A Phase 1 Randomized Single Oral Dose Cross-Over Study Investigating Desmetramadol Dose Proportionality And Food Effect In Normal Human Subjects
Phase: PHASE1
Conditions: Pain
Sponsor: Syntrix Biosystems, Inc.

Protocol version 1.2 
 
 
 
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A PHASE 1 RANDOMIZED SINGLE ORAL DOSE CROSS-OVER STUDY INVESTIGATING 
DESMETRAMADOL DOSE PROPORTIONALITY  AND FOOD EFFECT IN NORMAL 
HUMAN SUBJECTS  
 
Syntrix Protocol OMNI-PAIN-103 
 
Version: 1.2  
11 May 2020 
 
Study Agent:  
 
Desmetramadol 10 mg tablets 
 
 
Protocol Number: 
 
Syntrix-OMNI-PAIN-103 
 
IND Number: 
 
103,997 
 
 
Study Site:  
Celerion 
 
Principal Investigator:  
Robert Schwab, MD 
 
Sponsor: 
Syntrix Biosystems, Inc.  
 
Personnel: 
 
 
Stuart Kahn, MD (Project Director, Sponsor’s Medical Monitor) 
 
 
 
 
 
Aaron Schuler, PhD (Formulation Scientist) 
 
 
 
 
 
John Zebala, MD, PhD (Regulatory Affairs) 
 
 
 
 
 
 
 
 
 
 
 

Protocol version 1.2 
 
 
 
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Contact Information 
 
Clinical Site 
Principal Investigator 
Celerion 
 621 Rose Street 
Lincoln, NE 68502 
 Robert Schwab 
 
 
Sponsor 
Syntrix Biosystems, Inc. 
215 Clay Street NW 
Suite B5 
Auburn, WA  98001 
Fax:  253-833-8127 
Stuart Kahn 
Tel: 206-524-0214 
Alt Tel: 253-833-8009 x32  
Mobile: 206-330-7604 
 John Zebala 
253-833-8009 
Aaron Schuler 
Tel: 253-833-8009 x21 
 
 

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Principal Investigator Agreement 
 
Protocol Number: Syntrix-Omni-Pain-103 
 
I, the undersigned, have reviewed this protocol, including all attached information. 
 
I agree to conduct this clinical study in accordance with the E6 Guidance of the International Conference 
on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) 
“Good Clinical Practice: Consolidated Guidance”, and the U.S. Code of Federal Regulations governing 
the protection of human subjects (21 CFR 50), Institutional Review Boards (21 CFR 56) and the 
obligations of clinical investigators (21 CFR 312). Furthermore, I agree to maintain all study 
documentation for the time specified in this protocol. 
 
 
 
 
Principal Investigator Signature 
 
 
Printed Name 
 
 
 
