Clinical trial NCT03887429
Conditions: Impulse Control Disorders
Keywords: SXC-2023 Cognitive Control Impulsivity Delay Aversion Top Down Processing Behavioral Addiction
Sponsor: Promentis Pharmaceuticals, Inc.
Start date: 2019-03-04; Completion date: 2019-07-09
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to explore the safety, tolerability and activity of SXC-2023 or placebo when dosed for 5 days in adults with tobacco use disorder who voluntarily abstain from the use of cigarettes.

Detailed description:
This study is a Phase 2A, randomized, double-blinded, placebo-controlled, two-period crossover study to evaluate the effect of two doses of SXC-2023 on measures of impulsivity and inhibitory control, urge for cigarettes, and mood in non-treatment seeking smokers who are abstaining from smoking. The study consists of a screening period of up to 30 days, a 5 day randomized double-blind treatment period, a 9 day washout period, followed by a second 5 day randomized double-blind treatment period, with a safety follow-up period 7 days after the last dose of study medication.

Arms: arm 1: SXC-2023 200mg dosed once daily for 5 days, followed by 9 day washout, then Placebo dosed once daily for 5 days. arm 2: Placebo dosed once daily for 5 days, followed by 9 day washout, then SXC-2023 200mg dosed once daily for 5 days. arm 3: SXC-2023 800mg dosed once daily for 5 days, followed by 9 day washout, then Placebo dosed once daily for 5 days. arm 4: Placebo dosed once daily for 5 days, followed by 9 day washout, then SXC-2023 800mg dosed once daily for 5 days.
Interventions: intervention 1: SXC-2023 intervention 2: Placebos
Intervention descriptions: intervention 1: SXC-2023 oral capsules intervention 2: Matching Placebo oral capsules

Protocol documents:
Prot_SAP_001.pdf: 
 
Page 1 
PRO-202_Amend 3 Protocol_15 Apr 2019 
  
 
CLINICAL PROTOCOL 
 
 
An Exploratory, Placebo-Controlled, Crossover Study to Examine the Safety and 
Activity of SXC-2023 to Improve Behavioral Dynamics in Non-Treatment Seeking 
Adults Undergoing Acute Nicotine Withdrawal  
 
 
Protocol No.:  
 
PRO-202 
 
US IND No.:  
 
140669 
 
Phase:   
 
 
2A 
 
Amendment 3:                      15 April 2019 
 
Previous versions 
Amendment 2:                        26 November 2018 
Amendment 1:                        05 November 2018 
Original Protocol Date: 
24 July 2018  
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices 
(GCP), and applicable regulatory requirements. All required study documentation will be 
archived as required by regulatory authorities. 
 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Promentis 
Pharmaceuticals, Inc. Any viewing or disclosure of such information that is not authorized 
in writing by Promentis Pharmaceuticals, Inc. is strictly prohibited. Such information may 
be used solely for the purpose of reviewing or performing this study. 
 


Phase 2A Study Protocol_Amend 3 
Promentis Pharmaceuticals, Inc. 
Protocol No.:  PRO-202 
US IND No.: 140669 
 
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PRO-202_Amend 3 Protocol_15 Apr 2019 
PROTOCOL REVISION HISTORY 
Date/Name 
Description 
12 Apr 2019/ P. Cotter 
Design change from outpatient to inpatient study design (subjects confined at 
Celerion during treatment days of both Periods of the crossover) 
Administrative changes throughout document 
Clinical laboratory location change 
Principal Investigator change 
Changed from 1 site to 2 sites.  Change in Baylor site status, addition of 
Celerion site 
Added fasting requirements for Day 1 of Period 1 and Period 2 
Glutathione testing requirements for assay updated 
Number of subjects changed from up to 32 to up to 36 total subjects exposed 
to SXC-2023.  Celerion to run subjects in two groups 
Cue reactivity images from MUSC instead of MD Anderson 
Inclusion criteria:  change in starting age from 28yo to 25yo, addition of BMI, 
clarifications on remaining inclusion requirement timepoints, added 
requirements for female of non-childbearing potential subjects and included 
Aricept drug requirement. 
Exclusion criteria:  Change requirement for hepatitis- must be active, 
SSRI/SNRI requirement change allowing for subjects to be included if they 
have been on stable dose 30 days prior to screening, and clarified other 
requirements with examples. 
Change to Figure 1, Diagram of study design with number of subjects 
Removed all monetary incentives notations 
Added section on Confinement, Return visits and Follow up 
Change in max study duration from 61 days to 59 days 
Added items to contraceptive requirements for female subjects 
Schedule of assessments:  Increased number of timepoints for physical exams, 
safety labs, urine drug screens and ECG. 
Change in requirements for subjects returning on Day 1 of Period 2 
Added requirement for replacement of subjects in Group 1 of study 
Appendix J:  Added FTND questionnaire 
26 Nov 2018/ P. Cotter 
Added exclusion criteria stipulating that subjects will be excluded for any 
clinically significant laboratory, ECG, or vital sign abnormality.  
Vital signs assessment added at each study day. 
Included laboratory, VS, and ECG-based discontinuation criteria. 
Added exclusion criteria:  Removal of allowance of subjects to re-enter the 
study after a relapse. 
02 Nov 2018/ P. Cotter 
Included US IND No. 
Included Dr. Thomas Kosten as Co-PI 
Addition of 90-day toxicology data in rats and dogs 
Addition of MAD safety, PK data and Stopping Rules criteria 


Phase 2A Study Protocol_Amend 3 
Promentis Pharmaceuticals, Inc. 
Protocol No.:  PRO-202 
US IND No.: 140669 
 
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PRO-202_Amend 3 Protocol_15 Apr 2019 
Update to Rationale for dose selection  
Removal of two treatment pair doses 
Screening window change from -28 days to -30 days 
Clarification of Adverse event collection at screening 
Deleted in Section 6.2.3.1 “However, if a subject relapses during Period 1, 
he/she would be allowed one more chance to participate in this study by 
enrolling in the future, assuming that he/she meets the eligibility criteria upon 
re-screening.” 
Update to Statistics (Section 12.1), deletion of “There will be 6 within-subject 
differences for each pairwise treatment contrast. Twelve difference scores are 
powered to detect differences approximately twice the within-subject standard 
deviation.” 
 
 
 


Phase 2A Study Protocol_Amend 3 
Promentis Pharmaceuticals, Inc. 
Protocol No.:  PRO-202 
US IND No.: 140669 
 
Page 4 
PRO-202_Amend 3 Protocol_15 Apr 2019 
PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES 
 
An Exploratory, Placebo-Controlled, Crossover Study to Examine the Safety and 
Activity of SXC-2023 to Improve Behavioral Dynamics in Non-Treatment Seeking 
Adults Undergoing Acute Nicotine Withdrawal  
 
 
SPONSOR: 
Promentis Pharmaceuticals, Inc. 
826 North Plankinton Avenue, Suite 400 
Milwaukee, Wisconsin 53203, USA  
 
SPONSOR’S  
REPRESENTATIVE: 
Patricia P. Cotter 
Senior Director, Head of Clinical 
Operations 
Tel.:  +1 617 300 6172 
E-Mail:  pcotter@promentispharma.com 
 
 
 
 
 
 
______________________________ 
Signature 
 
_____________ 
Date 
 
 
 
 
PRINCIPAL 
INVESTIGATOR 
AND CLINICAL 
SITE: 
Robert Schwab, MD 
Celerion 
621 Rose Street 
Lincoln, Nebraska 68502, USA 
Tel.:  +1 402 476-2811 
 
 
 
 
 
 
______________________________ 
Signature 
 
_____________ 
Date 
15-April-2019


Phase 2A Study Protocol_Amend 3 
Promentis Pharmaceuticals, Inc. 
Protocol No.:  PRO-202 
US IND No.: 140669 
 
Page 5 
PRO-202_Amend 3 Protocol_15 Apr 2019 
ADDITIONAL KEY CONTACTS FOR THE STUDY 
 
 
Sponsor Representative 
Patricia P. Cotter 
Senior Director, Head of Clinical Operations 
Tel.:  +1 617 300 6172 
E-Mail:  pcotter@promentispharma.com 
 
Sponsor Representative 
 
(Back up) 
Chad Beyer, PhD, MBA 
Senior Vice President, Research and 
Development 
Tel.:  +1 267 614 4645 
E-Mail:  cbeyer@promentispharma.com 
 
Medical Monitor 
Thomas Beck, MD 
Chief Medical Officer 
Tel.:  +1 617 231 2403 
E-Mail:  tbeck@fprimecapital.com 
 
Certified Clinical Laboratory 
Celerion  
621 Rose Street 
Lincoln, Nebraska 68502, USA 
Tel.:  +1 402 476-2811 
Fax:  +1 402 939-0428 
 
Laboratory for Glutathione testing 
Laboratory Corporation of America 
1447 York Court 
Burlington, NC 27215-3361 
 
Statistical Analyses 
Celerion 
100 Alexis-Nihon Boulevard, Suite 360 
Montreal, Quebec H4M 2N8, Canada 
Tel.:  +1 514 744-9090 
Fax:  +1 514 744-8700 
 
and/or 
 
Celerion  
621 Rose Street 
Lincoln, Nebraska 68502, USA 
Tel.:  +1 402 476-2811 
Fax:  +1 402 939-0428 
 
 


Phase 2A Study Protocol_Amend 3 
Promentis Pharmaceuticals, Inc. 
Protocol No.:  PRO-202 
US IND No.: 140669 
 
Page 6 
PRO-202_Amend 3 Protocol_15 Apr 2019 
TABLE OF CONTENTS 
PROTOCOL REVISION HISTORY ..............................................................................2 
PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES ..........................4 
ADDITIONAL KEY CONTACTS FOR THE STUDY .................................................5 
TABLE OF CONTENTS ..................................................................................................6 
TABLE OF FIGURES .......................................................................................................9 
TABLE OF TABLES .........................................................................................................9 
1 
SYNOPSIS .................................................................................................................10 
2 
ABBREVIATIONS ...................................................................................................14 
3 
BACKGROUND AND RATIONALE ....................................................................17 
3.1 
Background ..........................................................................................................17 
3.1.1 
Preclinical Trials ............................................................................................18 
3.1.1.1 
Pharmacology ...........................................................................................18 
3.1.1.2 
Pharmacokinetics .....................................................................................18 
3.1.1.3 
Toxicity......................................................................................................18 
3.1.2 
Effects of SXC-2023 in Humans ...................................................................21 
3.1.2.1 
Safety .........................................................................................................22 
3.1.2.2 
Pharmacokinetics and Product Metabolism .........................................23 
3.2 
Rationale ...............................................................................................................25 
3.2.1 
Rationale for this Study and Study Design ..................................................25 
3.2.2 
Rationale for Dose Selection .........................................................................25 
3.3 
Risks and/or Benefits to Subjects .......................................................................25 
4 
STUDY OBJECTIVES ............................................................................................26 
4.1 
Primary Objectives ..............................................................................................26 
4.2 
Exploratory Objectives ........................................................................................26 
INVESTIGATIONAL PLAN .........................................................................................26 
4.3 
Overall Study Design and Plan ...........................................................................26 
4.4 
All Parts ................................................................................................................28 
4.5 
Confinement, Return Visits and Follow Up ......................................................28 
4.6 
Study Duration .....................................................................................................28 
4.7 
Study Conduct ......................................................................................................29 
5 
STUDY POPULATION ...........................................................................................29 
5.1 
Number of Subjects..............................................................................................29 
5.2 
Eligibility Criteria ................................................................................................29 
5.2.1 
Inclusion Criteria ...........................................................................................29 
5.2.2 
Exclusion Criteria ..........................................................................................30 
5.2.3 
Restrictions .....................................................................................................31 
5.2.3.1 
Smoking and Other Forms of Nicotine ..................................................31 
5.2.3.2 
Meals .........................................................................................................31 
5.2.3.3 
Prior/Concomitant Medications .............................................................31 
5.2.3.4 
Contraceptive Requirements ..................................................................32 
6 
STUDY PROCEDURES ..........................................................................................33 
6.1 
Screening (Day −30 to Day -1) ............................................................................33 
6.2 
Period 1 of Crossover...........................................................................................34 
6.2.1 
Day 1 ................................................................................................................34 


Phase 2A Study Protocol_Amend 3 
Promentis Pharmaceuticals, Inc. 
Protocol No.:  PRO-202 
US IND No.: 140669 
 
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PRO-202_Amend 3 Protocol_15 Apr 2019 
6.2.2 
Day 2, Day 3, and Day 4 ................................................................................35 
6.2.3 
Day 5 ................................................................................................................36 
6.3 
Washout Period (9 days) .....................................................................................36 
6.4 
Period 2 of Crossover...........................................................................................37 
6.5 
Follow-up Visit/Early Termination (7-10 days after last dose) .......................37 
6.6 
Early Withdrawal ................................................................................................37 
6.7 
Discontinuation of the Study ...............................................................................38 
7 
CRITERIA FOR EVALUATION ...........................................................................38 
7.1 
Safety Evaluation .................................................................................................38 
7.1.1 
Medical History, Demographic and Other Baseline Information .............38 
7.1.2 
Physical Examination ....................................................................................39 
7.1.3 
Vital Signs .......................................................................................................39 
7.1.4 
12-Lead Electrocardiograms.........................................................................40 
7.1.5 
Clinical Laboratory Tests..............................................................................40 
7.1.6 
Adverse Events ...............................................................................................41 
7.1.7 
Prior and Concomitant Medications ............................................................42 
7.2 
Glutathione Blood Collection ..............................................................................42 
7.3 
Neurocognitive Assessments and Scales.............................................................42 
7.3.1 
Barratt Impulsiveness Scale ..........................................................................42 
7.3.2 
Stop Signal Test, Cambridge Gambling Task, Paired Associates 
Learning, and Reaction Time .......................................................................42 
7.3.3 
Questionnaire on Smoking Urges .................................................................42 
7.3.4 
Positive and Negative Affect Schedule .........................................................42 
7.3.5 
Cigarette Evaluation Questionnaire .............................................................43 
7.3.6 
Cue Reactivity and Likert Assessments .......................................................43 
7.3.7 
Fagerstrom Test of Nicotine Dependence ....................................................43 
7.4 
Measurement of Nicotine Ingestion ....................................................................43 
8 
TEST ARTICLE AND ADMINISTRATION ........................................................44 
8.1 
Test Article Identification, Supply, Packaging, Labeling, and Storage ..........44 
8.2 
Study Drug Administration ................................................................................44 
8.3 
Study Drug Accountability and Destruction .....................................................44 
8.4 
Blinding .................................................................................................................44 
8.5 
Randomization .....................................................................................................45 
8.6 
Treatment of Overdose ........................................................................................45 
9 
ADVERSE EVENTS ................................................................................................45 
9.1 
Definition ..............................................................................................................46 
9.2 
Severity Scale for Adverse Events ......................................................................46 
9.3 
Relationship to Study Drug .................................................................................46 
9.4 
Reporting Adverse Events ...................................................................................46 
9.5 
Serious Adverse Events .......................................................................................47 
9.5.1 
Definition ........................................................................................................47 
9.5.2 
Initial Reporting .............................................................................................48 
9.5.3 
Follow-up ........................................................................................................48 
9.6 
Pregnancy .............................................................................................................48 
9.7 
Stopping Criteria with Rules for Subject Replacement ...................................49 
10 STUDY ADMINISTRATION .................................................................................49 


Phase 2A Study Protocol_Amend 3 
Promentis Pharmaceuticals, Inc. 
Protocol No.:  PRO-202 
US IND No.: 140669 
 
