A Phase 2B, 8-week, Randomized, Double-Blind, Placebo-Controlled, Parallel Study to Evaluate Efficacy, Safety and Tolerability of the Fatty Acid Amide Hydrolase (FAAH) Inhibitor PF-04457845 in Adults With DSM5 Current Cannabis Use Disorder (CUD)
Phase: PHASE2
Conditions: Cannabis Use Disorder
Sponsor: Yale University

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A Phase 2B, 8-Week, Randomized, Double-Blind, 
Placebo-Controlled, Parallel Group Study to Evaluate 
the Efficacy, Safety and Tolerability of the Fatty Acid 
Amide Hydrolase (FAAH) Inhibitor PF-04457845 in 
Adults with DSM-5 Current Cannabis Use Disorder 
(CUD)
 STUDY PROTOCOL
National Clinical Trial (NCT) Identified Number: NCT03386487
Principal Investigator: Deepak Cyril D’Souza, M.D.
                                                                         
IND Coordinating Center: IND#114,017 Mohini Ranganathan, M.D.
Funded by: National Institute of Drug Abuse (NIDA)
Protocol Version: 5.0
February 8, 2022
CONFIDENTIAL PROPERTY OF YALE UNIVERSITY
This document is a confidential information belonging to Yale University. Except as otherwise agreed in writing, by 
accepting or reviewing this document, you agree to hold this information in confidence and not copy or disclose it 
to others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual 
or suspected breach of this obligation, Yale University must be promptly notified.
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TABLE OF CONTENTS
1.
ADMINISTRATIVE INFORMATION
8
1.1
Statement of Compliance
8
1.2
Contacts
12
1.3
Protocol Summary Synopsis
13
1.4
Protocol Summary Schema
13
1.5
Schedule of Procedures
14
2.
INTRODUCTION AND BACKGROUND
15
2.1
Cannabis use disorder (CUD) is an increasingly recognized problem for which 
there are no FDA-approved or clinically-accepted pharmacological treatments
15
2.2
Changes associated with cannabis use disorder
15
2.3
Tolerance
16
2.4
Cannabis withdrawal syndrome
17
2.5
Sleep disturbances are an important manifestation of cannabis withdrawal
17
2.6
There is a need for effective treatments for cannabis use disorder
18
2.6.1
Psychotherapeutic approaches
18
2.6.2
Pharmacotherapeutic approaches
18
2.7
Potentiating endocannabinoid signaling as a treatment for CUD
19
2.8
Compared to THC, increased anandamide levels produce lower adaptive
changes at the CB1R
19
2.9
FAAH inhibitors have several advantages over THC or cannabis
19
2.9.1
FAAH-inhibitors are not rewarding
19
2.9.2
FAAH Inhibitors do not have negative interactions with THC
20
2.9.3
FAAH inhibitors have several advantages
20
3.
PRELIMINARY RESEARCH 
21
3.1
Animal Studies
21
3.2
 Human Phase 1 Studies
21
3.2.1
Pharmacokinetics
21
3.2.2
Pharmacodynamics           
21         
3.3
Human Phase 2 Osteoarthritis Study
22
3.4
Proof of Concept Study with PF-04457845 in CUD
23
3.4.1
Pharmacokinetics
25
3.4.2
Target Engagement
25
3.4.3
Adherence
25
3.4.4
Cannabis Withdrawal Inpatient
26
3.4.5
Cannabis Use
26
3.4.6
Urinary THC-COOH Levels
26
3.4.7
Feeling States
27
3.4.8
Polysomnography
27
3.4.9
Safety and Tolerability of PF-04457845
28
3.4.10 Summary of Preliminary Study Results
28
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4.
STUDY OBJECTIVES AND ENDPOINTS
29
4.1
Objectives
29
4.1.1
Primary Objective
29
4.1.2
Secondary and Exploratory Objectives
29
4.2
Endpoints
30
4.2.1
Primary Endpoint
30
4.2.2
Secondary Endpoints
30
4.2.3
Exploratory Endpoints
31
5.
STUDY DESIGN AND DESCRIPTION
35
5.1 Study Design
35
5.2 Study Population
35
5.3 Duration
35
5.4 End of Study Definition
35
6.
PARTICIPANT SELECTION
36
6.1
Inclusion Criteria
36
6.2
Exclusion Criteria
36
6.3
Concomitant Intervention
37
6.3.1
Pharmacokinetic Interactions with PF-04457845
37
6.3.2
Pharmacodynamic Interactions with PF-04457845
38
6.4
Contraception
38
6.4.1
Male Participants
38
6.4.2
Female Participants
38
6.4.3
Methods of Contraception
39
6.5
Pregnancy
39
6.6
Randomization Criteria
39
6.7
Enrollment
39
6.8
Enrollment by Race and Ethnicity
39
6.9
Screen Failures
40
7.
STUDY TREATMENTS
41
7.1
Allocation to Treatment
41
7.2
Breaking the Blind
41
7.3
 Dose Selection
41
7.4
Dose Administration:
41
7.5
Preparation/Handling/Storage/Accountability:
41
7.5.1
Acquisition and Accountability
41
7.5.2
Formulation and Packaging
42
7.5.3
Product Storage and Stability
42
7.5.4
Preparation and Dispensing
42
7.6
Study Intervention Adherence
43
7.6.1
Study Medication Adherence using the Cell Phone Assisted Remote 
Observation of Adherence (CAROMA)
43
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7.6.2
Plasma PF-04457845 Levels
43
7.6.3
Plasma Anandamide Levels
43
7.6.4
Weekly Pill Counts
43
8.
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
44
8.1 Discontinuation of Study Intervention
44
8.2 Participant Discontinuation/Withdrawal from the Study
44
8.2.1
Criteria for Discontinuation or Withdrawal of a Participant
44
8.3 Lost to Follow-Up
44
8.4 Trial Stopping Rules
45
9.
STUDY PROCEDURES
46
9.1
Recruitment
46
9.2
Informed Consent Procedures
46
9.3
Contact/Informant
46
9.4
Subject ID Number Assignment
47
9.5
Screening
47
9.5.1
Remote Screening Visits 
47
9.5.2
In Person Screening Visit 
48
9.5.3
Motivational Interviewing
49
9.5.4
Setting a Quit Date
49
9.5.5
Adherence (CAROMA Training)
49
9.6 Treatment Phase Study Visits (Week 1 – Week 8)
50
9.6.1
Week #1 (Quit Week)
50
9.6.2
In Person Treatment Phase Study Visits 
50
9.6.3
Remote Treatment Phase Study Visits
51
9.6.4
Adherence to Study Medication
53
9.6.5
Contingency Management
53
9.7 Follow-Up Phase Study Visits (Week 9 – Week 12)
53
9.7.1
Week 9 Study Visit
53
9.7.2
Week 10 – Week 12 Remote Study Visits
54
9.7.3
End of Study Visit
55
9.8 Participant Reimbursement
56
9.9 Early Termination Study Visit
57
10. ASSESSMENTS
58
10.1 Blood
58
10.2 Safety
58
10.2.1 Laboratory Tests
58
10.2.2 Vital Signs
59
10.2.3 Physical Examination
60
10.2.4 Electrocardiogram (ECG)
60
10.3 Pharmacokinetics
60
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10.3.1 PF-04457845 Levels
60
10.3.2 Plasma Anandamide Levels
60
10.3.3 DNA
61
10.4 Demographics, Medical History, and Medication History Procedure
61
10.4.1 Documentation of Concomitant Medications
62
10.4.2 Documentation of Concurrent Medical Conditions
62
10.4.3 Documentation of Concurrent Psychiatric Conditions
62
10.5 Structured Clinical Interview for DSM-5
62
10.6 Psychiatric Research Interview for Substance and Mental Disorders
62
10.7 Fagerstrom Test for Nicotine Dependence
63
10.8 Scale for Assessment of Lifetime Cannabis Use
63
10.9 Timeline Follow-Back
63
10.10 Marijuana Withdrawal Checklist
63
10.11 Marijuana Craving Questionnaire – Short Form
63
10.12 Marijuana Contemplation Ladder
63
10.13 Desire to Quit
63
10.14 Visual Analog Scale for Mood States
64
10.15 Systematic Assessment for Treatment Emergent Events
64
10.16 24-Hour Actigraphy
64
10.17 Subjective Sleep Measures
65
10.17.1 Sleep Disorders Questionnaire
65
10.17.2 Pittsburg Sleep Quality Index
65
10.17.3 Clinician Administered Evening/Morning Sleep Questionnaire
65
10.18 Rater Qualification and Certification Process
65
           
11. RISK/BENEFIT ASSESSMENT
66
11.1 Known Potential Risks
66
11.1.1 PF-04457845
66
11.1.2 Cannabis Withdrawal Symptoms
70
11.1.3 Phlebotomy
70
11.1.4 Behavioral/Cognitive Testing
70
11.1.5 Polysomnography (only at Yale)
70
11.2 Known Potential Benefits
70
11.3 Assessment of Potential Risks and Benefits
70
11.4 Mitigation of Risks
71
11.4.1 Screening
71
11.4.2 Effects of PF-04457845
71
11.4.3 Phlebotomy and IV Placement
71
11.4.4 Cannabis Withdrawal
71
11.4.5 Resumption of cannabis use in cannabis dependent participants 
who achieve abstinence
71
12. ADVERSE EVENT REPORTING
72
12.1 Reporting Period
72
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12.2 Capturing Adverse Events
72
12.3 Assigning Causality of Adverse Events
73
12.4 Adverse Event Outcome
74
12.5 Pre-Existing Conditions
75
12.6 Worsening of Adverse Events
75
12.7 Serious Adverse Events
75
12.8 Follow-up of Serious Adverse Events
76
12.9 Serious Adverse Event Reporting Requirements
76
12.10 Pregnancy Reporting Requirements 
76
12.11 Safety Reporting to Investigators, IRBs, and Regulatory Authorities
77
13. UNANTICIPATED PROBLEMS
78
13.1Definition of Unanticipated Problems
78
13.2Unanticipated Problem Reporting
78
14. STATISTICAL METHODS
79
14.1Sample Size Determination
79
14.2Efficacy Analysis
79
14.2.1 Primary Outcome
79
14.2.2 Secondary Outcome
80
14.3Safety Analysis
80
15. DATA HANDLING AND RECORDKEEPING
81
15.1 Case Report Forms 
81
15.2 Data Entry
81
15.3 Record Retention
81
15.4 Genetic Samples
82
15.5 Publication and Data Sharing
82
16. QUALITY CONTROL AND QUALITY ASSURANCE
83
16.1 Study Site Monitoring Visit
83
16.2 Data Monitoring
83
16.3 Protocol Deviations
83
16.4 Quality Assurance Audits and Regulatory Agency Inspections
83
16.5 Data Monitoring Committee
83
16.6 Study Discontinuation and Closure
84
16.6.1 Criteria for Premature Termination or Suspension of the Study
84
16.6.2 Criteria for Premature Termination or Suspension of Study Sites
84
16.6.3 Procedure for Premature Termination or Suspension of the Study or
the Participation of Study Sites
84
17. ETHICAL ASPECTS OF THE STUDY
85
17.1 IRB Approval
85
17.2 Participant Information, Informed Consent, and Participant Authorization
85
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17.3 Participant Confidentiality
86
17.4 Publication and Disclosure
86
17.5 Clinical Trials Registration
87
17.6 Future Use of Stored Specimens and Data
87
18. ABBREVIATIONS
88
19. PROTOCOL AMENDMENT HISTORY
89
20. REFERENCES
90
LIST OF APPENDICES
Appendix A: 
Study Organization Chart
103
Appendix B:
Advertisements
104
Appendix C:
Phone Screen Questionnaire
105
Appendix D:
Consent Questionnaire
109
Appendix E: 
Inclusion / Exclusion Criteria Checklist
110
Appendix F:
Collateral Contact Questionnaire
112
Appendix G:
Commitment to Attempt Quitting Questionnaire
113
Appendix H:
CAROMA Instructions
114
Appendix I:
BMI Calculation Table
115
Appendix J:
Responsibilities of the Investigator
116
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1.0 ADMINISTRATIVE INFORMATION:
1.1 Yale University Statement of Compliance: 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and 
any other product information provided by the Coordinating Center. I agree to conduct this study 
in accordance with the requirements of this protocol and also to protect the rights, safety, 
privacy, and well-being of study participants in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonization, E6 (R2) Good Clinical Practice: Consolidated 
Guideline.

United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 
812)

Regulatory requirements for reporting serious adverse events defined in Section 12.9 of 
this protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator as per FDA (Appendix J)
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Participants Protection and ICH GCP Training. The protocol, informed 
consent form(s), recruitment materials, and all participant materials will be submitted to the 
Institutional Review Board (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. In addition, all changes to the consent form will be IRB-approved; a determination will be 
made regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form.
_________________________________________
_______________________
Deepak Cyril D’Souza, M.D.
Date
Lead Principal Investigator
Professor of Psychiatry
Yale University, School of Medicine
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1.2 Columbia University Statement of Compliance: 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and 
any other product information provided by the Coordinating Center. I agree to conduct this study 
in accordance with the requirements of this protocol and also to protect the rights, safety, 
privacy, and well-being of study participants in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonization, E6 (R2) Good Clinical Practice: Consolidated 
Guideline.

United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 
812)

Regulatory requirements for reporting serious adverse events defined in Section 12.9 of 
this protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator as per FDA (Appendix J)
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Participants Protection and ICH GCP Training. The protocol, informed 
consent form(s), recruitment materials, and all participant materials will be submitted to the 
Institutional Review Board (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. In addition, all changes to the consent form will be IRB-approved; a determination will be 
made regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form.
_________________________________________
_______________________
Frances Levin
Date
Site Principal Investigator
Psychiatrist II
Research Foundation for Mental Hygiene
Columbia University Medical College
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1.3 Johns Hopkins Statement of Compliance: 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and 
any other product information provided by the Coordinating Center. I agree to conduct this study 
in accordance with the requirements of this protocol and also to protect the rights, safety, 
privacy, and well-being of study participants in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonization, E6 (R2) Good Clinical Practice: Consolidated 
Guideline.

United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 
812)

Regulatory requirements for reporting serious adverse events defined in Section 12.9 of 
this protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator as per FDA (Appendix J)
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Participants Protection and ICH GCP Training. The protocol, informed 
consent form(s), recruitment materials, and all participant materials will be submitted to the 
Institutional Review Board (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. In addition, all changes to the consent form will be IRB-approved; a determination will be 
made regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form.
_________________________________________
_______________________
Ryan Vandrey
Date
Site Principal Investigator
Associate Professor
John Hopkins University 
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1.4 Medical University of South Carolina Statement of Compliance: 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and 
any other product information provided by the Coordinating Center. I agree to conduct this study 
in accordance with the requirements of this protocol and also to protect the rights, safety, 
privacy, and well-being of study participants in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonization, E6 (R2) Good Clinical Practice: Consolidated 
Guideline.

United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 
812)

Regulatory requirements for reporting serious adverse events defined in Section 12.9 of 
this protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator as per FDA (Appendix J)
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Participants Protection and ICH GCP Training. The protocol, informed 
consent form(s), recruitment materials, and all participant materials will be submitted to the 
Institutional Review Board (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. In addition, all changes to the consent form will be IRB-approved; a determination will be 
made regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form.
_________________________________________
_______________________
Kevin Gray, M.D.
Date
Site Co-Principal Investigator
Professor of Psychiatry
Medical University of South Carolina
_________________________________________
_______________________
Aimee McRae-Clark, M.D.
Date
Site Co-Principal Investigator
Professor of Psychiatry
Medical University of South Carolina
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1.2 Contacts:
Please refer to Table 2 for the complete study organization chart. A separate contact information 
list will be provided to each site. 
Investigators will be provided with emergency medical contact information cards to be carried by 
each participant. General advice on protocol procedures should be obtained through the 
Coordinating Center. 
Coordinating Center – Yale University: 
Deepak Cyril D’Souza, M.D.
Christina Luddy, BS
Lead Principal Investigator
Study Coordinator
Mohini Ranganathan, M.D. 
Patrick D. Skosnik, Ph.D.
Coordinating Investigator / Medical Monitor
Actigraphy Investigator
Ralitza Gueorguieva, Ph.D.
Jose Cortes-Briones, Ph.D.
Senior Statistician
Statistician/Analyst
Research Foundation for Mental Hygiene (Columbia University):
Frances Levin, M.D.
John Mariani, M.D.
Site Principal Investigator:
Site Co-Investigator
Johns Hopkins University:
Ryan Vandrey, Ph.D.
Dustin Lee, Ph.D.
Site Principal Investigator
 
Site Co-Investigator
Medical University of South Carolina:
Kevin Gray, M.D.
Aimee McRae-Clark, PharmD.   
Site Principal Investigator
Site Co-Principal Investigator
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1.3 Protocol Summary Synopsis:
Title:
A Phase 2B, 8-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel 
Group Study to Evaluate the Efficacy, Safety and Tolerability of the Fatty Acid 
Amide Hydrolase (FAAH) Inhibitor PF-04457845 in Adults with DSM-5 Current 
Cannabis Use Disorder (CUD)
Study Description:
The efficacy, safety and tolerability of the FAAH Inhibitor PF-0447845 in reducing 
cannabis use will be studied in a 4-site randomized, double-blind, placebo-controlled, 
parallel-group, outpatient clinical trial comparing PF-04457845 (4mg) and placebo in 
DSM-5 CUD individuals. Participants will be randomized in a 1:1 ratio to either PF-
04457845 or placebo using random block sizes of 2 and 4, stratified by site and 
degree of cannabis use (CUD at the level of moderate (4-7 [of 11] symptoms) or 
severe (8-11 [of 11] symptoms)). Participants will receive motivational interviewing for 
2 weeks before being randomized to receive study medication to make a quit attempt 
within the first week of treatment. For a self-reported quit attempt, participants will be 
rewarded. Participants will receive active or placebo PF-04457845 for 8 weeks during 
which time they will be evaluated weekly with either in person or remote study visits. 
In addition, daily assessment of adherence to study medication and cannabinoid use 
will be conducted by cellphone. Measures of cannabinoid exposure, and problems 
related to the use of cannabis, will be assessed. 
Primary Objective:
To determine whether PF-04457845 is superior to placebo in reducing self-reported 
frequency (number of times per day) of cannabis use.
Primary Endpoint:
Change in the average number of times per day of self-reported cannabis 
consumption.
Study Population:
Up to approximately 260 individuals diagnosed with DSM5 Cannabis Use Disorder
Phase:
Phase 2B 
Description of Sites 
Enrolling 
Participants:
This multi-center trial will take place at four sites: Yale University School of Medicine, 
Columbia University Medical Center, John Hopkins University, & Medical University of 
South Carolina.
Description of Study 
Interventions:
For 8 weeks participants will receive 4mg daily of PF-04457845 or placebo.
Study Duration:
The duration of this study is approximately 3 years.
Participant Duration:
This trial is 14 weeks total, including: 1) a 2-week screening phase, 2) randomization 
to PF-04457845 or placebo for 8 weeks, and 3) a 4 week follow up phase for safety 
especially because the effects of the drug take ~ 2 weeks to washout.
1.4 Protocol Summary Schema: 
Table 1: Schematic of Study Design
Screening
Treatment Phase Outpatient
Follow–up Phase
Weeks (days)
(-14)
(-7)
1 (Quit 
Attempt 
after day 2)
2
3
4
5
6
7
8
9
10
11
12
End
Visit
1
2
3
5
6
7
8
9
10
11
12
13
14
15
16
In Person
X
X
X
X
X
X
X
Visit Type
Remote
X
X
X
X
X
X
X
X
PF-
04457845
x
x
x
x
x
x
x
x
Drug
Condition
Placebo
x
x
x
x
x
x
x
x
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1.5 Schedule of Procedures:
Table 2: Schedule of Procedures
       *Weekly visits after randomization occur every 7 days ± 3 days
Visit*  (R=Remote ; IP= In-Person)
Remote 
Screening
In-Person 
Screening
Week 1 
IP / R
Week 2 
R
Week 3 
IP / R
Week 4 
R
Week 5 
IP / R
Week 6 
R
Week 7 
IP / R
Week 8 
R
Week 9 
IP / R
Week 10 
R
Week 11 
R
Week 12 
R
End of Study 
IP / R
Study Phase
Pre-Randomization
Treatment Phase
Follow Up Phase
Day*
-14
-7
1
8
15
22
29
36
43
50
57
64
71
78
85
Informed Consent & Supplement to Consent Questionnaire
x
SCID
x
Psychiatric 
Evaluation
Demographic data
x
Chemistry, hematology, LFTs
x (IP)
x (IP) 
x (IP)
x (IP)
x (IP)
x (IP)
DNA Sample collection
x (IP)
UTOX (spot - on site)
x
x (IP)
x (IP)
x
x (IP)
x
x (IP)
x
x (IP)
x
x (IP)
x (IP)
Urine Pregnancy Test for WOCBP
x
x (IP)
x (IP)
x
x (IP)
x
x (IP)
x
x (IP)
x
x (IP)
x
x
x
x (IP)
Urinalysis
x (IP)
x (IP)
x (IP)
x (IP)
x (IP)
x (IP)
Physical Examination
x (IP)
x
EKG
x (IP)
x (IP)
x
Concomitant medication check
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Columbia Suicide Severity Rating Scale
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse Events (SAFTEE)
x
x (IP)
x (IP)
x 
x (IP)
x
x (IP)
x
x (IP)
x
x (IP)
x
x
x
x (IP)
Safety
Licensed Clinician (MD, RN, APRN, PA) check-in
x
x (IP)
x (IP)
x (IP)
x  
x
x
x
x
x
x
x
x
x
x
Lifetime Cannabis Use (SALCU)
x
Urine Creatinine: THC-COOH Quantification
x (IP)
x (IP)
x (IP)
x (IP)
x (IP)
x (IP)
x (IP)
TLFB-cannabis (30 day, 7 day)
-30
-7 (IP)
-7
-7
-7
-7
-7
-7
-7
-7
-7
-7
-7
-7
-7
$ spent on MJ
-30
-7 (IP)
-7
-7
-7
-7
-7
-7
-7
-7
-7
-7
-7
-7
-7
MJ Use 
Quantification
CAROMA (daily TLFB)
x
x
x
x
x
x
x
x
Willingness to Attempt Quitting (signed statement)
x
x (IP)
x (IP)
Contingency management for self-reported quit attempt
$50
Motivational Interviewing
x
x (IP)
Randomization of Participant
x (IP)
Desire to Quit
x
x (IP)
x (IP)
x
x (IP)
x
x (IP)
x
x (IP)
x
x (IP)
x (IP)
Marijuana Problems Scale
x
x (IP)
x 
x
x
x
MJ Withdrawal Checklist
x (IP)
x
x
x
x
x
x
x
x
x
x
MJ Craving Scale
x (IP)
x
x
x
x
x
x
x
x
x
x
VAS -Marijuana Ladder
x
x (IP)
x
x
x
x
x
x
x
x
x
x
Marijuana 
Problems
PRISM
x (IP)
x
x
FTND
x (IP)
x
x
x
Tobacco
TLFB-Nicotine/Tobacco (30 day, 7 day)
-30
-7 (IP)
-7
-7
-7
-7
-7
-7
-7
-7
-7
-7
-7
-7
-7
Alcohol
TLFB-Alcohol (30 day, 7 day)
-30
-7 (IP)
-7
-7
-7
-7
-7
-7
-7
-7
-7
-7
-7
-7
-7
Cognitive
Cogstate Battery (Attention, V. Memory, Exe Func)
x (IP)
x (IP)
VAS-Mood States
x (IP)
x
x
x
x
x
x
x
x
x
x
Behavioral
Quality of Life Enjoyment and Satisfaction
x
x
Weight
x (IP)
x (IP)
x (IP)
x (IP)
x (IP)
x
x
Vital Signs
x (IP)
x (IP)
x (IP)
x (IP)
x (IP)
x
x
24-Hour Actigraphy
x (IP)
x
x
x
x
x
x
x
x
x
x
x
x
x
Evening/Morning Sleep Questionnaire
x
x (IP)
x
x
x
x
x
x
x
x
x
x
Sleep
Pittsburgh Sleep Quality Index
x
x (IP)
x
x
x
x
x
x
x
x
x
x
Medication Dispensing
xx (IP)
xx (IP)
xx (IP)
xx (IP)
Weekly Pill Count
x
x
x
x
x
x
x
x
x
CAROMA (daily)
x
x
x
x
x
x
x
x
PF-04457845 Assay
x (IP)
x (IP)
x (IP)
Study 
Medication 
Adherence
Serum Endocannabinoids
x (IP)
x (IP)
x (IP)

