Conditions: Cocaine Use Disorder Substance Use Disorders Healthy Volunteers
Keywords: drug addiction cocaine use disorder cocaine dependance TMP-301 cocaine use CUD drug abuse
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 30
Healthy volunteers: yes

Brief summary:
A PHASE 1, RANDOMIZED, PLACEBO CONTROLLED, MULTIPLE ASCENDING DOSE (MAD) STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF TMP-301 IN HEALTHY SUBJECTS.

Detailed description:
This study will be a randomized, double-blind, placebo controlled, fixed sequence, MAD study. The study will be conducted in a single clinical research unit (CRU). The study will consist of up to 4 cohorts. Subjects will only participate in 1 cohort.

Screening will occur within approximately 28 days prior to the first scheduled study drug administration. Subjects who meet all inclusion criteria and none of the exclusion criteria and who consent to participation will be admitted to the CRU for baseline evaluations prior to dosing.

Subjects will be fasted overnight for 10 hours prior to the morning dose, followed by a 2 hour fast. Subjects are fasted for 2 hours prior to dosing and 2 hours following the evening dose for the cohort 1 (50 mg bid).

Subjects will be discharged from the CRU on Day 18. Subjects will return to the CRU on Day 25 for a follow-up visit and EOS procedures.

Caffeine (100 mg) will be included as probe CYP1A2 substrate in cohort 2 and subsequent cohorts.

The maximum duration of subject participation, including Screening, will be approximately 53 days.

Subjects who terminate the study early will perform follow-up procedures at the time of Early Termination.

Arms:
arm 1: Cohort 1= 50mg, capsules form, one capsule - two times per day - total 100mg/day;

Cohort 2= 50mg, capsule form, 1 capsules - one time per day- total 50mg/day

Cohort 3= 50mg, capsule form, 2 capsules - one time per day- total 100mg/day;

Cohort 4 = Dose Titration: 50mg, capsule form, 1 capsules - one time per day - total 50 mg/day - on Days 1-7; and 50 mg, capsule form, 2 capsules - one time per day - total 100mg/day - on Days 8-14;

Each cohort duration is 14 days of dosing arm 2: Cohort 1= Placebo, capsules form, one capsule - two times per day;

Cohort 2= Placebo, capsule form, 1 capsules - one time per day;

Cohort 3= Placebo, capsule form, 2 capsules - one time per day;

Cohort 4 = Dose Titration: Placebo, capsule form, 1 capsules - one time per day - on Days 1-7; and Placebo, capsule form, 2 capsules - one time per day - on Days 8-14;

Each cohort duration is 14 days of dosing

Interventions: intervention 1: Cohort 1 - TMP-301 intervention 2: Placebo intervention 3: Cohort 2 - TMP-301 intervention 4: Cohort 3 - TMP-301 intervention 5: Cohort 4 - TMP-301
Intervention descriptions: intervention 1: 50 mg BID Fasted intervention 2: Multiple ascending dose comparator intervention 3: 50 mg QD Fasted intervention 4: 50 mg QD Fed intervention 5: 25 mg QD Fed

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
A PHASE 1, RANDOMIZED, PLACEBO CONTROLLED, MULTIPLE ASCENDING 
DOSE (MAD) STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS OF TMP-301 IN HEALTHY SUBJECTS 
Protocol Number: 
TMP-301-HNV-101 
Altasciences Project Number: 
TPM-P1-726 
Investigational Product: 
TMP-301 
Phase of Development: 
1 
Sponsor: 
Tempero Bio Inc. 
1111 Broadway, Suite 1300 
Oakland, CA 94607 
United States 
COMPLIANCE 
The study will be conducted in accordance with standards of Good Clinical Practice, as defined by the 
International Council for Harmonization and all applicable federal and local regulations. 
Protocol Version 
Date 
Amendment 4  
Version 4.0 
Final 
October 02, 2023 
 
 
LIST OF TABLES 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information provided in this document is strictly confidential and is available for review to Investigator(s) 
and to the appropriate Independent Ethics Committee (IEC) or Institutional Review Board (IRB). It may not be 
used, divulged, published or otherwise disclosed without the written authorization from Altasciences or the 
Sponsor. 


 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................ 2 
STUDY SYNOPSIS.................................................................................................................... 7 
STUDY ADMINISTRATIVE STRUCTURE ........................................................................... 10 
1. 
INTRODUCTION .................................................................................................. 11 
1.1. 
Study Rationale ...................................................................................................... 11 
1.2. 
Background ............................................................................................................ 11 
1.3. 
Summary of Nonclinical Pharmacology .................................................................. 12 
1.4. 
Summary of Nonclinical Safety Pharmacology ....................................................... 12 
1.5. 
Summary of Nonclinical Pharmacokinetics ............................................................. 12 
1.6. 
Summary of Nonclinical Toxicology ...................................................................... 12 
1.7. 
Summary of Clinical Experience ............................................................................ 12 
1.8. 
Pharmacokinetics .................................................................................................... 12 
1.8.1. 
Pharmacokinetics of TMP-301 in Study HTL0014242-101 (Single 
Ascending Dose) .................................................................................................... 12 
1.8.2. 
Pharmacokinetics of TMP-301 in Study HTL0014242-103 (PET) .......................... 12 
1.8.3. 
Pharmacokinetics of TMP-301 in Cohort 1 of Study TMP-301-HNV-101 
(Preliminary) .......................................................................................................... 12 
1.9. 
Safety and Efficacy ................................................................................................. 13 
1.9.1. 
Study HTL0014242-101: Single Ascending Dose ................................................... 13 
1.9.2. 
Study HTL0014242-103: PET ................................................................................ 13 
1.9.3. 
Receptor Occupancy/Exposure Relationship ........................................................... 13 
1.9.4. 
Study TMP-301-HNV-101 Multiple Ascending Dose Cohort 1 .............................. 13 
1.10. 
Rationale for Dose Selection ................................................................................... 13 
1.10.1. 
TMP-301 Pharmacokinetic Model and Dose Regimen Simulations ......................... 13 
1.10.2. 
Rationale for Dose Selection of Cohort 2 ................................................................ 13 
1.11. 
Risk/Benefit Assessment ........................................................................................ 13 
1.11.1. 
Known Potential Risks............................................................................................ 13 
1.11.2. 
Primary Pharmacology and Associated Risks .......................................................... 13 
1.11.3. 
Non-clinical Safety Studies and Associated Risks ................................................... 13 
1.11.4. 
ADME and Associated Risks .................................................................................. 13 
1.11.5. 
Caffeine Risks ........................................................................................................ 13 
1.11.6. 
Known Potential Benefits ....................................................................................... 13 


 
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2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................... 14 
3. 
STUDY DESIGN ................................................................................................... 16 
3.1. 
Adaptive Features and Risk Management of Study Design ..................................... 16 
3.2. 
Maximum Tolerated Dose ...................................................................................... 16 
3.3. 
Overall Study Design .............................................................................................. 17 
3.4. 
Study Treatments .................................................................................................... 18 
4. 
SUBJECT POPULATION ...................................................................................... 19 
4.1. 
Inclusion Criteria .................................................................................................... 19 
4.2. 
Exclusion Criteria ................................................................................................... 20 
4.3. 
Withdrawal Criteria ................................................................................................ 22 
4.3.1. 
Before First Treatment Administration.................................................................... 22 
4.3.2. 
After First Treatment Administration ...................................................................... 22 
4.3.2.1. 
Stopping Rules ....................................................................................................... 23 
4.3.2.2. 
Trial Stopping Rules ............................................................................................... 24 
4.4. 
Lifestyle and/or Dietary Requirements .................................................................... 25 
4.5. 
Concomitant Treatment .......................................................................................... 26 
5. 
STUDY TREATMENTS ........................................................................................ 27 
5.1. 
Investigational Products .......................................................................................... 27 
5.1.1. 
TMP-301 ................................................................................................................ 27 
5.1.2. 
Placebo ................................................................................................................... 27 
5.2. 
Investigational Product Management ...................................................................... 27 
5.2.1. 
Packaging, Labeling and Dispensing ....................................................................... 27 
5.2.2. 
Storage and Handling ............................................................................................. 27 
5.2.3. 
Method of Assigning Subjects to Treatment Groups ............................................... 27 
5.2.4. 
Blinding.................................................................................................................. 27 
5.2.5. 
Study Drug Accountability ..................................................................................... 28 
5.3. 
Administration of Study Drug ................................................................................. 28 
5.3.1. 
Treatment Compliance ............................................................................................ 28 
5.4. 
Meals ...................................................................................................................... 28 
5.5. 
Other Protocol Restrictions ..................................................................................... 29 
6. 
STUDY PROCEDURES ........................................................................................ 30 
6.1. 
Safety Assessments................................................................................................. 34 
6.1.1. 
Medical History ...................................................................................................... 34 


 
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6.1.2. 
Psychiatric History ................................................................................................. 34 
6.1.3. 
Physical Examination ............................................................................................. 34 
6.1.4. 
Vital Signs .............................................................................................................. 34 
6.1.5. 
12-Lead Electrocardiogram ..................................................................................... 35 
6.1.6. 
Pharmacogenetic and Exploratory Biomarkers Sampling ........................................ 35 
6.1.7. 
Laboratory Evaluations ........................................................................................... 35 
6.1.8. 
Brief Psychiatric Rating Scale (BPRS) .................................................................... 35 
6.1.9. 
Clinician-Administered Dissociative States Scale (CADSS) ................................... 35 
6.1.10. 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................. 36 
6.1.11. 
Modified Mini-Mental State Examination (3MS) .................................................... 36 
6.1.12. 
Visual Analogue Alertness Scale (VAS) ................................................................. 37 
6.1.13. 
Rescue Therapy ...................................................................................................... 37 
6.2. 
Pharmacokinetic Assessments................................................................................. 37 
6.2.1. 
Pharmacokinetic Sample Processing, Storage and Shipping .................................... 39 
7. 
ADVERSE EVENTS DOCUMENTATION ........................................................... 40 
7.1. 
Definitions .............................................................................................................. 40 
7.2. 
Severity Assessment ............................................................................................... 40 
7.3. 
Causality Assessment ............................................................................................. 41 
7.4. 
Adverse Event Monitoring ...................................................................................... 41 
7.5. 
Reporting of Pregnancy .......................................................................................... 42 
7.6. 
Serious Adverse Event Reporting ........................................................................... 42 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ........................... 44 
8.1. 
Analysis Populations .............................................................................................. 44 
8.1.1. 
Safety Population.................................................................................................... 44 
8.1.2. 
Pharmacokinetic Population.................................................................................... 44 
8.2. 
Demographic Data and Other Baseline Characteristics ............................................ 44 
8.3. 
Safety ..................................................................................................................... 44 
8.3.1. 
Safety Endpoints ..................................................................................................... 44 
8.3.2. 
Safety Analysis ....................................................................................................... 44 
8.3.3. 
Safety Statistical Methodology ............................................................................... 44 
8.4. 
Pharmacokinetics .................................................................................................... 44 
8.4.1. 
Pharmacogenetic Statistical Methodology ............................................................... 44 
8.5. 
Planned Interim Analyses ....................................................................................... 45 


 
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8.6. 
Determination of Sample Size................................................................................. 45 
9. 
REFERENCES ....................................................................................................... 46 
APPENDIX 1. ETHICS .......................................................................................................... 48 
Institutional Review Board ........................................................................................................ 48 
Ethical Conduct of the Study ..................................................................................................... 48 
Subject Information and Consent............................................................................................... 48 
Subject Confidentiality .............................................................................................................. 48 
Safety Oversight........................................................................................................................ 49 
APPENDIX 2. DATA COLLECTION, RETENTION, AND MONITORING ........................ 50 
Case Report Forms .................................................................................................................... 50 
Data Management and Processing ............................................................................................. 50 
Quality Control and Quality Assurance ..................................................................................... 50 
Record Retention ...................................................................................................................... 50 
Monitoring of the Study ............................................................................................................ 50 
APPENDIX 3. ADMINISTRATIVE PROCEDURES ............................................................ 52 
Liabilities  ............................................................................................................................... 52 
Adherence to Protocol ............................................................................................................... 52 
COVID-19 Response Plan ......................................................................................................... 52 
Statement of Investigator ........................................................................................................... 52 
Delegation of Investigator Duties .............................................................................................. 52 
Premature Termination or Suspension of a Study ...................................................................... 53 
APPENDIX 4. PROTOCOL REVIEW AND APPROVALS .................................................. 54 
APPENDIX 5. LIST OF ABBREVIATIONS ......................................................................... 57 
APPENDIX 6. CLINICAL LABORATORY EVALUATIONS .............................................. 59 
APPENDIX 7. BRIEF PSYCHIATRIC RATING SCALE ..................................................... 60 
APPENDIX 8. CLINICIAN-ADMINISTERED DISSOCIATIVE STATES SCALE .............. 61 
APPENDIX 9. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – 
BASELINE/SCREENING VERSION .................................................................... 66 
APPENDIX 10. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – 
SINCE LAST VISIT VERSION ............................................................................. 68 
APPENDIX 11. MODIFIED MINI-MENTAL STATE EXAMINATION .............................. 70 
APPENDIX 12. VISUAL ANALOGUE SCALE .................................................................... 72 
APPENDIX 13. PRIME QUESTIONNAIRE FOR PSYCHOSIS RISK .................................. 73 


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APPENDIX 14. PSYCHIATRIC EMERGENCY MANAGEMENT ...................................... 74 
Psychiatric Adverse Event Monitoring: ..................................................................................... 75 
Psychiatric Emergency Determination: ...................................................................................... 75 
Psychiatric Emergency Management: ........................................................................................ 75 
Psychiatric Emergency Follow Up: ........................................................................................... 76 
LIST OF TABLES 
Table 1: 
Adaptive Features and Boundaries .......................................................................... 16 
Table 2: 
Dose Cohorts .......................................................................................................... 18 
Table 3: 
Schedule of Activities ............................................................................................. 31 
Table 4: 
Pharmacokinetic Blood and Urine Sampling Schedule ............................................ 37 
Table 5: 
Acceptable Windows for Timed PK Blood Specimen Collection Procedures .......... 39 
Table 6: 
Adverse Event Relationship to Study Drug ............................................................. 41 
LIST OF FIGURES 
Figure 1: 
Predicted TMP-301 Plasma Concentration vs Time Profiles Following 50 
mg QD or BID .......................................................... Commercially Confidential Information
Figure 2: 
Psychiatric Emergency Management ...................................................................... 74 


 
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STUDY SYNOPSIS 
Name of 
Sponsor/Company: 
Tempero Bio Inc. 
Name of Product: 
TMP-301 
Title of Study: 
A Phase 1, Randomized, Placebo Controlled, Multiple Ascending Dose (MAD) 
Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TMP-301 
in Healthy Subjects 
Study 
Development 
Phase: 
1 
Objectives: 
Primary objective: 
• 
To assess the safety and tolerability of TMP-301 following multiple 
ascending oral doses 
Secondary objectives: 
• 
To assess the pharmacokinetics (PK) profile of TMP-301 following 
multiple ascending oral doses 
Exploratory objectives: 
• 
To assess endpoints related to TMP-301 mechanism of action 
• 
To evaluate Cytochrome P1A2 (CYP1A2) genotypes and their 
association with phenotypes for potential impact on metabolism and to 
identify biomarkers of potential response to TMP-301 
• 
Identify TMP-301 metabolites in urine 
Endpoints: 
Primary endpoints: 
The primary objective will be assessed with the following endpoints: 
• 
Adverse events (AE) 
• 
Clinical laboratory tests 
• 
Vital sign measurements 
• 
12-lead electrocardiograms (ECG) 
• 
Physical examinations 
• 
Psychiatric assessments (Brief Psychiatric Rating Scale [BPRS], 
Clinician Administered Dissociative States Scale [CADSS], Columbia 
Suicide Severity Rating Scale [CSSRS], Modified MiniMental State 
Examination (3MS), and Visual Analogue Scale [VAS]) 
Secondary endpoints: 
The secondary objective will be assessed with the following endpoints: 
 
• Day 1:  
Partial areas defined as AUC0-12 and AUC0-24; maximum concentration 
(Cmax), time of maximum concentration (Tmax), concentration at 12 h (C12), 
concentration at 24 h (C24) where C 24 = Ctrough Day2 
 
• 
Day 14 (or last day of dosing): 
AUCss from time zero to the time the end of the (12 or 24 hour) dosing 
interval (AUC0-TAU,ss). For BID cohorts, AUC0-TAU,ss = AUC0-12,SS, and for 
QD cohorts, AUC0-TAU,ss = AUC0-24,SS; Cavg, ss, Cmax,ss, Tmax,ss, C12,ss, C24ss, and 
Cmin,SS, all at steady-state (SS), along with apparent total plasma clearance 
(CL/F) and apparent volume of distribution (Vz/F) 
 


 
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Additional PK evaluations will include: 
• 
Accumulation ratio derived as:  
• 
 AR_AUC0-12 BID= AUC0-12,ss / AUC0-12, Day 1  
• 
AR_AUC0-24QD = AUC0-24,ss / AUC0-24, Day 1 
• 
AR_Cmax = Cmax,ss / Cmax,FD, Day 1 
• 
AR_C12 = C12,ss / C12, Day 1 
• 
AR_C24= C24,ss / C24, Day 1  
 
Estimations of dose proportionality at steady state. Dose–
normalized PK parameters (Cmax, C12, C24, and AUC0-12 and AUC0-24, 
when appropriate) will be assessed graphically for dose-proportionality 
 
• 
Estimation of time to achieve steady state. (Ctrough will be displayed 
graphically and summarized descriptively by day to assess for steady 
state) 
 
• 
As a marker of CYP1A2 activity, the ratio of paraxanthine to caffeine 
concentration (at 4 hours post caffeine dose) will be reported on Day -1 
and Day 14. Change in CYP1A2 activity will be derived as 
CYP1A2_ratio = paraxanthine/caffeine concentration day 14 / 
paraxanthine/caffeine concentration day -1 
• 
Identify TMP-301 metabolites in urine 
Investigational 
Product, Dose, and 
Mode of 
Administration 
(proposed): 
TMP-301 50 mg capsules 
Mode of administration: Oral 
In cohort 1, twice daily (bid) 50 mg, and in cohort 2 once daily (qd) 50 mg dose 
of TMP-301 will be administered orally with approximately 240 mL of water.  
Cohort 3 and 4 doses TBD. 
Placebo, Dose, and 
Mode of 
Administration: 
Placebo-to-match TMP-301 
Mode of administration: Oral 
Study Design: 
This is a single center, double-blind, placebo-controlled, fixed-sequence, 
multiple ascending dose (MAD) study. 
Duration of 
Treatment and 
Subject 
Confinement: 
Duration of clinical trial (per subject): 
Screening: Day -28 to Day -3 (up to 27 days) 
Treatment period: Doses will be administered from Day 1 to Day 14  
Subjects will reside at the clinical unit from Day -2 (PM) to Day 18 (AM).  
Subjects will return on Day 25 for a follow-up visit and End of Study (EOS) 
procedures. 
Total study duration: up to 53 days (including Screening) 
Safety Meetings 
for Dose 
Adjustments: 
Following completion of each cohort, a Safety Review Committee (SRC) will 
review all available safety and PK data (through Day 15, 24 hours post last 
dose) to evaluate progression to the next dose cohort. 
The SRC will be comprised of the Investigator (or designee) at the 
Investigational site, the Study Manager and the Sponsor’s medical personnel at 
a minimum. Additional advisors could be invited as required. 
During the study, each prescheduled cohort may be conducted at the dose 
outlined in the protocol or may be adjusted to a lower or equivalent dose, on the 
basis of safety, tolerability, and PK data (if available) reported in the previous 
cohorts. An optional dose titration cohort may be added.  
Study Population: 
Healthy adult subjects 


 
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Planned Number 
of Subjects: 
A maximum of 32 subjects will be included in the study. Each of the 4 cohorts 
will include 8 subjects. 
Bioanalysis: 
TMP-301, caffeine and paraxanthine plasma concentrations will be measured 
by validated bioanalytical methods. 
Pharmacokinetic 
Analysis: 
The PK analysis will be fully detailed in a Statistical Analysis Plan (SAP). 
Statistical 
Analysis: 
The statistical analysis will be fully detailed in a SAP. 
 


 
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STUDY ADMINISTRATIVE STRUCTURE 
Commercially Confidential Information 


 
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1. 
INTRODUCTION 
1.1. 
Study Rationale 
TMP-301 is a selective negative allosteric modulator (NAM) for the metabotropic glutamate 
(mGlu) receptor 5 subtype (mGlu5) being developed by Tempero Bio Inc., for the treatment of 
substance abuse disorders. TMP-301 has been studied in 2 completed studies including a 
single-ascending dose (SAD) study to evaluate PK and safety/tolerability (HTL001242-101) and 
a PET imaging study to correlate exposure of a single dose of TMP-301 with mGlu5 RO 
(HTL001242-103). 
The present study is a multiple ascending dose (MAD) study to evaluate the safety, tolerability, 
pharmacokinetics (PK) of TMP-301 in healthy subjects. There will be up to 4 dose cohorts, and 
within each cohort subjects will be randomly assigned to receive either active drug or placebo. 
Study subjects will be administered active drug or placebo once daily (qd) or twice daily (bid) 
for 14 days (note: only the AM dose is administered on Day 14). 
In this study, genetic samples will be collected for possible exploratory pharmacogenetics 
research that may be conducted to investigate the association between genetic factors 
(genotypes) and clinical assessments (phenotypes). If conducted, these studies would aim to 
better identify inherited genetic factors which may predict response to treatment with TMP-301, 
predict relative susceptibility to drug-drug interactions, predict genetic predisposition to side 
effects, or provide more information regarding TMP-301 in the disease state and how subjects 
may respond to TMP-301. 
1.2. 
Background 
The mGlu receptors are a family of GPCRs involved in the modulation of synaptic transmission 
and neuronal excitability throughout the CNS1 and as such play important neuromodulatory roles 
throughout the nervous system. As a consequence, they have been recognised as attractive 
targets for therapeutic intervention for a number of psychiatric, neurological and substance abuse 
disorders.2 These receptors provide a mechanism by which the neurotransmitter glutamate can 
modulate cell excitability and synaptic transmission via second messenger signalling pathways. 
There are 8 mGlu receptors which are subdivided into 3 groups (I, II, and III) based on their 
sequence similarity and pharmacology. mGlu5 and mGlu1 belong to group I mGlu receptors.3 
Activation of mGlu5 by glutamate stimulates the G protein-coupled pathways increasing 
intracellular inositol trisphosphate concentration and calcium mobilisation.3 
There is significant preclinical evidence suggesting that mGlu5 inhibition is beneficial in 
substance use disorders. Mice with mutations in the gene that encodes mGluR5 are deficient in 
cocaine self-administration behaviors.4,5 Similarly, mGluR5 antagonists decrease cocaine self-
administration, cue-induced relapse and conditioned place preferences 6,7 while agonists of 
mGluR5 trigger relapse.8 The effect of mGluR5 antagonism extends to other substance use 
disorders. Rodent studies indicate that the mGluR5 antagonist MPEP can reduce alcohol 
consumption 9 and opiate self-administration.10 
Human clinical evidence is also consistent with a role for mGluR5 receptors in substance use 
disorders. Studies with [11C]ABP688, a PET ligand for mGluR5, in human cocaine users have 
found a reduction in mGluR5 availability during abstinence that is correlated with the duration of 


 
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abstinence.11 [18]FPEB, another mGluR5 PET ligand, has been used to show that alcohol-
dependent patients have decreased cerebral mGluR5 levels during abstinence. 12,13 In contrast, 
higher striatal mGluR5 availability was observed in relapsers than in abstainers and mGluR5 
reduction was associated with reduced craving scores during abstinence, indicating that mGluR5 
reduction could reduce craving and prevent relapse. Finally, a Phase 2 clinical study of the 
mGlu5 inhibitor mavoglurant, in patients with cocaine use disorder (CUD), demonstrated a 
reduction in the proportion of cocaine use days and alcohol use days in patients receiving 
mavoglurant relative to patients receiving placebo (NCT03242928 14). These findings suggest 
that a pharmacological blockade of mGluR5 could be a therapeutic approach for modulating 
cocaine or alcohol-seeking behavior and preventing relapse. 
1.3. 
Summary of Nonclinical Pharmacology 
Full details on nonclinical pharmacology are provided in the Investigator’s Brochure (Section 
4.1). 
1.4. 
Summary of Nonclinical Safety Pharmacology 
Full details on nonclinical safety pharmacology are provided in the Investigator’s Brochure 
(Section 4.1.4). 
1.5. 
Summary of Nonclinical Pharmacokinetics 
Full details on nonclinical pharmacokinetics are provided in the Investigator’s Brochure 
(Section 4.2). 
1.6. 
Summary of Nonclinical Toxicology 
Full details on nonclinical toxicology are provided in the Investigator’s Brochure (Section 4.3). 
1.7. 
Summary of Clinical Experience 
Commercially Confidential Information. 
1.8. 
Pharmacokinetics 
1.8.1. 
Pharmacokinetics of TMP-301 in Study HTL0014242-101 (Single Ascending 
Dose) 
Commercially Confidential Information 
1.8.2. 
Pharmacokinetics of TMP-301 in Study HTL0014242-103 (PET) 
Commercially Confidential Information 
1.8.3. 
Pharmacokinetics of TMP-301 in Cohort 1 of Study TMP-301-HNV-101 
(Preliminary) 
Commercially Confidential Information 