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PRO-202_Amend 3 Protocol_15 Apr 2019 
10.1 
Ethics .....................................................................................................................49 
10.1.1 
Institutional Review Board ...........................................................................49 
10.1.2 
Ethical Conduct of the Study ........................................................................49 
10.1.3 
Subject Information and Consent ................................................................49 
10.2 
Termination of the Study ....................................................................................50 
10.3 
Data Quality Assurance .......................................................................................50 
10.4 
Direct Access to Source Data/Documents ..........................................................50 
10.5 
Data Handling and Record Keeping ..................................................................50 
10.6 
Report Format ......................................................................................................51 
10.7 
Publication Policy.................................................................................................51 
11 STATISTICAL METHODS ....................................................................................51 
11.1 
Determination of Sample Size .............................................................................51 
11.2 
Analysis Populations ............................................................................................51 
11.3 
Statistical Analysis ...............................................................................................52 
11.3.1 
Subject Disposition.........................................................................................52 
11.3.2 
Protocol Deviations ........................................................................................52 
11.3.3 
Demographics and Baseline Characteristics ...............................................52 
11.3.4 
Safety Analysis ...............................................................................................52 
11.3.4.1 
Adverse Events .........................................................................................52 
11.3.4.2 
Other Safety Assessments........................................................................53 
11.3.4.3 
Concomitant Medications .......................................................................53 
11.3.5 
Analysis of Neurocognitive Assessments ......................................................53 
11.3.6 
Analysis of Glutathione Concentrations ......................................................54 
12 REFERENCES .........................................................................................................54 
APPENDIX A SCHEDULE OF EVENTS ....................................................................55 
APPENDIX B BASIC ELEMENTS OF INFORMED CONSENT .............................57 
APPENDIX C SUMMARY OF BLOOD DRAW VOLUMES ....................................59 
APPENDIX D BARRATT IMPULSIVENESS SCALE ..............................................60 
APPENDIX E CANTAB CONNECT TASK DESCRIPTIONS FOR 
PROMENTIS ............................................................................................................61 
APPENDIX F QUESTIONNAIRE ON SMOKING URGES ......................................68 
APPENDIX G POSITIVE AND NEGATIVE AFFECT SCHEDULE .......................69 
APPENDIX H CIGARETTE EVALUATION QUESTIONNAIRE ...........................70 
APPENDIX I  CUE REACTIVITY AND LIKERT SCALE ASSESSMENTS .........71 
APPENDIX J  FAGERSTROM TEST OF NICOTINE DEPENDENCE 
QUESTIONNAIRE ..................................................................................................72 
 
 
 


Phase 2A Study Protocol_Amend 3 
Promentis Pharmaceuticals, Inc. 
Protocol No.:  PRO-202 
US IND No.: 140669 
 
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PRO-202_Amend 3 Protocol_15 Apr 2019 
TABLE OF FIGURES 
Figure 1 
Diagram of Study Design ........................................................................28 
 
TABLE OF TABLES 
Table 1 
Reasons for Discontinuation ...................................................................38 
 
 


Phase 2A Study Protocol_Amend 3 
Promentis Pharmaceuticals, Inc. 
Protocol No.:  PRO-202 
US IND No.: 140669 
 
Page 10 
PRO-202_Amend 3 Protocol_15 Apr 2019 
1 SYNOPSIS 
Compound No. 
SXC-2023 – a novel small molecule activator of the cystine-glutamate antiporter (System xc- or 
Sxc) 
Study Protocol Title 
An Exploratory, Placebo-Controlled, Crossover Study to Examine the Safety and Activity of 
SXC-2023 to Improve Behavioral Dynamics in Non-Treatment Seeking Adults Undergoing Acute 
Nicotine Withdrawal  
Sites 
2 sites:  Baylor College of Medicine (site closed);  Celerion 
Phase of Development 
Phase 2A 
Dosage and Administration  
Double-blinded study drug:  
• 
SXC-2023 200 mg (4 x 50 mg capsules) dosed once per day (QD),  
• 
SXC-2023 800 mg (4 x 200 mg capsules) QD, or  
• 
Matching placebos QD 
On Day 1 of each Period, dosing will occur in the morning under fasted conditions.  For all other 
days, dosing will occur at least 2 hours after breakfast. 
Primary Objectives 
• 
To explore the safety and tolerability of SXC-2023 when dosed for 5 days in adults 
diagnosed with tobacco use disorder (i.e., cigarette smokers) who voluntarily abstain from 
the use of cigarettes. 
• 
To test the activity of SXC-2023 when dosed for 5 days on measures of 
abstinence-induced impulsivity and inhibitory control, urge for cigarettes, and mood. 
Exploratory Objectives 
• 
To explore the effects of 5 days of tobacco abstinence on levels of total and/or reduced 
glutathione (GSH) in blood/plasma. 
• 
To test the possible effects of SXC-2023 on levels of total and/or reduced GSH deficits 
via assay of blood/plasma GSH levels.  
Study Design 
This randomized, double-blinded, placebo-controlled, two-period crossover study will evaluate 
the effect of two doses of SXC-2023 on measures of impulsivity and inhibitory control, urge for 
cigarettes, and mood in non-treatment seeking smokers who are abstaining from smoking. To be 
eligible, subjects must meet the protocol-specified eligibility criteria which include a score of ≥4 
on the Fagerstrom Test of Nicotine Dependence (FTND) and an expelled carbon monoxide (CO) 
level of ≥10 ppm at screening and Day 1 of Period 1, prior to dosing.  


Phase 2A Study Protocol_Amend 3 
Promentis Pharmaceuticals, Inc. 
Protocol No.:  PRO-202 
US IND No.: 140669 
 
Page 11 
PRO-202_Amend 3 Protocol_15 Apr 2019 
To date, four (4) total subjects have been dosed at Baylor College of Medicine (BCM).  At Celerion, 
two groups of 14 subjects, a total of 28 subjects will be assigned to receive two treatment regimens: 
SXC-2023 200 mg QD and matching placebo or SXC-2023 800 mg QD and matching placebo, in 
a 2-treatment crossover design. Subjects will receive one treatment regimen per 5-day treatment 
period of the crossover with a 9-day washout between treatment periods (after the last study day of 
Period one and prior to first day of Period 2) where subjects will be able to smoke as usual. Subjects 
will be randomized to treatment pair comparison (SXC-2023 200 mg QD and matching placebo, or 
SXC-2023 800 mg QD and matching placebo and to treatment sequence within each pair).  Seven 
(7) subjects will be randomized to each of the 4-treatment pair sequence combinations.  Subjects 
who complete Period 1 in Group 1 but do not return on Day 1 of  Period 2 of the crossover will be 
replaced in Group 2.  A total of 4 subject replacements may be enrolled in Group 2.    
Subjects will be allowed to smoke until they enter the Celerion facility at the start the study on 
Period 1, Day 1. Subjects will abstain from nicotine ingestion each day of the treatment period 
starting at Day 1, and CO testing and Urine cotinine testing will be performed on Day 1 and Day 5 
of both periods of the crossover and, at the discretion of the PI, may be performed each day (Days 
2 through 4) of the treatment period to confirm nicotine abstinence.   
Measurements of neurocognitive control will be performed in the morning on Day 1 of both Periods, 
prior to study drug administration and on Day 5 (4-5 hours post dose) to assess the effect of SXC-
2023 on abstinence-induced measures of impulsivity and inhibitory control. Additional assessments 
will include measures of urge for cigarettes. Testing will include the Stop Signal Task (SST), 
Cambridge Gambling Task (CGT), Paired Associates Learning (PAL), Reaction Time (RTI), 
Questionnaire on Smoking Urges (QSU), Positive and Negative Affect Schedule (PANAS), the 
Fagerstrom Test for Nicotine Dependence (FTND) and the Cigarette Evaluation Questionnaire 
(CEQ). Cue reactivity will be evaluated using the International Affective Picture System (IAPS) 
images and those validated in the TRAIN lab at MUSC (PI Froeliger) (for neutral and positive 
images) and smoking images on Day 2 (following 24 hours of abstinence) and on Day 5, and two 
Likert scale assessments will also be performed on Days 2 and 5. Levels of GSH (either total GSH 
or reduced forms) will be collected in blood and/or plasma at baseline (prior to dosing on Day 1) 
and after 5 days of tobacco abstinence (4-5 hours after dosing on Day 5). Following the completion 
of the first 5 days of treatment with SXC-2023 200 mg QD, SXC-2023 800 mg QD, or placebo, 
subjects will be allowed to smoke ad lib during a 9-day washout period. Following the washout 
period, subjects will crossover into Period 2 of this study and will receive a different study drug or 
placebo and will repeat the study procedures and assessments employed in Period 1, unless noted 
otherwise.  
A follow-up visit will be scheduled to occur approximately 7-10 days after the last dose of study 
drug (SXC-2023 200 mg, SXC-2023 800 mg, or placebo) is administered. 
Study Duration 
The maximum anticipated subject participation will be approximately 59 days (30 days for the 
screening period, 5 days for Period 1 of the crossover, 9 days for the washout, 5 days for Period 2 
of the crossover, and maximum of 10 days until the follow-up visit). 
Number of Subjects (Planned Exposure) 
To date, 4 subjects have been dosed at BCM.  At Celerion, two groups of 14 subjects (a total of 28 
subjects) will be enrolled on the study.  Subjects who complete Period 1 in Group 1 but do not 
return on Day 1 of  Period 2 of the crossover will be replaced in Group 2.  A total of 4 subjects  will 
be allowed as replacements in Group 2.  With a 2-treatment crossover design, 16 possible subjects 
will be exposed to SXC-2023 200 mg vs. placebo, and 16 possible subjects to SXC-2023 800 mg 
vs. placebo during each period (n=32).  


Phase 2A Study Protocol_Amend 3 
Promentis Pharmaceuticals, Inc. 
Protocol No.:  PRO-202 
US IND No.: 140669 
 
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PRO-202_Amend 3 Protocol_15 Apr 2019 
Including an anticipated 10% dropout rate at Celerion, no more than 32 subjects will be exposed to 
SXC-2023.  At both sites, no more than 36 subjects will be exposed to SXC-2023 in this study. 
Inclusion Criteria 
Subjects must meet all the following inclusion criteria to be eligible for the study: 
1. Adult, female or male, 25-55 years of age, inclusive at screening. 
2. BMI ≥ 16.0 and ≤ 35.0 kg/m2 at screening. 
3. Has provided signed written informed consent and has willingness and ability to comply 
with all aspects of the protocol, including abstaining from the use of tobacco/nicotine 
products for two 5-day periods. 
4. Non-treatment seeking smokers regularly using tobacco with a FTND score ≥4 at 
screening and self-reported use of ≥10 cigarettes/day at screening. 
5. Has smoked for >5 years at screening. 
6. Meets Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) 
criteria for tobacco use disorder. 
7. Must have a score of ≥4 on the FTND and an expired-air CO level ≥10 ppm during initial 
screening and prior to first dose.  
8. For a female of childbearing potential: either be sexually inactive (abstinent as a life 
style) for 28 days prior to the first dosing and throughout the study or be using acceptable 
birth control methods as described in Section 5.2.2.4 of the protocol. 
9. Female of non-childbearing potential: must have undergone one of the following 
sterilization procedures, at least 6 months prior to the first dose: 
a. hysteroscopic sterilization; 
b. bilateral tubal ligation or bilateral salpingectomy; 
c. hysterectomy; 
d. bilateral oophorectomy; 
Or be postmenopausal with amenorrhea for at least 1 year prior to the first dose with serum 
follicle stimulating hormone levels consistent with postmenopausal status or have medically 
documented history of biological or congenital sterility. 
10. Has not used Aricept (a cholinersterase inhibitor) 30 days prior to screening.  
Exclusion Criteria  
Subjects meeting ANY of the following criteria must NOT be enrolled in this study. 
1. Subject is mentally or legally incapacitated or has significant emotional problems or 
clinically significant abnormality at the time of the screening visit or expected during the 
conduct of the study. 
2. Subject suffered a concussion 6 months or less prior to screening. 
3. Females who are pregnant or breastfeeding. 
4. Positive for active hepatitis, human immunodeficiency virus, coagulopathy, or hepatic 
illness. 


Phase 2A Study Protocol_Amend 3 
Promentis Pharmaceuticals, Inc. 
Protocol No.:  PRO-202 
US IND No.: 140669 
 
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PRO-202_Amend 3 Protocol_15 Apr 2019 
5. Use of Selective Serotonin or Norepinephrine Reuptake Inhibitors (SSRI/SNRI) for 
psychiatric illness (e.g. depression, anxiety, etc.), unless subject has been on a stable dose 
for at least 30 days prior to screening 
6. Use of antipsychotics or use of antiepileptics within 30 days prior to screening. 
7. Use of N-acetylcysteine within 30 days prior to screening. 
8. Use of Chantix or related smoking cessation medications (e.g., NicoDerm patch, 
Nicorette gum, etc) within 30 days prior to the first dose. 
9. Use of sulfasalazine (Azulfidine®) within 30 days prior to the first dose. 
10. DSM-5 criteria for alcohol/substance use disorder (except for tobacco use disorder).  
11. History or presence of clinically significant psychiatric condition (except for tobacco use 
disorder) or disease in the opinion of the Principal Investigator (PI) or designee. 
12. History of any illness that, in the opinion of the PI or designee, might confound the results 
of the study or poses an additional risk to the subject by their participation in the study. 
13. History of seizures. 
14. Any history of psychiatric hospitalization in the past year. 
15. Currently participating in a clinical study. 
16. Previously participated in any Phase 1 Promentis studies or dosed in this Phase 2A study.  
17. FTND score <4  and expelled CO levels <10 ppm at screening and prior to first dose. 
18. Any clinically significant laboratory, ECG and/or vital sign abnormalities at screening. 
19. Unable to read/understand/speak English. 
 
 


Phase 2A Study Protocol_Amend 3 
Promentis Pharmaceuticals, Inc. 
Protocol No.:  PRO-202 
US IND No.: 140669 
 
Page 14 
PRO-202_Amend 3 Protocol_15 Apr 2019 
2 ABBREVIATIONS 
AE 
Adverse event 
AUC 
Area under the concentration-time curve 
BIS 
Barratt Impulsiveness Scale 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CEQ 
Cigarette Evaluation Questionnaire 
CFR 
Code of Federal Regulations 
CGT 
Cambridge Gambling Task 
Cm 
Centimeter 
Cmax 
Maximum observed concentration 
CNS 
Central nervous system 
CO 
Carbon monoxide 
CRF/eCRF 
Case report form/electronic case report form 
CRO 
Contract research organization 
DG 
Days of gestation 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, fifth edition 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EE2 
Ethinyl estradiol 
FAS 
Full Analysis Set 
FE 
Food effect 
FTND 
Fagerstrom Test of Nicotine Dependence 
GCP 
Good Clinical Practice(s) 
GLP 
Good Laboratory Practice 
GSH 
Glutathione 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
Hr 
hour(s) 
IAPS 
International Affective Picture System 
ICD 
Impulse control disorder 
ICF 
Informed Consent Form 


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ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IND 
Investigational New Drug 
IRB 
Institutional review board 
ITT 
Intent-to-Treat 
Kg 
Kilogram 
m2 
Meters squared 
MAD 
Multiple ascending dose 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
Mg 
Milligram 
mL 
Milliliter 
mmHg 
Millimeters of mercury 
NAC 
N-acetylcysteine 
NET 
Norethindrone 
No. 
Number 
NOAEL 
No observed adverse effect level 
OC/DDI 
Oral contraceptive/drug-drug Interaction 
OTC 
Over-the-counter 
PAL 
Paired Associates Learning 
PANAS 
Positive and Negative Affect Schedule 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
Ppm 
parts per million 
PT 
Preferred term 
QA 
Quality assurance 
QD 
Once per day 
QSU 
Questionnaire on Smoking Urges 
QTcF 
Corrected QT Fridericia's 
RBC 
Red blood cell 
RTI 
Reaction Time 
SAD 
Single ascending dose 


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SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System organ class 
SSRI 
Selective serotonin reuptake inhibitor 
SST 
Stop Signal Task 
SXC 
System xc- 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to reach maximum observed concentration 
TTM 
Trichotillomania 
UA 
Urinalysis 
US 
United States 
VS 
Vital signs 
WHODD 
World Health Organization Drug Dictionary 
 


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3 BACKGROUND AND RATIONALE 
3.1 
Background 
Impaired cortical control over impulses, mood and urges is a hallmark feature of several 
disorders of the central nervous system (CNS), specifically, impulse control disorders (ICDs) 
such as trichotillomania (TTM), excoriation (skin picking) disorder, obsessive compulsive 
disorder, and various addictions. Dysfunction in areas of the brain responsible for regulating 
cortical control over urges and motor habits are purported to underlie the pathological 
progression of ICDs (Froeliger et al., 2017, Froeliger et al., 2015). Evidence supporting this 
contention arises out of functional magnetic resonance imaging studies linking behavioral 
dysfunction to abnormal signaling and connectivity in the brain’s inhibitory control circuitry 
namely, the cortico-striatal pathway that originates in the frontal cortex and innervates the 
lower limbic areas responsible for movement and reward.  
Several clinical studies (e.g., LaRowe et al., 2007; Amen et al., 2011; Froeliger et al., 2015) in 
non-treatment-seeking nicotine or cocaine addicts have shown that following a brief abstinence 
period, subjects in acute withdrawal exhibit deficits in inhibitory control, measurements of 
executive function (e.g., impulsiveness) and mood. Therefore, short periods of nicotine 
abstinence in otherwise healthy volunteers represent a consistent approach to evaluate and 
further characterize the ability of novel therapeutic agents designed to restore cortical function 
and overall behavioral control by reversing deficits in impulsive behavior. 
Promentis Pharmaceuticals is developing SXC-2023, a novel small molecule designed to 
activate System xc- (also known as the cystine-glutamate antiporter). By increasing cyst(e)ine 
levels, SXC-2023 increases the activity of System xc- in the brain. System xc- is expressed 
within the brain’s inhibitory pathway, namely the cortico-striatal pathway (Lutgen et al., 2014), 
and more specifically, on astrocytes within this area of the brain and throughout the CNS. The 
primary function of System xc- is to couple the uptake of one extracellular molecule of cystine 
to the release of one intracellular molecule of glutamate. As alterations in glutamate 
neurotransmission and/or oxidative imbalances in the CNS are proposed to contribute to the 
pathogenesis and maintenance of various ICD behaviors (e.g., TTM), this mechanism of 
activating System xc- may represent an important pathway to modulate glutamatergic 
neurotransmission and restore imbalances in oxidative stress to restore control of various 
pathological behaviors.  
SXC-2023 is currently under investigation for the treatment of TTM in adults (Investigational 
New Drug [IND] No. 133689).  
This current study is being performed to evaluate SXC-2023 on measures of 
abstinence-induced impulsivity and inhibitory control impairment, urge, and mood in smokers 
who have abstained from smoking. 
Refer to the Investigator’s Brochure, Version 5.0 (SXC-2023, 2018) for detailed background 
information on SXC-2023. 


