EL (Polyoxyl 35 castor oil), Tween 
80 (Polysorbate 80), Plurol® Oleique (polyglyceryl-3 dioleate);  
- Co-surfactant: propylene glycol;  
- Oil: sesame oil;  
- Antioxidant: BHT (butylated hydroxytoluene). 
Placebo Capsules 
The placebo softgel capsule formulation will be composed of polysorbate 80, polyoxyl 35 castor 
oil, propylene glycol, plurol oleique CC 497, sesame oil, and BHT, in the same relative proportions 
as the A1002N5S Softgel Capsules. The softgel shell will be composed of gelatin, glycerin and 
purified water. The inactive ingredients in Ananda formulation A1002N5S have all been previously 
approved by the FDA for use as excipients in oral medications or food additives. 
 
This formulation will be manufactured by Baxco Pharmaceutical Inc. under cGMP conditions.  


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Storage conditions will be the same as those of the A1002N5S Softgel Capsules (protected from 
light and kept at controlled room temperature (20-25o C)).
6.1.3 Product Storage and Stability 
The study drug (CBD or matching placebo) will be stored securely in the NYU-HHC Clinical 
Translational Science Institute (CTSI) located at Bellevue Hospital Center. A designated CTSI 
investigational pharmacist, in conjunction with the PI and designated study team members, will 
oversee the appropriate storage, accountability and dispensing of the study medication. Storage 
conditions for the A1002N5S Softgel Capsules will include: protected from light and kept at 
controlled room temperature (20-25o C). 
Chemical and Physical Stability of the Liquid Nanodomains Formulation A1002N5S 
Previous stability data of non-clinical batches have shown that the A1002N5S formulation is stable 
for at least 6 months at controlled room temperature.  Based on the lack of degradation to date in 
the stability studies, it is likely that the shelf life of the softgel capsules will be extended to 12 
months or longer.  
The chemical stability of the A1002N5S formulation was evaluated at 25o C and 40o C for three 
months.  No change in assay or impurities was detected.  
 
The examination of the physical stability of CBD formulated in the liquid nanodomain systems 
was conducted using a rapid and efficient measurement termed LUMiFugeTM analytical 
centrifugation. This technique enables the prediction the physical stability and shelf life of a 
product. The liquid nanodomain formulations were shown to be stable at 3000 rpm and even after 
17 hours of centrifugation. These conditions simulate the physical stability of the liquid 
nanodomains over minimum 2 years of storage and the results predict a shelf-life of at least two 
years based. 
The PI will track expiration dates of each softgel capsule to assure that expired softgel 
capsules are not administered to participants. The PI will obtain additional un-expired drug 
product as necessary. Final chemical stability tests of the clinical batches will be reported in the 
Certificate of Analysis prior to commencement of the clinical trial.  
6.1.4 Preparation 
Because the investigational product (CBD or matching placebo) is going to be prepared by 
ANANDA Scientific and shipped to receive in its ready-for-dispensation formulation, there will 
not be any preparation required prior to dispensation. The study drug will be dispensed by 
qualified study personnel.  
6.1.5 Dosing and Administration 
Participants will self-administer CBD vs placebo twice daily for a total of 600mg/day CBD 
(300mg po bid) vs. placebo during the 2-week pharmacologic treatment period. Participants 
will self-administer a quantity of 6 easy-to-swallow, soft gel capsules (each capsule containing 
either 50mg CBD or matching placebo with 0mg CBD), every morning following a light meal at 
approximately the same time of day, and an additional quantity of 6 capsules capsule 
approximately 6-12 hours later following a light meal.  
6.1.6 Route of Administration 
CBD or placebo will be administered orally in a liquid nanodomain formulation contained in soft 
gel capsules. 


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6.1.7
Starting Dose and Dose Escalation Schedule
All participants will receive 600mg/day CBD vs. placebo for 2 weeks of the pharmacologic 
treatment intervention period. Note: The first medication administration (CBD 300mg total, a 
total of 6 softgel capsules at 50mg; or placebo, 6 matching softgel capsules) will occur at visit 
Treatment 1 (T1). See section 6.3.1 Administration of Intervention section below for details. 
6.1.8 Dose Adjustments/Modifications/Delays 
If participants report AEs that are determined by the PI to be treatment-related during 
administration of study medication and are intolerable to the participant or represent a 
significant risk to the participant, daily administration will be reduced by 100-400mg/day every 
two days until symptoms are resolved or tolerable. Dose may be titrated back up toward the full 
dose as tolerated. Individuals who cannot tolerate the 600mg dose will remain on their 
maximum tolerable dose during the 2-week pharmacologic treatment period. Treatment will be 
discontinued immediately if continuing the medication places the participant at significant risk in 
the medical judgement of the PI. 
6.1.9 Duration of Therapy 
The duration of the active medication treatment portion of the study is 2 weeks.  
6.2 
Study Agent and Opioid Pharmacotherapy Accountability and Adherence 
Procedures 
Because the study will use hemp derived CBD, this substance is not considered a 
controlled substance under the controlled substances act (CSA) as outlined in the 2018 Farm 
Bill. Therefore, there will be no need to obtain controlled substance research licenses from the 
New York State Bureau of Narcotic Enforcement or federal DEA.  
The study drugs (CBD or matching placebo) will be stored securely in the NYU-HHC CTSI 
Investigational Pharmacy in designated areas within the CTSI located on the 4th floor of the CD 
Building at Bellevue Hospital Center.  The CTSI Investigational pharmacy team, in conjunction 
with the PI and designated study staff, will oversee the appropriate storage, accountability and 
dispensing of the study medication to the participants.  
Drug accountability related to study drug or placebo administration will be tracked using 
the Study Drug Dispensation/Accountability Log (BLINDED STUDY PERSONNEL) and 
Study 
Drug 
Participant 
Self-administration 
Log. 
The 
Study 
Drug 
Dispensation/Accountablity Log (BLINDED STUDY PERSONNEL) records dispensation of 
study drugs to participants at treatment visits where study drug is to be dispensed (see 6.3.1 
Administration of Intervention section below for details). The information included in the Study 
Drug Dispensation Log is: 1) Subject ID; 2) Subject initials; 3) Dispensed by unblinded NYU CTSI 
pharmacist; 4) Received by blinded study team member; 5) Checked for accuracy (i.e., participant 
name, dispensation date, expiration date, number of capsules); 6) Visit Number; 7) Quantity 
dispensed; 8) Dispensed by PI or designee to participant; 9) Date and time dispensed. The Study 
Drug Participant Self-administration Log will be used to assess medication compliance by 
having participants record daily self-administration of study medication (CBD or placebo). The log 
will record: 1) subject initials and identification number; 2) date and time of study drug self-
administration; 3) study medication (this will be listed as ‘study medication’ since participants will 
be blind to CBD or placebo); 4) number of capsules self-administered; and 5) whether they had 
food (light meal) prior to taking study medication. In addition, participants will use this log to record 
daily the use of prescribed opioid medication(s) and will record: 1) subject initials and identification 
number; 2) drug name; 3) dose of medication; 4) number of pills or capsules for oral medications; 
5) date of administration; and 6) time of administration.  


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6.3
Study Behavioral or Social Intervention(s)
There will be no behavioral or social interventions as part of this trial.  
6.3.1 Administration of Intervention 
Over the treatment period of 2-weeks, participants will receive daily pharmacologic treatment 
with either CBD (600mg oral daily use) or an identical capsule containing placebo, also taken 
daily by mouth. The dosing regimen will be twice a day, approximately 12 hours apart with a 
light meal prior to taking the medications. Each capsule of active drug contains 50mg of CBD 
and so participants will be taking 6 pills on each dosing occasion for a total of 12 pills per 
day.  
The first medication administration (either CBD 300mg total, a total of 6 softgel capsules at 
50mg; or placebo, 6 matching softgel capsules) will occur at visit Treatment 1 (T1). At the end of 
clinic visit Treatment 1, participants will be provided with enough doses of CBD (50mg in each 
capsule) or placebo (12 doses of either CBD or placebo to take orally twice daily) to make it to 
the next session T2: 2-days after initiating pharmacologic treatment. Subsequently, CBD or 
placebo will be dispensed at each study visit (T2 & T3) to provide enough medication for twice 
daily (of either CBD 300mg or placebo) dosing prior to the next clinic visit (approximately 72-84 
softgel capsules, respectively), until 2-weeks (T4). 
 
Regarding visits T1-T4 (see section 2.4.1.2 Risks of potential drug-drug interactions: P450 
system and opioids), participants will be administered the first daily morning dose of medication 
(CBD 300mg, six 50mg capsules, or placebo) for that treatment period and will be evaluated for 
at least 3 hours at a supervised clinical laboratory setting within the NYU-HHC Clinical & 
Translational Science Institute (NYU-HHC CTSI) at Bellevue Hospital before discharge 
home. After administration of study drug or placebo until discharge for visits T1-T4, participants 
will be continuously monitored by the study physician or CTSI nursing staff. Participants will be 
monitored with safety assessments with particular attention directed to detect any signs of 
opioid intoxication or overdose (i.e., physical examination signs, vital sign monitoring including 
respiration and oxygenation). Vital signs (Blood pressure, pulse) will be obtained at a minimum 
of every 30 minutes by study staff or with increased frequency (including continuous monitoring) 
if clinically necessary. The use of continuous pulse oximetry monitoring will occur post 
administration of the study drug or placebo until discharge from the clinic to assess oxygenation 
status. The study physician will assess for clinical signs and symptoms suggestive of opioid 
intoxication or overdose (i.e., miosis, respiratory suppression, decreased oxygenation, 
sedation/lethargy), and will take appropriate medical steps to assure patient safety (i.e., Narcan 
administration, oxygen administration, inpatient hospitalization, breaking the blind, discontinuing 
study medication). The Richmond Agitation-Sedation Scale (RASS) (see section 7.1.1 Study 
Specific Procedures for details) will be used to assess clinician-rated somnolence or sedation. 
Participants will not be permitted to leave the study site until they are able to pass a standard 
field sobriety test (one-leg stand, finger-finger test, Romberg’s test, walk-and-turn task, and 
counting backwards) (129). If there are no AEs during this time period or lasting intoxicating 
effects of the study drug (e.g., participants are able to pass field sobriety tests several hours 
after study drug administration), participants will be dispensed the proper quantity of study drug 
(CBD or placebo) to self-administer daily at home until the next scheduled study visit (e.g., a 1-
day, 6-day, or 1-week supply, depending on the visit).  
6.3.2 Procedures for Training Interventionalists and Monitoring Intervention Fidelity 
Not applicable. 


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6.3.3
Assessment of Subject Compliance with Study Intervention
The Study Drug Participant Self-Administration Log will be used to assess medication 
compliance by recording daily self-administration of study medications. Plasma concentrations 
of CBD will also be collected at T1-T4 visits and will be an additional assessment to verify 
treatment adherence. All treatment sessions, assessments, data entry, and analysis will be 
performed at the NYU-HHC CTSI at Bellevue Hospital Center. 
 
6.4 
Study Procedural Intervention Description Table 1: Study Endpoints/Assessments 


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6.4.1
Administration of Procedural Intervention/ Schedule of Assessments
1Rx= Pharmacologic Treatment Period 
 
2Liver function tests  
3Study medication or placebo dispensed at visit for daily use until the next visit 
4Blood drawn before starting CBD/PCB administration (0hr) 
5Blood draws after starting CBD/PCB administration (1hr/3hr) 
6Blood draws after starting CBD/PCB administration (1hr/3hr/5hr) 
Study Phase
Screen
Baseline
(Rx1)
Rx
Rx
Rx
Study Visit
S1, 2, 3
B1
1
2
3
4
Target Weeks
-6 to -2
-2 to 0
1-day
2-day
1
(-2d)
2
(-2d)
Time
T0
T1
T2
T3
T4
Inclusion/Exclusion Criteria
COVID-19 Screening
X
X
X
X
X
X
Screening Checklist
X
Informed Consent (ICF)
X
ICF Comprehension Quiz
X
ICF Documentation
X
Authorization for Release of Health Information
X
Confidential Contact Information 
X
Demographics (PhenX Tier-1)
X
Medical/Psychiatric History 
X
SCID-5
X
Alcohol Test 
X 
Physical Examination 
X 
Clinical Labs
X 
 
X2
X2
EKG 
X 
 
Birth Control Documentation
X 
X
X 
X
X
Urine Pregnancy Test 
X 
X
X 
X
X
X
Urine Drug Screen
X 
X
X 
X
X
X
Concomitant Medications
X 
X
X 
X
X
X
Eligibility (I/E) Checklist 
X 
X
 
Randomization 
 
X
 
CBD/PCB Dispensed
 
X3 
X3 
X3
X3
Safety Assessments 
Vital Signs
X 
X
X 
X
X
X
AEs 
X 
X
X 
X
X
X
Suicidality (C-SSRS)
X 
X
X 
X
X
X
Sedation (RASS)
 
X 
X
X
X
Field Sobriety Tests 
 
X 
X
X
X
Pharmacokinetics 
CBD Plasma Levels  
 
X5 
X4,5 
X4,6 
X4,5 
Opioid Plasma Levels 
 
X
X4 
X4 
X4
X4
Opioid—Related Outcomes
Opioid Maintenance Dose (MEDD) 
X 
X
X 
X
X
Opioid Craving (VAS)
 
X
X 
X
X
X
Secondary Efficacy Outcome: Pain Outcomes 
Brief Pain Inventory (BPI)
 
X
X 
X
X
X
Pain Catastrophizing Scale (PCS) 
 
X
X 
X
X
X
Mental Health Outcomes 
Anxiety (PROMIS) 
 
X
X 
X
X
X
Depression (PROMIS) 
 
X
X 
X
X
X
Sleep (PROMIS)
 
X
X 
X
X
X
Blinding Integrity  
 
 
X
Self-Administration Medication Log 
X 
X
X 
X
X
X
Participant Compensation 
X 
X
X 
X
X
X


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authorized in writing by the study sponsor 
Refer to Table 1 for study timeline and assessments. Measures assessed at each time point 
are described below. The eligibility checklist will be completed at the screening and baseline 
visits, followed by randomization to pharmacologic treatment of daily oral administration of drug 
(CBD 600mg or placebo) for 2-weeks.  Clinic visits will occur at baseline and then post-
randomization/initiation of pharmacologic treatment at the following time-points: 1-day (note: this 
represents the first day of drug administration), 2-day, 1-week, and 2-weeks.   
6.4.2 Procedures for Training of Clinicians on Procedural Intervention 
Not applicable. 
6.4.3 Assessment of Participant Compliance with Study Procedural Intervention 
See Section 6.3.3 above: Assessment of Subject Compliance with Study Intervention 
 
7 
Study Procedures and Schedule 
7.1 
 Study Procedures/Evaluations 
7.1.1 Study Specific Procedures 
Refer to Table 1 for study timeline and assessments. Measures assessed at each time 
point are described below.  
 
Following obtaining informed consent (including informed consent comprehension quiz and 
documentation of informed consent), the following will occur to determine study eligibility: 
 
 
Authorization of release of health information will be obtained in order to obtain relevant 
health information, in particular as it relates to establishing the inclusion criteria of 
participants with chronic radiculopathic pain syndromes maintained on chronic opioid 
therapy. All efforts will be made to obtain necessary health information from relevant 
treatment providers (i.e., pain specialists, internists).
 
A Locator form and PhenX Tier 1 measures will completed at screening to collect 
contact information, demographics, quality of life, HIV risk and status, and substance 
use measures (age of onset, past 30-day quantity and frequency, lifetime use for 
alcohol, tobacco, and other substances; www.phenxtoolkit.org).  
Medical screening will include height, weight, medical and psychiatric history, physical 
examination, complete blood count, serum chemistries including liver function tests 
(LFTs), serum pregnancy test, urinalysis, urine drug test, urine pregnancy test, 
concomitant medications assessment, and administration of an EKG. Note: Urine drug 
screenings, urine pregnancy tests, and birth control method documentation will be 
administered to assess recent drug use and to assess pregnancy status (in addition to 
screening) at all study visits, and follow-up LFTs will be obtained at 1-week and 2-weeks 
following initiation of pharmacologic intervention. Regarding the urine drug assessment 
at screening, the data will be used to determine eligibility (i.e., if consistent with an 
exclusionary substance use disorder assessed also with SCID-5; if consistent with 
exclusionary recreational or medicinal cannabis use). The licensed provider will also 
review participants’ controlled substance prescription history using the online 
Prescription Monitoring Program (PMP) ISTOP Registry in New York to inform study 
eligibility.  
 