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2.0 STUDY RATIONALE AND BACKGROUND
2.1 Cannabis use disorder (CUD) is an increasingly recognized problem for which there 
are no FDA-approved or clinically-accepted pharmacological treatments: Cannabis is the 
most widely used illicit substance in the United States (1) and globally. Globally, cannabis 
consumption has increased in the last quarter of the twentieth century (2). In the U.S., cannabis 
use rates have doubled in the last decade (3, 4) particularly in young people (5, 6). The 2015 
National Survey on Drug Use and Health (NSDUH) estimated that 22.2 million Americans aged 
12 or older were current users of cannabis (7). Moreover, the NSDUH reported that 
approximately 4.0 million people aged 12 or older had a cannabis use disorder in the past year. 
The legalization of “medical” and recreational cannabis use is sweeping across the U.S. (8, 9). 
To date, the District of Columbia and 28 states have legalized cannabis for the treatment of 
medical conditions and the District of Columbia and 8 states have also legalized cannabis for 
nonmedical (recreational use). The potency of cannabis has been steadily increasing (10), and 
a number of high-THC-containing products (e.g., wax, shatter) are commercially available. In 
parallel, there is growing recreational use of potent synthetic cannabinoids (11, 12). 
Diagnostic, epidemiological, laboratory and clinical studies provide compelling evidence for 
the existence of a cannabis dependence syndrome, currently termed cannabis use disorder 
(CUD) in DSM-5, that is characterized by and includes 1) the development of tolerance (13-16), 
2) the emergence of withdrawal symptoms on cessation of exposure (17-19), and 3) compulsive 
use, impaired control and continued use despite physical and psychological problems caused or 
exacerbated by such drug use (20-22). Individuals with CUD have difficulty containing use, 
spend too much time or money acquiring, using, or recovering from the effects of cannabis, 
make many failed attempts to quit or reduce use, have cravings and a desire to use, and use in 
contexts that are potentially dangerous (e.g., driving). The regular use of cannabis has been 
associated with a number of negative outcomes including cognitive deficits (23-26), motor 
vehicle accidents (27, 28), psychiatric symptoms and disorders (29-32), poor quality of life (33) 
and substantial comorbidity and disability (34). While not all cannabis users experience 
problems, nearly 3 of 10 marijuana/cannabis users manifested a cannabis use disorder in 2012-
2013 (3). 
While cannabis may be less likely than other drugs to produce dependence, after alcohol, it 
has the highest rate of dependence or abuse among all drugs (1). In fact, it is twice as prevalent 
as cocaine or opioids (35) likely because more people use cannabis. Around 10% of people 
who use cannabis will become dependent on it (36, 37), and that increases to about 17 % in 
those who start using in their teens. In the US, cannabis was the illicit drug with the highest rate 
of past year dependence or abuse in 2009 (38) and there were more treatment admissions for 
cannabis related problems than for cocaine or heroin (39, 40). As reviewed by Hall et al., 
chronic cannabis use is associated with many negative outcomes (41, 42) including cognitive 
dysfunction (43-48), psychosis (49), and possible structural brain abnormalities (50-56). 
There is increasing demand for effective treatments for CUDs. The US Treatment Episode 
Data Set (TEDS) reported that 17% of all admissions to substance abuse facilities were for 
cannabis (57), second only to opioids. Further, this represents a doubling of the rate since 
1993. The rates of CUDs and CUD-related problems highlights the need for effective 
treatments. However, there are no FDA-approved or clinically-accepted pharmacological 
treatments for cannabis CUD as yet. 
2.2 Changes associated with cannabis use disorder: Exposure to natural and synthetic 
agonists of the brain cannabinoid receptor (CB1R) is associated with a number of changes 
manifesting as behavioral tolerance that is accompanied by changes in the endocannabinoid 
(eCB) system. Furthermore, discontinuation following prolonged exposure to CB1R agonists 
leads to a withdrawal syndrome. The eCB system is a neuromodulatory system consisting of 
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two G-protein–coupled receptors, CB1R and CB2R; lipid ligands including anandamide (AEA) 
and 2-arachidonoylglycerol (2-AG); and enzymes involved in eCB biosynthesis and degradation 
(fatty acid amide hydrolase [FAAH], monoacylglycerol lipase [MAG-L] and 2-
arachidonoylglycerol hydrolase [ABHD6]) (for reviews see (58-60)). eCBs are synthesized and 
released on demand, following which they travel back to activate presynaptic CB1Rs resulting in 
braking the further release of neurotransmitters. eCBs are rapidly removed by a transport 
system that is yet to be fully characterized. CB1Rs are critical in mediating the psychoactive 
effects of cannabis and are expressed mainly in the brain whereas CB2Rs are mostly 
expressed peripherally. 
2.3 Tolerance: In humans, tolerance develops to the effects of CB1R agonists on mood, 
memory and cognition, heart rate, blood pressure and hormones, etc., (61-66) and the 
magnitude of tolerance is proportional to the dose and duration of exposure. The rate and time-
course of the development of tolerance to the various effects of CB1R agonists varies. In 
animals, tolerance to the analgesic, hypothermic and hypomotor effects develop within days 
(67, 68), while tolerance to the memory (69) and endocrine effects (70) take longer to develop. 
Exposure to CB1R agonists is accompanied by receptor downregulation, desensitization of 
receptor-mediated G-protein activation, and alterations in CB1R mRNA levels (13, 19, 71-77). 
These changes have a distinct regional and temporal profile and are related to the duration and 
magnitude of exposure to cannabinoids (77-79). While CB1R downregulation occurs within 
days, there are regional differences in the time course of these changes. Hippocampal CB1Rs 
exhibit the greatest magnitude of desensitization and downregulation in response to repeated 
THC administration while striatal CB1R 
adaptations develop more slowly and 
recover more quickly than in regions such 
as the hippocampus (71, 74-77). 
It is now clear from in vivo brain 
imaging studies by us (Figure 1) and 
others that repeated cannabis exposure is 
associated with downregulation of CB1Rs 
which tends to “normalize” with prolonged 
abstinence (80-82). 
Furthermore, and specifically relevant 
to the mechanism of action of the proposed 
treatment, in a recent in vivo imaging study, 
Boileau et al., showed that FAAH binding 
measured with positron emission 
tomography and [11C]CURB was 
significantly lower by 14-20% in the brains 
of chronic cannabis users (83). Furthermore, lower FAAH binding was negatively correlated with 
measures of cannabis exposure (cannabinoid concentrations in blood and urine). They 
suggested that lower FAAH binding levels in the brain may be a consequence of chronic and 
recent cannabis exposure and could contribute to cannabis withdrawal. Taken collectively, the 
lower FAAH binding in CUD may reflect a compensatory effort to increase AEA in response to 
low CB1R availability with chronic cannabis exposure. 
Interestingly, in animals, prolonged activation of CB1Rs with THC leads to decreased AEA 
levels in the striatum (84), and consistent with these findings, human cannabis users show 
reduced cerebrospinal fluid AEA levels (85). Thus, an alternative explanation for the low FAAH 
binding in chronic cannabis users, is that it might reflect an attempt to compensate for the 
reduction in striatal AEA levels associated with chronic downregulation of AEA release. Thus, if 
Figure 1: CB1R Availability in CUDs vs. HCs at Baseline, 
and after 28 days of abstinence (D'Souza et al., 2016); Fig 
1A: Reduced (15%) reduction in CB1R levels CUDs vs 
Controls; Fig 1B: CB1R levels increase with 28 days of 
abstinence from cannabis, but remain stable in controls
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reduced FAAH activity reflects a compensatory attempt to maintain endocannabinoid tone, 
treatment with inhibitors of FAAH, might be beneficial. 
2.4 Cannabis withdrawal syndrome: Abrupt discontinuation of CB1R agonists in cannabinoid 
dependent animals or the administration of CB1R antagonist to cannabinoid dependent animals 
leads to a withdrawal syndrome (86-91). In humans, a cannabis withdrawal syndrome has been 
reported from retrospective self-report studies (72), prospective outpatient studies (73, 74), and 
human laboratory studies involving the administration and discontinuation of cannabinoids (49, 
50, 75, 76). The typical withdrawal symptoms include anger, aggression, appetite change, 
weight loss, irritability, anxiety, restlessness, altered sleep, strange dreams, cannabis craving 
and physical discomfort (11, 49, 50, 73, 75, 77-80). Most symptoms appear within 1 day of 
abstinence, peak within 2–3 days, and typically resolve within 1–2 weeks. However, other 
studies (73, 80) suggest that withdrawal symptoms may persist longer than 4 weeks, and 
specifically sleep disturbances may persist for longer (92-94). Characteristic of a true withdrawal 
syndrome, abstinence symptoms occur with blind discontinuation and resolve with CB1R 
agonist re-administration (49, 75, 77, 81, 82). Avoidance of CWS might be one factor that 
contributes to the persistence of chronic cannabis use, and thus, medications that attenuate 
CWS may also improve treatment outcomes among individuals with CUD.
2.5 Sleep disturbances are an important manifestation of cannabis withdrawal: Several 
lines of experimental evidence suggest a role of CB1R in sleep (95, 96); therefore, it is not 
surprising that sleep disturbance is a common symptom of cannabis withdrawal and is clinically 
meaningful. About 76% of daily cannabis users who abruptly discontinue the use of cannabis 
report sleep disturbance (92, 93, 97). Difficulty sleeping and strange dreams have been 
reported with high cross-study reliability (92). These generally occur within 24 to 72 hours of 
discontinuation of cannabis use and persist for 6–7 weeks (93, 98). Resumption of cannabis use 
or administration of oral THC improves sleep or even reinstitutes subjectively normal sleep (66, 
99-102). Sleep disturbance is reported as a reason why individuals resume smoking cannabis 
(103) or use alcohol, sedative/hypnotic drugs, or illicit drugs in attempts to treat their sleep 
disturbance (98, 104). Similarly, certain drugs of abuse may be more rewarding in insomniacs 
(105), and preferred to a greater degree in persons who are sleep-restricted or deprived (106-
108). 
However, self-reports do not always accurately reflect actual sleep quality e.g. (109) and do 
not provide information about sleep architecture. A number of studies have used 
polysomnography (PSG) to complement self-report measures of sleep and to study sleep 
architecture during the period immediately following the abrupt cessation of cannabis use reviewed 
in (110-113). PSG studies of cannabis withdrawal have demonstrated increases in sleep onset 
latency and wakefulness after sleep onset reviewed in (110-112, 114-117). Total sleep time (TST), 
sleep efficiency (SEff), and slow-wave sleep (SWS) time is reduced (111, 112, 115, 118, 119). 
REM sleep is increased (REM rebound) (99, 114, 116-118, 120) and REM latency is shorter 
(111, 114). Changes in sleep architecture during CWS can begin as early as the first night of 
abstinence (118). Changes during withdrawal are more evident in heavy users (111). With 
continued abstinence, TST, SEff, and amount of REM sleep decline, while wake after sleep 
onset (WASO) increases. These disturbances progress over the first 2 weeks of cannabis 
abstinence (93, 97, 111) and persist for more than ~6 weeks (93). PSG evidence of sleep 
disturbance increase, as levels of THC-COOH decrease, suggesting an association between 
declining levels of cannabis and increasing sleep disturbance. Furthermore, quantity 
(joints/week) and duration (years) of cannabis use were positively associated with more PLMs. 
Vandrey et al., replicated most of the findings of Bolla et al., except that they showed increased 
sleep latency and time spent in REM sleep (14) which may be a result of differences in the 
samples studied. As stated by Bolla: “The treatment of sleep disturbance is a potential target for 
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the management of cannabis use disorders since poor sleep could contribute to treatment 
failure in heavy MJ users” (112).
Relief of withdrawal is a negative reinforcer for continued substance use (102, 103). 
Thus, individuals who experience CWS may use cannabis to relieve or avoid withdrawal 
(16). Since CWS may serve as negative reinforcement for relapse to cannabis use (121, 
122), treatments aimed at alleviating cannabis withdrawal might prevent relapse and 
reduce dependence. 
2.6 There is a need for effective treatments for cannabis use disorder: In parallel with the 
increase in cannabis use disorders, there is increasing demand for effective treatments for 
cannabis use disorders. For example, the percentage of hospital admissions for cannabis 
between 1993 and 2004 doubled (105). 
2.6.1 Psychotherapeutic approaches: Despite progress in developing interventions, these 
approaches which include motivational enhancement (MET), motivational interviewing (MI), 
cognitive behavioral treatment (CBT) and contingency management (CM) have had limited 
success reviewed in(17, 123). Most CUD patients do not achieve abstinence with these 
interventions (124-127). Even with the most efficacious treatment – combination of MET, CBT 
and CM, only ~50% achieve an initial 2-week period of abstinence, and of those who do, about 
half relapse within a year (128, 129). 
 2.6.2 Pharmacotherapeutic approaches: As reviewed by Hart et al., (2005), precipitated 
cannabinoid withdrawal syndrome (CWS) in laboratory animals has been used to test the 
efficacy of various drugs (THC, clonidine, prostaglandin E2, and lithium) (130-133). The results 
of these animal studies have provided the rationale for some of the clinical trials in humans. 
Almost every class of psychotropic drug has been tested for CUD (134-139) including drugs 
that 1) directly target the CB-1R system such as CB-1R agonists e.g., 9-delta-
tetrahydrocannabinol (THC) to substitute cannabis (101, 102, 140, 141), Nabiximols (142), 
Sativex (143) or CB1R antagonists to block cannabis effects (144, 145), 2) Anti-depressants: 
Bupropion (146), Nefazodone (147, 148), Fluoxetine (149), Escitalopram (150),Venlafaxine 
(151), Lofexidine (152), Baclofen (153) and Mirtazapine (154), Buspirone (155-157), and 
Vilazodone (158), 3) Mood stabilizers: Lithium (159) and Divalproex (101, 160), 4) 
Antipsychotics: Pericyazine (161), Aripiprazole (162), Quetiapine (163), 5) Other drugs: 
Gabapentin (164), Naltrexone (165-169), N-acetylcysteine (170, 171), Atomoxetine (172, 173), 
Entacapone (174) and some unpublished reports of pregnenolone, cannabidiol (CBD), 
Aprepitant, Citicholine, Guanfacine, Progesterone, and Nabilone. 
Most pharmacological trials have focused on the initial and immediate goal of alleviating the 
unpleasant abstinence symptoms associated with CWS. Few studies have targeted the long-
term goal of relapse prevention or reducing consumption. The study designs were mostly 
randomized, double-blind, placebo-controlled, counter balanced, with the exception of a few 
open label studies (139). The studies had small sample sizes (mean 60, range 6-300 
participants) and were of varying duration (1-13 weeks). None of the medications that have 
been tested for cannabis withdrawal and/or dependence have been shown to be consistently 
effective (134-139, 155, 175, 176). Most of the approaches yielded negative results. The few 
that did yield promising results have not all been consistently replicated. The evidence base for 
the gabapentin and N-acetylcysteine while showing some promise needs further investigation. 
Substitution treatment with CB1R agonists (e.g., THC) reduces cannabis withdrawal in a dose-
dependent manner (101, 102, 141). However, the reduction in cannabis withdrawal does not 
appear to translate into any reduction in relapse but may result in higher treatment retention 
(141). However, CB1R agonists such as THC and Nabilone have potent psychoactive effects 
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and other side effects that limit tolerability and are not without risk. THC is unlikely to be a useful 
treatment for under age 21 CUD patients because THC cannot be given to individuals who are 
under the age of 21, a group that has high rates of CUD. While low doses of oral THC might 
attenuate withdrawal symptoms, similar doses of THC have been shown to exhibit reinforcing 
properties in cannabis users, suggesting that abuse liability remains a concern with substitution 
therapy (177). Furthermore, substituting cannabis with THCs does not address the underlying 
changes in CB1R function associated with CUD. Thus, at present there are no FDA approved 
or clinically-accepted pharmacological treatments for cannabis use disorders.
2.7 Potentiating endocannabinoid signaling as a treatment for CUD: The endogenous 
cannabinoid system consists of at least two receptor subtypes (CB1R and CB2R) and several 
endogenous signaling molecules (endocannabinoids = eCBs) that bind to these receptors (178, 
179). The two best characterized endogenous ligands, anadamide (AEA) and 2-
arachindonoylglycerol (2-AG) are synthesized from membrane phospholipid precursors on-
demand by the enzymes N- Acylphosphatidylethanolamine-selective phospholipase D (NAPE-
PLD) and diacylglycerol lipase (DAGL), respectively.
Endocannabinoids are rapidly synthesized and released on demand. Endocannabinoid 
function can be potentiated via several pathways including by increasing levels of the principal 
eCBs, anandamide (AEA) and 2-AG. Levels of AEA and 2-AG are regulated by related 
synthases, degrading enzymes, and transporters. Fatty Acid Amide Hydrolase (FAAH) is the 
primary enzyme for hydrolysis of AEA (180-183). Thus, AEA levels can be increased by 
inhibiting FAAH. Genetic deletion of the FAAH gene or pharmacological inhibition of FAAH 
activity impairs AEA hydrolysis, resulting in up to 10-fold increases in brain AEA levels (184, 
185). FAAH knockout mice exhibit normal CB1R expression despite constitutively higher levels 
of endogenous fatty acid amides including AEA (186, 187). FAAH knockout mice also display 
wild-type behavioral responses in most tests, with mild to moderate hypoalgesic and anxiolytic-
like phenotypes (188, 189). There are a number of FAAH inhibitors available including URB597, 
OL-135, PF-04457845 and PF-622 reviewed in(190). FAAH Inhibitors have shown promising 
therapeutic efficacy in a variety of pathologies (191) without the psychoactive effects or the 
abuse liability of cannabis (192-194) and PF-04457845 has shown promising results for CUD. 
2.8 Compared to THC, increased anandamide levels produce lower adaptive changes at 
the CB1R: Anandamide and THC might differentially regulate CB1Rs. When FAAH-knockout 
mice were repeatedly administered equivalent maximally effective doses of anandamide or 
THC, those given THC demonstrated reduced cannabinoid-stimulated G-protein activity and 
receptor binding levels, which was associated with tolerance to in vivo effects and CB1R 
antagonist-precipitated withdrawal (187). In contrast, repeated anandamide administration 
produced receptor levels and receptor-mediated G-protein activity intermediate between 
vehicle- and THC-treated FAAH-knockout mice. Rimonabant precipitated a markedly reduced 
withdrawal in FAAH knockout mice treated sub-chronically with anandamide as compared with 
mice treated repeatedly with THC. Collectively, these findings suggest that unlike repeated 
exposure to direct acting CB1R agonists, repeated anandamide administration is not associated 
with the CB1R adaptive changes.
2.9 FAAH inhibitors have several advantages over THC or cannabis: 
2.9.1 FAAH-inhibitors are not rewarding: Animals treated sub-chronically with the FAAH inhibitor 
URB597 do not show CB1R antagonist precipitated withdrawal suggesting that unlike THC, 
FAAH inhibitors do not induce dependence (195). Furthermore, URB597 does not elicit 
conditioned place preference (196) and also does not generalize in rats trained to discriminate 
the drug effects of THC (193, 196). Also, unlike THC, URB597 is not self-administered by 
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monkeys does not prime reinstatement, and fails to increase self-administration in monkeys 
receiving either THC or cocaine (192). FAAH inhibitors such as URB597 do not elicit rewarding 
effects in the conditioned place preference test, and are not self-administered by monkeys 
(192). Furthermore, PF-04457845 does not elicit effects on motility, catalepsy and body 
temperature, which are the signature effects of cannabinoids (197). 
2.9.2 FAAH Inhibitors do not have negative interactions with THC: Despite having consistently 
elevated anandamide levels nearly 10-fold above that of the wild-type animals, FAAH-deficient 
mice have previously been demonstrated to display similar responses to acute THC 
administration in a battery of cannabinoid-sensitive behaviors as wild-type animals (184). This 
has some important implications for the use of FAAH inhibitors in individuals who are using 
cannabis, suggesting that in individuals receiving FAAH inhibitor treatment there should be no 
safety concerns if they were to use cannabis (relapse).
2.9.3 FAAH inhibitors have several advantages: The approach of substituting cannabis with 
THC or other direct acting CB1R agonists for CUD essentially creates a state of controlled 
dependence without addressing the underlying adaptive changes associated with CUD. 
Compared to THC or cannabis, FAAH inhibitors 1) do not have psychoactive effects, 2) are not 
rewarding, 3) do not increase the abuse liability of other addictive drugs, and 4) are not 
associated with tolerance or withdrawal.
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3.0 PRELIMINARY RESEARCH
PF-04457845, a potent and selective FAAH-inhibitor, is an orally active, long-acting, time-
dependent, highly efficacious and selective covalent inhibitor of FAAH (198-201). It has 
undergone preclinical and clinical (phase 2) testing by Pfizer. PF-04457845 inhibits human 
FAAH with high potency (kinact/Ki = 40300 M-1s-1; IC50 = 7.2 nM). 
3.1 Animal Studies: PF-04457845 has potent and long lasting antinociceptive effects in rats 
with oral administration. At 1 mg/kg PF-04457845 displays in vivo efficacy for over 24 hours with 
concomitant FAAH-inhibition, elevation of brain and plasma anandamide, N-palmitoyl 
ethanolamine (PEA), and N-oleoyl ethanolamine (OEA). Furthermore, unlike direct CB1R 
agonists even at high doses PF-04457845 does not have effects on motility, catalepsy, or body 
temperature, which are the classic central nervous 
system effects of CB1R agonists.
3.2 Human Phase 1 Studies: Randomized, double-
blind, placebo-controlled Phase 1 studies have been 
conducted in healthy male participants (n=64), aged 
21 to 55 to characterize the pharmacokinetics (PK), 
pharmacodynamics (PD), and tolerability of single 
and multiple oral doses of PF- 04457845 in healthy 
participants. Dose regimens included single doses 
from 0.1 to 40 mg and multiple doses from 0.5 to 8 
mg once daily (QD) for 14 days. Blood and urine 
were collected for PK analysis.
3.2.1 Pharmacokinetics: With single doses, absorption 
of PF-04457845 is rapid, and concentrations peak (Cmax) within an average of 2 hours post 
dose. Elimination of PF-04457845 is multi-phasic, with a half-life (t1/2) ranging from 12-23 
hours. With multiple dosing, steady-state plasma concentrations were attained by Day 7. An 
approximate 2-3 fold accumulation in exposure was observed between days 1 and 14. PK at 
steady-state appeared dose-proportional. There are no major food effects on PF-04457845. 
Urine excretion of PF-04457845 as intact parent was negligible. PK is commensurate with QD 
dosing.
3.2.2 Pharmacodynamics: Peripheral FAAH activity was measured ex vivo in blood leukocytes. 
Plasma concentrations of anandamide, PEA, OEA and N-linoleoylethanolamide (LEA) were 
measured as pharmacodynamic biomarkers. PEA, OEA, and LEA may have anti-inflammatory, 
sleep inducing, and appetite inducing effects. Inhibition of FAAH activity and elevation of a 
number of fatty acids has been demonstrated with single and multiple doses. Pharmacological 
washout takes 10 days after multiple dosing with 4 mg due to a combination of the time it takes 
for the drug to clear and the time that it takes for FAAH activity to recover. This slow 
pharmacological washout may offer the advantage of being less likely to result in withdrawal 
symptoms.
The effects of 5 doses of PF-04457845 (0, 0.5, 1, 4 and 8 mg) on cognitive function were 
tested in a randomized, double-blind, placebo-controlled, parallel group study of healthy 
volunteers (Pfizer; on file). Participants were repeatedly assessed several times a day and 
several days over 2 weeks using the CogState battery, a battery that assesses psychomotor 
function, visual attention, learning, executive function, and delayed recall, as well as a global 
measure of cognition across domains (202). While PF-04457845 was not associated with 
Figure 2: Almost complete FAAH inhibition 
with 1mg dose in humans
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changes in cognitive function in 
healthy adults when given over 14 
days, it is not clear what effects it 
might have on cognitive function in 
cannabis dependent individuals 
who are known to have cognitive 
deficits. Of note, oral THC 
attenuated some of the cognitive 
deficits associated with CWS 
(101).
3.3 Human Phase 2 
Osteoarthritis Study: The effects 
of 2 weeks of daily oral 
administration of PF-04457845 on 
pain relief in patients with 
osteoarthritis of the knee were 
studied in a phase 2a randomized, double-blind, double-dummy, placebo- and active-controlled, 
2-way cross-over, multi-center clinical trial (Pfizer; on file). An interim analysis was completed 
after 56 participants completed the study; 36 participants received PF-04457845 (4-mg) for 2 
weeks. PF-04457845 was well tolerated in patients with OA, with a safety profile that was 
indistinguishable from placebo. The study was conducted in 5 centers in Canada, Sweden, and 
the United States of America and randomized 76 participants. During the study, no participant 
died or had a Serious Adverse Event (SAE). No participant was permanently withdrawn due to 
an Adverse Event (AE). A total of 136 AEs (all causalities) were reported in 51%, 58%, and 51% 
of participants treated with PF-04457845, naproxen, and placebo, respectively. There were no 
clinically significant trends or clinically significant abnormalities in clinical laboratory tests, vital 
signs measurements, or ECG findings. Most AEs (97) were mild in severity; 31 AEs were 
moderate, and 2 AEs were severe (nightmare and headache in the placebo treatment group). 
Furthermore, PF-04457845 caused substantial increase in all of the FAAH concentrations 
(means of 3.4 to 13.5-fold increases) compared to placebo.
Figure 3: Effects of 5 doses of PF-04457845 on cognitive test performance 
over time in healthy individuals. Composite score performance remained 
within plus or minus one standard deviation unit across the study period.
Table 3: Treatment-Emergent Adverse Events Reported in ≥5% of Subjects in Any Treatment Group - 
All Causality/Treatment-Related
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In general, AEs were infrequent and there were no clear differences among treatment 
groups. The most frequently reported all-causality AEs across treatment groups were upper 
respiratory tract infection, headache, diarrhea, and back pain (Table 3). The most frequently 
reported treatment-related AEs across all treatment groups were headache, fatigue, and 
constipation, none of which were judged by the investigator to be related to PF-04457845. The 
only commonly reported treatment-emergent AE that was also judged related to PF-04457845 
was dizziness, which occurred in 1 participant. Treatment-related AEs were more commonly 
reported in the naproxen treatment group than in the PF-04457845 treatment group. The most 
common adverse events are presented in Table 3. There were no serious adverse events, or 
adverse events that caused functional un-blinding and no cannabinoid-type events.
3.4 Proof of Concept (POC) Study with PF-04457845 in CUD: We have completed 
conducting a preliminary study testing the safety and efficacy of PF-04457845. The study was 
conducted under IND#114,017. DSM-4 cannabis dependent participants with a clear previous 
episode of CWS were included in a randomized, double-blind, placebo-controlled study (Figure 
4). After a screening period, participants were randomized to receive placebo or PF-04457845 
(4mg). All participants were hospitalized for the 1st week on a locked inpatient research unit to 
achieve and maintain abstinence, and to precipitate CWS. The remaining 3-week treatment 
phase was conducted on an outpatient basis to assess relapse. The 4-week treatment phase 
was followed by 8 weeks of follow-up to assess safety.
                                                   
Of 218 DSM-IV cannabis dependent 
males screened, 70 participants were 
randomized (Figure 5) and 58 
completed the treatment phase of the 
Figure 4: Schedule of Procedures for the Preliminary Study Testing the Safety and Efficacy of PF-04457845 (4mg/placebo)
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study. Participation of the last two participants who would have met the target of 60 completers 
was terminated shortly after learning of the outcome of the phase I trial of BIA 10-2474. Both 
groups were equivalent at baseline in terms of daily cannabis use captured by the 30-day TLFB 
(Wald 
(1)=0.003, p=0.959) and urine THC-COOH levels (Wald 
(1)=0.004, p=0.947). There 
𝜒2
𝜒2
were no significant differences in other demographic variables (Table 4).
 