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3.1.1 
Preclinical Trials 
3.1.1.1 
Pharmacology 
In preclinical rodent models, SXC-2023 was found to produce anxiolytic activity as measured 
by an increase in the time spent in the open arm of the elevated plus maze, which is used to 
measure anxiety (a symptom of many psychiatric disorders and a clear indication of CNS 
penetration) and ameliorate N methyl-D-aspartate receptor antagonist (MK-801)-induced 
deficits in pre-pulse inhibition, which tests behavior that is dependent on cortical glutamatergic 
transmission. Additionally, acute and chronic (7-day) administration of SXC-2023 
significantly lowered the number of lever presses to reinstatement cocaine-seeking behavior. 
These studies, coupled with a study using rats engineered to lack a functional cystine-glutamate 
antiporter (specifically the xCT light chain protein), suggest that SXC-2023, through activation 
of System xc-, reverses deficits associated with glutamatergic dysfunction and heightened 
levels of oxidative stress implicated in the pathophysiology of ICDs. 
3.1.1.2 
Pharmacokinetics 
Following oral administration of SXC-2023, the absolute bioavailability in dogs, the only 
species in which this has been studied, is 17.2%. 
SXC-2023 is rapidly absorbed in all species following oral administration, with peak plasma 
concentrations typically occurring within 2 hours post-dose. In whole blood, most of the 
SXC-2023 and N-acetylcysteine (NAC) (a metabolite of SXC-2023) are present in the plasma, 
with high protein binding (>96%) at a concentration of 10 µM (2.81 µg/mL). Compared to 
total plasma concentrations, concentrations of SXC-2023 and metabolites (NAC and p-toluic 
acid) in red blood cells (RBCs) appear to be consistently lower . Metabolism of SXC-2023 was 
evaluated using rat, monkey, and human hepatocytes. In each species, the primary metabolites 
were NAC and p-toluic acid. Another possible minor pathway of SXC-2023 metabolism 
includes deamidation followed by cysteine conjugation. 
Based on preliminary data, the parent drug and both metabolites appear to have relatively short 
plasma half-lives (<6 hours). The metabolites are polar, therefore extensive renal clearance 
and urinary excretion are expected. 
Based on in vitro studies to assess the potential of SXC-2023 to inhibit, induce, or be 
metabolized by cytochrome P450 enzymes, it is anticipated that the likelihood of drug-drug 
interactions with SXC-2023 is minimal, with a possible exception for inhibition of cytochrome 
P450 P2C8 (showing half-maximal inhibitory concentration of enzyme activity of 570 μM). 
In vitro data indicate that SXC-2023 may be a substrate of organic anion transporting 
polypeptide 1B1 and 1B3, but not of P-glycoprotein or breast cancer resistance protein. 
3.1.1.3 
Toxicity 
The safety and toxicity associated with chronic SXC-2023 treatment was evaluated in 2 species 
(rats and dogs) following a 28- or 90-day dosing period. In the 90-day toxicity studies, the 


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reversibility, persistence, or delayed occurrence of any SXC-2023-related effects was 
evaluated after a 28-day recovery phase.  
Once-daily oral administration of SXC-2023 for 28 days at 500, 1000, and 2000 mg/kg/day 
was well tolerated in both male and female rats. While non-adverse hematology observations 
and findings consistent with chronic progressive nephropathy were observed in this 28-day 
dosing study, no adverse findings were noted. Based on these findings and taking into 
consideration the overall wellbeing of the animals, the Study Director at the nonclinical 
contract research organization (CRO) considered the no observed adverse effect level 
(NOAEL) to be the highest dose tested (2000 mg/kg/day). However, given the increase in 
kidney weights and greater severity of findings in the kidney tubules at the highest dose in both 
sexes, Promentis conservatively considers the NOAEL to be 1000 mg/kg/day.  
In the 90-day rat toxicity study, SXC-2023 was well tolerated at 100, 300, and 1000 mg/kg/day 
and resulted in no adverse findings. Reversible, non-adverse clinical pathology findings 
included a higher incidence of ketones in the urine, mildly higher urine volume, and minimally 
to mildly lower urinary pH in males administered ≥300 mg/kg/day and females administered 
1000 mg/kg/day. Mildly lower T3 and T4 serum levels occurred in males administered 1000 
mg/kg/day and were not accompanied by any TSH changes or microscopic correlates. 
Microscopic findings at the terminal and recovery sacrifices were limited to minimal to 
moderate basophilic tubules and minimal to slight degeneration of tubules in animals 
administered 1000 mg/kg/day, which correlated with SXC-2023-related increased kidney 
weight parameters at the terminal sacrifice. Due to the mild severity of findings and the lack 
of impact on the health and well-being of animals administered 1000 mg/kg/day, effects for 
this dose were considered non-adverse. Thus, the NOAEL was determined to be 1000 
mg/kg/day. 
In Beagle dogs, SXC-2023 had no effect on survival when administered at doses up to 
1200 mg/kg/day for 28 days. No CNS safety or measurements of CNS excitotoxicity 
differences in neuron integrity were noted between controls and animals administered the 
highest dose of SXC-2023 (1200 mg/kg/day). Emesis/vomitus, excessive salivation, liquid 
feces, and overall loss of body weight in animals administered 1200 mg/kg/day were observed. 
Similar findings were occasionally noted in animals administered 250 mg/kg/day and 500 
mg/kg/day, and these findings were observed in the control animals as well.  
Decreased thymus weight parameters occurred in male dogs at all doses, statistically 
significantly different from vehicle control at doses of 250 and 1200 mg/kg/day but not 500 
mg/kg/day. Decreased cortical lymphocytes were observed in some males and females 
administered ≥ 250 mg/kg/day. Incidence of decreased cortical lymphocytes was variable, 
without a clear dose response, with minimal to slight severity in animals administered 250 or 
500 mg/kg/day and minimal to marked severity in animals administered 1200 mg/kg/day. 
Given the lack of clinical pathology correlates and dose response, these findings in the thymus 
did not impact the function of the organ and could be attributed to stress given the emesis, 
weight loss, and need for supplementation. 
Also, in the high-dose group, lower testis weights in male dogs administered 1200 mg/kg/day 
were correlated with the microscopic findings of degeneration and atrophy (slight to moderate) 


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of the seminiferous tubules, which were considered adverse. No effects on seminiferous 
tubules or testes weight were observed in animals administered 250 mg/kg/day or 500 
mg/kg/day. Based on these findings, the Study Director of the nonclinical CRO defined the 
NOAEL as 500 mg/kg/day; however, based on the similar exposure levels at 500 and 1200 
mg/kg/day groups, Promentis conservatively defined the NOAEL in this study to be 
250 mg/kg/day for 28 days.  
In addition, there is no effect on the male or female reproductive systems in rats or dogs at the 
NOAELs. At higher doses, sperm granuloma was noted in rats (2000 mg/kg/day) and 
decreased testes weight with microscopic degeneration and atrophy of the seminiferous tubules 
were noted in dogs (1200 mg/kg/day). In dogs (the only species tested for these effects), there 
was no effect on testosterone, prolactin, progesterone, or estradiol. 
In the 90-day dog toxicity study, SXC-2023 was well tolerated at 30, 100, and 300 mg/kg/day. 
No SXC-2023-related findings or adverse microscopic or macroscopic findings were noted in 
this study.  Similarly, no changes in measurements of hematology, immune system, ophthalmic 
or cardiovascular system were found in this 90-day dog tox study.  Therefore, the NOAEL was 
determined to be 300 mg/kg/day. 
Good Laboratory Practice (GLP) development and reproductive toxicology studies have also 
been completed following chronic SXC-2023 treatment.  Doses selected for these studies were 
based on the results from previous non-GLP dose range finding studies in pregnant rats and 
rabbits.  
In a GLP study to test for effects resulting from SXC-2023 treatment to female Wistar 
Hannover rats on various fertility parameters, females were orally dosed with SXC-2023 at 
either 0, 100, 300 or 1000 mg/kg/day (n=22 female rats per dose group) once daily beginning 
15 days before cohabitation, during cohabitation and continuing until Day 7 of gestation. All 
rats survived to scheduled euthanasia. There were no SXC-2023-related clinical observations, 
effects on body weight, body weight gain, food consumption, estrous cyclicity, mating and 
fertility, ovary weights, ovarian and uterine parameters or maternal gross necropsy findings at 
doses up to 1000 mg/kg/day. Therefore, the NOAEL of oral SXC-2023 in rats for both maternal 
toxicity and female fertility and early embryonic development was 1000 mg/kg/day, the 
highest dose tested. 
In a study to detect adverse effects of SXC-2023 on pregnant Wistar Hannover rats and 
development of the embryo and fetus, female rats were orally dosed with SXC-2023 at either 
0, 100, 300 or 1000 mg/kg/day (n=20 rats per group) once daily on Days 7 through 17 of 
gestation (DGs 7 through 17). All rats survived to scheduled euthanasia on DG 21. There were 
no SXC-2023-related changes in mean maternal body weights, body weight gains or food 
consumption up to 1000 mg/kg/day, the highest dose tested. There were no SXC-2023-related 
changes in ovarian, uterine, or litter parameters, including embryo-fetal survival and mean fetal 
body weights. Lastly, there were no SXC-2023-related fetal external, visceral, or skeletal 
malformations or variations observed up to 1000 mg/kg/day, the highest dose tested. 
In a GLP study to assess possible adverse effects of SXC-2023 on pregnant New Zealand 
White rabbits and development of the embryo and fetus following daily oral exposure from 


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implantation to closure of the hard palate (gestation day 7 to 19 [DG 7 to 19]), pregnant rabbits 
were orally dosed with SXC-2023 at either 0, 30, 100 and 300 mg/kg/day (n=20/dose group) 
once daily on DG 7 to 19. One rabbit in the control group and one rabbit in the 300 mg/kg/day 
group aborted on DG 25. Additionally, one rabbit in the 300 mg/kg/day group was euthanized 
due to severe body weight loss and reduced food consumption on DG 24. Mean maternal body 
weight gain was lower than controls by 23% from DG 10 to 13, and by 35% from DG 16 to 20 
(65% of the control). There was a mean maternal body weight loss for the interval DG 14 to 
15 of -9.07g. During the post dose period, mean body weight gains in this group were higher 
than the control (131% of the control from DG 20 to 29) such that overall mean body weights 
on DG 29 were comparable across all groups (including control). 
There were no SXC-2023-related changes in ovarian, uterine, or litter parameters, including 
embryo-fetal survival and mean fetal body weights up to 300 mg/kg/day. Mean male, female, 
and combined fetal weights were lower in the 300 mg/kg/day dose group compared to the 
control values (95%, 93%, and 94% of the control, respectively). Each of the mean the values 
was within the Testing Facility Historical Control Data range. Although these values were 
within the Testing Facility Historical Control Data, they were lower than the concurrent 
control. There were no SXC-2023-related fetal external or visceral malformations or variations 
observed up to 300 mg/kg/day. Fetal ossification site averages per fetus were comparable 
across all groups (including control). 
Based on the lower maternal body weight gain and body weight loss, reduced food 
consumption, at 300 mg/kg/day, the NOAEL of SXC-2023 was determined to be 
100 mg/kg/day in this study.  
Based on results from a pivotal Ames mutagenicity assay, a human peripheral blood 
lymphocyte chromosome aberration assay, and an in vivo micronucleus assay in Wistar rats, 
SXC-2023 is considered not genotoxic. 
Refer to the Investigator’s Brochure, Version 5.0 (SXC-2023, November 2018) for detailed 
information on SXC-2023. 
3.1.2 
Effects of SXC-2023 in Humans 
As described below, SXC-2023 has been investigated in a randomized, double-blind, 
placebo-controlled, single ascending dose (SAD) and food effect (FE) study in healthy subjects 
(PRO-101) and a randomized, double-blind, placebo-controlled, multiple ascending dose 
(MAD) study in healthy subjects (PRO-104). In both studies, SXC-2023 was administered as 
enteric capsule(s) in 50-mg or 200-mg unit dose strengths as single doses (up to 1600 mg) or 
multiple doses (up to 800 mg once per day [QD] for 14 days). Additionally, an open label oral 
contraceptive/drug-drug 
interaction 
(OC/DDI) 
study 
(PRO-103) 
to 
evaluate 
the 
pharmacokinetic (PK) effects of a single dose of SXC-2023 (800 mg) and oral contraceptives 
(norethindrone [NET]/ethinyl estradiol [EE2]) was completed. 
Safety and PK findings are briefly summarized herein. Refer to the Investigator’s Brochure, 
Version 5.0 (SXC-2023, 2018) for further information about the safety and PK data of 
SXC-2023. 


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3.1.2.1 
Safety 
As of 26 November 2018, a total of 96 subjects have been exposed to SXC-2023.  Overall, 
SXC-2023 has been generally safe and well-tolerated in doses ranging from 50 mg to 1600 mg 
in the single ascending dose (SAD) and food effect (FE) study, 800 mg in combination with 
oral contraceptives and 200 mg to 800 mg multiple ascending dose study for 14 days.  The 
most common adverse events in subjects randomized to SXC-2023 in all Phase 1 studies 
include headache (frontal, generalized, occipital, or temporal) in 11% of subjects, dizziness in 
5%, and constipation, myalgia and somnolence in 3% each. 
 