 
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1.9. 
Safety and Efficacy 
1.9.1. 
Study HTL0014242-101: Single Ascending Dose 
Commercially Confidential Information 
1.9.2. 
Study HTL0014242-103: PET 
Commercially Confidential Information 
1.9.3. 
Receptor Occupancy/Exposure Relationship 
Commercially Confidential Information 
1.9.4. 
Study TMP-301-HNV-101 Multiple Ascending Dose Cohort 1  
Commercially Confidential Information 
1.10. 
Rationale for Dose Selection 
Commercially Confidential Information 
1.10.1. 
TMP-301 Pharmacokinetic Model and Dose Regimen Simulations 
Commercially Confidential Information 
1.10.2. 
Rationale for Dose Selection of Cohort 2 
Commercially Confidential Information 
1.11. 
Risk/Benefit Assessment 
1.11.1. 
Known Potential Risks 
Commercially Confidential Information 
1.11.2. 
Primary Pharmacology and Associated Risks 
Commercially Confidential Information 
1.11.3. 
Non-clinical Safety Studies and Associated Risks 
Commercially Confidential Information 
1.11.4. 
ADME and Associated Risks 
Commercially Confidential Information 
1.11.5. 
Caffeine Risks 
Commercially Confidential Information 
1.11.6. 
Known Potential Benefits 
Commercially Confidential Information 


 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
Primary 
Primary 
• 
To assess the safety and tolerability of 
TMP-301 following multiple ascending 
oral doses 
The primary endpoint is safety assessed after 
multiple-dose administrations by: 
• Adverse events (AE) 
• Clinical laboratory tests 
• Vital sign measurements 
• 12-lead electrocardiograms (ECG) 
• Physical examinations 
• Psychiatric assessments (Brief Psychiatric 
Rating Scale [BPRS], Clinician-Administered 
Dissociative States Scale [CADSS], Columbia 
Suicide Severity Rating Scale [C-SSRS], 
Modified Mini‑Mental State Examination 
(3MS) and Visual Analogue Scale [VAS]) 
Secondary 
Secondary 
• 
To assess the pharmacokinetics (PK) 
profile of TMP301 following 
multiple- ascending- oral doses 
 
The secondary objective will be assessed with the 
following endpoints: 
 
• Day 1:  
Partial areas defined as AUC0-12 and AUC0-24; 
maximum 
concentration 
(Cmax), 
time 
of 
maximum concentration (Tmax), concentration at 
12 h (C12), concentration at 24 h (C24) where C 24 
= Ctrough Day2 
 
• 
Day 14 (or last day of dosing): 
AUCss from time zero to the time the end of the 
(12 or 24 hour) dosing interval (AUC0-TAU,ss). For 
BID cohorts, AUC0-TAU,ss = AUC0-12,SS, and for 
QD cohorts, AUC0-TAU,ss = AUC0-24,SS; Cavg, ss, 
Cmax,ss, Tmax,ss, C12,ss, C24ss, and Cmin,SS, all at 
steady-state (SS), along with apparent total 
plasma clearance (CL/F) and apparent volume of 
distribution (Vz/F) 
•  
Exploratory 
Additional PK evaluations 
• 
To assess endpoints related to TMP-301 
mechanism of action  
• 
To evaluate CYP1A2 genotypes and 
their association with phenotypes for 
potential impact on metabolism and to 
identify biomarkers of potential 
response to TMP-301. 
• 
Identify TMP-301 metabolites in urine 
• 
Accumulation ratio derived as:  
o 
AR_AUC0-12 BID= AUC0-12,ss / AUC0-12, Day 1  
o 
AR_AUC0-24QD = AUC0-24,ss / AUC0-24, Day 1 
o 
AR_Cmax = Cmax,ss / Cmax,FD, Day 1 
o 
AR_C12 = C12,ss / C12, Day 1 
o 
AR_C24= C24,ss / C24, Day 1  
 
• 
Estimations of dose proportionality at 
steady state. Dose–normalized PK 
parameters (Cmax, C12, C24, and AUC0-12 and 
AUC0-24, when appropriate) will be 


 
Amendment 04 Version 4.0, 02 OCT 2023 
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OBJECTIVES 
ENDPOINTS 
assessed graphically for dose-
proportionality 
 
• 
Estimation of time to achieve steady state.  
(Ctrough will be displayed graphically and 
summarized descriptively by day to assess 
for steady state) 
 
• 
As a marker of CYP1A2 activity, the ratio 
of paraxanthine to caffeine concentration (at 
4 hours post caffeine dose) will be reported 
on Day -1 and Day 14. Change in CYP1A2 
activity will be derived as CYP1A2_ratio = 
paraxanthine/caffeine concentration day 14 / 
paraxanthine/caffeine concentration day -1 
 
 


 
Amendment 04 Version 4.0, 02 OCT 2023 
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3. 
STUDY DESIGN 
3.1. 
Adaptive Features and Risk Management of Study Design 
The rationale of having the following adaptive features is based on the hypothesis-forming 
approach of this clinical trial. Dose escalation or de-escalation, including titration, categories will 
be adapted as follows: 
Table 1: 
Adaptive Features and Boundaries 
Adaptive study design 
category 
Adaptive Features 
Boundaries 
Dose adjustment 
Doses for the subsequent 
cohorts will be 
determined/adapted based on 
tolerability, and PK data (if data 
through Day 15 permits and is 
available) collected in previous 
cohort.  
Doses are intended to escalate; 
however, they may be adjusted to 
a lower, an equivalent dose or a 
higher dose as per the adaptive 
features. For any cohort the mean 
maximum systemic exposure 
should not exceed or be predicted 
to exceed an AUC0-24 of 16,200 
h.ng/mL at steady state and/or a 
maximum serum concentration 
predicted to exceed a Cmax of 783 
ng/mLa 
The number of MAD cohorts 
The quantity of MAD cohorts 
may be adapted 
The maximal number of different 
dose level cohorts will be 4. 
Dose Titration 
Dose titration may be added in 
this study based on interim 
safety data reviews and 
tolerability to the study drug. 
Based on safety/tolerability 
findings in any of the previous 
cohorts, a 14 day dose titration 
cohort (7 days at initial dose + 7 
days at higher dose) may be 
added. 
Dosing with meals 
Dosing may be done in a fasted 
or fed state. 
At the selected dose level, the 
predicted effect of food on 
exposure will not exceed the 
thresholds described above. 
Abbreviations: MAD = multiple ascending dose; PK = Pharmacokinetics. 
 aExposure limits were based on 28D Rat NOAEL exposures, with an additional 10x safety factor. 
Commercially Confidential Information 
3.2. 
Maximum Tolerated Dose 
The Maximum Tolerated Dose (MTD) is defined as the highest dose that can be administered 
without clinically significant adverse events (AEs). The MTD will be determined by dose 
escalation until the stopping criteria are met as outlined in Section 4.3.2.1. 
The MTD is defined as the highest dose that does not cause unacceptable side effects. 


 
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3.3. 
Overall Study Design 
This study will be a randomized, double-blind, placebo controlled, fixed sequence, MAD study. 
The study will be conducted in a single clinical research unit (CRU). The study will consist of up 
to 4 cohorts. Each cohort will consist of 8 subjects (6:2 for active: placebo), for a maximum total 
sample size of approximately 32 subjects. Subjects will only participate in 1 cohort.  
Screening will occur within approximately 28 days prior to the first scheduled study drug 
administration. Screening data will be reviewed to determine subject eligibility. Subjects who 
meet all inclusion criteria and none of the exclusion criteria and who consent to participation will 
be admitted to the CRU for baseline evaluations prior to dosing. All baseline safety results 
should be available prior to the first study drug administration.  
In cohort 2, subjects will be fasted overnight for 10 hours prior to the morning dose, followed by 
a 2 hour fast. Subjects were fasted for 2 hours prior to dosing and 2 hours following the evening 
dose for the cohort 1 (50 mg bid). If dosing in a fed condition is selected for cohort 3 or 4 (see 
section 3.1), subjects will be fasted overnight for approximately 9 hours, then given standard 
breakfast followed by study treatment dosing 30 minutes after initiation of breakfast. 
Each subject will be randomly assigned to 1 of the following cohorts: 
• Cohort 1: Group 1 (6 subjects): 50 mg of TMP-301 bid 
Group 2 (2 subjects): placebo (matching TMP-301) bid 
• Cohort 2: Group 3 (6 subjects): 50 mg of TMP-301 qd  
Group 4 (2 subjects): placebo (matching TMP-301) qd 
• Cohort 3: Group 5 (6 subjects): Dose regimen of TMP-301 to be determined 
 
 
 
 
 
Group 6 (2 subjects): placebo (matching TMP-301) 
• Cohort 4: Group 7 (6 subjects): Dose regimen of TMP-301 to be determined 
 
 
 
 
 
Group 8 (2 subjects): placebo (matching TMP-301) 
Safety will be assessed and blood samples for PK will be collected throughout confinement. 
Subjects will be discharged from the CRU on Day 18. Subjects will return to the CRU on Day 25 
for a follow-up visit and EOS procedures.  
Caffeine (100 mg) will be included as probe CYP1A2 substrate in cohort 2 and subsequent 
cohorts. Ratio of plasma paraxanthine/caffeine will be determined in a blood sample 4 hours 
after administration of caffeine at baseline (Day-1) and on day 14. 
The maximum duration of subject participation, including Screening, will be approximately 
53 days. 
Subjects who terminate the study early will perform follow-up procedures at the time of Early 
Termination. 
Based on safety and tolerability findings in any of the cohorts, a 14-day dose titration cohort to 
evaluate the impact on TEAEs may be added as an additional cohort (7 days titration + 7 days 
stable dosing). 
The schedule of activities (SoA) of the study is described in Table 3. 


 
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3.4. 
Study Treatments 
The following treatments will be administered according to Table 2. 
• IP: TMP301 oral capsule 
• Placebo: Matching placebo 
Table 2: 
Dose Cohorts 
Cohort 
N 
(Active:Placebo) 
Dose 
Fasting 
Status 
Drug Administration 
1 
6:2 
Twice daily 
dose of 
50 mg 
Fasting Pre 
& 4 hours 
post dose 
Twice daily TMP-301 or 
placebo dosing from 
Days 1 to 13 and once in 
the morning on Day 14 
(for a total of 27 
consecutive study drug 
administrations) 
or 
Once daily TMP-301 or 
placebo to be 
administered in the 
mornings of Days 1-14. 
2 
6:2 
Once daily 
dose of 
50 mg 
Fasting Pre 
& 2 hours 
post dose  
or  
Fed 30 
minutes pre-
dose 
3 (Optional) 
6:2 
Dose and 
regimen to 
be 
determined 
4 (Optional) 
6:2 
Dose and 
regimen to 
be 
determined 
Caffeine (100 mg) will also be administered to enrolled subjects as part of the study on Day -1 
and Day 14. 


 
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4. 
SUBJECT POPULATION 
Subjects meeting all the inclusion criteria and none of the exclusion criteria at Screening may be 
eligible for participation in this study. Continued eligibility will be assessed upon admission to 
the clinical site, prior to the first study drug administration. 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or entered in the study. 
4.1. 
Inclusion Criteria 
1. Provision of signed and dated informed consent form (ICF) 
2. Stated willingness to comply with all study procedures and availability for the duration of 
the study 
3. Healthy adult male or female  
4. If male, meets one of the following criteria: 
a. Is able to procreate and agrees to use one of the accepted contraceptive regimens and 
not to donate sperm from the first study drug administration to at least 90 days after 
the follow-up visit. An acceptable method of contraception includes one of the 
following: 
− Abstinence from heterosexual intercourse 
− Male condom with spermicide or male condom with a vaginal spermicide (gel, 
foam, or suppository) 
Or 
b. Is unable to procreate; defined as surgically sterile (ie, has undergone a vasectomy at 
least 180 days prior to the first study drug administration) 
5. If female, meets one of the following criteria: 
a. Physiological postmenopausal status, defined as the following: 
− absence of menses for at least 12 months prior to the first study drug 
administration (without an alternative medical condition); and 
− Follicle stimulating hormone (FSH) levels ≥ 40 mIU/mL at Screening; 
Or 
 
b. Surgical postmenopausal status, defined as the following: 
− bilateral oophorectomy, salpingectomy, or tubal ligation; hysterectomy  
6. Aged at least 18 years but not older than 59 years, inclusive, at the time of informed 
consent 
7. Body mass index (BMI) within 18.5 kg/m2 to 32.0 kg/m2, inclusively 
8. Minimum body weight of at least 50.0 kg 


 
Amendment 04 Version 4.0, 02 OCT 2023 
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9. Non- or ex-smoker (An ex-smoker is defined as someone who completely stopped using 
nicotine products for at least 90 days prior to the first study drug administration) 
10. Must be willing to abstain from drinking coffee or caffeine containing beverages during 
the study, except where part of the study procedures 
11. Has supine blood pressure and pulse rate within the following ranges after 5 minutes rest: 
systolic blood pressure 90 to 140 mmHg, diastolic blood pressure 50 to 90 mmHg, and 
pulse rate 45 to 90 bpm at Screening and at check in 
12. Have no clinically significant diseases captured in the medical history or evidence of 
clinically significant findings on the physical examination (including vital signs) and/or 
ECG, as determined by an Investigator 
13. Has clinical laboratory test results within the reference ranges of the testing laboratory, 
with the exception of results outside the reference ranges that are deemed not clinically 
significant by the Investigator (or designee) at Screening and check-in 
4.2. 
Exclusion Criteria 
1. Female who is lactating 
2. Female who is pregnant according to the pregnancy test at Screening or prior to the first 
study drug administration 
3. Female using the following systemic contraceptives: oral, patch or vaginal ring, in the 
28 days prior to the first study drug administration and during the study 
4. Female using hormone replacement therapy in the 28 days prior to the first study drug 
administration and during the study 
5. Female using the following systemic contraceptives: injections or implant, or hormone 
releasing intrauterine device in the 13 weeks prior to the first study drug administration 
and during the study 
6. Drinking excessive amounts of tea, coffee, chocolate, and/or beverage or eating food 
containing caffeine (> 2 cups/day) 
7. Use of tobacco or nicotine containing products (including but not limited to; cigarettes, 
electronic cigarettes, pipes, cigars, chewing tobacco, nicotine patch, or nicotine gum) 
within 90 days prior to the first study drug administration and the inability to abstain 
from nicotine containing products until the follow-up visit.  
8. Past or current history of any mental, behavioral, or neurodevelopmental disorder as 
defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
(DSM-5) or significant risk of developing a psychosis (assessed by PRIME screen) or a 
personal history of psychotic symptoms (hallucinations or delusions) with or without a 
formal psychiatric diagnosis. Subjects with family history of significant mental, 
behavioral, or neurodevelopmental disorders unless determined by the Investigator (or 
designee) and agreed by the Medical Monitor to be non-clinically significant (NCS) will 
be excluded. 


 
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9. History or clinical manifestation of any metabolic, allergic, dermatological, hepatic, 
renal, hematological, pulmonary, gastrointestinal, neurological, respiratory, or endocrine 
disorder, unless determined by the Investigator (or designee) and agreed by the Medical 
Monitor to be NCS 
10. Active or history of cardiovascular or cerebrovascular disease, including hypertension, 
angina, ischemic heart disease, transient ischemic attacks, bundle branch block, evidence 
of myocardial ischemia, stroke, and peripheral arterial disease sufficient to cause 
symptoms and/or require therapy to maintain stable status 
11. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee) 
12. Active neoplastic disease or history of any neoplastic disease within 5 years of Screening 
(except for basal or squamous cell carcinoma of the skin or carcinoma in situ that has 
been definitely treated with standard of care) 
13. Active infection (eg, sepsis, pneumonia, abscess) or a serious infection (eg, resulting in 
hospitalization or requiring parenteral antibiotic treatment) within 6 weeks prior to dosing 
14. History of stomach or intestinal surgery or resection that would potentially alter 
absorption and/or excretion of orally administered drugs (uncomplicated appendectomy 
and hernia repair will be allowed) 
15. Any of the following at Screening and/or prior to the first study drug administration: 
a. QT interval corrected for heart rate using Fridericia’s method (QTcF) > 450 ms 
confirmed by repeat measurement 
b. QRS duration > 110 ms confirmed by confirmed by repeat measurement 
c. PR interval > 220 ms confirmed by repeat measurement 
d. Findings which would make QTc measurements difficult or QTc data uninterpretable  
e. History of additional risk factors for torsades de pointe (eg, heart failure, 
hypokalemia, family history of long QT syndrome) 
16. Maintenance therapy with any drug or significant history of drug dependency or alcohol 
abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic) 
17. Positive test result for alcohol, cotinine, and/or drugs of abuse at Screening or prior to the 
first drug administration 
18. Positive screening results to HIV Ag/Ab combo, hepatitis B surface antigen or hepatitis C 
virus tests 
19. Any other clinically significant abnormalities in laboratory test results at Screening that 
would, in the opinion of an Investigator, increase the subject's risk of participation, 
jeopardize complete participation in the study, or compromise interpretation of study data 
20. Intake of an IP in the 28 days prior to the first study drug administration 
21. Use of any prescription drugs in the 28 days prior to the first study drug administration, 
that in the opinion of an Investigator would put into question the status of the participant 
as healthy 


 
Amendment 04 Version 4.0, 02 OCT 2023 
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22. Use of St. John’s wort in the 28 days prior to the first study drug administration and 
during the study 
23. Consumption of any foods or beverages which alter CYP1A2 activity, e.g., barbecued 
food or cruciferous vegetables, such as broccoli and cauliflower, within 14 days prior to 
(first) check-in (a list of prohibited foods will be provided to subjects) 
24. Consumption of any foods or beverages containing Seville-type oranges, grapefruit, or 
poppy seeds within 7 days prior to (first) check-in 
25. Receipt of blood products within 2 months prior to check-in 
26. Donation of 1 unit of blood to American Red Cross or equivalent organization or 
donation of over 500 mL of blood in the 56 days prior to the first study drug 
administration 
27. Donation of plasma in the 7 days prior to the first study drug administration 
28. Poor peripheral venous access 
29. History or significant hypersensitivity to TMP301 or any related products (including 
excipients of the formulations) as well as severe hypersensitivity reactions (like 
angioedema) to any drugs 
30. Subjects who, in the opinion of the Investigator (or designee; including input from 
subjects’ general practitioner, as applicable), should not participate in this study 
31. Subject hospitalized for any reason in a period of 30 days before the start of the study 
32. Subjects who are investigational site staff members or directly involved in the conduct of 
the study and their family members or subjects who are employed by the Sponsor 
4.3. 
Withdrawal Criteria 
4.3.1. 
Before First Treatment Administration 
Before the first treatment administration, inclusion/exclusion criteria will govern the subjects to 
be dosed. Subjects withdrawn before first treatment administration will not be followed up and 
will not undergo End-of-Study/Early Termination assessments. Other safety assessments may be 
performed if required. 
Subjects are free to withdraw their consent to participate in the study at any time, without 
prejudice. The reason for their withdrawal or for deciding to end their participation will be 
documented. 
4.3.2. 
After First Treatment Administration 
Subjects may, at any time, voluntarily withdraw from the study or be removed from the study at 
the discretion of an Investigator or Sponsor. If such withdrawal occurs, or if the subject fails to 
return for visits, an Investigator should determine the primary reason for a subject’s premature 
withdrawal from the study and record the reason in the subject’s study documents.  
If a subject is withdrawn, the Sponsor will be notified and the date and reason(s) for the 
withdrawal will be documented in the subject’s electronic Case Report Form (eCRF). If a subject 


 
Amendment 04 Version 4.0, 02 OCT 2023 
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is withdrawn, the Investigator should make every effort to perform a final study visit 7 days after 
the last administration of the investigational product (IP) and complete the assessments and 
procedure outlined in the SOA. Other procedures may be performed at the Investigator’s (or 
designee’s) and/or Sponsor’s discretion. If the subject is in-house, these procedures should be 
performed before the subject is discharged from the clinic, where possible. The Investigator (or 
designee) may also request that the subject return for an additional follow-up visit. All 
withdrawn subjects will be followed until resolution of all their AEs or until the unresolved AEs 
are judged by the Investigator (or designee) to have stabilized. 
Subjects who are withdrawn for reasons not related to the study drug may be replaced following 
discussion between the Investigator and the Sponsor. Subjects withdrawn as a result of AEs 
thought to be related to the study drug will not be replaced. 
In the case of a clinically significant illness detected during the trial (including Coronavirus 
Disease 2019 [COVID]-19 diagnosis), the Principal Investigator (or delegate) will, in concert 
with the Sponsor, determine the most appropriate course of action on an individual basis. 
Evaluations will include but are not limited to: 
• The safety of the subject and other study participants 
• The possible effect the illness would have on the results gathered during the trial, and 
their ability to be appropriately analyzed or interpreted 
• The possibility of suspending participation then re-initiating it after recovery 
• The implication of any inclusion or exclusion criteria that would contradict possible 
actions 
• The implication of any adherence to regulatory guidelines that may be affected by 
actions decided, for example group effect analysis 
• The sample size calculation, current number of subjects, and possibility of 
replacement subjects 
Evaluations and decision-making for subject removal will be documented in the study file, 
reported to the Sponsor, reviewed during cohort safety evaluation and discussed where 
appropriate in the Clinical Study Report (CSR). 
4.3.2.1. 
Stopping Rules 
4.3.2.1.1. Individual Subject Stopping Rules 
A subject will be withdrawn, and study treatment discontinued, if any of the following criteria 
are met: 
• Change in compliance with any inclusion/exclusion criterion that is clinically relevant 
and affects subject safety as determined by the Investigator (or designee). 
Any clinically relevant sign, symptom, or intercurrent illness that, in the opinion of 
the Investigator (or designee), warrants subject withdrawal. 