3.4.1 Pharmacokinetics: Plasma was sampled to assay levels of PF-04457845 by an 
independent laboratory (GVK Sciences) in a subset of participants using a proprietary method 
with permission from Pfizer. While PF-04457845 could not be detected in the placebo group, 
there were significantly higher levels in the PF-04457845 group across all timepoints except 
after the discontinuation of treatment (week 5) (Figure 6). 
Figure 5: Consort Diagram for Preliminary Study
Table 4: Demographics for Preliminary Study
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3.4.2 Target Engagement: Levels of 
AEA that were expected to increase 
following treatment with PF-04457845 
were assayed in a subset of 
participants by the laboratory of Alex 
Makriyannis at North Eastern 
University. Relative to the placebo 
group, plasma levels of AEA, PEA 
and OEA were higher in the PF-
04457845 group on days 0, 2, and 4, 
and weeks 2, 3, and 4, but not at 
baseline (day -1) and after the 
discontinuation of treatment (week 5) 
(Figure 7, Table 5). These results 
demonstrate target engagement 
of PF-04457845 in CUD individuals. 
Taken together, the levels of PF-
04457845 and AEA provide 
confirmation of 1) adherence to 
treatment and 2) target specific effects of PF-04457845. Similarly, PF-04457845 also produced 
significant increases in plasma oleoylethanolamine (OEA) levels (Table 5).
3.4.3 Adherence: Adherence to study medication was visually confirmed to be at least 95% of 
higher as reported elsewhere (203). Concordance between expected and actual remaining 
study medication counted at weekly study visits was 87.69% and as noted above, participants 
assigned to active study medication had detectable plasma drug levels, and increases in serum 
endocannabinoid levels, while those assigned to placebo did not.
3.4.4 Cannabis Withdrawal Inpatient: As a 
reminder, only participants with a previous 
episode of CWS were included in the study, and 
all participants were hospitalized on the Clinical 
Neuroscience Research Unit to achieve and 
maintain abstinence. There were significant 
interaction effects between drug and time 
(Wald 
(4)=24.408, p<0.001) and between drug, 
𝜒2
time, and desire to quit (Wald 
(4)=14.790, 
𝜒2
p=0.005). Post hoc analyses revealed lower 
cannabis withdrawal scores in the FAAH-I vs. 
placebo-treated group on day 0 (pAdj=0.048) and 
day1 (pAdj =0.035), the first and second days of 
treatment. No other comparisons survived multiple comparisons correction.
3.4.5 Cannabis Use: At the end of treatment (4 weeks) there was a significant main effect of 
drug (Wald 
(1)=13.371, p<0.001) such that the PF-04457845 treated group had lower 
𝜒2
cannabis use compared to the placebo group (Figure 9). Of note, mean cannabis use in the PF-
04457845 treated group was below 1 joint/day at the end of the treatment. Furthermore, there 
Figure 6: Plasma PF-04457845 Levels
Figure 7: Plasma Anandamide (AEA) Levels
Figure 8: Cannabis Withdrawal (Inpatient)
Table 5: Plasma Endocannabinoid (eCB) Levels
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was a trend to significance for the main effect of desire to quit (Wald 
(1)=3.473, p=0.062) 
𝜒2
which was driven by lower cannabis use in the group with high desire to quit compared to the 
group with low desire to quit.
3.4.6 Urinary THC-COOH Levels: At the end of treatment (week 4) There was a main effect of 
drug (Wald 
(1)=6.760, p=0.009) on urinary THC-COOH levels that was driven by a reduction 
𝜒2
in urinary THC-COOH levels in the FAAH-I group compared to the placebo group (Figure 10). A 
significant drug x desire to quit interaction effect was observed (Wald 
(1)=4.380, p=0.036). 
𝜒2
Exploratory analyses revealed that urinary THC-COOH levels correlated with self-reported 
cannabis use (TLFB) week 4 (rho=0.540, pAdj<0.001).
3.4.7 Feeling States: The drug by time 
interaction was significant for VAS 
depression (Wald 
(4)=13.328, p=0.01); 
𝜒2
the PF-04457845 treated group had lower 
scores on day 0 (p =0.019) and day 1 
(0.067) (Table 6). The drug by time 
interaction was significant for VAS anxious 
(Wald 
(4)=12.03, p=0.017); the PF-
𝜒2
04457845 treated group had lower scores 
on day 0 (p =0.052). The drug by time 
interaction was significant for VAS 
depression (Wald 
(4)=13.269, p=0.01); 
𝜒2
the PF-04457845 treated group had lower 
scores on day 0 (p =0.012) and day 1 
(0.011). There were no significant effects 
of interest on VAS irritable and hungry.
3.4.8 Polysomnography: For time in stage 
N1, a main effect of time (Wald 𝜒2
(4)=11.960, p=0.018) and a drug x time 
interaction was observed (Wald 𝜒2
(4)=10.676, p=0.030) (Figure 12). No 
THC GC/MS Result (ng/mL)
0
200
400
600
800
1000
Placebo
FAAH-I
Figure 9: Daily Cannabis Use at the End of 
Treatment
Figure 10: Urinary THC-COOH Levels at 
End of Treatment
Table 6: Feeling States (Visual Analog Scale) During Acute Withdrawal 
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pairwise differences survived correction for multiple comparisons. While no differences were 
observed for stage N2 (Figure 12), a significant drug x time interaction was observed for stage 
N3 (Wald 
(4)=10.084, p=0.039). Pairwise comparisons revealed that the PF-04457845 group 
𝜒2
exhibited increased time in stage N3 on day 2 (pAdj=0.005) (Figure 11). For time in REM, a 
significant main effect of time (Wald 
(4)=19.343, p=0.001) and a trend towards a main effect 
𝜒2
of drug (Wald 
(4)= 3.032, p=0.082) were observed. The latter was driven by a reduction in 
𝜒2
REM time in the PF-04457845 group compared to the placebo group. For secondary PSG 
measures (Figure 13), a main effect of time was observed for number of awakenings (Wald 𝜒2
(4)=42.606, p<0.001), sleep efficiency (Wald 
(4)= 15.512, p=0.004), total sleep time (Wald 
𝜒2
𝜒2
(4)=15.512, p=0.004), and wake time during sleep period (Wald 
(4)=9.806, p=0.044). Finally, 
𝜒2
a main effect of drug (PF-04457845 >Placebo) was observed for latency to reach first REM 
period (Wald 
(1)=5.355, p=0.021) (Table 7).
𝜒2
PF-04457845
Placebo
Classification
Definitely 
Related
Possibly 
Related
Not 
Related
Definitely 
Related
Possibly 
Related
Not 
Related
Blood and 
Lymphatic System
0
0
1
0
0
0
Cardiac
0
1
0
0
0
0
ENT
0
0
1
0
0
0
Eye
0
0
3
0
1
0
GI
0
2
4
0
2
5
General
0
1
1
0
0
0
Infection
0
0
1
0
0
0
Investigations
0
0
1
0
0
0
Musculoskeletal
0
2
7
0
0
1
Nervous System
1
8
6
2
7
8
Psychiatric
0
0
0
0
0
1
Respiratory
0
0
9
0
1
3
Skin and 
Subcutaneous
1
1
5
3
0
1
Figure 11: Time in Stage N3 Deep Sleep
Figure 12: Effects on Sleep N1, N2, and REM
Figure 13: Effects on Sleep Architecture
Table 7: PSG Secondary Outcomes
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Table 8: Adverse Events from Preliminary Study
3.4.9 Safety and Tolerability of PF-04457845: Clinical laboratory tests for safety completed at 
screening, during inpatient stay (Day 0, Day 4), at all weekly appointments during treatment, 
and during follow up phase (Week 8). Participants monitored by inpatient nursing and research 
staff during the ~1 week long inpatient phase. Participants were evaluated by a study doctor at 
all outpatient visits. There were no serious adverse events associated with this trial. The rates of 
minor adverse events were no different between the 2 groups (Table 8). The DSMB met every 6 
months and had no concerns nor recommendations.
3.4.10 Summary of Preliminary Study Results: The completed preliminary double-blind, 
randomized placebo-controlled study with PF-04457845 in DSM-4 cannabis dependent (CUD) 
participants demonstrated: 1) the capacity to recruit and retain cannabis use disorder 
participants; 2) the capacity to visually confirm study medication adherence, a critical 
prerequisite for interpreting clinical trials data, using a simple, inexpensive and novel approach; 
3) biological confirmation of medication adherence (plasma PF-04457845 levels), 4) biological 
confirmation of target engagement (increased AEA levels), 4) a reduction in cannabis use, 
urinary THC-COOH, cannabis withdrawal, mood disturbances with PF-04457845 treatment, 5) a 
normalization of disturbances in stage N3 sleep measured by polysomnography (PSG) with PF-
04457845, and 6) excellent tolerability and safety. 
4.0 STUDY OBJECTIVES AND ENDPOINTS
4.1 Objectives:
4.1.1 Primary Objective: To determine whether 4 mg PF-04457845 once daily x 8 weeks is 
superior to placebo in reducing self-reported frequency of cannabis use.  
4.1.2 Secondary and Exploratory Objectives: 
1)
To determine the safety and tolerability of 4 mg PF-04457845 QD x 8 weeks
2)
To determine whether over the 8 weeks of treatment 4 mg PF-04457845 QD weeks is 
superior to placebo in reducing cannabis use.
3)
To determine whether over the 8 weeks of treatment 4 mg PF-04457845 QD weeks is 
superior to placebo in reducing the problems associated with cannabis use.
4)
To determine whether over the 8 weeks of treatment 4 mg PF-04457845 QD weeks is 
superior to placebo in reducing sleep disturbances. 
5)
To determine whether over the 8 weeks of treatment 4 mg PF-04457845 QD weeks is 
superior to placebo in improving participant reported quality of life.
6)
To determine whether over the 8 weeks of treatment 4 mg PF-04457845 QD weeks is 
superior to placebo in reducing the severity of DSM-5 CUD.
7)
To determine whether over the 8 weeks of treatment 4 mg PF-04457845 QD weeks is 
superior to placebo in reducing cannabis withdrawal syndrome. 
Vascular
0
0
1
0
0
1
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8)
To determine whether over the 8 weeks of treatment 4 mg PF-04457845 QD weeks is 
superior to placebo in reducing cannabis craving. 
9)
To explore whether genetic factors (e.g., polymorphism of the FAAH gene) influence 
the response to PF-04457845 
10) To assess adherence to PF-04457845 over the 8 weeks of treatment.
11) To assess the effects of PF-04457845 compared with placebo on plasma 
endocannabinoid levels.
12) To evaluate the PD (plasma anandamide), and PK/PD relationships of PF-04457845.
13) To correlate changes in exposure to PF-04457845 and clinical response.
14) To correlate changes in plasma anandamide levels with clinical response to PF-
04457845.
15) To identify potential biomarkers of disease activity and drug response in the serum, 
such as inflammatory mediators.
4.2 Endpoints: 
There is no established endpoint for CUD in the literature. Furthermore, there is no US FDA 
approved drug treatment for CUD that could provide guidance on selection of an endpoint. Most 
previous studies have used some measure of cannabis exposure as an endpoint. 
4.2.1 Primary Endpoint: 
There are significant problems to accurately measuring the amount of cannabis exposure. 
Cannabis and cannabinoids may be used by smoking, vaping or per orally. Even within 
smoking, cannabis and cannabinoids may be smoked as joint, blunt, bowl, etc. There are no 
standard units of consumption: joints come in different shapes and sizes. The potency (THC 
content) and the THC:CBD ratio can vary considerably. Finally, urine toxicological estimation of 
exposure is also fraught with challenges, especially if abstinence is not the goal. Given these 
challenges to measuring amount of use, self-reported frequency of use has been chosen as an 
endpoint. 
Specifically, the change from baseline to the last 4 weeks of the treatment phase in the 
average number of occasions per day of self-reported consumption of cannabis and 
cannabinoids captured using the daily TLFB data collected during CAROMA calls. A cannabis 
use occasion is defined as every time a participant initiates the use of cannabis. This will differ 
based on the method of use (see below). For example, if a participant uses blunts, or joints, 
every time he/she lights the joint, will be counted as one occasion. Baseline is defined as the 
last two weeks before the second screening visit; specifically, this is the TLFB capturing last 
week use done at the day -7 screening visit and the day of randomization. 
Table 9: Defining an Occasion of Cannabis Use
Method of Use
Definition of Occasion of Use
Joint, blunt, roach, etc.
Every time a joint is lit and used = a new occasion
Bong
Every time a bong is prepared for use, and used
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Bowl
Every time a bowl is packed and used = a new occasion
4.2.2 Secondary Endpoints:
1) To evaluate the safety and tolerability of 4 mg PF-04457845 QD x 8 weeks in cannabis 
use disorder patients as indexed by the % of participants who a) experience at least 1 
treatment-emergent related and/or possibly related adverse event, b) meet the markedly 
abnormal criteria for safety laboratory tests at least once post-dose, or c) who meet the 
markedly abnormal criteria for vital sign measurements at least once post-dose.
2) To evaluate whether over the 8 weeks of treatment 4 mg PF-04457845 QD is superior to 
placebo in reducing cannabis use as measured by amount (grams) used per week (TLFB). 
3) To determine whether over the 8 weeks of treatment 4 mg PF-04457845 QD is superior to 
placebo in reducing the severity of problems associated with cannabis use measured by 
the Psychiatric Research Interview for Substance and Mental Disorders (PRISM).
4) To determine whether over the 8 weeks of treatment 4 mg PF-04457845 QD weeks is 
superior to placebo in reducing sleep disturbances measured by actigraphy.
4.2.3 Exploratory Endpoints: 
1)
To determine whether over the 8 weeks of treatment 4 mg PF-04457845 QD is 
superior to placebo in reducing cannabis withdrawal syndrome as measured by the 
visual analog scale for mood states (anxiety, depression, and irritability)
2)
To determine whether over the 8 weeks of treatment 4 mg PF-04457845 QD is 
superior to placebo in reducing the problems associated with cannabis use measured 
by the Marijuana Problems Scale composite score.
3)
To determine whether over the 8 weeks of treatment 4 mg PF-04457845 QD is 
superior to placebo in reducing cannabis withdrawal syndrome as measured by the 
Cannabis Withdrawal Scale. 
4)
To evaluate whether over the 8 weeks of treatment 4 mg PF-04457845 QD is superior 
to placebo in reducing cannabis use as measured by:
a.
average of creatinine corrected urinary THC-COOH levels.
b.
% creatinine corrected THC-COOH negative UDS during 8-week treatment 
phase.
c.
days of use per week (TLFB).
d.
$ spent per week (TLFB).
e.
the % of days of self-reported abstinence from cannabis during the 8-week 
treatment phase (TLFB).
f.
total duration of self-reported abstinence (days) from cannabis during the 8-week 
treatment phase (TLFB). 
5)
To assess adherence to PF-04457845 as indexed by:
a.
Visual confirmation (by video) 
b.
PF-04457845 plasma concentrations, and
c.
Anandamide plasma concentrations.
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6)
To determine whether over the 8 weeks of treatment 4 mg PF-04457845 QD is 
superior to placebo in reducing cannabis craving as measured by the Marijuana 
Craving Questionnaire-Short Form total score.
7)
To determine whether over the 8 weeks of treatment 4 mg PF-04457845 QD is 
superior to placebo in reducing the number of symptoms reported per DSM-5 CUD.
8)
To determine whether over the 8 weeks of treatment 4 mg PF-04457845 QD weeks is 
superior to placebo in improving participant-reported quality of life as measured by the 
Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form version (Q-LES-
Q-SF) total score and subscales.
9)
Polymorphism of relevant genes (e.g., FAAH gene) will moderate the change in 
cannabis use with PF-04457845 treatment
10)
Over 8 weeks plasma endocannabinoid levels will be higher with PF-04457845 
compared with placebo.
11)
To evaluate the PD (plasma anandamide), and PK/PD relationships of PF-04457845.
12)
To correlate changes in exposure to PF-04457845 and clinical response.
13)
To correlate changes in plasma anandamide levels with clinical response to PF-
04457845.
14)
Change in serum levels of soluble biomarkers, such as inflammatory mediators, 
and their relationship to participant characteristics and change in study 
assessments.
15)
To determine whether over the 8 weeks of treatment 4 mg PF-04457845 QD weeks is 
superior to placebo in reducing sleep disturbances measured by:
a.
sleep report questionnaires, 
16)
To evaluate the safety and tolerability of 4 mg PF-04457845 QD x 8 weeks in cannabis 
use disorder patients:
a.
% of participants who meet the markedly abnormal criteria for safety 
electrocardiogram parameters at least once post-dose.
b.
% of participants with treatment-emergent suicidal ideation or suicidal behavior 
as measured using the Columbia-Suicide Severity Rating Scale (C-SSRS).
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Table 10: Primary and Secondary Objectives, Measures, and Endpoints
Objective/s
Instrument/s
Endpoint/s
Outcome/s
Primary
To determine whether PF-04457845 is 
superior to placebo in reducing self-
reported frequency of cannabis use.
TLFB
Change from baseline in the average 
number of times per day of self-reported 
consumption of cannabis or a cannabis 
containing product.
Differences between groups in 
the change from baseline use 
(2 weeks prior to 
randomization) in the average 
number of times per day of 
self-reported consumption of 
cannabis or a cannabis 
containing product in the last 
4 weeks of the treatment.
Self-report
% of participants who experience at least 1 
treatment-emergent adverse event.
Laboratory parameters 
(hematology, chemistry, liver 
functions)
% of participants who meet the markedly 
abnormal criteria for safety laboratory tests 
at least once post-dose.
To determine the safety and tolerability 
of 4 mg PF-04457845 QD x 8 weeks in 
cannabis use disorder patients.
Systolic and diastolic blood 
pressure and heart rate
% of participants who meet the markedly 
abnormal criteria for vital sign 
measurements at least once post-dose.
% who self-reported AEs or 
exhibited clinically significant 
changes during 1) 8-week 
treatment phase (from the first 
dose until the last dose), and 
2) the 4-week follow up phase 
(to assess any lingering post 
treatment safety issues)
To determine whether PF-04457845 
QD weeks is superior to placebo in 
reducing cannabis use.
TLFB
∆ in amount (grams) used
To determine whether PF-04457845 is 
superior to placebo in reducing the 
problems associated with cannabis 
use.
Psychiatric Research Interview 
for Substance and Mental 
Disorders (PRISM)
∆ in total score
Secondary
To determine whether PF-04457845 is 
superior to placebo in reducing sleep 
disturbances.
Actigraphy
∆ in duration of sleep latency, total sleep, 
wake after sleep onset, sleep efficiency, 
and ambient light
Change from baseline (2 
weeks prior to randomization) 
until the last dose
EKG
% of participants who meet the markedly 
abnormal criteria for safety 
electrocardiogram parameters at least once 
post-dose.
To determine the safety and tolerability 
of 4 mg PF-04457845 QD x 8 weeks in 
cannabis use disorder patients.
Columbia Suicide Severity Rating 
Scale
% of participants with treatment-emergent 
suicidal ideation or suicidal behavior
% who self-reported AEs or 
exhibited clinically significant 
changes during 1) 8-week 
treatment phase (from the first 
dose until the last dose), and 
2) the 4-week follow up phase 
(to assess any lingering post 
treatment safety issues)
∆ in weekly average of creatinine corrected 
urinary THC-COOH levels
Urine
∆ in the % creatinine corrected THC-COOH 
negative UDS
∆ in $ spent
∆ in # days of use
∆ in the % of days of self-reported 
abstinence from cannabis during the 8-week 
treatment phase
To determine whether PF-04457845 
QD weeks is superior to placebo in 
reducing cannabis use.
TLFB
total duration of self-reported abstinence 
(days) from cannabis between
To determine whether PF-04457845 is 
superior to placebo in reducing the 
problems associated with cannabis use.
Marijuana Problem Scale
∆ in total score
To determine whether PF-04457845 QD 
is superior to placebo in reducing the 
severity of CUD.
DSM-5 CUD
∆ in severity
Cannabis Withdrawal Scale
∆ in total score
To determine whether PF-04457845 QD 
is superior to placebo in reducing 
cannabis withdrawal syndrome.
Visual analog scale (VAS) for 
mood states (anxiety, depression, 
etc)
∆ in total score
To determine whether PF-04457845 QD 
weeks is superior to placebo in improving 
participant-reported quality of life.
Quality of Life Enjoyment and 
Satisfaction Questionnaire-18 
item version (Q-LES-Q-18)
∆ in total and subscale scores
Exploratory
To determine whether PF-04457845 QD 
is superior to placebo in reducing 
cannabis craving.
Marijuana Craving Questionnaire
∆ in total score
Change from baseline (2 weeks 
prior to randomization) until the 
last dose
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To determine whether PF-04457845 QD 
is superior to placebo in reducing 
cognitive deficits.
Cogstate Battery
∆ in composite score
To determine whether PF-04457845 is 
superior to placebo in reducing sleep 
disturbances.
Sleep report questionnaires
∆ in total score
Visual confirmation (by video)
% of confirmed observations
Over 8 weeks
PF-04457845 plasma 
concentrations
Difference in PF-04457845 plasma 
concentrations between placebo and PF-
04457845 groups
To assess adherence to PF-04457845.
Anandamide plasma 
concentrations
Difference in plasma anandamide 
concentrations between placebo and PF-
04457845 groups
Over the time period starting the 
first dose until the last dose
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5.0 STUDY DESIGN AND DESCRIPTION
5.1 Study Design: The efficacy, safety and tolerability of the Fatty Acid Amide Hydrolase 
(FAAH) Inhibitor PF-04457845 in adults with DSM-5 current Cannabis Use Disorder (CUD) will 
be evaluated in a 4-site (Columbia University, Johns Hopkins, Medical University of South 
Carolina and Yale University), randomized, double-blind, placebo-controlled, parallel-group, 
outpatient clinical trial comparing PF-04457845 (4mg) and placebo DSM-5 CUD individuals 
(Table 1). Participants will be randomized in a 1:1 ratio to either PF-04457845 or placebo using 
a random block sizes of 2 and 4, stratified by site and degree of cannabis use (CUD at the level 
of moderate (4-7 [of 11] symptoms) or severe (8-11 [of 11] symptoms)) based on DSM5 criteria. 
These variables were chosen because they are the most likely to strongly affect outcomes 
measures. The trial includes a 1) 2-week screening phase, 2) 8-week treatment phase 
(randomization to PF-04457845 or placebo) for, and 3) 4-week follow up phase (for safety 
especially because the effects of the drug take ~ 2 weeks to washout). The duration of the 
treatment phase was chosen because the available toxicity data that Pfizer has collected is up 
to 12 weeks in humans. 
During the screening period, participants will be required to set a quit attempt date that falls 
within the first week of treatment after at least 2 days of taking study medication. Participants 
will receive motivational interviewing to facilitate a quit attempt and will be rewarded for a 
successful attempt. 
5.2 Study Population: Approximately 260 total participants (target of approximately 65 
participants at each of the four participating sites based on competitive enrollment) of both 
genders and all ethnic/racial and socioeconomic backgrounds will be randomized for a total of 
178 participants completing the study (approximately 45 subjects per site). All patients will meet 
DSM-5 criteria for cannabis use disorder. The complete inclusion and exclusion criteria is further 
described in Section 6.1 and Section 6.2. Final determination for eligibility will be made by each 
site’s principal investigator. 
5.3 Duration: Screening activities will be completed up to approximately 14 days (up to a 
maximum of 60 days) prior to randomization on the Week 1 visit. The total duration of this study 
(from signed consent to the last follow-up visit) will be approximately 14 weeks. The study is 
expected to last 3 years.
5.4 End of Study Definition: A participant is considered to have completed the study if he or 
she has completed the 8-week treatment phase of the trial.                                                                                    
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6.0 STUDY POPULATION
6.1 Inclusion Criteria: Participants must meet all of the following inclusion criteria to be eligible 
for enrollment into the study:
1) Ages 18-60 years, inclusive (age verified using one form of picture identification with 
date of birth). 
2) Male or Female. 
3) Individuals with DSM-V criteria for CUD of at least moderate severity (≥ 4 [of 11] 
symptoms).
4) Current cannabis consumption greater than or equal to 30 joints/month (approximately 
daily) over the past 3 months
5) Positive for urinary THC-COOH on two separate occasions during screening (> 
50ng/ml).
6) Primary drug currently being used is cannabis.
7) Primary method of cannabis consumption (>80% of the time) is smoking cannabis.
8) Must express a willingness at screening to set a date within the first week of 
randomization to attempt to quit using cannabis.
9) Physically healthy i.e., no clinically unstable medical conditions at the discretion of the 
investigator.
10) Have given informed consent, and have capacity to consent and comply with study 
procedures.
11) Must be able to read English as per the judgment of the site investigators. Participants 
are required to be able to read because there are several self-administered measures 
that they must read, understand and provide written answers. 
12) Must provide the name of at least 1 contact (preferably 2), who would assist study staff 
in locating them during the study period.
13) For women of childbearing potential (WOCBP) and men, willingness to practice birth 
control and to inform study staff immediately if either they (for women) or their partner 
(for men) becomes pregnant.
14) Must be willing to complete a number of study assessments and procedures remotely. 
6.2 Exclusion Criteria: Participants presenting with any of the following exclusion criteria will 
be excluded from participation:
1) Clinically significant unstable medical disorders (as determined by the site investigator) 
that will increase potential risk or interfere with study participation e.g., ongoing seizure 
disorder, uncompensated congestive heart failure, uncontrolled severe diabetes, 
uncontrolled severe hypertension, etc.
2) Laboratory tests with clinically significant abnormalities (as determined by the site 
investigator) 
3) Positive urine toxicology screen for another drug with clinical evidence of use disorder 
for that drug (with the exception of THC-COOH at screening). 
4) Pregnancy by history and or laboratory confirmation (serum HCG).
5) Lactation.
6) Other DSM-5 substance use disorder in the past three months (excluding cannabis, 
nicotine, caffeine, and mild alcohol use disorder [≤ 3 criteria]).
7) Physiological dependence on another prescribed (e.g. benzodiazepine), not prescribed 
licit (e.g. alcohol or benzodiazepine) or illicit substance (e.g. opioid) requiring medical 
management, such as alcohol, opioids, or benzodiazepines, excluding caffeine, and 
nicotine.
8) Abstinence from cannabis for more than 1 week at the time of randomization.
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9) Meeting DSM-5 criteria for current serious mental illness (e.g., major depression, bipolar 
disorder, schizophrenia, any psychotic illness, including substance-induced psychosis, 
and current substance-induced mood disorder.) 
a.
Individuals who meet criteria for current major depression at a mild severity* may be 
included at the discretion of the site principal investigator.
* Per the DSM-5, current major depression at a mild severity is defined as: “Few, if 
any, symptoms in excess of those required to make the diagnosis are present, the 
intensity of the symptoms is distressing but manageable, and the symptoms result in 
minor impairment in social or occupational functioning.”(228)  
10) Lifetime history of DSM-5 bipolar disorder or any psychotic disorder.
11) Meeting DSM-5 criteria for any psychiatric disorder that may, according to t he 
investigator's judgment, require initiation of a pharmacological or non-pharmacological 
intervention over the course of the study.
12) Taking psychotropic medication/s that could interfere with interpretation of the study 
results or interact with study medication. Includes but is not limited to opioid analgesics, 
sedative hypnotics, or other known CNS depressants, etc. Exceptions include 
preexisting treatment with sleep agents, antidepressants for preexisting stable insomnia 
or depression, respectively. 
13) Current moderate risk for suicide as measured by the Columbia Suicide Severity Rating 
Scale (CSSRS) suicidal ideation (in the last month) score of greater than 2 and a history 
of recent (past 1 year) serious suicide attempt (lethality score of >2 on CSSRS).
14) Current or past history of significant violence (past 2 years).
15) Currently in a residential treatment setting in which substance use is monitored and 
restricted, since the restricted access to drugs could represent an important confounding 
variable.
16) Participants who, in the investigator's opinion, would be unable to comply with study 
procedures or assessments, or would be unacceptable study candidates (e.g., poses 
threat to staff).
17) Participation in a clinical trial and receipt of investigational drug(s) during past 30 days.
18) Known allergy to FAAH-inhibitors.
19) Primary method of cannabis consumption (>80% of the time) is using vaporized 
cannabis or ingesting edibles.
20) Co-medication with CYP3A inhibitor, CYP3A inducers, or P-glycoprotein substrates, 
within 48 hours or 5 half-lives prior to baseline, at the discretion of the site investigator.
6.3 Concomitant Interventions: Participants must be instructed to not take any medications, 
including over-the counter products, vitamins, or supplements during the study without first 
consulting with and getting the approval of the investigator. 
Similarly, since specific behavioral treatments developed for cannabis dependence e.g., 
MET or CBT may increase abstinence (17, 123), and in doing so obscure the effects of a 
medication treatment, participants will be asked to refrain from starting any such treatment until 
after completing the trial. Participants always have the option of dropping out from the trial to 
purse these or other interventions.
6.3.1 Pharmacokinetic interactions with PF-04457845: In vitro studies using recombinant human 
cytochrome P450 (CYPs) enzymes suggest that CYP3A4 is the predominant isoform 
responsible for the oxidative metabolism of PF-04457845.  Therefore, drugs that induce or 
inhibit CYP3A4 may reduce or increase PF-04457845 levels. While not absolutely 
contraindicated, treatment with the following drugs should be carefully evaluated. The following 
list provides some, but not all, of the drugs knows to induce or inhibit CYP3A4: 
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
Drugs that Induce CYP3A4 reduce PF-04457845 levels which may result in sub-
therapeutic levels of PF-04457845. This includes: Carbamazepine, Dexamethasone, 
Ethosuximide, Glucocorticoids, Griseofulvin, Phenytoin, Primidone, Progesterone, 
Rifabutin, Rifampin, Nafcillin, Nelfinavir, Nevirapine, Oxcarbazepine, Phenobarbital, 
Phenylbutazone, Rofecoxib, St. John’s Wart, Sulfadimidine, Sulfinpyrazone, and 
Troglitazone.

Drugs that Inhibit CYP3A4 increase PF-04457845 levels which may result in above 
normal levels of PF-04457845. This includes: Amiodarone, Anastrozole, Azithromzcin, 
Cimetidine, Clarithromycin, Clotrimazole, Cyclosporine, Danazol, Delavirdine, 
Dexamethasone, Diethyldithiocarbamate, Diltiazem, Dirithyromycin, Disulfiram, 
Entacapone, Erythromycin, Ethinyl estradiol, Fluconazole, Fluoxetine, Fluvoxamine, 
Gestodene, Grapefruit juice, Indinavir, Isoniazid, Ketoconazole, Metronidazole, 
Mibefradil, Miconazole, Nefazodone, Nelfinavir, Nevirapine, Norfloxacin, Norfluoxetine, 
Omeprazole, Oxiconazole, Paroxetine, Propoxyphene, Quinidine, Quinine, Quinupristine 
and dalfopristin, Ranitidine, Ritonavir, Saquinavir, Sertindole, Sertraline, Troglitazone, 
Troleandomycin, Valproic acid. 
6.3.2 Pharmacodynamic interactions with PF-04457845: Due to the mechanism of action as 
selective inhibitor of fatty acid amide hydrolase, pharmacodynamic drug interactions may be 
hypothesized for the following compounds or situations: metabolic diseases such as abdominal 
obesity and associated metabolic changes, and diabetes; β-amyloid-linked events; Huntington’s 
disease; sedative use; and other compounds influencing the endocannabinoid system such as 
cannabinoid receptor ligands (rimonabant); use of Nonsteroidal Anti-inflammatory Drugs.  As a 
result of the above hypothetical pharmacodynamic interactions special care may have to be 
taken when PF-04457845 is administered to patients with a background of metabolic diseases 
and use of sedatives and other CNS active compounds such as analgesics / anti-
inflammatories. None of these are absolute contraindications.  In the absence of 
pharmacodynamic studies, clinical judgement will need to be exercised to determine the 
risk:benefit of other drugs taken concomitantly with PF-04457845.
6.4 Contraception: Participants will be provided with information on acceptable methods of 
contraception as part of the informed consent process, and will be required to use one of the 
below approved methods of contraception for the duration of the study. Participants will be 
asked to inform the study staff immediately if either they or their sexual partner has become 
pregnant while participating in the study. Participants will be asked to document their method of 
contraception and sign to acknowledge that they will continue to use contraception from signing 
of consent until two weeks after the last dose of study medication.
6.4.1 Male Participants: From signing of informed consent until 2 weeks after the last dose of 
study medication, non-sterilized male participants who are sexually active with a female partner 
of childbearing potential must agree to use barrier contraception (e.g. a condom with or without 
spermicidal cream or jelly). In addition, they must be advised not to donate sperm during this 
period.
6.4.2 Female Participants: From signing of informed consent until 2 weeks after the last dose of 
study medication, female participants of childbearing potential (Women of Child Bearing 
Potential: WOCBP) who are sexually active with a non-sterilized male partner must use a highly 
effective method of contraception (from the list below). In addition, they must be advised not to 
donate ova during this period.
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6.4.3 Methods of Contraception: Acceptable contraceptive methods for WOCBP participants 
include: double barrier contraception or a combination of a barrier contraception and a hormonal 
implant, injectable, combined oral contraceptive, or a male partner who has had a vasectomy; 
IUD or tubal ligation. 
6.5 Pregnancy: If any participant is found to be pregnant during the study, participation in the 
treatment phase must be immediately terminated. The participant should stop taking the study 
medication and return any remaining study medication as soon as possible. If possible, the 
participant should complete the follow up phase which is to collect safety data. Furthermore, the 
investigator should make every effort to ensure that the participant has established follow up 
care with a medical provider (OBGYN). The pregnancy should be followed up by the site 
investigator to determine outcome (including spontaneous or voluntary termination), details of 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
6.6 Randomization Criteria: Participants who meet all inclusion and exclusion criteria will be 
randomized at the time of the Week 1 visit in a 1:1 ratio of PF-04457845 to placebo using 
random block sizes of 2 and 4, stratified by site and degree of cannabis use (CUD at the level of 
moderate (4-7 [of 11] symptoms) or severe (8-11 [of 11] symptoms)) based on DSM-5 criteria. 
These variables were chosen because they are the most likely to strongly affect outcomes 
measures. Random treatment assignment will be done using a centralized randomization 
process.
6.7 Enrollment: 
Participants will be enrolled 
at each site by competitive 
enrollment (or at a rate of 
approximately 8 subjects 
per month or about 2 
subjects per month per site) 
until up to approximately 
260 participants have been 
enrolled, or until 8 weeks 
before the drug expiry date 
(Figure 14). The current 
batch of PF-04457845’s 
expiration date is currently 
10/31/2022.
6.8 Enrollment by Race and Ethnicity: The sample recruited for this study needs to be 
composed of as close to70% men and 30% women as possible. Additionally, the sample will be 
composed of approximately 4% American Indian/Alaska Native, 6% Asian, 30% Black or African 
American, 50% White, and 9% greater than one race. Please refer to Table 11 for planned 
inclusion enrollment broken down by ethnic categories. To ensure that these ethnic and racial 
divides are met, each site will submit to the Coordinating Center periodic enrollment reports 
(every 6 months). The Coordinating Center will then instruct each site on which ethnic 
categories still need to be met. 
Table 11: Targeted Enrollment by Ethnic Categories
Racial Categories
Not Hispanic or Latino
Hispanic or Latino
Total
Figure 14: Participant Enrollment
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Female
Male
Unknown
Female
Male
Unknown
American Indian or 
Alaska Native
1
6
0
0
0
0
7
Asian
2
13
0
0
0
0
15
Native Hawaiian or 
Other Pacific Islander
0
0
0
0
0
0
0
Black or African 
American
24
42
0
2
17
0
85
White
35
80
0
3
11
0
129
More than One Race
6
6
0
5
7
0
24
Unknown
0
0
0
0
0
0
0
Total
68
147
0
10
35
0
260
6.9 Screen Failures: Screen failures are defined as participants who consent to participate in 
the clinical trial but are not subsequently randomized to the study intervention or entered in the 
study. A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. If the participant 
is found to be ineligible at Screening, the investigator should complete the source document. 
Minimal information includes demographics, screen failure details, eligibility criteria, and any 
serious adverse events (SAE). Subject ID numbers assigned to participants who fail screening 
should not be reused.
The primary reason for screen failure should be recorded in the source document using one of 
the following categories: 

Adverse Event.