Date 

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Table of Contents 
Contact Information ....................................................................................................................................... ii 
Principal Investigator Agreement ................................................................................................................. iii 
Table of Contents ......................................................................................................................................... iv 
List of Abbreviations ................................................................................................................................... vii 
Protocol Summary (Synopsis) ...................................................................................................................... ix 
Schematic of Study Design ......................................................................................................................... xii 
1 
BACKGROUND AND SCIENTIFIC RATIONALE ........................................................................... 1 
1.1 
Background Information ................................................................................................................. 1 
1.1.1 
Tramadol and desmetramadol: Background and Pharmacology ............................................. 1 
1.1.2 
Unmet Need: Absent Tramadol Efficacy in Patients with Low CYP2D6 Activity ................ 3 
1.1.3 
Significant Negative Impact on Patient Care and Safety ........................................................ 4 
1.2 
Description of the Study Agent ...................................................................................................... 5 
1.2.1 
Pilot Study of Desmetramadol in a Human Subject ................................................................ 5 
1.2.2 
Phase 1 PK and PD Study in Normal Healthy Volunteers ...................................................... 6 
1.3 
Rationale ......................................................................................................................................... 8 
1.3.1 
Overall Study Design .............................................................................................................. 8 
1.3.2 
Dosage ..................................................................................................................................... 9 
1.3.3 
Study Population ..................................................................................................................... 9 
1.3.4 
Study Endpoints ....................................................................................................................... 9 
1.4 
Potential Risks and Benefits ........................................................................................................... 9 
2 
STUDY OBJECTIVES ........................................................................................................................ 10 
3 
STUDY DESIGN ................................................................................................................................. 10 
3.1 
Description of the Study Design ................................................................................................... 10 
3.2 
Study Endpoints ............................................................................................................................ 11 
3.2.1 
Primary Endpoint-Pharmacokinetic Responses .................................................................... 11 
3.2.2 
Secondary Endpoint-Safety ................................................................................................... 11 
3.3 
Study Site ...................................................................................................................................... 12 
4 
STUDY POPULATION ...................................................................................................................... 12 
4.1 
Subject Inclusion Criteria ............................................................................................................. 12 
4.2 
Subject Exclusion Criteria ............................................................................................................ 13 
5 
STUDY AGENT/INTERVENTIONS ................................................................................................. 14 
5.1 
Study Drug (Desmetramadol) ....................................................................................................... 14 
5.1.1 
Formulation, Packaging, and Labeling .................................................................................. 14 
5.1.2 
Study Drug Storage and Stability .......................................................................................... 14 
5.1.3 
Preparation, Administration, and Dosage of Study Drug ...................................................... 14 
5.1.4 
Study Drug Shipping and Accountability Procedures ........................................................... 15 
5.2 
Assessment of Subject Compliance with Study Drug .................................................................. 15 
5.3 
Concomitant Medications and Procedures ................................................................................... 15 
5.4 
Precautionary and Prohibited Medications and Procedures ......................................................... 15 
5.4.1 
Prohibited Medications and Procedures ................................................................................ 15 
6 
STUDY PROCEDURES and EVALUATIONS ................................................................................. 16 
6.1 
Screening (≤ 30 days Before Day-1) and Check-In (Day -1) ....................................................... 16 
6.2 
Randomization and Study Drug Treatment Period 1 (Day 1 Through Day 3). ............................ 16 
6.3 
Study Drug Treatment Period 2 (Day 4 through Day 6) ............................................................... 17 
6.4 
Study Drug Treatment Period 3 (Day 7 through Day 9) ............................................................... 17 
6.5 
Study Drug Treatment Period 4 (Day 10 through Day 11) ........................................................... 18 
6.6 
Subject Samples ............................................................................................................................ 18 