Psychiatric and substance use disorder (SUD) screening will occur including 
administration of the Structured Clinical Interview for DSM-5 (SCID-5) Research 


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Version/Non-patient (SCID-RV/NP for DSM-5®) Version 1.0.0 (139) to determine 
exclusionary psychiatric and SUD diagnoses. Note: Only relevant sections (mood 
disorders, psychotic disorders, and substance use disorders) to determine eligibility will 
be administered to participants during screening. 
Safety  
Safety will be assessed by collection of adverse events and vital signs at all visits after 
treatment is initiated. Safety will be assessed by collection of adverse events using the Systemic 
Assessment for Treatment of Emergent Events (SAFTEE) (140) measure at all visits after 
treatment is initiated. LFTs will be obtained at screening, 1-week, and 2-weeks following 
initiation of pharmacologic intervention. Any subject who has LFTs > 2 x ULN will be discontinued 
from study participation and will be referred for appropriate follow-up. Following screening, urine 
drug assessments will be collected at every subsequent study visit, T0-T4. The results of the urine 
drug assessments will be evaluated to determine ongoing safety of study participation (i.e., 
potential adverse drug-drug interactions) and continued study eligibility. For instance, if the urine 
drug assessment(s) reveal evidence for a prior (that was not detected at screening) or new onset 
exclusionary substance use disorder, the participant will be deemed no longer eligible for study 
participation. If a participant is no longer eligible for study participation because they have an 
exclusionary substance use disorder, the PI (a substance abuse expert) will refer the participant 
for appropriate substance abuse and mental health treatment.    
Risk of suicidality will be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS) 
(131) as part of each study visit, including screening and baseline. There are two version of the 
C-SSRS that will be used: one for ‘screening or baseline’ and one ‘since last visit’ version.  
See Section 2.4.1 (Known Potential Risks and Risk Mitigation Strategies) above for safety 
plan to mitigate risk related to potential drug-drug interactions between CBD and other drugs (i.e., 
opioids). The Richmond Agitation-Sedation Scale (RASS) will be used to measure clinician-rated 
somnolence or sedation. The RASS is a 10-point scale with four levels to describe the agitated 
patient (+1 to +4), one level to describe the calm and alert patient (0) and another five levels to 
describe a sedated patient (-1 to -5) (141, 142). The rating is performed in three steps 
(observation, response to verbal stimulation and response to physical stimulation), is user friendly, 
and can be performed quickly. The RASS is one of the most frequently used sedation scales 
(143) and has been demonstrated to be both valid and reliable (141, 144). It is an appropriate 
scale to measure clinically significant somnolence associated with opioid intoxication.  
Pharmacokinetics: Plasma opioid and CBD concentrations 
Opioid analgesic plasma concentrations will be obtained at baseline (prior to initiating 
pharmacologic treatment) by taking 2 samples over an approximately 2-week period prior to 
initiating the pharmacologic intervention at T1. Note: the baseline plasma levels will be drawn 
at the same time relative to when they take their opioid medication(s). The baseline opioid 
plasma value will be the average of the two samples taken during this period of time (with one 
sample during the period between baseline and T1 and the 2nd sample taken at the beginning 
of T1 prior to initiating the first pharmacologic intervention). Further PK samples will be drawn 
at the following time points (post-randomization and after receiving the first dose of study 
medication): 2-day (T2), 1-week (T3), and 2-weeks (T4), and these will also be drawn at the 
same time relative to when they take their opioid medication(s). At these assessment time-
points: 1) Opioid plasma concentrations will be sampled, using the same methodology used to 
obtain the baseline plasma level; 2) CBD plasma concentrations will be obtained as well. 
Trough CBD concentrations will be sampled at the same time that the opioid plasma 
concentration will be assessed and subsequently within the first several hours after 


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CBD/placebo administration with samples drawn at approximately 1-hour and 3-hours post 
CBD/placebo administration during visits (T1-T4) at the CTSI, with an additional sample taken 
5-hours post CBD administration during the T3 visit. To minimize the number of blood draws 
at these assessment time-points, an IV catheter will be placed to obtain the 3-4 blood samples. 
Plasma CBD and opioid concentrations will be determined via High Performance Liquid 
Chromatography/Tandem Mass Spectrometry (LC-MS/MS) by a laboratory at the University of 
Buffalo.  
 
 
Pain Outcomes
Pain Catastrophizing: Pain catastrophizing will be measured by the Pain Catastrophizing Scale 
(PCS) (132) at baseline and the following post-randomization time-points: 2-day, 1-week, and 
2-weeks. The PCS is a 13-item self-report scale, with each item rated on a 5-point scale: 0 (Not 
at all) to 4 (all the time). It is broken into three subscales (magnification, rumination, and 
helplessness); results observational and treatment outcome trials have suggested that the PCS 
has very good prognostic value in assessing pain outcomes in patients with chronic pain 
syndromes (145-148).  
Pain Intensity and pain-related interference: The severity of chronic pain will be evaluated with 
the Brief Pain Inventory (BPI) (133, 149) at baseline and the following post-randomization time-
points: 1-day, 2-day, 1-week, and 2-weeks. The BPI has two dimensions: intensity and 
interference. Pain intensity is rated on a 0 (no pain) to 10 (worst pain imaginable) scale as the 
worst in the past 24 hours, least in the past 24 hours, average pain and current pain. Pain 
interference is measured in 7 areas: general activity, mood, walking ability, work, sleep, 
enjoyment of life and relationships on a 0 (no interference) to 10 (interferes completely) scale. 
The composite mean of these scores are used as a pain interference score. 
Mental Health Outcomes 
Anxiety will be measured with the 29-item PROMIS® (134) (Patient-Reported Outcomes 
Measurement Information System) Anxiety long form scale, assessed at baseline and the 
following post-randomization time-points: 1-day, 2-day, 1-week, and 2-weeks. 
Depression will be measured with the 8-item PROMIS® (134) (Patient-Reported Outcomes 
Measurement Information System) Depression short form scale, assessed at baseline and the 
following post-randomization time-points: 1-day, 2-day, 1-week, and 2-weeks. 
Sleep Disturbances will be measured with the 27-item PROMIS® (Patient-Reported Outcomes 
Measurement Information System) Sleep-Related Impairment (SRI) (135), at baseline and the 
following post-randomization time-points: 1-day, 2-day, 1-week, and 2-weeks. 
Opioid Use-Related Outcomes  
Opioid Craving will be measured with the Visual Analog Scale (VAS) (136), (150) at baseline, 1-
day, 2-day, 1-week, and 2-weeks. 
Opioid maintenance dose (measured in MEDD): assessed at screening, baseline, 1-day, 1-
week, and 2-weeks.  
 
MEDD will be calculated using 2 reference documents:  
o Guideline and conversion table to calculate MEDD from Centers for Medicaid 
and Medicare Services (CMS)  
o Guidelines from the Centers for Disease Control and Prevention (CDC) intended 
for calculating total daily dose of opioids for safer dosage of opioid 
pharmacotherapy  


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7.1.2
Standard of Care Study Procedures
Participants will continue to get standard of care treatment for their chronic radicular pain 
syndromes. In addition, as part of participation in this clinical trial, participants will receive 
additional medical attention and care as part of a clinical research program (i.e., physical exam, 
laboratory analyses, clinical assessments, administration of study medications, longitudinal 
assessments). 
 
7.2 
Laboratory Procedures/Evaluations 
7.2.1 Clinical Laboratory Evaluations 
Serum will be collected at screening for: complete blood count, pregnancy test, and serum 
chemistries including liver function tests (LFTs). Further, in addition to obtaining baseline liver 
function tests (LFTs), after initiating study medication or placebo, subsequent LFTs will be 
obtained at 1-week and 2-weeks (final study visit). Opioid analgesic plasma concentrations will 
be collected at the same time relative to when participants take their daily opioid analgesic 
medications at baseline (prior to initiating pharmacologic treatment) and at the following post-
randomization/post-start of study medication administration visits: 1-day, 2-day, 1-week, and 
2-weeks. CBD plasma concentrations will be obtained at all study visits (1-day, 2-day, 1-week, 
and 2-weeks) following initiation of study drug administration and will occur at the following 
time assessment points at these visits: trough (pre-dose), 1-hour post drug-administration, and 
3-hours post drug administration. 
7.2.2 Other Assays or Procedures 
See section 7.2.1 
7.2.3 Specimen Preparation, Handling, and Storage 
Plasma (~1ml/sample) will be stored at -70° C, and will be labeled with study number, participant 
number, visit number, and time-point. Plasma CBD concentrations will be determined via High 
Performance Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS) and plasma 
opioid concentrations will be quantified by highly sensitive enzyme linked immunosorbent assay 
(ELISA) kits by a laboratory at the University of Buffalo.  
7.2.4 Specimen Shipment 
Specimens will be shipped at a minimum of every 6 months on dry ice with appropriate labeling 
for shipment of biological specimens on dry ice, according to the study’s SOP. Opioid and 
Cannabinoid Plasma Case Report Form will be utilized to record dates and times that each 
specimen was collected and shipped. Specimens may be shipped overnight between 9:00am 
and 5:00pm on business days.  
 
7.3 
Study Schedule 
7.3.1 Screening  
Screening Visit (S1-3) 
 
Screening Visit Checklist 
 
Obtain informed consent of potential participant verified by signature on written informed 
consent for screening form. 
o Obtain informed consent comprehension quiz. Participant must pass the quiz in 
order to be eligible for the study 
o Document informed consent process including comprehension quiz 
o Provide participant with a copy of the informed consent 
 
Obtain authorization of release of health information (e.g., to speak to treating pain 
and opioid treatment provider(s) or other relevant health care providers) 


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Obtain demographic information, drug, alcohol, and tobacco use history 
 
Review medical and psychiatric history to determine eligibility based on 
inclusion/exclusion criteria. 
 
Review concurrent medications to determine eligibility based on inclusion/exclusion 
criteria. 
 
Perform medical examinations needed to determine eligibility based on 
inclusion/exclusion criteria. 
 
Collect urine for urine drug analysis, urinalysis, urine pregnancy test 
 
Collect blood (~10cc, or about 2 teaspoons) for complete blood count, serum chemistries 
including LFTs, and serum pregnancy test 
 
Record results of evaluations of safety and opioid-use related outcomes 
 
Provide participant with Medication Self-Administration Log for tracking opioid 
medication self-administration, to be used for particular opioid’s plasma level and future 
plasma draw scheduling 
 
Schedule additional Screening Visits (S2/S3) if necessary, as per PI discretion  
 
Schedule study visits for participants who are eligible and available for the duration of 
the study 
7.3.2 Enrollment/Baseline 
Enrollment/Baseline Visit: T0 
 
Collect urine for urine drug analysis and urine pregnancy test 
 
Record vital signs, results of examinations, and other assessments 
 
Review concurrent medications 
 
Record results of evaluations of safety, pain outcomes, mental health outcomes, and 
opioid-use related outcomes 
 
Pharmacokinetic assessment: Collect 1 blood sample (1 or 2 tablespoons) over an 
approximate 2 week period prior to T1  
 
Record adverse events as reported by participant or observed by investigator 
 
Note: this visit will occur over approximately 2-weeks prior to visit T1 
 
7.3.3 Intermediate Visits 
7.3.3.1 1-day (first day of pharmacologic treatment): T1   
 
Collect urine for urine drug analysis and urine pregnancy test 
 
Record vital signs, results of examinations, and other assessments 
 
Review concurrent medications 
 
Record results of evaluations of safety outcomes  
 
Record results of evaluations of safety, pain outcomes, mental health outcomes, and 
opioid-use related outcomes 
 
Pharmacokinetic assessment at NYU-HHC CTSI prior to administering first dose of CBD 
300mg or placebo: after establishing an IV heplock for the three blood samples to be 
drawn for PK assessments, collect 1 blood sample (1 or 2 tablespoons). This 
assessment will be averaged with the opioid plasma concentration sample taken 
during the baseline period to form the baseline opioid plasma concentration.  
 
Administer first dose of CBD 300mg or placebo in the NYU-HHC CTSI after a light meal 
 
Pharmacokinetic assessment at NYU-HHC CTSI subsequent to administering first dose 
of CBD 300mg or placebo: collect 2 blood samples (1 or 2 tablespoons each) 
approximately 1-hour and 3-hours after administering CBD 300mg or placebo, 
respectively.  
 
Monitor closely for a minimum of 3 hours for safety (i.e., signs and symptoms suggestive 
of opioid toxicity) prior to discharge home 


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Record adverse events as reported by participant or observed by investigator 
 
Record participant’s adherence to treatment program 
 
Participants will not be permitted to leave the study site until they are able to pass a 
standard field sobriety test 
 
At the end of clinic visit T1, participants will be provided with enough doses of CBD 
50mg/dose or placebo (12 doses total) to take CBD 300mg or placebo orally twice daily, 
following a light meal, to make it to the next session T2: 2-days after initiating 
pharmacologic treatment. Note: of these 12 doses, participants will take 6 of them for the 
nighttime dose in between T1 and T2. The remaining 6 doses will be brought into the 
CTSI for the am dose at the T2 visit.  
 
7.3.3.2 2-day (second day of pharmacologic treatment): T2   
 
Collect urine for urine drug analysis and urine pregnancy test 
 
Record vital signs, results of examinations, and other assessments 
 
Review concurrent medications 
 
Record results of evaluations of safety outcomes 
 
Record results of evaluations of safety, pain outcomes, mental health outcomes, and 
opioid-use related outcomes 
 
Pharmacokinetic assessment at NYU-HHC CTSI prior to administering first daily dose of 
CBD 300mg or placebo: after establishing an IV heplock for the three blood samples to 
be drawn for PK assessments, collect 1 blood sample (1 or 2 tablespoons) to assess 
both opioid plasma and CBD trough plasma concentrations.  
 
Administer first dose of CBD 300mg or placebo in the NYU-HHC CTSI after a light meal 
 
Pharmacokinetic assessment at NYU-HHC CTSI subsequent to administering first daily 
dose of CBD 300mg or placebo: collect 2 blood samples (1 or 2 tablespoons each) 
approximately 1-hour and 3-hours after administering CBD 300mg or placebo, 
respectively.  
 
Monitor closely for a minimum of 3 hours for safety (i.e., signs and symptoms suggestive 
of opioid toxicity) prior to discharge home 
 
Record adverse events as reported by participant or observed by investigator 
 
Record participant’s adherence to treatment program 
 
Participants will not be permitted to leave the study site until they are able to pass a 
standard field sobriety test 
 
At the end of clinic visit T2, participants will be provided with enough doses of CBD 
50mg/dose or placebo (72 doses total) to take CBD 300mg or placebo orally twice daily, 
following a light meal, to make it to the next session T3: 1-week after initiating 
pharmacologic treatment. Note: participants will bring in the final 6 doses into the CTSI 
for the am dose at the T3 visit.  
 
7.3.3.3 1-week: T3   
 
Collect urine for urine drug analysis and urine pregnancy test 
 
Record vital signs, results of examinations, and other assessments 
 
Review concurrent medications 
 
Record results of evaluations of safety outcomes  
 
Record results of evaluations of safety, pain outcomes, mental health outcomes, and 
opioid-use related outcomes 
 
Collect blood for LFTs (approximately 1 teaspoon) 
 
Pharmacokinetic assessment at NYU-HHC CTSI prior to administering first daily dose of 
CBD 300mg or placebo: after establishing an IV heplock for the four blood samples to be 


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drawn for PK assessments, collect 1 blood sample (1 or 2 tablespoons) to assess both 
opioid plasma and CBD trough plasma concentrations.  
 
Administer first daily dose of CBD 300mg or placebo in the NYU-HHC CTSI after a light 
meal 
Pharmacokinetic assessment at NYU-HHC CTSI subsequent to administering first daily 
dose of CBD 300mg or placebo: collect 3 blood samples (1 or 2 tablespoons each) 
approximately 1-hour, 3-hours, and 5-hours after administering CBD 300mg or placebo, 
respectively.  
Monitor closely for safety (i.e., signs and symptoms suggestive of opioid toxicity)
 
Record adverse events as reported by participant or observed by investigator 
 
Record participant’s adherence to treatment program 
 
Participants will not be permitted to leave the study site until they are able to pass a 
standard field sobriety test 
 
At the end of clinic visit T3, participants will be provided with enough doses of CBD 
50mg/dose or placebo (84 doses total) to take CBD 300mg or placebo orally twice daily, 
following a light meal, to make it to the next session T4: 2-week after initiating 
pharmacologic treatment. Note, participants will bring in the final 6 doses into the CTSI 
for the am dose at the T4 visit. 
 
7.3.4 
Final Study Visit at 2-weeks: T4  
 
Collect urine for urine drug analysis and urine pregnancy test 
 
Record vital signs, results of examinations, and other assessments 
 
Review concurrent medications 
 
Record results of evaluations of safety outcomes  
 
Record results of evaluations of safety, pain outcomes, mental health outcomes, and 
opioid-use related outcomes 
 
Collect blood for LFTs (approximately 1 teaspoon) 
 
Pharmacokinetic assessment at NYU-HHC CTSI prior to administering first daily dose of 
CBD 300mg or placebo: after establishing an IV heplock for the three blood samples to 
be drawn for PK assessments, collect 1 blood sample (1 or 2 tablespoons) to assess 
both opioid plasma and CBD trough plasma concentrations.  
 