Did not meet inclusion criteria or did meet exclusion criteria (specify reason).

Important protocol deviation.

Lost to follow-up.

Voluntary withdrawal (specify reason).

Other (specify reason).
Individuals who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened if the reason that they were excluded is no longer an issue (e.g., an underage 
participant who now falls within the permitted age range, or a participant who has stopped 
taking a prohibited medication). However, participants who were initially screen failures cannot 
be rescreened for this study more than twice. Rescreened participants should be assigned the 
same participant number as for the initial screening.
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7.0 STUDY INTERVENTION
7.1 Allocation to Treatment: Participants will be assigned a unique subject ID number that will 
be recorded in the randomization log. Then, prior to dosing, a randomization number will be 
allocated. This number will be retained throughout the study and will correspond to a treatment 
schedule determined by a randomization code. Participants will be made aware that there is a 
50% chance that they will receive a placebo as a part of this research protocol. 
All randomizations will be maintained centrally by the Coordinating Center, using the 
REDCap application. Participants will be randomized in a 1:1 manner. The randomizations will 
be stratified by site and severity of cannabis use (CUD at the level of moderate (4-7 [of 11] 
symptoms) or severe (8-11 [of 11] symptoms)) based on DSM-5 criteria. 
7.2 Breaking the Blind: All study personnel will be blinded to the study treatment. To minimize 
the potential for bias, treatment randomization information will be kept confidential and will not 
be released to the investigator or investigator site personnel until after the study database has 
been locked. 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. Blinding codes will only be broken in emergency situations for reasons of participant 
safety, where knowledge of treatment allocation is necessary to provide emergency care. 
Whenever possible, the investigator or co-investigator should consult with a member of the 
Coordinating Center prior to breaking the blind. When the blinding code is broken, the date, 
time, and reason the blind is broken must be fully documented in the source documents. 
To preserve the blind, blood will be sampled for PF-04457845 assay from all participants 
regardless of whether they have been randomized to PF-04457845 or placebo. 
7.3 Dose Selection: Given the FAAH inhibition mechanism and our understanding of the 
PK/PD relationship, if >95% inhibition of FAAH is not achieved, AEA levels are not 
reliably/robustly elevated. The minimum dose of PF-04457845 that produced >95% FAAH 
inhibition was 4 mg QD PF-04457845. PK at steady-state is dose-proportional. There are no 
major food effects on PF-04457845. Pharmacological washout takes 10 days after multiple 
dosing with 4mg due to a combination of the time it takes for drug clearance and FAAH activity 
recovery; the slow washout may offer the advantage of being less likely to result in withdrawal 
symptoms. The dose of 4mg PF-04457845 /day produces the maximal inhibition of FAAH, is 
safe as shown in the preliminary study, and furthermore, a higher dose does not afford any 
advantage.
7.4 Dose Administration: PF-04457845 (4mg) or matching placebo capsules will be taken by 
mouth at approximately the same time every morning. Exceptions about the time that the 
participant takes the study medication may be made at the discretion of the investigator if taking 
the study medication under observation (see below) conflicts with the participant’s schedule 
(e.g., work). The study medication is not yet approved by the Food and Drug Administration for 
clinical use. This study will be conducted under an existing IND (#114,017). This will be 
explained to participants prior to signing the informed consent document. 
7.5 Preparation/Handling/Storage/Accountability:
7.5.1 Acquisition and Accountability: To note, the study medication for this clinical trial was 
initially owned by SpringWorks Therapeutics, Inc. Ownership of the PF-04457845 study 
medication was transferred from SpringWorks to Jazz Pharmaceuticals as of October 
2020.Upon receipt of the PF-04457845/placebo capsules from Jazz Pharmaceuticals, the site 
principal investigator and research pharmacist must verify the contents of the shipments against 
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the packing list. The verifier should ensure that the quantity is correct, and the study drug is in 
good condition. If quantity and conditions are acceptable, investigator or designee should 
acknowledge the receipt of the shipment If there are any discrepancies between the packing list 
versus the actual product received, the Coordinating Center must be contacted to resolve the 
issue with Jazz Pharmaceuticals. The packing list should be filed in the investigator’s essential 
document file.
The investigator at each site must maintain 100% accountability for all drug received and 
dispensed during the site’s participation in the study. Proper drug accountability includes, but is 
not limited to:

Continuously monitoring expiration dates if provided to the investigator

Frequently verifying that the actual inventory matches the documented inventory

Verifying that the log is completed with, at a minimum, the subject ID, name of 
investigator, date and amount dispensed, date and amount returned, lot number for 
each dose, and that all containers used are documented accurately on the log.

Verifying that all required fields are completed accurately and legibly.
At the end of the study, each site will be provided with instructions as to the disposition of any 
unused investigational product. Drug supplies will be counted and reconciled at the site before 
being returned to the Coordinating Center. If Jazz Pharmaceuticals authorizes destruction at the 
study site, the investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions provided 
by Jazz Pharmaceuticals. Prior to October 2020 the investigator must ensure that the materials 
are destroyed in compliance with any special instructions provided by SpringWorks.
7.5.2 Formulation and Packaging: PF-04457845 (4mg) and matching placebo capsules will be 
provided by Jazz Pharmaceuticals (prior to 2021 study medication was provided by 
SpringWorks Therapeutics). Weekly quantities of the capsules will be dispensed by the 
pharmacy in prescription bottles (10 capsules per bottle). Study medication will be dispensed to 
the participants at the in-person treatment phase study visits (Week 1, Week 3, Week 5, and 
Week 7 Visits), during which they will be provided with enough study medication to last until 
their next in-person treatment phase study visit (2 weeks of study medication).   
7.5.3 Product Storage and Stability: Each site’s research pharmacist will ensure that all 
investigational product is stored in a secured area under recommended storage conditions and 
in accordance with applicable regulatory requirements. The PF-04457845 tablets have a 
recommended storage condition of 2-8 degrees Celsius. The clinical use period will be assigned 
based on the 5 degree Celsius stability data. 
The site investigator must ensure that the Coordinating Center-supplied drug is used in 
accordance with the protocol and is dispensed only to participants enrolled in the study. To 
document appropriate use of Coordinating Centered supplied drug, the investigator must 
maintain records of all Coordinating Centered-supplied drug delivery to the site, site inventory, 
dispensation and use by each participant, and return to the Coordinating Center.
7.5.4 Chemistry, manufacturing and compounding (CMC): Chemistry manufacturing and 
compounding information is provided in the IND for PF-04457845, IND#114,017, and can also 
be found in the Investigator’s Brochure for PF-04457845.
7.6 Study Intervention Adherence:
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7.6.1 Study Medication Adherence using the Cell Phone 
Assisted Remote Observation of Adherence (CAROMA): 
Adherence to study medication will be conﬁrmed using the 
CAROMA method as described elsewhere (203). Every morning 
5 days per week (Monday-Friday), research staff will video-call 
participants to visually observe them swallow the study 
medication using a standardized protocol (Figure 15). Every 
morning, within a time period pre-determined by agreement, 
participants will be called on the cell phone and will be observed 
removing study medication from the packaging and swallowing 
the medication with water or juice. For privacy, participants will 
be first asked to ensure that nobody else is in the room. 
Participants will be asked to have water or juice handy. 
Participants will then be instructed to 1) hold the study capsule 
up to the camera, 2) show research staff that the medication is on their tongue, and 3) then hold 
the camera up to their mouth for a mouth check after swallowing. The research assistant will log 
visual confirmation of compliance. Participants will receive additional compensation for 
CAROMA visits, and for returning the smartphone when they complete the study, which is 
outlined in the economic considerations section below. If participants fail to complete the 
CAROMA visit, it will be assumed to be an event of nonadherence and payment will be forfeited. 
Please refer to Appendix H for detailed instructions on the CAROMA visit. 
Participants will be provided with a cellphone that has the hardware, software, and service 
necessary to transmit high quality video. Prior to randomization, each participant will receive 
training on how to use the cell phones and also trained on the CAROMA compliance protocol. 
For this, each participant will be placed in one clinic office with the phone. A research staff 
member will video call the participant from another location in the clinic and will observe the 
participant consuming one M&M candy (or similar) with a glass of water. All participants will 
need to have at least one successful training session prior to randomization. 
The CAROMA video calls will not be recorded. Immediately following each call, research 
staff will document visual confirmation of the participant taking his/her study medication, the 
time that the medication was taken. 
7.6.2 Plasma PF-04457845 Levels: Adherence will also be confirmed later by measuring PF-
04457845 levels in plasma from blood sampled at Week 1, Week 5, and Week 9 study visits. 
7.6.3 Plasma Anandamide Levels: Adherence will also be confirmed later by measuring 
anandamide levels in plasma from blood sampled at Week 1, Week 5, and Week 9 study visits.
7.6.4 Weekly Pill Counts: At each in-person visit (Week 3, Week 5, Week 7, and Week 9), 
research staff will reconcile the number of capsules actually returned with the number that were 
expected to be returned. Virtual pill counts will also be conducted via video call at each remote 
study visit (Week 2, Week 4, Week 6, and Week 8) to reconcile the number of remaining 
capsules the participant has in their possession with the expected number of remaining 
capsules.  
Figure 15: Cellphone Assisted 
Remote Observation of Medication 
Adherence (CAROMA)
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8.0 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
8.1 Discontinuation of Study Intervention: Discontinuation from PF-04457845 does not mean 
discontinuation from the study. Attempts will be made to complete the remaining study 
procedures as indicated by the study protocol. If a clinically significant finding is identified 
(including, but not limited to changes from baseline) after enrollment, the investigator or 
qualified designee will determine if any change in participant management is needed. Any new 
clinically relevant finding will be reported as an adverse event (AE). Every attempt should be 
made to collect the data that would be collected at a termination visit (Week 9 Visit) as listed in 
1.5 Schedule of Procedures:
Table 2. If the participant is prematurely 
withdrawn from the treatment phase, he/she may be entered into the 4-week follow up phase.
8.2 Participant Discontinuation/Withdrawal from the Study: Participants are free to withdraw 
from participation in the study at any time upon request. The investigator may discontinue a 
participant’s study participation at any time during the study if the participant meets the study 
termination criteria. In addition, a participant may discontinue his or her participation without 
giving a reason at any time during the study. 
8.2.1 Criteria for Discontinuation or Withdrawal of a Participant: The primary reason for 
discontinuation or withdrawal of the participant from the study or study drug should be recorded 
using the following categories. 
1) Adverse Event: The participant has experienced an AE that requires early termination 
because continued participation imposes an unacceptable risk to the participant’s 
health or the participant is unwilling to continue because of the AE.
2) Important Protocol Deviation: The discovery post-randomization that the participant 
failed to meet protocol entry criteria or did not adhere to protocol requirements, and 
continued participation poses an unacceptable risk to the participant’s health.
3) Lost to Follow-Up: The participant did not return to the study site and multiple attempts 
to contact the participant were unsuccessful. Attempts to contact the participant must 
be documented.
4) Voluntary Withdrawal: The participant wishes to withdraw from the study. The reason 
for withdrawal, if provided, should be recorded. Please note: all attempts should be 
made to determine the underlying reason for the withdrawal and where possible, the 
primary underlying reason should be recorded.
5) Pregnancy: The participant is found to be pregnant. Note: if the participant is found to 
be pregnant, the participant must be withdrawn immediately.
6) Nonadherence with Study Drug during Treatment Phase: based on the assessment of 
the investigator an out-of-adherence participant may be withdrawn from the study.
8.3 Lost to Follow-Up: A participant will be considered lost to follow up if he/she fails to 
complete 2 scheduled consecutive weekly visits or 10 consecutive days of missed study 
medication (~20% of nonadherence) during the treatment phase and is unable to be contacted 
by the study site staff. The following actions must be taken if a participant fails to return to the 
clinic or is non-contactable for the remote study visits:

The site will attempt to contact the participant and reschedule the missed visit and 
counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee will make 
every effort to regain contact with the participant. These contact attempts should all be 
documented in the participants study file.
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
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow up.
8.4 Trial Stopping Rules: The study will be completed as planned unless one or more of the 
following criteria are satisfied that require temporary suspension or early termination of the 
study.                                                                                                                                                                        

New information about the safety of PF-04457845 that alters the risk to benefit ratio in a 
significantly negative manner.

If the planned interim analysis reveals a worsening of cannabis use in the PF-04457845 
treatment group

For three or more serious adverse events, related to the study, from the same 
cause. SAE is defined as something that:
1. is life-threatening 
2. results in in-patient hospitalization or prolongation of existing hospitalization 
3. results in persistent or significant disability or incapacity 
4. results in a congenital anomaly or birth defect OR 
5. results in death
6. based upon appropriate medical judgment, may jeopardize the participant’s health 
and may require medical or surgical intervention to prevent one of the other outcomes 
listed in this definition, or 
7. adversely affects the risk/benefit ratio of the study
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9.0 STUDY PROCEDURES
The following sections describe the study procedures to be performed and data to be collected. 
For each procedure, participants are to be assessed by the same investigator or site personnel 
whenever possible. Please refer to 1.5 Schedule of Procedures:
Table 2 for a detailed schedule of study procedures. 
9.1 Recruitment: Participants will be recruited from the community with advertising (print, radio, 
television, online [Craigslist, Facebook, Instagram], and subway) or by clinical referrals. The 
advertisements ask “Is Marijuana or Cannabis a Problem for You? If so, you may qualify for a 
free and confidential research treatment study.” This study will also be registered on 
clinicaltrials.gov, an online listing of clinical trials that is available to the public, which also will 
serve as a recruitment source. The advertisements for this study are located in Appendix B.
Interested participants will be informed of the study and will first be screened on the phone 
to initially determine eligibility (see phone screen in Appendix C). If participants pass the initial 
screening for the study, they will then be invited for a full evaluation to assess eligibility based 
on the inclusion and exclusion criteria. Information collected during the phone screen will only 
be used in the event that the participant continues to participate in the study. For those found 
ineligible, the information collected during the phone screen will be kept with the permission of 
the participant for the duration of the study to ensure that participants are not phone screened 
on multiple occasions. After determining initial eligibility, research staff will provide a brief 
description of the research and the participant will present to the clinic for the screening 
procedure.
9.2 Informed Consent Procedures: The consent process is a multistep process, whereby 
information about the risks and benefits of the study will be provided to potential participants. 
Participants will be required to read the informed consent form and the investigator or her/his 
designee will additionally describe the risks and discomforts. The consent process may be 
completed remotely or in person. As part of the consenting process, one form of picture 
identification with date of birth will be copied and kept on file to verify the participant meets age 
inclusion requirements. Once all screening procedures have been collected, research staff as 
well as the principal investigator will review all relevant information and determine, based on the 
inclusion and exclusion criteria, if the participant will continue with the remaining study 
procedures.
To ensure that the study participant understands the study, the participant will be asked 
questions about the study procedures and the risks associated with participation. Participants 
will be asked to pass a study questionnaire to document their understanding of the study. This 
consent questionnaire is located in Appendix D. If any concern arises that the study participant 
did not fully understand the study, the principal investigator (PI) or her/his designee may decide 
that the participant is not suitable for participation. If the participant is still interested after all 
questions have been answered, the PI will ask the participant to sign the informed consent form. 
Any participant who appears incapable of providing informed consent will be excluded. 
9.3 Contact/Informant: As a requirement for entry into this study, participants will need to 
identify an individual who is can serve as a contact and as a collateral source of information. Or 
two people could serve in these roles. A family member or a significant other/spouse is 
preferred. The participant will need to sign a hospital approved release of information to permit 
the study team to contact the individual. The contact/informant could be contacted to locate the 
participant during the study. The contact/informant will also be contacted to provide collateral 
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information that will be used to determine the participant’s eligibility (Appendix F). Furthermore, 
the contact/informant may help corroborate information provided by the participant which in turn 
will enhance the reliability of the information, as described elsewhere (204).
9.4 Subject ID Number Assignment: A unique subject ID number will be assigned to each 
participant at the time that informed consent is obtained/explained, and this is the subject id 
number that will be used throughout the study. Subject ID numbers will be maintained by the 
Coordinating Center. Each subject ID number will be composed of the ID for the site where the 
participant was screened and then sequential numbering. The subject ID’s for each site are as 
follows:

Columbia University: CU### (i.e. CU001, CU002, CU003…)

John Hopkins University: JH### (i.e. JH001, JH002, JH003...)

Medical University of South Carolina: SC### (i.e. SC001, SC002, SC003...)