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7 
ADVERSE EVENTS ........................................................................................................................... 18 
7.1 
Specification of Safety Parameters ............................................................................................... 18 
7.2 
Definitions .................................................................................................................................... 19 
7.2.1 
Adverse Event ....................................................................................................................... 19 
7.2.2 
Serious Adverse Event .......................................................................................................... 19 
7.2.3 
Unexpected Adverse Event ................................................................................................... 19 
7.2.4 
Life-Threatening Event ......................................................................................................... 19 
7.3 
Assessment of Adverse Events ..................................................................................................... 19 
7.3.1 
Severity Grading .................................................................................................................... 19 
7.3.2 
Definition of Relationship of Adverse Events to Study Drug ............................................... 20 
7.4 
Reporting Adverse Events ............................................................................................................ 20 
7.5 
Follow-up of Subjects with Adverse Events ................................................................................. 21 
8 
Assessment of Risk .............................................................................................................................. 21 
8.1 
Criteria for Interrupting the Study Based on Dose-Limiting Toxicity ......................................... 21 
8.1.1 
Rules for Discontinuing Study Drug in an Individual Subject .............................................. 21 
8.1.2 
Suspension of the Study ........................................................................................................ 22 
8.1.3 
Confirmatory Testing of Significant (grade 3 and 4) Laboratory Abnormalities ................. 22 
8.2 
Subject Withdrawal from the Study .............................................................................................. 22 
8.3 
Replacement of a Subject Who Withdraws from Study Treatment .............................................. 22 
9 
STATISTICAL CONSIDERATIONS ................................................................................................. 23 
9.1 
Randomization Procedures ........................................................................................................... 23 
9.2 
Plan for Statistical Summaries and Analyses ............................................................................... 23 
9.2.1 
General Considerations ......................................................................................................... 23 
9.2.2 
Disposition of Subjects .......................................................................................................... 23 
9.2.3 
Demographic Characteristics ................................................................................................. 24 
9.2.4 
Safety Endpoints .................................................................................................................... 24 
9.2.5 
PK Analysis ........................................................................................................................... 25 
9.3 
Planned Interim Analysis .............................................................................................................. 25 
9.4 
Procedures for Deviations from Planned Statistical Analyses ...................................................... 25 
9.5 
Appropriate Method and Timing for Analyzing Outcome Measures ........................................... 25 
9.5.1 
Methods and Timing for the Primary End-Point ................................................................... 25 
9.6 
Study Hypotheses ......................................................................................................................... 26 
9.7 
Sample Size Considerations .......................................................................................................... 26 
9.8 
Maintenance of Trial Randomization List .................................................................................... 28 
9.9 
Subject Enrollment and Follow-Up .............................................................................................. 28 
9.10 Safety Review ............................................................................................................................... 28 
9.11 Final Analysis Plan ....................................................................................................................... 28 
10 
ADMINISTRATIVE PROCEDURES ............................................................................................. 29 
10.1 Institutional Review Board Approval ........................................................................................... 29 
10.2 Informed Consent ......................................................................................................................... 29 
10.3 Direct Access to Source Data/Documents, Study Monitoring, Data Collection .......................... 29 
10.4 DATA ANALYSIS ....................................................................................................................... 30 
10.5 Modification of the Protocol ......................................................................................................... 30 
10.6 Protocol Deviation(s) .................................................................................................................... 30 
10.7 Departure from the Protocol ......................................................................................................... 31 
10.8 Suspension of the Study ................................................................................................................ 31 
10.9 Study Termination by the Sponsor ............................................................................................... 31 
10.10 
Use of Information and Publications ......................................................................................... 31 

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10.11 
Record Retention ....................................................................................................................... 32 
10.12 
Exclusion of Minorities, and Children (Special Populations) ................................................... 32 
10.13 
Subject Confidentiality .............................................................................................................. 32 
Appendix A: Schedule of Procedures/Evaluations ...................................................................................... 33 
Appendix B.  Calculation of Selected Inclusion Criteria ............................................................................ 35 
Appendix C: Toxicity Grading Scale for Clinical Laboratory Values1 ....................................................... 36 
Appendix D: Toxicity Grading Scale for Clinical AEs¹ .............................................................................. 37 
References ................................................................................................................................................... 38 