In all studies, changes from baseline in vital sign measurements and electrocardiogram (ECG) 
findings were also assessed. Vital signs were normal and no evidence of ECG abnormalities 
such as corrected QT (QTc) prolongation, was seen.  In addition, no abnormal laboratory 
findings reported were considered clinically significant by the Investigator. 
In the PRO-103 and PRO-104 studies, safety laboratory results indicated that several subjects 
exhibited notable shifts in urinalysis measures of occult blood or red blood cells postdose.  
These were most likely due to several subjects with menses during the studies.   
PRO-101: SAD/FE Study 
The SAD/FE study examined the safety and tolerability of single oral doses of SXC-2023 
ranging from 50 mg to 1600 mg. A total of 48 healthy, adult male and female subjects were 
enrolled in 6 cohorts of 8 subjects each (6 active and 2 placebo).  
SXC-2023 was safe and well-tolerated. A total of 36 subjects were dosed with SXC-2023 on 
Study PRO-101 in six cohorts (50 mg, 100 mg, 200 mg, 400 mg, 800 mg and 1600 mg). 
Overall, adverse events across body systems were mild or moderate.  In subjects who received 
SXC-2023, the most common AEs were headache (in 5 subjects), followed by constipation, 
nausea, vomiting, and presyncope (in 2 subjects each). There were no serious adverse events 
(SAEs) reported or subject discontinuations related to AEs, or deaths in this study.  
Additionally, there was no evidence of impact on safety parameters for SXC-2023 in the 
presence of food. 
Safety was also assessed by the incidence of changes from baseline in clinical laboratory, vital 
sign measures, and ECG findings. Safety laboratory results and vital signs were normal and no 
evidence of ECG abnormalities, such as corrected QT (QTc) prolongation, was seen.   
PRO-103: OC/DDI Study 
 
This open label OC/DDI study evaluated the effect of a single dose of SXC-2023 800 mg on 
the PK of single doses of 1 mg NET/0.035 mg EE2 (Ortho-Novum 1/35), in 28 healthy oral 
contraceptive-naïve females.  
 
Overall, AEs were reported by 36% of subjects, with 21% following EE2/NET alone and 18% 
following EE2/NET + SXC-2023.  The most common AEs were dizziness and headache, 
reported by 11% of subjects each.  The majority of AEs were mild in severity, with 6 
considered moderate in severity.  All AEs resolved by end of study and there were no clinically 


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important trends in AEs, clinical laboratory, vital signs, ECG, or physical examination 
assessments.  There were no deaths, SAEs, or subject discontinuations in this study.   
  
PRO-104: MAD Study  
The MAD study examined the safety, tolerability and PK of multiple oral doses (14 days) of 
SXC-2023 in four cohorts (200 mg QD, 400 mg QD, 400 mg twice daily and 800 mg QD) of 
10 subjects each (8 active and 2 placebo per cohort). Forty total subjects have been dosed with 
SXC-2023 or placebo.  
The MAD study examined the safety, tolerability and PK of multiple oral doses (14 days) of 
SXC-2023 in four cohorts (200 mg QD, 400 mg QD, 400 mg twice daily [BID] and 800 mg 
QD) of 10 subjects each (8 active and 2 placebo).  
Overall, SXC-2023 was well tolerated across all doses without any SAEs. Additionally, there 
were no subject discontinuations or deaths reported in this study. Adverse events were reported 
by 45% of SXC-2023-treated subjects regardless of attribution. The most common in subjects 
who received SXC-2023 was headache, reported by 12.5% (4/32) of subjects. All AEs were 
mild (Grade 1) to moderate (Grade 2) in severity in all dose groups; of those considered 
possibly related to study treatment, the majority of Grade 2 events were reported in the placebo 
group.  
All AEs resolved by the end of study and there were no clinically important trends in AEs, 
physical examination or clinical laboratory assessments. However, two subjects treated with 
SXC-2023 with treatment emergent adverse events (TEAEs) of urinary tract infection or 
asymptomatic bacteriuria recorded notable post-baseline laboratory results, including positive 
shifts in urinalysis measures of occult blood, leukocyte esterase, and red and white blood cells, 
as well as positive urine nitrites and urine culture growth.   
There was no observed impact on neurocognitive assessments or suicidality via the Columbia-
Suicide Severity Rating Scale (C-SSRS). 
3.1.2.2 
Pharmacokinetics and Product Metabolism 
PRO-101: SAD/FE Study 
The PK of SADs of SXC-2023 was evaluated in Study PRO-101. Six cohorts of subjects 
received SADs of SXC-2023 (50 mg, 100 mg, 200 mg, 400 mg, 800 mg fasted, 800 mg fed, 
and 1600 mg). SXC-2023 concentrations were measurable in all subjects; NAC and p-toluic 
acid were measurable in a few sporadic samples across the dose levels tested. Plasma SXC-
2023 concentrations increased with increasing dose and were dose-proportional to 1600 mg. 
On average, maximum observed concentration (Cmax) ranged from 1,094 ng/mL for the 50 mg 
dose to 35,217 ng/mL for the 1600 mg dose. Time to reach maximum observed concentration 
(tmax) was consistent across doses and was approximately 3.0 to 3.5 hours. The elimination 
half-life for SXC-2023 was approximately 3 to 6 hours over the 50 to 1600 mg dose range 
tested. Co-administration of SXC-2023 800 mg with a high-fat meal resulted in lower Cmax and 


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a delay in tmax. Exposure, as assessed by area under the concentration-time curve (AUC), was 
slightly increased following administration of SXC-2023 with a high-fat meal. 
PRO-103: OC/DDI Study 
Concomitant SXC-2023 administration does not have an impact on the PK of NET or EE2. 
Changes in EE2 drug exposure were not seen with concomitant SXC-2023 and the 90% 
confidence intervals for EE2 were within the 80-125% confidence limits demonstrating 
bioequivalence. For NET, the confidence intervals suggest that NET levels are slightly higher 
with concomitant SXC-2023; the test/reference ratios were 116% for Cmax and approximately 
124% for the AUC parameters and the upper bounds for the confidence intervals were just 
outside the 125% upper range. These changes, however, were not considered clinically 
relevant. 
PRO-104: MAD Study 
Based on preliminary quality-controlled data, following single dose administration, the mean 
Cmax of SXC-2023 under fasted conditions ranged from 6305 ng/mL for the 200 mg QD dose 
to 30, 540 ng/mL for the 800 mg dose. On Day 14, the mean Cmax of SXC-2023 under fasted 
conditions ranged from 7990 ng/mL for the 200 mg QD dose to 30,540 ng/mL for the 800 mg 
dose. Median tmax was consistent across doses and dosing days and ranged from 2 to 6 hours. 
The elimination half-life for SXC-2023 was approximately 3.4 to 6.2 hours over the 200 mg 
to 800 mg dose range on Day 1 and 9.4 to 11.7 hours over the 200 mg to 800 mg dose range 
on Day 14. Minimal accumulation was evident for SXC-2023 following repeated QD and BID 
dosing and mean accumulation ratios were 1.08 to 1.58 over the 200 mg to 800 mg dose ranged 
tested and the PK of SXC-2023 was dose proportional with respect to Cmax and AUC on Day 1 
and Day 14. 
The urinary excretion data demonstrated that very little of the administered dose of SXC-2023, 
<0.2%, was excreted in urine over the 200 mg to 800 mg dose range. 
Following administration of single and multiple oral doses of SXC-2023 200 mg to 800 mg 
under fasted conditions, plasma and urine NAC levels were not quantifiable using the validated 
free NAC method in any subject throughout the sampling interval.  
Following administration of SXC-2023 under fasted conditions, p-toluic acid was generally 
measurable in all subjects on Day 1 and Day 14. Mean maximum concentrations for p-toluic 
acid ranged from 31.98 ng/mL for the 200 mg dose group to 140.1 ng/mL for the 800 mg dose 
group on Day 1. On Day 14, mean maximum concentrations ranged from 44.09 ng/mL to 
84.11 ng/mL over the 200 mg to 800 mg dose range tested. 
Many subjects also had no measurable concentrations of urine p-toluic acid following dosing 
with SXC-2023; no clear pattern or trends in urinary excretion could be established. 


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3.2 
Rationale 
3.2.1 
Rationale for this Study and Study Design 
Impaired cortical control over impulses, mood, urges, and other behaviors is a hallmark feature 
of several disorders of the CNS, specifically, ICDs such as TTM. Several clinical studies (e.g., 
LaRowe et al., 2007; Amen et al., 2011; Froeliger et al., 2015) in non-treatment-seeking 
tobacco or cocaine addicts have shown that following a brief abstinence period, subjects in 
acute withdrawal exhibit deficits in inhibitory control, measurements of executive function 
(e.g., impulsiveness) and mood. Therefore, short periods of tobacco abstinence in otherwise 
healthy volunteers represent a consistent approach to evaluate and further characterize the 
ability of novel therapeutic agents designed to restore cortical function and overall behavioral 
control by reversing deficits in impulsive behavior. 
SXC-2023 is currently under investigation for the treatment of TTM in adults (IND No. 
133689). This study is being performed to evaluate and assess the dose range of SXC-2023 
that can modify measurements designed to assess impulsivity and inhibitory control, urge for 
cigarettes, and mood for 5 days in smokers who have abstained from smoking.  
3.2.2 
Rationale for Dose Selection 
The proposed doses of SXC-2023 in this study are 200 mg QD and 800 mg QD. These doses 
were selected based on nonclinical activity of SXC-2023 in various rat models showing 
behavioral activity at a dose range of 10 to 30 mg/kg, which, based on allometric scaling, is 
equivalent to approximately 100 to 300 mg in human equivalent dosing. These data support 
the starting dose of 200 mg in the current study.   
The safety and tolerability profile in the SAD/FE study performed in healthy male and female 
volunteers, where subjects received single doses up to 1600 mg, support the higher dose of 
800 mg proposed in the current study. Additionally, support for these doses comes from recent 
safety and tolerability profiles captured in a MAD study performed in healthy volunteers, 
showing that 14-day oral administration of SXC-2023 at 200 mg QD, 400 mg QD and BID 
and 800 mg QD was generally safe and well tolerated.  
3.3 
Risks and/or Benefits to Subjects 
As mentioned in Section 3.1.2.1, SXC-2023 was studied in a Phase 1, double-blind, 
placebo-controlled, SAD/FE study (Study PRO-101) in healthy volunteers. SXC-2023 was 
safe and well tolerated at doses of 50 mg to 1600 mg. The safety monitoring practices 
employed by this protocol (i.e., physical examination, vital signs, 12-lead ECGs, clinical 
laboratory tests, and AEs) were adequate to protect the subjects’ safety and detected all 
expected treatment-emergent AEs (TEAEs). 
In the MAD study, SXC-2023 was generally safe and well tolerated at doses of 200 mg to 800 
mg QD and 400 mg BID. The safety monitoring practices employed by this protocol (i.e., 
physical examination, vital signs, 12-lead ECG, neurocognitive testing, clinical laboratory 
tests, and AEs) are adequate to protect the subjects’ safety and detected all expected TEAEs. 


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Additionally, cognitive tests were included as part of a broader cognitive safety assessment 
along with the C-SSRS to ensure that there were no CNS side effects. 
In the current study, subjects will be monitored to detect AEs during the study and followed 
appropriately to ensure resolution of AEs. Further, clinical laboratory tests, physical 
examination, vital signs, and ECGs will be used to evaluate safety. 
The approximate volume of blood planned for collection from each subject over the course of 
the study presents no undue risk to the subjects. 
There will be no direct health benefit for study participants from receipt of the study drug. An 
indirect health benefit to the healthy subjects enrolled in this study is the free medical tests 
received at screening and during the study, as well as brief periods of abstinence from tobacco 
use. 
4 STUDY OBJECTIVES  
4.1 
Primary Objectives 
• To explore the safety and tolerability of SXC-2023 when dosed for 5 days in adults 
diagnosed with tobacco use disorder (i.e., cigarette smokers) who voluntarily abstain 
from the use of cigarettes. 
• To test the activity of SXC-2023 when dosed for 5 days on measures of 
abstinence-induced impulsivity and inhibitory control, urge for cigarettes, and mood. 
4.2 
Exploratory Objectives 
• To explore the effects of 5 days of tobacco abstinence on levels of total and/or 
reduced glutathione (GSH) in blood/plasma. 
• To test the possible effects of SXC-2023 on levels of total and/or reduced GSH 
deficits via assay of blood/plasma GSH levels.   
INVESTIGATIONAL PLAN 
4.3 
Overall Study Design and Plan 
This randomized, double-blinded, placebo-controlled, crossover study will evaluate the effect 
of two doses of SXC-2023 on measures of impulsivity and inhibitory control, urge for 
cigarettes, and mood in non-treatment seeking smokers who are abstaining from smoking. To 
be eligible, subjects must meet the protocol-specified eligibility criteria which include a score 
of ≥4 on the Fagerstrom Test of Nicotine Dependence (FTND) at screening and an expelled 
carbon monoxide (CO) level of ≥10 ppm at screening and on Day 1 of Period 1, prior to dosing.  
On Day 1 of Period 2, subjects who have a score of < 4 on the FTND and have a CO level of 
<10 ppm can continue on study.   
To date, four (4) total subjects have been dosed at Baylor.  At Celerion, two groups of 14 
subjects, a total of 28 subjects, will be assigned to receive two treatment regimens: SXC-2023 


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200 mg QD vs. matching placebo or SXC-2023 800 mg QD and matching placebo, in a 
2-treatment crossover design. Subjects will receive one treatment regimen per 5-day treatment 
period of the crossover with a 9-day washout between treatment periods where subjects will 
be able to smoke as usual. Subjects will be randomized to treatment pair comparison (SXC-
2023 200 mg QD vs. matching placebo, SXC-2023 800 mg QD vs. matching placebo) and to 
treatment sequence within each pair. Twenty eight total subjects are planned. Seven (7) 
subjects will be randomized to each of the 4-treatment pair sequence combinations.  However, 
subjects who complete Period 1 in Group 1 but do not return on Day 1 of  Period 2 of the 
crossover will be replaced in Group 2.  A total of 4 subject replacements may be enrolled in 
Group 2.    
Subjects can smoke as usual up until they enter the Celerion facility for start of the study on 
Period 1, Day 1. Subjects will abstain from ingesting all forms of nicotine during both Periods 
of the crossover.  Subjects participating at Celerion will be confined with no access to 
cigarettes/nicotine throughout the duration of Period 1 and Period 2 of the study.  Subjects who 
relapse during Period 1 or Period 2 of the study will be terminated from the study and not 
permitted to re-screen.  
Measurements of neurocognitive control will be performed on Day 1 prior to study drug 
administration and approximately 4-5 hours post dose on Day 5 to assess the effect of SXC-
2023 on abstinence-induced measures of impulsivity and inhibitory control. Additional 
assessments will include measures of urge for cigarettes and mood. Neurocognitive testing will 
include the Stop Signal Task (SST), Cambridge Gambling Task (CGT), Paired Associates 
Learning (PAL), Reaction Time (RTI), Questionnaire on Smoking Urges (QSU), Positive and 
Negative Affect Schedule (PANAS), and the Cigarette Evaluation Questionnaire (CEQ). Cue 
reactivity will be evaluated using the International Affective Picture System (IAPS) images 
(for neutral and positive images) and those validated in the TRAIN lab at MUSC (PI Froeliger) 
and smoking images on Day 2 (following 24 hours of abstinence) and on Day 5, and two Likert 
scale assessments will be performed on Days 2 and 5. Levels of GSH in whole blood will be 
collected at baseline (prior to dosing on Day 1) and after 5 days of tobacco abstinence (after 
dosing on Day 5). Following the completion of the first 5 days of treatment with SXC-2023 
200 mg QD, SXC-2023 800 mg QD, or placebo, subjects will be allowed to go home and 
smoke ad lib during a 9-day washout period. Following the washout period, subjects will 
crossover into Period 2 of this study and will receive a different study drug and will repeat the 
study procedures and assessments employed in Period 1, unless noted otherwise in Section 6.4.  
A follow-up visit will be scheduled to occur approximately 7-10 days after the last dose of 
study drug (SXC-2023 200 mg, SXC-2023 800 mg, or placebo) is administered. 
The study design in outlined in Figure 1. The Schedule of Events is provided in Appendix A, 
and list and description of the assessments performed at each study day are presented in Section 
6. 