Administer first daily dose of CBD 300mg  or placebo in the NYU-HHC CTSI after a light 
meal 
 
Pharmacokinetic assessment at NYU-HHC CTSI subsequent to administering first daily 
dose of CBD 300mg or placebo: collect 2 blood samples (1 or 2 tablespoons each) 
approximately 1-hour and 3-hours after administering CBD 300mg or placebo, 
respectively.  
 
Monitor closely for safety (i.e., signs and symptoms suggestive of opioid toxicity) 
 
Record adverse events as reported by participant or observed by investigator 
 
Record participant’s adherence to treatment program 
 
Participants will not be permitted to leave the study site until they are able to pass a 
standard field sobriety test 
 
To evaluate the effectiveness of the blind, both treatment and investigator treatment 
assignment guesses (i.e., whether participant received investigational drug vs placebo) 
will be collected 
 
7.3.5 Withdrawal/Early Termination Visit 
If the subject withdraws or if early termination occurs, the following procedures/evaluations would 
be ideal to obtain at a final study visit: safety assessments, pain outcomes, mental health 
outcomes, and opioid-related outcomes.  


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7.3.6
Unscheduled Visit
Unscheduled visits will be documented on an unscheduled visit form. 
 
7.4 
Concomitant Medications, Treatments, and Procedures 
All concomitant prescription medications taken during study participation will be recorded on the 
case report forms (CRFs). 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 CRF are concomitant prescription medications, over-the-counter medications 
and non-prescription medications. 
 
7.5 
Justification for Sensitive Procedures 
This trial employs a double-blind methodology as part of the pharmacologic intervention. The 
study drug (CBD) will be formulated in identical and blinded capsules to the inactive placebo 
agent. The double-blind methodology aims to reduce investigator and participant biases. To 
evaluate the effectiveness of the blind, both participant and investigator treatment assignment 
guesses (i.e., whether received investigational drug vs placebo) will be collected at the following 
time-points (post-initiation of pharmacologic treatment): 4-weeks (T4), and 16-weeks (T8) (See 
section 10.6.2 Evaluation of Success of Blinding). 
7.5.1 Precautionary Medications, Treatments, and Procedures 
Participants currently using the following concomitant medications will be excluded from study 
participation: 1) medications (including opioid analgesics) metabolized primarily by CYP2C19 
isoenzymes; 2) medications significantly or primarily metabolized by CYP3A4 with the potential 
for adverse drug-drug interactions with CBD (i.e., ketoconazole, rifampicin). We will instruct 
participants to subjects to avoid consuming grapefruit or grapefruit juice during the duration of 
the study; 3) medications known to have adverse drug-drug interactions with CBD (i.e., 
valproate) or the potential to cause significant drug-drug interactions (i.e., clobazam); 4) 
recreational or medical cannabis or any product containing CBD.  
 
7.6 
Prohibited Medications, Treatments, and Procedures 
See Section 7.5.1 above. 
7.7 
Prophylactic Medications, Treatments, and Procedures 
Participants will receive study medication (CBD or placebo) on top of standard of care treatment 
for chronic radiculopathy pain syndromes. Concomitant medication use will be tracked closely 
throughout the trial for safety/risk assessments. 
7.8 
Rescue Medications, Treatments, and Procedures 
Regarding visits T1-T4, participants will be administered the first daily morning dose of 
medication (CBD 300mg or placebo) with food for that treatment period and will be evaluated for 
several hours at a supervised clinical laboratory setting within the NYU-HHC Clinical & 
Translational Science Institute (NYU-HHC CTSI) at Bellevue Hospital. Participants will be 
closely monitored with safety assessments with particular attention directed to detect any signs 
of opioid intoxication or overdose (i.e., physical examination signs, vital sign monitoring 
including respiration and oxygenation). If participants develop clinical signs and symptoms 
suggestive of opioid intoxication or overdose (i.e., respiratory suppression, decreased 
oxygenation, lethargy), they will be immediately evaluated clinically and appropriate medical 
steps will be taken to assure patient safety (i.e., Narcan administration, oxygen administration, 
inpatient hospitalization, breaking the blind, discontinuing study medication). Participants will not 
be permitted to leave the study site until they are able to pass a standard field sobriety test 
(one-leg stand, finger-finger test, Romberg’s test, walk-and-turn task, and counting backwards) 


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(129). The PI will use clinical discretion in the event that a participant cannot complete the field 
sobriety test due to disability. 
 
Per July 2020 FDA drug safety communication (https://www.fda.gov/drugs/drug-safety-and-
availability/fda-recommends-health-care-professionals-discuss-naloxone-all-patients-when-
prescribing-opioid-pain), the study team will communicate with all clinicians prescribing opioids 
to subjects enrolled in study that they provide a naloxone prescription for each participant. 
7.9 
Participant Access to Study Agent at Study Closure 
Participants will not be able to access investigational study medication (CBD) used in this trial 
beyond the 2-week treatment period.  
 
8 
Assessment of Safety 
8.1 
Specification of Safety Parameters  
Safety and toxicity monitoring will be performed throughout the study for all participants. Safety 
variables to be assessed include AEs, vital signs, and safety laboratory values, when collected.  
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 
study monitor. At each study visit following screening, designated study team members will 
inquire about the occurrence of AE/SAEs since the last visit.  
Since the GI disturbance of diarrhea is one of the most common adverse effects attributed to 
CBD, diarrhea will be queried as an AE of special interest in this trial. 
8.1.1 Definition of Adverse Events (AE) 
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: 
 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
8.1.2 Definition of Serious Adverse Events (SAE) 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event (SAE) 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, 


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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.  
 
8.1.3 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) 
 Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
8.2 
Classification of an Adverse Event 
8.2.1 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. 
8.2.2 Relationship to Study Agent 
The clinician’s assessment of an AE's relationship to the study drug 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. 


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 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 (de-challenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory re-
challenge 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 (de-challenge). Re-challenge 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. 
 
8.2.3 Expectedness 
Unexpected: An AE is considered unexpected if it is not listed in the Investigator Brochure (IB) 
or is not listed at the specificity or severity that has been observed, or not previously observed 
in animal toxicity studies for CBD. Unexpected also refers to AEs that are mentioned in the IB 
as occurring with a class of drugs or as anticipated from the pharmacologic properties of the 
drug, but are not specifically mentioned as occurring with CBD.  
8.3 
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, or upon review by 
a 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 


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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 study sponsor 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 sponsor 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.  
 
8.4 
Reporting Procedures – Notifying the IRB, FDA, DSMB  
8.4.1 Adverse Event Reporting 
To the IRB: In accordance with local IRB requirements, all AEs occurring during the course of 
the clinical trial regardless of relationship to study activities will be collected, documented, and 
reported by the PI or designee to the IRB on an annual basis in the application for the study’s 
continuation renewal. Staff education, re-training or appropriate corrective action plan will be 
implemented when unreported or unidentified AEs or SAEs are discovered, to ensure future 
identification and timely reporting.  
To the FDA: In accordance with FDA reporting requirements, all AEs occurring during the 
course of the clinical trial will be collected, documented, and reported by the PI or IND Sponsor. 
On an annual basis, as part of the update to the study IND, the IND Sponsor will submit to the 
FDA:  
A list of all AEs that have occurred during the reporting period
 
A summary of all IND safety reports submitted during the past year 
 
A list of all subjects who died during the participation in the investigation, listing cause of 
death for each,  
 
And a list of subjects who dropped out during the course of the investigation in 
association with any adverse experience, whether or not thought to be drug related. 
To the DSMB: All AEs occurring during the course of the clinical trial, regardless of relationship 
to study activities, will be reported to the DSMB at regular meetings. Prior to each DSMB 
meeting, the PI will prepare a report to the Board including review of aggregate analysis of AEs 
and SAEs. 
Following each meeting, the board will provide the PI with a report including a recommendation 
to continue the study unchanged, continue with modifications of the protocol and/or the consent 
form to protect participant safety, or terminate the study. This report will then be submitted to the 
FDA as part of the annual report to the study IND, and the IRB in the application for the study’s 
annual continuation renewal.  
To the Study Investigational Product Provider: ANANDA Scientific 


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The PI shall promptly inform ANANDA Scientific of any significant safety issues occurring during 
the course of the study that might affect the performance of the study and of any AEs and SAEs 
experienced by subjects during the study. The PI shall share with ANANDA Scientific any 
associated CRFs and source data, safety reports related to such AEs and SAEs, and permit 
access to anonymized pharmacokinetic data of study subjects.   
To NIH/NIDA 
All AEs occurring during the course of the clinical trial regardless of relationship to study 
activities will be collected, documented, and reported by the PI or designee to NIH/NIDA on an 
annual basis in the annual Research Performance Progress Report (RPPR). 
8.4.2 Serious Adverse Event Reporting 
SAEs will be promptly reported to the Clinical Research Coordinator and PI. The PI or qualified 
designee will distinguish Serious Adverse Events (SAEs) from Adverse Events (AEs). The 
details of the event will be documented and reported as follows: 
To the FDA: The PI is required to report certain study events in an expedited fashion to the 
FDA. These written notifications of AEs are referred to as IND/IDE safety reports.  
The following describes the IND safety reporting requirements by timeline for reporting and 
associated type of event: 
 Within 7 calendar days (via telephone or facsimile report) 
Any study event that is: 
– associated with the use of the study drug 
– unexpected, and 
– 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 AE 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. 
Each written notification must be submitted on an FDA Form 3500A. The PI is also required to 
identify in IND safety reports all previous reports concerning similar AEs and to analyze the 
significance of the current event in light of the previous reports. 
FDA contact for reporting IND safety reports 
Rachel Jang, PharmD, Regulatory Project Manager at Rachel.Jang@fda.hhs.gov or Rigoberto 
Roca MD, Director, Division of Anesthesiology, Addiction Medicine, and Pain Medicine, Office of 
Neuroscience, FDA Center for Drug Evaluation and Research.  
To the IRB: The IRB Chair or Administrator will be notified immediately for SAEs that are at 
least possibly related to study participation only. If the IRB administrator determines that 
reporting of the incident/issue is required, it will be submitted to the IRB within 48 hours of the 
IRB direction/response.  


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The team will also submit summary information related to all SAEs, AEs, and UPs in the annual 
application for continuation to the IRB. 
To the Study Sponsors: 
NIH/NIDA 
All SAEs will be documented and reported to NIDA within 72 hours with copies included in the 
participant’s file. 
CBD drug manufacturer: ANANDA Scientific 
If an SAE occurs after the subject signs informed consent through the end of study participation, 
the PI or a qualified designee will complete the SAE Form and send it via email to contacts 
designated by ANANDA Scientific within 48 hours of the site becoming aware of the SAE. The 
form must be completed and submitted to ANANDA Scientific any time a serious medical event 
has occurred in a participant during the clinical trial, whether or not it is considered related to the 
study treatment, including active comparators and placebo.  
DSMB 
All SAEs will be documented and reported to the DSMB within 72 hours with copies included in 
the participant’s file. 
Ensure that an investigator has reviewed and signed the SAE form prior to submission. 
Every exposure during pregnancy (participant) should be reported on an SAE worksheet as a 
case of special interest from the time of study enrolment to the end of study participation. 
8.4.3 Unanticipated Problem Reporting 
Incidents or events that meet the OHRP criteria for UPs involving risks to subjects or others 
require notification of the local IRB. The phrase “unanticipated problems involving risks to 
subjects or others” is found but not defined in the HHS regulations at 45 CFR part 46. Any 
incident, experience, or outcome that meets all of the following criteria is considered to be 
Reportable New Information (RNI) and is required to be promptly reported to the local IRB: 
 
unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the characteristics 
of the subject population being studied; 
 
related or possibly related to participation in the research (in this guidance 
document, possibly related means that, in the opinion of the PI, the incident, experience, 
or outcome was more likely than not caused by procedures involved in the research); 
and 
 
suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
OHRP recognizes that it may be difficult to determine whether a particular incident, experience, 
or outcome is unexpected and whether it is related or possibly related to participation in the 
research. OHRP notes that an incident, experience, or outcome that meets the three criteria 
above generally will warrant consideration of substantive changes in the research protocol or 
informed consent process/document or other corrective actions in order to protect the safety, 
welfare, or rights of subjects or others.  
The RNI report will include the following information: 


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Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
 
A detailed description of the event, incident, experience, or outcome; 
 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP; 
 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
UPs must be reported using the following timeline: 
UPs that are SAEs will be reported to the IRB and to the study sponsor according to 
SAE reporting procedures described above (within 48 hours of the investigator becoming 
aware of the event).
UPs that meet the requirements for RNI will be reported to the IRB as soon as possible 
and within 5 working days of the site becoming aware of the event. 
 
All other UPs not related to study activities or that do not result in harm to participants 
will be reported to the IRB annually in the application for the study’s continuation 
renewal. 
8.4.4 Reporting of Pregnancy 
Pregnancy information on clinical study subjects is collected by the investigator. If a subject 
should become pregnant during the course of the study, the investigator or qualified designee 
will contact the IRB and ANANDA Scientific within 5 working days of the PI or qualified designee 
first becoming aware of the pregnancy.  
Pregnancies resulting in congenital abnormalities or birth defects in offspring meet the 
requirements for an SAE and will be collected, documented, and reported according to the 
procedures outlined above for SAEs. 
8.5  
Reporting Procedures – Notifying the Study Sponsor 
Not applicable as PI is the sponsor-investigator 
8.6 
 Reporting Procedures – Notifying the FDA  
 See section 8.4.2 Serious Adverse Event Reporting  
8.7      Reporting Procedures – Participating Investigators  
Not applicable. 
8.8 
Study Halting Rules 
The study may be stopped if there are untoward and concerning levels of AE or SAE outcomes 
attributable to CBD or study participation. If the DSMB finds it is likely that CBD is contributing to 
negative outcomes, they will consider solutions including protocol changes or potentially stopping 
the study. Anticipated AEs of concern will be opiate overdose, respiratory suppression, and 
greater than 3x increase in ALT and AST. All SAEs will be documented and reported to the DSMB 
within 72 hours for review. 
8.9 
Safety Oversight: DSMP 
Data and Safety Monitoring Plan (DSMP) 
Title: A phase I/II, randomized, double-blind, placebo-controlled, single-center study of the 
effects of Cannabidiol (CBD) on opioid plasma levels in participants with chronic radiculopathies 
maintained on chronic opioid therapy (COT) 


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Grant Number: R21DA048986-01
PI: Stephen Ross MD 
Medical Monitor: Stephen Ross MD 
All significant changes to the protocol must be approved by the NIDA Program Officer
prior to implementation. 
 
All SAEs must be reported to NIDA/NIH within 72 hours. 
 
An annual DSMP report will be sent to NIDA/NIH. 
Brief description of the protocol: see section 4 Study Design and Endpoints
Primary and secondary outcome measures: see section 4 Study Design and Endpoints 
Inclusion/exclusion criteria: see section 5 Study Enrollment and Withdrawal 
Sample size: see section 10.5 Sample Size  
 
List of participating enrolling clinics or data collection centers: see section 5 Study 
Enrollment and Withdrawal  
 
Projected timetable: see R21 enrollment projections graph above  
 
Target population distribution (e.g., women, minorities) 
Inclusion of Women
Participants will not be excluded based on gender. However, there are sex differences between 
men and women among opioid-abusing chronic pain patients. Women are more likely to be 
prescribed opioids than men, more likely to take higher daily doses (151, 152) and are at higher 
risk for opioid-related overdoses leading to hospitalization (153). It is expected that at least 50% 
of the participants in this trial will be women.   
 
Inclusion of Minorities 
No participants will be excluded because of ethnic or racial identity.  However, numerous studies 
have demonstrated that African-Americans are less likely that Caucasians to be treated with 
opioid medications for pain (154, 155) despite evidence than African-Americans experience 
greater pain-related severity and disability compared to Caucasians (156). Concerted efforts will 
be made to recruit minority participants (especially African-Americans but also Latinos and other 
ethnic minorities) through Bellevue Hospital and the Manhattan VA, which have highly diverse 
and prevalent ethnic minority populations.   
 