 
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Page 24 of 76
• Non-compliance with the study restrictions or other unanticipated logistical event that 
might affect subject safety or study assessments/objectives, or as considered 
applicable by the Investigator (or designee). 
• Occurrence of a serious adverse event associated with active IP administration. 
• A subject experiences increased ALT or AST ≥3 × ULN. 
• A subject has a creatinine > 1.2 x ULN or an increase in serum creatinine by ≥ 
30 µmol/L (or 0.34 mg/dL) within 24 hours or an increase in serum creatinine to ≥ 
1.5 x baseline within 7 days. 
• A subject has an increase of > 60 msec from baseline (predose on Day 1 of each 
treatment period, as applicable) in QTcF. 
• A subject with any QTcF > 500 msec confirmed by the average of 2 additional ECG 
recordings performed at least 5 minutes apart, or other clinically significant 
conduction disturbance or arrhythmia. 
• A subject has a heart rate < 45 bpm or heart rate > 130 bpm, confirmed by a repeat 
assessment 
• A subject has a systolic blood pressure < 80 or > 155 mmHg, or a diastolic blood 
pressure > 100 mmHg, confirmed by a repeat assessment 
In the event of a subject meeting any of the above withdrawal criteria, the Sponsor’s Medical 
Monitor may deem it necessary for unblinding to occur. 
4.3.2.2. 
Trial Stopping Rules 
During active dosing of a cohort, the Investigator must contact the Sponsor immediately to 
discuss whether to suspend dosing if an AE or laboratory abnormalities indicate that continued 
dosing of subsequent subjects would not be tolerated or would jeopardize the subjects’ safety. 
The Sponsor alone may suspend dosing at any time for any reason. 
Active dosing of all subjects within a cohort must be stopped with any of the following: 
• If 1 SAE occurs in a subject receiving active IP 
• If ‘severe’ non-serious adverse reactions (ie, severe non-serious adverse events 
considered as, at least, possibly related to TMP-301) in 2 subjects in the same cohort, 
independent of within or not within the same system-organ-class.  
• One or more subjects fulfill Hy’s law defined as increases in aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 × upper limit of 
normal (ULN) and total bilirubin ≥2 × ULN (confirmed with repeat testing) where no 
other reason can be found to explain the combination of increases, e.g., elevated 
serum alkaline phosphatase (ALP) indicating cholestasis, viral hepatitis, or 
administration of another drug. 
• Occurrence of 1 death attributable to the study treatment 
If any of the above scenarios occur, all active dosing will stop, and no new cohorts will be 
initiated. Further discussion will then occur within the SRC, and a safety review will be 


 
Amendment 04 Version 4.0, 02 OCT 2023 
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conducted. Following the SRC review, the study may continue if the Investigator and Sponsor 
agree it is safe to proceed.  If the study is stopped, the MTD will be declared at the next lowest 
dose that was found to be safe and tolerable. 
Following completion of a dosing cohort, a safety evaluation will take place to determine if it is 
safe to dose escalate in a subsequent cohort.  If any of the following occur, no subsequent dose 
escalation will occur: 
• ≥2 subjects within the same cohort meet the same individual subject stopping rule at 
least possibly related to study treatment (see section 4.3.2.1.1). 
• ≥2 subjects within the same cohort experience any severe AEs at least possibly 
related to study treatment. 
• ≥2 subjects within the same cohort experience clinically significant laboratory 
abnormalities of the same character at least possibly related to study treatment. 
• ≥1 subjects with a serious adverse event considered at least possibly related to study 
treatment. 
If cohort dose escalation is stopped, the MTD will be declared as the next lowest dose that was 
found to be safe and tolerable. 
4.4. 
Lifestyle and/or Dietary Requirements 
• Subjects will be prohibited from consuming food or beverages containing Seville-
type oranges, grapefruit, or poppy seeds within 7 days prior to (first) check-in and 
during the study. 
• Subjects will eat only the food provided by the study site during confinement at the 
CRU. 
• Subjects will not be permitted to use tobacco or nicotine containing products 
(including but not limited to; cigarettes, electronic cigarettes, pipes, cigars, chewing 
tobacco, nicotine patch, or nicotine gum) within 90 days prior to the first study drug 
administration and must be willing to abstain from nicotine containing products until 
the follow-up visit.  
• Subjects will be prohibited from consuming alcohol for 48 hours prior to dosing and 
throughout the study. Throughout the study, in case of any doubt about alcohol 
consumption, a test for alcohol may be performed if requested by an Investigator. 
• Subjects will be prohibited from consuming any foods or beverages which alter 
CYP1A2 activity (e.g., barbecued food or cruciferous vegetables, such as broccoli 
and cauliflower) for 14 days prior to check-in and through the end of the study (a list 
of prohibited foods will be provided to subjects).  
• Subjects must abstain from caffeine for 48 hours prior to check-in and will be 
prohibited from drinking coffee or caffeine containing beverages throughout the 
study, except when caffeine is being administered as part of the study procedures. 


 
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• Males who are sexually active will be made aware of the possible male-mediated fetal 
toxicity associated with the study drug. Male subjects will be expected to use an 
acceptable contraceptive regimen and not to donate sperm as described in Section 4.1. 
4.5. 
Concomitant Treatment 
In addition to the drugs prohibited as per the exclusion criteria (Section 4.2), subjects will also be 
prohibited from taking any over the counter (OTC) products for 14 days prior to the first dosing 
and for the entire duration of the study.  
Medications that are substrates, inhibitors, or inducers of CYP1A2 are specifically prohibited 
(including, but not limited to, those containing caffeine (except where part of the study design), 
tizanidine, theophylline, naproxen, fluvoxamine, cimetidine, fluoroquinolones, or ticlopidine).  
Occasional use of paracetamol/acetaminophen at doses ≤ 2 grams/day will be permitted at the 
Investigator’s discretion. 
Except for medication which may be required to treat AEs, no other treatment, medication, or 
dietary supplement (including herbal/vitamin supplements) other than the study drugs will be 
allowed from the first dosing until all study activities and evaluations have been completed. 
Subjects will be instructed to notify the study site about any new medications taken after the start 
of the study treatment. All medications and significant non-drug therapies (including physical 
therapy and blood transfusions) administered after the subject has received the study treatment 
must be listed in the subject case report form (CRF). The drug name and dose taken will be 
noted. An Investigator or delegate and/or the Sponsor will decide whether the subject will be 
permitted to remain in the study, depending on the drug used, the time of drug intake, etc. 


 
Amendment 04 Version 4.0, 02 OCT 2023 
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5. 
STUDY TREATMENTS 
5.1. 
Investigational Products 
All IPs, including the placebo, will be provided by the Sponsor. 
5.1.1. 
TMP-301 
5.1.2. 
Placebo 
Commercially Confidential Information 
5.2. 
Investigational Product Management 
5.2.1. 
Packaging, Labeling and Dispensing 
Commercially Confidential Information 
5.2.2. 
Storage and Handling 
All study drugs will be shipped from the sponsor or sponsor resources to the CRU’s pharmacy. 
TMP-301 should be stored between 2°C and 8°C and kept in a tightly closed container. The 
product should not be used if expired and should not be frozen. 
The CRU’s pharmacy will maintain an inventory record of the IPs received, stored (in a secure 
restricted area), and dispensed. IPs will be provided to study subjects only. 
5.2.3. 
Method of Assigning Subjects to Treatment Groups 
Altasciences will generate the randomization code with a computer program according to the 
study design, the number of subjects and the number of treatments. Within each cohort, subjects 
will be randomized (3:1) to receive TMP-301 or placebo. The random allocation of each IP to 
each subject will be done in such a way that the study is balanced. Once generated, the 
randomization code will be final and will not be modified. 
Subjects who sign the ICF and are randomized but do not receive the study treatment may be 
replaced. Subjects who sign the ICF, are randomized and receive the study treatment, and 
subsequently withdrawn as a result of AEs thought to be related to the study drug will not be 
replaced. Subjects who sign the ICF, are randomized and receive the study treatment, and are 
subsequently withdrawn for reasons not related to the study drug may be replaced.  
5.2.4. 
Blinding 
The randomization code may be made available to the personnel of the bioanalytical facility The 
treatment assignment will not be known by the study participants. 
Furthermore, the randomization code will not be available to the physician and clinical staff 
involved in the collection, monitoring, revision, or evaluation of AEs, as well as clinical staff 
who could have an impact on the outcome of the study, and including the pharmacokineticist (or 
delegate), until database lock, or designation that unblinding information is required by the SRC 
to determine the next dose. 


 
Amendment 04 Version 4.0, 02 OCT 2023 
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The preparation of the products will be done by designated personnel that are not directly 
involved in the clinical aspects of the trial. 
The randomization code must not be broken except in emergency situations where the 
identification of a subject’s study treatment is required by an Investigator for further treatment to 
the subject or to complete a SAE report. Randomization information will be held by designated 
individual(s). The date and reason for breaking the blind must be recorded. 
The results of the PK analyses will be made available only to the personnel responsible for 
evaluating the safety data before proceeding with the next dose level. 
5.2.5. 
Study Drug Accountability 
Complete and accurate inventory records of all study drugs will be maintained. This includes 
acknowledgment of receipt of each shipment of study product (quantity and condition), subject 
dispensing records, and returned or destroyed study product. 
At the conclusion of the study, all unused IPs and all medication containers will be returned to 
the Sponsor unless the Sponsor has approved other arrangements. Drug accountability will be 
performed at the completion of the trial. 
5.3. 
Administration of Study Drug 
For cohort 1, the study drug will be administered twice daily (12 hours apart) on Days 1-13 and 
once in the morning on Day 14. For cohort 2 (and Cohorts 3-4 if done) the study drug will be 
administered once daily in the morning on Days 1-14.  The date and time of each dose will be 
recorded. For each subject, all scheduled post dose activities and assessments will be performed 
relative to the time of the first study drug administration. 
Commercially Confidential Information  
On Day -1, caffeine will be administered at approximately 9:00 am with approximately 240 mL 
of water at ambient temperature test.  On Day 14, caffeine will be administered with the study 
drug and approximately 240 mL of water.  
5.3.1. 
Treatment Compliance 
The study drug will be dispensed only to eligible subjects and administered under the supervision 
of study personnel. Treatment compliance will be verified according to the site’s standard 
operating procedures (SOPs). 
5.4. 
Meals 
Food intake will be controlled for each confinement period and for all subjects. 
Subjects will be required to fast overnight for 10 hours prior to the morning dose and for at least 
2 hours following dosing. Subjects will also be required to fast for 2 hours prior to the evening 
dose and 2 hours following dosing for bid dosing. 
For cohort 3 and 4, dosing may be conducted in the fed state (see section 3.1).  In that case, 
subjects will be required to fast overnight for approximately 9 hours.  Each subject will be served 


 
Amendment 04 Version 4.0, 02 OCT 2023 
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a standard breakfast, and the study treatment will be administered 30 minutes after initiation of 
the meal. 
Fluid intake other than water will be controlled for each confinement period and for all subjects. 
Each dose of TMP-301 will be administered with approximately 8 oz or 240 mL or water. Water 
will be permitted as needed except from 1-hour predose until 1 hour after dosing (except for 
water consumed for the dose administration).  For cohort 3 and 4, if dosing is conducted in the 
fed state, there will be no water restriction during the meal. 
5.5. 
Other Protocol Restrictions 
Subjects will remain in bed (seated or semi-reclined) for at least the first 4 hours following drug 
administration. However, should AEs occur, subjects may be placed in an appropriate position. 
During this interval and after the 4-hour period, subjects will be permitted to get up under 
supervision. Subjects will not engage in strenuous activity at any time during the confinement 
periods. 


 
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6. 
STUDY PROCEDURES 
An overview of the study activities for each participant is detailed in Table 3. 
Subjects may leave the clinical site on Day 18. However, they may be advised to stay at the 
clinical site for safety reasons, if judged necessary by the Investigator or delegate in charge.  
Unless otherwise stated in the protocol, the Standard Operating Procedures (SOPs) of the study 
facilities, which are available for all activities relevant to the quality of the study, will be 
followed during this study. When the nominal time for multiple events occurs simultaneously, 
the events will be staggered using their acceptable windows (acceptable windows for each 
assessment are specified in the following sections of this protocol), with priority given to those 
events related to primary study endpoints. 
Any deviation from protocol procedures should be noted in the source documentation, recorded 
as a protocol deviation, and compiled for reporting in the CSR. 


 
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Table 3: 
Schedule of Activities 
Study 
Procedures 
Screening 
Check-in 
Baseline 
Caffeine 
test 
Day 1 
Days 2-3 
Day 4 
Days 5-6 
Day 7 
Days 8-13 
Day 14 
Days15-17 
Discharge 
Follow-
up/EOS 
visit 
Day 
Days-
28 to -
1 
Day -2 
Day -1 
 
 
 
 
 
 
 
 
Day 18  
Day 25z 
(±2 
days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Admission to Unit 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
 
Psychiatric History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X b 
 
 
 
 
 
 
 
 
 
Xp 
 
Psychiatric Examinationsc 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Urine Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testd 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
FSHe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height and body weight 
Xf 
 
 
 
 
 
 
 
 
 
 
X 
X 
Genotyping sampleg 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Exploratory Biomarkers sample 
 
 
 
Xh 
Xh 
 
 
Xh 
 
Xh 
 
X 
 
Check-in 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Check-out 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Nonresidential visit 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
TMP-301 or Placeboi 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Caffeine 100 mg oral 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Caffeine Plasma sampling 
 
4 hr post 
dose 
 
 
 
 
 
 
4 hr 
post 
dose 
 
 
 


 
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Study 
Procedures 
Screening 
Check-in 
Baseline 
Caffeine 
test 
Day 1 
Days 2-3 
Day 4 
Days 5-6 
Day 7 
Days 8-13 
Day 14 
Days15-17 
Discharge 
Follow-
up/EOS 
visit 
Plasma PK Samplingj,k,l  
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
96.00aa  
X 
Urine Samplingl 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Adverse Event Recording 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant Medication Monitoring 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry, Hematology, and 
Urinalysism 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
96.00 aa 
X 
Vital Signs: Blood Pressure, Pulse Rate and 
Oral Body Temperaturen,o 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
96.00 aa 
X 
12-lead ECGq,r 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
96.00 aa 
X 
VAS Alertness Scales,t 
 
 
 
X 
 
 
 
X 
 
X 
 
96.00 aa 
 
BPRS, CADSSt,u,v,x 
X 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
3MSt,v,w,x 
X 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
C-SSRSy 
X 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: BPRS = Brief Psychiatric Rating Scale; CADSS = Clinician-Administered Dissociative States Scale; 3MS = Modified Mini-Mental State; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; FSH = follicle-stimulating hormone; PK = pharmacokinetic(s). 
 
a Interim medical history. 
b Symptom directed physical examination and at Investigator discretion. 
c Clinical Interview for DSM-5 (SCID-5 CT) will be conducted by appropriately trained staff. This psychiatric examination will include an assessment of 
premorbid personality, personal and developmental history, alcohol and substance use history, forensic history, past psychiatric history.  The PRIME 
questionnaire will also be administered to screen for risk of psychosis.  A psychiatric exam (full or partial) can take place at any time during the study at the 
discretion of the PI, if there is a relevant concern. 
d In all females. Serum pregnancy test at Screening and urine pregnancy tests at all other times. A positive urine pregnancy test will be confirmed with a serum 
pregnancy test. 
e In all females to determine postmenopausal status. 
f Height measured at Screening only. 
g The genotyping samples will be stored and may be processed and analyzed to assess genotyping of drug metabolizing systems. 
h Day 1 at pre-dose, 1, 4, and 8 hours; day 2 pre-dose; and days 7 and 14 at pre-dose, 1, 4, and 8 hours. 
i For BID Cohorts: Dosing twice daily interval from Day 1 to Day 13, two intakes separated by 12.00 hours (note: only the AM dose is administered on Day 14).  
For QD Cohorts: Dosing once daily in the morning from Day 1 to Day 14. 
j Timing of PK blood samples may be changed based on emerging data. 
k At each protocol specified timepoint for PK (including predose baseline) out to 12.00 hours postdose. (Section 6.2). 


 
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l Serial blood will be collected on Day 1, and 14 at predose, 0.5, 1.00, 2.00, 3.00, 4.00, 6.00, 8.00, and 12.00 hours. Trough (predose AM) and 8 hr and 12 hr 
samples will be collected on Days 2, 7 and 11. Trough samples (predose AM) will be collected on Days 5, 9 and 12. Additional PK samples will be drawn after 
the last dose on Day 14 at 24.00 (Day 15), 28.00 (Day 15), 48.00 (Day 16), 52.00 (Day 16), 72.00 (Day 17), and 96.00 (Day 18) hours postdose and Day 25 at 
the follow-up EOS visit (Day25 ± 2 days). Urine will be collected on Day 1 (0 to 4, 4 to 8, 8 to 12, 12 – 24 hr) and Day 14 (0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 
to 48 (Day 15), and 48 – 72 hr (Day 16)). See Table 4.  
m Day 1 predose, then 24.00 (Day 2) and 72.00 hours (Day 4) postdose, then every 2 days (Days 6, 8, 10, 12, 14, 16) post dose at approximately 10 am ± 1 hour. 
n Days 1 and 7: Prior to morning dosing and 0.5, 1.00, 2.00, 3.00, 4.00, 6.00, 8.00, and 12.00 hours. Days 2, 4, 6, 8, 10, and 12: Prior to dosing and 4.00 and 
12.00 hours postdose. Day 14: Prior to dosing and 0.5, 1.00, 2.00, 3.00, 4.00, 6.00, 8.00, 12.00, 24.00 (Day 15), 48.00 (Day 16), 72.00 (Day 17), 96.00 (Day 
18) hours postdose. 
o At baseline on Day 1, predose vital sign measurements (except oral body temperature) will be conducted in triplicate (with an interval of approximately 10 - 30 
minutes between each recording). The average value of each parameter will be considered as baseline value. 
p Symptom-directed physical examination. 
q Days 1 and 7: Predose and at 4.00, 6.00, 8.00, and 12.00 hours postdose. Days 2, 4, 6, 8, 10, and 12: Predose and 4.00 and 12.00 hours postdose. Day 14: Prior 
to dosing and 0.5, 1.00, 2.00, 3.00, 4.00, 6.00, 8.00, 12.00, 24.00 (Day 15), 48.00 (Day 16), 72.00 (Day 17), 96.00 (Day 18) postdose. 
r At baseline in Day 1 predose, ECG recordings will be conducted in triplicate at (-45, -30, and -15 minutes). The average value of each parameter will be 
considered as baseline value. 
s Day 1, 7, and 14: Predose then 4.00, 6.00, and 12.00 hours postdose and Day 18. 
t May also be conducted at other times if deemed appropriate based on emerging data. 
u Check-in, then 6.00 and 24.00 hours postdose on Day 1, Day 7, and Day 14. 
v Conducted as part of the psychiatric examination. 
w Check-in , and 24.00 hours postdose on Day 1, Day 7, and Day 14. 
x Subjects will be screened within 28 days prior to dosing. A psychiatric examination will be performed at Screening by a suitably trained psychiatrist or 
appropriately trained staff using a clinical interview. This will include an assessment of premorbid personality, personal and developmental history, alcohol and 
substance use history, forensic history, past psychiatric history, and mental state examination. 
y Every other day from Day 1 to discharge. 
z Approximately 1 week after last dose. 
aa 96 hours after the last (Day 14) dose  
 


 
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6.1. 
Safety Assessments 
Safety assessments will include physical examination, psychiatric assessments, vital signs, 
12-lead ECG, clinical laboratory tests, and AE monitoring. At the discretion of an Investigator, 
additional safety assessments may be performed as needed to ensure subject safety. 
The Investigator or delegate in charge will be present at the clinical site for at least the first 
4 hours following first drug administration and will remain available at all times throughout the 
study. 
6.1.1. 
Medical History 
The medical history at Screening will include all queries by the medical and clinical staff related 
to the subject’s well-being and history of relevant past medical events/experiences. Medical 
history will include all demographic data (age, sex, race, body weight, height, and BMI) and 
baseline characteristics. Alcohol and smoking habits will also be recorded. 
6.1.2. 
Psychiatric History 
Clinical Interview for DSM-5 (SCID-5 CT) will be conducted by appropriately trained clinical 
staff at Screening. This psychiatric examination will evaluate the subject’s psychiatric history 
and include an assessment of premorbid personality, personal and developmental history, 
alcohol, and substance use history, forensic history, past psychiatric history. 
The 12 question PRIME screen will be self-administered by subjects at Screening.  After 
completion, study staff will review the subject’s responses.   A positive screen is a score of 6 on 
any one question or a score of 5 on any two questions.  Subjects with a positive PRIME screen 
will be excluded from the study, as they are considered at high risk of developing psychosis (see 
Appendix 13). 
6.1.3. 
Physical Examination 
A physical examination will be performed by a medically qualified and licensed individual as 
outlined in Table 3. 
The physical examination will include a general review of the following body systems (at 
minimum): head and neck, cardiovascular, respiratory, gastrointestinal, brief neurological and 
general appearance, unless a symptom-oriented physical exam is indicated. 
6.1.4. 
Vital Signs 
Vital signs will be measured as outlined in Table 3. Baseline vital signs (as well as subsequent 
predose and/or post-dose 24 hours) will be measured approximately  2 hours prior to dosing. All 
other vital signs will be assessed within +/- 20 minutes of the nominal time point. 
Blood pressure and pulse rate will be measured after being in supine position for at least 3 
minutes. Efforts will be made to apply the blood pressure cuff when the subject is placed in 
supine position for ECG collection. Repeat measurements may be performed at investigator’s 
discretion to verify out of range or suspect values, including during screening and check-in. 


 
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6.1.5. 
12-Lead Electrocardiogram 
Twelve-lead ECGs will be performed as outlined in Table 3. 
Predose and/or post-dose 24 hour ECGs should be completed approximately 2 hours prior to the 
morning dose. All other ECG assessments should be completed within +/- 20 minutes of the 
nominal time point. ECG assessments will be collected after being in supine position for at least 
10 minutes. 
6.1.6. 
Pharmacogenetic and Exploratory Biomarkers Sampling 
A blood sample will be collected for CYP 1A2 or other genotyping on Day 1 as outlined in 
Table 3.  Blood samples will also be collected on Day 1 and during designated times (per 
Table 3) during the treatment period for exploratory biomarker analysis. 
6.1.7. 
Laboratory Evaluations 
Laboratory evaluations will be performed as outlined in Table 3. 
The laboratory evaluations to be conducted for this study are presented in Appendix 6. 
Additional clinical laboratory tests may be performed by the medical laboratory as part of larger 
standard test panels (not required for subject safety). 
The Investigator or delegate in charge will assess each abnormal value to determine if it is 
clinically significant. Postdose clinically significant laboratory values will be reported as AEs, if 
applicable, as judged by the Investigator or delegate in charge. Only test results required by the 
protocol and/or abnormal results will be entered in the clinical database and reported in the CSR, 
based on report requirement. 
6.1.8. 
Brief Psychiatric Rating Scale (BPRS) 
The BPRS scale is designed for the assessment of psychiatric symptoms or disorders (eg, 
depression, anxiety, hallucinations, and unusual behavior). 
The scale must be administered by a psychiatrist or other individual that is suitably qualified by 
education or training. See Appendix 7 for a sample assessment. The assessment will be 
performed as outlined in Table 3. 
The BPRS will be completed at check-in on Day -2 and at approximately 6.00 and 24.00 hours 
after dosing on Day 1. The BPRS will also be completed  approximately 6.00 and 24.00 hours 
after dosing on Days 7 and 14. The acceptable window for BPRS will be within 2 hours 
following the 6.00 hours nominal timepoint and approximately 3 hours prior to next dose for the 
24.00 hour timepoint. 
All the 24.00 hour post-dose assessments are intended to be completed prior to next day dosing 
as applicable. 
PD procedures should be carried out in the following order when required: (1) 3MS, (2) CADSS, 
(3) BPRS, (4) C-SSRS. 
6.1.9. 
Clinician-Administered Dissociative States Scale (CADSS) 
The CADSS scale is designed for the assessment of dissociative states in adults. 


 
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The scale must be administered by a psychiatrist or other individual that is suitably qualified by 
education or training. See Appendix 8 for a sample assessment. The assessment will be 
performed as outlined in Table 3. 
The CADSS will be completed at check-in on Day -2 and at approximately 6.00 and 24.00 hours 
after dosing on Day 1. The CADSS will also be completed approximately 6.00 and 24.00 hours 
after dosing on Days 7 and 14. The acceptable window for CADSS will be within 2 hours 
following the 6.00 hours nominal timepoint and approximately 3 hours prior to next dose for the 
24.00 hours timepoint. 
All the 24 hours post-dose assessments are intended to be completed prior to next day dosing as 
applicable. 
PD procedures should be carried out in the following order when required: (1) 3MS, (2) CADSS, 
(3) BPRS, (4) C-SSRS. 
6.1.10. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire designed for the assessment of suicidal ideation and behavior in 
adolescents and adults. 
To monitor for a history of (the past 2 years to present) or for the emergence of suicidal ideation 
and behavior, subjects will undergo C-SSRS evaluations at the time points indicated in Table 3. 
The questionnaire must be administered by a psychiatrist or other individual that is suitably 
qualified by education or training. See Appendix 9 for a sample C-SSRS – Baseline/Screening 
version assessment and Appendix 10 for a sample postdose C-SSRS (Since Last Visit Version) 
assessment. 
The C-SSRS will be completed at screening, check-in on Day -2 and it will be assessed 
approximately 3 hours prior to dosing on Days 1, 3, 5, 7, 9, 11, 13, 15, 17 and on day 18 prior to 
discharge, and at the follow-up/EOS visit.  
PD procedures should be carried out in the following order when required: (1) 3MS, (2) CADSS, 
(3) BPRS, (4) C-SSRS. 
If there is a positive result for suicidality on the C-SSRS after Screening (defined by a subject 
answering “yes’ to questions 4 or 5 on the suicidal ideation portion of the C-SSRS), the subject 
will be evaluated by an Investigator or medically qualified sub-investigator for continuation in 
the study. 
If a subject becomes suicidal during the study, an Investigator or medically qualified 
sub-investigator should provide the appropriate treatment to the subject. 
6.1.11. 
Modified Mini-Mental State Examination (3MS) 
The 3MS is an examination designed for the assessment of dementia in adults. 
The examination must be administered by a psychiatrist or other individual that is suitably 
qualified by education or training. See Appendix 11 for a sample assessment. The assessment 
will be performed as outlined in Table 3. 
The 3MS will be completed at check-in and at approximately 24.00 hours after dosing on Day 1. 
The 3MS will also be completed approximately 24.00 hours after dosing on Days 7 and 14. The 


 
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acceptable window for 3MS will be approximately 3 hours prior to next dose for the 24 hours 
timepoint. 
All the 24 hours post-dose assessments are intended to be completed prior to next day dosing as 
applicable. 
PD procedures should be carried out in the following order when required: (1) 3MS, (2) CADSS, 
(3) BPRS, (4) C-SSRS. 
6.1.12. 
Visual Analogue Alertness Scale (VAS) 
The VAS alertness scale is designed to assess the alertness of subjects across a continuum scale 
with values from 0 to 10. 
The scale will be administered by the VAS team or other individual that is suitably qualified by 
education or training. See Appendix 12 for a sample assessment. The assessment will be 
performed as outlined in Table 3. 
The VAS should be completed prior to TMP-301 administration and at approximately 4.00, 6.00, 
and 12.00 hours after dosing on Days 1, 7, and 14. This assessment will also occur on Day 18 
prior to discharge.  
6.1.13. 
Rescue Therapy 
A crash cart with the necessary resuscitation equipment, including parenteral naloxone, will be 
available in case of a medical emergency. 
In the event of a psychiatric emergency, the Investigator may use medication to treat psychosis, 
agitation or anxiety.  Details for the recommended medication to treat these emergencies can be 
found in Appendix 14 : Psychiatric Emergency Management. 
6.2. 
Pharmacokinetic Assessments 
The complete blood sampling schedule is presented in Table 4. 
Evaluation of CYP 1A2 activity using caffeine as a CYP 1A2 probe substrate.  
Paraxanthine/caffeine ratio will be measured at baseline (day -1) and day 14, from 4h blood 
sample post caffeine dose (100 mg). 
Table 4: 
Pharmacokinetic Blood and Urine Sampling Schedule 
 
Nominal Timea (hours)  
Day 
Blood 
Urine 
Day 1a 
0.00 
Day 1 


 
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Nominal Timea (hours)  
0.50 
 
0 to 4  
4 to 8 
8 to 12 
12- 24 
 
1.00 
2.00 
3.00 
4.00 
6.00 
8.00 
12.00 
Days 2, 7, 11  
0.00 
No Urine Collection  
8.00 
12.00 
Days 5, 9, and 12  
0.00 
No Urine Collection  
Day 14 
 
0.00 
Day 14  
0 to 4  
4 to 8 
8 to 12 
12- 24 
24-48 (Day 15) 
48-72 (Day 16) 
0.50 
1.00 
2.00 
3.00 
4.00 
6.00 
8.00 
12.00 
24.00 (Fasted) (Day 15)  
28.00 (Fed) (Day 15) 
48.00 (Fasted) (Day 16) 
52.00 (Fasted) (Day 16) 
72.00 (Day 17) 
96.00 (Day 18) 
264.00 (Day 25 ± 2 days) 
aNominal times listed are relative to the morning dose on the corresponding day. 
Blood samples will be collected by direct venipuncture into a labeled tube containing the 
appropriate anticoagulant as specified by the bioanalytical facility. As an option to the subject or 
if judged necessary by the clinical staff, blood samples may be collected from an indwelling 
cannula, which will be placed in the vein of the subject. 