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Figure 1 
Diagram of Study Design 
 
As discussed in Section 5.1, subjects will be enrolled in 2 groups. 
4.4 
All Parts 
Safety will be monitored throughout the study by repeated clinical and laboratory evaluations.   
Subjects who do not return prior to start of Period 2 in Group 1, may be replaced in Group 2.  
A total of 4 subject replacements may be enrolled in Group 2.    
4.5 
Confinement, Return Visits and Follow Up 
Twenty-eight (28) subjects will be housed on Day 1, at the time indicated by the CRU, until 
the end of Period 1 procedures on Day 5.  A subject may be required to remain at the CRU for 
longer at the discretion of the PI or designee.  The subjects will leave the site and will be 
instructed to smoke if they like, prior to their return to site on Day 1 of Period 2.  All subjects 
will be released after all procedures are performed on Day 5 of Period 2.  All subjects who 
receive a dose of study drug/placebo (including subjects who terminate the study early) will 
return to the CRU approximately 7 days after the last study drug/placebo administration for 
follow up procedures, and to determine if any AEs have occurred since the last study visit.    
4.6 
Study Duration 
Subjects will be dosed for 5 consecutive days in each treatment period. The maximum 
anticipated subject participation will be approximately 59 days (30 days for screening period, 
5 days for Period 1 of the crossover, 9 days for the washout, 5 days for Period 2 of the 
crossover, and maximum of 10 days until the follow-up visit). 


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4.7 
Study Conduct 
Please see the Schedule of Events (Appendix A) for a summary of the study assessments and 
procedures. Please see Section 6 for a listing and description of study procedures. 
5 STUDY POPULATION 
5.1 
Number of Subjects 
A total of 36 subjects may be enrolled on this study.  To date, four (4) subjects were enrolled 
at Baylor College of Medicine.   
At Celerion, subjects will be enrolled in two (2) groups.  Up to 32 subjects are planned to enter 
this study (a total of 28 subjects will be enrolled with an additional 4 subjects to be used as 
replacements).  With a crossover design illustrated in Figure 1, 14  subjects will be exposed to 
SXC-2023 200 mg and placebo, and 14  subjects to SXC-2023 800 mg and placebo.  Four 
subjects can be used as replacements.  Subjects who do not return prior to start of Period 2 in 
Group 1, may be replaced in Group 2.   
Including an anticipated 10% dropout rate at Celerion, no more than 32 subjects will be 
exposed to SXC-2023.   
At both sites, no more than 36 total subjects will be exposed to SXC-2023 in this study. 
5.2 
Eligibility Criteria 
5.2.1 
Inclusion Criteria 
Subjects eligible for the study must meet all the following inclusion criteria: 
1. Adult, female or male, 25-55 years of age, inclusive at screening.   
2. BMI ≥ 16.0 and ≤ 35.0 kg/m2 at screening. 
3. Has provided signed written informed consent and has willingness and ability to 
comply with all aspects of the protocol, including abstaining from the use of and 
tobacco/nicotine products for two 5-day periods. 
4. Non-treatment seeking smokers regularly using tobacco with a FTND score ≥4 at 
screening and self-reported use of ≥10 cigarettes/day at screening. 
5. Has smoked for > 5 years at screening. 
6. Meets Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) 
criteria for tobacco use disorder. 
7. Must have a score of  ≥4 on the FTND and expired-air CO level ≥10 ppm during initial 
screening visit and prior to first dose. 


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8. For a female of childbearing potential: either be sexually inactive (abstinent as a life 
style) for 28 days prior to the first dosing and throughout the study or be using 
acceptable birth control methods as described in Section 5.2.2.4. 
9. Female of non-childbearing potential: must have undergone one of the following 
sterilization procedures, at least 6 months prior to the first dose: 
• hysteroscopic sterilization; 
• bilateral tubal ligation or bilateral salpingectomy; 
• hysterectomy; 
• bilateral oophorectomy; 
Or be postmenopausal with amenorrhea for at least 1 year prior to the first dose with 
serum follicle stimulating hormone levels consistent with postmenopausal status or have 
medically documented history of biological or congenital sterility. 
10. Has not used Aricept (a cholinersterase inhibitor) 30 days prior to screening.  
5.2.2 
Exclusion Criteria 
Subjects who meet any one of the following criteria must NOT be enrolled in the study: 
1. Subject is mentally or legally incapacitated or has significant emotional problems or 
clinically significant abnormality at the time of the screening visit or expected during 
the conduct of the study. 
2. Subject suffered a concussion 6 months or less prior to screening. 
3. Females who are pregnant or breastfeeding. 
4. Positive for active hepatitis, human immunodeficiency virus, coagulopathy, or hepatic 
illness. 
5. Use of Selective Serotonin or Norepinephrine Reuptake Inhibitors (SSRI/SNRI) for 
psychiatric illness (e.g. depression, anxiety, etc.), unless subject has been on a stable 
dose for at least 30 days prior to screening. 
6. Use of  antipsychotics or antiepileptics within 30 days prior to screening 
7. Use of N-acetylcysteine within 30 days prior to screening. 
8. Use of Chantix or related smoking cessation medications (e.g., NicoDerm path, 
Nicorette gum, etc) within 30 days prior to the first dose. 
9. Use of sulfasalazine (Azulfidine®) within 30 days prior to the first dose. 
10. DSM-5 criteria for alcohol/substance use disorder (except for tobacco use disorder).  


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11. History or presence of clinically significant psychiatric condition (except for tobacco 
use disorder) or disease in the opinion of the Principal Investigator (PI) or designee. 
12. History of any illness that, in the opinion of the PI or designee, might confound the 
results of the study or poses an additional risk to the subject by their participation in 
the study. 
13. History of seizures. 
14. Any history of psychiatric hospitalization in the past year. 
15. Currently participating in a clinical study. 
16. Previously participated in Phase 1 Promentis studies or dosed in this Phase 2A study.  
17. FTND score <4 at screening and  expelled CO levels <10 ppm at screening and prior 
to first dose. 
18. Any clinically significant laboratory, ECG and/or vital sign abnormalities at screening. 
19. Unable to read/understand/speak English. 
 
5.2.3 
Restrictions 
5.2.3.1 
Smoking and Other Forms of Nicotine 
Subjects are to abstain from smoking cigarettes and ingesting all forms of nicotine (e.g., 
vape/e-cig, any form of nicotine replacement therapy including nicotine gum or patches, 
chewing tobacco) from Day 1 (starting on Day 1) through Day 5 in each period of the 
crossover. Testing for CO and urine cotinine will be performed prior to dosing on Day 1 and 
Day 5 of each study Period and at the discretion of the PI, on all other study days to confirm 
abstinence.  Subjects who do not abstain from all forms of nicotine use during Period 1 and 
Period 2 will be released from participating in the study.  
5.2.3.2 
Meals 
On Day 1 of each study Period, subjects must be fasted prior to first dose of study drug.  
Subjects will not eat for at least 1 hour after dosing.  On all other days during each Period, 
blinded study drug (SXC-2023 or placebo) will be administered at least 2 hours after breakfast 
and subjects will not  eat for at least 1 hour after dosing. Water is permitted at all times. 
5.2.3.3 
Prior/Concomitant Medications 
Subjects who have used the following will NOT be permitted in the study: 
• Antipsychotics or antiepileptics within 30 days prior to screening.   


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• SSRI/SNRI for psychiatric illness is not permitted unless subject has been on a stable 
dose for at least 30 days prior to screening. 
• NAC within 30 days prior to screening. 
• Chantix or related smoking cessation medications within 30 days prior to the first dose. 
• Sulfasalazine (Azulfidine®) within 30 days prior to the first dose. 
• Aricept within 30 days prior to screening. 
• Positive urine screen for drugs of abuse at screening or check-in. 
5.2.3.4 
Contraceptive Requirements 
Contraceptive requirements for male subjects are as follows: 
1. A non-vasectomized, male subject must agree to use a condom with spermicide or 
abstain from sexual intercourse during the study until 30 days beyond the last dose of 
study drug. (No restrictions are required for a vasectomized male provided his 
vasectomy has been performed 4 months or more prior to the first dose of study drug. 
A male who has been vasectomized less than 4 months prior to the first dose of study 
drug must follow the same restrictions as a non-vasectomized male). 
2. Males must also agree not to donate sperm from the first dose until 30 days after the 
last dose administration. 
Contraceptive requirements for female subjects are as follows: 
1. For a female of childbearing potential: either be sexually inactive (abstinent as a life 
style) for 28 days prior to the first dosing and throughout the study or be using one of 
the following acceptable birth control methods:  
• Oral contraceptives or mini pill used for at least 3 months prior to the first dose 
except for subjects ≥ 35 years of age. 
• Non-hormone releasing intrauterine device and progestin containing intrauterine 
device for at least 30 days prior to the first dose and with either a physical (e.g., 
condom, diaphragm, or other) or a chemical (e.g., spermicide) barrier method from 
the time of screening and throughout the study.  
• Subdermal hormonal implant (i.e. implanon) 
• Double physical barrier method (e.g., condom and diaphragm with spermicide) 
from 14 days prior to the first dose and throughout the study. 


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In addition, female subjects of childbearing potential will be advised to remain sexually 
inactive or to keep the same birth control method for at least 7 days following the last 
dose. 
2. Female of non-childbearing potential: must have undergone one of the following 
sterilization procedures, at least 6 months prior to the first dose: 
• Hysteroscopic sterilization 
• Bilateral tubal ligation or bilateral salpingectomy 
• Hysterectomy 
• Bilateral oophorectomy 
Or be postmenopausal with amenorrhea for at least 1 year prior to the first dose. 
6 STUDY PROCEDURES 
6.1 
Screening (Day −30 to Day -1) 
All assigned subject numbers must be maintained in real time in the electronic database. A 
copy will be filed in the Investigator Binder. 
The following assessments will be performed: 
• Informed consent must be obtained before any other study assessments or procedures. 
• Assessment of inclusion/exclusion criteria. 
• Demographics, medical history, and drug use history will be recorded. 
• Prior/concomitant medications will be recorded. 
• A full physical examination will be performed. 
• Vital signs (blood pressure and heart rate) will be recorded after the study subject has 
been resting supine for ≥5 minutes. 
• A 12-lead ECG will be completed after the study subject has been resting supine for 
≥5 minutes. 
• Safety laboratory tests (hematology, chemistry, coagulation, urinalysis) and screening 
serology tests will be performed. 
• Urine drug screen and serum pregnancy tests (in female subjects) will be performed. 
• Expelled CO levels will be measured and must be ≥10 ppm. 


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• A urine sample will be collected for assessment of urine cotinine. 
• The FTND will be completed and the score must be ≥4. 
• The Barratt Impulsiveness Scale (BIS), will be performed on the iPad to capture trait 
impulsivity at the start of the study and to also confirm each subject’s ability to read, 
write, and understand English. 
• Subjects will be trained on the Cambridge Neuropsychological Test Automated 
Battery (CANTAB) iPad device installed with the SST, CGT, RTI, and PAL.  
• Any AEs occurring after informed consent is obtained will be recorded. AEs occurring 
after informed consent signature but before the first dose of blinded study drug will be 
collected as medical history. 
• Subjects will be instructed that they are allowed to smoke as usual during the screening 
period, prior to start of the Day 1 Period 1 and during the study washout (9 day) period. 
6.2 
Period 1 of Crossover 
6.2.1 
Day 1  
Subjects will arrive at the site on Day 1 of the first period of the crossover having smoked as 
usual. 
The following must be done prior to dosing: 
• CO testing will be performed. Subjects with <10 ppm on the CO test will be released 
from participating in the study.  A self-report of number of cigarettes smoked in the 
last 24 hours and approximate time of last cigarette smoked prior to Celerion facility 
entry will also be captured. 
•  Urine cotinine samples will be collected for all subjects (at Day 1 of each period of the 
crossover and at the PI or designee’s discretion on other days)  and subsequently 
assayed for cotinine to biochemically ascertain if there was any new nicotine exposure 
during the study.  
• Serum pregnancy tests will be performed for female subjects. 
• A 12-lead ECG will be completed after the study subject has been resting supine for 
≥5 minutes. 
• A blood sample for GSH will be taken. 
• Fasting state blood sample and urine sample will be taken for clinical laboratory tests 
(hematology, coagulation, chemistry, and urinalysis). 
• CANTAB testing (SST, CGT, RTI, PAL) will be performed on the iPad. 


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Additional tests on the iPad will include scales to measure craving for cigarettes (QSU), mood 
(PANAS), self-reported reinforcement (CEQ), FTND will be completed and the score must be 
≥4.   
• Vital signs (blood pressure and heart rate) will be recorded after the study subject has 
been resting supine for ≥5 minutes. 
• Drug screen will be performed. 
• Abbreviated physical examination. 
Subjects will then be randomly assigned to one of two doses of SXC-2023 or matching 
placebo. Capsules will be administered on site by qualified personnel to confirm dosing 
requirements (see Section 8.2 for dosing procedures).  
AEs and concomitant medications will be recorded. 
Subjects will not  eat for at least 1 hour after dosing.  
6.2.2 
Day 2, Day 3, and Day 4 
The study procedures for each of these days will be identical (unless otherwise specified). 
Subjects are to continue to abstain from smoking and ingesting nicotine each day.  
Each day (unless otherwise specified), the following will occur: 
• At the discretion of the PI or designee, CO will be measured and subjects will be 
questioned about abstinence. Subjects with >5 ppm on CO test will be released from 
participating in the study.  
• At the discretion of the PI or designee, urine cotinine samples may be collected and 
subsequently assayed to biochemically ascertain if there was any new nicotine 
exposure.   
• On Day 2 only, the following assessments will be performed prior to dosing: cue 
reactivity with two Likert scale assessments (see Section 7.3.6).  
• Subjects will be given their assigned dose of study drug (see Section 8.2 for dosing 
procedures) in the morning, at least 2 hours prior to breakfast or at least 1 hour post. 
• Any AEs or concomitant medications will be recorded. 
• Vital signs (blood pressure and heart rate) will be recorded after the study subject has 
been resting supine for ≥5 minutes. 
• At the discretion of PI or designee, symptom-driven physical exam will be performed 


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6.2.3 
Day 5  
The following will be performed prior to dosing (unless otherwise stated): 
• CO will be measured and subjects will be questioned about abstinence. Subjects with 
>5 ppm on CO test will be released from participating in the study.  
• Urine cotinine samples will be collected in all subjects and subsequently assayed for 
cotinine to biochemically ascertain if there was any new nicotine exposure.  
• Abbreviated physical examination. 
• Vital signs (blood pressure and heart rate) will be recorded after the study subject has 
been resting supine for ≥5 minutes. 
• Subjects will receive their assigned dose of blinded study drug (see Section 8.2 for 
dosing procedures).  
• Any AEs or concomitant medications will be recorded. 
• After dosing, ECG will be recorded after the study subject has been resting supine for 
≥5 minutes. 
• After dosing, blood will be collected to measure levels of GSH.  
• Clinical laboratory testing (hematology, coagulation, chemistry, and urinalysis) will be 
performed after dosing. 
• At approximately 4-5 hours post-dose, subjects will undergo the same neurocognitive 
testing used on Day 1, with the cue reactivity and two Likert scales being done prior to 
the other neurocognitive assessments.  
• The CANTAB assessments should also be performed 4-5 hours post-dose. 
Assessments of craving (QSU), mood (PANAS), and self-reported reinforcement 
(CEQ) will follow the CANTAB assessments on the iPad. 
• Subjects will be released from the site and will be allowed to smoke as usual. 
6.3 
Washout Period (9 days) 
Following Day 5 of Period 1, subjects will enter a washout period of 9 days during which they 
will be permitted to smoke and/or ingest nicotine.  
Subjects may start smoking as soon as they are released from the site at the conclusion of Day 
5 and may then smoke prior to entry in the Celerion facility on Day 1 of Period 2.  


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6.4 
Period 2 of Crossover 
In Period 2 of the crossover portion of the study, subjects will repeat Days 1 through 5. They 
will be treated with a different treatment than they received in Period 1 of the crossover, based 
on the randomized assignment. The procedures are identical for Days 1 through 5 above 
(Section 6.2), except for the following:  
• FTND will be administered on Day 1. Subjects with <4 score on FTND can continue 
to participate in the study. 
• CO testing will be performed. Subjects with <10 ppm on the CO test can continue to 
participate in the study. 
All subjects who decide to withdraw consent or dropped from the study will not be able to re-
enter the study. 
6.5 
Follow-up Visit/Early Termination (7-10 days after last dose) 
Subjects who complete the crossover portion of the study will return for a follow-up visit 
approximately 7 days  after the last dose. Subjects who terminate the study early will also be 
asked to return for the follow-up visit at the same interval as post last dose. 
The following assessments will be performed: 
• Abbreviated Physical examination will be performed, and an assessment of smoking 
status/smoking behaviors (including the number of cigarettes/packs of cigarettes 
smoked since the last dose) will be recorded. 
• Vital signs (blood pressure and heart rate) will be assessed after the study subject has 
been resting supine for ≥5 minutes. 
• A 12-lead ECG will be completed after the study subject has been resting supine for 
≥5 minutes. 
• Clinical laboratory testing (hematology, coagulation, chemistry, and urinalysis) will be 
performed. 
• Serum pregnancy tests will be performed for female subjects. 
• Any AEs or concomitant medications will be recorded. 
6.6 
Early Withdrawal 
While subjects are encouraged to complete the study, all subjects are free to withdraw from 
participating in this study at any time and for whatever reason, specified or unspecified, and 
without prejudice. If the subject withdraws, the reason will be carefully documented in specific 
language. Subjects who withdraw from the study will not be allowed to re-enter. 