Inclusion of Children 
Children under the age of 18 are excluded.  
Months 1-6
Study Preparation, 
Final Staff Training, 
IRB Approval
Months 7-20
Participant 
Recruitment & Data 
Collection
Months 21-24
Data Cleaning, 
Analysis, 
Manuscript 
Preparation


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Data acquisition and transmission: see section 11 source documents and access to source 
data  
Data entry methods: see section 11 source documents and access to source data 
 
Data analysis plan: see section 10 Statistical Considerations  
 
Quality assurance plan: see section 12 Quality Assurance and Quality Control 
 
Reporting mechanisms of AEs/SAEs to the IRB, FDA, and NIDA: see section 8 Assessment 
of Safety 
 
Reporting mechanisms of IRB actions to NIDA: see section 8 Assessment of Safety 
 
Report of changes or amendments to the protocol: All significant changes to the protocol must 
be approved by the NIDA Program Officer prior to implementation.  
Trial stopping rules: See section 8.8 Study Halting Rules  
Conflict of interest: See section 17 Conflict of Interest Policy  
Potential risks and benefits for participants: see section 2.4 Potential Risks & Benefits  
Collection and reporting of AEs and SAEs: see section 8 Assessment of Safety 
Management of SAEs or other study risks: see section 8 Assessment of Safety  
Plans for Interim Analysis of efficacy data: see section 10.4.7 Planned Interim Analysis 
Responsibility for data and safety monitoring  
Medical and Safety Monitoring 
The research team (project manager, coordinators, and research assistants) will submit any 
adverse events to the PI. The PI is responsible for reviewing all AEs and serious adverse events 
(SAEs) reported. All SAEs will be reviewed at the time they are reported in the electronic data 
capture system. All AEs will be reviewed on a weekly basis to observe trends or unusual events. 
The PI will generate and present reports for Data Safety Monitoring Board (DSMB) meetings. 
The DSMB will receive listings of AEs and summary reports of all SAEs at a frequency 
requested by the DSMB, but at least annually.  Furthermore, the DSMB will be informed of 
expedited reports of SAEs. A DSM Report will be submitted to NIDA annually. 
 
Data and Safety Monitoring Board (DSMB) 
An independent Data and Safety Monitoring Board (DSMB) will be established, comprising at 
least three individuals appointed by the PI. The members of the DSMB will have any of the 
following backgrounds/expertise: pain, addiction, clinical trials expertise, biostatistics. This 
committee will be led by a chairperson and will meet (in person or by teleconference) prior to 
enrollment of the first participant, and at least annually thereafter, including meetings following 
completion of treatment of the first 5 completers, after completion of treatment of the first 10 
completers, and upon completion of enrollment for the trial. Prior to each meeting, the PI will 
prepare a report to the Board including review of: 
 


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• Protocol and ICF changes
• Protocol violations and deviations 
• Documentation of informed consent  
• Enrollment and retention 
• Investigator or key personnel changes 
• Aggregate analysis of adverse events/serious adverse events 
• Protection of confidentiality 
 
Following each meeting, the board will provide the PI with a report including a recommendation 
to continue the study unchanged, continue with modifications of the protocol and/or the consent 
form to protect participant safety, or terminate the study. 
 
DSMB Members 
Kyle Kampman, MD (chair of DSMB) 
Professor of Psychiatry
University of Pennsylvania Perelman School of Medicine 
Center for Studies of Addiction 
kampman@pennmedicine.upenn.edu
Joshua Lee, MD 
Professor, Department of Population Health 
Professor, Department of Medicine 
NYU Grossman School of Medicine 
Afrin Sagir, MD, MBBS 
Assistant Professor of Anesthesiology and Critical Care
Penn Spine Center
Department of Anesthesiology and Critical Care
Hospital of the University of Pennsylvania
Perelman School of Medicine
Frequency of DSM reviews: see section above- Responsibility for data and safety monitoring  
Content of DSM report DSM Board Plan: see section above- Responsibility for data and 
safety monitoring 
9 
Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
GCP, and with applicable regulatory requirement(s).  
 
Site staff will be required to audit source documentation, including informed consent forms and 
HIPAA forms, regulatory documents and case report forms on a biannual basis. Site staff will be 
responsible for local quality assurance and will verify that study procedures are properly 
followed and that site staff are trained and able to conduct the protocol appropriately. If the site 
staff’s review of study documentation indicates that additional training of study personnel is 
needed, this will be arranged as per the PI. Study team members will review each other’s data 
for completeness, accuracy, and fidelity to the protocol. 
 


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10
Statistical Considerations
10.1 
Statistical and Analytical Plans (SAP) 
A formal SAP will be developed prior to un-blinding and database lock 
10.2 
Statistical Hypotheses 
Hypothesis 1a (safety and tolerability): Compared to placebo, CBD will be well tolerated by 
participants with no treatment-related serious adverse events (SAEs) or persisting CBD-related 
AEs.  
Hypothesis 1b (plasma opioid concentrations): Compared to placebo, CBD will not increase 
plasma opioid concentrations by greater than or equal to 150% at any of the assessment time-
points post-randomization (1-day, 2-day, 1-week, and 2-weeks) relative to baseline. 
Hypothesis 2 (pain measures: secondary efficacy outcome): Compared to placebo, CBD will 
be associated with a greater reduction in pain measures relative to baseline.  
Exploratory Aim 1: Compared to placebo, CBD will be associated with a greater reduction in 
anxiety relative to baseline. 
Exploratory Aim 2: Compared to placebo, CBD will be associated with a greater improvement in 
depression relative to baseline.  
Exploratory Aim 3: Compared to placebo, CBD will be associated with a greater improvement in 
insomnia relative to baseline.  
Exploratory Aim 4: Compared to placebo, CBD will be associated with a greater reduction in 
opioid craving relative to baseline.  
Exploratory Aim 5: Compared to placebo, CBD will be associated with a greater reduction in 
maintenance opioid dose relative to baseline. 
10.3 
Analysis Datasets 
The following datasets will be analyzed: 
 Intention-to-Treat (ITT) Analysis Dataset (i.e., all randomized participants) 
 The Modified Intention-to-Treat (m-ITT) population will contain all randomized patients 
who receive at least one dose of double-blind study medication and from whom at least 
one post-baseline efficacy measurement is obtained while on study medication.  
 Safety Analysis Dataset: subset of participants for whom safety analyses will be 
conducted (e.g., participants who took at least one dose of investigational product) 
 Evaluable or Per-Protocol Analysis Dataset: The evaluable subset of participants will be 
defined as having received daily study medication or placebo for a 2-week treatment 
period (through T4). 
 
10.4 Description of Statistical Methods 
10.4.1 General Approach 
Regarding the continuous outcomes to be assessed, a Mixed Model for Repeated 
Measures (MMRM) statistical analysis will be performed to assess treatment effects of CBD 
relative to placebo. The model at each time point will include terms for treatment, time, and 
treatment by time interaction as factors and the baseline value for each score as a covariate. 
Parameter estimation will be based on restricted maximum likelihood (REML) and to begin an 


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unstructured covariate matrix. If the model fails to converge, the alternative form of the covariance 
matrix will be chosen based on Schwarz’ Bayesian Criterion.  Model-based LS means will be 
obtained for change from baseline to each time point for each treatment group. At each time point, 
contrasts between CBD and placebo will be obtained. The main focus of the statistical analysis 
will be to characterize the effect sizes and response rates across outcome domains. The modified 
intent to treat (m-ITT) population will contain all randomized patients who receive at least one 
dose of double-blind study medication and from whom at least one post-baseline efficacy 
measurement is obtained while on study medication. The efficacy analysis will be based on the 
m-ITT population as well as a per protocol analysis given the pilot nature of the trial. Two-sided 
hypothesis testing will be utilized. Tests with p-values less than or equal to 0.05 will be considered 
statistically significant, while those less than or equal to 0.10 will be considered suggestive. Since 
this trial is the first use of this type of treatment, no adjustments of p-values for multiple 
comparisons will be made. Thus, all control of type 1 error is contrast-wise. Mean treatment effect, 
Cohen’s d, standard errors, and 95% confidence intervals will be derived from fully adjusted 
models on outcomes averaged across the treatment period.  
10.4.2 Analysis of the Primary Endpoint(s) 
For Hypothesis 1a (safety and tolerability), the incidence of AEs and SAEs will be summarized 
and tabulated for each group (CBD vs placebo) by system organ class, preferred term, severity, 
and likelihood of its relationship to the pharmacologic treatment. Between group differences in 
frequency of AEs and SAEs (T0-T4) will be analyzed using chi-squared tests. 
For Hypothesis 1b (plasma opioid concentrations), the respective outcomes will be analyzed 
with an MMRM to assess between-group and within-group differences in change from baseline. 
The primary contrast is change from baseline to 2-day, and 1-week post-randomization/initiation 
of pharmacologic treatment with secondary analyses contrasting changes from baseline to 2-
weeks post-randomization.     
10.4.3 Analysis of the Secondary Endpoint(s) 
For Hypothesis 2 (pain measures: secondary efficacy outcome), the respective outcomes will 
be analyzed with an MMRM to assess between-group and within-group differences in change 
from baseline. The primary contrast is change from baseline to 1-week post-
randomization/initiation of treatment with secondary analyses contrasting changes from baseline 
to final treatment visit at 2-weeks post-randomization. 
10.4.4 Safety Analyses 
See 10.4.2 Analysis of the Primary Endpoint(s) section regarding Hypothesis 1a (safety and 
tolerability) and Hypothesis 1b (safety and plasma opioid concentrations). 
AEs and SAEs, when present, will be collected on an AE Case Report Form at study visits. The 
form will include an assessment of clinical significance and study relatedness. Serious Adverse 
Events (SAEs) will be documented on an additional SAE form. Visual analog scales will be used 
to assess abuse potential. 
 
 
The study may be stopped if there are untoward and concerning levels of AEs or SAE outcomes 
attributable to CBD or study participation. If the DSMB finds it is likely that CBD is contributing to 
negative outcomes, they will consider solutions including protocol changes or potentially 
stopping the study. 


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10.4.5 Adherence and Retention Analyses
The Study Drug Participant Self-administration Log will be used to assess medication 
adherence by recording daily self-administration of study medications. Plasma concentrations of 
CBD will also be collected at T1-T4 will be an additional assessment to verify treatment 
adherence.   
 
Number of participants that complete the treatment phase of the study (through T4) and are lost 
to follow-up will be collected. Frequency of and reasons for discontinuation of the intervention or 
study follow-up will also be tallied.  
10.4.6 Baseline Descriptive Statistics 
Treatment groups will be compared on several baseline characteristics, including sex, age, 
race/ethnicity, education level, baseline measures of opioid maintenance medication [measured 
in morphine equivalent daily doses (MEDD)], opioid craving, pain measures (PCS, BPI), 
anxiety (PROMIS Anxiety), depression (PROMIS Depression), and sleep (PROMIS SRI). 
Categorical data will be tallied, and means and standard deviations of continuous scores will be 
calculated. 
 
10.4.7 Planned Interim Analysis 
10.4.7.1 Safety Review (see section 8.9 Safety Oversight: DSMB) 
The DSMB will meet (in person or by teleconference) following completion of treatment of the first 
5 completers, after completion of treatment of the first 10 completers, and upon completion of 
enrollment for the trial. Prior to each meeting, the PI will prepare a report to the Board including 
review of the aggregate analysis of adverse events/serious adverse events. 
Following each meeting, the board will provide the PI with a report including a recommendation 
to continue the study unchanged, continue with modifications of the protocol and/or the consent 
form to protect participant safety, or terminate the study. The study may be stopped if there are 
untoward and concerning levels of AE or SAE outcomes attributable to CBD or study participation. 
If the DSMB finds it is likely that CBD is contributing to negative outcomes, they will consider 
solutions including protocol changes or potentially stopping the study. 
10.4.7.2  
Efficacy Review 
There will be no interim efficacy analysis as part of this clinical trial. 
10.4.8  
Additional Sub-Group Analyses 
None. 
 
10.4.9  
Multiple Comparison/Multiplicity 
See 10.4.1 General Approach section above.
10.4.10  
Tabulation of Individual Response Data 
Aside from AEs/SAEs, individual response data will not be presented.  
10.4.11 
Exploratory Analyses 
For Hypothesis 3 (anxiety), Hypothesis 4 (depression), Hypothesis 5 (sleep), Hypothesis 6 
(opioid craving), and Hypothesis 7 (opioid sparing), the respective outcomes will be analyzed 
with t-tests to assess changes from baseline. 


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10.5
Sample Size/Power Calculation
We will screen approximately 30 participants, and enroll approximately 20 participants to meet 
our recruitment goal (through week 2/T4). In this pilot study, the affordable sample sizes are 
obviously quite limited. Previously, Zheng et al. conducted a randomized controlled trial using 
electroacupuncture [real electroacupuncture (REA) versus sham electroacupunture (SEA)] as a 
therapeutic intervention to decrease opioid-like medication (OLM) dose in patients with chronic 
pain syndromes (33).  Using a sample size of 35 (REA=17, SEA=18), at the end of the 
treatment period, reductions in OLM consumption in the REA versus SEA groups were 39% and 
25%, respectively (p=0.056). With the sample size of 20 in this current proposal, we hope to 
identify comparable or stronger evidence of CBD in reducing pain (in hypothesis 2) and change 
in plasma opioid concentrations from baseline to specified time (e.g., 1-week) in hypothesis 1b, 
in patients with chronic radiculopathies maintained on COT. A two-sided t-test of mean 
differences at 2 weeks requires an effect size of .91 common standard deviation to have .80 
power.  
 
10.6 Measures to Minimize Bias: Blinding Integrity Assessments 
10.6.1 Enrollment/Randomization/Masking Procedures 
The trial will employ a double-blind pharmacologic intervention methodology where the 
investigational drug (CBD) and matched placebo oral softgel capsules will be masked in 
identically appearing capsules provided by the drug sponsor. Randomization will be performed 
at the completion of the Baseline visit, and as close as possible to the first drug 
administration at the T1 session in order to restrict the intent-to-treat sample to patients who 
actually receive study medication.   
10.6.2 Evaluation of Success of Blinding 
To evaluate the effectiveness of the blind, both participant and investigator treatment assignment 
guesses (i.e., whether participant received investigational drug vs placebo) will be collected at 2-
weeks (T4). 
10.6.3 Breaking the Study Blind/Participant Code 
Breaking the blind will occur by PI judgment based on clinical safety considerations. Intentional 
and unintentional breaking of the blind will be reported to the appropriate regulatory entities (i.e., 
IRB, FDA, sponsor). 
11 Source Documents and Access to Source Data/Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject 
files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. It is acceptable to use CRFs as source documents. If 
this is the case, it should be stated in this section what data will be collected on CRFs and what 
data will be collected from other sources. 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space 
on the CRF is left blank because the procedure was not done or the question was not asked, 
write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries should be 
printed legibly in black ink.  If any entry error has been made, to correct such an error, draw a 


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single straight line through the incorrect entry and enter the correct data above it.  All such 
changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it. 
Access to study records will be limited to IRB-approved members of the study team. The 
investigator will permit study-related monitoring, audits, and inspections by the IRB/EC, the 
sponsor, government regulatory bodies, and University compliance and quality assurance 
groups of all study related documents (e.g., source documents, regulatory documents, data 
collection instruments, study data etc.). The investigator will ensure the capability for inspections 
of applicable study-related facilities (e.g., pharmacy, diagnostic laboratory, etc.). 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
12 Quality Assurance and Quality Control 
Data quality assurance (QA) includes all those planned and systematic actions that are 
established to ensure that the trial is performed and the data are generated, documented 
(recorded), and reported in compliance with GCP and the applicable regulatory requirements(s) 
(ICH E6 1.46). Data quality control (QC) includes the operational techniques and activities 
undertaken within the quality assurance system to verify that the requirements for quality of the 
trial-related activities have been fulfilled (ICH E6 1.47).  
QC procedures will be implemented beginning with the data entry system, and data QC 
checks on the database will be generated. Any missing data or data anomalies will be identified 
for clarification/resolution.  
Following written SOPs, the monitors will verify that the clinical trial is conducted and data 
are generated, documented (recorded), and reported in compliance with the protocol, GCP, and 
the applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)). The investigational site will provide direct access to all trial 
related sites, source data/documents, and reports for the purpose of monitoring and auditing by 
the sponsor, and inspection by local and regulatory authorities.  
 
13 Ethics/Protection of Human Subjects 
13.1 
Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 
CFR Part 56, and/or the ICH E6. 
13.2 
Institutional Review Board 
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. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether previously consented participants need to be re-consented. 
 
13.3 
Informed Consent Process 
13.3.1 Consent and Other Informational Documents Provided to Participants 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study product.  
 


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The following consent materials are submitted with this protocol:
 
Telephone Pre-screening Form 
 
Key Information form 
 
Main Informed Consent Form 
 
Main Consent Comprehension Quiz 
13.3.2 Consent Procedures and Documentation 
An IRB-approved pre-screening form will be used to pre-screen individuals expressing interest 
in the study, to assess whether they are likely to qualify for the study. Interested patients who 
pass the pre-screening will be referred for informed consent. Pre-screening data will be 
immediately destroyed for patients who do not pass pre-screening or for patients who pass the 
pre-screening but decide not to enroll in the study.  
 
Interested patients will be provided with an informed consent form including all pertinent details 
of the study including description of the following: the assessment interview and questionnaires; 
the follow-up interviews; description of experimental treatment; risks and benefits of study 
procedures; alternatives to participation in the study; confidentiality; emergency treatment and 
compensation for injury; payment for participation; a statement that patients will be informed of 
any new findings affecting the risks or benefits of the study; a statement that participation is 
voluntary and that the patient may withdraw at any time; and information about whom to contact 
with questions or in case of emergency. The consent form will also include assurances of 
confidentiality and a statement that participation is entirely voluntary, that the decision to 
participate will in no way influence other aspects of the patient’s treatment, and that the 
participant is free to withdraw participation at any time. The investigator will explain the research 
study to the participant and answer any questions that may arise. All participants will receive a 
verbal explanation in terms suited to their comprehension of the purposes, procedures, and 
potential risks of the study and of their rights as research participants. Participants will have the 
opportunity to carefully review the written consent form and ask questions prior to signing. 
 