 
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The time of PK blood sample collection will be calculated relative to the time of treatment 
administration. The actual time of all PK blood draws will be recorded in case report form and 
reported for all subjects. 
Windows for timed PK blood sample collections are presented in Table 5. PK samples collected 
outside of the pre-specified windows will be documented as protocol deviations. Since actual 
times are to be used for the PK analysis, deviations will be reflected in the analysis unless 
indicated otherwise upon review of the data. 
Table 5: 
Acceptable Windows for Timed PK Blood Specimen Collection Procedures 
Elapsed Time  
Accepted Window 
Pre-dose 
Up to –2 hours 
> 0 hour to ≤ 30 minutes 
± 10 minutes 
> 30 minutes to ≤ 4 hours 
± 10 minutes 
> 4 hours to ≤ 12 hours 
± 10 minutes 
> 12 hours to ≤ 24 hours 
± 10 minutes 
> 24 hours to ≤ 72 hours 
± 2 hours 
> 72 hours 
± 4 hours 
TMP-301 concentrations for PK assessments will be obtained through bioanalysis of the plasma 
derived from the blood samples drawn during this study, using a validated bioanalytical method. 
6.2.1. 
Pharmacokinetic Sample Processing, Storage and Shipping 
Blood samples for PK determination will be processed, stored, and shipped according to the 
sample processing instructions supplied by the bioanalytical facility.  


 
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7. 
ADVERSE EVENTS DOCUMENTATION 
7.1. 
Definitions 
An AE is defined as any untoward medical occurrence in a subject administered an IP and which 
does not necessarily have a causal relationship with the treatment. An AE can therefore be any 
unfavorable and unintended sign (including a clinically significant abnormal clinical laboratory 
finding, for example), symptom, or disease temporally associated with the use of an IP, whether 
or not related to the IP. 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable possibility the 
drug caused the AE. ‘Reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the AE. A SAR implies a lesser degree of certainty about 
causality than adverse reaction, which means any AE caused by a drug. 
An AE may be: 
• A new illness, 
• Worsening of a concomitant illness, 
• An effect of the study drug including comparator; it could be an abnormal clinical 
laboratory value as well as a significant shift from baseline within normal range 
which an Investigator considers to be clinically important. 
Surgical procedures themselves are not AEs. They are therapeutic measures for conditions that 
required surgery. The condition for which the surgery is required is an AE, if it occurs or is 
detected during the study period. Planned surgical measures permitted by the clinical study 
protocol and the conditions(s) leading to these measures are not AEs, if the condition(s) was 
(were) known before the start of study treatment. In the latter case, the condition should be 
reported as medical history. 
A SAE or reaction is any untoward medical occurrence that at any dose: 
• Results in death, 
• Is life-threatening, 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability or incapacity (defined as a substantial 
disruption of a person’s ability to conduct normal life functions), 
• Is a congenital anomaly or birth defect, 
• Is an important medical event that may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed above (according to medical 
judgment of an Investigator) 
7.2. 
Severity Assessment 
All AEs will be graded per the FDA’s Guidance for Industry on Toxicity Grading for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. 


 
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Every effort will be made to obtain an adequate evaluation of the severity. 
7.3. 
Causality Assessment 
An Investigator will determine the relationship of any AE to the study drug using the guidelines 
presented in Table 6.  
Table 6: 
Adverse Event Relationship to Study Drug 
Relationship to Drug 
Comment 
Reasonable Possibility 
A temporal relationship exists between the AE onset and 
administration of the IP that cannot be readily explained by the 
subject’s clinical state or concomitant therapies. 
Furthermore, the AE appears with some degree of certainty to be 
related, based on the known therapeutic and pharmacologic actions 
or AE profile of the IP. 
In case of cessation or reduction of the dose the AE may abate or 
resolve and it may reappear upon rechallenge. 
No Reasonable Possibility 
Evidence exists that the AE has an etiology other than the IP. 
For SAEs, an alternative causality must be provided (eg, preexisting 
condition, underlying disease, intercurrent illness, or concomitant 
medication). 
AE = adverse event; IP = investigational product; SAE = serious adverse event 
7.4. 
Adverse Event Monitoring 
This section described the general process of adverse event monitoring.  For specific psychiatric 
adverse event monitoring and management of psychiatric emergencies, see Appendix 14: 
Psychiatric Emergency Management. 
For the purposes of this study, the monitoring period for AEs extends from Screening until the 
EOS visit. From screening to the first dose of the study, AEs will be recorded as screening events 
or as part of the medical history, as applicable. AEs occurring after initiation of study drug will 
be indicated as TEAEs in the CSR. 
Subjects will be questioned on their health status at the beginning of each study period and 
before each departure from the clinical site. Open-ended questions will be asked. 
During the study, all AEs spontaneously reported by the subject, observed by the clinical staff or 
elicited by general questioning will be recorded for all subjects and reported in the CRF. 
If necessary, every effort will be made to obtain an adequate follow-up of the subjects. Should 
any subject choose to withdraw from the study, they will be advised of the safety precautions to 
be taken. 
Any AE which remains unresolved as of the last visit will require an evaluation and follow-up 
until the AE has been resolved or a reasonable explanation for its persistence found or is deemed 
mild and safely resolving. 
In the case of AEs deemed related to the IP, every effort will be made to determine the final 
outcome. 


 
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It is an Investigator’s responsibility to ensure subjects experiencing AEs receive appropriate 
follow-up, treatment where required, and that every action is well documented. 
Classification of AEs will be performed by System Organ Class (SOC) and Preferred Term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA), version 25.0 or higher. 
Concomitant medications will be coded using the World Health Organization drug dictionary 
(WHO-DDE March 2021 or later). 
7.5. 
Reporting of Pregnancy 
Pregnancy in a female study subject shall be reported to the Sponsor within 24 hours of the 
knowledge of its occurrence by an Investigator or delegate (for pregnancies occurring during the 
course of the study or immediately following the end of the study). Because of the possibility the 
fetus/embryo could have been exposed to the study drug through the parent and for the subject’s 
safety, the pregnancy will be followed up to determine its outcome, including spontaneous or 
voluntary termination, details of birth, presence or absence of any birth defects, congenital 
anomalies, or maternal and/or newborn complications. 
Pregnancy that occurs within 90 days after the follow-up visit in a female partner of a male study 
subject shall be reported to the Sponsor within 24 hours of the knowledge of its occurrence by 
the clinical site that such pregnancy occurred during the course of the study or right after. 
Because of the possibility that the fetus/embryo could have been exposed to the study drug 
through the parent and for the safety of the subject’s female partner, the pregnancy will be 
followed up to determine its outcome, including spontaneous or voluntary termination, details of 
birth, presence or absence of any birth defects, congenital anomalies, or maternal and/or newborn 
complications. 
The pregnancy will be recorded and reported by the clinical site to the Sponsor. Pregnancy 
follow-up will also be properly recorded to ensure quality and completeness of the data 
belonging to the study drug and will include an assessment of the possible causal relation 
between the study drug and any pregnancy outcome. Any SAE experienced during pregnancy 
will be reported on an SAE Report Form. 
7.6. 
Serious Adverse Event Reporting 
For the purposes of this study, any psychiatric emergency (see Appendix 14 : Psychiatric 
Emergency Management) will be considered a SAE and will be reported as outlined below. 
The CRU will notify any SAE to the Sponsor, without regard to causality, within 24 hours after 
becoming aware of its occurrence. 
If, during follow-up, any non-serious AE worsens and eventually meets the criteria for an SAE, 
that AE should be recorded as a new SAE. 
The initial SAE report must be as complete as possible, including details of the current illness 
and SAE, and an assessment of the causal relationship between the event and the IPs. 
Information not available at the time of the initial report (e.g., an end date for the AE, laboratory 
values received after the report, or hospital discharge summary) must be documented. All 
follow-up information must be reported as soon as the relevant info is available. 


 
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The notification should be directed to the following Sponsor representative: 
Commercially Confidential Information 
An SAE will be considered “unexpected” if the AE is not listed in the Investigator’s Brochure or 
is not listed at the specificity or severity that has been observed; or, if an Investigator’s Brochure 
is not required or available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application. "Unexpected," as used in this 
definition, also refers to AEs that are mentioned in the Investigator brochure as occurring with a 
class of drugs or as anticipated from the pharmacological properties of the drug but are not 
specifically mentioned as occurring with the particular drug under investigation. 
The CRU will determine whether any serious unexpected, related AE must be reported to the 
Institutional Review Board (IRB). If so, the event will be reported via fax or email within 15 
calendar days of an Investigator or staff becoming aware of the event. 
The Sponsor will determine whether the SAE must be reported in an expedited manner to the 
applicable regulatory agencies. If so, the Sponsor will report the event to those agencies and to 
all participating Investigators. 
If reports of any new and unexpected AEs become available to the Sponsor during the clinical 
portion of this study (related or not to the present study), the Sponsor has to advise the CRU, 
through its clinical Investigator, of those events. 


 
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8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Populations 
8.1.1. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of one of the IP or 
placebo. 
The number of subjects who were included, who discontinued, and who completed the study will 
be tabulated. The primary reasons for discontinuation will be provided. 
8.1.2. 
Pharmacokinetic Population 
In most cases, the decision of which subjects will be included in the PK analysis is to be taken 
before the start of the sample analysis by the bioanalytical facility. 
The PK population will be described in an SAP. Generally, the PK population includes all the 
subjects who received the study drug or equivalent and have at least one postdose evaluable 
concentration values in any biological matrix. 
8.2. 
Demographic Data and Other Baseline Characteristics 
Statistics for demographic and baseline data will be detailed in a SAP. 
8.3. 
Safety 
8.3.1. 
Safety Endpoints 
The safety endpoint will be assessed by the number, severity, and type of TEAEs. 
8.3.2. 
Safety Analysis 
The clinical laboratory tests and the measurements of vital signs, ECGs, physical examinations, 
psychiatric assessments, and other safety parameters will be used to perform the safety statistical 
analysis. 
8.3.3. 
Safety Statistical Methodology 
Statistics for summary of AEs and safety results will be fully detailed in a SAP. 
8.4. 
Pharmacokinetics 
The PK analysis will be carried out according to Altasciences SOPs. Pharmacokinetic data 
handling and statistical analysis will be fully detailed in an SAP. 
8.4.1. 
Pharmacogenetic Statistical Methodology 
The exploratory pharmacogenetic studies are designed to investigate the association between 
genetic factors (genotypes) and clinical assessments (phenotypes) which are collected during the 
clinical trial. Without prior evidence of a strong association, a number of possible associations 
are evaluated with exploratory analyses. A range of statistical tests (chi-square tests, ANCOVAs, 


 
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linear and logistic regression) are used for the analyses. Additional data from subsequent clinical 
trials are often needed to confirm associations. Alternatively, if the numbers of subjects enrolled 
in the study are too small to complete proper statistical analyses, these data may be combined, as 
appropriate, with those from other studies to enlarge the data set for analysis. 
8.5. 
Planned Interim Analyses 
No formal interim analyses will be performed; blinded safety data will be reviewed by an 
Investigator and the Sponsor’s Medical Monitor following completion of each TMP-301 dose 
level. 
The SAP will describe the planned interim analyses in greater detail. 
8.6. 
Determination of Sample Size 
No formal sample size analysis was performed. It is estimated that approximately 24 subjects 
should be sufficient to meet the objectives of the study. 


 
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9. 
REFERENCES 
1. Niswender, C.M. and P.J. Conn, Metabotropic glutamate receptors: physiology, 
pharmacology, and disease. Annu Rev Pharmacol Toxicol, 2010. 50: p. 295-322. 
2. Mihov Y, Hasler G. Negative allosteric modulators of metabotropic glutamate receptors 
subtype 5 in addiction: a therapeutic window. International Journal of 
Neuropsychopharmacology. 2016 Jul 1;19(7). 
3. Watkins, J.C. and D.E. Jane, The glutamate story. Br J Pharmacol, 2006. 147 Suppl 1: p. 
S100-8. 
4. Bird MK et al., Lohmann P, West B, Brown RM, Kirchhoff J, Raymond CR, Lawrence 
AJ. The mGlu5 receptor regulates extinction of cocaine-driven behaviours. Drug and 
Alcohol Dependence. 2014 Apr 1;137:83-9. 
5. Chiamulera C et al., Reinforcing and locomotor stimulant effects of cocaine are absent in 
mGluR5 null mutant mice. Nature neuroscience. 2001 Sep;4(9):873-4. 
6. Bäckström P, Hyytiä P. Ionotropic and metabotropic glutamate receptor antagonism 
attenuates cue-induced cocaine seeking. Neuropsychopharmacology. 2006 
Apr;31(4):778-86. 
7. Kumaresan V et al., Metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate 
cocaine priming-and cue-induced reinstatement of cocaine seeking. Behavioural brain 
research. 2009 Sep 14;202(2):238-44. 
8. Moussawi K et al., N-Acetylcysteine reverses cocaine-induced metaplasticity. Nature 
neuroscience. 2009 Feb;12(2):182-9. 
9. Hodge CW et al., The mGluR5 antagonist MPEP selectively inhibits the onset and 
maintenance of ethanol self-administration in C57BL/6J mice. Psychopharmacology. 
2006 Jan;183(4):429-38. 
10. Brown RM, Stagnitti MR, Duncan JR, Lawrence AJ. The mGlu5 receptor antagonist 
MTEP attenuates opiate self-administration and cue-induced opiate-seeking behaviour in 
mice. Drug and alcohol dependence. 2012 Jun 1;123(1-3):264-8. 
11. Milella, M.S., et al., Limbic system mGluR5 availability in cocaine dependent subjects: A 
high-resolution PET [C-11]ABP688 study. NeuroImage, 2014. 98. 
12. Leurquin-Sterk, G., et al., Cerebral dopaminergic and glutamatergic transmission relate 
to different subjective responses of acute alcohol intake: an in vivo multimodal imaging 
study. Addiction Biology, 2018. 23(3): p. 931-944. 
13. Ceccarini, J., et al., Recovery of decreased metabotropic glutamate receptor 5 availability 
in abstinent alcohol-dependent patients. Journal of Nuclear Medicine, 2019: p. 
jnumed.119.228825. 
14. NCT03242928. Available from: https://clinicaltrials.gov/ct2/show/NCT03242928. 
15. Gregory KJ, Dong EN, Meiler J, Conn PJ. Allosteric modulation of metabotropic 
glutamate receptors: structural insights and therapeutic potential. Neuropharmacology. 
2011 Jan 1;60(1):66-81. 
16. Trenkwalder, C., et al., Mavoglurant in Parkinson's patients with l-Dopa-induced 
dyskinesias: Two randomized phase 2 studies. Mov Disord, 2016. 31(7): p. 1054-8. 
17. Berry-Kravis, E., et al., Mavoglurant in fragile X syndrome: Results of two randomized, 
double-blind, placebo-controlled trials. Sci Transl Med, 2016. 8(321): p. 321ra5. 
18. ClinicalTrial.Gov, Long-term, Safety, Tolerability and Efficacy Study of AFQ056 in Adult 
Patients With Fragile X Syndrome. ClinicalTrial.Gov Identifier NCT01348087. 2016. 


 
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19. Walles, M., et al., Metabolism and disposition of the metabotropic glutamate receptor 5 
antagonist (mGluR5) mavoglurant (AFQ056) in healthy subjects. Drug Metab Dispos, 
2013. 41(9): p. 1626-41. 
20. Friedmann, C.T., et al., Phase II double-blind controlled study of a new anxiolytic, 
fenobam (McN-3377) vs placebo. 1980. 
21. Itil, T. and M. HUQUE, The clinical and quantitative EEG effects and plasma levels of 
fenobam (McN-3377) in subjects with anxiety: an open rising dose tolerance and efficacy 
study. 1978. 
22. Pecknold, J.C., et al., Treatment of anxiety using fenobam (a nonbenzodiazepine) in a 
double-blind standard (diazepam) placebo-controlled study. J Clin Psychopharmacol, 
1982. 2(2): p. 129-33. 
23. Kagedal, M., et al., A positron emission tomography study in healthy volunteers to 
estimate mGluR5 receptor occupancy of AZD2066 - estimating occupancy in the absence 
of a reference region. Neuroimage, 2013. 82: p. 160-9. 
24. Kalliomaki, J., et al., Evaluation of the effects of a metabotropic glutamate receptor 5-
antagonist on electrically induced pain and central sensitization in healthy human 
volunteers. Eur J Pain, 2013. 17(10): p. 1465-71. 
25. ClinicalTrial.Gov, Study to Investigate the Pharmacodynamic Effect of a Single Dose of 
AZD2516 in Healthy Male Subjects. ClinicalTrial.Gov Identifier NCT00154634. 2012. 
26. ClinicalTrial.Gov, AZD2066 Neuropathic Pain - Mechanical Hypersensitivity (NP-MH). 
ClinicalTrial.Gov Identifier NCT00939094. 2012. 
27. Keywood, C., M. Wakefield, and J. Tack, A proof-of-concept study evaluating the effect 
of ADX10059, a metabotropic glutamate receptor-5 negative allosteric modulator, on 
acid exposure and symptoms in gastro-oesophageal reflux disease. Gut, 2009. 58(9): p. 
1192-9. 
28. Zerbib, F., C. Keywood, and G. Strabach, Efficacy, tolerability and pharmacokinetics of 
a modified release formulation of ADX10059, a negative allosteric modulator of 
metabotropic glutamate receptor 5: an esophageal pH-impedance study in healthy 
subjects. Neurogastroenterol Motil, 2010. 22(8): p. 859-65, e231. 
29. Carradori, S. and R. Silvestri, New Frontiers in Selective Human MAO-B Inhibitors. J 
Med Chem, 2015. 58(17): p. 6717-32. 


 
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APPENDIX 1. ETHICS 
Institutional Review Board 
This protocol and the ICF will be submitted to an IRB (or Independent Ethics Committee [IEC]) 
prior to initiation of the study and the study will not start until the Board has approved the 
documents. Notification of the Board’s approval will be appended to the final report. 
Ethical Conduct of the Study 
This study will be conducted in compliance with the study protocol, the ethical principles that 
have their origins in the Declaration of Helsinki, the International Council for Harmonisation 
(ICH) Guideline E6 for Good Clinical Practice (GCP), the FDA GCP Code of Federal 
Regulations (CFR) Title 21 (part 56), the European regulation EU 536/2014 and the Tri-Council 
Policy Statement (Canada). 
Subject Information and Consent 
Before screening activities commence, each volunteer will be given a copy of the ICF to read, as 
well as a full explanation of the purpose of the study, the procedures to be carried out, and the 
potential AE(s). Once this essential information is provided to the volunteer and the Investigator 
or delegate in charge has the conviction the volunteer understands the implications of 
participating in the study, and if the volunteer chooses to continue the screening process, they 
will be requested to sign and date a properly executed ICF prior to enrollment. Subjects will be 
assured they may withdraw from the study at any time without jeopardizing their medical care or 
future study participation (for which they qualify). 
Subjects will be given a signed copy of the ICF. If an amended or revised ICF is introduced 
during the study, each subject’s further consent must be obtained. 
This study includes an exploratory pharmacogenetic component which requires a separate 
informed consent. The aim of the planned exploratory pharmacogenetics research studies will be 
to better identify inherited genetic factors which may predict response to treatment with 
(TMP-301), predict relative susceptibility to drug-drug interactions, predict genetic 
predisposition to side effects, or provide more information regarding (TMP-301) in the disease 
state and how subjects may respond to (TMP-301). The pharmacogenetic assessments are 
exploratory and are not intended to be used for regulatory judgments pertaining to the safety or 
efficacy of the investigational drug. However, these data may be considered for voluntary 
submission, consistent with applicable regulatory guidance on this topic, in order to develop the 
knowledge base necessary to establish the validity of new genomic biomarkers. 
Subject Confidentiality 
Investigators and the Sponsor will preserve the confidentiality of all subjects taking part in the 
study, in accordance with GCP and local regulations. Subjects should be identified by a unique 
subject identifier on all study documents provided to the Sponsor. In compliance with Federal 
regulations/ICH GCP Guidelines, it is required an Investigator and institution permit authorized 
representatives of the company, of the regulatory agency(s), and IRB access to review the 
subject’s original medical records for verification of study-related procedures and data. An 


 
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Investigator is obligated to inform the subject that his/her study-related records will be reviewed 
by the above named representatives without violating the subject’s confidentiality. 
The Sponsor will store the biological samples in a secure storage space with adequate measures 
to protect confidentiality. 
The samples will be retained while research on the study treatment continues but no longer than 
5 years (or other period), as per local requirements. 
During the conduct of the study, an individual participant can choose to withdraw consent to 
have biological specimens stored for future research. However, withdrawal of consent with 
regard to biosample storage may not be possible after the study is completed. 
Safety Oversight 
Safety oversight will be under the direction of the SRC composed of individuals with the 
appropriate expertise, including Sponsor’s Medical Monitor, and the PI. Additional advisors 
could be invited as required. The SRC will operate under the rules of an approved dose 
escalation plan that will be written and reviewed at the organizational meeting of the SRC. At 
this time, each data element that the SRC needs to assess will be clearly defined.  Additionally, 
the SRC may conduct ad hoc safety reviews at any point during the conduct of the study. 