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Reasons for premature discontinuation from the study, which will be listed on the Subject 
Disposition case report form (CRF), are defined as follows: 
Table 1 
Reasons for Discontinuation 
Adverse Event  
Subject is withdrawn from the study due to an AE or any clinically 
significant laboratory, vital signs or ECG abnormalities. 
Complete AE form and attempt to follow the event until it is 
resolved or deemed stable. 
Subject Request 
Subject withdraws consent. If reason is provided, explain in 
comments on Subject Disposition CRF.  
Protocol Violation 
Investigator wishes to terminate the subject from study treatment due 
to a protocol violation. Site monitor or Sponsor should be contacted 
before making decision. Explain in comments on the CRF. 
Lost to Follow-Up 
Subject does not return during Period 2 of the crossover. The 
Investigator will make reasonable efforts to contact subject and 
determine reason for discontinuation (phone call and if not reached 
by phone then follow with a registered letter). If not reached, the 
subject will be documented as “lost to follow-up.”  Subjects lost to 
follow up may be replaced. 
Other 
Any other reason for early subject withdrawal from study treatment 
or the study. Explain in comments. 
AE=adverse event; CRF=case report form 
Subjects withdrawing prematurely after taking study drug must undergo follow-up assessments 
at the time of termination (or as close as possible) and 7 days post last dose in case of reported 
AEs requiring resolution (Section 6.5). All study data from withdrawals must be retained. 
When an SAE or possibly or probably related AE persists at the end of the study, the PI will 
ensure a follow-up of the subject until the PI and Sponsor agree the event is satisfactorily 
resolved or stabilized. 
6.7 
Discontinuation of the Study 
The study will be discontinued if the Sponsor judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and Good Clinical 
Practice (GCP). 
 
7 CRITERIA FOR EVALUATION 
7.1 
Safety Evaluation 
7.1.1 
Medical History, Demographic and Other Baseline Information 
Medical history:  
• General medical/surgical history 


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• Information collected includes condition/procedure, year of onset, and year ended or 
condition continuing 
• For procedures and events such as accidents or fractures, year of occurrence should be 
entered for both year of onset and year ended. 
Medication history: 
• Information 
on 
all 
medications 
(investigational 
products, 
prescription, 
over-the-counter [OTC], and herbal medications) taken within the 30 days prior to the 
screening visit. 
Drug use history: 
• Information on prior and current drug and alcohol use will be recorded. 
Demographics: 
• Age (based on date of birth and date of screening visit) 
• Ethnic origin (Hispanic/Latino or Not Hispanic/Latino) 
• Race (White, American Indian/Alaska Native, Asian, Native Hawaiian or Other Pacific 
Islander, Black/African American) 
• Height (cm), without shoes 
• Body weight (kg), without shoes 
• Body mass index (weight [kg]/height [m2]) 
7.1.2 
Physical Examination 
A full physical examination at screening only will be performed as per the Schedule of Events 
(Appendix A). Abbreviated physical examinations will be performed on Days 1 and 5 of both 
Periods and follow up.  Symptom-driven physical examinations may be performed at other 
times, if deemed necessary by the PI or designee. 
7.1.3 
Vital Signs 
The following vital signs will be measured during all subject visits and inpatient days during 
the study:  
• Blood pressure (systolic and diastolic [mm Hg]) 
• Heart rate (beats per minute) 
Single measurements of blood pressure and heart rate will be performed as outlined in the 
Schedule of Events (Appendix A). Blood pressure and heart rate measurements will be 


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performed after the study subject has been resting supine for ≥5 minutes. Blood pressure 
measurements will be taken with the appropriate cuff size using automated equipment. The 
same arm is preferred for all measurements.  
Any clinically significant vital sign abnormality will be recorded as an AE and subject will be 
discontinued from the study.  
7.1.4 
12-Lead Electrocardiograms 
Standard safety 12-lead ECGs will be performed during the study as outlined in the Schedule 
of Events (Appendix A). The 12-lead ECGs will be taken after the subject has been resting 
supine for ≥5 minutes. The following ECG parameters will be collected: PR interval, QRS 
interval, RR interval, QT interval, and QTcF interval. 
All ECGs must be interpreted by a qualified physician or qualified designee for the presence 
of abnormalities. Any clinically significant ECG abnormality will be recorded as an AE and 
subject will be discontinued from the study. A subject will be withdrawn from the study by the 
PI or his/her designee if, in their medical judgment, ECG findings are present which make 
continued study participation not in the subject’s best interest. 
7.1.5 
Clinical Laboratory Tests 
Blood and urine samples will be collected for routine clinical laboratory testing (hematology, 
coagulation, chemistry, and urinalysis) and analysis as outlined in the Schedule of Events 
(Appendix A). Additional, unscheduled testing may be performed during the study if medically 
indicated. 
Any value outside the normal range will be flagged for the attention of the PI or designee at 
the site. The PI or designee will indicate whether or not the value is of clinical significance. 
• If the result of any test (or single repeat test, if done) from the samples taken during 
screening is indicated as clinically significant, the study subject will NOT be allowed 
into the study. Results of laboratory tests performed prior to dosing on Day 1 of each 
treatment period will be reviewed prior to dosing. 
• If a clinically significant abnormality is found in the samples taken after treatment (e.g., 
on Day 5), it should be recorded as an AE, if deemed necessary by the PI and will result 
in subject discontinuation from the study. The study subject will be followed until the 
test(s) has (have) normalized or stabilized. 
The following laboratory parameters will be reported: 
• Hematology: hemoglobin, hematocrit, RBC count, leukocyte count with differential, 
mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, and absolute platelet count 
• Coagulation: prothrombin time/International normalized ratio, activated partial 
thromboplastin time 


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• Chemistry: sodium, potassium, chloride, albumin, glucose, blood urea nitrogen, 
creatinine, bilirubin (total and direct), alkaline phosphatase, aspartate aminotransferase, 
alanine aminotransferase, gamma-glutamyl transpeptidase, uric acid and creatine 
phosphokinase 
• Serum Pregnancy Test (in female subjects) 
• Serology: HIV antibody, hepatitis B surface antigen, and hepatitis C virus antibody 
• Urinalysis: pH, specific gravity, glucose, ketones, nitrite, protein, bilirubin, leukocyte 
esterase, and blood will be performed. If urinalysis is positive for blood, protein, nitrite, 
and/or leukocyte esterase, microscopic urinalysis will be performed  
• Urine drug screen: This test may include the following: amphetamines, cocaine, 
tetrahydrocannabinol, 
benzodiazepines, 
tricyclic 
antidepressants, 
barbiturates, 
3,4-methylenedioxymethamphetamine, opiates, phencyclidine, oxycodone, and 
propoxyphene. 
• Urine cotinine 
An estimate of blood draw volumes over the course of the study is provided in Appendix C. 
7.1.6 
Adverse Events 
For detailed information on collection, definition, categorization, and reporting of AEs/SAEs 
during the study, refer to Section 9. 
AEs will be monitored and the following information recorded:  
• Standard medical terminology 
• Whether the event was a treatment-emergent adverse event (TEAE) 
• Whether event was a serious adverse event (SAE) 
• Date and time of onset 
• Severity of event 
• Relationship of event to study drug 
• Action taken regarding study drug due to the event 
• Clinical outcome of event (resolved or ongoing) 
• If resolved, provide date of resolution 


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7.1.7 
Prior and Concomitant Medications 
Site personnel should document any medications (prescription and OTC, including herbal 
medications and vitamins) the subject received within 30 days prior to screening and 
throughout the study. Recorded details should include: medication name, start date and time, 
stop date and time, dose, route, frequency, and reason for use. The concomitant medication 
names will be coded according to the World Health Organization Drug Dictionary (WHODD) 
and classified by anatomical therapeutic chemical categories. 
7.2 
Glutathione Blood Collection 
Blood samples will be collected at the times indicated in the Schedule of Events (Appendix 
A). Instructions for the sampling, processing, and storage of laboratory samples will be 
provided in the laboratory manual. 
7.3 
Neurocognitive Assessments and Scales 
The following neurocognitive assessments will be assessed during the study: BIS, SST, CGT, 
PAL, RTI, QSU, PANAS, CEQ, FTND and cue reactivity with Likert scale assessments. 
Descriptions are provided herein. 
7.3.1 
Barratt Impulsiveness Scale 
The BIS will be employed to capture trait impulsivity and to confirm each subject’s ability to 
read, write, and understand English at screening only on the iPad device. The scale is presented 
in Appendix D. 
7.3.2 
Stop Signal Test, Cambridge Gambling Task, Paired Associates Learning, and 
Reaction Time 
Subjects will be trained on the CANTAB iPad device with SST, CGT, PAL, and RTI at 
screening and the tests will be repeated as indicated in Appendix A. The SST and CGT will be 
used to assess impulsivity and inhibitory control at times. The PAL and RTI will be used to 
assess visual memory and motor/mental response speed. 
These assessments are described in further detail in Appendix E. 
7.3.3 
Questionnaire on Smoking Urges 
The QSU is a 10-question assessment of a subject’s desire and urge to smoke on the iPad 
device. The QSU will assess cravings at the times indicated in Appendix A. The questionnaire 
is presented in Appendix F. 
7.3.4 
Positive and Negative Affect Schedule 
The PANAS consists of several words that describe different feelings and emotions and will 
be used to assess mood at times indicated in Appendix A on the iPad device. This scale is 
presented in Appendix G. 


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7.3.5 
Cigarette Evaluation Questionnaire 
This assessment is a self-reported questionnaire with 12 questions to assess smoking behaviors 
and reinforcement and will performed at times indicated in Appendix A on the iPad device. 
The modified CEQ will be used and the questionnaire is provided in Appendix H. 
7.3.6 
Cue Reactivity and Likert Assessments 
Participants will be supplied with a laptop computer programmed (using E-Prime) to present 
images to participants. Images will include 3 categories: neutral, positive, and smoking. 
Neutral and positive images will be those extracted from IAPS and those validated in the 
TRAIN lab at MUSC (PI Froeliger), and smoking images will be from MUSC. The program 
will present images in sequence for 2 seconds each with a 1-second black screen between 
images. Each category will be presented in full (10 images over 30 seconds) and followed by 
a 88-point Likert scale assessing the urge for a cigarette followed by an 8-point Likert scale 
assessing mood. Subsequent categories will be presented and each time the same Likert scales 
will be completed. Subjects will use the Likert scales in Appendix I to complete the 
assessments. 
7.3.7 
Fagerstrom Test of Nicotine Dependence 
A standard instrument for assessing the intensity of physical addiction to nicotine.  This 
contains six items that evaluate the quantity of cigarette consumption, the compulsion to use, 
and dependence as indicated Appendix J. This will be completed in the iPad device. 
7.4 
Measurement of Nicotine Ingestion 
Expelled CO tests will be performed at screening, Day 1 and Day 5 of each Period, and on 
other treatment days, per the PI or designee’s discretion.  The results at screening and Day 1 
of Period 1 must be ≥10 ppm in order for the subject to be eligible for the study.   
Subjects should expel ≥10 ppm on Day 1 of Period 2, however, if a subject expels <10ppm, 
subject will be allowed to continue on study. 
Urine cotinine samples will be collected on Days 1 and 5 of each treatment period, and on 
other treatment days, per the PI or designee’s discretion.  This will  subsequently be assayed 
to biochemically ascertain if there was any nicotine exposure (tobacco, e-cig, nicotine 
gum/patches, etc.) in all subjects.  
Those subjects with evidence that they did not abstain on Day 1(after study entry) and Days 2-
5 of Period 1 or Day 1 (after study re-entry) and Days 2-5 of Period 2 will be  terminated from 
the study and will not be allowed to re-screen. 


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8 TEST ARTICLE AND ADMINISTRATION 
8.1 
Test Article Identification, Supply, Packaging, Labeling, and Storage 
SXC-2023 will be supplied as 50-mg and 200-mg capsules for use in this study. Placebo 
capsules will be matching SXC-2023 to maintain the blind. Subjects assigned to 200 mg QD 
will receive 4 x 50-mg capsules, and subjects assigned to 800 mg will receive 4 x 200-mg 
capsules. 
SXC-2023 is stable at room temperature and requires no special protection or handling; special 
protection from light is not required. SXC-2023 should be stored at 20℃ to 25℃, with 
excursions allowed between 15℃ to 30℃. 
All supplies will be packaged and labeled according to applicable local and regulatory 
requirements. All supplies must be stored in a locked area, accessible to authorized persons 
only, until needed for dispensing/dosing. 
8.2 
Study Drug Administration 
On Day 1 of each treatment period, subjects will fast prior to first dose in the morning.  Subjects 
may receive a meal at least one hour post dose.  On other days, subjects will be administered 
study drug (SXC-2023 200 mg, SXC-2023 800 mg, or matching placebo) at least 2 hours after 
breakfast.   The SXC-2023 or placebo dose will be administered with water.  
Qualified personnel will administer study drug. After dosing, unit personnel will perform a 
hand and mouth check to ensure the subjects have swallowed the dose administered.  
Subjects will fast for at least 1 hour after dosing. Water is permitted. 
8.3 
Study Drug Accountability and Destruction 
The Sponsor will supply sufficient quantities of SXC-2023 and matching placebo to allow 
completion of this study. The lot numbers and expiration dates (where available) of the study 
drugs supplied will be recorded in the final report. 
Records will be made of the receipt and dispensing of the study drugs supplied. At the 
conclusion of the study, any unused study drugs will be returned to the Sponsor or designee, 
or destroyed, as per Sponsor instructions. If no supplies remain, this fact will be documented 
in the product accountability records. 
8.4 
Blinding 
Subjects will be randomized to treatment assignments. Treatments will be double-blinded to 
avoid bias by the subject, PI, and study site staff, with the exception of Pharmacy personnel. 
If the PI deems it is necessary to break the blind in the interest of a subject’s safety, unblinding 
may occur. The PI must attempt to contact the Medical Monitor and must document the reason 
for breaking the blind.  Pharmacy personnel will be unblinded. 


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8.5 
Randomization 
Up to 32 subjects (28 subjects to be enrolled with an additional 4 subjects as replacements, if 
necessary) will be randomized to treatment pair comparison (SXC-2023 200 mg QD vs. 
matching placebo, and SXC-2023 800 mg QD vs. matching placebo) and to treatment sequence 
within each pair. Seven (7) subjects will be randomized to each of the 4 treatment pair sequence 
combinations (see Figure 1).  
8.6 
Treatment of Overdose 
Standard symptomatic support measures should be used in the case of excessive pharmacologic 
effects or overdose. No antidotes are available. 
In the instance that a subject ingests more than 3 times the allotted dose, standard symptomatic 
support measures should be used. No antidotes are available. Gastrointestinal reaction would 
be anticipated, and the subject should be clinically followed for 48 hours. 
9 ADVERSE EVENTS 
Starting at the time of informed consent, subjects will be asked to spontaneously report all AEs 
that occur during the trial until discharge from the study. Additionally, subjects will be queried 
about AEs at each study visit and inpatient day. AE queries should be performed in a 
nonspecific manner such as “How have you felt since the last visit?”, “How do you feel?”, or 
“Are there any recent changes to your health?” 
After the ICF is signed and before study drug is administered, AEs that are not procedure 
related will be captured and reported as medical history.  AEs occurring after first dose of study 
drug will be captured in the AE page of the CRF.  Non-serious AEs will be collected through 
the Follow-up visit. SAEs will be collected through 30 days post last dose (as reported through 
subject-initiated contact following the Follow-up visit). 
Cases of pregnancy that occur during the study or up to 30 days following last dose of study 
drug should be reported, however, will not be considered an AE unless there is a suspicion that 
the study drug may have interfered with the effectiveness of a contraceptive medication. Data 
on fetal outcome and breast-feeding are collected for regulatory reporting and drug safety 
evaluation. Study site personnel will record the occurrence and nature of each subject’s pre-
existing conditions, including clinically significant signs and symptoms of the disease under 
treatment in the study. Any clinically significant findings from ECGs, laboratory tests, vital 
sign measurements, etc. reported after the first dose of study drug (SXC-2023 or placebo) 
should be reported as an AE.  
All AEs related to protocol procedures are reported to the Sponsor or its designee. The PI will 
be instructed to report to the Sponsor or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, and study drug via CRF. 