The participants may withdraw consent at any time throughout the course of the trial. A copy of 
the signed informed consent document will be given to the participants for their records. The 
rights and welfare of the participants will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this study. A 
main ICF Comprehension Quiz will be included and an appropriately trained and delegated 
study staff member will administer the Comprehension Quiz to determine if sufficient 
comprehension of the study exists to proceed with study participation.   
 
A copy of the signed informed consent document will be stored in the subject’s research record. 
The consent process, including the name of the individual obtaining consent, will be thoroughly 
documented in the subject’s research record. Any alteration to the standard consent process 
(e.g., consent document presented orally) and the justification for such alteration will likewise be 
documented.   
13.4 
Participant and Data Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information  
 The rights of a research subject to revoke their authorization for use of their PHI.  


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In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e., that the subject is alive) 
at the end of their scheduled study period. 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB 
or pharmaceutical company supplying study product may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and study drug records for the participants in this study. The clinical 
study site will permit access to such records. 
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 local IRB and Institutional regulations. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at NYU Langone Health (NYULH). This will not 
include the participant’s contact or identifying information. Rather, individual participants and 
their research data will be identified by a unique study identification number. The study data 
entry and study management systems used by clinical sites and by NYULH research staff will 
be secured and password protected. At the end of the study, all study databases will be de-
identified and archived at the NYULH. 
Confidentiality of research material will be ensured by storing the research materials in locked 
cabinets. Material will be available only to project staff, and only as needed. All project staff will 
be thoroughly trained in issues relating to confidentiality. Participants will be identified in case 
report forms (CRFs) by initials and an identification code. Data will be entered into TrialMaster® 
programs designed specifically to protect patient privacy and confidentiality. Published reports will 
be based on group data; no individual data will be reported.  
To further protect the privacy of study participants, a Certificate of Confidentiality will be 
obtained from the NIH/NIDA. This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research records to 
refuse to disclose identifying information on research participation in any civil, criminal, 
administrative, legislative, or other proceeding, whether at the federal, state, or local level. By 
protecting researchers and institutions from being compelled to disclose information that would 
identify research participants, Certificates of Confidentiality help achieve the research objectives 
and promote participation in studies by helping assure confidentiality and privacy to participants. 
13.4.1 Research Use of Stored Human Samples, Specimens, or Data 
 Intended Use: Samples and data collected under this protocol may be used to evaluate 
study eligibility and plasma concentrations of opioids and cannabinoids. No genetic 
testing will be performed. 
 Samples will only be used for study-specific analyses and then destroyed. Samples will 
not be banked for future research. 


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13.5
Future Use of Stored Data
Data collected for this study will be stored in locked cabinets in NYULH Psychiatry Department 
space within the Ross Lab area in the psychiatry department at One Park Avenue. After the 
study is completed, the de-identified, archived data will be transmitted to and stored at GRM 
Document Management for use by other researchers including those outside of the study. 
Permission to transmit data to GRM Document Management will be included in the informed 
consent. 
 
When the study is completed, access to study data will be provided through GRM Document 
Management. 
 
14 Data Handling and Record Keeping 
14.1 Data Collection and Management Responsibilities 
 
Data collection, interpretation, analysis, review, and reporting is the responsibility of the clinical 
trial staff at the site under the supervision of the site PI. The investigator is responsible for 
ensuring the accuracy, completeness, legibility, and timeliness of the data reported. 
 
All source documents will be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black ink will be used to ensure clarity of reproduced copies. When 
making changes or corrections, cross out the original entry with a single line, and initial and date 
the change. Do not erase, overwrite, or use correction fluid or tape on the original. Copies of the 
electronic CRF (eCRF) will be provided for use as source documents and maintained for 
recording data for each participant enrolled in the study. Data reported in the eCRF derived from 
source documents will be consistent with the source documents or the discrepancies will be 
explained and captured in a progress note and maintained in the participant’s official electronic 
study record. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) 
and clinical laboratory data will be entered into “Research Electronic Data Capture” using 
TrialMaster®, a 21 CFR Part 11-compliant data capture system. The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify 
data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly 
from the source documents.  
14.2 
Study Records Retention 
Study documents will be retained for the longer of 3 years after close-out, 5 years after final 
reporting/publication, 2 years after the last approval of a marketing application is approved for 
the drug for the indication for which it is being investigated, or 2 years after the investigation is 
discontinued and FDA is notified if no application is to be filed or if the application has not been 
approved for such indication. No records will be destroyed without the written consent of the 
sponsor-investigator, if applicable.  
14.3 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of 
Procedures (MOP) requirements. The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions 
are to be developed by the site and implemented promptly. 
 
These practices are consistent with ICH E6: 
 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 


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 5.1 Quality Assurance and Quality Control, section 5.1.1
 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
Protocol deviations will be reported to the NYU SOM IRB and NIDA per their guidelines, 
respectively. The site PI/study staff is responsible for knowing and adhering to IRB 
requirements.  
14.4 
Publication and Data Sharing Policy 
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted 
a clinical trials registration policy as a condition for publication. The ICMJE defines a clinical trial 
as any research project that prospectively assigns human subjects to intervention or concurrent 
comparison or control groups to study the cause-and-effect relationship between a medical 
intervention and a health outcome. Medical interventions include drugs, surgical procedures, 
devices, behavioral treatments, process-of-care changes, and the like. Health outcomes include 
any biomedical or health-related measures obtained in patients or participants, including 
pharmacokinetic measures and adverse events. The ICMJE policy, and the Section 801 of the 
Food and Drug Administration Amendments Act of 2007, requires that all clinical trials be 
registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the 
National Library of Medicine. Other biomedical journals are considering adopting similar 
policies. For interventional clinical trials performed under NIH IC grants and cooperative 
agreements, it is the grantee’s responsibility to register the trial in an acceptable registry, so the 
research results may be considered for publication in ICMJE member journals. The ICMJE does 
not review specific studies to determine whether registration is necessary; instead, the 
committee recommends that researchers who have questions about the need to register err on 
the side of registration or consult the editorial office of the journal in which they wish to publish. 
 
FDAAA mandates that a "responsible party" (i.e., the sponsor or designated principal 
investigator) register and report results of certain "applicable clinical trials": 
 
 Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I 
investigations of a product subject to FDA regulation 
 Trials of Devices: Controlled trials with health outcomes of a product subject to FDA 
regulation (other than small feasibility studies) and Pediatric Postmarket Surveillance 
studies 
 NIH grantees must take specific steps to ensure compliance with NIH implementation of 
FDAAA 
 
15 Study Finances 
15.1 
Funding Source 
This study is financed through a grant from the US National Institutes of Health (NIH)/National 
Institute on Drug Abuse (NIDA). 
15.2 
Costs to the Participant 
Participants will not incur any costs as a result of participating in the study. 


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15.3
Participant Reimbursements or Payments
Participants will receive monetary compensation for research assessments as follows:  
Screen (S) = $50, Baseline (T0) = $25, 1-day assessment (T1) = $75, 2-day assessment (T2) = 
$75, 1-week assessment (T3) = $100, 2-week assessment (T4) = $75. Participants completing 
all of the assessments would therefore receive a total of $400.  
 
16 Study Administration 
16.1 Study Leadership 
The study will be led by PI Stephen Ross and the core study team leadership will consist of the 
PI and the co-Is (Doan, Blessing, Cheatle). 
 
Role for Dr Cheatle: As part of the review process with NIDA for this grant, NIDA stipulated that 
an NIH-funded pain and addiction clinical trialist be added as a study member. Dr Cheatle has 
this requested background and so was added as a sub-investigator as part of the grant and 
study. His roles will include assisting with: study design, use of optimal outcome measures, 
recruitment strategies, strategies for reduction in opioid maintenance dose, data analysis, and 
writing of manuscripts. Note that Dr Cheatle will not have access to participant identifiers and 
will not interact with research participants.  
17 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the trial. The 
study leadership in conjunction with the NIDA has established policies and procedures for all 
study group members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest.  
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by the NYU Langone Conflict of Interest Management Unit (CIMU) with a committee-
sanctioned conflict management plan that has been reviewed and approved by the study 
sponsor prior to participation in this study. All NYULH investigators will follow the applicable 
conflict of interest policies. 
 
 
 


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authorized in writing by the study sponsor 
18
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on treatment outcome in patients with nonspecific low back pain: a systematic review. Spine. 
2014;39(3):263-73. Epub 2013/11/21. doi: 10.1097/brs.0000000000000110. PubMed PMID: 24253796. 
149. 
Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, Haythornthwaite JA, 
Jensen MP, Kerns RD, Ader DN, Brandenburg N, Burke LB, Cella D, Chandler J, Cowan P, Dimitrova R, 
Dionne R, Hertz S, Jadad AR, Katz NP, Kehlet H, Kramer LD, Manning DC, McCormick C, McDermott 
MP, McQuay HJ, Patel S, Porter L, Quessy S, Rappaport BA, Rauschkolb C, Revicki DA, Rothman M, 
Schmader KE, Stacey BR, Stauffer JW, von Stein T, White RE, Witter J, Zavisic S. Interpreting the clinical 
importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. The journal 
of pain : official journal of the American Pain Society. 2008;9(2):105-21. Epub 2007/12/07. doi: 
10.1016/j.jpain.2007.09.005. PubMed PMID: 18055266. 
150. 
Childress AR, McLellan AT, O'Brien CP. Abstinent opiate abusers exhibit conditioned craving, 
conditioned withdrawal and reductions in both through extinction. British journal of addiction. 
1986;81(5):655-60. Epub 1986/10/01. PubMed PMID: 3466632. 
151. 
Williams RE, Sampson TJ, Kalilani L, Wurzelmann JI, Janning SW. Epidemiology of opioid 
pharmacy claims in the United States. Journal of opioid management. 2008;4(3):145-52. Epub 
2008/08/23. doi: 10.5055/jom.2008.0019. PubMed PMID: 18717509. 
152. 
Campbell CI, Weisner C, Leresche L, Ray GT, Saunders K, Sullivan MD, Banta-Green CJ, Merrill 
JO, Silverberg MJ, Boudreau D, Satre DD, Von Korff M. Age and gender trends in long-term opioid 
analgesic use for noncancer pain. American journal of public health. 2010;100(12):2541-7. Epub 
2010/08/21. doi: 10.2105/ajph.2009.180646. PubMed PMID: 20724688; PMCID: PMC2978198. 
153. 
Coben JH, Davis SM, Furbee PM, Sikora RD, Tillotson RD, Bossarte RM. Hospitalizations for 
poisoning by prescription opioids, sedatives, and tranquilizers. American journal of preventive medicine. 
2010;38(5):517-24. Epub 2010/04/23. doi: 10.1016/j.amepre.2010.01.022. PubMed PMID: 20409500. 
154. 
Anderson KO, Green CR, Payne R. Racial and ethnic disparities in pain: causes and 
consequences of unequal care. The journal of pain : official journal of the American Pain Society. 
2009;10(12):1187-204. Epub 2009/12/01. doi: 10.1016/j.jpain.2009.10.002. PubMed PMID: 19944378. 
155. 
Meghani SH, Byun E, Gallagher RM. Time to take stock: a meta-analysis and systematic review 
of analgesic treatment disparities for pain in the United States. Pain medicine (Malden, Mass). 
2012;13(2):150-74. Epub 2012/01/14. doi: 10.1111/j.1526-4637.2011.01310.x. PubMed PMID: 22239747. 
156. 
Burgess DJ, Nelson DB, Gravely AA, Bair MJ, Kerns RD, Higgins DM, van Ryn M, Farmer M, 
Partin MR. Racial differences in prescription of opioid analgesics for chronic noncancer pain in a national 
sample of veterans. The journal of pain : official journal of the American Pain Society. 2014;15(4):447-55. 
Epub 2014/01/21. doi: 10.1016/j.jpain.2013.12.010. PubMed PMID: 24440840. 
 


Study number: s21-00230
Page 72
Version: 12/13/2022 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
19
Attachments
These documents are relevant to the protocol, but they are not considered part of the protocol.  
They are stored and modified separately. As such, modifications to these documents do not 
require protocol amendments. 
 
 


Study number: s21-00230
Page 73
Version: 7/8/2022 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor 
Interventional Template Version: 05 JAN 2017 
 
20
Schedule of Events
1Rx= Pharmacologic Treatment Period 
2Liver function tests  
3Study medication or placebo dispensed at visit for daily use until the next visit 
4Blood drawn before starting CBD/PCB administration 
5Blood draws after starting CBD/PCB administration 
Study Phase 
Screen
Baseline 
(Rx1) 
Rx 
Rx
Rx 
Study Visit 
S1, 2, 3
B1 
1 
2 
3 
4
Target Weeks 
-4 to -2
-2 to 0
1-day
2-day
1 
(-2d)
2
(-2d)
Time 
T0
T1
T2
T3
T4
Inclusion/Exclusion Criteria
COVID-19 Screening
X
X
X
X
X
X 
Screening Checklist 
X
 
Informed Consent (ICF) 
X
 
ICF Comprehension Quiz
X
 
ICF Documentation
X
 
Authorization for Release of Health Information
X
 
Confidential Contact Information  
X
 
Demographics (Phen X Tier-1) 
X
 
Medical/Psychiatric History  
X
 
SCID 5 
X
 
Alcohol Test 
X
 
Physical Examination 
X
 
Clinical Labs
X
X2
X2 
EKG 
X
 
Birth Control Documentation 
X
X
X
X
X 
Urine Pregnancy Test
X
X
X
X
X
X 
Urine Drug Screen
X
X
X
X
X
X 
Concomitant Medications 
X
X
X
X
X
X 
Eligibility (I/E) Checklist 
X
X
 
Randomization 
X
 
CBD/PCB Dispensed 
X3 
X3 
X3
X3 
Safety Assessments 
Vital Signs
X
X
X
X
X
X 
AEs 
X
X
X
X
X
X 
Suicidality (C-SSRS) 
X
X
X
X
X
X 
Sedation (RASS)
X
X
X
X 
Field Sobriety Test
X
X
X
X 
Pharmacokinetics 
CBD Plasma Levels  
X5 
X4,5 
X4,5
X4,5
Opioid Plasma Levels
X
X4 
X4 
X4
X4 
Opioid—Related Outcomes 
Opioid Maintenance Dose (MEDD) 
X
X
X
X
X 
Opioid Craving (VAS) 
X
X
X
X
X 
Secondary Efficacy Outcome: Pain Outcomes 
Brief Pain Inventory (BPI)
X
X
X
X
X 
Pain Catastrophizing Scale (PCS) 
X
X
X
X
X 
Mental Health Outcomes
Anxiety (PROMIS) 
X
X
X
X
X 
Depression (PROMIS)  
X
X
X
X
X 
Sleep (PROMIS)
X
X
X
X
X 
Blinding Integrity  
X 
Self-Administration Medication Log 
X
X
X
X
X
X 
Participant Compensation 
X
X
X
X
X
X 

ICF_000.pdf: 
 
 
Official Title: 
A Phase I/II, Randomized, Double-blind, Placebo-controlled, Single-
center Study of the Effects of Cannabidiol (CBD) on Opioid Plasma 
Levels in Participants With Chronic Radiculopathic Pain Syndromes 
Maintained on Chronic Opioid Therapy (COT)   
NCT Number: 
NCT04760613 
Study Number: 
21-00230 
Document Type:  
Informed Consent Form 
Date of the 
Document: 
• 
June 14, 2022 
 
 


Study #: i21-00230 
Version Date:  1/10/2022 
Page 1 of 20 
 
 
 
Last Updated: 1/10/2022 
Research Subject 
Informed Consent Form 
Title of Study: 
A Phase I/II, Randomized, Double-Blind, Placebo-Controlled Trial of 
Cannabidiol for chronic radiculopathic pain syndromes maintained on chronic 
opioid therapy 
s21-00230      
Principal 
Investigator: 
Stephen Ross, MD  
Department of Psychiatry 
NYU School of Medicine 
462 1st Avenue, A838 
Email: Stephen.Ross@nyulangone.org 
Telephone: 212-263-6289 
Emergency 
Contact: 
Stephen Ross, MD 
Cell phone: (917) 848-7830 
1. 
About volunteering for this research study 
You are being invited to take part in a research study. Your participation is voluntary which means you 
can choose whether or not you want to take part in this study. 
 
People who agree to take part in research studies are called “subjects” or “research subjects”. These 
words are used throughout this consent form.  Before you can make your decision, you will need to know 
what the study is about, the possible risks and benefits of being in this study, and what you will have to 
do in this study. You may also decide to discuss this study and this form with your family, friends, or 
doctor.  If you have any questions about the study or about this form, please ask us. If you decide to take 
part in this study, you must sign this form. We will give you a copy of this form signed by you for you to 
keep. 
2. 
What is the purpose of this study? 
 