 
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APPENDIX 2. DATA COLLECTION, RETENTION, AND MONITORING 
Case Report Forms 
The subject level data is entered by the site into a study specific 21 CFR Part 11 compliant 
electronic clinical database to accurately collect data for each subject included in a clinical trial. 
Screen failure data may be part of the analysis data at the discretion of the Sponsor, when 
included in the contracted scope of work. 
Data Management and Processing 
Data management develops documentation to define activities performed during the data 
management conduct of the study trial. The electronic data capture (EDC) system is the tool used 
to conduct all data management data cleaning activities for monitoring, data review and queries. 
Data management will use a combination of automated programmed edits and manual data 
review listings to issue queries for non-conforming or discrepant data. Data management 
activities are performed in accordance with the SOPs and study-specific data management 
documents. 
Database locking is guided by the Data Management Locking Checklist based on the concept 
that all site activities are complete; data are considered clean and without errors and CRF signoff 
by the Principal Investigator or delegate has been completed. User access is removed as part of 
the locking process. 
Data from the clinical database will be output as SAS® datasets. All data will be included with 
the final report provided to the Sponsor. 
Quality Control and Quality Assurance 
Designated personnel from the quality assurance (QA) unit(s) will be responsible for maintaining 
QA of the clinical, PK, statistical and bioanalytical facilities to ensure that the trial is conducted 
and data are generated, documented and reported in compliance with the protocol, ICH 
Guideline E6 for GCP, applicable requirements as outlined in the FDA and OECD Principles of 
Good Laboratory Practice (GLP), and the Reflection paper for laboratories that perform the 
analysis or evaluation of clinical trial samples (EMA/INS/GCP/532137/2010). 
Designated personnel from each corresponding operation unit will be responsible to maintain and 
assure the quality control (QC) of all data generated and documented in compliance with the 
protocol. 
Record Retention 
All essential documents and records will be maintained by the clinical site in accordance with, 
and for the period specified in the applicable regulatory requirement(s) (FDA CFR 312.57 [C]). 
Monitoring of the Study 
The Sponsor or its representative may monitor the study in order to maintain current and 
personal knowledge of the study through review of the records, comparison with source 
documents, observation and discussion of the conduct and progress of the study. The clinical site 


 
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will permit trial-related monitoring, audits, institutional review board (IRB)/independent ethics 
committee (IEC) review, and regulatory inspection(s) by providing direct and/or virtual access, 
where possible, to source data/documents. 


 
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APPENDIX 3. ADMINISTRATIVE PROCEDURES 
Liabilities 
It is the Sponsor’s responsibility to guarantee sufficient insurance coverage should any serious 
events or deaths result, either directly or indirectly, from the execution of the present protocol. 
Adherence to Protocol 
Excluding an emergency situation in which proper treatment is required for the protection, safety 
and well-being of the study subjects, the study will be conducted as described in the approved 
protocol and performed according to ICH/GCP and the applicable regulatory requirements. Any 
deviation from the protocol will be recorded and explained. 
If amendments to the protocol and/or amendments or revisions to the ICF are required, the 
modifications will be documented and submitted to an IRB for approval. 
COVID-19 Response Plan 
Regulatory authorities have recognized that the COVID-19 pandemic may impact the conduct of 
clinical trials of medical products. Challenges may arise, for example, from quarantines, site 
closures, travel limitations, interruptions to the supply chain for the IP(s), or other considerations 
if site personnel or study participants become infected with COVID-19. These challenges may 
lead to difficulties in meeting protocol-specified procedures, including administering or using the 
IP or adhering to protocol-mandated visits and laboratory/diagnostic testing. To accommodate 
these challenges and mitigate safety risks associated with COVID-19, protocol modifications 
may be required which include (and are not limited to): 
• Conducting the study in multiple (smaller) subject groups; 
• Altering the timing of study procedures and subject confinement; 
• Modification of standard inclusion or exclusion criteria; 
The exact mitigations will be documented in the study Risk Assessment and Mitigation Plan. 
Additional health checks including COVID-19 testing, body temperature monitoring, etc. may be 
performed during the trial, even if not planned within the protocol. 
Statement of Investigator 
The FDA 1572 form, Statement of Investigator [Title 21, CFR Part 312], will be signed by the 
Investigator, and will be kept on file. 
Delegation of Investigator Duties 
An Investigator will ensure all personnel involved in the trial are adequately qualified and 
informed about the protocol, any amendments to the protocol, the study treatments, and their 
trial-related duties and functions. 
An Investigator will maintain a list of sub-investigator(s) and other appropriately-qualified 
persons to whom he/she delegates significant trial-related duties. 


 
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Should an Investigator delegate the supervision of the IP administration to a designated person, 
this individual must have the appropriate professional-legal qualifications and certifications. An 
Investigator should also ensure key staff personnel have the appropriate medical qualifications to 
effectively conduct or supervise any potential resuscitation procedures. 
Premature Termination or Suspension of a Study 
The Sponsor or its representative may terminate the study at any time for scientific or corporate 
reasons. 
If the trial is prematurely terminated or suspended for any reason, the clinical site or an 
Investigator (or delegate) should promptly inform the trial subjects, should assure appropriate 
therapy and follow-up for the subjects and should inform the regulatory authority(ies) when 
required. 


 
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APPENDIX 4. PROTOCOL REVIEW AND APPROVALS 


 
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TITLE: A PHASE 1, RANDOMIZED, PLACEBO CONTROLLED, MULTIPLE-ASCENDING 
DOSE (MAD) STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS OF TMP-301 IN HEALTHY SUBJECTS 
 
I have carefully read this study protocol and agree it contains all necessary information required 
to conduct this study. I agree to conduct the study according to this protocol and in accordance 
with GCP and the applicable regulatory requirements. 
___________________________ 
Principal Investigator Name (Please Print) 
___________________________ 
____________________ 
Principal Investigator Signature 
Date (yyyy/mm/dd) 
Altasciences Clinical Kansas Inc. 


 
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TITLE: A PHASE 1, RANDOMIZED, PLACEBO CONTROLLED, MULTIPLE-ASCENDING 
DOSE (MAD) STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS OF TMP-301 IN HEALTHY SUBJECTS 
On behalf of the Sponsor, I approve of, and agree to comply with, all of the procedures contained 
within this protocol. 
_____________________________ 
____________________ 
Dan Meyers MD Date (yyyy/mm/dd) 
Chief Medical Officer 
Tempero Bio Inc. 


 
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APPENDIX 5. LIST OF ABBREVIATIONS 
3MS 
Modified Mini Mental State Examination 
 
AE 
adverse event 
 
ALP 
alkaline phosphatase 
 
ALT 
alanine aminotransferase 
 
ANOVA 
analysis of variance 
 
AST 
aspartate aminotransferase 
 
bid 
twice daily 
 
BMI 
body mass index 
 
bpm 
beats per minute 
 
BPRS 
Brief Psychiatric Rating Scale 
 
CADSS 
Clinician Administered - Dissociative States Scale 
 
CFR 
Code of Federal Regulations 
 
COVID-19 
Coronavirus Disease 2019 
 
CRF 
Case Report Form 
 
CRU 
Clinical Research Unit 
 
CSR 
Clinical Study Report 
 
C-SSRS 
Columbia Suicide Severity Rating Scale 
 
CYP 
Cytochrome P1A2 
 
ECG 
electrocardiogram 
 
EOS 
End of Study 
 
eGFR 
Estimated Glomerular Filtration Rate 
 
FDA 
Food and Drug Administration 
 
FSH 
follicle-stimulating hormone 
 
GCP 
Good Clinical Practice 
 
HIV 
Human Immunodeficiency Virus 
 
ICF 
informed consent form 
 
ICH 
International Council for Harmonisation 
 
IEC 
Independent Ethics Committee 
 
IP 
investigational product 
 
IRB 
Institutional Review Board 
 
IU 
international unit 
 
kg 
kilogram 
 
L 
liter 
 


 
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MAD 
multiple ascending dose 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
mg 
milligram 
 
mL 
milliliters 
 
mmHg 
millimeter of mercury 
 
N/AP 
not applicable  
 
ng 
nanograms 
 
OECD 
Organization for Economic Co-operation and Development 
 
OTC 
over-the-counter 
 
PD 
PK 
pharmacodynamic 
pharmacokinetic 
 
PR 
time between P and R wave 
 
PRIME 
Prevention through Risk Identification, Management, and Education  
 
PT 
preferred term 
 
QA 
Quality Assurance 
 
QC 
Quality Control 
 
QRS 
complex between Q and S wave 
 
QTcF 
QT Interval Corrected for Heart Rate using Fridericia's Correction Formula 
 
SAD 
single-ascending dose 
 
SAE 
serious adverse event 
 
SAP 
Statistical Analysis Plan 
 
SoA 
Schedule of Activities 
 
SOC 
System Organ Class 
 
SOP 
standard operating procedure 
 
SRC 
Safety Review Committee  
 
ST 
ST segment of the Electrocardiogram 
 
TEAE 
treatment-emergent adverse event 
 
ULN 
upper limit of normal 
 
VAS 
Visual Analogue Scale 
 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced  
 


 
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APPENDIX 6. CLINICAL LABORATORY EVALUATIONS 
Clinical Laboratory Test Panel 
Description 
General biochemistry: 
Alanine aminotransferase, albumin, alkaline phosphatase, aspartate aminotransferase, bilirubin total and 
conjugated bilirubin if total bilirubin is elevated, blood urea nitrogen, calcium, chloride, Creatinine 
phosphokinase (CPK), Bicarbonate (CO2), creatinine (including eGFR calculated using the CKD-EPI 
calculation, cholesterol total, glucose, LDH, phosphorous, potassium, protein total, sodium, 
triglycerides, and uric acid 
Coagulation: 
Prothrombin time (PT)/INR and partial thromboplastin time (aPTT) levels 
Endocrinology: 
FSH1 
Hematology: 
White cell count with differential (absolute values of neutrophil, lymphocyte, monocyte, eosinophil, and 
basophil), red cell count, hemoglobin, hematocrit, mean corpuscular volume, and platelet count 
Serologya: 
Human immunodeficiency virus (HIV) Ag/Ab Combo, Hepatitis B surface antigen, and 
Hepatitis C virus 
Urinalysis: 
Color, clarity, specific gravity, pH, leukocyte, protein, glucose, ketones, bilirubin, blood, nitrite, 
urobilinogen. Microscopic examination will only be performed if the dipstick test is outside of the 
reference range for leukocyte, blood, nitrite or protein 
Urine drug screen: 
Alcohol, amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, cotinine, methadone, 
opiates, oxycodone, fentanyl, phencyclidine, and tricyclic antidepressants 
Pregnancy test: 
Serum pregnancy test or urine pregnancy test 
aScreening visit only. 
 


 
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APPENDIX 7. BRIEF PSYCHIATRIC RATING SCALE 
 


 
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APPENDIX 8. CLINICIAN-ADMINISTERED DISSOCIATIVE STATES 
SCALE 
The Clinician Administered Dissociative States Scale (CADSS) 
J. Douglas Bremner, Carolyn Mazure, Frank W. Putnam 
Name 
ID 
Date 
 
Subjective Items: 
1. 
Do things seem to be moving in slow motion? 
0= 
Not at all. 
1= 
Mild, things seem slightly slowed down, but not very noticeable.  
2= 
Moderate, things are moving about twice as slow as normally. 
3= 
Severe, things are moving so slowly that they are barely moving. 
4= 
Extreme, things are moving so slowly, I have the perception that everything has come to a 
stop, as if time is standing still. 
2. 
Do things seem to be unreal to you, as if you are in a dream?  
0= 
Not at all. 
1= 
Mild, things seem a little unreal, but I’m well aware of where I’m at. 
2= 
Moderate, things seem dreamlike, although I know I am awake. 
3= 
Severe, things seem very dreamlike, although I know that I am here, I have the feeling like I 
might be asleep. 
4= 
Extreme, I feel like nothing is real, like I should pinch myself to wake up, or ask someone if 
this is a dream. 
3. 
Do you have some experience that separates you from what is happening;  
for instance, do you feel as if you are in a movie or a play, or as if you are a robot?  
0= 
Not at all. 
1= 
Mild, I feel a little bit separated from what is happening, but I am basically here. 
2= 
 Moderate, I feel somewhat separated from what is going on, or I feel as if I am in a movie or 
a play. 
3= 
Severe, I feel extremely separated from what is happening, but I can understand what 
people are saying. 
4= 
Extreme, I feel as if everyone around me is talking a foreign language, so that I cannot 
understand what they are saying, or I feel as if I am on the outside looking in, or like I am a 
robot or a machine. 
4. 
Do you feel as if you are looking at things from outside of your body?  
0= 
Not at all. 
1= 
Mild, I feel somewhat disconnected from myself, but I am basically all together.  
2= 
Moderate, I feel like I am just outside of my body, but not looking down upon myself from 
far above. 
3= 
Severe, I feel like I am twenty feet or more away from my body, looking down from above. 
4= 
Extreme, I feel as if I am hundreds of feet above myself, looking down at myself and 
everyone else here. 
5. 
Do you feel as if you are watching the situation as an observer or a spectator? 
0= 
Not at all. 
1= 
Mild, I feel slightly detached from what is going on, but I am basically here.  
2= 
Moderate, I feel somewhat removed as an observer or a spectator, but I am 
definitely in this room. 
3= 
Severe, I feel very much as if I am an observer or a spectator, but I am still here in this room. 
4= 
Extreme, I feel completely removed from what is happening, as if I am not a part of this 
experience in any way, but totally removed from what is happening, as an observer or a 
spectator. 


 
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6. 
Do you feel disconnected from your own body?  
0= 
Not at all. 
1= 
Mild, I feel a little bit disconnected from myself, but I am basically all here. 
2= 
Moderate, I feel somewhat detached from my own body, but I am basically alltogether. 
3= 
Severe, I feel detached from my own body, but not far removed from my body, and I feel as 
if it is me there. 
4= 
Extreme, I feel like I am completely out of my body, as if I am looking at my own body from a 
long way off, as if there is another person there. 
7. 
Does your sense of your own body feel changed: for instance, does your own body feel unusually 
large or unusually small? 
0= 
Not at all. 
1= 
Mild, I have a vague feeling that something about my body has changed, but I can’t say 
exactly what it is. 
2= 
Moderate, I feel like my body has increased or decreased in size slightly, or that it feels 
somewhat as if it is not my body. 
3= 
Severe, I feel as if my body has increased to twice its normal size, or decreased to twice its 
normal size, or I very much feel as if this is not my body. 
4= 
Extreme, I feel as if my body has swelled up to at least ten times its normal size, or as if it is 
ten times as small, or as if my arms have become like toothpicks. 
8. 
Do people seem motionless, dead, or mechanical?  
0= 
Not at all. 
1= 
Mild, people seem a little bit more motionless, dead, or mechanical than would be normal. 
2= 
Moderate, people seem to be at least twice as motionless or mechanical than would be 
normal. 
3= 
Severe, people seem to be barely moving, or barely alive, or very mechanical. 
4= 
Extreme, it’s as if everyone were frozen or completely like machines. 
9. 
Do objects look different than you would expect? 
0= 
Not at all. 
1= 
Mild, things seem slightly different than normal, although it is barely perceptible. 
2= 
Moderate, things are somewhat distorted, but I have no problems recognizing things around 
me. 
3= 
Severe, things are much more distorted or unreal than normal, but I am able to recognize 
things in the room. 
4= 
Extreme, like everything is distorted, not real, I feel like I cannot recognize anything, 
everything is alien or strange. 
10. 
Do colors seem to be diminished in intensity?  
0= 
Not at all. 
1= 
Mild, things seem slightly paler than usual if I think about it. 
2= 
Moderate, colors are somewhat diminished, but still recognizable. 
3= 
Severe, colors are extremely pale, in no way as vivid as they usually are. 
4= 
Extreme, as if everything is in black and white, or all the colors have been washed out. 


 
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11. 
Do you see things as if you were in a tunnel, or looking through a wide angle photographic lens? 
0= 
Not at all. 
1= 
Mild, I feel a little bit like I am looking through a tunnel, or a wide angle lens. 
2= 
Moderate, the periphery of my vision is blacked out, but I still have most of my visual field, 
or things are somewhat like a wide angle lens. 
3= 
Severe, it seems as if I’m looking through a tunnel, or through a wide angle lens, but I can see 
everything clearly. 
4= 
Extreme, as if I’m looking through a pair of binoculars backwards, where everything around 
the periphery is blacked out, and I can see a little point of light at the end of a tunnel, with 
little tiny people and objects, or I am seeing things as if through a wide lens and things are 
incredibly expanded. 
12. 
Does this interview [assessment, questionnaire] seem to be taking much longer than you would have 
expected? 
0= 
Not at all. 
1= 
Mild, it seems as if this interview has gone on for at least twice as long as the true elapsed 
time. 
2= 
 Moderate, it seems as if this interview has gone on for at least two hours.  
3= 
Severe, it seems as if at least ten hours have gone on since the start of the 
interview. 
4= 
Extreme, it seems as if time is standing still, so that we have been here at this point in 
time forever. 
13. 
Do things seem to be happening very quickly, as if there is a lifetime in a moment?  
0= 
Not at all. 
1= 
Mild, things are happening slightly faster than normal. 
2= 
Moderate, things seem to be happening at least twice as fast as normal. 
3= 
Severe, things seem to be happening at least 10 times faster than normal. 
4= 
Extreme, as if this whole experience has happened at once, or as if there is a lifetime in 
a moment. 
14. 
Have there been things which have happened during this interview [assessment] that now you can’t 
account for? 
0= 
Not at all. 
1= 
Mild, there may have been things which happened which now I can’t account for, but nothing 
pronounced. 
2= 
Moderate, at least once there were things which happened which now I can’t account 
for. 
3= 
Severe, at least twice I have lost several minutes of time, so that now there are things I 
cannot account for. 
4= 
Extreme, large pieces of time are missing, of ten minutes or more, so that I am confused 
about what has happened. 
15. 
Have you spaced out, or in some other way lost track of what was going on during this experience? 
0= 
Not at all. 
1= 
Mild, I have had some episodes of losing track of what is going on, but I have followed 
everything for the most part. 
2= 
Moderate, I have lost at least a minute of time, or have completely lost track of what is 
going on now. 
3= 
Severe, I have lost several segments of time of one minute or more. 
4= 
Extreme, I have lost large segments of time of at least 15 minutes or more. 


 
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16. 
Have sounds almost disappeared or become much stronger than you would have expected? 
0= 
Not at all. 
1= 
Mild, things are either a little quieter than normal, or a little louder than normal, but it is 
not very noticeable. 
2= 
Moderate, things have become about twice as soft as normal, or twice as loud as normal. 
3= 
Severe, things have become very quiet, as if everyone is whispering, or things have 
become very loud (although not deafening). 
4= 
Extreme, things have become completely silent, or sounds are so loud that it is deafening, 
and I feel as if I am going to break my eardrums. 
17. 
Do things seem very real, as if there is a special sense of clarity? 
0= 
Not at all. 
1= 
Mild, things seem to be a little bit more real than normal.  
2= 
Moderate, things seem to be more real than normal. 
3= 
Severe, things seem to be very real or have a special sense of clarity. 
4= 
Extreme, things seem to have an incredible sense of realness or clarity. 
18. 
Does it seem as if you are looking at the world through a fog, so that people and objects appear far 
away or unclear? 
0= 
Not at all. 
1= 
Mild, things seem somewhat foggy and unclear, or I do have the feeling that things are 
far away, but there is not a major effect on how I perceive things around me. 
2= 
Moderate, things seem very foggy and unclear, or things seem like they are far away, but I 
can identify the interviewer and objects in the room easily. 
3= 
Severe, I can barely see things around me, such as the interviewer and the objects in the room. 
4= 
Extreme, I cannot make anything out around me. 
19. 
Do colors seem much brighter than you would have expected?  
0= 
Not at all. 
1= 
Mild, colors seem a little bit brighter than normal, but not more than twice as bright. 
2= 
Moderate, colors seem brighter, about twice as bright as normal. 
3= 
Severe, colors seem very bright, at least five times as bright as normal. 
4= 
Extreme, colors seem extremely bright, almost fluorescent, at least 10 times as bright as 
normal. 
20. 
Do you feel confused about who you really are?  
0= 
Not at all. 
1= 
Mild, I feel a little bit confused about who I am. 
2= 
Moderate, I feel confused about who I am, but I basically know who I am. 
3= 
Severe, I feel very confused about who I am, and at times I wonder if I am a person, or if 
I am many people. 
4= 
Extreme, I feel as if there were two or more sides to myself. 
21. 
Do you feel like there are different parts of yourself which do not fit together? 
0= 
Not at all. 
1= 
Mild, I feel like there are different sides of myself, but they’re basically part of myself. 
2= 
Moderate, I feel like I have different parts which don’t quite fit together. 
3= 
Severe, there are two or more sides to myself which have unique characteristics.  
4= 
Extreme, I have two or more parts to myself with unique personality 
characteristics. 


 
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22. 
Do you have gaps in your memory?  
0= 
Not at all. 
1= 
Mild, there are some recent things which I cannot remember. 
2= 
Moderate, there have been a few gaps in my memory which lasted a few minutes.  
3= 
Severe, there have been large gaps in my memory which lasted for more than a few minutes. 
4= 
Extreme, I cannot piece together what is happening from one moment to the next due to large 
gaps in my memory. 
23. 
Do you feel like you have more than one identity?  
0= 
Not at all. 
1= 
Mild, I feel like there is more to me than my personality, but it’s basically part of my identity. 
2= 
Moderate, I feel like I have more than one personality, but the personalities are not really 
distinct. 
3= 
Severe, I have two or more personalities, although they are not fully developed as distinct 
entities. 
4= 
Extreme, I have two or more personalities which are distinct and have their own names and 
other unique characteristics. 
 


 
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APPENDIX 9. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-
SSRS) – BASELINE/SCREENING VERSION 
 


 
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APPENDIX 10. COLUMBIA-SUICIDE SEVERITY RATING SCALE 
(C-SSRS) – SINCE LAST VISIT VERSION 
 


 
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APPENDIX 11. MODIFIED MINI-MENTAL STATE EXAMINATION 
 
 


 
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APPENDIX 12. VISUAL ANALOGUE SCALE 
Each subject will have to complete the Visual Analogue Scale (VAS) Alertness Scale with 
anchor points of “Very drowsy”, “Neither drowsy nor alert”, and “Very Alert” before dosing and 
at various times during study drug administration. 
Example:  
 


 
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APPENDIX 13. PRIME QUESTIONNAIRE FOR PSYCHOSIS RISK 
At screening, all subjects will be administered this 12-item questionnaire to determine their risk 
of developing psychosis.  Responses to all items are scored on a 0-6 scale.  Any subject which 
scores a 6 on any individual item, or 5 on at least 2 items will be considered at high risk of 
developing psychosis and will be excluded from the study. 
For accurate results, the subject must be entirely honest in their response to all 12 questions.  
Subjects should rate their level of agreement with the statement as follows:  Definitely disagree 
(0), Somewhat disagree (1), Slightly disagree (2), Not Sure (3), Slightly agree (4), Somewhat 
agree (5), Definitely agree (6). 
Items: 
1. I think that I have felt that there are odd or unusual things going on that I can’t explain. 
2. I think that I might be able to predict the future. 
3. I may have felt that there could possibly be something interrupting or controlling my 
thoughts, feelings, or actions. 
4. I have had the experience of doing something differently because of my superstitions. 
5. I think that I may get confused at times whether something I experience or perceive may 
be real or may be just part of my imagination or dreams. 
6. I have thought that it might be possible that other people can read my mind, or that I can 
read other’s minds. 
7. I wonder if people may be planning to hurt me or even may be about to hurt me. 
8. I believe that I have special natural or supernatural gifts beyond my talents and natural 
strengths. 
9. I think I might feel like my mind is “playing tricks” on me. 
10. I have had the experience of hearing faint or clear sounds of people or a person mumbling 
or talking when there is no one near me. 
11. I think that I may hear my own thoughts being said out loud. 
12. I have been concerned that I might be “going crazy”. 
 