Yale University: YU### (i.e. YU001, YU002, YU003...)
9.5 Screening: Participants will be evaluated at the study site to confirm that they meet the 
participant selection criteria for the study. The participant’s identity obtained at screening will be 
verified with one form of picture identification. Screening will be spread across approximately 2 
weeks (up to a maximum of 60 days) and will be divided into both remote and in-person 
screening sessions.  
Upon completion of the phone screen, participants who seem to meet the general criteria of the 
study will be invited to complete the virtual portion of screening. Prior to the first virtual session, 
interested participants will be mailed a packet of information. This packet will include the 
following: a urine toxicology quick dip cup, urine pregnancy test for WOCBP, and an 
evening/morning sleep questionnaire. Participants who are unable to complete the informed 
consent electronically will also be mailed a blank consent form and supplement to consent 
questionnaire. Participants who do not have access to a computer will also be mailed the 
following self-report assessments: VAS Marijuana Ladder, Marijuana Problems Scale, and 
Pittsburg Sleep Quality Index.
9.5.1 Remote Screening Visits: The first portion of screening will be conducted remotely. In 
order to standardize the remote screening process, the virtual screening sessions will be broken 
into a minimum of two sessions over the course of one week (+/- 3 days) that are no longer than 
2 hours each. Prior to beginning each remote visit, research staff will confirm that the study 
participant is in an area where they have privacy and will be undisturbed. During the virtual 
screening process, the following procedures will be completed: 
1)
Obtain written informed consent (must be completed first).
2)
Have participant complete the Supplement to Consent questionnaire.
3)
Collect demographics.
Safety:
4)
Obtain complete medical and psychiatric history. 
5)
Obtain complete history of all prescription or nonprescription medications, dietary and 
herbal supplements within the past 6 months. 
6)
Administer the Structured Clinical Interview for DSM-5, RV
7)
Administer the Columbia Suicide Severity Rating Scale (C-SSRS)
8)
Have participant provide a urine sample for drug testing via a urine toxicology quick dip 
cup. Participant will be asked to hold the quick dip cup results up to the screen for 
research staff to visually assess the test results. 
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9)
Have WOCBP participants complete a pregnancy test. Participant will be asked to hold 
the test up to the screen so that research staff can visually see the test result. 
10) An initial check-in visit will be completed with a licensed clinician (MD, RN, APRN, PA).
Cannabis and Other Drug Outcomes:
11) Obtain history of drug, alcohol, and tobacco use with the following assessments: 
i.
Scale for Assessment of Lifetime Cannabis Use (SALCU) to capture first use, 
heaviest use, lifetime use, and past 30-day use.
ii.
Modified timeline follow-back approach to estimate last 30-day cannabis use.
iii.
Timeline follow-back approach to estimate last 30-day alcohol and tobacco 
use.
12) Have the participant complete the following assessments via an electronic survey. Of 
note, if the participant does not have access to a computer then these self-report 
assessments will be mailed to the participant prior to the virtual screening visit and the 
coordinating center should be notified.
i.
VAS Marijuana Ladder.
ii.
Marijuana Problems Scale.
iii.
Evening/Morning Sleep Questionnaire.
iv.
Pittsburgh Sleep Index.
13) Record the participant’s desire to quit.
14) PRISM lifetime, last 12 months and last 30 days.
15) Motivational Interviewing, if the participant has access to a computer. If the participant 
does not have access to a computer then this will be completed during the face to face 
screening visit. 
9.5.2 In Person Screening Visit: All participants who seem to be eligible for the study after 
completion of the virtual screening visits will be invited to come in for an in-person screening 
visit. During this visit, the following procedures will be completed in person:
Safety:
1)
Obtain informant/contact information and have participant sign release of information to 
obtain permission to contact informant/contact.
2)
Collect blood for hematology, clinical chemistry, LFTs, and DNA. Label and store blood 
sample for DNA extraction.
3)
Collect urine to test for:
i.
Urinalysis (including creatinine)
ii.
Presence of drugs of abuse via urine toxicology quick dip cup
iii.
Quantitative analysis for cannabinoids (THC-COOH)
iv.
Urine pregnancy test for WOCBP
4)
Alcohol breath test may be conducted at the discretion of the investigator. 
5)
Record vital signs (sitting blood pressure, heart rate and temperature).
6)
Record height and weight.
7)
Complete physical and neurological examination, as well as a check-in visit with a 
licensed clinician. 
8)
Record standard 12-lead electrocardiogram (ECG).
Cannabis and Other Drug Outcomes:
8) Modified timeline follow-back approach to estimate last week cannabis use (capture 
days since the date that the initial 30 day TLFB was conducted at virtual screening).
9) Nicotine dependence will be evaluated using the Fagerstrom Test for Nicotine 
Dependence.
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10) Timeline follow-back approach to estimate last 7-day alcohol and tobacco use.
11) VAS Marijuana Ladder.
12) Marijuana Problems Scale.
13) Marijuana Craving Scale.
14) Evening/Morning Sleep Questionnaire.
15) Pittsburg Sleep Quality Index.
16) Marijuana Withdrawal Checklist. 
17) Desire to Quit.
18) VAS mood states.
19) Start actigraphy. A charged actigraph will placed around the wrist of the participant’s 
non-dominant hand.
20) Motivational Interviewing, only if the participant was unable to complete this during the 
virtual screening sessions.
21) Quit date: During screening participants will counseled to attempt a quit date that will fall 
sometime within the first week of treatment (Quit Week). The participants will be asked 
to sign a commitment to quit document (Appendix G) that includes the following 
statement: “I agree that I will attempt to quit using cannabis or cannabis based products 
during the first week of the treatment phase of the study, and if successful I could 
receive $50.”
In extenuating circumstances, or at the convenience of the research participant, the completion 
of some screening procedures may deviate from the above schedule and may be completed at 
the other screening visit or at an alternately scheduled time prior to randomization. However, the 
following screening procedures must be completed prior to all other screening procedures: 
obtain written informed consent (must be completed first), have participant complete the 
Supplement to Consent questionnaire, obtain informant/contact information and have participant 
sign release of information to obtain permission to contact informant/contact, and collect 
demographics information.
9.5.3 Motivational Interviewing: Participants will receive motivational interviewing by a trained 
rater during the screening period leading up to the quit date (does not need to be a licensed 
clinician). The motivational interviewing will be conducted via completion of the eCheckup To 
Go program, created by San Diego State University. The rater will facilitate the completion of 
this program with the participant and will then review the results generated by this program with 
the participant. All participants who have access to a computer will be asked to complete the 
motivational interviewing during the virtual screening session. Research staff will remain on the 
video call with the participant throughout the completion of the motivational interviewing to 
answer any questions that the participant may have. When the participant attends the in person 
screening visit they will be given a hard copy of their motivational interviewing results to the 
participant to take home. In the event that a participant is unable to complete the motivational 
interviewing remotely (i.e. if they don’t have access to a computer), it may be completed during 
the in person screening session. 
9.5.4 Setting a Quit Date: During screening participants will counseled to attempt a quit date to 
fall sometime within the first week of treatment, at least two days after taking the study 
medication (Quit Week). The participants will be asked to sign a commitment to quit document 
(Appendix G) that includes the following statement: “I agree that I will attempt to quit using 
cannabis or cannabis based products during the first week of the treatment phase of the study, 
and if successful I could receive $50.”
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9.5.5 Adherence (CAROMA training): Participants will be provided with a cellphone with the 
hardware, software and service necessary to transmit high quality video. Prior to randomization, 
the participant will be trained how to use the phone and also trained on the adherence protocol. 
For this, the participant will be placed in one clinic office with the phone. A research staff 
member will video call the participant from another location in the research clinic and observe 
the participant consuming one placebo capsule or M&M candy with a glass of water. All 
participants will need to have at least one successful training session prior to randomization. 
This cellphone will be used for completion of the CAROMA calls and for completion of the study 
procedures/visits that are conducted remotely. Participants will return the phone to research 
staff at the End of Study visit. 
9.6 Treatment Phase Study Visits (Week 1 – Week 8): 
9.6.1 Week #1 (Quit week): At the week 1 visit, prior to randomization, the inclusion and 
exclusion criteria should be re-reviewed. Confirm with the participant that they will make an 
attempt to quit using marijuana, and their previously agreed upon quit date. Please note, the 
quit date should be at least two days after the subject has started taking the study medication. 
Therefore, the quit date will fall between day 3 and day 7. 
9.6.2 In-Person Treatment Phase Study Visits (Week 1, Week 3, Week 5, and Week 7 Visits) 
Procedures: During the treatment phase of the study, Week 1, Week 3, Week 5, and Week 7 
study visits will be conducted both in-person and remotely. It is preferable that the remote 
portion of these study visits are completed prior to the in-person portion of the visit, and that 
both portions of the visit are completed on the same day (+/- 1). At these visits, the following 
study procedures will be completed (1.5 Schedule of Procedures:
Remote Portion of Visit: Safety Procedures: 
1) Review of medical and psychiatric history, including a review of all prescription or 
nonprescription medications, dietary and herbal supplements the participant is taking.
2) Administer the Columbia Suicide Severity Rating Scale (C-SSRS).
Remote Portion of Visit: Cannabis and Other Drug Outcomes:
3) 7-Day Timeline Follow Back Approach for Nicotine/Tobacco.
4) 7-Day Timeline Follow Back Approach for Alcohol.
5) 7-Day Modified Timeline Follow Back Approach for Cannabis: to verify the information 
on the participant’s marijuana use that has been previously captured during the daily 
CAROMA calls, including the assigned dollar value.
6) The participant’s desire to quit will be captured.
7) PRISM (Week 5 only)
Self-Report Assessments for Remote Portion of Visit: Participants will be instructed to 
complete each of the below questionnaires via an electronic survey (using the REDCap 
platform). These questionnaires are to be completed while the participant is on their virtual call 
with research staff to ensure that the questionnaires are being completed on the day of the 
study visit and that research staff is available to answer any questions and confirm that all 
questions have been answered. In the event that the participant does not have access to a 
computer and it is not feasible to complete these assessments electronically, a packet of 
blank questionnaires will be given to the participant at the end of each in-person study visit, 
that they will then complete during the remote portion of the next in-person visit. The 
participant will then return these completed assessments to research staff at their next in-
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person visit. The coordinating center should be notified if these self-report assessments 
cannot be completed electronically.
8) Marijuana Problems Scale (administered at Week 1 only).
9) Marijuana Withdrawal Checklist. 
10) Marijuana Craving Scale.
11) Fagerstrom Test of Nicotine Dependence (administered at Week 1 only).
12) VAS Marijuana Ladder.
13) Pittsburg Sleep Quality Index
14) Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Week 1 only)
In-Person Safety Visit Procedures:
1) Record vital signs (sitting blood pressure, heart rate and temperature) and weight.
2) Alcohol breath test may be done at the discretion of the investigator based on clinical 
suspicion.
3) Obtain blood and urine samples (hematology, clinical chemistry, LFTs) and urine 
samples (urinalysis) for safety laboratory tests (Week 1, Week 5, and Week 7 only). 
4) Obtain urine sample for on site drug testing via a urine toxicology quick dip cup and for 
quantitative urine toxicology.
5) Blood drawn for PF-04457845 assay and serum endocannabinoid levels at the week 1 
and week 5 visits only.
6) Collect urine for on-site urine drug testing and quantitative urine toxicology.
7) Administer urine pregnancy test for WOCBP
8) Ask participant about any adverse events. May be initially assessed remotely if the 
remote portion of the study visit occurs prior to the in-person portion of the study visit.
9) Pill counts will be performed for all medication dispensed since the last in-person study 
visit (2 weeks of medication). 
10) Medication will be dispensed for the following two weeks (so the participant will have 
enough study medication until their next in-person study visit).
11) A check-in visit will be completed with a licensed clinician (MD, RN, APRN, PA). The 
Week 1 and Week 3 check-in visit should be completed in-person. Of note, the MD 
check-in visits must be completed last so that the MD has all of the necessary 
information to evaluate the participant. 
In-Person Miscellaneous Outcomes:
12) Download actigraphy data, charge actigraph, and return to participant.
13) CogState Battery (Week 1 only).
14) VAS Mood States
15) Evening Morning Sleep Questionnaire
Of note, prior to the participant leaving each in-person visit research staff will provide them with 
a quick dip urine toxicology cup to complete during the following week’s remote visit and a 
pregnancy test for WOCBP to complete during the next week’s remote visit. They will also be 
provided with a hard copy of the VAS Mood States and Evening Morning Sleep Questionnaires. 
In the event that the participant does not have access to a computer, they will also be provided 
with a packet of the blank self-report assessments to be completed during the following week’s 
remote visit.
9.6.3 Remote Treatment Phase Study Visits (Week 2, Week, 4, Week 6, and Week 8) 
Procedures: The Week 2, Week 4, Week 6, and Week 8 study visits will be conducted remotely, 
utilizing the same method as the daily CAROMA calls (video call using the clinic provided cell 
phone). Prior to beginning each remote visit, research staff will confirm that study participant is 
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in an area where they have privacy and will be undisturbed. During each remote study visit, the 
following procedures will be completed (1.5 Schedule of Procedures:
Safety:
1)
Review of medical and psychiatric history, including a review of all prescription or 
nonprescription medications, dietary and herbal supplements the participant is taking. 
Research staff will review this information with the participant, and will relay the updated 
information to the licensed clinician prior to the remote MD check-in visit.
2)
Urine pregnancy test for WOCBP. At each in-person study visit, all WOCBP participants 
will be given a pregnancy test to take home for the following week’s remote visit. During 
the remote visit, participants will be asked to put the phone down, take the pregnancy 
test, and then hold the pregnancy test up to the screen, so that research staff can 
visually see the results of the test.
3)
Urine drug testing via the quick dip urine toxicology cup. At each in-person study visit, 
all participants will be given a quick dip urine toxicology cup to take home for the 
following week’s remote visit. During the remote visit, participants will be asked to put 
the phone down, give a urine sample into the test cup, and then hold the test cup up to 
the screen, so that research staff can visually see the results of the urine toxicology 
quick dip.
4)
Administer the Columbia Suicide Severity Rating Scale (C-SSRS). Any information 
obtained by research staff should be relayed to the licensed clinician prior to the remote 
MD check in visit.
5)
Ask participant about any adverse events. Any information obtained by research staff 
should be relayed to the licensed clinician prior to the remote MD check in visit. 
6)
A check-in visit will be completed with a licensed clinician (MD, RN, APRN, PA), 
remotely. Research staff will assist in the coordination of this visit by arranging a time 
on the day of the remote study visit for the licensed clinician and research participant to 
have a video call.
Cannabis and other Drug Outcomes:
7)
7-Day Timeline Follow Back Approach for Nicotine/Tobacco. 
8)
7-Day Timeline Follow Back Approach for Alcohol.
9)
7-Day Modified Timeline Follow Back Approach for Cannabis: to verify the information 
on the participant’s marijuana use that has been previously captured during the daily 
CAROMA calls, including the assigned dollar value.
10) The participant’s desire to quit will be captured.
11) Participants will be asked to confirm that they have received their study medication for 
the following week. A virtual pill count will be performed by the participant opening the 
current week’s study medication bottle, pouring the remaining medication into their 
hand, and holding their phone up to their hand so that research staff can visually see 
how much study medication remains. 
Self-Report Assessments: Participants will be instructed to complete each of the below 
questionnaires via an electronic survey (using the REDCap platform). These questionnaires 
are to be completed while the participant is on their video call with research staff to ensure 
that the questionnaires are being completed on the day of the study visit and that research 
staff is available to answer any questions and confirm that all questions have been answered. 
In the event that the participant does not have access to a computer and it is not feasible to 
complete these assessments electronically, a packet of blank questionnaires will be given to 
the participant at the end of each in-person study visit, that they will then complete during the 
remote portion of the next in-person visit. The participant will then return these completed 
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assessments to research staff at their next in-person visit. The coordinating center should be 
notified if these self-report assessments cannot be completed electronically.    
12) Marijuana Withdrawal Checklist. 
13) Marijuana Craving Scale.
14) Fagerstrom Test of Nicotine Dependence (week 4, and week 8 visits only).
15) VAS Mood States (paper copy of questionnaire provided to participant to complete).
16) VAS Marijuana Ladder.
17) Evening Morning Sleep Questionnaire  (paper copy of questionnaire provided to 
participant to complete).
18) Pittsburg Sleep Quality Index
Should there be any perceived safety concerns, the participant may be asked to come into the 
clinic during the week of the remote study visit. For example, if unscheduled clinical labs need to 
be obtained as a result of a previous abnormal value, the participant will be asked to come into 
the clinical to complete only the blood draw, and all other procedures will be completed 
remotely. 
9.6.4 Adherence to Study Medication: Approximately every morning, within a time period 
predetermined by agreement, participants will be called on the cell phone and will be observed 
removing study medication from the packaging and swallowing the medication with water or 
juice. The research assistant will log visual confirmation of adherence. A brief time line follow 
back assessment of cannabis and other drug use will be conducted. The entire process takes 
less than 5 minutes to complete.
9.6.5 Contingency Management: Participants will be asked about their use of cannabis or 
cannabinoid products daily on the CAROMA call. A successful “quit” attempt is defined as 1) an 
intentional (not lack of availability), 2) reduction (by 50% or more) in 3) the # of occasions of 
cannabis use in a day, 4) lasting a day (24 hours) or more, 5) compared to the average daily # 
of occasions of cannabis use captured by the last week screening TLFB for cannabis. 
Participants who have a successful quit attempt before the week 2 study visit will be eligible to 
receive $50.
9.7 Follow-Up Phase Study Visits (Week 9 – Week 12): Upon completion of the 8-week 
treatment phase, participants will complete weekly follow up visits for four weeks primarily for 
safety purposes given that the effects of the study medication may take up to two weeks to 
wash out. 
9.7.1 Week 9 In-Person Study Visit: The week 9 visit will serve as the end of treatment visit. 
This is an in-person study visit. The following procedures will be completed at this visit: 
Remote Portion of Visit: Safety Procedures: 
1) Review of medical and psychiatric history, including a review of all prescription or 
nonprescription medications, dietary and herbal supplements the participant is taking.
2) Administer the Columbia Suicide Severity Rating Scale (C-SSRS).
Remote Portion of Visit: Cannabis and Other Drug Outcomes:
3) 7-Day Timeline Follow Back Approach for Nicotine/Tobacco.
4) 7-Day Timeline Follow Back Approach for Alcohol.
5) 7-Day Modified Timeline Follow Back Approach for Cannabis: to verify the information 
on the participant’s marijuana use that has been previously captured during the daily 
CAROMA calls, including the assigned dollar value.
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6) The participant’s desire to quit will be captured.
7) PRISM
Self-Report Assessments for Remote Portion of Visit: Participants will be instructed to 
complete each of the below questionnaires via an electronic survey (using the REDCap 
platform). These questionnaires are to be completed while the participant is on their virtual call 
with research staff to ensure that the questionnaires are being completed on the day of the 
study visit and that research staff is available to answer any questions and confirm that all 
questions have been answered. In the event that the participant does not have access to a 
computer and it is not feasible to complete these assessments electronically, a packet of 
blank questionnaires will be given to the participant at the end of each in-person study visit, 
that they will then complete during the remote portion of the next in-person visit. The 
participant will then return these completed assessments to research staff at their next in-
person visit. The coordinating center should be notified if these self-report assessments 
cannot be completed electronically.
8) Marijuana Problems Scale.
9) Marijuana Withdrawal Checklist. 
10) Marijuana Craving Scale.
11) VAS Marijuana Ladder.
12) Pittsburg Sleep Quality Index
13) Quality of Life Enjoyment and Satisfaction Questionnaire Short Form
In-Person Safety Visit Procedures:
1) Complete physical and neurological examination (this counts for check in with licensed 
clinician). 
2) Record vital signs (sitting blood pressure, heart rate and temperature).
3) Alcohol breath test may be done at the discretion of the investigator based on clinical 
suspicion.
4) Record height and weight.
5) Obtain blood (hematology, clinical chemistry, LFTs) and urine samples (urinalysis) for 
safety laboratory tests. 
6) Obtain urine sample for on site drug testing via a urine toxicology quick dip cup and for 
quantitative urine toxicology.
7) Blood drawn for PF-04457845 assay and serum endocannabinoid levels.
8) Administer urine pregnancy test for WOCBP
9) Record standard 12-lead electrocardiogram (ECG).
10) Ask participant about any adverse events. May be initially assessed remotely if the 
remote portion of the study visit occurs prior to the in-person portion of the study visit.
11) Pill counts will be performed for all medication dispensed since the last in-person study 
visit (2 weeks of medication). 
In-Person Miscellaneous Outcomes:
12) Download actigraphy data, charge actigraph, and return to participant.
13) CogState Battery.
14) VAS Mood States
15) Evening Morning Sleep Questionnaire
9.7.2 Week 10 – Week 12 Remote Study Visits: At the Week 10, Week 11, and Week 12 follow 
up visits, safety data will be collected on the participant remotely. The following procedures will 
be completed for each participant: 
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1)
A check-in visit will be completed with a licensed clinician (MD, RN, APRN, PA). 
Research staff will assist in the coordination of this visit by arranging a time on the day 
of the remote study visit for the licensed clinician and research participant to have a 
video call.
2)
Review of medical and psychiatric history, including a review of all prescription or 
nonprescription medications, dietary and herbal supplements the participant is taking. 
Research staff will review this information with the participant, and will relay the updated 
information to the licensed clinician prior to the remote MD check-in visit.
3)
Urine pregnancy test for WOCBP. At the Week 9 in-person study visit, all WOCBP 
participants will be provided with urine pregnancy tests to be completed remotely during 
the Week 10, Week 11, and Week 12 virtual study visits.  During the remote visit, 
participants will be asked complete the pregnancy test and then hold the test up to the 
screen, so that research staff can visually see the results of the test.
4)
Ask participant about any adverse events. 
5)
Administer the Columbia Suicide Severity Rating Scale (C-SSRS).
6)
7-Day Timeline Follow Back data will be collected for cannabis, alcohol, and 
nicotine/tobacco. 
7)
Marijuana Problems Scale (Week 11 only). Participants will be instructed to complete 
this assessment via an electronic survey (using the REDCap platform). This self-report 
assessment will be completed while the participant is on their virtual call with research 
staff. In the event that the participant does not have access to a computer or it is not 
feasible to complete electronically, a paper assessment will be given to the participant 
at the Week 9 visit which will then be returned at the End of Study Visit. 
9.7.3 End of Study In-Person Visit: At the end of week 12 (~day 85), a visit will be conducted 
that will mark the end of the study. This visit will be completed both in-person and remotely. It is 
preferable that the remote portion of these study visits are completed prior to the in-person 
portion of the visit, and that both are completed on the same day (+/- 1).The following 
procedures will be completed at this visit. 
Remote Portion of Visit: Safety Procedures: 
1) Review of medical and psychiatric history, including a review of all prescription or 
nonprescription medications, dietary and herbal supplements the participant is taking.
2) Administer the Columbia Suicide Severity Rating Scale (C-SSRS).
Remote Portion of Visit: Cannabis and Other Drug Outcomes:
3) 7-Day Timeline Follow Back Approach for Nicotine/Tobacco.
4) 7-Day Timeline Follow Back Approach for Alcohol.
5) 7-Day Modified Timeline Follow Back Approach for Cannabis: to verify the information 
on the participant’s marijuana use that has been previously captured during the daily 
CAROMA calls, including the assigned dollar value.
6) The participant’s desire to quit will be captured.
Self-Report Assessments for Remote Portion of Visit: Participants will be instructed to 
complete each of the below questionnaires via an electronic survey (using the REDCap 
platform). These questionnaires are to be completed while the participant is on their virtual call 
with research staff to ensure that the questionnaires are being completed on the day of the 
study visit and that research staff is available to answer any questions and confirm that all 
questions have been answered. In the event that the participant does not have access to a 
computer and it is not feasible to complete these assessments electronically, a packet of 
blank questionnaires will be given to the participant at the end of each in-person study visit, 
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that they will then complete during the remote portion of the next in-person visit. The 
participant will then return these completed assessments to research staff at their next in-
person visit. The coordinating center should be notified if these self-report assessments 
cannot be completed electronically.
7)
Marijuana Problems Scale.
8)
Marijuana Withdrawal Checklist. 
9)
Marijuana Craving Scale.
10) VAS Marijuana Ladder.
11) Pittsburg Sleep Quality Index
In-Person Safety Visit Procedures:
16) A check-in visit will be completed with a licensed clinician (MD, RN, APRN, PA). 
17) Record vital signs (sitting blood pressure, heart rate and temperature).
18) Alcohol breath test may be done at the discretion of the investigator based on clinical 
suspicion.
19) Record height and weight.
20) Obtain blood (hematology, clinical chemistry, LFTs) and urine samples (urinalysis) for 
safety laboratory tests. 
21) Obtain urine sample for on site drug testing via a urine toxicology quick dip cup and for 
quantitative urine toxicology.
22) Blood drawn for PF-04457845 assay and serum endocannabinoid levels.
23) Administer urine pregnancy test for WOCBP
24) Ask participant about any adverse events. May be initially assessed remotely if the 
remote portion of the study visit occurs prior to the in-person portion of the study visit.
In-Person Miscellaneous Outcomes:
25) Download actigraphy data.
26) VAS Mood States
27) Evening Morning Sleep Questionnaire
9.8 Participant Reimbursement: All participants will be compensated for their participation in 
various study procedures. Please refer to Table 12 for the full breakdown of participant payment. 
In addition, participants will receive escalating payments contingent on attending their 
appointments and completing study related procedures. Participants will be repeatedly told 
before the study and reminded once enrolled in the study that the contingency management 
payments are not linked to abstinence from cannabis. Participants will be compensated for the 
remote study visits at the next subsequent in-person visit.  
Table 12: Participant Payments
STUDY VISITS
REGULAR 
PAYMENTS
ADHERENCE 
PAYMENTS
TOTAL
Screening
$50
$0
$50
Week 1
$40
$0
$40
Successful quit attempt
$50
$0
$50
Week 2
$20
$20
$40
Week 3
$25
$25
$50
Week 4
$30
$35
$65
Week 5
$35
$50
$85
Week 6
$40
$70
$110
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Week 7
$45
$95
$140
Week 8
$50
$125
$175
Week 9
$55
$160
$215
Week 10
$60
$0
$60
Week 11
$65
$0
$65
Week 12
$70
$0
$70
End of study
$75
$0
$75
Payment for returning phone
$50
$0
$50
Total
$760
$580
$1,340
9.9 Early Termination Study Visit: If a participant decides to withdraw from the study after 
randomization or is terminated by the site principal investigator for any reason after 
randomization, an early termination study visit will be conducted to close out the participant from 
the study. At this visit the participant will be instructed to return all unused study medication. The 
Week 9 procedures will be attempted at an early termination visit, which will be conducted per 
Section 9.7.1, both in person and remotely.
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10.0 ASSESSMENTS:                                      
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. When a protocol-required test cannot be performed, study staff will be 
instructed to document the reason for the missed test and any corrective and preventative 
actions which s/he has taken to ensure that required processes are adhered to as soon as 
possible. Any protocol deviations should be documented in the study log. 
10.1 Blood: Total blood sampling volume for the individual participants is approximately 420 mL 
over approximately 14 weeks of the study. The actual times of blood sampling may change. 
Additional blood samples may be taken for safety assessments at times specified by the 
Coordinating Center, provided the total volume taken during the study does not exceed 450 mL 
(safety, PF-04457845 levels, endocannabinoid levels). 
10.2 Safety:
10.2.1 Laboratory Tests: The following safety laboratory tests will be performed at the following 
study visits: Screening, Week 1, Week, 5, Week 7, Week 9, and End of Study Visit (end of 
Week 12). They are conducted periodically throughout the duration of the study to monitor 
electrolyte and liver/kidney function. Additional laboratory results may be generated on the 
samples (without additional blood volume drawn) as a result of the method of analysis, the type 
of analyzers used, or as derived or calculated values; if such results are available, they may 
also be reported. Unscheduled clinical labs may be obtained at any time during the study to 
assess any perceived safety concerns. 
Hematology: Hemoglobin, Hematocrit, RBC Count, MCV, MCHC, RDW, MCH, MPV, Platelet 
Count, WBC Count, Total Neutrophils (Abs), Eosinophils (Abs), Monocytes (Abs), Basophils 
(Abs), Lymphocytes (Abs); Collected using one 10cc Lavender-top Tube (tube contains EDTA 
as an anticoagulant).
Chemistry: BUN and Creatinine, BUN/Creatinine Ratio, Glucose, Calcium, Sodium, Potassium, 
Chloride, Total CO2, AST, ALT, Total Bilirubin, Direct Bilirubin, Alkaline Phosphatase, Urine 
acid, Albumin, Total protein, HDL, LDL, Cholesterol; Collected using one 10 cc Tiger-top Tube 
(tube does not contain an anticoagulant but does contain a clot activator and serum separator 
gel).
Urinalysis: Color, Appearance, Specific Gravity, pH, Glucose, Protein, Blood, Ketones, Nitrites, 
Leukocyte esterase, Bilirubin, Urobilinogen, Bacteria, Casts, Crystals, Yeast, Amorphous 
Sediment, Epithelial Cells, WBC, RBC; Collected using one 10cc urinalysis preservative tube 
(tube includes a preservative of chlorhexidine, ethylparaben, and sodium propionate).
On-Site Urine Drug Testing: At every study visit, participants will be tested using a urine drug 
quick dip. A 12-panel all-in-one drug test cup with a built-in temperature strip (CLIA waived) 
should be used for these quick dip urine drug tests. The minimum requirement for drug testing 
includes: 
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1.
Amphetamines (Detection Period: 1-2 days; Cutoff Level: 1000 ng/mL)
2.
Barbiturates (Detection Period: 1-4 days; Cutoff Level: 200 ng/mL)
3.
Buprenorphine (Detection Period: 1-3 days; Cutoff Level: 10 ng/mL)
4.
Benzodiazepines (Detection Period: 1-2 days; Cutoff Level: 200 ng/mL)
5.
Cocaine (Detection Period: 2-4 days; Cutoff Level: 300 ng/mL)
6.
THC-COOH (Detection Period: up to 5+ days; Cutoff Level: 50 ng/mL)
7.
Methamphetamines (Detection Period: 2-4 days; Cutoff Level: 500 ng/mL)
8.
Methylenedioxymethamphetamine (Detection Period: 2-4 days; Cutoff Level: 1000 
ng/mL)
9.
Methadone (Detection Period: 1-3 days; Cutoff Level: 300 ng/mL)
10. Opiates (Detection Period: 2-3 days; Cutoff Level: 300 ng/mL)
11. Oxycodone (Detection Period: 1-3 days; Cutoff Level: 100 ng/mL)
12. Phencyclidine (Detection Period: 7-14 days; Cutoff Level: 25 ng/mL)
If during the in-person visits a sample tests positive for any drug (other than THC) on site, a 
sample will be sent to the laboratory for confirmation. 
Participants may undergo random urine drug testing at the discretion of the investigator. Spot 
urine drug testing conducted prior to dosing must be positive for cannabinoids for participants to 
receive study medication.
On Site Urine and Serum Pregnancy Test: Urine HCG testing should first be performed using a 
urine pregnancy spot kit. If the result yields a positive result, then a serum HCG test will be sent 
out for confirmation. If the result yields a positive result during one of the remote study visits the 
participant will be asked to come in to the clinic to provide a blood sample and study medication 
will be suspended. For the serum HCG test, a blood serum sample will be collected using one 10 
cc Tiger-top Tube (tube does not contain an anticoagulant but does contain a clot activator and 
serum separator gel). 
Quantitative Urine Cannabinoids Toxicology: Urine samples will be collected at each of the in-
person visits as specified in the Schedule of Procedures (1.5 Schedule of Procedures:
Table 2). At each in-person visit, a urine sample will be obtained from the 
participant, pipetted into one 1.5 mL cryovial tube (urine sample should be filled up to the top 
line of the tube), and will be stored in a -80 degree Celsius freezer until the sample is ready for 
shipment. Samples will be shipped in batches, on dry ice, directly to the lab of Dr. Tom Cooper 
at the Nathan Kline Institute: 140 Old Orangeburg Road Orangeburg, NY 10962. The 
Coordinating Center will instruct each individual site on when to ship these samples to Dr. 
Cooper, at intervals of approximately 6 months. Levels of THC-COOH the principal inactive 
metabolite of cannabis will be assayed by the lab of Tom Cooper at the Nathan Kline Institute in 
6 month batches using a GCMS method (205). Assays have intra- and inter-assay RSD% of 
10% at 1 ng/ml with 0.5 ng/ml as the lower limit of detection. Creatinine corrected THC-COOH 
levels will be reported.
10.2.2 Vital Signs: Blood pressure, pulse rate, oral temperature, height and body weight will be 
measured periodically and recorded, as specified in 1.5 Schedule of Procedures:
Table 2, the Study Procedures Table. Sitting blood pressure will be 
measured with the participant’s arm supported at the level of the heart, and recorded to the 
nearest mm Hg after at least 5 minutes of rest. The same arm (preferably the dominant arm) 
will be used throughout the study.
The same size blood pressure cuff, which has been properly sized and calibrated, will be 
used to measure blood pressure each time. The use of automated devices for measuring BP 
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and pulse rate are acceptable, although, when done manually, pulse rate will be measured in 
the brachial/radial artery for at least 30 seconds. When the timing of these measurements 
coincides with a blood collection, blood pressure and pulse rate should be obtained prior to the 
nominal time of the blood collection.
A participant should have weight and height measured while wearing indoor clothing and 
with shoes off. The standard for collecting height is inches without decimal places and for 
weight it is pounds with one decimal place. BMI will be calculated for each participant through 
the Table listed in Appendix I.
10.2.3 Physical Examinations: Completed physical and neurological examinations will be 
conducted at screening and at the end of the treatment phase or early termination visit. 
Physical examinations will be conducted by a physician, trained physician assistant, or nurse 
practitioner, as designated by the site principal investigator. 
10.2.4 Electrocardiogram (ECG): ECGs should be collected after the participant has rested 
quietly for at least 10 minutes in a supine position. When the timing of these measurements 
coincides with a blood collection, the ECG should be obtained prior to the nominal time of the 
blood collection, blood pressure, and pulse rate. 
A standard 12-lead ECG will be recorded. A qualified individual appointed by the site 
investigator will make comparisons to baseline measurements. If interpreted as abnormal, the 
local investigator will assess the findings as either abnormal clinically significant, or abnormal not 
clinically significant. The interpretation of the ECG will be recorded in the source documents. 
ECG traces recorded on thermal paper will be photocopied to avoid degradation of the trace over 
time. 
10.3 Pharmacokinetics:
10.3.1 PF-04457845 Levels: Blood will be sampled for PF-04457845 levels as specified in the 
Schedule of Procedures (1.5 Schedule of Procedures:
Table 2). 
Given that adherence will be confirmed visually, the PF-04457845 levels will be assayed in only 
a random sampling of approximately 1/3 of participants from each site to confirm adherence, as 
specified by the Coordinating Center. Assays will be conducted by laboratory of Alex 
Makriyannis at Northeastern University using a proprietary assay with existing permission from 
SpringWorks and Jazz Pharmaceuticals. The serum sample to be analyzed for PF-04457845 
levels should be collected in one 4 cc lavender top tube (tube containing K2-EDTA). Blood 
samples should be collected as close to approximately 1 hour after the participant has taken 
their daily dose of study medication (PF-04457845/placebo). The time at which the blood 
sample has been drawn at should be documented, along with the time that the study medication 
was taken that day. The sample should then be centrifuged at approximately 1700g for about 10 
minutes at 4 degrees Celsius, pipetted into appropriately labeled 1.5 mL screw capped 
polypropylene tubes (1 mL of serum sample per tube; 2 polypropylene tubes), and then stored 
in a -80 degree Celsius freezer within 1 hour of collection. Samples will be stored on site until 
they are to be sent directly to WuXi by each site, at the end of the study. 
Shipment of Pharmacokinetic Samples: Each site will store blood samples to be assayed for 