The purpose of this research study is to see how safe and effective Cannabidiol (CBD) is for the 
treatment of chronic non-cancer spinal radiculopathic pain conditions in people maintained on an 
ongoing dose of opioid pain medications. We will assess the effects of CBD on opioid medication use, 
pain as well as aspects of thinking, emotions and behavior. 
 
CBD is a drug found in the marijuana plant that does not appear to have addictive properties and is not 
known to be psychoactive (affect your mind). Even though the United States Food and Drug 
Administration (FDA) has approved CBD in the form of Epidiolex® for childhood seizure disorders, it has 
not approved CBD as a safe or effective treatment for chronic non-cancer radiculopathic pain conditions. 
Therefore, the use of CBD to treat opioid use and pain associated with chronic spinal non-cancer 
radiculopathy is considered experimental. Animal and human studies suggest that CBD may be helpful in 
treating opioid addiction and pain.   
 
CBD works by activating receptors (proteins) in the brain known to effect a variety of processes such as 
immune function, appetite, pain sensation, mood, memory and the way you respond to stressful 


Study #: i21-00230 
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Last Updated: 1/10/2022 
situations. Even though CBD is found in the marijuana plant, it does not make people feel “high” the 
same way that marijuana does. 
 
You will be randomly assigned (like a flip of a coin) to either CBD or a placebo group. You have a 50% (1 
in 2) chance to be assigned to either group. Placebo means that you will receive capsules to take daily 
that will not have any CBD in them. You and your study doctor will not know whether you are taking CBD 
or placebo. In the event of an emergency, your study doctor can find out this information.  
 
You are being asked to participate in this study because you want to decrease or stop your opioid 
analgesic maintenance dose but are not currently enrolled in another clinical trial assessing the effects of 
an anti-pain intervention.   
3. 
How long will I be in the study? How many other people will be in the study? 
 
Approximately 40 subjects will receive medication in this study at NYULMC. Up to 60 people will be 
consented in the study in order to reach the target of 40 subjects to receive medication. The total 
duration of participation in the study, including screening and follow-up visits, will be approximately 26 
weeks. The total approximate time of contact during these 26 weeks is estimated at 40 hrs. 
4. 
What will I be asked to do in the study? 
If you agree to participate, the following will occur: 
 
Screening Visit (4 hours) 
 
If you agree to be in this study, the first visit will be the screening visits. The purpose of the screening 
visits is to make sure that you meet all of the conditions to participate in the study. The screening visits 
include medical and mental health evaluations, as well as assessments of your pain condition and opioid 
medication use. The medical evaluation must be done in-person at the study site, but you have the 
option to complete other portions of the screening visit at home, before you come to the study site to 
complete the medical evaluation. 
 
Medical Evaluation (Approximately 1 hour) 
 
You will have the following procedures done: 
 
• 
Medical/Psychiatric history 
• 
Demographics (age, race and ethnicity, gender, etc.) 
• 
SCID-5 (Diagnostic Exam) 
• 
Physical Exam 
• 
Electrocardiogram (ECG or EKG), which measures the electrical activity of your heart 
• 
Safety clinical laboratory measures: 10 cc of blood (about 2 teaspoons) will be drawn with a 
needle from a vein in your arm to check blood counts and the functioning of your liver and other 
organs (if you are a women of childbearing potential, we will also collect blood for a serum 
pregnancy test) 
• 
Urine sample (approximately 1 tablespoon) will be collected for: 
o Urinalysis 
o To test for the presence of several drugs, including cocaine, methamphetamine, opiates, 
and marijuana. This test will be performed on site. You will be able to collect this urine in a 


Study #: i21-00230 
Version Date:  1/10/2022 
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Last Updated: 1/10/2022 
bathroom without anyone watching you. You will be informed of the results of the 
laboratory tests when they become available. Unless you are taking a medication for  
medical purposes, if you test positive for any of the drugs listed (including recreational or 
medical marijuana or any product containing CBD), you will not be allowed to participate 
in the study. 
o Women of child bearing potential will also have a urine pregnancy test done 
• 
Vital signs (heart rate, blood pressure, and temperature) 
 
• 
It is a requirement of the study that you are willing to allow for initial and ongoing 
communication between the study team and your treatment provider(s) prescribing chronic 
opioid therapy for chronic radicular pain condition. If it is necessary to determine your eligibility 
for the study, we may ask to see your personal information in records from hospitals, clinics, or 
doctor’s offices where you may have received care in the past. We may also ask to speak with 
other clinicians who have treated you for medical and/or psychiatric conditions, but will not reveal 
the nature of the study without your permission.  
 
• 
As part of the July 2020 FDA drug safety communication (https://www.fda.gov/drugs/drug-safety-
and-availability/fda-recommends-health-care-professionals-discuss-naloxone-all-patients-when-
prescribing-opioid-pain), the study team will communicate with all of your treatment providers 
prescribing opioids to you that they provide a naloxone prescription you. Naloxone is an opioid 
overdose antidote medication and will be used to manage risks related to opioid medication use. 
 
You will receive a diagnostic interview assessing substance use and psychiatric disorders. This includes 
questions about symptoms of the most important mental illnesses, including use, abuse, and 
dependence on/of alcohol and drugs. We will also ask you in detail about your recent use of alcohol and 
drugs and about any current medications you are taking. We will also ask you about suicidal thoughts 
and behaviors and will monitor you for suicidal thoughts and behaviors throughout the trial at each study 
visit. If you qualify to participate in the study, you will be scheduled for a Baseline visit and 6 assessment 
visits over the next 24 weeks. Please refer to the Schedule of Assessments as follows: 
 
In order to participate in this study, you will also need to identify at least two people who would know your 
whereabouts in case study personnel needed to find you during the study. The locator people may be 
told that we are calling from NYU, and may be given the name and phone number of study staff, but will 
not be given any other information about your participation without your permission. If we are unable to 
reach you with the information you have provided on the locator form, we may use publicly available data 
on the internet, like Facebook, in an effort to find updated contact information. 
 
You will be given a Medication Self-Administration Log to record the prescription opioid medication(s) 
that you take. Between your Screening Visit and T1 Visit, this Medication Self-Administration Log will 
help us determine the precise time that your opioid medication is at its lowest level, which is crucial for 
determining when to take blood samples and schedule further visits. After the T1 Visit, you will also begin 
recording your doses of the study drug (CBD or placebo) on this log. You will be asked to bring the log to 
each of the remaining study visits. After the T8 visit (16-week), you will no longer be recording your use 
of study drug or your prescription opioid(s).  
 
Baseline Visit (T0): Approximately 4 hours 
 
At the baseline session (T0), prior to beginning the study treatment, you will be asked to complete a 
number of questionnaires and interviews, many of which will be repeated at later assessment sessions. 
These include questionnaires about any recent medication, drug and alcohol use (since the last visit), 
problems you may have experienced related to opioids, your motivation and confidence to reduce your 
analgesic opioid dose, your craving for opioids, your degree of pain, any thoughts or actions indicating 


Study #: i21-00230 
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Last Updated: 1/10/2022 
harm to yourself or others and your current mood and sleep patterns. We will also check your vital signs 
(heart rate, blood pressure, and temperature) and collect a urine sample (approximately 1 tablespoon) to 
test for the presence of several drugs (including cocaine, opioids, methamphetamines and marijuana). 
 
If you are a woman of childbearing potential we will also perform a urine pregnancy test to minimize the 
risk of undetected pregnancy while you are in the study. 
 
We will also need to collect a blood sample (1 or 2 tablespoons) to test for levels of prescription opioid 
analgesic plasma levels in your system. This sample will be sent to outside laboratories for testing, and 
will be accessible only to laboratory personnel. We will also collect several samples of blood to test for 
opioid and CBD levels over the course of the study: 3 samples at 1-day (T1), 3 samples at 2-day (T2), 3 
samples at 1-week (T3), 3 samples at 2-weeks (T4), and 3 samples at 4-weeks (T6) after starting the 
medication intervention.   
 
T1 (1-day) visit (beginning of study medication): Approximately 4 hours 
 
At the T1 visit, you will be asked to complete questionnaires about any recent medication, drug and 
alcohol use (since the last visit), problems you may have experienced related to opioids, your motivation 
and confidence to reduce your analgesic opioid dose, your craving for opioids, your degree of pain, any 
thoughts or actions indicating harm to yourself or others and your current mood and sleep patterns. We 
will also check your vital signs (heart rate, blood pressure, and temperature) and collect a urine sample 
(approximately 1 tablespoon) to test for the presence of several drugs (including cocaine, opioids, 
methamphetamines and marijuana). 
 
If you are a woman of childbearing potential we will also perform a urine pregnancy test to minimize the 
risk of undetected pregnancy while you are in the study. 
 
We will also need to collect 3 blood samples (1 or 2 tablespoons for each sample) over several hours at 
our NYU-HHC Clinical and Translational Science Institute (CTSI) at Bellevue Hospital to test for levels of 
prescription opioid analgesic plasma levels and CBD plasma levels in your system. To minimize the 
amount of needle sticks, we will place an initial intravenous catheter in one of your veins to collect the 3 
blood samples. These samples will be sent to outside laboratories for testing, and will be accessible only 
to laboratory personnel.  
 
Study Medication 
 
At the T1 visit, you will receive your first dose of study medication (CBD or placebo) by mouth following a 
light meal. Specifically, you will receive 6 capsules of CBD (50mg per capsule) or the placebo. We will 
monitor you closely for a minimum of 3 hours to assess for safety. If there are no safety concerns 
following this initial administration during the T1 visit, we will give you instructions on how to use the 
study medication at home and will provide you with enough of the study medication to last until your next 
scheduled visit. You will be given medication to take home with you, and you will be instructed to take the 
medication each day. You will take 6 capsules in the morning (total dose of 300mg of CBD if you 
received CBD as study drug) and 6 capsules in the evening (approximately 12 hours apart), following a 
light meal, for the duration of 16 weeks. Sometimes we will ask you to bring your morning dose with you 
to a research visit to take in the laboratory. For the T2 visit, we ask that you bring in 6 capsules of your 
study medication to take in the morning at the NYU-HHC CTSI. 
 
You will be instructed to start using your Medication Self-Administration Log to record all of the doses of 
the study drug (CBD or placebo) in addition to the prescription opioid medication(s) that you take, which 
you have been recording since the Screening Visit. You will be asked to bring this log to each of the 


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Last Updated: 1/10/2022 
remaining study visits. After the T8 visit (16-week), you will no longer be recording your use of study drug 
or your prescription opioid(s).  
 
T2 (2-day) visit:  Approximately 4 hours 
 
At the T2 visit, you will be asked to complete questionnaires about any recent medication, drug and 
alcohol use (since the last visit), problems you may have experienced related to opioids, your motivation 
and confidence to reduce your analgesic opioid dose, your craving for opioids, your degree of pain, any 
thoughts or actions indicating harm to yourself or others and your current mood and sleep patterns. We 
will also check your vital signs (heart rate, blood pressure, and temperature) and collect a urine sample 
(approximately 1 tablespoon) to test for the presence of several drugs (including cocaine, opioids, 
methamphetamines and marijuana). 
 
If you are a woman of childbearing potential we will also perform a urine pregnancy test to minimize the 
risk of undetected pregnancy while you are in the study. 
 
We will also need to collect 3 blood samples (1 or 2 tablespoons for each sample) over several hours at 
our NYU-HHC Clinical and Translational Science Institute (CTSI) at Bellevue Hospital to test for levels of 
prescription opioid analgesic plasma levels and CBD plasma levels in your system. To minimize the 
amount of needle sticks, we will place an initial intravenous catheter in one of your veins to collect the 3 
blood samples. These samples will be sent to outside laboratories for testing, and will be accessible only 
to laboratory personnel.  
 
Study Medication 
 
At the T2 visit, you will receive your morning dose of study medication (CBD or placebo) by mouth 
following a light meal. We will monitor you for a minimum of 3 hours to assess for safety. If there are no 
safety concerns following this initial administration during the T2 visit, we will give you instructions on 
how to use the study medication at home and will provide you with enough of the study medication to last 
until your next scheduled visit. You will be given medication to take home with you, and you will be 
instructed to take the medication each day.  You will take 6 capsules in the morning (total dose of 300mg 
of CBD if you received CBD as study drug) and 6 capsules in the evening (approximately 12 hours 
apart), following a light meal, unless there was an adjustment (i.e., decrease) in your dose. 
 
For the T3 visit, we ask that you bring in 6 capsules of your study medication to take in the morning at 
the NYU-HHC CTSI. You will also need to bring in your self-administration log. 
 
T3 (1-week) visit:  Approximately 4 hours 
 
At the T3 visit, you will be asked to complete questionnaires about any recent medication, drug and 
alcohol use (since the last visit), problems you may have experienced related to opioids, your motivation 
and confidence to reduce your analgesic opioid dose, your craving for opioids, your degree of pain, any 
thoughts or actions indicating harm to yourself or others and your current mood and sleep patterns. We 
will also check your vital signs (heart rate, blood pressure, and temperature) and collect a urine sample 
(approximately 1 tablespoon) to test for the presence of several drugs (including cocaine, opioids, 
methamphetamines and marijuana). 
 
If you are a woman of childbearing potential we will also perform a urine pregnancy test to minimize the 
risk of undetected pregnancy while you are in the study. 
 
We will also need to collect 3 blood samples (1 or 2 tablespoons for each sample) over several hours at 
our NYU-HHC Clinical and Translational Science Institute (CTSI) at Bellevue Hospital to test for levels of 


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Last Updated: 1/10/2022 
prescription opioid analgesic plasma levels and CBD plasma levels in your system. To minimize the 
amount of needle sticks, we will place an initial intravenous catheter in one of your veins to collect the 3 
blood samples. These samples will be sent to outside laboratories for testing, and will be accessible only 
to laboratory personnel.  
 
Study Medication 
 
At the T3 visit, you will receive your morning dose of study medication (CBD or placebo) by mouth 
following a light meal. We will monitor you for a minimum of 3 hours to assess for safety. If there are no 
safety concerns following this initial administration during the T3 visit, we will give you instructions on 
how to use the study medication at home and will provide you with enough of the study medication to last 
until your next scheduled visit. You will be given medication to take home with you, and you will be 
instructed to take the medication each day. You will take 6 capsules in the morning (total dose of 300mg 
of CBD if you received CBD as study drug) and 6 capsules in the evening (approximately 12 hours 
apart), following a light meal, unless there was an adjustment (i.e., decrease) in your dose. 
 
For the T4 visit, we ask that you bring in 6 capsules of your study medication to take in the morning at 
the NYU-HHC CTSI. You will also need to bring in your self-administration log. 
 
T4 (2 week) visit:  Approximately 4 hours 
 
At the T4 visit, you will be asked to complete questionnaires about any recent medication, drug and 
alcohol use (since the last visit), problems you may have experienced related to opioids, your motivation 
and confidence to reduce your analgesic opioid dose, your craving for opioids, your degree of pain, any 
thoughts or actions indicating harm to yourself or others and your current mood and sleep patterns. We 
will also check your vital signs (heart rate, blood pressure, and temperature) and collect a urine sample 
(approximately 1 tablespoon) to test for the presence of several drugs (including cocaine, opioids, 
methamphetamines and marijuana). We will also collect approximately 1 teaspoon of blood to assess 
your liver function. We will also ask you to guess whether you believe you are receiving the CBD or 
placebo. 
 
If you are a woman of childbearing potential we will also perform a urine pregnancy test to minimize the 
risk of undetected pregnancy while you are in the study. 
 
We will also need to collect 3 blood samples (1 or 2 tablespoons for each sample) over several hours at 
our NYU-HHC Clinical and Translational Science Institute (CTSI) at Bellevue Hospital to test for levels of 
prescription opioid analgesic plasma levels and CBD plasma levels in your system. To minimize the 
amount of needle sticks, we will place an initial intravenous catheter in one of your veins to collect the 3 
blood samples. These samples will be sent to outside laboratories for testing, and will be accessible only 
to laboratory personnel.  
 
Study Medication 
 
At the T4 visit, you will receive your morning dose of study medication (CBD or placebo) by mouth with 
food. We will monitor you for a minimum of 3 hours to assess for safety. If there are no safety concerns 
following this initial administration during the T4 visit, we will give you instructions on how to use the 
study medication at home and will provide you with enough of the study medication to last until your next 
scheduled visit. You will be given medication to take home with you, and you will be instructed to take the 
medication each day. You will take 6 capsules in the morning (total dose of 300mg of CBD if you 
received CBD as study drug) and 6 capsules in the evening (approximately 12 hours apart), following a 
light meal, unless there was an adjustment (i.e., decrease) in your dose. 
 


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For the T5 visit, we ask that you bring in 6 capsules of your study medication to take in the morning at 
the NYU-HHC CTSI. You will also need to bring in your self-administration log. 
 