 


 
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APPENDIX 14. PSYCHIATRIC EMERGENCY MANAGEMENT 
Inhibitors or antagonists of mGlu5, including TMP-301, are associated with psychiatric adverse 
events which can include dissociation and hallucination.  Although most psychiatric AEs with 
this class of drugs are mild, there is a risk of psychiatric AEs evolving into emergencies, where 
there is an immediate risk of harm to either the treated subject, or others in the subject’s 
surroundings.  The purpose of this appendix is to define the procedures for identification and 
management of potential psychiatric emergencies in subjects enrolled in this study.  These 
procedures have been designed to ensure the safety of subjects and staff and to provide 
continuity of care through the resolution of the psychiatric emergency. 
Figure 2 shows an overview of psychiatric emergency management in this study.  The 
subsequent sections of this appendix provide details of the specific steps in the emergency 
management procedure.  The Investigator(s) implementing this management plan will have 24/7 
access to a psychiatrist to assist in the decisions required to implement the plan.  Full supporting 
operational details are described in the psychiatric event monitoring plan (PEMP). 
Figure 1: 
Psychiatric Emergency Management 
 


 
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Psychiatric Adverse Event Monitoring: 
Psychiatric AE monitoring follows the same general process of monitoring for any AE as 
described in Section 7.4 of the protocol. Specifically, subjects will be monitored for evidence of 
psychiatric AEs from the time of ICF signature to the end of the study in the following ways: 
• Study staff observations 
− Open-ended health status questions at the start and end of domiciling periods and 
observation of subject behavior during domiciling periods 
− Review of subject responses to scheduled BPRS (6.1.8), CADSS (6.1.9), C-SSRS 
(6.1.10), 3MS (6.1.11) and VAS (6.1.12) assessments 
• Spontaneous subject reports of new symptoms or other complaints 
If any of these sources raise the suspicion of a psychiatric AE, a formal evaluation by the 
Investigator will occur to confirm the AE.  Once an event is confirmed to be a psychiatric AE, it 
will be assigned severity (see Section 7.2) and causality (see Section 7.3). 
Psychiatric Emergency Determination: 
Confirmed psychiatric AEs will be further evaluated by the Investigator to determine if it is also 
a psychiatric emergency.  This determination will be conducted in consultation with a 
psychiatrist, and will be based on the following criterion:  
• Subject is judged to be an immediate threat to themselves and/or others. 
Subjects with psychiatric AEs which are not judged to be emergencies will be observed for 
resolution or worsening of the AE at the clinical study site.  If the AE worsens, the subject will 
be re-evaluated to determine if the psychiatric emergency criterion is met. 
Subjects with confirmed psychiatric emergencies will have study treatment immediately 
discontinued.  Furthermore, any psychiatric emergency will be considered a serious adverse 
event (SAE) and will be reported to health authorities and/or local ethics committee according to 
relevant regulations. 
Psychiatric Emergency Management: 
Subjects with confirmed psychiatric emergencies will be evaluated to determine if they require a 
higher level of management than the clinical study site can provide.  This determination will take 
place between the PI psychiatrist, consulting psychiatrist (if PI is unavailable), and the sponsor’s 
medical monitor. 
If a higher level of management is not required, the subject will remain at the clinical study site 
where they will be monitored and managed under the direction of the Investigator.  The subject 
will be closely monitored until the psychiatric emergency has been resolved, and the subject is 
no longer judged to be a risk to themselves or others.  With the resolution of the psychiatric 
emergency, the subject will undergo the same process as any other subject who has had study 
treatment discontinued (see Table 3 for EOS assessments). 
Rescue medication can be used to treat psychiatric emergencies with manifestations of 
psychosis, or significant agitation and/or anxiety.  The decision to provide rescue medication will 


 
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be at the discretion of the PI, according to their best medical judgement, and in consultation with 
the sponsor’s medical monitor.  The following medications can be considered (Neither of these 
medications are likely to have any interactions with TMP-301): 
• Risperidone 0.5 – 2 mg PO every 2 hours prn (≤6 mg total in 24 hours) 
• Lorazepam 0.5 – 2 mg PO (or 1 mg IM) every 6 hours prn (≤10 mg total in 24 hours) 
If a higher level of management is required, subjects will be directly transferred to an inpatient 
psychiatric facility emergency room for further evaluation.  During transfer, and at all times 
during the evaluation prior to admission to the facility, the subject will be accompanied by study 
staff. The clinical study staff, under the direction of the PI, will be in contact with the psychiatric 
facility to provide key information about the psychiatric emergency as well as the relevant details 
about the study treatment and procedures. Once admitted to the inpatient psychiatric facility, the 
subject will be cared for according to the standard procedures of the facility.  Clinical study staff 
will be in regular contact with the facility to receive updates and to provide any additional 
information required for optimal care of the subject.  The subject will be released from the 
facility once the emergency has resolved, and the subject is judged safe and appropriate to be 
released in the clinical opinion of qualified experts at the facility, or the subject refuses further 
treatment.  Medical records from the psychiatric facility will be shared with the clinical study site 
after the subject is released. 
Psychiatric Emergency Follow Up: 
All psychiatric emergencies will be closely monitored with direct clinical care (either at the 
clinical study site or the inpatient psychiatric facility) until resolution - when the subject is no 
longer a risk to themselves or others. The determination of resolution of a psychiatric emergency 
can be made either at the clinical study site by the study PI or at the inpatient psychiatric facility 
(either in the emergency room or after an inpatient stay) by appropriately trained medical staff.  
After the determination of resolution, the patient will be discharged home.   The clinical site will 
call the subject within 24 hours of discharge for a status check.  The subject will return to the 
clinical study site within 7 days of discharge for end of study assessments.   
For subjects with an active psychiatric emergency who leave either the clinical study site or 
inpatient psychiatric facility against medical advice, all reasonable efforts will be made to 
monitor the subject’s status until resolution can be documented.  This will include daily phone 
calls to the subject and/or their family or contacts and home visits where feasible.  Every 
reasonable effort will be made to facilitate the subject’s return to appropriate medical care, either 
at the inpatient psychiatric facility, or at another medical facility where appropriate.  Following 
stabilization and resolution of the psychiatric emergency, the subject will return to the clinical 
study site within 7 days of discharge for end of study assessments. 
 

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN 
 
 
For: 
Tempero Bio Inc. 
 
 
 
PROTOCOL No. TMP-301-HNV-101 
PROTOCOL VERSION: Final v3.3 (Amendment 03), 2023/07/18 
 
 
A Phase 1, Randomized, Placebo Controlled, Multiple Ascending Dose (MAD) Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of TMP-301 in Healthy Subjects 
 
Altasciences Project No. TPM-P1-726 
 
Prepared by: 
Altasciences Company Inc. 
575 Armand-Frappier Boulevard 
Laval, Quebec 
Canada, H7V 4B3 
 
 
Version: Final 1.0 
Date: 2023/10/23 
 
 


 
 
 
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STATISTICAL ANALYSIS PLAN APPROVAL 
We have carefully read this statistical analysis plan and agree it contains the necessary 
information required to handle the statistical analysis of study data. 
 
 


 
 
 
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VERSION CONTROL 
Version 
Date 
Author 
Description of Changes 
Final V 
1.0     
2023/10/23  Commercially Confidential Information 
Not Applicable 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN APPROVAL ....................................................................... 2 
VERSION CONTROL ................................................................................................................ 3 
TABLE OF CONTENTS ............................................................................................................ 4 
TABLE OF TABLES .................................................................................................................. 7 
ABBREVIATIONS .................................................................................................................... 8 
1 
INTRODUCTION ........................................................................................................... 10 
2 
STUDY OBJECTIVES .................................................................................................... 11 
3 
STUDY DESIGN ............................................................................................................ 13 
3.1 
General Description..................................................................................................... 13 
3.2 
Treatments .................................................................................................................. 14 
3.3 
Study Procedures ......................................................................................................... 14 
3.4 
Randomization and Unblinding Procedures ................................................................. 14 
3.4.1 
Method of Assigning Subjects to Treatment Groups ........................................... 14 
3.4.2 
Blinding ............................................................................................................. 15 
3.5 
Determination of Sample Size ..................................................................................... 15 
4 
ANALYSIS POPULATIONS .......................................................................................... 16 
5 
DATA HANDLING AND PRESENTATION ................................................................. 17 
5.1 
Safety Analysis Presentation ....................................................................................... 17 
5.2 
Pharmacokinetic Analysis ........................................................................................... 18 
5.3 
Baseline ...................................................................................................................... 19 
5.4 
Methods for Handling Missing Data ............................................................................ 19 
6 
STUDY SUBJECTS ........................................................................................................ 20 
6.1 
Disposition .................................................................................................................. 20 
6.2 
Protocol Deviations ..................................................................................................... 20 
7 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................. 21 
8 
SAFETY ANALYSIS ...................................................................................................... 22 
8.1 
Adverse Events ........................................................................................................... 22 
8.2 
Clinical Laboratory Evaluations .................................................................................. 23 
8.2.1 
Viral Screen ....................................................................................................... 24 
8.2.2 
Urine Drug Screen (UDS) and Urine Alcohol Testing ........................................ 24 
8.2.3 
Coagulation ........................................................................................................ 24 
8.2.4 
Pregnancy and Follicle Stimulating Hormone (FSH) Tests ................................. 24 


 
 
 
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8.3 
Vital Signs .................................................................................................................. 24 
8.4 
Electrocardiograms...................................................................................................... 24 
8.5 
Physical Examination Findings.................................................................................... 25 
9 
PSYCHIATRIC ASSESSMENTS AND ANALYSIS ...................................................... 26 
9.1 
Brief Psychiatric Rating Scale (BPRS) ........................................................................ 26 
9.1.1 
BPRS Assessment .............................................................................................. 26 
9.1.2 
BPRS Visit Windows ......................................................................................... 27 
9.1.3 
BPRS Endpoints ................................................................................................ 27 
9.1.4 
BPRS Analysis................................................................................................... 27 
9.2 
Clinician Administered Dissociative States Scale (CADSS) ........................................ 27 
9.2.1 
CADSS Assessment ........................................................................................... 27 
9.2.2 
CADSS Visit Windows ...................................................................................... 28 
9.2.3 
CADSS Endpoints ............................................................................................. 28 
9.2.4 
CADSS Analysis................................................................................................ 28 
9.3 
Columbia-Suicide Severity Rating Scale (C-SSRS) ..................................................... 28 
9.3.1 
C-SSRS Assessment .......................................................................................... 28 
9.3.2 
C-SSRS Analysis ............................................................................................... 29 
9.4 
Modified Mini-Mental State Examination (3MS) ........................................................ 29 
9.4.1 
3MS Assessment ................................................................................................ 29 
9.4.2 
3MS Visit Windows ........................................................................................... 32 
9.4.3 
3MS Endpoints .................................................................................................. 32 
9.4.4 
3MS Analysis .................................................................................................... 32 
9.5 
Alertness Visual Analogue Scale (VAS) ...................................................................... 32 
9.5.1 
Alertness VAS Assessment ................................................................................ 32 
9.5.2 
Alertness VAS Endpoints ................................................................................... 32 
9.5.3 
Alertness VAS Analysis ..................................................................................... 33 
9.6 
Psychiatric Assessments Analysis ............................................................................... 33 
10 
PHARMACOKINETIC ANALYSIS ............................................................................... 34 
10.1 Missing Values ............................................................................................................ 34 
10.2 Measurements Below the Lower Limit of Quantitation ................................................ 34 
10.3 Actual Time ................................................................................................................ 34 
10.4 Non-Compartmental Analysis ..................................................................................... 34 
10.5 Visit Windows ............................................................................................................ 36 
10.6 Pharmacokinetic Statistical Methodology .................................................................... 37 
10.6.1 
Summary Statistics ............................................................................................. 37 
10.6.2 
Dose Proportionality .......................................................................................... 37 
11 
INTERIM ANALYSES AND DATA SAFETY MONITORING ..................................... 39 
12 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES ................................................. 40 


 
 
 
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13 
GENERAL INFORMATION RELATED TO DATA PRESENTATIONS ...................... 41 
14 
REFERENCES ................................................................................................................ 42 
APPENDIX A 
STUDY SCHEDULE(S) ........................................................................... 43 


 
 
 
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TABLE OF TABLES 
Table 1: Objectives and Related Endpoints................................................................................ 11 
Table 2: Dose Cohorts ............................................................................................................... 14 
Table 3: Acceptable Windows for Timed PK Blood Specimen Collection Procedures ............... 20 
Table 4: Clinical Laboratory Assessments ................................................................................. 23 
Table 5: BPRS Details............................................................................................................... 26 
Table 6: 3MS Details ................................................................................................................ 29 
Table 7: Pharmacokinetic Parameters of TPM-301 .................................................................... 35 
Table 8: Acceptable PK Visit Windows .................................................................................... 37 
 


 
 
 
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ABBREVIATIONS 
AE 
adverse event 
ANOVA 
analysis of variance 
aPTT 
partial thromboplastin time 
AUC0-TAU,FD 
AUC from time zero to the time the end of the 12-hr dosing interval after 
the first dose 
BID 
twice daily 
BMI 
body mass index 
BPRS 
Brief Psychiatric Rating Scale 
CADSS 
Clinician-Administered Dissociative States Scale 
CFB 
change from baseline 
CI 
confidence interval 
CL/F 
total plasma clearance 
Cmax,FD 
maximum concentration after the first dose 
Cmin,FD 
minimum concentration after the first dose 
CRF 
case report form 
CRU 
clinical research unit 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CSR 
clinical study report 
CV% 
percentage coefficient of variation 
DMP 
data management plan 
DTS 
deviation tracking system  
ECG 
electrocardiogram 
Emax 
maximum postdose effect 
Emin 
minimum postdose effect 
EOS 
end of study 
FSH 
follicle stimulating hormone 
HIV 
Human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IP 
Investigational product 
λZ 
elimination rate constant 
LLOQ 
lower limit of quantitation 
ln 
natural log 
LSMeans 
least-square means 
MAD 
multiple ascending dose 
Max 
maximum 
Mean 
arithmetic mean 
MedDRA 
Medical Dictionary for Regulatory Activities 


 
 
 
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Min 
minimum 
3MS 
Modified Mini‑Mental State Examination 
n 
number of available data 
N 
number of observations 
NCA 
non-compartmental analysis  
NR 
not reported 
PK 
pharmacokinetic(s) 
PT 
preferred term 
Q1 
first quartile 
Q3 
third quartile 
R2 
coefficient of determination 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
SOP 
standard operating procedure 
SS 
steady-state 
Tmax 
time of maximum concentration 
Tmax,FD 
time of maximum concentration after the first dose 
TEAE 
treatment-emergent adverse event 
TEmax 
time to maximum postdose effect 
TEmin 
time to minimum postdose effect 
TFLs 
tables, figures, and listings 
TS 
total score 
UDS 
urine drug screen 
VAS 
Visual Analogue Scale 
Vz/F 
volume of distribution 
WHODrug 
World Health Organization Drug Dictionary 
 
 


 
 
 
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1 INTRODUCTION 
This study is a multiple ascending dose (MAD) study to evaluate the safety, tolerability, 
pharmacokinetics (PK) of TMP-301 in healthy subjects. There will be up to 4 dose cohorts, and 
within each cohort subjects will be randomly assigned to receive either active drug or placebo. 
Study subjects will be administered active drug or placebo once daily (qd) or twice daily (bid) 
for 14 days (note: for bid cohorts, only the AM dose is administered on Day 14). 
This Statistical Analysis Plan (SAP) provides a detailed description of the statistical methods and 
procedures to be implemented for the analyses of data from the Clinical Study Protocol TPM-P1-
726 (TMP-301-HNV-101). The analyses described in the SAP are based upon the final version 
of the Clinical Study Protocol 4.0 (Amendment 04), dated 2023/10/02. 
 
 


 
 
 
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2 STUDY OBJECTIVES 
The objectives of the study and corresponding study endpoints are detailed in Table 1. 
Table 1: Objectives and Related Endpoints 
Objective 
Endpoint 
Primary  
• 
To assess the safety and tolerability of 
TMP-301 following multiple ascending 
oral doses 
The primary endpoint is safety assessed after 
multiple-dose administrations by: 
• Adverse events (AE) 
• Clinical laboratory tests 
• Vital sign measurements 
• 12-lead electrocardiograms (ECG) 
• Physical examinations 
• Psychiatric assessments (Brief Psychiatric 
Rating Scale [BPRS], Clinician-Administered 
Dissociative States Scale [CADSS], Columbia 
Suicide Severity Rating Scale [C-SSRS], 
Modified Mini‑Mental State Examination 
(3MS) and Alertness Visual Analogue Scale 
[VAS]) 
Secondary  
• 
To assess the pharmacokinetics (PK) 
profile of TMP-301 following multiple 
ascending oral doses 
 
• Day 1:  
Partial areas defined as AUC0-12 and AUC0-24; 
maximum concentration (Cmax), time of maximum 
concentration (Tmax), concentration at 12 h (C12), 
concentration at 24 h (C24) where C 24 = Ctrough Day2 
• 
Day 14 (or last day of dosing): 
AUCss from time zero to the time the end of the 
(12 or 24 hour) dosing interval (AUC0-TAU,ss. For 
BID cohorts, AUC0-TAU,ss = AUC0-12,SS, and for QD 
cohorts, AUC0-TAU,ss = AUC0-24,SS; Cavg, ss, Cmax,ss, 
Tmax,ss, C12,ss, C24ss, and Cmin,SS, all at steady-state 
(SS), along with apparent total plasma clearance 
(CL/F) and apparent volume of distribution (Vz/F) 
 
Exploratory 


 
 
 
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• 
To assess endpoints related to TMP-301 
             mechanism of action 
• 
To evaluate CYP1A2 genotypes and 
             their association with phenotypes for           
             potential impact on metabolism and to      
             identify biomarkers of potential response     
             to TMP-301. 
 
  
 
Accumulation ratio derived as: 
• 
AR_AUC0-12 BID= AUC0-12,ss / AUC0-12, Day 1  
• 
AR_AUC0-24QD = AUC0-24,ss / AUC0-24, Day 1 
• 
AR_Cmax = Cmax,ss / Cmax,FD, Day 1 
• 
AR_C12 = C12,ss / C12, Day 1 
• 
AR_C24= C24,ss / C24, Day 1  
 
• 
Estimations of dose proportionality at steady 
State. Dose–normalized PK parameters (Cmax, 
C12, C24, and AUC0-12 and AUC0-24, when 
appropriate) will be assessed graphically for 
dose-proportionality 
For BID cohorts, AUC0-TAU,SS = AUC0-12,SS, 
For QD cohorts, AUC0-TAU,SS = AUC0-24,SS 
 
• 
Estimation of time to achieve steady state 
(Ctrough will be displayed graphically and 
summarized descriptively by day to assess for 
steady state) 
 
• 
As a marker of CYP1A2 activity, the ratio of 
paraxanthine to caffeine concentration (at 4 
hours post caffeine dose) will be reported on 
Day -1 and Day 14. Change in CYP1A2 
activity will be derived as CYP1A2_ratio = 
paraxanthine/caffeine concentration day 14 / 
paraxanthine/caffeine concentration day -1 
 
              
Abbreviations: AE = adverse event; ECG = electrocardiogram; PK = pharmacokinetics 
 
 


 
 
 
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3 STUDY DESIGN 
3.1 
General Description 
This study will be a randomized, double-blind, placebo -controlled, fixed -sequence, MAD 
study. The study will be conducted in a single clinical research unit (CRU). The study will 
consist of up to 4 cohorts. Each cohort will consist of 8 subjects (6:2 for active: placebo), for a 
maximum total sample size of approximately 32 subjects. Subjects will only participate in 1 
cohort. 
Screening will occur within approximately 28 days prior to the first scheduled study drug 
administration. Screening data will be reviewed to determine subject eligibility. Subjects who 
meet all inclusion criteria and none of the exclusion criteria and who consent to participation will 
be admitted to the CRU for baseline evaluations prior to dosing. All baseline safety results 
should be available prior to the first study drug administration. 
In cohort 2, subjects will be fasted overnight for 10 hours prior to the morning dose, followed by 
a 2 hour fast. Subjects were fasted for 2 hours prior to dosing and 2 hours following the evening 
dose for the cohort 1 (50 mg bid). If dosing in a fed condition is selected for cohort 3 or 4, 
subjects will be fasted overnight for approximately 9 hours, then given breakfast followed by 
study treatment dosing 30 minutes after initiation of breakfast. 
Each subject will be randomly assigned to 1 of the following cohorts: 
Cohort 1: 
 
• Group 1 (6 subjects): 50 mg of TMP-301 bid 
• Group 2 (2 subjects): placebo (matching TMP-301) bid 
 
 
 
Cohort 2: 
 
• Group 3 (6 subjects): 50 mg of TMP-301 qd 
• Group 4 (2 subjects): placebo (matching TMP-301) qd 
 
 
 
Cohort 3: 
 
• Group 5 (6 subjects): Dose regimen of TMP-301 to be determined 
• Group 6 (2 subjects): placebo (matching TMP-301)  
 
 
 
Cohort 4: 
 
• Group 7 (6 subjects): Dose regimen of TMP-301 to be determined 
• Group 8 (2 subjects): placebo (matching TMP-301)  
Safety will be assessed and blood samples for PK will be collected throughout confinement. 
Subjects will be discharged from the CRU on Day 18. Subjects will return to the CRU on Day 25 
for a follow-up visit and End-of-Study (EOS) procedures. 
Caffeine (100 mg) will be included as probe CYP1A2 substrate in cohort 2 and subsequent 
cohorts. Ratio of plasma paraxanthine/caffeine will be determined in a blood sample 4 hours 
after administration of caffeine at baseline (Day-1) and on day 14. 
The maximum duration of subject participation, including Screening, will be approximately 
53 days. Subjects who terminate the study early will perform follow-up procedures at the time of 
Early Termination. 
Based on safety and tolerability findings in any of the cohorts, a 14-day dose titration cohort to 
evaluate the impact on treatment-emergent adverse events (TEAEs) may be added as an 
additional cohort (7 days titration + 7 days stable dosing). 


 
 
 
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3.2 
Treatments 
The following treatments will be administered according to Table 2. 
• IP: TMP-301 oral capsule 
• Placebo: Matching placebo 
Table 2: Dose Cohorts 
Cohort 
N 
(Active:Placebo) 
Dose 
Fasting 
Status 
Drug Administration 
1 
6:2 
Twice daily 
dose of 
50 mg 
Fasting Pre 
& 4 hours 
post dose 
Twice daily TMP-301 or 
placebo dosing from 
Days 1 to 13 and once in 
the morning on Day 14 
(for a total of 27 
consecutive study drug 
administrations) 
or 
Once daily TMP-301 or 
placebo to be 
administered in the 
mornings of Days 1-14. 
2 
6:2 
Once daily 
dose of 
50 mg 
Fasting Pre 
& 2 hours 
post dose  
or  
Fed 30 
minutes pre-
dose 
3 (Optional) 
6:2 
Dose and 
regimen to 
be 
determined 
4 (Optional) 
6:2 
Dose and 
regimen to 
be 
determined 
Caffeine (100 mg) will also be administered to enrolled subjects as part of the study on Day -1 
and Day 14. 
 
3.3 
Study Procedures 
For complete details on the study assessments to be performed for each cohort, refer to 
APPENDIX A. 
3.4 
Randomization and Unblinding Procedures 
3.4.1 Method of Assigning Subjects to Treatment Groups 
Altasciences will generate the randomization code with a computer program according to the 
study design, the number of subjects and the number of treatments. Within each cohort, subjects 
will be randomized (3:1) to receive TMP-301 or placebo. The random allocation of each IP to 
each subject will be done in such a way that the study is balanced. Once generated, the 
randomization code will be final and will not be modified. 
Subjects who sign the ICF and are randomized but do not receive the study treatment may be 
replaced. Subjects who sign the ICF, are randomized and receive the study treatment, and 


 
 
 
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subsequently withdrawn as a result of AEs thought to be related to the study drug will not be 
replaced. Subjects who sign the ICF, are randomized and receive the study treatment, and are 
subsequently withdrawn for reasons not related to the study drug may be replaced. 
3.4.2 Blinding 
The randomization code may be made available to the personnel of the bioanalytical facility. The 
treatment assignment will not be known by the study participants. 
Furthermore, the randomization code will not be available to the physician and clinical staff 
involved in the collection, monitoring, revision, or evaluation of AEs, as well as clinical staff 
who could have an impact on the outcome of the study, and including the pharmacokineticist (or 
delegate), until database lock, or designation that unblinding information is required by the SRC 
to determine the next dose. 
The preparation of the products will be done by designated personnel that are not directly 
involved in the clinical aspects of the trial. 
The randomization code must not be broken except in emergency situations where the 
identification of a subject’s study treatment is required by an Investigator for further treatment to 
the subject or to complete a SAE report. Randomization information will be held by designated 
individual(s). The date and reason for breaking the blind must be recorded. 
The results of the PK analyses will be made available only to the personnel responsible for 
evaluating the safety data before proceeding with the next dose level. 
3.5 
Determination of Sample Size 
No formal sample size analysis was performed. It is estimated that approximately 24 subjects 
should be sufficient to meet the objectives of the study. 
 
 


 
 
 
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4 ANALYSIS POPULATIONS 
• 
Enrolled Population 
The Enrolled population will include all subjects who signed the informed consent form (ICF). 
• 
Screened Population 
The Screened population will include all subjects who meet the eligibility criteria. 
• 
Randomized Population 
The Randomized population will include all subjects who are assigned a randomization number. 
• 
Safety Population 
The Safety population will include all subjects who received at least 1 dose of one of the 
investigational product (IP) or placebo. The number of subjects who were included, who 
discontinued, and who completed the study will be tabulated. The primary reasons for 
discontinuation will be provided. 
• 
Pharmacokinetic (PK) Population 
The PK population will include all subjects who have received at least 1 dose of the 
investigational product and have sufficient PK data to derive at least 1 PK parameter. 
Subjects who do not complete the sampling schedule may be included in the PK analysis for only 
the PK parameters that are judged not to be affected by the missing sample(s). 
 