PF-04457845 levels on site in a -80 degree Celsius freezer. Samples will be stored on site, and 
will be shipped on dry ice directly to the lab of Dr. Makriyannis at Northeastern University, in 
batches of at least 50 samples. The Coordinating Center will instruct each individual site on 
which random sampling of participants should be shipped.
10.3.2 Plasma Anandamide Levels: Blood will be sampled for plasma anandamide and other 
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endocannabinoid levels as specified in the Schedule of Procedures (1.5 Schedule of 
Procedures:
Shipment of Plasma Anandamide Samples: Each site will store blood samples to be assayed for 
anandamide levels on site at -80 degree Celsius. Samples will be shipped on dry ice directly to 
the lab of Dr. Makriyannis at Northeastern University, approximately every 6 months. 
10.3.3 DNA: A single nucleotide polymorphism (SNP) in the gene encoding for FAAH - C385A 
variance was reported to be significantly associated with changes in withdrawal after 
abstinence, and happiness after smoking cannabis (206-208). Recently, 3 specific CUD risk 
alleles were reported for the first time in a Yale-led study by Gelernter et al., 216 (209). These 
included rs143244591 in novel antisense transcript RP11-206M11.7; rs146091982 in the solute 
carrier family 35 member G1 gene (SLC35G1); and rs77378271 in the CUB and Sushi multiple 
domains 1 gene (CSMD1). These and other genes will be studied in an exploratory manner to 
examine for genetic moderators of response to PF-04457845. DNA will be sent to the laboratory 
of Dr. Gelernter at Yale.
One 10cc PAXgene Blood DNA tube (sterile vacutainer plastic tube with hemogard closure 
and K3 EDTA additive) should be collected for DNA analysis for all participants at the screening 
visit and appropriately labeled. Each sample should be frozen first at -20 degrees Celsius for 24 
hours, and then transferred to a -80 degree Celsius freezer, in the original 10cc tube that it was 
collected in. 
DNA will be extracted from whole blood samples using the salting out method implemented 
in the PaxGene (PreAnalytix Inc.) DNA extraction systems. DNA samples are aliquoted into 96 
PCR plates at a concentration of 10ng/μl. These working PCR plates are stored at -20ºC until 
their use for genotyping. Stock DNA samples are stored at -80ºC. The PCR reactions are 
prepared either manually or using the TECAN GENESIS pipetting robots. To minimize 
possibility for cross contamination, one TECAN robot is dedicated to pre-PCR and another to 
post-PCR use. PCR will be conducted using MJR PTC-200 (96 or 384 wells), MJR PTC-225 
Tetrad (4x384 wells) or ABI GeneAmp 9700 cyclers (384 wells). We will use the TaqMan 
method for SNP genotyping, which is in routine use in this laboratory. In the TaqMan method, a 
primer is allowed to hybridize on top of the SNP site. In the presence of a mismatch between 
the primer and the variant base, the affinity of the primer to the template is less than in the case 
of a perfect match. PCR primers hybridized adjacent to the SNP site are then allowed to be 
elongated. In the presence of a mismatch, the hybridization primer is displaced. If the 
hybridization primer is not displaced, it emits fluorescence, which is detected by the PCR 
machine. SNP assays will be ordered from Applied Biosystems Inc.‚s (ABI) Assay-on-Demand 
collection or they will be custom designed and ordered from ABI‚s Assay-by-Design service. An 
ABI 7900 HT real time PCR machine, located at the Yale-VA Laboratory of Psychiatric 
Genetics, will be used to analyze TaqMan SNP assays. Variants of the cannabinoid receptor 
gene and other relevant genes will be studied.
Shipment of DNA Samples: Each site will store samples at -80 degrees Celsius. Samples will be 
sent in large batches (every 6 months) directly to the laboratory of Dr. Joel Gelernter at Yale 
University. 
10.4 Demographics, Medical History, and Medication History Procedure: At the screening 
visits, extensive demographic information will be collected including date of birth or age, sex, 
ethnicity, race as described by the participant, smoking status, reproductive status, alcohol 
consumption, and caffeine consumption of the participant. 
10.4.1 Documentation of Concomitant Medication: Concomitant medication is any drug given in 
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addition to the study drug. These may be prescribed by a physician or obtained by the 
participant over the counter. Concomitant medication is not provided by the Coordinating 
Center. At each study visit, participants will be asked whether they have taken any medication 
other than the study drug (used from signing of informed consent through the end of the study), 
and all medications including vitamin supplements, over-the-counter medications, and oral 
herbal preparations, must be recorded in the source documents. Permitted concomitant 
medications will be left to the direction of the site principal investigator. When in doubt the site 
investigator should contact the overall medical monitor or the study principal investigator to 
discuss.
10.4.2 Documentation of Concurrent Medical Conditions: Concurrent medical conditions are 
those significant ongoing conditions or diseases that are present at signing of informed consent. 
This includes clinically significant laboratory, ECG, or physical examination abnormalities noted 
at screening, according the judgment of the investigator. The condition (i.e., diagnosis) should 
be described.
Participants with stable, chronic, nonemergent, well-controlled conditions may be permitted 
to participate at the discretion of the site investigator. Conditions that will be excluded: 1) 
serious or acute conditions e.g., appendicitis, 2) conditions that require frequent and significant 
medical interventions e.g., sickle cell crisis, 3) conditions that interfere with the primary outcome 
of interest e.g., alcohol or nicotine withdrawal, intoxication or dependence, etc. When in doubt 
the site investigator should contact the overall medical monitor or the PI to discuss. 
10.4.3 Documentation of Concurrent Psychiatric Conditions: Concurrent psychiatric conditions 
are those significant ongoing psychiatric conditions that are present at the signing of informed 
consent. Any concurrent psychiatric conditions should be well documented at screening. 
Participants with stable, chronic, nonemergent, well-controlled psychiatric conditions may be 
permitted to participate at the discretion of the site investigator e.g., anxiety disorder. Conditions 
that will be excluded: serious, acute conditions e.g., acutely suicidality, or conditions that require 
frequent and significant medical interventions e.g., bipolar disorders, conditions that interfere 
with the primary outcome of interest e.g., alcohol or nicotine withdrawal, intoxication or 
dependence, etc. When in doubt the site investigator should contact the overall medical monitor 
or the PI to discuss.
Disallowed psychiatric problems include: a) Schizophrenia Spectrum and other Psychotic 
disorder in lifetime (current or past), b) Bipolar or related disorder in lifetime (current or past), 
and c) current Major Depressive Disorder.
10.5 Structured Clinical Interview for DSM-5: to diagnose any significant psychiatric disorders 
(210). 
10.6 Psychiatric Research Interview for Substance and Mental Disorders (PRISM): is a 
semi-structured diagnostic interview designed to deal with the problems of psychiatric diagnosis 
when participants drink heavily or use drugs. This interview will help differentiate between 
primary disorders, substance-induced disorders, and the effects of intoxication and withdrawal. 
For training and quality control purposes, the PRISM interviews will be audio recorded. The 
interviewees’ Subject ID number and the study visit week that the interview is being conducted 
at will be stated at the beginning of the recording. The participants name will not be included in 
the recording. Participants will be asked at screening if they are willing to consent to the audio 
recording being conducted. If the participant does not consent to this, the PRISM interview will 
still be conducted, but will not be audio recorded. The audio recordings will be transferred to Dr. 
Hasin at Columbia University for training and quality control purposes via each site’s IRB 
approved method of data transfer.   
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10.7 Fagerstrom Test for Nicotine Dependence (FTND): will be used to estimate nicotine 
dependence (211).
10.8 Scale for Assessment of Lifetime Cannabis Use (SALCU): this scale developed and 
being refined at our laboratory that examines estimates first use, heaviest use, lifetime use, 
frequency, amount, type and preferred method. Cannabis use is estimated with by assigned $ 
value and weight with the help of a prop (see adjacent figure) that displays both joints of 
increasing sizes and the increasing amounts of oregano (as a proxy of cannabis) that have 
been carefully weighed. The prop (Figure 16) helps participant more accurately estimate the 
amount of and frequency of cannabis used.
10.9 Timeline Follow-Back (TLFB): This approach will be used to estimate cannabis use (212) 
at baseline, and periodically throughout the study. 
Some TLFB data will be captured in face-to-face 
visits, while some will be captured during the 
CAROMA calls. Last 30 day, last week and last day 
use will be captured at different times. Frequency, 
quantity, and assigned-dollar value will be captured. 
The # of exposures within the defined time period i.e., 
week will be summed is the outcome of interest. Only 
for cannabis, a prop (Figure 16) will be used to 
facilitate accurate estimation of amount used. The 
same approach will be used to assess alcohol and 
tobacco use.
10.10 Marijuana Withdrawal Checklist: A 
withdrawal discomfort score (summary score) will be 
computed by summing the 10 most frequently 
reported items of the Marijuana Withdrawal Checklist (213) reported in previous studies will be 
used to track withdrawal symptoms. Each item of the marijuana withdrawal checklist is rated on 
a 4-point scale (none, mild, moderate, severe). 
10.11 Marijuana Craving Questionnaire-Short Form (MCQ-12): consists of 12 statements 
about the respondent’s feelings and thoughts about smoking cannabis as he/she is completing 
the questionnaire (i.e., right now) (214, 215). 
10.12 Marijuana Contemplation Ladder: Participants are asked to rate where they are 
re:changing their use of marijuana (216) with a score of 1 (“I enjoy using marijuana and have 
decided I’ll never change it. I have no interest in changing the way I use marijuana”) to a score 
of 10 (“I have changed my marijuana use and will never go back to the way I used marijuana 
before”).
10.13 Desire to Quit: Participants will be asked to rate their desire to quit using marijuana. 
Please rate how interested you are right now to quit or reduce your use of cannabis or 
cannabinoid products. Participants will be asked to respond to that question by selecting one of 
the following responses: 0 = I’m not really interested; 1 = I’m somewhat interested; 2 = I’m 
seriously interested. 
10.14 Visual Analog Scale for Mood States: Participants will be asked to rate 12 feeling 
states including "anxious", "depressed", "irritable", "tired", "hungry", and "energetic" by scoring 
Figure 16: Prop to Estimate Cannabis Use
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the perceived intensity of these feeling states at that moment on a 100mm line (0= not at all, 
100=extremely). This is a simple, quick and replicable method to capture information about 
mood states. Additionally, the Marijuana Ladder (216), a visual analog measure, will be used to 
assess a cannabis user’s stage of change. 
10.15 Systematic Assessment for Treatment Emergent Events (SAFTEE): (217-219) Safety 
and adverse events will be captured using the SAFTEE’s general and specific inquiry forms, 
which take ~ 20 minutes to administer. 
10.16 24-Hour Actigraphy: Throughout the study, participants will wear a 
wrist actigraph [wgt3x-bt Monitor (Actigraphcorp®)] with technology that 
has been developed for sleep-wake assessment and allows access to raw 
accelerometer data (Figure 17) (http://actigraphcorp.com/actigraph-wgt3x-
bt/). Wrist actigraphy has been validated and used successful in healthy, 
clinical, and substance-using populations (220-224). The wrist actigraph is 
a comfortable wristwatch-like device that measures arm accelerations 
and hence is a proxy for activity. Ambient light is also measured to assist 
in determining sleep onset/wake times. It is tamper-proof and water-
resistant, and will be worn ~24-hrs/day during the course of the study 
(removed only for swimming, bathing, and other fully submerged 
activities) on the participant’s non-dominant wrist. The wgt3x-bt is well-suited for a clinical trial, 
as it maintains 25 straight days of battery life before the need to recharge, and it can collect and 
store 180 total days of data before the need to upload. The use of the actigraph will begin during 
the baseline/lead-in period so that participants become accustomed to wearing it, using it as 
directed, and to collect baseline 
sleep/activity data. 24-Hour 
actigraphy will be used to assess 
sleep-wake, activity levels, and 
circadian phase during the lead-in 
and treatment phase, where it will 
be compared to self-reported data. 
The actigraphy outcome measures 
will include sleep latency, total 
sleep time, wake after sleep onset, 
sleep efficiency, and ambient light. 
Analysis of sleep-related 
actigraphy data will performed with 
ActiLife+Sleep feature package 
(Figure 18), which is ActiGraph's 
premier actigraphy data analysis 
software platform 
(http://actigraphcorp.com/actilife/). 
The software is fully customizable, 
and raw data can be exported for 
analysis via 3rd party software platforms if required.
Each participant will be fitted with the actigraph. The serial number of the watch will be 
recorded to be linked to the subject ID. At every study visit, data will be downloaded and the 
device will be charged before being returned to the participant.
10.17 Subjective Sleep Measures:
Figure 17: Wrist Actigraph 
WGT3X-BT Monitor
Figure 18: ActiLife + Sleep Software Screen Shot
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10.17.1 Sleep Disorders Questionnaire: This questionnaire (202) is administered during 
screening to discriminate between 4 types of sleep disorders – sleep apnea, narcolepsy, 
psychiatric sleep disorders, and periodic limb movement disorder. This questionnaire will be 
used in establishing participant eligibility for participation. 
10.17.2 Pittsburg Sleep Quality Index (PSQI): This self-administered questionnaire queries 
normal sleep patterns and sleep problems (203). This will be given to participants at Screening, 
Week 1, Week 5, Week 9, and Week 12 (1.5 Schedule of Procedures:
Table 2). Higher scores indicate poor sleep and PSQI at screening will be analyzed as a 
covariate in the main outcome measures.
10.17.3 Clinician Administered Evening/Morning Sleep Questionnaire: Participant will be asked 
about the quality and quantity of their sleep, as well as how well-rested and alert they feel in the 
morning and at the end of the day (204). Instead of asking participants to fill out this 
questionnaire on their own, the same questions will be asked when participants are contacted 
everyday as part of the CAROMA procedure. In addition, participants note their sleep-wake 
schedule and timing of when medication was taken, as well as their daily intake of caffeinated 
beverages, nicotine, alcohol, and any other drugs or medications. The questionnaire will be 
given to participants at every clinic visit (1.5 Schedule of Procedures:
Table 2) to report on the night before and the morning of the visit. This questionnaire 
is the primary instrument for assessing subjective sleep quality, sleep-wake cycle outside of the 
sleep laboratory, and retrospective, subjective measurement of alertness. Subjectively reported 
sleep quality, alertness, and sleep schedule data from the Evening/Morning Sleep 
Questionnaire are secondary outcome measures in this study. 
10.18 Rater Qualification and Certification Process: To ensure collection of quality data from 
scales administered by raters, raters assigned to this study will be required to fulfill qualification 
and/or training requirements. The process for qualifying and training raters will be described in 
manuals provided by rater training and assessment vendors. Furthermore, the study will include 
additional steps related to monitoring the quality of rater activity, which will be described in the 
manuals provided by these vendors.
All raters will be required to successfully fulfill the full scope of rater training requirements for 
any scale they will be administering prior to rating any participants in this study. The sites will be 
responsible for ensuring that they have qualified raters who can conduct assessments in the 
study prior to enrollment of study participants.
Raters will be required to complete and submit experience details and curriculum vitae (if 
applicable) to the rater vendor in a timely manner. Once the rater’s experience level is reviewed 
and deemed adequate, then study-assigned raters will be approved to participate in the rater 
certification process.
11.0 RISK/BENEFIT ASSESSMENT
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11.1 Known Potential Risks: The risks from this study include: 1) effects of PF-04457845, 2) 
cannabis withdrawal syndrome, 3) blood drawing, and 4) behavioral and cognitive testing.
11.1.1 PF-04457845: The full investigator brochure contains detailed safety information about 
PF-0445784. Presented below is a synopsis of the safety, pharmacokinetics, and 
pharmacodynamics of PF-04457845.
Animals Studies: PF-04457845 has potent and long lasting antinociceptive effects in rats with 
oral administration. At 1 mg/kg displays PF-04457845 in vivo efficacy for over 24 hours with 
concomitant FAAH inhibition, and elevation of brain and plasma anandamide, N-palmitoyl 
ethanolamine (PEA) and N-oleoyl ethanoamine (OEA). Furthermore, unlike direct CB1 R 
agonists even at high doses PF-04457845 does not have effects on motility, catalepsy, or body 
temperature, which are the classic central nervous system effects of CB1R agonists. 
Humans Phase 1 Studies: Randomized, double-blind, placebo-controlled phase 1 studies have 
been conducted in healthy male participants (n=64), aged 21 to 55 to characterize the 
pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of single and multiple oral 
doses of PF-04457845 in healthy participants. Dose regimens included single doses from 0.1 to 
40mg and multiple doses from 0.5 to 8mg once daily (QD) for 14 days. Blood and urine were 
collected for PK analysis. 
Pharmacokinetics: With single doses, absorption of PF-04457845 is rapid, and concentrations 
peak (Cmax) within an average of 2 hours post dose. Elimination of PF-04457845 is multi-
phasic, with a half-life (t1/2) ranging from 12-23 hours. With multiple dosing steady-state plasma 
concentrations were attained by Day 7. An approximate 2-3 fold accumulation in exposure was 
observed between days 1 and 14. PK at steady-state appeared dose-proportional. There are no 
major food effects on PF-04457845. Urine excretion of PF-04457845 as intact parent was 
negligible. PK is commensurate with QD dosing. Phase 1 safety: Several phase 1 studies have 
been conducted. Safety assessments including adverse events monitoring, physical 
examinations, 12-lead ECGs, vital signs (blood pressure, pulse rate and body temperature) and 
laboratory safety tests were conducted at intervals throughout all studies. Continuous cardiac 
monitoring, via telemetry was conducted up to 8 hours post-dose in the SRD study and up to 4 
hours post-dose on Day 1, 7 and 14 of the MRD study. All observed or reported AEs were 
recorded for all participants and AEs were classified as mild, moderate or severe and their 
relationship to study drug was assessed by the investigator. As illustrated (Figure 19) the drug 
and its effects persist for up to 2 weeks after last dose; this is the reason for the 4-week safety 
follow-up.
Pharmacodynamics: Peripheral FAAH activity was measured ex vivo in blood leukocytes. 
Plasma concentrations of anandamide, PEA, OEA and N-linoleoylethanolamide (LEA) were 
measured as pharmacodynamic biomarkers.  PEA, OEA and LEA have anti-inflammatory, sleep 
inducing and appetite inducing effects. Inhibition of FAAH activity and elevation of a number of 
fatty acids has been demonstrated with single and multiple doses. Pharmacological washout 
takes 10 days after multiple dosing with 4mg due to a combination of the time it takes for the 
drug to clear and the time that it takes for FAAH activity to recover. This slow pharmacological 
washout may offer the advantage of being less likely to result in withdrawal symptoms. 
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PF-04457845 has undergone extensive testing in animals. All the necessary toxicology 
testing was completed to permit FDA approved phase 1 and 2 studies. PF-04457845 was 
evaluated in a 7-day rat dose range inding study where higher doses were explored to define 
the maximum tolerated dose.
The preclinical safety strategy included 4-week definitive toxicity studies in male and female 
rats and dogs, standard genetic toxicology assessments, and safety pharmacology studies 
including CNS and pulmonary evaluations in rats as well as cardiovascular evaluation in dogs) 
to support clinical development through Phase 1 and 2 clinical trials. PF-04457845 has met or 
surpassed all of the safety requirements to support nomination as a clinical candidate. These 
include the in vitro dofetilide binding, hERG patch-clamp assays, the panel of CEREP selectivity 
assays, the BioLum Ames, the in vitro micronucleus assay, rat cardiovascular safety study and 
4- week definitive toxicity studies in 2 species (rats and dogs).
Table 13: Summary of Safety Profile for PF-04457845
Assay
Result
Biolum Ames
Negative
Micronucleus Test
Negative
Dofetilide Binding
Ki = 3.41 µM
hERG (IKr) Assay
IC50 = 4.7 µM
Affinity for other receptors, transporters and 
enzymes (Ki in parenthesis)
CB1 (14 µM), CB2 (5.1 µM), 5HT2A (1.6 µM) and Cl channel 
(3 µM)
Evaluation of cardiovascular effects in oral PF-
04457845 in rats
No effect on heart rate or blood pressure up to 426-fold 
projected human Cmax (ss)
7-Day rat in vivo toleration
No adverse effects at 820-fold and 608-fold the projected 
human efficacious Cmax (ss) and AUC (0-24 hr), respectively
8mg
4mg 
0.5mg
0mg
8mg
4mg 
0.5mg
0mg
Daily Dosing for 14 days 
   Daily Dosing for 14 
Last 
dose
Last 
dose
Figure 19:a) Pharmacokinetics of repeated PF-04457845 administration in healthy human subjects.  b) 
Pharmacodynamics of repeated PF-04457845 administration in healthy human subjects.
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Cognitive safety data: PF-04457845 was not 
associated with changes in cognitive function in 
healthy adults when given over 14 days 
(Figure 20). The cognitive effects of PF-
04457845 were investigated in study 
B0541002 by CogState Ltd. The study was a 
phase 1, double-blind (Coordinating Center 
open), randomized, placebo-controlled, parallel 
group, oral multiple-dose trial to evaluate the 
safety, tolerability, pharmacokinetics and 
pharmacodynamics of PF-04457845 in healthy 
volunteers. The CogState test battery 
consisted of a series of computerized tasks 
that assessed a range of cognitive functions. 
Cognitive functions assessed included 
psychomotor function, visual attention, learning, 
executive function, and delayed recall, as well as a global measure of cognition across domains 
(i.e., composite). Each test administration was completed in approximately 15 minutes. 
Participants were assessed 15 times (including 2 practice sessions at screening). Across a wide 
dose range, including the dose proposed in this study, given over 14 days PF-04457845 was 
not associated with changes in cognitive function in healthy adults when given over 14 days. 
Phase 2A (Osteoarthritis): Pfizer conducted a phase 2a randomized, double-blinded, double-
dummy, placebo- and active-controlled, 2-way cross-over, flare-enriched multi-center clinical 
trial to examine the pain relief produced by 2 weeks of daily oral administration of PF-04457845 
in patients with osteoarthritis of the knee. PF-04457845 was well tolerated in patients with OA, 
with a safety profile that was indistinguishable from placebo. The study was conducted in 5 
centers in Canada, Sweden, and the United States of America and randomized 76 participants. 
During the study, no participant died or had a Serious Adverse Event (SAE). No participant was 
permanently withdrawn due to an Adverse Event (AE). A total of 136 AEs (all causalities) were 
reported in 51%, 58%, and 51% of participants treated with PF-04457845, naproxen, and 
placebo, respectively. There were no clinically significant trends or clinically significant 
abnormalities in clinical laboratory tests, vital signs measurements, or ECG findings. Most AEs 
were mild in severity; 31 AEs were moderate, and 2 AEs were severe (nightmare and headache 
in the placebo treatment group).
In 
general, 
Figure 20: Effects of 5 doses of PF-04457845 on 
cognitive test performance over time in healthy 
individuals. Composite score performance remained 
within plus or minus one standard deviation unit across 
the study period.
Table 14: Treatment Emergent Adverse Events Reported in a ≥5% of Subjects in Any Treatment 
Group - All Causality/Treatment-Related
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AEs were infrequent and there were no clear differences among treatment groups. The most 
frequently reported all-causality AEs across treatment groups were upper respiratory tract 
infection, headache, diarrhea, and back pain (Table 14).
The most frequently reported treatment-related AEs across all treatment groups were 
headache, fatigue, and constipation, none of which were judged by the investigator to be related 
to PF-04457845. The only commonly reported treatment-emergent AE that was also judged 
related to PF-04457845 was dizziness, which occurred in 1 participant. Treatment-related AEs 
were more commonly reported in the naproxen treatment group than in the PF-04457845 
treatment group. The most common adverse events are presented in Table 14. There were no 
serious adverse events, or adverse events that caused functional un-blinding and no 
cannabinoid-type events.
Phase 2A (Cannabis Use Disorder): Details of the study design are provided (earlier). Of 218 
DSM-IV cannabis dependent males screened, 70 participants were randomized (Figure 5) and 
58 completed the treatment phase of the study. Participation of the last two participants who 
would have met the target of 60 completers was terminated shortly after learning of the outcome 
of the phase I trial of BIA 10-2474 (see below).
 Clinical laboratory tests for safety completed at screening, during inpatient stay (Day 0, 
Day 4), at all weekly appointments during treatment, and during follow up phase (Week 8). 
Participants monitored by inpatient nursing and research staff during the ~1 week long inpatient 
phase. Participants were evaluated by a study doctor at all outpatient visits. There were no 
serious adverse events associated with this trial. The rates of minor adverse events were no 
different between the 2 groups (Table 8). The DSMB met every 6 months and had no concerns 
nor recommendations.
Premature discontinuation of the Proof of Concept (POC) Trial: On 1/18/2016, we halted our 
POC trial voluntarily after learning about the neurological SAEs that occurred during Biotrial’s 
FAAH Inhibitor study (BIA 10-2474) in France. At the time, there was very limited information 
available about the structure of the drug, its pharmacodynamics, or the doses that were being 
tested, and whether BIA 10-2474 shared any similarities with PF-04457845 and other FAAH-
Inhibitors in development. Because of this, we halted our trial out of an abundance of caution. 
Two participants were participating in the inpatient treatment portion of the study at that time, so 
the principal investigator discontinued their participation the same day. The two participants 
were examined and provided with information about the SAEs that occurred in the other clinical 
trial, and given the opportunity to ask questions. In addition to putting our trial on hold, we 
notified our IRB and DSMB within 24 hours of learning of these events. In February 2016, the 
FDA put all trials using FAAH inhibitors on a full clinical hold while the events related to BIA 10-
2474 were investigated.
As more information became available, it became clear that these SAEs were likely a result 
of off-target effects, rather than due to FAAH Inhibition. None of the participants that have 
completed the trial here at Yale have had similar side effects. Similarly, other pharmaceutical 
companies that manufacture FAAH inhibitors such as Merck, Johnson & Johnson, Sanofi, and 
Vernalis have not observed neurological side effects similar to BIA 10-2474 in any of their trials. 
In September 2016, the FDA completed their review of the events at Biotrial in France and 
removed the full clinical hold on FAAH inhibitors in the US. They released this statement before 
removing the hold:
“The U.S. Food and Drug Administration, with information received from the European 
Medicines Agency (EMA) and the French national medicines agency (ANSM), has completed a 
comprehensive review of safety information relevant to the investigational new drug BIA 10-
2474 and the potential implications for related drugs under investigation in the U.S. The Agency 
has found, based on the available information, that BIA 10-2474 exhibits a unique toxicity that 
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does not extend to other drugs in the class, called fatty acid amide hydrolase (FAAH) inhibitors. 
There are no clinical trials with BIA 10-2474 underway in the U.S. The first phase 1 clinical trial 
of BIA 10-2474 was conducted in France in January, 2016, and resulted in the death of one 
enrolled participant and hospitalization of 5 others. Four of these 5 participants experienced 
neurological injury. Based on these findings, the FDA is working with Coordinating Centers to 
establish the appropriate path forward for FAAH inhibitors under investigation in the U.S. We 
are also working to ensure healthy participants, patients, and investigators participating in FAAH 
inhibitor clinical trials are fully informed of the risks and potential benefits of these experimental 
therapies.”
Phase 2A (PTSD): Of the 80 participants screened for this study, 27 participants have 
completed all three test days. This study was designed to study whether the administration of 
PF-04457845 will facilitate extinction learning in healthy control participants and participants 
with a diagnosis of PTSD. Comprised of three test days, the first day has two phases: 
habituation, during which the participants are familiarized with the testing apparatus and 
conditioned stimuli, and acquisition, in which the positive conditioned stimulus is paired with the 
unconditioned stimulus, an electric shock delivered by a Biopac 150. The second day has two 
phases: drug administration, in which PF-04457845 or placebo will be administered prior to the 
extinction learning phase, FAAH inhibition occurs and endocannabinoid levels rise, and 
extinction learning, in which the association learned in the acquisition phase is weakened or 
eliminated. The third day has one phase; extinction recall, in which participants will be assigned 
to extinction recall, which has different environmental cues. Single doses of PF-0445784 were 
well-tolerated. There were no serious adverse events associated with this study.
11.1.2 Cannabis Withdrawal Symptoms: The typical withdrawal symptoms in humans include: 
cannabis craving, anger, aggression, appetite change, weight loss, irritability, anxiety, 
restlessness, altered sleep, strange dreams and physical discomfort (39, 40, 99, 225). Less 
common symptoms include: chills, depressed mood, stomach pain and sweating. Most 
symptoms appear within 1 day of abstinence, peak within 2–3 days, and resolve within 1–2 
weeks. Two studies evaluated symptom time course for at least four weeks (45 days and 28 
days, respectively). Both studies observed prominent withdrawal symptoms during the initial 
two to three weeks of abstinence, some of which persisted through the entire study period (63, 
70). The findings of these studies suggest that withdrawal symptoms may persist longer than 4 
weeks. Characteristic of a true withdrawal syndrome, abstinence symptoms occur with blind 
discontinuation and resolve with CB1R agonist re- administration. Finally, the administration of 
cannabis or THC attenuates withdrawal symptoms.
These symptoms that people experience when they stop smoking marijuana are uncomfortable 
but not life threatening. The marijuana withdrawal symptoms will be monitored closely. If 
intolerable, participants will be able to withdraw from further study participation. 
11.1.3 Phlebotomy: Bruising, infection and thrombosis can occur during phlebotomy. These 
risks can be minimized by having these procedures performed by experienced personnel using 
good clinical technique. Participants will have no more than 3 oz. of blood drawn over the 
entire study period. These amounts are well within the Red Cross blood standards.
11.1.4 Behavioral/Cognitive Testing: Some participants may experience the behavioral as 
boring or frustrating. Trained research staff will work closely with participants and if necessary 
provide them with breaks.
11.2 Known Potential Benefits: Study participation may facilitate a reduction of cannabis use 
for study participants. Group data collected from this study will also inform the development of 
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this drug for the treatment of CUD, for which there are no currently approved pharmacological 
treatments.
11.3 Assessment of Potential Risks and Benefits: Cannabis is the most widely used illicit 
substance worldwide. In 2009, cannabis was the illicit drug with the highest rate of past year 
dependence or abuse; there were more treatment admissions for cannabis in the US than for 
any other drug including cocaine or heroin. There are no approved pharmacological treatments 
for CUD and as stated in the FOA: “the development of safe and effective medications to treat 
these disorders is an urgent public health need.” Furthermore, in keeping with the expectation 
stated in the FOA the proposed study represents a collaboration with the pharmaceutical 
industry. 
In the completed phase 2A study, PF-04457845 reduced cannabis withdrawal, reduced self-
reported cannabis use, reduced urinary levels of THC-COOH and restored stage 3 sleep deficits 
in cannabis dependent individuals with an excellent tolerability and safety profile. For the 
proposed study, the potential risks to participants appear low. Furthermore, the study entails no 
financial or social risk to the participant.
FAAH inhibitors are a new chemical entity. There are very few FAAH-inhibitors that are 
available for use in humans, and none are available commercially. The proposed study has the 
potential to yield important knowledge towards continued development of this treatment 
approach for an unmet need. Therefore, the proposed study has a favorable risk/benefit profile.
11.4 Mitigation of Risk: 
11.4.1 Screening: For the proposed study, participants will be carefully screened to exclude 
participants with any significant medical or psychiatric problems. The screening process is 
rigorous and includes a structured clinical interview for DSM, a psychiatric and medical 
evaluation by a psychiatrist, laboratory tests, EKG, etc. An outside informant specified by the 
participant will be contacted to confirm the history. This process should screen out unsuitable 
participants. 
11.4.2 Effects of PF-04457845: Once enrolled into the study, participants will be seen weekly by 
a clinician. Furthermore, participants will also be contacted almost daily as part of CAORMA and 
this will provide additional information re: tolerability. The research assistant making the 
CAROMA call will pass along to the Investigator or her/his designee any tolerability or safety 
issues discovered on the CAROMA call. Laboratory testing will also be conducted during the 
study to detect any clinically significant changes. At study visits, formal assessment for AEs 
(discussed below) will also be done. These overlapping mechanisms to monitor participants for 
safety should greatly minimize the risk to participants.
11.4.3 Phlebotomy and IV Placement: Bruising, infection and thrombosis can occur when 
phlebotomy is performed. These risks are minimized by having these procedures performed by 
experienced personnel using good clinical technique. Participants who have recently donated 
blood will need to wait for eight weeks before participating in the study. Sterile procedures will 
be followed to minimize the likelihood of infection.
11.4.4 Cannabis Withdrawal: Most symptoms appear within one day of abstinence, peak within 
two to three days, and resolve within one to two weeks. Research staff will be available to 
provide support and reduce anxiety. 
11.4.5 Resumption of cannabis use in cannabis dependent participants who achieve 
abstinence: At the end of the study, interested participants will be offered information to 
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substance use treatment programs in their area. 
12.0 ADVERSE EVENT REPORTING
An AE is defined as any untoward medical occurrence in a clinical investigation participant 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically 
significant abnormal laboratory value), symptom, or disease temporally associated with the use 
of a drug whether or not it is considered related to the drug. All observed or volunteered AEs 
regardless of treatment group or suspected causal relationship to the investigational product(s) 
will be reported as described in the following sections.
The site principal investigator will be responsible for monitoring the data and assuring 
protocol adherence. At a minimum of every six months (including when re-approval of the 
protocol is sought), each site should notify the Coordinating Center of all adverse events. The 
Coordinating Center will then conduct safety reviews across all sites participating in the study. 
During the review process, the study principal investigator and coordinating physician 
investigator (responsible for medical oversight) will evaluate whether the study should continue 
unchanged, require modification/amendment, continue or close to enrollment. Either the study 
principal investigator or institutional review boards overseeing the study have the authority to 
stop or suspend the study or require modifications.
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to the Coordinating Center. For all AEs, sufficient information 
should be obtained by the investigator to determine the causality of the AE. The investigator is 
required to assess causality. Follow-up by the investigator may be required until the event or its 
sequelae resolve or stabilize at a level acceptable to the investigator, and the Coordinating 
Center concurs with that assessment.
As part of ongoing safety reviews conducted by the Coordinating Center, any non-serious 
adverse event that is determined by the Coordinating Center to be serious will be reported by 
the Coordinating Center as a SAE. To assist in the determination of case seriousness further 
information may be requested from the investigator to provide clarity and understanding of the 
event in the context of the clinical trial.
12.1 Reporting Period: For SAEs, the active reporting period begins from the time that the 
participant provides informed consent, which is obtained prior to the participant’s participation in 
the study, through the last follow up visit (end of study visit). Should an investigator be made 
aware of any SAE occurring any time after the active reporting period, it must be promptly 
reported.
12.2 Capturing Adverse Events: Safety and adverse events will be captured using the 
Systematic Assessment for Treatment Emergent Events (SAFTEE) general and specific inquiry 
forms, which take approximately 20 minutes to administer. Collection of adverse events will 
commence from the time the participant signs the informed consent to participate in the study 
and will continue until the last safety follow up visit. At each study visit, the investigator will 
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assess whether any subjective AEs have occurred. A neutral question, such as “How have you 
been feeling since your last visit?” may be asked. Participants may report AEs occurring at any 
other time during the study. All participants experiencing AEs, whether considered associated 
with the use of the study drug or not, must be monitored until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to Baseline or until there is a 
satisfactory explanation for the changes observed. All AEs will be documented, whether or not 
the investigator concludes that the event is related to the drug treatment. Any medical condition 
that is present at the time that the participant is screened will be considered as baseline and not 
reported as an AE. However, if the study participant’s condition deteriorates at any time during 
the study, it will be recorded as an AE.
The following information will be documented for each event:
1. Event term.
2. Start and stop date and time.
3. Pattern of AE (Frequency).
4. Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of 
study drug(s) (related or not related).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the 
details of the suspected procedure.
7. Action concerning study drug.
8. Outcome of event.
9. Seriousness.
The different categories of intensity (severity) are characterized as follows:

Mild: The event is transient and easily tolerated by the participant. The event does not 
generally interfere with usual activities of daily living.

Moderate: An AE that is usually alleviated with additional specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research participant.

Severe: An AE that interrupts usual activities of daily living, significantly affects clinical 
status, or may require intensive therapeutic intervention, and are usually potentially life-
threatening or incapacitating. The term “severe” does not necessarily equate to “serious”.
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily a serious event. For example, a headache may be severe (interferes significantly 
with participant’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
Action Concerning the Study Drug: For every adverse event, the action taken concerning the 
study drug will be documented on the source document. 

Drug withdrawn: a study drug is stopped due to the particular AE.

Dose not changed: the particular AE did not require stopping a study drug.

Unknown: only use if it has not been possible to determine what action has been taken.

Not Applicable: study drug was stopped for a reason other than the particular AE (the 
study has been terminated, the participant died, dosing with study drug was already stopped 
before the onset of the AE)

Dose Interrupted: the dose was interrupted due to the particular AE.
12.3 Assigning Causality of Adverse Events: Causality to study procedures should be 
determined for all adverse events. The degree of certainty about causality will be graded using 
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the categories below. In a clinical trial, the study product must always be suspect.

Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study intervention (dechallenge) should be 
clinically plausible. The event must be pharmacologically or phenomenologically definitive, 
with use of a satisfactory rechallenge procedure if necessary.

Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time after administration of the study intervention, is unlikely to 
be attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (dechallenge). Rechallenge information is not required 
to fulfill this definition.

Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate.

Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments).

Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician.
The investigator’s assessment of causality must be provided for all AEs (serious and
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse reporting requirements 
if applicable. An investigator’s causality assessment is the determination of whether there exists 
a reasonable possibility that the investigational product caused or contributed to an AE; 
generally the facts (evidence) or arguments to suggest a causal relationship should be provided. 
If the investigator does not know whether or not the investigational product caused the event, 
then the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the Coordinating Center If the investigator’s causality assessment is “unknown but 
not related to investigational product”, this should be clearly documented on study records.
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable. Adverse events will be monitored for each participant participating in 
the study and attributed to the study procedures / design by the study principal investigator 
(Deepak Cyril D’Souza) according to the following categories:

Definite: Adverse event is clearly related to investigational procedures(s)/agent(s).

Probable: Adverse event is likely related to investigational procedures(s)/agent(s). 

Possible: Adverse event may be related to investigational procedures(s)/agent(s).

Unlikely: Adverse event is likely not to be related to the investigational 
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procedures(s)/agent(s). 

Unrelated: Adverse event is clearly not related to investigational procedures(s)/agent(s).
12.4 Adverse Event Outcome: For every adverse event, the outcome must be documented in 
the source document as one of the following.

Recovered/resolved – participant returned to first assessment status with respect to the 
AE.

Recovering/resolving – the intensity is lowered by 1 or more stages; the diagnosis or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but 
has not returned to the normal range or Baseline; the participant died from a cause other 
than the particular AE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs, or symptoms; the 
intensity of the diagnosis, signs/symptoms, or laboratory value on the last day of the 
observed study period has got worse than when it started; is an irreversible congenital 
anomaly; the participant died from another cause with the particular AE state remaining 
“not recovered/not resolved”.

Resolved with sequelae – the participant recovered from an acute AE but was left with 
permanent/significant impairment (e.g., recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – the AEs are considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or 
residence change at the end of the participant’s participation in the study.
The overall principal investigator will conduct a review of all adverse events upon completion of 
every study participant. The principal investigator will evaluate the frequency and severity of the 
adverse events and determine if modifications to the protocol or consent form are required.
12.5 Pre-Existing Conditions: Pre-existing conditions, present at the time of signing informed 
consent, are considered to be concurrent medical conditions and should not be recorded as 
adverse events. All pre-existing conditions and their severity need to be documented at the time 
of the screening visit. If the participant experiences a worsening or complication of such a 
concurrent medical condition, the worsening or complication should be recorded appropriately 
as an adverse event. Investigators should ensure that the event term recorded captures the 
change in the condition. 
12.6 Worsening of Adverse Events: If the participant experiences a worsening or complication 
of an AE after the first administration of study drug or any change in study drug, the worsening or 
complication should be recorded as a new AE. Investigators should ensure that the AE term 
recorded captures the change in the condition (e.g., “worsening of…”).
12.7 Serious Adverse Events: An SAE is defined as any untoward medical occurrence that at 
any dose:
1.
Results in death.
2.
Is life threatening.

The term “life threatening” refers to an event in which the participant was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe.
3.
Requires inpatient hospitalization or prolongation of existing hospitalization.
4.
Results in persistent or significant disability/incapacity.
5.
Is a congenital anomaly/birth defect.
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6.
Is an important medical event that a) may require intervention to prevent items 1 through 5 
above, or b) may expose the participant to danger, even though the event is not 
immediately life threatening or fatal or does not result in hospitalization
Each adverse event is to be assessed to determine if it meets the criteria for a serious 
adverse event. An adverse event may be graded as severe but still not meet the criteria for a 
Serious Adverse Event. Similarly, an adverse event may be graded as moderate but still meet 
the criteria for an SAE. It is important for the PI to consider the grade of the event as well as its 
“seriousness” when determining whether reporting to the HIC or HSC is necessary.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life-threatening and/or result 
in death or hospitalization. However, if it is determined that the event may jeopardize the 
participant or may require intervention to prevent one of the other AE outcomes, the important 
medical event should be reported as serious. Examples of such events are intensive treatment 
in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse.
12.8 Follow-up of Serious Adverse Events: If information not available at the time of the first 
report becomes available at a later date, the investigator should complete a follow-up SAE form 
or provide other written documentation and notify the Coordinating Center within 24 hours of 
receipt. Copies of any relevant data from the hospital notes (e.g., ECGs, laboratory tests, 
discharge summary, postmortem results) should be sent to the addressee, if requested. All 
SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
12.9 Serious Adverse Event Reporting Requirements: If an SAE occurs, the Coordinating 
Center is to be notified within 24 hours of investigator awareness of the event, using a standard 
reporting form (e.g. local institutional SAE form, CIOMS, MedWatch 3500a, or similar), 
regardless of the suspected causal relationship between the SAE and the study drug. In 
particular, if the SAE is fatal or life-threatening, notification to must be made immediately, 
irrespective of the extent of available AE information. This timeframe also applies to additional 
new information (follow-up) on previously forwarded SAE reports. In the rare event that the 
investigator does not become aware of the occurrence of an SAE immediately (e.g., if an 
outpatient study participant initially seeks treatment elsewhere), the investigator is to report the 
event within 24 hours after learning of it and document the time of his/her first awareness of the 
AE. The Coordinating Center will submit any SAE report to Jazz Pharmaceuticals via email 
(AEReporting@Jazzpharma.com) on behalf of the investigator within 1 business day after it was 
received at the Coordinating Center.
For all SAEs, the investigator is obligated to pursue and provide information to the 
Coordinating Center in accordance with the timeframes for reporting specified above. In 
addition, an investigator may be requested to obtain specific additional follow-up information in 
an expedited fashion. This information collected for SAEs is more detailed than that captured on 
the AE source document. In general, this will include a description of the AE in sufficient detail 
to allow for a complete medical assessment of the case and independent determination of 
possible causality. Information on other possible causes of the event, such as concomitant 
medications and illnesses must be provided. In the case of a participant death, a summary of 
available autopsy findings must be submitted as soon as possible to the Coordinating Center. 
12.10 Pregnancy Reporting Requirements: In the case of a pregnancy in a female participant 
or a female partner of a male participant, the site must notify the Coordinating Center within 24 
hours of awareness. The Coordinating Center will report to Jazz Pharmaceuticals via email 
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(AEReporting@jazzpharma.com) using the Jazz Pregnancy Query Form within 1 business day 
after receiving notification from the site. The Pregnancy Query Form must be further completed 
and sent to Jazz Pharmaceuticals via email (AEReporting@jazzpharma.com) as additional 
details of the pregnancy become available, and at the time that the outcome of the pregnancy is 
known. The pregnancy should be followed up to determine outcome (including spontaneous or 
voluntary termination), details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications.
While pregnancy itself is not considered an AE or SAE, any pregnancy complications or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. An 
abnormal pregnancy outcome (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy, etc.) are considered SAEs and will be reported as such.
12.11 Safety Reporting to Investigators, IRBs, and Regulatory Authorities: The 
Coordinating Center will be responsible for reporting all suspected unexpected serious adverse 
reactions (SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and 
IRBs, as applicable. All SAEs will be reported to NIDA within 72 hours of the principal 
investigator becoming aware of the event. The Coordinating Center will also prepare an 
expedited report for other safety issues where these might materially alter the current benefit-
risk assessment of a study drug or that would be sufficient to consider changes in the study 
drug administration or in the overall conduct of the trial. The study site also will forward a copy 
of all expedited reports to his or her IRB in accordance with local regulations.
The primary responsibility for monitoring data and safety will lie with the principal 
investigator (Deepak Cyril D’Souza), along with the site investigators and the research team. 
Each local investigator will meet with the research team at least once per week to discuss the 
safety of the study. The study principal investigator (Deepak Cyril D’Souza) will conduct a 
review of all adverse events upon completion of every study participant. The principal 
investigator will evaluate the frequency and severity of the adverse events and determine if 
modifications to the protocol or consent form are required.
As recommended the Serious Adverse Event Reporting and Tracking System (SAETRSII) 
will be used when reporting to NIDA.

Actions of the Yale Human Investigations Committee will be reported to NIDA within 10 
days of receipt of such correspondence from the Yale HIC.

Changes or major amendments to the protocol will also be reported to the NIDA SO 
and PO for their approval prior to implementation.
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13.0 UNANTICIPATED PROBLEMS
13.1 Definition of Unanticipated Problems: The Office for Human Research Protections 
(OHRP) considers unanticipated problems involving risks to participants or others to include, in 
general, any incident, experience, or outcome that meets all of the following criteria:

Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied;

Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and

Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized.
13.2 Unanticipated Problem Reporting: The investigator will report unanticipated problems 
(UPs) to the reviewing Institutional Review Board (IRB) and to the Data Coordinating Center 
(DCC)/lead principal investigator (PI). The UP report will include the following information:

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.
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:

UPs that are serious adverse events (SAEs) will be reported to the IRB and to the 
DCC/study Coordinating Center within 48 hours of the investigator becoming aware of 
the event.

Any other UP will be reported to the IRB and to the DCC/study Coordinating Center 
within 5 days of the investigator becoming aware of the problem.

All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), 
and the Office for Human Research Protections (OHRP) within 5 days of the IRB’s 
receipt of the report of the problem from the investigator.]
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14.0 STATISTICAL METHODS
All data obtained during the course of the study will be uploaded to an electronic database 
created by the Yale Center for Analytical Sciences (YCAS). Baseline and demographic data will 
be summarized for all treatment groups, and summary statistics will be provided by treatment 
group for the primary and all secondary outcomes. Treatment compliance measures and 
retention in treatment will be calculated by group and time and presented in tabular form. The 
full analysis set will be based on the modified Intent-To-Treat (ITT) principle, consisting of all 
participants who receive at least one dose of randomized study medication, and have a baseline 
and at least one post-baseline measurement. The per-protocol population will include all 
participants in the full analysis set but without any major protocol violations. Analyses of the per-
protocol population will be considered secondary. The data will first be scanned for potential 
outliers. All outliers will be double-checked prior to analysis and as necessary, sensitivity 
analyses without outliers will be performed. Descriptive statistics (mean, standard deviation, 
range, frequency) will be computed for each variable first and presented in tabular form. 
Continuous variables will be checked for normality using normal probability plots and 
Kolmogorov-Smirnov tests. In case of non-normal distribution, transformations will be applied or 
non-parametric tests (226) will be used as necessary. A significance cutoff of 0.05 will be used 
to test the primary hypothesis whereas analyses of secondary outcomes will be adjusted using 
the Bonferroni-Holm procedure. Effect sizes and associated 95% confidence intervals will be 
calculated for the primary and all secondary outcomes in order to inform the design of future 
studies. All analyses will be performed in the latest version of SAS software. 
14.1 Sample Size Determination: Since there are no published studies on the effect of FAAH 
inhibitors on cannabis use reduction in humans, we estimated the expected size of the effect of 
PF-04457845 on cannabis use based on a subsample of participants from the completed Phase 
2A study. In the phase 2A study we forced everyone into abstinence by hospitalizing them for 
one week. The proposed study design is different: participants are neither hospitalized nor 
forced into abstinence, which is more ecologically valid and consistent with most treatments for 
CUD being outpatient. Therefore, to estimate the expected size of the effect of PF-04457845 on 
cannabis use, we selected a subsample of participants from the preliminary study whose use of 
cannabis during the first week after being hospitalized continued to be high enough to meet the 
met the inclusion criteria of the original study of using >1 joint/day. Analyses revealed that the 
effect size of the difference in cannabis use by the end of the study was medium-small (d=0.42). 
To detect such an effect size with 80% power, we require a sample size of 178 participants 
assuming two-sided alpha = 0.05. Based on the completed study, and the experience of the 3 
other sites a ~25% dropout rate is expected and therefore, 237 participants will need to be 
studied to obtain complete data in 178 participants. 
14.2 Efficacy Analysis: 
14.2.1 Primary Outcome: To test the efficacy of PF-04457845 treatment on cannabis use the 
group (placebo vs. active) differences in change from baseline use in the average number of 
times per day of self-reported consumption of cannabis or a cannabis containing product will be 
tested using ANCOVA with treatment group as the main predictor of interest  and stratification 
variables (site [4 sites] and degree of cannabis exposure [medium and high] = 8 strata) as 
additional factors in the model. Multiple imputation of outcome data will be performed using 
PROC MI in SAS using regression imputation with baseline average number of times per day, 
treatment and baseline participant-level characteristics (age, sex, cannabis use, tobacco use, 
alcohol use) as predictors in the imputation model. Significantly higher change from baseline in 
the active group compared to the placebo group at 0.05 significance level will be considered 
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supportive of our hypothesis. In addition to statistical testing, we will present least square mean 
estimates with 95% confidence limits for change from baseline by treatment group. We will also 
present estimates of treatment effects by site and baseline degree of cannabis exposure (high 
user or medium user) and evaluate whether treatment effects vary significantly by stratification 
factor (this assessment will be secondary to the primary evaluation of average treatment effects 
across strata). Other secondary and sensitivity analyses of the primary outcome include: (1) 
mixed model analysis with average number of times per day of self-reported consumption of 
cannabis or a cannabis containing product as the outcome, treatment group (active vs. 
placebo), site (4 levels), degree of cannabis exposure (medium, high) as between-participant 
factors, and time (baseline, first four weeks of the treatment period, last four weeks of the 
treatment period) as a within-participant factor; (2) tipping point analysis to assess sensitivity of 
conclusions to assumptions about missing data; (3) analyses of the per-protocol sample. In the 
mixed model analysis all available data on individuals will be used and the best fitting variance-
covariance structure (among compound symmetry, compound symmetry heterogeneous, 
autoregressive of first order (AR(1)), autoregressive heterogeneous (ARH(1)), and unstructured) 
will be selected using Schwarz’s Bayesian Criterion (BIC). Post-hoc analyses will provide 
information about treatment effect across the different time points, and the potential influence of 
the data collection site and baseline degree of cannabis exposure on the outcome trajectories. 
Additional exploratory analyses will be conducted to assess the effect of gender, desire to quit, 
lifetime cannabis use, tobacco use, alcohol use, and other drug use on the outcomes by 
including them into the models. Mixed models use all available data and are unaffected by data 
missing at random. Sensitivity analyses under missing not at random assumptions will also be 
performed. 
14.2.2 Secondary Outcomes: The same analytic strategy will be followed for secondary 
outcomes compared to the primary outcome. Primary analyses will be based on ANCOVA with 
multiple imputation on the modified intent-to-treat sample, secondary analyses will include 
mixed models, tipping point analyses and analyses of the per protocol sample. The emphasis 
will be on effect estimation. Testing in the primary analyses will be adjusted using the 
Bonferroni-Holm method. For each eCB, plasma levels will be assessed by fitting a mixed 
effects model with treatment, time, site, and the interaction terms as fixed effects, and tobacco 
use as covariate. Exploratory analyses will be conducted to assess the effect of variables such 
as gender and use of other substances on endocannabinoids. Since we expect floor effects for 
the blood levels of PF-04457845 in the placebo condition, PF-04457845 blood level will be 
assessed by using non-parametric models (226, 227) with treatment, time, site, and the 
interaction terms as factors. 
14.3 Safety Analysis: The review and summary of safety will be performed on the modified 
intent-to-treat sample. Events or abnormalities will be searched from the time of the first dose 
until 5 half-lives after the last dose. Clinical laboratory data will be summarized quantitatively 
using descriptive statistics such as changes from baseline summarized by mean, standard 
deviation, median, minimum and maximum, and summarized qualitatively by tabulating clinical 
abnormalities. Vital signs, BMI, weight will be summarized using descriptive statistics. Group 
differences in the percentage of participants who report AEs or exhibit clinically significant 
changes during 1) 8-week treatment phase (from the first dose until the last dose), and 2) the 4-
week follow up phase (to assess any lingering post treatment safety issues) will be summarized 
in tabular form and presented. Data permitting, exploratory analyses may be performed to 
evaluate the statistical significance of between-group differences (e.g. using Fisher’s exact tests 
for adverse events, t-tests or non-parametric equivalent for changes in continuous measures) 
and evaluation of the effects of duration of drug exposure or drug dose on any adverse events 
(e.g. using exact logistic regression) and laboratory measures (e.g. using mixed effects models).
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15.0 DATA HANDLING AND RECORDKEEPING
15.1 Case Report Forms: As used in this protocol, the term CRF should be understood to refer 
to either a paper form or an electronic data record or both, depending on the data collection 
method used in this study.
A CRF is required and should be completed for each included participant. The completed 
original CRFs should not be made available in any form to third parties, without written 
permission from the Coordinating Center. The investigator has ultimate responsibility for the 
collection and reporting of all clinical, safety and laboratory data entered on the CRFs and any 
other data collection forms (source documents) and ensuring that they are accurate, authentic / 
original, attributable, complete, consistent, legible, timely (contemporaneous), enduring and 
available when required. The CRFs must be signed by the investigator or by an authorized staff 
member to attest that the data contained on the CRFs is true. Any corrections to entries made in 
the CRFs, source documents must be dated, initialed and explained (if necessary) and should 
not obscure the original entry.
In most cases the source documents are the hospital or the physician's chart. In these 
cases, data collected on the CRFs must match those charts. In some cases, the CRF may also 
serve as the source document. In these cases, a document should be available at the 
investigator’s site and clearly identify those data that will be recorded in the CRF, and for which 
the CRF will stand as the source document.
The Coordinating Center will supply study sites with access to CRFs. The Coordinating 
Center will make arrangements to train appropriate site staff in the use of the CRF. These forms 
are used to transmit the information collected in the performance of this study to the 
Coordinating Center and regulatory authorities. CRFs must be completed in English.
15.2 Data Entry: Each site will be responsible for entering data into the electronic data base. 
After completion of the data entry process, computer logic checks will be run to identify items, 
such as inconsistent dates, missing data, and questionable values. Queries may be issued by 
the Coordinating Center and will need to be answered by the site.
Corrections will be recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was 
made, and the reason for change. The principal investigator must review both the paper and 
electronic CRFs for completeness and accuracy. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the CRFs.
After all data for a participant has been entered electronically, the data will be locked. Any 
change of, modification of, or addition to the data on the CRFs should be made by the 
investigator with use of change and modification records of the CRFs. The principal investigator 
must review the data change for completeness and accuracy, and must e-sign and date the 
electronic eCRFs.
15.3 Record Retention: The investigator will have to agree to keep all study-specific 
documents, the identification log of all participating participants, medical records, temporary 
media such as thermal sensitive paper, source worksheets, all original signed and dated 
informed consent forms, participant authorization forms regarding the use of personal health 
information (if separate from the informed consent forms), copies of all paper CRFs and query 
responses/electronic copy of eCRFs, including the audit trail, and detailed records of drug 
disposition to enable evaluations or audits from regulatory authorities or from the Coordinating 
Center or designees. Any source documentation printed on degradable thermal sensitive paper 
should be photocopied by the site and filed with the original in the participant’s chart to ensure 
long-term legibility.
All study records should be retained by the investigator according to local regulations, or 
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as specified by the study principal investigator, whichever is longer. 
15.4 Genetic Samples: Results of genetic tests will not be available to the participant, nor will 
we add them to medical records. (If a participant wants to know their risk for genetic diseases, 
we will refer them to a genetic counselor.) Additionally, the biological materials collected will be 
identified by code number rather than by name to maintain confidentiality. These procedures 
should prevent any confidential information from becoming known to anyone other than the 
scientists and research staff involved in this study. We believe that the chance of this 
information becoming known to others in such a way that it would be harmful to study 
participants is small.
All samples will be identified by a code number and will never been coded with any PHI. 
Once samples have been sent to be analyzed, the individuals working at the laboratory will not 
have access to the link between the names and the code numbers. This link between the 
names and code numbers will be held by the investigator for seven years after the research has 
been completed after which time the link will be destroyed and the data will be kept for an 
indefinite amount of time. 
In the event that the materials collected for this project are shared or distributed for future 
research, they will first be stripped of any identifying information before distribution. Any material 
will only be shared in the event that another investigator provides a written request for the 
materials. In this request, the inquiring investigator must provide a hypothesis and specific aims 
that are deemed as appropriate by this investigator. Furthermore, the inquiring investigator must 
ensure this investigator that the same protections will be afforded to the genetic information and 
that the requesting investigator adhere to appropriate confidentiality guidelines. It is only then 
that materials will be shared or distributed.
15.5 Publication and Data Sharing: This study will be conducted in accordance with the 
following publication and data sharing policies and regulations: 
National Institutes of Health (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. 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of 
NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results 
Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and 
results information from this trial will be submitted to ClinicalTrials.gov. In addition, every 
attempt will be made to publish results in peer-reviewed journals. Data from this study may be 
requested from other researchers 3 years after the completion of the primary endpoint by 
contacting the study principal investigator. 
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16.0 QUALITY CONTROL AND QUALITY ASSURANCE
16.1 Study Site Monitoring Visits: Monitoring visits to the study site will be conducted 
periodically during the study by the Yale Center for Clinical Investigation (YCCI) or similar 
organization to ensure that all aspects of the protocol are followed. Source documents will be 
reviewed for verification of data recorded on the eCRFs. Source documents are defined as 
original documents, data, and records. The investigator and the study site guarantee access to 
source documents by the Coordinating Center or designee and by the IRB.
All aspects of the study and its documentation will be reviewed by the Coordinating Center 
or designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study drug, participant medical records, informed consent documentation, 
documentation of participant authorization to use personal health information (if separate from 
the informed consent forms), and eCRFs and associated source documents. It is important that 
the investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process.
16.2 Data Monitoring: A data monitoring plan will be developed to assess the data in an 
ongoing manner over the course of the study to ensure validity and integrity of key study 
endpoint data.
16.3 Protocol Deviations: Should it become necessary to deviate from the protocol in order to 
eliminate an immediate hazard to study participants or some other unexpected circumstances 
arises, the investigator should consult with the Coordinating Center or designee and if 
necessary the IRB to determine the appropriate course of action. 
The site should document all protocol deviations in the participant’s source documents. In the 
event of an important protocol deviation, the site should notify the Coordinating Center or 
designee (and IRB as required). Important deviations include, but are not limited to, those that 
involve fraud or misconduct, increase the health risk to the participant, or confound 
interpretation of primary study assessment. Important protocol deviations will be reviewed at 
regular intervals by the Coordinating Center and designee.
16.4 Quality Assurance Audits and Regulatory Agency Inspections: The study site also 
may be participant to quality assurance audits by the Coordinating Center or designees. In this 
circumstance, the Coordinating Center -designated auditor e.g., YCCI will contact the site in 
advance to arrange an auditing visit. The auditor may ask to visit the facilities where laboratory 
samples are collected, where study drug is stored and prepared, and any other facility used 
during the study. In addition, there is the possibility that this study may be inspected by 
regulatory agencies, including: the Food and Drug Administration (FDA), the National Institute of 
Drug Abuse (NIDA). If the study site is contacted for an inspection by a regulatory body, the 
Coordinating Center should be notified immediately.
16.5 Data Monitoring Committee: This study does not include endpoints related to assessing 
mortality or major adverse health outcomes, and the study population is not at expected risk of 
serious safety events. The NIDA data and safety monitoring board (DSMB) that is independent 
of the study and project teams will periodically review unblinded safety data during conduct of 
the study to complement the routine safety monitoring approach for drugs at this stage of 
development. The NIDA DSMB will meet at least semiannually, but may meet more frequently if 
deemed necessary, to assess safety and efficacy data. The NIDA DSMB will provide its input to 
the Coordinating Center. A report of the NIDA DSMB meetings will be prepared and circulated 
to the IRBs and NIDA. 
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16.6 Study Discontinuation and Closure: 
16.6.1 Criteria for Premature Termination or Suspension of the Study: The study will be 
completed as planned unless one or more of the following criteria are satisfied that require 
temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study 
drug that indicates a change in the known risk/benefit profile for the compound, 
such that the risk/benefit is no longer acceptable for participants participating in the 
study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objectives or compromises participant safety.
16.6.2 Criteria for Premature Termination or Suspension of Study Sites: A study site may be 
terminated prematurely or suspended if the site (including the investigator) is found in significant 
violation of GCP, protocol, or contractual agreement, is unable to ensure adequate performance 
of the study, or as otherwise permitted by the contractual agreement.
16.6.3 Procedures for Premature Termination or Suspension of the Study or the Participation of 
Study Sites: In the event that the Coordinating Center, an institutional review board (IRB), or 
regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the overall principal investigator; the procedure will be followed by the 
investigational site during the course of termination or study suspension. The principal 
investigator will promptly inform study participants, the institutional review board, and 
Coordinating Center, and will provide the reason(s) for termination or suspension. Study 
participants will be contacted, as applicable, and be informed of changes to the study visit 
schedule.
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17.0 ETHICAL ASPECTS OF THE STUDY
                                                                                                                                                                                 