T5 (3 week) visit:  Approximately 4 hours 
 
At the T5 visit, you will be asked to complete questionnaires about any recent medication, drug and 
alcohol use (since the last visit), problems you may have experienced related to opioids, your motivation 
and confidence to reduce your analgesic opioid dose, your craving for opioids, your degree of pain, any 
thoughts or actions indicating harm to yourself or others and your current mood and sleep patterns. We 
will also check your vital signs (heart rate, blood pressure, and temperature) and collect a urine sample 
(approximately 1 tablespoon) to test for the presence of several drugs (including cocaine, opioids, 
methamphetamines and marijuana). We will also collect approximately 1 teaspoon of blood to assess 
your liver function. We will also ask you to guess whether you believe you are receiving the CBD or 
placebo. 
 
If you are a woman of childbearing potential we will also perform a urine pregnancy test to minimize the 
risk of undetected pregnancy while you are in the study. 
 
Study Medication 
 
At the T5 visit, you will receive your morning dose of study medication (CBD or placebo) by mouth with 
food. We will monitor you for a minimum of 3 hours to assess for safety. If there are no safety concerns 
following this initial administration during the T5 visit, we will give you instructions on how to use the 
study medication at home and will provide you with enough of the study medication to last until your next 
scheduled visit. You will be given medication to take home with you, and you will be instructed to take the 
medication each day. You will take 6 capsules in the morning (total dose of 300mg of CBD if you 
received CBD as study drug) and 6 capsules in the evening (approximately 12 hours apart), following a 
light meal, unless there was an adjustment (i.e., decrease) in your dose. 
 
For the T6 visit, we ask that you bring in 6 capsules of your study medication to take in the morning at 
the NYU-HHC CTSI. You will also need to bring in your self-administration log. 
 
T6 (4-week) visit:  Approximately 4 hours 
 
At the T6 visit, you will be asked to complete questionnaires about any recent medication, drug and 
alcohol use (since the last visit), problems you may have experienced related to opioids, your motivation 
and confidence to reduce your analgesic opioid dose, your craving for opioids, your degree of pain, any 
thoughts or actions indicating harm to yourself or others and your current mood and sleep patterns. We 
will also check your vital signs (heart rate, blood pressure, and temperature) and collect a urine sample 
(approximately 1 tablespoon) to test for the presence of several drugs (including cocaine, opioids, 
methamphetamines and marijuana). We will also ask you to guess whether you believe you are receiving 
the CBD or placebo. 
 
If you are a woman of childbearing potential we will also perform a urine pregnancy test to minimize the 
risk of undetected pregnancy while you are in the study. 
 
We will also need to collect 3 blood samples (1 or 2 tablespoons for each sample) over several hours at 
our NYU-HHC Clinical and Translational Science Institute (CTSI) at Bellevue Hospital to test for levels of 
prescription opioid analgesic plasma levels and CBD plasma levels in your system. We will also collect 
approximately 1 teaspoon of blood to assess your liver function. To minimize the amount of needle 
sticks, we will place an initial intravenous catheter in one of your veins to collect the 3 blood samples. 


Study #: i21-00230 
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These samples will be sent to outside laboratories for testing, and will be accessible only to laboratory 
personnel.  
 
Study Medication 
 
At the T6 visit, you will receive your morning dose of study medication (CBD or placebo) by mouth 
following a light meal. We will monitor you for a minimum of 3 hours to assess for safety. If there are no 
safety concerns following this initial administration during the T6 visit, we will give you instructions on 
how to use the study medication at home and will provide you with enough of the study medication to last 
until your next scheduled visit. You will be given medication to take home with you, and you will be 
instructed to take the medication each day. You will take 6 capsules in the morning (total dose of 300mg 
of CBD if you received CBD as study drug) and 6 capsules in the evening (approximately 12 hours 
apart), following a light meal, unless there was an adjustment (i.e., decrease) in your dose. 
 
For the T7 visit, we ask that you bring in 6 capsules of your study medication to take in the morning at 
the NYU-HHC CTSI. You will also need to bring in your self-administration log. 
 
T7 (8 week) visit:  Approximately 2 hours 
 
At the T7 visit, you will be asked to complete questionnaires about any recent medication, drug and 
alcohol use (since the last visit), problems you may have experienced related to opioids, your motivation 
and confidence to reduce your analgesic opioid dose, your craving for opioids, your degree of pain, any 
thoughts or actions indicating harm to yourself or others and your current mood and sleep patterns. We 
will also check your vital signs (heart rate, blood pressure, and temperature) and collect a urine sample 
(approximately 1 tablespoon) to test for the presence of several drugs (including cocaine, opioids, 
methamphetamines and marijuana). We will also collect approximately 1 teaspoon of blood to assess 
your liver function.   
 
If you are a woman of childbearing potential we will also perform a urine pregnancy test to minimize the 
risk of undetected pregnancy while you are in the study. 
 
Study Medication 
 
At the T7 visit, we will provide you with enough of the study medication to last until your next scheduled 
visit. You will be given medication to take home with you, and you will be instructed to take the 
medication each day. You will take 6 capsules in the morning (total dose of 300mg of CBD if you 
received CBD as study drug) and 6 capsules in the evening (approximately 12 hours apart), following a 
light meal, unless there was an adjustment (i.e., decrease) in your dose. This will be the final medication 
administration and there will not be an option to receive any further study medication. 
 
You will also need to bring in your self-administration log for the last time and will not need to continue to 
record your daily use of prescription opioid(s) or study medications. 
 
T8 (16 week) visit:  Approximately 4 hours 
 
At the T8 visit, you will be asked to complete questionnaires about any recent medication, drug and 
alcohol use (since the last visit), problems you may have experienced related to opioids, your motivation 
and confidence to reduce your analgesic opioid dose, your craving for opioids, your degree of pain, any 
thoughts or actions indicating harm to yourself or others and your current mood and sleep patterns. We 
will also check your vital signs (heart rate, blood pressure, and temperature) and collect a urine sample 
(approximately 1 tablespoon) to test for the presence of several drugs (including cocaine, opioids, 
methamphetamines and marijuana). We will also collect approximately 1 teaspoon of blood to assess 


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your liver function. We will also ask you to guess whether you believe you are receiving the CBD or 
placebo. 
 
If you are a woman of childbearing potential we will also perform a urine pregnancy test to minimize the 
risk of undetected pregnancy while you are in the study. 
 
Study Medication 
You will not receive any further study medication for the remainder of the trial until the final study visit T9 
(24-weeks). 
 
T9 (24 week) visit:  Approximately 2 hours (may be conducted remotely) 
 
At the T9 visit (final study visit), you will be asked to complete questionnaires about any recent 
medication, drug and alcohol use (since the last visit), problems you may have experienced related to 
opioids, your motivation and confidence to reduce your analgesic opioid dose, your craving for opioids, 
your degree of pain, any thoughts or actions indicating harm to yourself or others and your current mood 
and sleep patterns. We will also collect approximately 1 teaspoon of blood to assess your liver function.   
 
Potential for dose adjustments or cessation of study medication   
 
If you are experiencing potential negative side effects from the study medication, it is possible to have 
your study medication adjusted by the study physician. The medication administration may be 
discontinued by the study physician if it is deemed that continued administration of the medication would 
post a significant medical risk.   
 
Information about blood samples collected for opioid and CBD analyses 
 
Any personal information that could identify you will be removed from the blood sample specimens. The 
blood samples will be shipped to the University of Buffalo where the pharmacokinetic analyses 
(measuring opioid analgesic plasma levels and CBD plasma levels) will take place.  
 
Any identifiable specimen collected and/or used for the purposes of this research will not be used or 
distributed for future research studies. 
 
Identifiers will be removed from the identifiable private information. After such removal, the information 
may be used for future research studies or shared with other researchers and we will not request 
additional informed consent from you to use these specimens or information as we have noted here.  
 
 
 
 
 


Study #: i21-00230 
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Last Updated: 1/10/2022 
 
1Rx= Pharmacologic Treatment Period 
2Liver function tests  
3Study medication or placebo dispensed at visit for daily use until the next visit 
4Blood drawn before starting CBD/PCB administration 
5Blood draws after starting CBD/PCB administration 
Study Phase 
Screen 
Baseline 
  (Rx1) 
Rx 
Rx 
Rx 
Rx 
Rx 
Rx 
Rx 
F/U 
Study Visit 
S1, 2, 3 
B1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Target Weeks 
-4 to -2 
-2 to 0 
1-day 
2-day 
1 
(-2d) 
2 
(-2d) 
3 
(-2d) 
4 
(-2d) 
8 
(-4d) 
16 
(-4d) 
24 
(-4d) 
Time 
 
T0 
T1 
T2 
T3 
T4 
T5 
T6 
T7 
T8 
T9 
 
Inclusion/Exclusion Criteria 
COVID-19 Screening 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Screening Checklist 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consent (ICF) 
X 
 
 
 
 
 
 
 
 
 
 
ICF Comprehension Quiz 
X 
 
 
 
 
 
 
 
 
 
 
ICF Documentation 
X 
 
 
 
 
 
 
 
 
 
 
Authorization for Release of Health 
Information 
X 
 
 
 
 
 
 
 
 
 
 
Confidential Contact Information  
X 
 
 
 
 
 
 
 
 
 
 
Demographics (Phen X Tier-1) 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric History  
X 
 
 
 
 
 
 
 
 
 
 
SCID-5 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical Labs 
X 
 
 
 
 
 
 
X2 
X2 
X2 
X2 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
Birth Control Documentation 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
Urine Pregnancy Test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Drug Screen 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Eligibility (I/E) Checklist 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
CBD/PBO dispensed 
 
 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
 
 
 
Safety Assessments 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Suicidality (CSSRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sedation (RASS) 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Field Sobriety Tests 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Pharmacokinetics 
CBD Plasma Levels  
 
 
X4 
X4,5 
X4,5 
X4,5 
 
X4,5 
 
 
 
Opioid Trough Plasma Levels 
 
X 
X5 
X4 
X4 
X4 
 
X4 
 
 
 
 
Opioid—Related Outcomes 
Primary Efficacy Outcome: Opioid 
Dose (MEDD) 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
Motivation: Change Opioid Use 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Opioid Misuse (COMM)  
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Opioid Craving (VAS) 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Opioid Withdrawal (SOWS) 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
Pain Outcomes 
Brief Pain Inventory (BPI) 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Pain Catastrophizing Scale (PCS) 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Quality of Life (PROMIS) 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Mental Health Outcomes 
Anxiety (PROMIS)  
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Depression (PROMIS)  
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Sleep (PROMIS) 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Blinding Integrity  
 
 
 
 
 
 
 
X 
 
X 
 
Self-Administration Medication Log 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Participant Compensation 
X 
X 
 
 
X 
 
 
X 
 
X 
X 


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5. What are the possible risks or discomforts? 
 
Risk of Study Drug 
 
The available evidence suggests that CBD is safe and well-tolerated in human subjects. Oral CBD has 
been administered in clinical trials to both healthy volunteers and patients with various medical 
conditions, as single or multiple doses ranging from 10 mg to 6000 mg. In most of the studies CBD was 
well tolerated and no severe or serious adverse events (AE) were reported. Hence, CBD is generally 
considered to have a favorable safety profile.   
 
In a study published recently involving healthy volunteers, oral CBD doses of up to 6000 mg (single 
administration) and up to 1500 mg/d (multiple dose) were associated with only mild or moderate AEs, 
and none resulted in the early termination of participation. The most common AEs in all the trial arms 
were diarrhea, nausea, headache, and tiredness. Diarrhea and headache were more common in 
subjects taking CBD compared with placebo.  
 
The recommended dose of the FDA-approved Epidiolex® (oral CBD administered mostly to children to 
treat seizure disorders, Dravet Syndrome and Lennox-Gastaut) ranges from 5 mg/kg/day to 5 mg/kg 
twice daily (10 mg/kg/day). Occasionally 20 mg/kg/day have also been administered. Since the drug has 
only been approved recently, no post-marketing safety data is available, and the following information is 
based on controlled and uncontrolled clinical trials experience. The most common adverse reactions that 
occurred in Epidiolex®-treated patients (incidence at least 10% or at least 10 out of every 100 patients) 
and greater than placebo) were  
 
• 
Sleepiness 
• 
Decreased appetite 
• 
Diarrhea  
• 
Decreased energy 
• 
Rash 
• 
Difficulty sleeping 
• 
Infections 
• 
Increase in liver enzymes: CBD (in the form of Epidiolex™) has been reported to be associated 
with dose-related elevations in liver transaminases (ALT and/or AST). There also was a clear 
dose association: 8% (8 out of 100) elevations overall in the 10 mg/kg group and 16% (16 out of 
100) in the 20 mg/kg group. Elevated liver enzymes do not necessarily signal a serious liver 
problem. There do not appear to be reports of CBD-treated patients who have experienced liver 
failure. Identified risk factors for transaminase elevation included taking other medications such 
with valproic acid (a medication used to treat seizure disorders, mood conditions and migraine 
headaches), and elevated baseline liver function tests. Most events of transaminase elevation 
occurred within 30 to 90 days after initiation of CBD treatment although rare cases were observed 
up to 200 days after initiation of treatment, particularly in patients also taking valproic acid. These 
abnormalities generally resolved with discontinuation of cannabidiol or dose decreases in 
cannabidiol or valproic acid, yet elevated levels also resolved spontaneously without changing the 
dose of CBD 
o We will assess your liver function at screening as well as at 4- weeks, 8-weeks, 16-
weeks, and 24-weeks after starting study medication.  
 
There is a theoretical risk that CBD may raise your prescription opioid levels, especially during the first 
month of receiving CBD, if you end up in the group receiving CBD. Increased opioid levels can potentially 
be dangerous and could result in an opioid overdose and death. To minimize this risk, we will closely 


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monitor you, especially during the first month after starting study medication since this represents the 
greater risk period from the perspective of increased opioid levels. We will specifically protect you from 
potential increased opioid levels in the study by the following:  
 
• 
We will educate you on the signs and symptoms that may indicate increased opioid levels. These 
typically include feeling lethargic, slowed breathing, and small pupil size. We will provide with a 
contact number to reach study personnel in between the weekly visits for the first month of 
receiving study medication.  
o You will be able to reach the principal investigator Dr. Stephen Ross at any time by calling 
917-848-7830 
 
• 
Regarding visits T1-T6, you will be administered the first daily morning dose of medication (CBD 
300mg or placebo) for that treatment period and will be evaluated for a minimum of 3 hours at a 
supervised clinical laboratory setting within the Ross Lab area at Bellevue Hospital (i.e., A8) or 
the NYU-HHC Clinical & Translational Science Institute (NYU-HHC CTSI) at Bellevue Hospital. 
You will be closely monitored with safety assessments with particular attention directed to detect 
any signs of opioid intoxication or overdose (i.e., physical examination signs, vital sign monitoring 
assessing your breathing and oxygenation status). If you develop clinical signs and symptoms 
suggestive of opioid intoxication or overdose (i.e., respiratory suppression (breathing poorly), 
decreased oxygenation, lethargy (tiredness/lack of energy)), you will be immediately evaluated 
clinically and appropriate medical steps will be taken to assure your safety (i.e., Narcan/naloxone 
administration, oxygen administration, inpatient hospitalization, breaking the blind (your doctor will 
confirm whether you were taking CBD or placebo), discontinuing study medication).  
o You will not be permitted to leave the study site for visits T1-T6 until you are able to pass 
a standard field sobriety test. 
 
• 
 As part of July 2020 FDA drug safety communication (https://www.fda.gov/drugs/drug-safety-
and-availability/fda-recommends-health-care-professionals-discuss-naloxone-all-patients-when-
prescribing-opioid-pain), the study team will communicate with all treatment providers, who are 
prescribing prescription opioids to you, that they provide a naloxone prescription for you. 
Naloxone is an opioid blocking medication that is used as an antidote (or to cancel the effects of 
opioids) to treat opioid overdoses. The study team will train you on the use of naloxone. In the 
case of an opioid overdose, naloxone would be administered to you by a family member, 
spouse/partner, friend or healthcare provider. It would be important that whoever is in close 
contact with you (i.e. living with you, sees you regularly) is trained in how to administer naloxone 
if necessary.   
 
The CBD and placebo medications for this study are provided by ANANDA Scientific. Note that the 
specific drug product to be used in this trial has only been studied in healthy volunteers (and at lower 
doses than will be used in this trial) and has not been administered to patients previously. Also, note that 
this drug products is not Epidiolex™ (the marketed and approved CBD drug product) and is an 
experimental drug product. In a human safety study conducted on the formulation of CBD (A1002N5S) 
that will be used in this study, a total of 12 AE’s occurred after the start of dosing.  None were serious, all 
were considered mild, and none were considered related to the study drugs.  The most frequent AE was 
headache (6/12, 50.0%) reported by 5 (out of the 15) subjects. 
 