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9.1 
Definition 
An adverse event (AE) can be any unfavorable and unintended sign, including an abnormal 
laboratory, ECG and vital sign abnormality finding, symptom or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the study drug. 
A treatment-emergent adverse event (TEAE) is any AE that newly appeared, increased in 
frequency, or worsened in severity following initiation of study drug. 
When a serious adverse event (SAE) or possibly or probably treatment-related AE persists at 
the end of the study, the PI will ensure a follow-up of the subject until the PI and Sponsor agree 
the event is satisfactorily resolved or stabilized. 
9.2 
Severity Scale for Adverse Events 
The severity of an AE is to be scored according to the following scale: 
Mild: 
Awareness of sign or symptom, but easily tolerated 
Moderate: 
Discomfort enough to cause interference with usual activity 
Severe: 
Incapacitating with inability to work or perform usual activity 
9.3 
Relationship to Study Drug 
The relationship of an AE to study treatment is to be assessed according to the following 
definitions: 
Unrelated: Should be reserved for those events which occur prior to study treatment or for 
those events which cannot be even remotely related to study participation (e.g., 
injuries sustained in an automobile accident). 
Possible: 
The suspected AE may or may not follow a reasonable temporal sequence from 
study treatment administration but seems to be the type of reaction that cannot 
be dismissed as unlikely. The event could have been produced or mimicked by 
the subject’s clinical state or by other modes of therapy concomitantly 
administered to the subject. 
Probable: 
The suspected AE follows a reasonable temporal sequence from study treatment 
administration, abates upon discontinuation of the treatment, and cannot be 
reasonably explained by the known characteristics of the subject’s clinical state. 
9.4 
Reporting Adverse Events 
All clinical events, including either observed or volunteered problems, complaints or 
symptoms are to be recorded on the AE page(s) of the CRF. The need to capture this 
information is not dependent upon whether the clinical event is associated with study 
treatment. Adverse clinical events resulting from concurrent illnesses or reactions to 


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concurrent medications are also to be recorded. In order to avoid vague, ambiguous, or 
colloquial expressions, the AE should be recorded in standard medical terminology rather than 
the subject’s own words. 
Each adverse clinical event is to be evaluated for duration, severity, and whether the event may 
be associated with the study drug or other causes. Start and stop dates, relationship to study 
drug, medical management, and alternative causality of event must be recorded in the AE 
section of the CRF. SAEs and AEs believed to be possibly or probably related to study drug 
must be followed until resolution or stabilization. 
9.5 
Serious Adverse Events 
9.5.1 Definition 
An SAE is any untoward medical occurrence that at any dose results in any of the following 
outcomes: 
• Death 
• Is life threatening (an event in which the subject is at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it 
was more severe) 
• A persistent or significant disability/incapacity 
• Results in congenital anomaly, or birth defect 
• Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be 
considered as serious) 
• Other medically important events  
• Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above. These events, including those that may result in disability, 
should also usually be considered 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. If a subject becomes pregnant during treatment, this should 
be reported as if it were a SAE. 
Refer to Section 9.6 in case of pregnancy. 


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9.5.2 Initial Reporting 
Any SAE, occurring in a subject receiving treatment or if the PI becomes aware of any SAE 
post-treatment, must be reported by the PI to the Medical Monitor within 24 hours even if the 
SAE does not appear to be drug-related. This should be done by telephone or by sending a 
faxed copy of the SAE form plus other related information. 
A Sponsor Designee will contact the PI with any follow-up questions related to the event. 
The Sponsor Designee must be notified immediately of all deaths. Deaths must be reported, 
regardless of cause, from the time of informed consent and up to 28 days after completion of 
study medication administration, irrespective of the PI’s opinion regarding drug relationship. 
Documentation of cause of death and copy of autopsy or hospital report must be provided. 
Medical Monitor 
Thomas Beck, MD 
Chief Medical Officer 
Promentis Pharmaceuticals, Inc. 
Address: One Main Street, 13th floor, Cambridge MA 02142 
Telephone: +1 617 231 2403 
Mobile: 508-259-8446 
Email: tbeck@fprimecapital.com  
9.5.3 Follow-up 
All additional follow-up evaluations must be reported to the Medical Monitor. Such data 
should be sent to the Sponsor within 10 calendar days. All SAEs will be followed until the PI 
and Sponsor agree the event is satisfactorily resolved. The Sponsor will be responsible for 
completing the safety report and for notifying the relevant authorities of any SAE as outlined 
in the International Conference on Harmonisation (ICH) Guidelines. The PI will also ensure 
that the appropriate ethics committee is notified of the SAE. 
9.6 
Pregnancy 
If a pregnancy does occur during or 30 days after completion of study medication 
administration, each pregnancy must be reported by the PI to the Sponsor Designee using the 
Pregnancy Report Form within 24 hours of becoming aware of the pregnancy. The PI must 
follow up and document the course and the outcome of all pregnancies even if the subject was 
withdrawn from the clinical study. 
Pregnancy alone is not regarded as an AE unless there is a suspicion that the study drug may 
have interfered with the effectiveness of a contraceptive medication. Elective abortions without 
complications should not be regarded as AEs, unless they were therapeutic abortions (see 
below). Hospitalization for normal delivery of a healthy newborn should not be considered an 
SAE. 


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All outcomes of pregnancy must be reported by the PI to the Sponsor on the pregnancy 
outcome report form within 30 days after he/she has gained knowledge of the normal delivery 
or elective abortion. 
Any SAE that occurs during pregnancy must be recorded on the SAE report form (e.g., 
spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in an 
aborted fetus, stillbirth or neonatal death]) and reported within 24 hours in accordance with the 
procedure for reporting SAEs. 
For more information on pregnancy reporting, please refer to the Safety Monitoring Plan.  
9.7 
Stopping Criteria with Rules for Subject Replacement  
 
Any patient who experiences an adverse experience judged to be severe (independent of 
attribution), an abnormal laboratory, ECG or vital signs deemed clinically significant or an 
SAE as defined in Section 10.5.1 of the protocol shall be immediately discontinued from the 
study and followed for safety, as per the protocol.  Subjects who discontinue in Period 1 
maywill not be replaced.    
 
10 STUDY ADMINISTRATION 
10.1 
Ethics  
10.1.1 
Institutional Review Board 
This protocol and all appropriate amendments will be reviewed by an institutional review board 
(IRB), and the study will not start until the IRB has approved the protocol or a modification 
thereof. The IRB is constituted and operates in accordance with the principles and requirements 
described in the United States (US) Code of Federal Regulations (CFR) (21 CFR Part 56).  
10.1.2 
Ethical Conduct of the Study 
This study will be carried out in accordance with the protocol, US 21 CFR Parts 50, 56, and 
312, the ethical principles set forth in the Declaration of Helsinki, GCP, and the ICH 
harmonized tripartite guideline regarding GCP (E6 Consolidated Guidance, April 1996). 
10.1.3 
Subject Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign and 
date an ICF summarizing the discussion prior to screening and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care. 
Subjects will be given a copy of their signed ICF. The requirements of informed consent are 
provided in Appendix B. 


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10.2 
Termination of the Study 
Promentis reserves the right to terminate the study in the interest of subject welfare.  All 
members of the Investigator’s staff have signed confidentiality agreements. By signing this 
protocol, the Investigator and investigational staff will regard all information provided by the 
Sponsor and all information obtained during the course of the study as confidential. The 
Investigator must guarantee the privacy of the subjects taking part in the study. Subjects will 
be identified throughout documentation and evaluation by a unique subject study number. 
Throughout the study, a subject’s source data will only be linked to the Sponsor’s clinical study 
database or documentation via a unique identification number. If subject name appears on any 
study document, it must be redacted before the copy of the documents is supplied to the 
Sponsor. Any information concerning the subjects (clinical notes, identification numbers, etc.) 
must be kept on file by the Investigator who will ensure that it is revealed only to the Sponsor, 
IRB, or regulatory authorities for the purposes of trial monitoring, auditing or official 
inspections. As required, in the case of an event where medical expenses are the responsibility 
of the Sponsor, personal information, i.e., full name, social security details, etc., may be 
released to the Sponsor. Appropriate precautions will be taken to maintain confidentiality of 
medical records and personal information in strictest confidence and in accordance with local 
data protection laws. 
10.3 
Data Quality Assurance 
Designated personnel will be responsible for implementing and maintaining quality assurance 
(QA) and quality control systems to ensure that the study is conducted, and that data are 
generated, documented and reported in compliance with the study protocol, GCP and Good 
Laboratory Practice requirements as well as applicable regulatory requirements and local laws, 
rules and regulations relating to the conduct of the clinical study. 
All clinical data will undergo a 100% quality control check prior to clinical database lock. Edit 
checks are then performed for appropriate databases as a validation routine using SAS® or 
comparable statistical program to check for missing data, data inconsistencies, data ranges, etc. 
Corrections are made prior to database lock. 
10.4 
Direct Access to Source Data/Documents 
Site will ensure that the Sponsor, IRB and inspection by domestic and foreign regulatory 
authorities will have direct access to all study-related sites, source data/documents, and reports 
for the purpose of monitoring and auditing (ICH [E6] 5.1.2 & 6.10). In the event that other 
study-related monitoring should be done by other parties, they will be required to sign a 
confidentiality agreement prior to any monitoring and auditing. 
10.5 
Data Handling and Record Keeping 
Electronic data capture (EDC) will be used for this study and electronic case report forms 
(eCRFs) will be developed according to the study protocol specifications. Data will be 
transcribed from original source by the Investigator staff into the eCRF. 
All raw data generated in connection with this study, together with the original copy of the 
final report, will be retained by Sponsor until at least 5 years after the last approval of a 


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marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 5 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period however if required by the applicable regulatory 
requirements or by an agreement with the Sponsor. It is the responsibility of the Sponsor to 
inform the PI/Institution as to when these documents no longer need to be retained. 
10.6 
Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common 
Technical Document for the Registration of Pharmaceuticals for Human Use M4 and the 
ICH M2 Expert Working Group), the final report will be written according to the 
ICH E3 Guideline (Structure and Content of Clinical Study Reports). 
10.7 
Publication Policy 
All unpublished information given to site by the Sponsor shall not be published or disclosed to 
a third party without the prior written consent of the Sponsor. 
The data generated by this study are considered confidential information and the property of 
the Sponsor. This confidential information may be published or disclosed only by the Sponsor 
or in collaboration with participating personnel from the Sponsor or upon Sponsor’s prior 
written consent to publish the article. 
11 STATISTICAL METHODS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP). The SAP will be finalized by the 
Sponsor prior to locking the study database. The SAP may modify the plans outlined in the 
protocol; however, any major modifications of endpoint definition and/or analysis will be 
reflected in a protocol amendment. Statistical analyses other than those described in the 
protocol will be documented in the SAP.  
Statistical analyses will be done using SAS Version 9.4 or later, unless noted otherwise. 
Unless otherwise noted, continuous variables will be summarized using number of 
non-missing observations, mean, standard deviation, median, minimum, and maximum; 
categorical variables will be summarized using the frequency count and the percentage of 
subjects in each category.  
11.1 
Determination of Sample Size 
No formal sample size calculation was performed. 
11.2 
Analysis Populations 
Safety Population: All subjects who receive a dose of blinded study drug (SXC-2023 or 
placebo) will be included in the safety evaluations. 


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Full Analysis Set (FAS)/Intent-to-Treat (ITT) Population: All subjects randomized to blinded 
study drug (SXC-2023 or placebo) will be included in the FAS and will be analyzed as 
randomized. 
Per Protocol Population (PP): All subjects randomized to blinded study drug (SXC-2023 or 
placebo) with no major protocol violations or deviations. 
11.3 
Statistical Analysis 
11.3.1 
Subject Disposition 
The number of subjects enrolled, completed, or discontinued from the study and the reason for 
study discontinuation will be tabulated by treatment group as appropriate. The number of 
discontinued subjects will be broken down by treatment period of the study. Subject count by 
analysis population will also be tabulated.  
11.3.2 
Protocol Deviations 
All deviations will be listed. Protocol deviations will be categorized as major or minor. Major 
protocol deviations will be agreed upon by medical, clinical, and statistical staff prior to 
database lock. Subjects with major protocol deviations, or data points that are judged to be 
major protocol deviations will be excluded from the PP Population. 
11.3.3 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be listed and summarized by treatment and 
overall using the Safety Population.  
11.3.4 
Safety Analysis 
All subject data will be listed with pertinent information, e.g., demographics, treatment group. 
All safety and tolerability data will be summarized using descriptive statistics. Safety data will 
be listed and summarized in tabular and/or graphical form. No formal statistical testing will be 
performed on these data. Summaries will be provided by treatment group. 
Descriptive statistics will be calculated for quantitative safety data and frequency counts will 
be compiled for classification of qualitative safety data. 
11.3.4.1 
Adverse Events 
AEs will be coded using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA®). 
The number and percentage of subjects experiencing TEAEs, treatment-emergent SAEs, and 
TEAEs leading to study discontinuation will be summarized for treatment group/period by 
MedDRA system organ class (SOC) and/or preferred term (PT).  
Summaries of TEAEs may include:  


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• by PT in descending order of frequency  
• by SOC and PT  
• by SOC, PT, and severity  
• by SOC, PT, and relationship to study drug (unrelated vs. related) 
o AEs of possible or probable relationship to study drug will be combined for the 
“related” summaries.  
11.3.4.2 
Other Safety Assessments 
Summary statistics for vital signs, including blood pressure and heart rate, will be presented 
for each scheduled time point measured and for the change from baseline to each time point. 
Concomitant medications will be listed by subject and coded using the most current version of 
the World Health Organization (WHO) drug dictionary available at Celerion. Medical History 
will be coded using the most current version of Medical Dictionary for Regulatory Activities 
(MedDRA®) available at Celerion.Clinical laboratory data and change from baseline will be 
summarized by the scheduled time point. Subject incidences of change in classification with 
respect to the laboratory normal ranges will be summarized as shift tables. Baseline will be the 
last value obtained before the first dose of study drug. Clinically significant clinical laboratory 
abnormalities (as judged by the investigator) will be included in the AE tabulations.  
Clinically significant physical examination abnormalities will be reported and included in the 
AE tabulations.  
A normal-abnormal shift table will be presented for ECGs. 
11.3.4.3 
Concomitant Medications 
Concomitant medications will be coded using the most current WHODD and listed by 
treatment. 
11.3.5 
Analysis of Neurocognitive Assessments 
Within-subject contrasts for the BIS, SST, CGT, RTI, PAL, QSU, PANAS, CEQ, and Cue 
reactivity with Likert assessments will be analyzed using a mixed effects analysis of variance 
model, with treatment, sequence, and period as fixed effects and subject within sequence as a 
random effect. Estimates of the treatment effect (least squares means with 95% confidence 
intervals) will be obtained from this model. Impact for potential covariates will be explored 
using this same model. 
The primary analyses will use the PP Population. Subjects who have missing values for a study 
endpoint will not be used in the statistical analysis for that endpoint. No data will be imputed.  
Analyses may be repeated using the FAS.  