 


 
 
 
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5 DATA HANDLING AND PRESENTATION 
All safety and statistical outputs will be generated using SAS software, version 9.4 or higher. 
The PK outputs will be generated using WinNonlin version 8.0 or higher. 
All programs used to generate statistical analyses will be validated according to Altasciences’ 
Standard Operating Procedures (SOPs). 
The analyses described in this plan are considered a priori, in that they have been defined prior to 
database lock and prior to breaking the blind. Any analyses performed subsequent to database 
lock and breaking the blind will be considered post hoc and exploratory, and will be identified in 
the Clinical Study Report (CSR). 
5.1 
Safety Analysis Presentation 
Adverse events and medical history will be classified using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology as defined in the study Data Management Plan 
(DMP). 
Prior and concomitant medications will be coded with the World Health Organization Drug 
Dictionary (WHODrug) as defined in the study DMP. 
In general, all safety summary tables will be presented for the Safety population. Summaries for 
AEs will be presented by treatment. Summaries for other safety endpoints will be presented by 
treatment if the endpoints are measured end of Study only. 
In general, the data listings will include all subjects in the Randomized population up to the point 
of study completion or discontinuation; exceptions will be listings pertaining to a subset of 
subjects only (eg, subjects with protocol deviations) or a subset of records/events (eg, abnormal 
laboratory values). Limited data for those not included in the Randomized population, eg, who 
failed screening, may be presented, as appropriate. 
Categorical variables will be summarized using number of observations (N), number of available 
data (n), and the percentage of available data (%) for each class. Continuous variables will be 
summarized using descriptive statistics, including N, n, arithmetic mean (mean), standard 
deviation (SD), minimum (min), median, and maximum (max). 
The following general considerations may be applied: 
• Study Day will be derived from the reference date (eg, the day of the first dose of study 
drug) and date of event as: 
Study Day = (date of event – reference date) +1, if event is on or after the reference date; 
Study Day = date of event – reference date, if event is before the reference date. 
• Duration will be calculated using the general formula: (end date - start date) +1. 
• If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table (eg, a character string is reported for a parameter of the numerical type), a 
coded value may be appropriately determined and used in the statistical analyses. In 
general, a value below the lower limit of normal range such as ‘<10’ or ‘≤5’ will be 
treated as half of the lower limit, ‘5’ or ‘2.5’, respectively, and a value above the upper 
limit of normal range such as ‘>100’ will be replaced with a number deemed 


 
 
 
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scientifically reasonable, eg, 101. However, the actual values as reported in the database 
will be presented in data listings. 
• Unscheduled assessments will not be included in descriptive summary, except for 
baseline consideration. When assessments are repeated for a given time point or 
performed at unscheduled times, only the result which is the closest to the dosing time 
will be included in summary tables. 
In general, summary statistics for raw variables (ie, variables measured at the study site or 
central laboratory) will be displayed as follows: 
• Minima and maxima will be displayed to the same number of decimal places as the raw 
data 
• Means, medians, and quartiles (if presented) will be displayed to 1 additional decimal 
place 
• Standard deviations will be displayed to 2 additional decimal places 
• Percentages will be displayed to 1 decimal place; Percentages between 0 and 0.1 
(exclusive) will be displayed as ‘<0.1’ 
• P-values will be displayed to 3 decimal places; P-values that are less than 0.001 will be 
displayed as ‘<0.001’ 
Derived variables (ie, variables that are not measured by the study site but are calculated for 
analysis based on other measured variables) will be displayed with the same precision as the raw 
data, as appropriated, then follow the similar rules in presentation of summary statistics. 
5.2 
Pharmacokinetic Analysis 
In general, all PK summary tables will be presented for the PK population. 
Individual raw PK concentrations will be displayed with the same precision as received from the 
bioanalytical laboratory. 
Precision for individual PK parameters will be displayed as follows: 
• Cmax, Cmin, CL/F, Vz/F and AUCs will be displayed with the same precision as the raw 
PK concentration data 
• Parameters associated with time (eg, time of maximum concentration [Tmax]) will be 
displayed with 2 decimal places 
• Percentages will be displayed with 2 decimal places 
• Ratios will be displayed with 2 decimal places 
• Coefficient of determination (R2) and elimination rate constant (λz) will be displayed with 
4 decimal places 
Summary statistics for concentration and PK parameters will be displayed with the same 
precision as the individual values, with the exception of number of observations (n) and CV% 
which will be presented with 0 and 1 decimal place, respectively. 


 
 
 
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5.3 
Baseline 
Unless otherwise specified, the baseline value will be defined as the last non-missing evaluation 
prior to the first dose of study drug, including unscheduled assessment(s), if applicable. 
5.4 
Methods for Handling Missing Data 
In general, no imputations of values for missing safety data (ie, blank, “Not Done”, “Not 
Applicable”, etc.) will be performed and data presentations will reflect the data point as it 
appears in the Case Report Form (CRF) or electronic data file. 
 
 


 
 
 
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6 STUDY SUBJECTS 
Unless otherwise specified, all available data will be listed and summary table for disposition 
will be presented for all enrolled subjects. 
6.1 
Disposition 
Subject disposition will be summarized by cohort (TMP-301 50 mg BID Fasted, TMP-301 50 
mg QD Fasted, TMP-301 XX mg and TMP-301 XX mg), pooled placebo and overall, including: 
• Number of subjects screened (if applicable) 
• Number of subjects randomized (if applicable) 
• Number of subjects who received study drug 
• Number (%) of subjects who completed the study 
• Number (%) of subjects discontinued from the study overall and by primary reason for 
discontinuation 
• Number (%) of subjects included in each of the analysis populations 
The percentages will be calculated using the number of subjects who received study drug. 
Listings of subject’s disposition, Randomization details, and subjects included in each of the 
analysis populations will be provided. In addition, a listing of screen failures including reason for 
failure will be presented. 
6.2 
Protocol Deviations 
All protocol deviations related to study inclusion or exclusion criteria, conduct of the study, 
subject management, or subject assessment (including PK sample processing deviations) will be 
listed for the Randomized populations. Information for PK sampling time deviations will be 
derived programmatically, and presented in a listing. 
Deviations will be collected in the clinic deviation tracking system (DTS) and presented in a 
general protocol deviation listing. 
Table 3: Acceptable Windows for Timed PK Blood Specimen Collection Procedures 
Elapsed Time  
Accepted Window 
Pre-dose 
No window specified 
> 0 hour to ≤ 30 minutes 
± 10 minutes 
> 30 minutes to ≤ 4 hours 
± 10 minutes 
> 4 hours to ≤ 12 hours 
± 10 minutes 
> 12 hours to ≤ 24 hours 
± 10 minutes 
> 24 hours to ≤ 72 hours 
± 2 hours 
> 72 hours 
± 4 hours 
 
 
 


 
 
 
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7 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Unless otherwise specified, summary tables for demographics and other baseline characteristics, 
and all available data will be listed based on the Randomized population. 
Demographic and baseline characteristics including age, sex, ethnicity, race, height, weight (at 
screening), and body mass index (BMI) will be listed and summarized by cohort (TMP-301 50 
mg BID Fasted, TMP-301 50 mg QD Fasted, TMP-301 XX mg and TMP-301 XX mg), pooled 
placebo and overall. Descriptive statistics will be presented for age, height, weight, and BMI, 
while frequency counts and percentages will be presented for sex, ethnicity, and race. 
The following will be presented in listings: 
• Medical history 
• Prior and concomitant medications 
• Alcohol Habits 
• Substance Use Habits 
• Gynecological History 
• Psychiatric History 


 
 
 
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8 SAFETY ANALYSIS 
Unless otherwise specified, summary tables for safety assessments will be presented for the 
Safety population. All available data will be listed by cohort and subject based on the 
Randomized population.  
8.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered an investigational product and which does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including a clinically significant abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of an investigational product, whether or not related to 
the investigational product. 
Treatment-emergent AEs (TEAEs) are AEs not present prior to but reported following the 
exposure to study treatment or AEs already present that worsen in intensity or frequency 
following exposure to study treatment. 
All TEAEs will be assigned to the last treatment taken by the subject where the date and time of 
the last treatment dosing is on or before of the start date and time of the event. Any TEAE started 
during follow-up period will be assigned to the last treatment that the subject has taken. 
In case that the time of onset or time of resolution is unknown, treatment-emergent or assignment 
would be determined considering the worst case scenario and/or on case-by-case basis, as 
deemed appropriate. Treatment-emergent AEs with missing severity or relationship to study 
treatment will also be classified to the worst case (eg, severe and/or related, as appropriate) in 
corresponding summaries. 
An overall summary of AEs will be presented by cohort (TMP-301 50 mg BID Fasted, TMP-301 
50 mg QD Fasted, TMP-301 XX mg and TMP-301 XX mg), pooled placebo and overall active 
including: 
• Number of AEs reported, overall only 
• Number of TEAEs reported 
• Number (%) of subjects with at least one TEAE 
• Number (%) of subjects with at least one study drug-related TEAEs  
• Number (%) of TEAEs by relationship to study treatment (ie, Reasonable Possibility or 
No Reasonable Possibility) 
• Number (%) of TEAEs by severity 
• Number of serious AEs (SAEs) 
• Number (%) of subjects with at least one SAE 
• Number (%) of subjects with at least one study drug-related SAE  
• Number (%) of subjects with a TEAE leading to discontinuation 
• Number (%) of subjects with outcome of death 
Frequency tables will be presented by cohort, pooled placebo and overall: 
• Number (%) of subjects with TEAEs by system organ class (SOC) and preferred term 


 
 
 
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(PT) 
• Number (%) of subjects with drug-related TEAEs by SOC and PT 
• Number (%) of subjects with TEAEs by relationship to study treatment 
• Number (%) of subjects with TEAEs by severity 
• Number (%) of subjects with SAEs by system organ class (SOC) and preferred term (PT) 
All adverse event data will be presented in a listing. 
8.2 
Clinical Laboratory Evaluations 
General biochemistry, hematology, and urinalysis assessments, and other laboratory tests are 
listed in Table 3. 
Table 4: Clinical Laboratory Assessments 
Clinical Laboratory Test 
Panel 
Description 
General biochemistry: 
Alanine aminotransferase, albumin, alkaline phosphatase, aspartate 
aminotransferase, bilirubin total and 
conjugated bilirubin if total bilirubin is elevated, blood urea nitrogen, 
calcium, chloride, Creatinine 
phosphokinase (CPK), Bicarbonate (CO2), creatinine (including eGFR 
calculated using the CKD-EPI 
calculation, cholesterol total, glucose, LDH, phosphorous, potassium, 
protein total, sodium, 
triglycerides, and uric acid 
Coagulation: 
Prothrombin time INR and partial thromboplastin time (aPTT) levels 
Endocrinology: 
FSH1 
Hematology: 
White cell count with differential (absolute values of neutrophil, 
lymphocyte, monocyte, eosinophil, and basophil), red cell count, 
hemoglobin, hematocrit, mean corpuscular volume, and platelet count 
Serology1 
Human immunodeficiency virus (HIV) Ag/Ab Combo, Hepatitis B 
surface antigen, and Hepatitis C virus 
Urinalysis: 
Color, clarity, specific gravity, pH, leukocyte, protein, glucose, 
ketones, bilirubin, blood, nitrite, urobilinogen. Microscopic 
examination will only be performed if the dipstick test is outside of the 
reference range for leukocyte, blood, nitrite or protein 
Urine drug screen: 
Alcohol, amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, cotinine, methadone, opiates, phencyclidine, and tricyclic 
antidepressants 
Pregnancy test: 
Serum pregnancy test or urine pregnancy test 
1Screening visit only 


 
 
 
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Laboratory data will be summarized by the type of laboratory test, visit. Descriptive statistics (n, 
mean, SD, minimum, median, and maximum), and the number of subjects with laboratory test 
results below, within, and above normal ranges will be tabulated by laboratory test and visit. 
All laboratory data will be listed by laboratory panel and test. Laboratory abnormalities and 
clinically significant abnormalities will also be listed. 
8.2.1 Viral Screen 
A screening viral screen will be done for HIV Ag/Ab Combo, Hepatitis B surface antigen, and 
Hepatitis C virus. The results of the viral screen will be listed. 
8.2.2 Urine Drug Screen (UDS) and Urine Alcohol Testing 
UDS will test for the following drugs of abuse: alcohol, amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, cotinine, methadone, opiates, phencyclidine, and 
tricyclic antidepressants. 
The results of UDS and urine alcohol testing will be listed. 
8.2.3 Coagulation 
A listing will be presented for coagulation data. 
8.2.4 Pregnancy and Follicle Stimulating Hormone (FSH) Tests 
A listing will be done for pregnancy and FSH tests. Serum pregnancy test will be done at 
screening. Urine pregnancy test will be done at check-in and discharge. For postmenopausal 
women, FSH test will be done at screening. 
8.3 
Vital Signs 
Vital signs will include systolic and diastolic blood pressures, pulse rate, and oral body 
temperature. 
Scheduled time points will include Days 1 and 7: Prior to morning dosing and 0.5, 1.00, 2.00, 
3.00, 4.00, 6.00, 8.00, and 12.00 hours. Days 2, 4, 6, 8, 10, and 12: Prior to dosing and 4.00 and 
12.00 hours postdose. Day 14: Prior to dosing and 0.5, 1.00, 2.00, 3.00, 4.00, 6.00, 8.00, 12.00, 
24.00 (Day 15), 48.00 (Day 16), 72.00 (Day 17), 96.00 (Day 18) hours postdose. 
At baseline on Day 1, predose vital sign measurements (except oral body temperature) will be 
conducted in triplicate (with an interval of approximately 10 - 30 minutes between each 
recording). The average value of each parameter will be considered as baseline value. 
Vital signs will be summarized using descriptive statistics (n, mean, SD, minimum, median, and 
maximum). All vital signs, including oral temperature, will be listed. Clinically significant 
abnormal findings will be listed. 
Summary tables on observed and change from baseline values will be presented by visit, time 
point, cohort and pooled placebo and overall. 
8.4 
Electrocardiograms 
The 12-lead ECG data will include ventricular rate, PR, QRS, QT, and interpretation. 
Scheduled time points will include Days 1, 7, and 14: Predose and at 4.00, 6.00, 8.00, and 12.00 
hours postdose. Days 2, 4, 6, 8, 10, and 12: Predose and 4.00 and 12.00 hours postdose. Day 14: 


 
 
 
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Prior to dosing and 0.5, 1.00, 2.00, 3.00, 4.00, 6.00, 8.00, 12.00, 24.00 (Day 15), 48.00 (Day 16), 
72.00 (Day 17), 96.00 (Day 18) postdose. 
At baseline in Day 1 predose, ECG recordings will be conducted in triplicate at (-45, -30, and -15 
minutes). The average value of each parameter will be considered as baseline value. 
12-Lead ECG data  absolute and change from baseline values in ventricular rate, PR, QRS, and 
QT intervals) will be summarized by parameter, visit, time point using descriptive statistics (n, 
mean, SD, minimum, median, and maximum). Clinically significant findings in ECG data will be 
listed. 
8.5 
Physical Examination Findings 
Physical examination include a general review of the following body systems (at minimum): 
head and neck, cardiovascular, respiratory, gastrointestinal, brief neurological and general 
appearance, unless a symptom-oriented physical exam is indicated. 
Physical examination findings will be presented in a listing by cohort, subject and visit and 
clinically significant physical examinations will be presented in a separate listing. 


 
 
 
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9 PSYCHIATRIC ASSESSMENTS AND ANALYSIS 
Unless otherwise specified, all available psychiatric assessments and analysis will be presented 
for the Safety population. Listings will be based on the Randomized population. 
Missing data for subjects who are administered all scheduled study treatments will be considered 
as random non-informative missing for analysis purposes. Missing values will be examined on a 
case-by-case basis to confirm this. Reasons for missing data will be displayed in the listings. No 
further imputation will be applied to any missing values. 
Assessments done outside the acceptable visit windows may be excluded from by-time point 
summary statistics; this will be determined on a case-by-case basis prior to unblinding. 
Analyses will be based on actual assessment times, except for predose (baseline) times, which 
will automatically be considered as time 0 as appropriate for analysis. If the actual time is 
missing, the nominal time will be used. 
9.1 
Brief Psychiatric Rating Scale (BPRS) 
9.1.1 BPRS Assessment 
The BPRS scale is designed for the assessment of psychiatric symptoms or disorders (e g., 
depression, anxiety, hallucinations, and unusual behavior). 
The BPRS should be completed at Screening, Check-in on Day -2, 7 and 14. It will also be 
completed at approximately 6 and 24 h after dosing on Days 1, 7, and 14. 
Baseline will be considered to be on Day -1. 
Table 5: BPRS Details 
Scale 
Number 
of Items 
Score Range Per 
Item 
Total 
Possible 
Score 
Scoring Interpretation 
Data Collection 
Brief 
Psychiatric 
Rating Scale 
(BPRS) 
18 Items 
1-7 point Likert scale 
1=not present 
2=very mild 
3=mild 
4=moderate 
5=moderately severe 
6=severe 
7=extremely severe 
126 
Severity increases with increasing 
score 
A score of 18 is generally 
expected for healthy volunteers. 
Scores ≥ 25 reflect the presence 
of psychiatric symptoms and 
should be considered 
exclusionary 
Total Score cutoff criteria for 
patients diagnosed with 
schizophrenia or experiencing 
psychosis are:  
Mildly ill ≥ 31 
Moderately ill ≥ 41 
Markedly ill ≥ 53 
In- or out patients with paranoid, 
disorganized or undifferentiated 
schizophrenia (DSM-IV), BPRS 
total score ≥36, BPRS psychotic 
subscore ≥23 and at least two 
BPRS psychosis items ≥41 
• Score for each item (1-7) 
• Score Range: 18-126 
Cutoff Score: ≥25 
• If an item is not 
assessed, the BPRS 
Total Score will not be 
computed 


 
 
 
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9.1.2  BPRS Visit Windows 
The acceptable windows for BPRS will be within 2 h following the 6 hours nominal time point 
and within 3 h prior to next dose for the 24 h time point. All the 24 h postdose assessments are 
intended to be completed prior to next day dosing as applicable. 
Psychiatric assessments should be carried out in the following order when required: (1) 3MS, (2) 
CADSS, (3) BPRS, (4) C-SSRS. 
9.1.3 BPRS Endpoints 
Derived endpoints will include: 
• BPRS_TSCFB = Total Score Change from Baseline (CFB) = BPRS_TS at each postdose 
time point – BPRS_TSB at baseline 
• BPRS_TS%CFB = Total Score Percent Change from Baseline (CFB) 
9.1.4 BPRS Analysis 
Tables and listings will be presented for absolute values and derived endpoints described below. 
Inferential analysis will be provided for the derived endpoints (refer to SAP Section 9.6 for more 
detailed information). 
In addition, a table and listing with Number of Subjects excluded at Screening (i.e., Number of 
subjects with BPRS_TS at Screening ≥ 25) will be presented. 
9.2 
Clinician Administered Dissociative States Scale (CADSS) 
9.2.1 CADSS Assessment 
The CADSS scale is designed for the assessment of dissociative states in adults. 
The CADSS will be completed at Screening, Check-in on Day -2, and at approximately 6 and 24 
h after dosing on Day 1. The CADSS will also be completed prior to dosing and at 
approximately 6 and 24 h after dosing on Days 7 and 14. 
Baseline will be considered to be on Day -1. 


 
 
 
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Table 5: CADSS Details 
Scale 
Number 
of Items 
Score Range Per 
Item 
Total 
Possible 
Score 
Scoring Interpretation 
Data Collection 
Clinician 
Administered 
Dissociative 
States Scale 
(CADSS) 
23 
0-4 point Likert scale 
0=not at all 
1=mild 
2=moderate 
3=severe 
4=extreme 
92 
Severity increases with increasing 
score 
No official cut off criteria for 
scoring 
Baseline scores for normal healthy 
males were 1.67 (2.96)2  
• Score for each item (0-
4)  
Score Range: 0-92 
 (general dissociation) 
o Of note Items can be 
segregated into factors 
e.g. Altered visual and 
auditory perception 
(items 2, 9, 10, 11, 16, 
18)  
o Altered time and 
perception (Items 1, 
12, 15)  
Depersonalization 
( Items 3, 4, 5, 6, 20)3 
9.2.2 CADSS Visit Windows 
The acceptable window for CADSS will be within 2 hours following the 6 h nominal timepoint 
and within 3 h prior to next dose for the 24 h time point. All of the 24 h postdose assessments are 
intended to be completed prior to next day dosing as applicable. 
Psychiatric assessments should be carried out in the following order when required: (1) 3MS, (2) 
CADSS, (3) BPRS, (4) C-SSRS. 
9.2.3 CADSS Endpoints 
Derived endpoints will include: 
• CADSS_TSCFB = Total Score Change from Baseline (CFB) = CADSS_TS at each 
postdose time point – CADSS_TSB at baseline 
• CADSS_TS%CFB = Total Score Percent Change from Baseline (CFB) 
9.2.4 CADSS Analysis 
Tables and listings will be presented for absolute values and derived endpoints described below. 
Inferential analysis will be provided for the derived endpoints (refer to SAP Section 9.6 for more 
detailed information). 
9.3 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
9.3.1 C-SSRS Assessment 
The C-SSRS is a questionnaire designed for the assessment of suicidal ideation and behavior in 
adolescents and adults. 
To monitor for a history of (the past 2 years to present) or for the emergence of suicidal ideation 
and behavior, subjects will undergo C-SSRS evaluations at Screening, Check-in on Day -2, and 
within 3 hours prior to dosing on Days 1, 3, 5, 7, 9, 11, 13, 15, 17 and on day 18 prior to 
Discharge, and at the follow-up/EOS visit. 