Since it is possible that there is a theoretical risk of adverse drug interactions between CBD and 
grapefruit (in terms of grapefruit potentially increasing levels of CBD when the two are taken together), 
you are to avoid consuming grapefruit or grapefruit juice during the duration of the study. 
 


Study #: i21-00230 
Version Date:  1/10/2022 
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Last Updated: 1/10/2022 
There is a chance you will not actually be taking medicine that will treat your condition. In this case, your 
condition might not improve or could get worse. You could miss the benefits or harms (if any) of the study 
medication. 
 
It is possible that there are unforeseeable risks associated with the study medication or other aspects of 
participation in the trial.  
 
Other Risks 
 
Blood Drawing Risks 
 
Drawing blood may cause temporary pain and discomforts from the needle stick, occasional bruising, 
sweating, feeling faint or lightheaded, and in rare cases infection. 
 
Risks of Assessment Procedures 
 
There are no known psychological risks associated with the questionnaires used in the study, most of 
which have been used extensively in clinical populations. It is possible that discussion of substance use 
and psychiatric symptoms may cause you some emotional discomfort or temporary stress. One of the 
investigators of the project will be available to meet with you if you become distressed about any aspect 
of the study and wish to discuss it. 
 
Risks to Confidentiality and Potential Legal Consequences 
 
Information from this study may be submitted to the U.S. Food and Drug Administration (FDA). Medical 
records that identify you and the consent form you signed may be inspected by the FDA and the New 
York University School of Medicine’s Institutional Review Board (the Human Research Protections 
Office). Because of the need to release information to these parties, absolute confidentiality cannot be 
guaranteed. The results of this research project may be presented at meetings or in publications. 
However, your identity will not be disclosed in those presentations. 
 
For more information about risks and side effects, ask a study investigator. 
6. Can I be in the study if I am pregnant or breastfeeding? 
Because taking part in this study may harm an embryo, fetus, or breastfeeding baby, you should not 
become pregnant, breastfeed a baby, or father a child while participating in this study. Other risks may 
not yet be known. 
 
If you are currently pregnant, you will not be able participate in the study. You should not become 
pregnant while you are participating in this study.  If you are able to become pregnant, you will be 
required to use a medically accepted method of birth control while you participate in the study:  
 
• 
Hormonal methods like birth control capsules, patches, vaginal rings or implants,  
• 
Barrier methods such as condoms or a diaphragm used with spermicide (a foam, cream or gel that 
kills sperm),  
• 
Intrauterine device (IUD),  
• 
Abstinence (no sex).   
If you become or you think you have become pregnant during the study, you must tell the principal 
investigator right away and must tell your obstetrician or other health care provider caring for you during 


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Last Updated: 1/10/2022 
your pregnancy that you took part in this study.  If you become pregnant, you will have to stop taking part 
in the study for safety reasons.  The principal investigator may ask you to provide information about the 
outcome of your pregnancy and the health of your baby. 
 
Note to Men  
 
Because the effects of participating in this study on sperm are unknown, you will be required to use a 
medically accepted method of birth control while you participate in the study using one of the methods 
described above.  
7. 
What if new information becomes available? 
During the course of this study we may find more information that could be important to you. This 
includes information that might cause you to change your mind about being in the study.  We will notify 
you as soon as possible if such information becomes available. 
8. 
What are the possible benefits of the study?  
There may or may not be benefits to you from participating in this study. It is possible that some study 
subjects who receive CBD may experience a reduction in their opioid pain medication use and pain 
during the study. However, if you receive such benefit, because CBD is not FDA-approved for treating 
opioid use or pain in chronic spinal non-cancer radiculopathy, your doctor cannot prescribe it after you 
finish the study. Also, you may not get any benefit from being in this research study. Knowledge gained 
through this study may aid the development of more effective treatments for individuals with chronic non-
cancer radiculopathy pain who are on opioid pain medications.  
9. 
What other choices do I have if I do not participate?  
Standard of care for outpatient treatment of chronic radiculopathic pain consists of a variety of treatments 
including medications, physical therapy/rehabilitation, psychological (i.e., cognitive-behavioral therapy, 
mindfulness-based interventions), interventional (i.e., nerve blocks, neurostimulators, joint injections), 
and other (i.e., acupuncture, massage, chiropractic) modalities. These alternatives may be discussed 
with your personal physician. 
10. Will I be paid for being in this study? 
In return for your time and the inconvenience of participating in this study, you will be compensated for 
the study visits you complete. 
 
Subjects will receive monetary compensation for research assessments as follows:  
 
Study Visit 
Amount 
Screen (S) 
$20 
Baseline (T0) 
$60 
1-week assessment (T3) 
$40 
4-week assessment (T6) 
$40 
16-week (T8) 
$40 
24-week (T9) 
$40 


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Last Updated: 1/10/2022 
If you do not complete all of the visits, you will be paid for each of the visits you complete. If you 
complete all study visits, you will be compensated a total of $240. 
 
As is required by the laws that apply to NYU Langone, in order for you to receive a payment (i.e., check, 
Clincard, or bank gift card), you need to give the study staff either your Social Security number or your 
Alien Registration number and will be asked to complete a IRS W9.  If you do not have either of these 
numbers or are not willing to complete the IRS, you may be in the study but will not receive any payment. 
 
You are required to track all payments made to you by NYU Langone for your participation in any 
research for this calendar year. You must let us know immediately if/when the total research payments 
presently equal or is likely to exceed $600.00 total (not including travel reimbursements) for this calendar 
year. If your total payments (for one or more studies) reach $600.00, please advise the study principal 
investigator, Stephen Ross, MD who can be contacted at: 917-848-7830 or 
Stephen.Ross@nyulangone.org.  
  
In order to receive payments for your participation in research, you may need to provide your Social 
Security number. This is because NYU Langone is required to report to the Internal Revenue Service 
(IRS) any amounts that are paid to research participants that are equal to or greater than $600.00, and 
you may be taxed on these research payments above $600.00. If you will receive payments in any 
amount by a check, you will need to provide your Social Security number or Alien Registration 
number and will be asked to complete an IRS W9.  If you do not have either of these numbers or are not 
willing to complete the IRS, you may be in the study but will not receive any payment. 
11. Will I have to pay for anything? 
You will not be billed for the cost of tests and procedures directly associated with this study.  
You and/or your health insurance may be billed for the costs of medical care during this study if these 
expenses would have happened even if you were not in the study, or if your insurance agrees in 
advance to pay. If you have health insurance, the cost of these services will be billed to your insurance 
company. If your insurance does not cover these costs or you do not have insurance, these costs will be 
your responsibility. 
 
12. What happens if I am injured from being in the study? 
 
We will offer you the care needed to treat injuries directly resulting from taking part in this research. We 
may bill your insurance company or other third parties, if appropriate, for the costs of the care you get for 
the injury, but you may also be responsible for some of them.  
For medical emergencies contact 911. If you think you have been injured as a result of taking part in this 
research study, tell the principal investigator as soon as possible. The principal investigator’s name and 
phone number are listed at the top of page 1 of this consent form.  
There are no plans for the NYU School of Medicine or Medical Center to pay you or give you other 
compensation for the injury. You do not give up your legal rights by signing this form.   
13. When is the study over? Can I leave the Study before it ends? 
This study is expected to end after all subjects have completed all visits, and all information has been 
collected.  This study may also be stopped or your participation ended at any time by your physician, the 
study sponsor, or the Food and Drug Administration (FDA) without your consent because: 


Study #: i21-00230 
Version Date:  1/10/2022 
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Last Updated: 1/10/2022 
• 
The principal investigator feels it is necessary for your health or safety.  Such an action would not 
require your consent, but you will be informed if such a decision is made and the reason for this 
decision. 
• 
You have not followed study instructions.  
• 
The study sponsor, the principal investigator, the Food and Drug Administration (FDA) or other 
body responsible for monitoring the safety of the study has decided to stop the study. 
 
If you decide to participate, you are free to leave the study at any time. Leaving the study will not 
interfere with your future care, payment for your health care or your eligibility for health care benefits. 
14. How will you protect my confidentiality?  
Your medical information is protected health information, or “PHI”, and is protected by federal and state 
laws, such as the Health Insurance Portability and Accountability Act, or HIPAA. This includes 
information in your research record as well as information in your medical record at NYU Langone 
Health. In compliance with NYU Langone Health policies and procedures and with HIPAA, only those 
individuals with a job purpose can access this information. 
Medical information created by this research study may become part of your medical record. We may 
include your research information in your medical record for several reasons, including for the billing of 
services provided in connection with the study, to securely document any medical services you receive, 
and so that other members of the NYU Langone Health community who may treat you have access to 
important information about your health.  
You have a right to access information in your medical record.  In some cases, when necessary to 
protect the integrity of the research, you will not be allowed to see or copy certain information relating to 
the study while the study is in progress, but you will have the right to see and copy the information once 
the study is over in accordance with NYU Langone Health policies and applicable law. 
 
Certificate of Confidentiality 
 
To help us further protect your confidentiality, this research is covered by a Certificate of Confidentiality 
from the National Institutes of Health (NIH). The NIH has issued a Certificate of Confidentiality for this 
research. This adds special protection for the research information (data, documents, or biospecimens) 
that may identify you. 
 
Research information protected by this Certificate of Confidentiality cannot be disclosed to anyone else 
who is not connected with the research, without your consent. With this Certificate of Confidentiality, the 
researchers may not disclose or use research information that may identify you in any federal, state, or 
local civil, criminal, administrative, legislative, or other action, suit, or proceeding, or be used as 
evidence, for example, if there is a court subpoena, without your consent. However, disclosure, without 
your consent, is still necessary if there is a federal, state, or local law that requires disclosure (such as to 
report child abuse or communicable diseases). 
 
The Certificate of Confidentiality cannot be used to refuse a request for information from appropriate 
government agencies responsible for project oversight. 
 


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Last Updated: 1/10/2022 
The Certificate of Confidentiality does not prevent you from releasing information about yourself and your 
involvement in this research, including for your medical treatment. Federal regulations may also allow for 
the use or sharing of information for other scientific research. 
 
By agreeing to be in this research and signing below, you are giving your consent to share research 
information with others at NYU Langone Health. This means that your research information, including lab 
results and information about the investigational drug used in this study, may be included in your NYU 
Langone Health electronic medical record. 
15. HIPAA Authorization 
 
As noted in the Confidentiality section above, federal law requires us, and our affiliated researchers, 
health care providers, and physician network to protect the privacy of information that identifies you and 
relates to your past, present, and future physical and mental health conditions. We are asking for your 
permission (authorization) to use and share your health information with others in connection with this 
study- in other words, for purposes of this research, including conducting and overseeing the study.   
 
Your treatment outside of this study, payment for your health care, and your health care benefits will not 
be affected even if you do not authorize the use and disclosure of your information for this study.  
 
What information may be used or shared with others in connection with this study? 
 
 All information in your research record for this study may be used and shared with those individuals 
listed in this section. Additionally, information in your medical record that the research team believes may 
be important to the study may be accessed by those listed here. This includes, for example, results from 
your physical examinations, laboratory tests, procedures, questionnaires, and diaries.  
 
Who may use and share information in connection with this study?   
 
The following individuals may use, share, or receive your information for this research study: 
• 
The research team, including the Principal Investigator, study coordinators, and personnel 
responsible for the support or oversight of the study 
• 
The study sponsor: The National Institute on Drug Abuse (NIDA)/The National Institutes of Health 
(NIH) 
• 
Governmental agencies responsible for research oversight (e.g., the Food and Drug 
Administration or FDA).  
• 
Health care providers, including your doctors and others who provide services to you in 
connection with this study, and laboratories or other individuals who analyze your health 
information in connection with this study.  
• 
The Data & Safety Monitoring Board (DSMB) 
• 
The data team: DataCore at New York University Langone to manage and maintain integrity of 
study data 
• 
University of Buffalo (under the direction of Gene Morse) who will be conducting the 
pharmacokinetic analyses of the opioid and CBD plasma collections 
• 
GRM Document Management to save and store study data once the study has been completed 
 
Your information may be re-disclosed or used for other purposes if the person who receives your 
information is not required by law to protect the privacy of the information. 
 


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What if I do not want to give permission to use and share my information for this study? 
 
Signing this form is voluntary. You do not have to give us permission to use and share your information, 
but if you do not, you will not be able to participate in this study.  
 
Can I change my mind and withdraw permission to use or share my information? 
 
Yes, you may withdraw or take back your permission to use and share your health information at any 
time for this research study.  If you withdraw your permission, we will not be able to take back information 
that has already been used or shared with others.  To withdraw your permission, send a written notice to 
the principal investigator for the study noted at the top of page 1 of this form.  If you withdraw your 
permission, you will not be able to stay in this study. 
 
How long may my information be used or shared?   
 
Your permission to use or share your personal health information for this study will never expire unless 
you withdraw it. 
16. Electronic Medical Record and Release of Study Related Information 
 
What is an Electronic Medical Record?  
 
An Electronic Medical Record (EMR) is an electronic version of your medical chart within NYU Langone 
Health. An EMR is simply a computer version of a paper medical record.  
 
If you are or have been a patient at NYU Langone Health in the past, you have an EMR at NYU Langone 
Health. Information from your research participation will be added to this EMR.  
 
If you have never been a patient at NYU Langone Health, you may not have an EMR at NYU Langone 
Health. In connection with your participation in this study, an EMR will be created for you. The purpose of 
your EMR at NYU Langone Health will be to facilitate this research study and allow the researchers to 
maintain information arising from your participation in this research study. The creation of this EMR is a 
requirement of your participation in this study. In order to create your EMR, the study team will need to 
obtain basic information about you that would be similar to the information you would provide the first time 
you visit a hospital or medical facility, for example, your name, the name of your primary doctor, the type 
of insurance you have, your date of birth and other health-related information.  
 
What may be placed in the EMR?  
 
Information related to your participation in the research (e.g., laboratory tests, research-related notes, 
imaging studies, and clinical procedures, etc.) will be placed in your EMR maintained by NYU Langone 
Health. 
 
This information will be accessible to other members of the NYU Langone workforce that are not part of 
the research team. Information within your EMR may also be shared with others who NYU Langone Health 
has determined may appropriately have access to your EMR (e.g. Health Insurance Company, disability 
provider, etc.).  
 
 


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Will I have access to research-related information within the Electronic Medical Record?  
 
The 21st Century Cures Act allows patients increased access to their EMR. If you agree to participate in 
this study, this means that any research-related information placed in your EMR will be available to you 
immediately.  
 
As a research participant, this means that you have immediate access to any research-related information 
that is placed in your EMR before the researchers have had an opportunity to review the information.  
 
In this study, some research-related information in your EMR will not be available to you until the end of 
the study. This information will not be accessible in your EMR immediately in order to protect the integrity 
of the research trial results. 
 
Results in the medical record that will not be immediately accessible:  
• 
Results of the blood testing that is being done, including tests of blood counts, opioid and CBD 
levels, and pregnancy. 
 
The researchers will provide you access to this research-related information in your EMR when the study 
is over.  
17. Optional permission for future use 
NYULMC would also like to store, use, and share your health information from this study in research 
databases or registries for future research conducted by NYULMC or its research partners. To give this 
additional permission, check the box below and write your initials where indicated. You may still 
participate in this study even if you do not give us this additional permission. 
 
NYULMC will continue to protect the confidentiality and privacy of this information as required by law and 
our institutional polices. If you give this additional permission, you will continue to have the rights 
described in this form.  You have the right to take back this additional permission at any time.  
 
  I agree to allow the study team to store, use, and share my health information from this study in 
research databases or registries for future research conducted by NYULMC or its research partners.  
  I do not want the study team to store, use, or share my health information from this study in research 
databases or registries for future research conducted by NYULMC or its research partners.  
 
 
 
____________________________________________________     _____________ 
Signature of Subject ________________________________________  Date ______________ 
18. The Institutional Review Board (IRB) and how it protects you 
The IRB reviews all human research studies – including this study. The IRB follows Federal Government 
rules and guidelines designed to protect the rights and welfare of the people taking part in the research 
studies. The IRB also reviews research to make sure the risks for all studies are as small as possible.  
The NYU IRB Office number is (212) 263-4110.  The NYU School of Medicine’s IRB is made up of: 
• 
Doctors, nurses, non-scientists, and people from the Community 


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19. Who can I call with questions, or if I’m concerned about my rights as a research subject? 
If you have questions, concerns or complaints regarding your participation in this research study or if you 
have any questions about your rights as a research subject, you should speak with the Principal 
Investigator listed on top of the page 1 of this consent form.  If a member of the research team cannot be 
reached or you want to talk to someone other than those working on the study, you may contact the 
Institutional Review Board (IRB) at (212) 263-4110.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website site at any time. 
 
When you sign this form, you are agreeing to take part in this research study as described to you. 
This means that you have read the consent form, your questions have been answered, and you have 
decided to volunteer.   
 
 
 
 
Name of Subject (Print) 
 
Signature of Subject 
 
Date 
 
 
 
Name of Person Obtaining Consent 
(Print) 
 
Signature of Person Obtaining Consent 
 
Date