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Results of the BIS, SST, CGT, RTI, PAL, QSU, PANAS, CEQ, and Cue reactivity with Likert 
assessments will be summarized descriptively by treatment. Between-subject by period 
treatment contrasts will also be performed.  
Planned analyses will follow standardized instruction manuals for neurocognitive assessments, 
where such manuals exist.  
Results will be presented with no adjustment for multiplicity.  
11.3.6 
Analysis of Glutathione Concentrations 
GSH concentrations will be listed and summarized descriptively. 
12 REFERENCES 
Amen SL, Piacentine LB, Ahmad ME, et al. Repeated N-acetyl cysteine reduces cocaine 
seeking in rodents and craving in cocaine-dependent humans. Neuropsychopharmacology. 
2011;36(4):871-8. 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition. 5th ed. Washington, DC: American Psychiatric Association; 2013. 251-254. 
Froeliger B, McConnell PA, Bell S, et al. Association between baseline corticothalamic-
mediated inhibitory control and smoking relapse vulnerability. JAMA Psychiatry. 
2017;74(4):379-386. 
Froeliger B, McConnell PA, Stankeviciute N, McClure EA, Kalivas PW. The effects of 
N-Acetylcysteine on frontostriatal resting-state functional connectivity, withdrawal symptoms 
and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study. Drug Alcohol 
Depend. 2015;156:234-42. 
LaRowe SD, Myrick H, Hedden S, et al. Is cocaine desire reduced by N-acetylcysteine? Am J 
Psychiatry. 2007;164(7):1115-7. 
Lutgen V, Resch J, Qualman K, et al. Behavioral assessment of acute inhibition of system xc- 
in rats. Psychopharmacology. 2014;231(23):4637-47. 
SXC-2023 Investigator’s Brochure, Version 5.0; 2018. 


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APPENDIX A SCHEDULE OF EVENTS 
Procedures 
Screen  
 
Period 1 of Crossover  
 
Home 
 
Period 2 of Crossover 
 
Follow-
up/ET 
Day -30 
to Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Washout  
9 days  
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
7-10 Days 
Post last 
dose  
Confinement 
 
X 
 
X 
 
Abstain from 
smoking  
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
drug use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam  
X 
Xa 
Xa 
Xa 
 
Xa 
Xa 
Xa 
Xa (PE, 
smoking 
status) 
Vital signs (BP, HR) 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Safety labs 
(hematology, 
coagulation, 
chemistry, UA) 
X 
Xb  
(pre) 
 
 
 
X 
(post) 
 
Xb  
(pre) 
 
 
 
X 
(post) 
X 
Serum pregnancy 
(females) 
X 
X 
(pre) 
 
 
 
 
 
X (pre) 
 
 
 
 
X 
Screening serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
ECG 
X 
X 
(pre) 
 
 
 
X 
 
X 
(pre) 
 
 
 
X 
X 
Breath CO/subject 
interview 
X 
X 
(pre) 
Xc 
X  
(pre) 
 
X  
(pre) 
Xc 
X 
(pre) 
 
Urine Cotinine 
X 
X 
(pre) 
Xc 
X  
(pre) 
 
X  
(pre) 
Xc 
X 
(pre) 
 
FTND 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
BIS 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Procedures 
Screen  
 
Period 1 of Crossover  
 
Home 
 
Period 2 of Crossover 
 
Follow-
up/ET 
Day -30 
to Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Washout  
9 days  
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
7-10 Days 
Post last 
dose  
QSU, PANAS, CEQ 
 
X 
(pre) 
 
 
 
X 
(post) 
 
X (pre) 
 
 
 
X 
(post) 
 
CANTAB (SST, 
CGT, RTI, PAL) 
X 
(training) 
X 
(pre) 
 
 
 
X 
(post) 
 
X (pre) 
 
 
 
X 
(post) 
 
Cue reactivity and 
Likert assessments 
 
 
X (pre) 
 
 
X 
(post) 
 
 
X (pre) 
 
 
X 
(post) 
 
Randomization 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Study drug 
administration 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
GSH blood sample 
 
X 
(pre) 
 
 
 
X 
(post) 
 
X (pre) 
 
 
 
X 
(post) 
 
Adverse events 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Abbreviations: BIS= Baratt Impulsiveness Scale; BP=blood pressure; CANTAB=Cambridge Neuropsychological Test Automated Battery; CEQ= Cigarette 
Evaluation Questionnaire; CGT=Cambridge Gambling Task; CO=carbon monoxide; ECG=electrocardiogram; ET=early termination; FTND=Fagerstrom Test of 
Nicotine Dependence; GSH= glutathione; hr=hour(s); HR=heart rate; PAL=Paired Associates Learning; PANAS=Positive and Negative Affect Schedule; 
PE=physical examination; post=post-dose; pre=pre-dose; QSU=Questionnaire on Smoking Urges; RTI=Reaction Time; SST=Stop Signal Task; UA=urinalysis 
 
a  Physical exam:  Day 1 and Day 5 of both Periods and FU/ET, abbreviated physical exams will be  performed.  Days 2-4 of both Periods, per PI or designee’s discretion, symptom driven abbreviated exam may be performed. 
 
b  Fasting state safety labs 
 
c  Breath CO and Urine cotinine:  Per PI or designee discretion 


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APPENDIX B BASIC ELEMENTS OF INFORMED CONSENT 
a)  Basic Elements of Informed Consent 
The following information must be provided to each subject in obtaining informed consent. The 
subject (or subject's legal representative) should be provided with a copy of the signed written 
informed consent. 
1. 
State that the study involves RESEARCH. 
 
a. Explain the PURPOSES of the research. 
 
b. State the expected DURATION of the subject's participation. 
 
c. Describe the PROCEDURES to be followed. 
 
d. Identify any EXPERIMENTAL procedures. 
2. 
Describe any reasonably foreseeable RISKS OR DISCOMFORTS to the subject.  
3. 
Describe any BENEFITS to the subject or to others that may reasonably be expected from 
the research. 
4. 
Note appropriate ALTERNATIVE procedures or courses of treatment, if any, that might 
be advantageous to the subject. 
5. 
a. Describe the extent, if any, to which CONFIDENTIALITY of records identifying the 
subject will be maintained. 
 
b. Note that the Food and Drug Administration MAY INSPECT the records. 
6. 
For research involving more than minimal risk, explain if any COMPENSATION or 
medical treatments are available should injury occur. If so, explain (a) what they consist 
of, OR (b) where further information may be obtained. 
7. 
State whom to contact for ANSWERS to pertinent questions about (a) the research, and 
(b) research subject's rights, and (c) whom to contact in the event of a research-related 
injury to the subject. 
8. 
State that: 
 
a. 
participation is VOLUNTARY, 
b. 
refusal to participate will involve NO PENALTY or loss of benefits to which the 
subject is otherwise entitled, and 
c. 
the subject MAY DISCONTINUE participation at any time without penalty or loss of 
benefits to which the subject is otherwise entitled. 
 


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b).  Additional Elements of Informed Consent 
When appropriate, one or more of the following elements of information shall also be provided 
to each subject: 
1. 
A statement that the particular treatment or procedure may involve risks to the subject (or 
to the embryo or fetus, if the subject is or may become pregnant) which are currently 
unforeseeable. 
2. 
Anticipated circumstances under which the subject’s participation may be terminated by 
the Investigator without regard to the subject’s consent. 
3. 
Any additional costs to the subject that may result from participation in the research. 
4. 
The consequences of a subject's decision to withdraw from the research and procedures for 
orderly termination of participation by the subject. 
5. 
A statement that significant new findings developed during the course of the research which 
may relate to the subject's willingness to continue participation will be provided to the 
subject. 
6. 
The approximate number of subjects involved in the study. 
 
c).  The following statement shall be provided to each clinical trial subject in informed consent 
documents and processes. “A description of this clinical trial will be available on 
http://www.clinicaltrials.gov, as required by U.S. Law. This web site will not include information 
that can identify you. At most, the web site will include a summary of the results. You can search 
this web site at any time.” 
 
d).  The informed consent requirements in these regulations are not intended to preempt any 
applicable federal, state, or local laws which require additional information to be disclosed for 
informed consent to be legally effective.  
 
e).  Nothing in these regulations is intended to limit the authority of a physician to provide 
emergency medical care to the extent the physician is permitted to do so under applicable 
Federal, State, or Local law. 
 
 
REFERENCE: 21 CFR Part 50.25 -- PROTECTION OF HUMAN Subjects, Basic elements of 
informed consent.  
 
 


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APPENDIX C SUMMARY OF BLOOD DRAW VOLUMES  
Sample Type 
Number of 
Time 
Points 
Approximate 
Volume per Time 
Point (mL) 
Approximate Sample 
Volume Over Course 
of Study (mL) 
Laboratory safety tests (including 
hematology, coagulation, serum 
chemistry) and serology (at screening 
only) 
6 
16 
96 
Glutathione (GSH) 
4 
6 
24 
Total Blood Volume (mL)→ 
120 
 
 


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APPENDIX D BARRATT IMPULSIVENESS SCALE  
 
 
 


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APPENDIX E CANTAB CONNECT TASK DESCRIPTIONS FOR 
PROMENTIS  
 
Version 1.0  
20 July 2018  
Introduction  
The CANTAB Connect electronic data capture (EDC) system will be used to run cognitive 
tests, capture subject responses and record data for transfer to Cambridge Cognition Limited.  
The system offers a simple touch-screen interface to guide the test administrator through the 
process of entering required subject information e.g. subject number, any required 
demographic details and selecting the appropriate visit. The system then automatically 
administers the CANTAB tests for the subject and visit selected.  
The system informs the subject how to complete each CANTAB task and each task includes 
practice and assessed phases. The system automatically records all subject responses. 
CANTAB Connect automatically synchronizes with the server at the end of each session to 
transfer data to the secure server.  
The following CANTAB Connect tasks will be used in the clinical study.  
Reaction Time (RTI)  
In this reaction time task the participant must hold down a button at the bottom of the iPad 
screen, with the index finger of their dominant hand, until a yellow spot briefly appears in one 
of five circles at the top of the screen. Once the yellow spot has flashed in one of the circles 


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the subject must release the button and with the same finger touch inside the circle where the 
yellow spot appeared as quickly as they can.  
The voiceover introduces the RTI test to the participant explaining how the test should be 
completed. There is a short practice phase prior to the assessed phase. The participant will see 
five circles at the top of the screen and a button at the bottom of the screen.  
 
 
The voiceover prompts the participant to practice touching the button at the bottom of the 
screen and then informs the subject that they should hold this button down until a yellow spot 
flashes in one of the circles above. Once they see the yellow spot appear they should release 
their finger from the button as quickly as they can and using the same finger touch the circle 
where the yellow spot appeared. Once they have touched the circle they must return their finger 
to the button and hold the button until they see another yellow spot flash in one of the circles 
above and then once again touch the circle where the yellow spot appeared.  
 
 
 


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The RTI task includes a practice phase (10 trials) followed by the assessed phase. The 
voiceover reminds the subject that they should go as quickly as they can whilst trying to avoid 
making any mistakes. 30 assessed trials are then presented.  
The key outcome measures for this task are median reaction and movement time.  
Stop Signal Task (SST)  
The Stop Signal Task (SST) is a classic stop signal reaction time test that measures the 
participant’s ability to inhibit a response. The subject is shown two buttons on the screen, one 
on the right side of the screen and the other on the left hand side of the screen. Arrows appear 
in the middle of the screen and the participant learns to press the button corresponding to the 
direction in which the arrow points.  
The task starts with a practice phase where the subject simply responds by touching the button 
on the left side of the screen when the arrow points to the left and the button on the right hand 
side when the arrow points to the right. A stop signal (an auditory tone) is then introduced. If 
a stop signal is presented, the participant must inhibit their response i.e. try not to touch the on-
screen button. A stop signal occurs on 25% of trials.  
 
 
 
The assessed phase with the stop signal (tone) is presented in 4 blocks. At the end of each 
assessed block, a graphic representing the participant’s performance is shown on screen. 
Depending on the participant’s performance on the previous block the participant is 
encouraged to either go faster or slower on the next block, whilst trying not to touch the button 
whenever they hear the tone.  
 


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The time between the arrow being shown on screen, and the delay interval between the 
participant hearing the tone (Stop Signal Delay (SSD)) is varied throughout the task.  
Paired Associates Learning (PAL)  
The paired Associates Learning task consists of a number of stages, which the subject must 
complete in order. For each stage, boxes are displayed on the screen. These boxes are opened 
one at a time, in a randomised order. Two or more of the boxes will contain a pattern. The 
patterns shown in the boxes are then displayed in the middle of the screen, one at a time, and 
the subject must touch the box where the pattern was originally located.  
 
 
 


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When the participant successfully identifies the correct box for all of the patterns the test moves 
to the next level. The PAL test gradually becomes more difficult with the number of boxes that 
contain a pattern increasing from 2 trials with 2 boxes that contain a pattern, 1 trial with 
4 patterns, 1 trial with 6 patterns. Following successful completion of the trial with 6 boxes 
containing a pattern, 8 boxes are presented on the screen.  
If the participant is not successful, the boxes will reopen to remind the participant where the 
patterns were. The participant will have up to 4 chances to correctly identify the location of 
the patterns at each level. If the participant fails after 4 attempts at any level the test will end. 
If a participant is successful at the 8 box level the final level will show 12 boxes on screen with 
each box containing a pattern.  
 
 
 


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Cambridge Gambling Task (CGT)  
The participant is presented with a row of 10 color squares at the top of the screen. Some of 
the squares are blue in color others red. Beneath these colored squares are two buttons, one 
labelled red and the other blue. The participant is informed that a yellow token is hidden in one 
of the colored boxes. The participant should touch the red button at the bottom of the screen if 
they think it is more likely that the yellow token will be hidden in a red box or the blue button 
if they think it is likely to be hidden in a blue box. 
 
 
 
If the participant is correct they see the words You Win. If incorrect the participant will see 
You Lose.  
 
 


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In the assessed phase the participant is given 100 points and can bet on their decision. The 
proportion of the total score that the participant wants to bet is selected as the number on the 
screen counts up or down from 100% by tapping the Red or Blue box to place the desired bet 
amount.  
The participants total score increases or decreases incrementally dependent on successful or 
unsuccessful bet outcome. The total score is displayed at the top of the screen. 
 
 
 
The participant must try to amass as many points as possible.  
 
 


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APPENDIX F QUESTIONNAIRE ON SMOKING URGES  
 
 
 
 
 


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APPENDIX G POSITIVE AND NEGATIVE AFFECT SCHEDULE 
 


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APPENDIX H CIGARETTE EVALUATION QUESTIONNAIRE 
 
I. Have you smoked since your last visit? (0) No (1) Yes  
If yes, proceed with the questions, if no, do not continue with the questions.  
Please mark the number that best represents how the last cigarette you smoked made you feel, based 
on these questions:  
(1) not at all (2) very little (3) a little (4) moderately (5) a lot (6) quite a lot (7) extremely  
1. Was smoking satisfying?  
 
2. Did cigarettes taste good?  
 
3. Did you enjoy the sensations in your throat and chest?  
 
4. Did smoking calm you down?  
 
5. Did smoking make you feel more awake?  
 
6. Did smoking make you feel less irritable?  
 
7. Did smoking help you concentrate?  
 
8. Did smoking reduce your hunger for food?  
 
9. Did smoking make you dizzy?  
 
10. Did smoking make you nauseous?  
 
11. Did smoking immediately relieve your craving for a cigarette?  
 
12. Did you enjoy smoking?  
 


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APPENDIX I  CUE REACTIVITY AND LIKERT SCALE 
ASSESSMENTS 
Images will include 3 categories: neutral, positive, and smoking. Neutral and positive images 
will be those extracted from IAPS and those validated in the TRAIN lab at MUSC (PI 
Froeliger), and smoking images will be from MUSC.USC The program will present images in 
sequence for 2 seconds each with a 1-second black screen between images. Each category will 
be presented in full (10 images over 30 seconds) and followed by a 8-point Likert scale 
assessing the urge for a cigarette followed by an 8-point Likert scale assessing mood. 
Subsequent categories will be presented and each time the same Likert scales will be 
completed. 
Response to the assessments will range from 1 to 8 as follows: 
Urge Question – “I Have An Urge For A Cigarette” 
Answer: 1 (strongly disagree) – 2 – 3 – 4 (neutral) – 5 – 6 – 7- 8 (strongly agree) 
Mood Question – “Please Rate How You Feel?” 
The image with the 8-point scale below will be shown with each block. 
 
 
 
 


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APPENDIX J  FAGERSTROM TEST OF NICOTINE DEPENDENCE 
QUESTIONNAIRE