 
 
 
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The C-SSRS will be used to assess both behavior and ideation that tracks all suicidal events and 
provides a summary of suicidal ideation and behavior. It assesses the lethality of attempts and 
other features of ideation (frequency, duration, controllability, reasons for ideation, and 
deterrents), all of which are significantly predictive of completed suicide. 
Two versions of the C-SSRS will be used in this study: the Baseline/Screening version (lifetime 
history and past 12 months) and the Since Last Visit version. The Screening version of the C-
SSRS will be administered at the Screening visit. The Since Last Visit version of the C-SSRS 
will be administered at all subsequent assessment times. 
9.3.2 C-SSRS Analysis 
A frequency table will be used to summarize Baseline/Screening and Since Last Visit responses 
for each cohort, and C-SSRS Question, e.g. Wish to be Dead, Non-Specific Thought, Active 
Ideation (Not Plan) without Intent, Active Ideation with Some Intent, without Plan, Active 
Ideation with Plan and Intent. 
A listing by Baseline/Screening and Since Last Visit responses will be output by cohort, subject, 
C-SSRS Category, and C-SSRS Question, e.g. Suicidal Ideation: Wish to be Dead, Non-Specific 
Thought, and Suicidal Behavior: Actual Attempt,, Engaged in Non-Suicidal Self-Injurious 
Behavior?, Interrupted Attempt, Aborted Attempt, Preparatory Acts or Behavior, Suicidal 
Behavior, Suicide. 
9.4 
Modified Mini-Mental State Examination (3MS) 
9.4.1 3MS Assessment 
The 3MS is an examination designed for the assessment of dementia in adults. 
The 3MS will be completed at Screening, Check-in on Day -1, and at approximately 24 h after 
dosing on Day 1. The 3MS will also be completed prior to dosing and at approximately 24 h 
after dosing on Days 7 and 14. 
Baseline will be considered to be on Day -1. 
Table 6: 3MS Details 
Scale 
Number 
of Items 
Score Range Per 
Item 
Total 
Possible 
Score 
Scoring Interpretation 
Data Collection 
Modified 
Mini-Mental 
State (3MS) 
15 items 
with 
subscores 
Variable Likert 
scoring for each item 
100 
Better performance correlated with 
increasing score. Scores ≤ 77 may 
be indicative of dementia 
Normal cognition = 78–100  
Moderate cognitive impairment ≤ 
77  
Severe cognitive impairment ≤ 49  
• Score for each item 
(0-7) 
• Total score/100 
Scoring calculation: 
1. When and where born?  
1a.         Date  Day 
 
 
(0 or 1) 
Month   
 
(0 or 1) 


 
 
 
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Year  
 
 
(0 or 1) 
 
 
 
 
1a. Score = 0 to 3 
1b.       Place   Town  
 
 
(0 or 1) 
Province/Country                   (0 or 1) 
 
 
 
 
1b. Score = 0 to 2 
 
 
1 Score = Sum of 1a + 1b (ie, 0 to 5) 
2. Three Words (Number of presentations ___) 
2a.  
Shoes  
 
(0 or 1) 
2b. 
Blue  
 
(0 or 1) 
2c.  
Modesty                   (0 or 1) 
 
 
2 Score = Sum of 2a + 2b + 2c (ie, 0 to 3) 
3.         3a. Counting Forwards   
(0 or 1) 
            3b. Counting Backwards  
(0 to 2) 
3c. Spell “World” 
 
(0 or 1) 
 
 
3 Score = Sum of 3a + 3b + 3c (ie, 0 to 5) 
4. First Recall 
4a.  
Shoes  
 
(0 or 3) 
4b. 
Blue  
 
(0 or 3) 
4c.  
Modesty                   (0 or 3) 
 
 
4 Score = Sum of 4a + 4b + 4c (ie, 0 to 9) 
5. Today’s Date 
5a.                Today’s date  
(0 or 3) 
5b. 
Year  
 
(0 or 3) 
5c.  
Season  
 
(0 or 3) 
5d. 
Month  
 
(0 or 3) 
5e.  
Day of week 
(0 or 3) 
 
 
 
 
5 Score = Sum of 5a + 5b + 5c + 5d + 5e (ie, 0 to 15) 
6. Spatial Orientation 
            6a.                 Province (0 or 1) 
6b. 
Country (0 or 1) 
6c.                 City 
(0 or 1) 
6d. 
Place 
(0 or 1) 


 
 
 
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6e.                 Street 
(0 or 1) 
 
 
 
6 Score = Sum of 6a + 6b + 6c + 6d + 6e (ie, 0 to 5) 
7. Naming 
7a.                  (0 or 1) 
7b. 
 (0 or 1) 
7c.                  (0 or 1) 
7d. 
 (0 or 1) 
7e.                  (0 or 1)  
 
 
7 Score = Sum of 7a + 7b + 7c + 7d + 7e (ie, 0 to 5) 
8. Four legged animals Score 0 to 10 
9. Similarities 
9a. (0 to 2) 
9b.(0 to 2) 
9c. (0 to 2)  
 
 
9 Score = Sum of 9a + 9b + 9c (ie, 0 to 6) 
10. Repetition 
           10a. 
Province (0 to 2) 
10b. 
Country (0 or 1) 
10c. 
City 
(0 or 1) 
10d. 
Place 
 (0 or 1)  
 
 
10 Score = Sum of 10a + 10b + 10c + 10d (ie, 0 to 5) 
11. Obeys commands Score 0 to 3 
12. Writing Score 0 to 5 
13. Copy 
13a. 
 (0 to 4) 
13b. 
 (0 to 4) 
13c. 
 (0 to 2)  
 
 
13 Score = Sum of 13a + 13b + 13c (ie, 0 to 10) 
14. 3-Stage command 
14a. 
 (0 or 1) 
14b. 
 (0 or 1) 
14c. 
 (0 or 1)  
 


 
 
 
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14 Score = Sum of 14a + 14b + 14c (ie, 0 to 3) 
15. Second Recall 
15a.  
Shoes  
 
(0 or 3) 
15b. 
Blue  
 
(0 or 3) 
15c.  
Modesty                   (0 or 3) 
 
 
15 Score = Sum of 15a + 15b + 15c (ie, 0 to 9) 
Total 3MS Score = Sum of Scores for Items 1 to 15 = 0-100 
9.4.2 3MS Visit Windows 
The acceptable window for 3MS will be within 3 hours prior to next dose for the 24 hours time 
point. All the 24 hours postdose assessments are intended to be completed prior to next day 
dosing as applicable. 
PD procedures should be carried out in the following order when required: (1) 3MS, (2) CADSS, 
(3) BPRS, (4) C-SSRS. 
9.4.3 3MS Endpoints 
Derived endpoints will include: 
• 3MS_TSCFB = Total Score Change from Baseline (CFB) = CADSS_TS at each postdose 
time point – 3MS_TSB at baseline 
• 3MS_TS%CFB = Total Score Percent Change from Baseline (CFB) 
9.4.4 3MS Analysis 
Tables and listings will be presented for absolute values and derived endpoints described below. 
Inferential analysis will be provided for the derived endpoints (refer to SAP Section 9.6 for more 
detailed information). 
9.5 
Alertness Visual Analogue Scale (VAS) 
9.5.1 Alertness VAS Assessment 
The VAS alertness scale is designed to assess the alertness of subjects across a continuum scale 
with values from 0 to 10. 
The VAS should be completed prior to TMP-301 administration at Screening, and at 
approximately 4, 6 and 12 h after dosing on Days 1, 7, and 14. This assessment will also occur 
on Day 18 prior to Discharge. 
9.5.2 Alertness VAS Endpoints 
Derived endpoints will include: 
• Emax(Maximum postdose effect) 
• Emin(Minimum postdose effect) 
• TEmax(Time of postdose maximum effect) 
• TEmin(Time of postdose minimum effect) 


 
 
 
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Emax and Emin will be calculated based on the postdose values; the predose value will be 
excluded. 
TEmax and TEmin will be calculated as the time from time 0 to Emax and Emin, respectively, as 
appropriate. The first time of peak effect is used if the value is reported at more than one time 
point. 
9.5.3 Alertness VAS Analysis 
Alertness VAS values will be summarized and listed for absolute values and derived endpoints. 
No inferential analyses will be performed. 
9.6 
Psychiatric Assessments Analysis 
Psychiatric measures at each time point will be summarized by treatment (placebo and each dose 
of TMP-301) using descriptive statistics and presented graphically. Derived endpoints will also 
be summarized by treatment using descriptive statistics. Only summary statistics will be output 
for Emax TEmax, Emin and TEmin. Descriptive statistics will include n, mean, standard error (SE), 
minimum, first quartile (Ql), median, third quartile (Q3) and maximum for all psychiatric 
assessment values, and endpoints other than TEmax and TEmin. For TEmax and TEmin, minimum, 
Q1, median, Q3 and maximum will be output. 
A mixed-effects model for a parallel study design will be used to compare the derived endpoints 
between treatments (e.g., BPRS_TSCFB, BPRS_TS%CFB, CADSS_TSCFB, CADSS_TS%CFB, 
3MS_TSCFB, and 3MS_TS%CFB). The model will include treatment (dosing group), day, and dose 
(1st or 2nd) as fixed effects, and the baseline measurement as a covariate. P-values for key 
components of variance, least-square means (LSMeans), and 95% CI for contrasts will be output. 
For each endpoint, the following comparisons will be made: 
• Contrast 1: TMP-301 50 mg BID vs. Pooled Placebo 
• Contrast 2: TMP-301 50 mg QD vs. TMP-301 50 mg BID 
• Contrast 3: TMP-301 50 mg QDvs. Pooled Placebo 
• Contrast 4: TMP-301 XX mg vs. TMP-301 50 mg BID 
• Contrast 5: TMP-301 XX mg vs. TMP-301 50 mg QD 
• Contrast 6: TMP-301 XX mg vs. Pooled Placebo 


 
 
 
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10 PHARMACOKINETIC ANALYSIS 
The PK analysis will be carried out according to Altasciences SOPs. 
10.1 Missing Values 
The lack of concentration values due to failure to collect the sample, a lost or compromised 
sample or due to the subject’s early termination from the study will be termed “missing” in the 
dataset, and no imputation will be done. 
If the actual collection time of a postdose PK sample is unknown, but a valid concentration value 
has been measured, the sample will be set to missing in the PK analysis and will be presented in 
listing excluded from descriptive statistics.  
10.2 Measurements Below the Lower Limit of Quantitation 
Concentration values below the lower limit of quantitation (LLOQ) associated with predose and 
postdose collection times will be replaced with zero for the non-compartmental analysis (NCA). 
Concentration values below the LLOQ will be replaced with zero for mean PK profile 
representations as well as for descriptive statistic calculations. 
Concentration values below the LLOQ that are embedded between two quantifiable 
concentrations will be replaced with missing for mean PK profile representations as well as for 
descriptive statistic calculations. 
10.3 Actual Time 
The NCA will be based on actual sampling times. 
The individual concentration-time profiles will be presented using actual sampling times whereas 
the mean concentration-time profiles and tables presenting summary statistics of 
concentration-time series will be presented using nominal sampling times. 
10.4 Non-Compartmental Analysis 
The following configuration for the NCA analysis (with Phoenix® WinNonlin® version 8.0, or 
higher) will be used: 
• Data: 
Serial sampled data 
• Model/Dose options Type:  
Plasma (200 -202) / Extravascular 
• AUC Calculation Method: 
Linear Up Log Down 
• Lambda Z (λZ) calculation: 
Best fit method for λZ Linear-Log regression 
Reasons for excluding PK parameters will include the following: 
• AUC: AUC parameters will not be estimated if less than 3 consecutive measurable 
concentrations are observed 
• PK parameters requiring λz estimation (eg, Vz/F) will be set to Not Reported (NR) in the 
tables and listings if they meet one of the following: 
 R2 < 0.8  
The PK parameters for TMP-301 are presented in Table 6. 


 
 
 
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Table 7: Pharmacokinetic Parameters of TMP-301  
Parameter 
Definition 
PK Parameters Day 1 
Cmax 
Maximum observed concentration occurring at time Tmax  after the first dose 
Tmax 
Time of maximum observed concentration after the first dose 
AUC0-12,  
( For  BID dosing) 
Area under the concentration time curve over the dosing interval, calculated 
from 0 to 12 hours (dosing interval) after the first dose  
(The nominal time will be used to estimate AUC using the NCA built-in tool in 
Phoenix® WinNonlin®. This means that actual times off by more than 1 minute from tau 
will be extrapolated/intrapolated as per Phoenix® WinNonlin®’s built-in formulas. If 
extrapolation/intrapolation is not possible, then no value is reported by the software.)  
 
AUC0-24,  
( For  QD dosing) 
Area under the concentration time curve over the dosing interval, calculated 
from 0 to 24 hours (dosing interval) after the first dose  
(The nominal time will be used to estimate AUC using the NCA built-in tool in 
Phoenix® WinNonlin®. This means that actual times off by more than 1 minute from tau 
will be extrapolated/intrapolated as per Phoenix® WinNonlin®’s built-in formulas. If 
extrapolation/intrapolation is not possible, then no value is reported by the software.)  
C12 
 
Observed concentration occurring at time 12 h  
C24 
Observed concentration occurring at time 24 h  
(C24 Day 1 = Ctrough Day 2) 
PK Parameters Days 2, 5, 7, 9, 11 and 12 
Ctrough 
Observed concentration at the end of the dosing interval 
PK Parameters Day 14  
Cmax,  ss   
Maximum observed concentration at  steady -state occurring at time Tmax,  ss 
Cavg 
Average concentration, calculated as AUC0-Tau,  ss /Tau 
Tmax,  ss   
Time of maximum observed concentration at steady-state 
Cmin,  ss 
Minimum observed concentration after the first dose of a multiple regimen  
AUC0-TAU,  ss 
Area under the concentration time curve over the dosing interval at steady-
state. 
(The nominal time will be used to estimate AUC using the NCA built-in tool in Phoenix® 
WinNonlin®. This means that actual times off by more than 1 minute from tau will be 
extrapolated/intrapolated as per Phoenix® WinNonlin®’s built-in formulas. If 
extrapolation/intrapolation is not possible, then no value is reported by the software.)  
For QD dosing:  AUC0-TAU,SS = AUC0-24,SS 
For  BID dosing AUC0-TAU,SS =  AUC0-12,SS 
C12, ss 
 
Observed concentration occurring at time 12 h 


 
 
 
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10.5 Visit Windows 
Windows for timed PK blood sample collections are presented in Table 7. PK samples collected 
outside of the pre-specified windows will be documented as protocol deviations. Since actual 
times are to be used for the PK analysis, deviations will be reflected in the analysis unless 
indicated otherwise upon review of the data. 
Parameter 
Definition 
C24, ss 
Observed concentration occurring at time 24 h 
CL/F 
Apparent total clearance at steady-state, calculated as Dose/ AUC0-TAU,  ss 
Vz/F  
Apparent volume of distribution at steady-state, calculated as Dose/λZ *  
AUC0-TAU, SS   
AR_Cmax 
Accumulation ratio derived as Cmax, ss  / Cmax,FD Day 1 
 
AR_AUC0-12 BID 
Accumulation ratio derived as AUC0-12,ss / AUC0-12,Day 1  
AR_AUC0-24 QD 
Accumulation ratio derived as AUC0-24,ss / AUC0-24, Day 1  
AR_C12 
Accumulation ratio derived as C12,ss/C12,Day 1 
AR_C24 
Accumulation ratio derived as C24,ss/C24,Day 1 
(C24 Day 1 = Ctrough Day 2) 
CYP1A2_ratio  
Ratio of CYP1A2 activity derived as paraxanthine/caffeine concentration day 14 
/ paraxanthine/caffeine concentration day -1 
The following PK parameters will be used for PK calculation on Day 14  and presented in the 
PK listings only 
λz Upper  
Upper limit on time for values included in the calculation of λz 
λz Lower  
Lower limit on time for values included in the calculation of λz 
λz  
Apparent elimination rate constant, estimated by linear regression of the terminal 
linear portion of the log concentration versus time curve 
R2 
Goodness of fit for the terminal phase 
Number of 
Points 
Number of data points in computing λZ 


 
 
 
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Table 8: Acceptable PK Visit Windows 
Elapsed Time 
Accepted Window 
Predose 
No window specified 
> 0 hour to ≤ 30 minutes 
± 1 minute 
> 30 minutes to ≤ 4 hours 
± 2 minutes 
> 4 hours to ≤ 12 hours 
± 5 minutes 
> 12 hours to ≤ 24 hours 
± 10 minutes 
> 24 hours to ≤ 72 hours 
± 2 hours 
> 72 hours 
± 4 hours 
10.6 Pharmacokinetic Statistical Methodology 
All tables, figures, and listings (TFLs), when appropriate, will be stratified by treatment. 
10.6.1 Summary Statistics 
Summary statistics of the individual concentration data and derived parameters will be calculated 
with Phoenix® WinNonlin® for the PK population. Summary statistics will be calculated for 
concentration at each individual time point and for all PK parameters. 
Ctrough will be displayed graphically and summarized descriptively by day to assess for steady 
state. 
Appropriate dose–normalized PK parameters (Cmax, ss, C12, ss, C24, ss, and AUC0-TAU, ss, when 
appropriate) will be assessed graphically for dose-proportionality.Concentration data will be 
summarized by group using the following statistics: number of observations (n), arithmetic mean 
(mean), SD, min, median, max, and CV%. The PK parameters will be summarized using these 
same statistics, as well as geometric mean and geometric mean CV%. 
No comparison between fed and fast state will be provided. 
10.6.2 Dose Proportionality 
Natural log-transformed PK parameters (Cmax, ss, C 12, ss , C24, ss, and AUC0-TAU, ss) will be assessed 
statistically for proportionality. Proportionality analysis will be done using a power model. The 
power model is defined as: 
ln(PK parameter) = α + β • ln(Dose) + ε 
where α is the intercept, β is the slope and ε is the error term. A linear model with ln-transformed 
dose as a continuous effect will be fitted. A point estimate and a 90% confidence interval will be 
derived for the slope (β). 
The parameter can be considered to be dose-proportional if the 90% CIs for the slope coefficient 
that include 1 will suggest evidence of dose proportionality. 
Dose proportionality may be assessed within different dose ranges if deemed appropriate with at 
least three doses. 


 
 
 
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Otherwise, if there are only two cohorts completed, Statistical inference will be based on a 
bioequivalence approach for a parallel group design and expressing the relative difference as a 
geometric mean ratio and 90% CI using ANOVA model based on dose normalized PK 
parameters. 
No comparison between fed and fast state will be provided. 
 
 
 


 
 
 
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11 INTERIM ANALYSES AND DATA SAFETY MONITORING 
No formal interim analyses will be performed; blinded safety data will be reviewed by an 
Investigator and the Sponsor’s Medical Monitor following completion of each TMP-301 dose 
level. 
 
 


 
 
 
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12 CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
Added below analysis population definitions: 
• 
Enrolled Population 
The Enrolled population will include all subjects who signed informed consent. 
• 
Screened Population 
The Screened population will include all subjects who meet the eligibility criteria. 
• 
Randomized Population 
The Randomized population will include all subjects who are assigned a randomization number. 
 
 


 
 
 
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13 GENERAL INFORMATION RELATED TO DATA PRESENTATIONS 
The formats and layouts of TFLs are provided in a separate document as common displays. Their 
numbering and general content follow the International Conference on Harmonisation (ICH) E3 
guidelines. Actual formats and layouts may be altered slightly from those presented as necessary 
to accommodate actual data or statistics. 


 
 
 
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14 REFERENCES 
1. Peuskens, J., Bech, P., Möller, H.J., Bale, R., Fleurot, O., Rein, W. (1999). Amisulpride vs. 
risperidone in the treatment of acute exacerbations of schizophrenia. Amisulpride study 
group. Psychiatry Res, 88(2), 107-17. 
2. Piazza, G.G., Iskandar, G., Hennessy, V. et al (2022). Pharmacological modelling of 
dissociation and psychosis: an evaluation of the Clinician Administered Dissociative States 
Scale and Psychotomimetic States Inventory during nitrous oxide (‘laughing gas’)-induced 
anomalous states. Psychopharmacology, 239, 2317–2329.  
3. van Schalkwyk, G. I., Wilkinson, S. T., Davidson, L., Silverman, W. K., Sanacora, G. 
(2018). Acute psychoactive effects of intravenous ketamine during treatment of mood 
disorders: analysis of the Clinician Administered Dissociative State Scale. Journal of 
affective disorders, 227, 11-16. 
 


 
 
 
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APPENDIX A STUDY SCHEDULE(S) 
 
 
 


 
 
 
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Study 
Procedures 
Screening 
Check-in 
Baseline 
Caffeine 
test
Day 1 
Days 2-3 
Day 4 
Days 5-6 
Day 7 
Days 8-13 
Day 14 
Days15-17 
Discharge 
Follow-
up/EOS 
visit 
Day 
Days-
28 to 
-1 
Day -
2 
Day -
1 
 
 
 
 
 
 
 
 
Day 18  
Day 25z 
(±2 
days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Admission to Unit 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
 
Psychiatric History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X b 
 
 
 
 
 
 
 
 
 
Xp 
 
Psychiatric Examinationsc 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Urine Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testd 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
FSHe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height and body weight 
Xf 
 
 
 
 
 
 
 
 
 
 
X 
X 
Genotyping sampleg 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Exploratory Biomarkers sample 
 
 
 
Xh 
Xh 
 
 
Xh 
 
Xh 
 
X 
 
Check-in 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Check-out 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Nonresidential visit 
X 
 
 
 
 
 
 
 
 
 
 
 
X 


 
 
 
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Study 
Procedures 
Screening 
Check-in 
Baseline 
Caffeine 
test
Day 1 
Days 2-3 
Day 4 
Days 5-6 
Day 7 
Days 8-13 
Day 14 
Days15-17 
Discharge 
Follow-
up/EOS 
visit 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
TMP-301 or Placeboi 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Caffeine 100 mg oral 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Caffeine Plasma sampling 
 
4 hr 
post 
dose 
 
 
 
 
 
 
4 hr 
post 
dose 
 
 
 
Plasma PK Samplingj,k,l  
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
96.00aa  
X 
Urine Samplingl 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Adverse Event Recording 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant Medication Monitoring 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry, Hematology, and 
Urinalysism 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
96.00 aa 
X 
Vital Signs: Blood Pressure, Pulse Rate and 
Oral Body Temperaturen,o 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
96.00 aa 
X 
12-lead ECGq,r 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
96.00 aa 
X 
VAS Alertness Scales,t 
 
 
 
X 
 
 
 
X 
 
X 
 
96.00 aa 
 
BPRS, CADSSt,u,v,x 
X 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
3MSt,v,w,x 
X 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
C-SSRSy 
X 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: BPRS = Brief Psychiatric Rating Scale; CADSS = Clinician-Administered Dissociative States Scale; 3MS = Modified Mini-Mental State; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; FSH = follicle-stimulating hormone; PK = pharmacokinetic(s). 
 
a Interim medical history. 
b Symptom directed physical examination and at Investigator discretion. 


 
 
 
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c Clinical Interview for DSM-5 (SCID-5 CT) will be conducted by appropriately trained staff. This psychiatric examination will include an assessment of 
premorbid personality, personal and developmental history, alcohol and substance use history, forensic history, past psychiatric history.  The PRIME 
questionnaire will also be administered to screen for risk of psychosis.  A psychiatric exam (full or partial) can take place at any time during the study at the 
discretion of the PI, if there is a relevant concern. 
d In all females. Serum pregnancy test at Screening and urine pregnancy tests at all other times. A positive urine pregnancy test will be confirmed with a serum 
pregnancy test. 
e In all females to determine postmenopausal status. 
f Height measured at Screening only. 
g The genotyping samples will be stored and may be processed and analyzed to assess genotyping of drug metabolizing systems. 
h Day 1 at pre-dose, 1, 4, and 8 hours; day 2 pre-dose; and days 7 and 14 at pre-dose, 1, 4, and 8 hours. 
i For BID Cohorts: Dosing twice daily interval from Day 1 to Day 13, two intakes separated by 12.00 hours (note: only the AM dose is administered on Day 14).  
For QD Cohorts: Dosing once daily in the morning from Day 1 to Day 14. 
j Timing of PK blood samples may be changed based on emerging data. 
k At each protocol specified timepoint for PK (including predose baseline) out to 12.00 hours postdose. (Section 6.2). 
Serial blood will be collected on Day 1, and 14 at predose, 0.5, 1.00, 2.00, 3.00, 4.00, 6.00, 8.00, and 12.00 hours. Trough (predose AM) and 8 hr and 12 hr 
samples will be collected on Days 2, 7 and 11. Trough samples (predose AM) will be collected on Days 5, 9 and 12. Additional PK samples will be drawn after 
the last dose on Day 14 at 24.00 (Day 15), 28.00 (Day 15), 48.00 (Day 16), 52.00 (Day 16), 72.00 (Day 17), and 96.00 (Day 18) hours postdose and Day 25 at 
the follow-up EOS visit (Day25 ± 2 days). Urine will be collected on Day 1 (0 to 4, 4 to 8, 8 to 12, 12 – 24 hr) and Day 14 (0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 
to 48 (Day 15), and 48 – 72 hr (Day 16)). See Table 4.  
m Day 1 predose, then 24.00 (Day 2) and 72.00 hours (Day 4) postdose, then every 2 days (Days 6, 8, 10, 12, 14, 16) post dose at approximately 10 am ± 1 hour. 
n Days 1 and 7: Prior to morning dosing and 0.5, 1.00, 2.00, 3.00, 4.00, 6.00, 8.00, and 12.00 hours. Days 2, 4, 6, 8, 10, and 12: Prior to dosing and 4.00 and 
12.00 hours postdose. Day 14: Prior to dosing and 0.5, 1.00, 2.00, 3.00, 4.00, 6.00, 8.00, 12.00, 24.00 (Day 15), 48.00 (Day 16), 72.00 (Day 17), 96.00 (Day 
18) hours postdose. 
o At baseline on Day 1, predose vital sign measurements (except oral body temperature) will be conducted in triplicate (with an interval of approximately 10 - 30 
minutes between each recording). The average value of each parameter will be considered as baseline value. 
p Symptom-directed physical examination. 
q Days 1 and 7: Predose and at 4.00, 6.00, 8.00, and 12.00 hours postdose. Days 2, 4, 6, 8, 10, and 12: Predose and 4.00 and 12.00 hours postdose. Day 14: Prior 
to dosing and 0.5, 1.00, 2.00, 3.00, 4.00, 6.00, 8.00, 12.00, 24.00 (Day 15), 48.00 (Day 16), 72.00 (Day 17), 96.00 (Day 18) postdose. 
r At baseline in Day 1 predose, ECG recordings will be conducted in triplicate at (-45, -30, and -15 minutes). The average value of each parameter will be 
considered as baseline value. 
s Day 1, 7, and 14: Predose then 4.00, 6.00, and 12.00 hours postdose and Day 18. 
t May also be conducted at other times if deemed appropriate based on emerging data. 
u Check-in, then 6.00 and 24.00 hours postdose on Day 1, Day 7, and Day 14. 
v Conducted as part of the psychiatric examination. 
w Check-in, and 24.00 hours postdose on Day 1, Day 7, and Day 14. 
x Subjects will be screened within 28 days prior to dosing. A psychiatric examination will be performed at Screening by a suitably trained psychiatrist or 
appropriately trained staff using a clinical interview. This will include an assessment of premorbid personality, personal and developmental history, alcohol and 
substance use history, forensic history, past psychiatric history, and mental state examination. 
y Every other day from Day 1 to discharge. 
z Approximately 1 week after last dose. 


 
 
 
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aa 96 hours after the last (Day 14) dose