This study will be conducted in accordance with the International Ethical Guidelines for 
Biomedical Research Involving Human Participants (Council for International Organizations of 
Medical Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki 
(World Medical Association 2008). Each investigator will conduct the study according to 
applicable local or regional regulatory requirements and align his or her conduct in accordance 
with the “Responsibilities of the Investigator” that are listed in Appendix J. 
17.1 IRB Approval: It is the responsibility of the investigator to have prospective approval of the 
study protocol, protocol amendments, informed consent documents, and other relevant 
documents, e.g., recruitment advertisements, if applicable, from the IRB. All correspondence 
with the IRB should be retained in the Investigator File. Copies of IRB approvals should be 
forwarded to the Coordinating Center. The only circumstance in which an amendment may be 
initiated prior to IRB approval is where the change is necessary to eliminate apparent immediate 
hazards to the participants. In that event, the investigator must notify the IRB and the 
Coordinating Center in writing immediately after the implementation.
The Coordinating Center or designee will require documentation noting all names and 
titles of members who make up the respective IRB. If any member of the IRB has direct 
participation in this study, written notification regarding his or her abstinence from voting must 
also be obtained. This protocol, the Investigator’s Brochure, a copy of the informed consent 
form, and, if applicable, participant recruitment materials and/or advertisements and other 
documents required by all applicable laws and regulations, must be submitted to the local IRB 
for approval. The IRB’s written approval of the protocol and participant informed consent must 
be obtained and submitted to the Coordinating Center or designee before commencement of 
the study. The IRB approval must refer to the study by exact protocol title, number, and version 
date; identify versions of other documents (e.g., informed consent form) reviewed; and state the 
approval date. The Coordinating Center or designee will ship drug/notify site once the 
Coordinating Center or designee has confirmed the adequacy of site regulatory documentation.
Study sites must adhere to all requirements stipulated by their respective IRB. This may 
include notification to the IRB regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by participants, local safety reporting 
requirements, reports and updates regarding the ongoing review of the study at intervals 
specified by the respective IRB, and submission of the investigator’s final status report to IRB. 
All IRB approvals and relevant documentation for these items must be provided to the 
Coordinating Center or designee.
17.2 Participant Information, Informed Consent, and Participant Authorization: All parties 
will ensure protection of participant personal data and will not include participant names on any 
Coordinating Center forms, reports, publications, or in any other disclosures, except where 
required by laws. Participant names, address, birth date and other identifiable data will be 
replaced by a numerical code consisting of a numbering system provided by the Coordinating 
Center in order to de-identify trial participants. In case of data transfer, the Coordinating Center 
will maintain high standards of confidentiality and protection of participant personal data. 
The Coordinating Center will provide the protocol and consent form that sites can use to 
submit to their IRB. Any substantive changes made to the consent form or protocol provided 
by the Coordinating Center will need approval prior to submission to the local IRB. The 
investigator or her/his designee must ensure that each study participant, or his/her legal 
representative, is fully informed about the nature and objectives of the study and possible risks 
associated with participation. The investigator, or her/his designee, will obtain written informed 
consent from each participant before any study-specific activity is performed. Copies of the 
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signed informed consent form, the signed participant authorization form (if applicable), and 
participant information sheet (if applicable) shall be given to the participant. The site 
investigator will retain the original of each participant’s signed consent document.
All revised informed consent forms must be reviewed and signed by relevant participants or 
the relevant participant’s legally acceptable representative in the same manner as the original 
informed consent. The date the revised consent was obtained should be recorded in the 
participant’s medical record, and the participant should receive a copy of the revised informed 
consent form.
Participants who consented and provided a PGx sample for DNA and RNA analysis can 
withdraw their consent and request disposal of a stored sample at any time prior to analysis. 
The Coordinating Center is to be notified when consent has been withdrawn.
17.3 Participant Confidentiality: The Coordinating Center and designees affirm and uphold 
the principle of the participant’s right to protection against invasion of privacy. Throughout this 
study, a participant’s source data will only be linked to the Coordinating Center’s clinical trial 
database or documentation via a subject ID number. As permitted by all applicable laws and 
regulations, limited participant attributes, such as sex, age, or date of birth, and participant 
initials may be used to verify the participant and accuracy of the participant’s unique ID number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
Coordinating Center requires the investigator to permit the monitor or the Coordinating Center’s 
designee, representatives from any regulatory authority (e.g., FDA, Medicines and Healthcare 
products Regulatory Agency, Pharmaceuticals and Medical Devices Agency), the Coordinating 
Center’s designated auditors, and the appropriate IRBs to review the participant’s original 
medical records (source data or documents), including, but not limited to, laboratory test result 
reports, ECG reports, admission and discharge summaries for hospital admissions occurring 
during a participant’s study participation, and autopsy reports. Access to a participant’s original 
medical records requires the specific authorization of the participant as part of the informed 
consent process. 
Copies of any participant source documents that are provided to the Coordinating Center 
must have certain personally identifiable information removed (ie, participant name, address, 
and other identifier fields not collected on the participant’s eCRF).
There is a risk of loss of confidentiality in this study. All participant information will be kept 
confidential and only members of the investigative team with appropriate IRB/HIC and HIPAA 
training will have access to the study data. Data will be maintained and secured in locked file 
cabinets or password protected electronic media. A numbering code will be used to assign a 
unique identifier to each participant. 
For the Cellphone Assisted Remote Observation of Medication Adherence (CAROMA) 
procedures, participants will be called and observed taking study medications. The CAROMA 
procedure is not recorded, broadcast, nor will the likeness of the participants be used for 
anything other than what has been specified. The potential for loss of confidentiality is if 
someone taps the phone while a call is being made, but this risk is no different from someone 
tapping into a phone (audio) conversation between the participant and the research team. The 
phones used for this practice will be encrypted by sites’ Information Technology Service so that 
loss of confidentiality is minimized. CAROMA was set up with input from Yale ITS in order to 
conform to Yale’s policies.
17.4 Publication and Disclosure: The investigator is obliged to provide the Coordinating 
Center with complete test results and all data derived by the investigator from the study. During 
and after the study, only the Coordinating Center may make study information available to other 
study investigators or to regulatory agencies, except as required by law or regulation. Except as 
otherwise allowable in the study site agreement, any public disclosure (including publicly 
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accessible websites) related to the protocol or study results, other than study recruitment 
materials and/or advertisements, is the sole responsibility of the Coordinating Center. The 
Coordinating Center may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the study site agreement. In the event of any discrepancy 
between the protocol and the study site agreement, the study site agreement will prevail. The 
investigator needs to obtain a prior written approval from the Coordinating Center to publish any 
information from the study externally such as to a professional association.
17.5 Clinical Trials Registration: In order to ensure that information on clinical trials reaches 
the public in a timely manner and to comply with applicable laws, regulations, and guidance, the 
Coordinating Center (Yale University) will register this study on clinicaltrials.gov and will 
maintain the record at a minimum of every 6 months. All sites will be referred to in this record.
17.6 Future Use of Stored Specimens and Data: Data collected for this study will be analyzed 
and stored at the Coordinating Center. After the study is completed, the de-identified, archived 
data will be transmitted to and stored at the FAAH-Inhibitor Phase 2A Study Data Repository, 
for use by other researchers including those outside of the study. Permission to transmit data to 
the FAAH-Inhibitor Phase 2A Study Data will be included in the informed consent. 
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), 
de-identified biological samples will be stored at the FAAH-Inhibitor Phase 2A Study Biosample 
Repository with the same goal as the sharing of data with the FAAH-Inhibitor Phase 2A Study 
Data Repository. These samples could be used to research the causes of cannabis use 
disorder and related conditions, its complications and other conditions for which individuals with 
cannabis use disorder are at increased risk, and to improve treatment. The FAAH-Inhibitor 
Phase 2A Study Biosample Repository will also be provided with a code-link that will allow 
linking the biological specimens with the phenotypic data from each participant, maintaining the 
blinding of the identity of the participant. 
During the conduct of the study, an individual participant can choose to withdraw consent to 
have biological specimens stored for future research. However, withdrawal of consent with 
regard to biosample storage may not be possible after the study is completed. 
When the study is completed, access to study data and/or samples will be provided through the 
FAAH-Inhibitor Phase 2A Study Data Repository.
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18.0 ABBREVIATIONS:
2-AG: 2-arachidonoylglycerol
ABHD6: 2-arachidonoylglycerol hydrolase
AE: Adverse Event
AEA: Anandamide
CAROMA: Cell Phone Assisted Remote Observation of Adherence
CB1R: Cannabinoid Receptor
CBD: Cannabidiol
CBT: Cognitive Behavioral Treatment
CFR: Code of Federal Regulations
CM: Contingency Management
CNS: Central Nervous System
CONSORT: Consolidated Standards of Reporting Trials
C-SSRS: Columbia Suicide Severity Rating Scale
CUD: Cannabis use disorder 
CWS: Cannabinoid Withdrawal Syndrome
DSMB: Data Safety Monitoring Board
eCB: Endocannabinoid System
ECG: Electrocardiogram
FAAH: Fatty Acid Amide Hydrolase Inhibitor
FDA: Food Drug Administration
FTND: Fagerstrom test for Nicotine Dependence
IND: Investigational New Drug
IRB: Institutional Review Board
LEA: N-linoleoylethanolamine
MAG-L: Monoacylglycerol lipase
MCQ-12: Marijuana Craving Questionnaire-Short Form
MET: Motivational Enhancement
MI: Motivational Interviewing
NIH: National Institute of Health
OEA: N-oleoyl ethanolamine
PD: Pharmacodynamics
PD: Plasma Anandamide
PEA: N-palmitoyl ethanolamine
PK: Pharmacokinetics
POC: Proof of Concept
PRISM: Psychiatric Research Interview for Substance and Mental Disorders
PSG: Polysomnography
QD: Once Daily
Q-LES-Q-18: Quality of Life Enjoyment and Satisfaction Questionnaire
SAE: Serious Adverse Event
SAFTEE: Systematic Assessment for Treatment Emergent Events
SALCU: Scale for Assessment of Lifetime Cannabis Use
THC: delta-9-tetrahydrocannabinol
TLFB: Timeline Follow Back
US: United States
VAS: Visual Analog Scale
WOCBP: Women of Childbearing Potential
YCAS: Yale Center for Analytical Studies
YCCI: Yale Center for Clinical Investigation
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19.0 PROTOCOL AMENDMENT HISTORY:
Version
Date
Description of Change
Brief Rationale
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APPENDIX A: STUDY ORGANIZATION CHART

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APPENDIX B: ADVERTISEMENTS
Radio Advertisement: 
Do you smoke marijuana/cannabis? Is it interfering with work or school? If you want to quit 
using marijuana you may be eligible for a paid research study. A research clinic at __(study 
site)__ is studying a medication that may help people quit marijuana/cannabis, __(IRB 
number)__. If you are male or female, between the ages of 18 and 60, smoke 
marijuana/cannabis, and want to quit, please call us at __(phone number)__. All calls and 
information gathered are confidential. Again that’s __(phone number)__.
Online Advertisement: 
Title: SMOKE MARIJUANA/CANNABIS? Want to quit?
Do you smoke marijuana regularly and want to quit?
A research group at __(study site)__ is running a paid clinical trial investigating a 
medication designed to help with the symptoms of marijuana withdrawal. 
Participants must be:

Ages 18-50

In good physical and mental health 

Willing to try quitting marijuana/cannabis for eight weeks
Participants must NOT be: 

Abusing any other drugs or alcohol 
If you would like to try quitting marijuana/cannabis and want more information about 
this study, please call us at (XXX) XXX-XXXX
All information is kept confidential.
IRB # XXXXXXXXXX
Mini-Flier Advertisement:
Full Page Advertisements:
  
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APPENDIX C: PHONE SCREEN QUESTIONNAIRE
Read Verbatim to Participant:
“We would like to ask you some general information to determine whether you might qualify for 
studies at our research group. This information will only be used to determine your eligibility to 
participate in research. This information will be stored in secure research files. If you do not want 
any information about you stored, we will terminate this interview now. If you agree to proceed 
ahead with this preliminary interview and seem to be eligible to participate in this study, we may 
invite you for a face to face meeting. Would you like to continue?”
YES / NO
Name (First Last): _____________________________________________________________
Age at Phone Screen: ___________ DOB: ______________ Gender: ____________________
Phone #1: _____________________ Phone Type: ______________________
Phone #2: _____________________ Phone Type: ______________________
Email Address: __________________________________________________
Preferred contact? Phone #1 / Phone #2 / Email Address
Highest level of education: ________________________
What race do you identify with: _____________________
Are you currently participating in research or within the past 30 days (Details: Where, Meds, 
Blood, etc): YES / NO
____________________________________________________________________________
____________________________________________________________________________
Can we keep your information on file to be able to contact you for future studies: YES / NO
Are you currently working? YES / NO  
If yes, current job: __________________________ How long at current job: _________
If no, why: _____________________________________________________________
Do you have a flexible Schedule: YES / NO 
____________________________________________________________________________
Do you use marijuana/cannabis: YES / NO
How often do you typically use 
marijuana/cannabis:___________________________________________
How much do you spend per month on marijuana/cannabis: 
____________________________________
How long have you smoked at this rate:_____________________________________________
Would you say that marijuana/cannabis is your primary drug of choice (or do you like to use 
anything else with marijuana/cannabis)?  Yes / No 
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About how many drinks do you have a week? What days do you typically drink? What types of 
alcohol do you consume? (determine alcohol for the month): 
____________________________________________________________________________
____________________________________________________________________________
Date of your last drink: ___________________________ 
How many drinks did you have: ____________________
Has alcohol ever been a problem for you: YES / NO   Have you ever had a DWI: YES / NO   
Have you used any other street drugs in the past 3 months? (MJ, Salvia, Spice, Cocaine, 
Heroin, Speed, Hallucinogens, prescription meds recreationally? etc.): Yes / No   
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
Can you remember the last time you quit smoking even if it was just for a few days or weeks 
(why, when, how long, etc.) 
____________________________________________________________________________
____________________________________________________________________________
What street drugs have you used over your lifetime? (MJ, Salvia, Spice, Cocaine, Heroin, 
Speed, Hallucinogens, prescription meds recreationally, etc.)?
How much caffeine do you have per day? __________________________________ 
Do you currently smoke or use tobacco: Yes / No   
How much tobacco do you currently use:______________________________
Were you ever a cigarette smoker? Yes / No When and how much did you use?:____________
Drug
Date of 
last use
Time period of 
Heaviest Use 
Frequency (daily, 
weekly….)
Approx amount per use 
(gram, oz., joint, # pills)
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Do you have any medical problems right now: Yes / No
Do you use any prescription or over the counter medication or vitamins or supplements (type 
and duration)?
____________________________________________________________________________
____________________________________________________________________________
Do you have diabetes: Yes / No   __________________________
Any Surgeries: Yes / No   
(what and when) ______________________________________________________________    
Any seizures or fainting spells: Yes / No   
____________________________________________________________________________
____________________________________________________________________________
Are you allergic to any medications? Yes / No   
____________________________________________________________________________
____________________________________________________________________________
Are you allergic to any food? Yes / No   
____________________________________________________________________________
____________________________________________________________________________
Have you had any medical problems in the past: Yes / No   
If yes, please specify:
Head (Such as: Head Injury? Loss of consciousness or Infection of the brain?)
______________________________________________________________________
Heart (Such as: Heart Attack or Heart disease?)
______________________________________________________________________
Lungs or Asthma (Such as: Lung disease?)
______________________________________________________________________
Liver (Such as: Liver disease?)
______________________________________________________________________
Kidney (Such as: Kidney disease?)
______________________________________________________________________
Stomach (Such as: Intestinal problems?)
______________________________________________________________________
Circulatory (Such as: High blood pressure?)
______________________________________________________________________
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Have you given any blood donations recently: Yes / No When: __________________________
Any other medical issues or important things that we should be aware of? 
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
Have you ever seen a counselor or therapist: Yes / No   
If yes, please explain (Duration, Diagnosis, Time-period, Meds, problem resolved?): 
____________________________________________________________________________
____________________________________________________________________________
Have you ever been hospitalized for any psychiatric, mental, or emotional problems: Yes / No   
If yes, please explain (when, how long, how close to event): 
____________________________________________________________________________
Notes:_______________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
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APPENDIX D: CONSENT QUESTIONNAIRE
This is a questionnaire to help us to test your understanding of the study protocol. For you to 
qualify for this study, you will need to pass this quiz. To pass, you will need to score at least a 
75%, and you will have 2 chances to do so. Incorrect answers on your first attempt will tell us 
those parts of the study you did not understand well, so that we can go over the consent form 
again with you. 
1.
You are invited to participate in this study because of (choose one best response): 
a.
use of heroin
b.
use of cannabis
c.
use of alcohol
d.
use of tobacco
2.
Is this study voluntary?
YES
NO
3.
Once you start the study, are you free to stop at any time?
YES
NO 
4.
Please circle the names of the 2 study medications that you may receive in this study:
TX-12235946
Abilify
Placebo
Thiothixene
PF-04457845
Methadone
5.
What is the chance of you receiving the active study medication?
a.
50:50
c. 30:70
b.
60:40
d. 90:10
6.
Will you be told what medication you have been assigned to take? 
YES
NO
7.
How long will you be asked to take the study medication?
a.
2 weeks
d. 8 weeks
b.
4 weeks
e. 10 weeks
c.
6 weeks
8.
Do you have to pay for the study medication? 
YES
NO
9.
 Will urine be collected for drug testing?
YES
NO
10. Will blood be drawn in this study?
YES
NO
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APPENDIX E: INCLUSION / EXCLUSION CRITERIA CHECKLIST
INCLUSION CRITERIA
1. Ages 18-60 years, inclusive (age verified picture identification). 
Yes       No 
2. Male or Female.
Yes       No 
3. Individuals with DSM-V criteria for CUD of at least moderate severity (≥ 
4 [of 11] symptoms).
Yes       No 
4. Current cannabis consumption greater than or equal to 30 joints/month 
(approximately daily) over the past 3 months
Yes       No 
5. Positive for urinary THC-COOH on two separate occasions during 
screening (> 50ng/ml).
Yes       No 
6. Primary drug of choice cannabis.
Yes       No 
7. Must express a willingness at screening to set a date within the first 
week of randomization to attempt to quit using cannabis.
Yes       No 
8. Physically healthy i.e., no clinically unstable medical conditions at the 
discretion of the investigator.
Yes       No 
9. Have given written informed consent, and have capacity to consent and 
comply with study procedures.
Yes       No 
10.Must be able to read English as per the judgment of the site 
investigators. Participants are required to be able to read because there 
are several self-administered measures that they must read, understand 
and provide written answers.
Yes       No 
11.Must provide the name of at least 1 contact (preferably 2), who would 
assist study staff in locating them during the study period.
Yes       No 
12.For women of childbearing potential (WOCBP) and men, willingness to 
practice birth control and to inform study staff immediately if either they 
(for women) or their partner (for men) becomes pregnant.
Yes       No 
13.Must be willing to complete a number of study assessments and 
procedures remotely. 
Yes       No
EXCLUSION CRITERIA
1.
Clinically significant unstable medical disorders (as determined by the 
site investigator) that will increase potential risk or interfere with study 
participation e.g., ongoing seizure disorder, uncompensated congestive 
heart failure, uncontrolled severe diabetes, uncontrolled severe 
hypertension, etc.
Yes       No 
2.
Laboratory tests with clinically significant abnormalities (as determined 
by the site investigator) 
Yes       No 
3.
Positive urine toxicology screen for another drug with clinical evidence of 
use disorder for that drug (with the exception of THC-COOH at 
screening). 
Yes       No 
4.
Pregnancy by history and or laboratory confirmation (serum HCG).
Yes       No 
5.
Lactation.
Yes       No 
6.
Other DSM-5 substance use disorder in the past three months 
(excluding cannabis, nicotine, caffeine, and mild alcohol use disorder [≤ 
3 criteria]).
Yes       No 
7.
Physiological dependence on another prescribed (e.g. benzodiazepine), 
not prescribed licit (e.g. alcohol or benzodiazepine) or illicit substance 
Yes       No 
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(e.g. opioid) requiring medical management, such as alcohol, opioids, or 
benzodiazepines, excluding caffeine, and nicotine.
8.
Abstinence from cannabis for more than 1 week at the time of 
randomization.
Yes      No 
9.
Meeting DSM-5 criteria for current serious mental illness (e.g., major 
depression, bipolar disorder, schizophrenia, any psychotic illness, 
including substance-induced psychosis, and current substance-induced 
mood disorder. Individuals who meet criteria for current major 
depression at a mild severity may be included at the discretion of the  
site principal investigator.  
Yes       No 
10. Lifetime history of DSM-5 bipolar disorder or any psychotic disorder.
Yes       No 
11. Meeting DSM-5 criteria for any psychiatric disorder that may, according 
to the investigator's judgment, require initiation of a pharmacological or 
non-pharmacological intervention over the course of the study.
Yes       No 
12. Taking psychotropic medication/s that could interfere with interpretation 
of the study results or interact with study medication. Includes but is not 
limited to opioid analgesics, sedative hypnotics, or other known CNS 
depressants, etc. Exceptions include preexisting treatment with sleep 
agents, antidepressants for preexisting stable insomnia or depression, 
respectively. 
Yes       No 
13. Current moderate risk for suicide as measured by the Columbia Suicide 
Severity Rating Scale (CSSRS) suicidal ideation (in the last month) 
score of greater than 2 and a history of recent (past 1 year) serious 
suicide attempt (lethality score of >2 on CSSRS).
Yes       No 
14. Current or past history of significant violence (past 2 years).
Yes       No 
15. Currently in a residential treatment setting in which substance use is 
monitored and restricted, since the restricted access to drugs could 
represent an important confounding variable.
Yes       No 
16. Participants who, in the investigator's opinion, would be unable to 
comply with study procedures or assessments, or would be 
unacceptable study candidates (e.g., poses threat to staff).
Yes       No 
17. Participation in a clinical trial and receipt of investigational drug(s) during 
past 30 days.
Yes       No 
18. Known allergy to FAAH-inhibitors
Yes       No 
19. Co-medication with CYP3A inhibitor, CYP3A inducers, or P-glycoprotein 
substrates, within 48 hours or 5 half-lives prior to baseline, at the 
discretion of the site investigator
Yes       No 
Eligible: Y / N
PI Signature: ___________________________________________
Date: ___ / ___ / ____
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APPENDIX F: COLLATERAL CONTACT QUESTIONNAIRE
Date: ___ / ___ / _____
Collateral Contact Name: _______________________
Phone Number: ( ___ ) ____ - ______
Relationship to Participant: ________________________
Dear ___________,
__(participant)__ is being considered for a research study at our center. To qualify for the study, 
participants are expected to be free of any medical or psychiatric history. __(participant)__ has 
identified you as a reliable source of information. __(participant)__ has signed a release of 
information to permit us to contact you. 
To the best of your knowledge, does __(participant)__ have any history of mental illness? Y / N
If yes, please explain:____________________________________________________
To the best of your knowledge, does (participant) have any history of medical problems? Y / N
If yes, please explain:____________________________________________________
To the best of your knowledge, does __(participant)__ have any history of substance abuse 
problems with marijuana/cannabis? Y / N
To the best of your knowledge, does _(participant)_ have any history of substance abuse 
problems with any substance other than marijuana/cannabis (i.e. alcohol, cocaine, heroin, etc.)? 
Y / N
To the best of your knowledge, is there any reason __(participant)__ should not participate in a 
research study? Y / N
If yes, why not? ________________________________________________________
Thank you for your time.
Sincerely,
__(site principal investigator)__
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APPENDIX G: COMMITMENT TO ATTEMPT QUITTING QUESTIONNAIRE
1. Identify your personal reasons for quitting. For some, those reasons are to feel better, to live 
longer, to set a good example for their children, to cut their risk of heart attack or to save money. 
Of all the reasons to quit, yours matter most.
My main reasons for quitting are: 
____________________________________________________________________________
____________________________________________________________________________
2. Think of people, places and things that you associate with using. Identify ways to change 
your routine to make using more difficult, impossible or unnecessary. For example, ride your 
bike, go to the movies, walk the dog, try a new recipe, visit the dentist for a cleaning, get a 
manicure, start a garden, write a love letter . . .
My new routines and behaviors: 
____________________________________________________________________________
____________________________________________________________________________
3. What sets off cravings? List as many as you can think of, such as drinking alcohol or coffee, 
being around other smokers or working under pressure. Plan ways to avoid these triggers and 
quell urges.
My strategies for overcoming cravings include: 
____________________________________________________________________________
____________________________________________________________________________
4. Where can you find support and encouragement? Think of family members, friends and co-
workers who are willing to help you if you need them to. 
My support network includes: 
____________________________________________________________________________
____________________________________________________________________________
5. You should set a quit date that falls within the first week of the treatment phase. For you the 
first week of treatment will begins on __/__/__ and ends on __/__/__. If you use mostly when 
relaxing or socializing, pick a weekday. If you smoke mostly at work, pick a day on a weekend 
or during a vacation. Once you set the date, try and share this with those who support you, and 
stick to it. 
 I agree that I will attempt to quit using cannabis or cannabis based products during the first 
week of the treatment phase of the study, and if successful I could receive $50. My quit date is: 
__/__/__
Committed to and signed by: ___________________________________________on __/__/__ 
In the presence of: ___________________________________________________ on __/__/__ 
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APPENDIX H: CELL PHONE ASSISTED REMOTE OBSERVATION OF ADHERENCE 
(CAROMA) INSTRUCTIONS
Cellphone Assisted Remote Observation of Medication Adherence (CAROMA) refers to the 
system of visually confirming daily medication compliance for the purposes of a clinical trial 
using cellphones. Participants in this trial are provided with a cellphone with video capabilities 
(iPhone) and video calling software (Skype) necessary to transmit high quality video. Video 
calling is conducted using the Skype application over a cellular network, without relying on 
whether the participant has internet access. Participants are instructed to not use the phone for 
personal reasons. 
At the baseline visit, the research team trains participants on how to use the phone prior to the 
initiation of study medication. Several practice runs are conducted with the participant during the 
in person visit, where participants are observed taking M&Ms using Skype. Upon showing 
sufficient understanding of the phone itself and the CAROMA protocol, participants are given a 
phone to bring home during the duration of the treatment phase of the trial. For the duration of 
the treatment phase, participants are contacted daily, Monday through Friday, at a pre-
determined time for observation of medication dosing. Each CAROMA call proceeds as follows: 
1) Greet the participant and ask them how they are doing.
2) Ask the participant if they have their study medication and water (or preferred beverage).
3) Instruct the participant to put the medication in their hand and display this to research 
staff.
4) Instruct the participant to open their mouth and put the study medication on their tongue 
so that research staff could verify that the medication has been placed in the 
participant’s mouth. 
5) Ask the participant to swallow the medication and take a few sips of their drink. 
6) The participant should then open their mouth and move their tongue from side to side so 
that the research staff could verify the medication has been swallowed.
7) Thank the participant for their time and remind them of the following day’s CAROMA visit 
or of their next study visit, as appropriate. 
Please Note: 

Successful CAROMA check-in’s last under 5 minutes per participant. Unsuccessful 
CAROMA calls should be followed by a second attempt at contact via Skype, and then a 
phone call to the participant’s personal cell phone (or preferred method of contact). 

CAROMA calls are not for AE assessment. However, if a participant is to report an AE it 
should be captured and reported to the site principal investigator.
The following information should be documented for each CAROMA call:
Day # _____ of Dosing
Date: ___ / ___ / _____
Rater: _____________
    Visual Assessment of Dosing Compliance
Participant compliant with dosing regimen?
      Yes         No: _______________________ (# pills / doses missed)
# of Pills Expected to be Taken: ___________
# of Pills Actually Taken: ________________
Time Medication Taken: ____ : ____ am / pm
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APPENDIX I: BMI CALCULATION TABLE
BMI
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
Height 
(inches)
Body Weight (pounds)
58
91
96 100 105 110 115 119 124 129 134 138 143 148 153 158 162 167 172
59
94
99 104 109 114 119 124 128 133 138 143 148 153 158 163 168 173 178
60
97 102 107 112 118 123 128 133 138 143 148 153 158 163 168 174 179 184
61
100 106 111 116 122 127 132 137 143 148 153 158 164 169 174 180 185 190
62
104 109 115 120 126 131 136 142 147 153 158 164 169 175 180 186 191 196
63
107 113 118 124 130 135 141 146 152 158 163 169 175 180 186 191 197 203
64
110 116 122 128 134 140 145 151 157 163 169 174 180 186 192 197 204 209
65
114 120 126 132 138 144 150 156 162 168 174 180 186 192 198 204 210 216
66
118 124 130 136 142 148 155 161 167 173 179 186 192 198 204 210 216 223
67
121 127 134 140 146 153 159 166 172 178 185 191 198 204 211 217 223 230
68
125 131 138 144 151 158 164 171 177 184 190 197 203 210 216 223 230 236
69
128 135 142 149 155 162 169 176 182 189 196 203 209 216 223 230 236 243
70
132 139 146 153 160 167 174 181 188 195 202 209 216 222 229 236 243 250
71
136 143 150 157 165 172 179 186 193 200 208 215 222 229 236 243 250 257
72
140 147 154 162 169 177 184 191 199 206 213 221 228 235 242 250 258 265
73
144 151 159 166 174 182 189 197 204 212 219 227 235 242 250 257 265 272
74
148 155 163 171 179 186 194 202 210 218 225 233 241 249 256 264 272 280
75
152 160 168 176 184 192 200 208 216 224 232 240 248 256 264 272 279 287
76
156 164 172 180 189 197 205 213 221 230 238 246 254 263 271 279 287 295
BMI
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
Height 
(inches)
Body Weight (pounds)
58
177 181 186 191 196 201 205 210 215 220 224 229 234 239 244 248 253 258
59
183 188 193 198 203 208 212 217 222 227 232 237 242 247 252 257 262 267
60
189 194 199 204 209 215 220 225 230 235 240 245 250 255 261 266 271 276
61
195 201 206 211 217 222 227 232 238 243 248 254 259 264 269 275 280 285
62
202 207 213 218 224 229 235 240 246 251 256 262 267 273 278 284 289 295
63
208 214 220 225 231 237 242 248 254 259 265 270 278 282 287 293 299 304
64
215 221 227 232 238 244 250 256 262 267 273 279 285 291 296 302 308 314
65
222 228 234 240 246 252 258 264 270 276 282 288 294 300 306 312 318 324
66
229 235 241 247 253 260 266 272 278 284 291 297 303 309 315 322 328 334
67
236 242 249 255 261 268 274 280 287 293 299 306 312 319 325 331 338 344
68
243 249 256 262 269 276 282 289 295 302 308 315 322 328 335 341 348 354
69
250 257 263 270 277 284 291 297 304 311 318 324 331 338 345 351 358 365
70
257 264 271 278 285 292 299 306 313 320 327 334 341 348 355 362 369 376
71
265 272 279 286 293 301 308 315 322 329 338 343 351 358 365 372 379 386
72
272 279 287 294 302 309 316 324 331 338 346 353 361 368 375 383 390 397
73
280 288 295 302 310 318 325 333 340 348 355 363 371 378 386 393 401 408
74
287 295 303 311 319 326 334 342 350 358 365 373 381 389 396 404 412 420
75
295 303 311 319 327 335 343 351 359 367 375 383 391 399 407 415 423 431
76
304 312 320 328 336 344 353 361 369 377 385 394 402 410 418 426 435 443
APPENDIX J: RESPONSIBILITIES OF THE INVESTIGATOR
APPROVED BY THE YALE UNIVERSITY IRB 5/1/2022

APPROVED BY THE YALE UNIVERSITY IRB 5/1/2022
Page 116 of 116
The responsibilities imposed on investigators by the FDA are summarized in the “Statement of 
Investigator” (Form FDA 1572), which must be completed and signed before the investigator 
may participate in this study.
The investigator agrees to assume the following responsibilities:
1.
Conduct the study in accordance with the protocol.
2.
Personally conduct or supervise the staff who will assist in the protocol.
3.
Ensure that study related procedures, including study specific (nonroutine/nonstandard 
panel) screening assessments are NOT performed on potential participants, prior to the 
receipt of written approval from relevant governing bodies/authorities.
4.
Ensure that all members of the study team assisting in the conduct of the study are informed 
of these obligations.
5.
Secure prior approval of the study and any changes by an appropriate IRB that conform to 21 
Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
6.
Ensure that the IRB will be responsible for initial review, continuing review, and approval of 
the protocol. Promptly report to the IRB all changes in research activity and all anticipated 
risks to participants. Make at least yearly reports on the progress of the study to the IRB, 
and issue a final report within 3 months of study completion.
7.
Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8.
Obtain valid informed consent from each participant who participates in the study, and 
document the date of consent in the participant’s medical chart. Valid informed consent is 
the most current version approved by the IRB. Each informed consent form should contain a 
participant authorization section that describes the uses and disclosures of a participant’s 
personal information (including personal health information) that will take place in connection 
with the study. If an informed consent form does not include such a participant authorization, 
then the investigator must obtain a separate participant authorization form from each 
participant or the participant’s legally acceptable representative.
9.
Maintain current records of the receipt, administration, and disposition of SpringWorks/Jazz 
Pharmaceuticals-supplied drugs, and return all unused PF-04457845/placebo to Jazz 
Pharmaceuticals at the end of the study.
10. Report adverse reactions to the Coordinating Center (Yale University) every 6 months. In 
the event of an SAE, notify the Coordinating Center within 24 hours.
11. If the investigator/institution retains the services of any individual or party to perform trial-
related duties and functions, the investigator/institution should ensure that this individual or 
party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
APPROVED BY THE YALE UNIVERSITY IRB 5/1/2022