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List of Abbreviations 
 
AE  
 
 
Adverse Event 
ALT 
 
 
Alanine Aminotransferase 
ANOVA 
 
Analysis of Variance 
AST 
 
 
Aspartate Aminotransferase 
API 
 
 
Active Pharmaceutical Ingredient 
AUC  
 
Area Under the Curve  
AUMC 
 
Area Under the First Moment Curve 
BMI 
 
 
Body Mass Index 
BP  
 
 
Blood Pressure 
BPM  
 
Beats Per Minute 
BUN  
 
Blood Urea Nitrogen 
CBC  
 
Complete Blood Count  
CFR 
 
 
Code Federal Regulations 
CI  
 
 
Confidence Interval 
CIOMS 
 
Council for International Organizations of Medical Sciences 
CONSORT 
 
Consolidated Standards of Reporting Trials 
CPU  
 
Clinical Pharmacology Unit 
CRF 
 
 
Case Report Form 
CRO  
 
Contract Research Organization 
CRP 
 
 
C-Reactive Protein 
Cssmax  
 
Concentration steady state maximum 
Cssmin  
 
Concentration steady state minimum 
CYP  
 
Cytochrome P-450 
DLDD  
 
Drug Liking, Drug Disliking 
DSM  
 
Data and Safety Monitoring 
DSMB  
 
Data and Safety Monitoring Board 
ECG  
 
Electrocardiogram 
EM 
 
 
Extensive metabolizers 
EMA  
 
European Medicines Agency 
FDA  
 
Food and Drug Administration 
FWA  
 
Federal-Wide Assurance 
GCP  
 
Good Clinical Practice 
GLP 
 
 
Good Laboratory Practice 
GMP  
 
Good Manufacturing Practice 
HBV  
 
Hepatitis B Virus 
hCG 
 
 
Human Chorionic Gonadotropin 
HCV  
 
Hepatitis C Virus 
HIPAA 
 
Health Assurance Portability and Accountability Act 
HIV 
 
 
Human Immunodeficiency Virus 
HR  
 
 
Heart Rate 
HZ  
 
 
Heterozygous  
IB  
 
 
Investigator’s Brochure 
ICF 
 
 
Informed Consent Form 
ICH 
International Conference for the Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IM  
 
 
Intermediate metabolizer 

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IND 
 
 
Investigational New Drug 
IRB 
 
 
Institutional Review Board 
ISM 
 
 
Independent Safety Monitor 
ITT 
 
 
Intent-To Treat 
IVIVC  
 
In-Vitro In-Vivo correlation 
LOQ  
 
Limit of Quantification 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MM 
 
 
Medical Monitor 
MOP  
 
Manual of Procedures 
M1  
 
 
Metabolite 1 
N  
 
 
Number (typically refers to subjects) 
NDA  
 
New Drug Application 
NE  
 
 
Norepinephrine 
NET 
 
 
Norepinephrine Transporter 
NIDA  
 
National Institute On Drug Abuse 
NIH 
 
 
National Institutes of Health 
O-DMT 
 
O-Desmethyltramadol 
OHRP  
 
Office for Human Research Protection 
OHSR  
 
Office for Human Subjects Research 
PACU  
 
Post-Anesthetic Care Unit 
PE  
 
 
Physical Exam 
PHI 
 
 
Protected Health Information 
PI  
 
 
Principal Investigator 
PID#  
 
Participant Identification Number 
PK  
 
 
Pharmacokinetic 
PM 
 
 
Poor metabolizers 
QA 
 
 
Quality Assurance 
QC  
 
 
Quality Control 
RR  
 
 
Respiratory Rate 
SAE 
 
 
Serious Adverse Event 
SID#  
 
Screening Identification Number 
SR  
 
 
Slow release 
SMC  
 
Safety Monitoring Committee 
SOP 
 
 
Standard Operating Procedure 
SRSDE 
 
Subject-Rated Strength of Drug Effect 
SSP 
 
 
Study Specific Procedure 
TDAA  
 
Take Drug Again Assessment 
TEA 
 
 
Treatment Enjoyment Assessment 
VAS  
 
Visual Analogue Scale 
UM 
 
 
Ultra-rapid metabolizer 
WBC  
 
White Blood Cell 
WHO  
 
World Health Organization 
 

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Protocol Summary (Synopsis) 
 
Protocol Number: OMNI-PAIN-103 
 
Clinical Trial Phase: Phase 1 
 
Sponsor: Syntrix Biosystems, Inc.  
 
IND Sponsor: Syntrix Biosystems, Inc. 
 
Objectives: 
 
 
The purpose of the study is to investigate in healthy human subjects desmetramadol dose-
proportionality and food effect (desmetramadol is the M1 metabolite of tramadol).  Dose proportionality 
will be assessed for 10, 20 and 30 mg single oral doses, and food effect will be assessed for the 30 mg 
single oral dose.   
 
 
 
Primary Objectives: 
 
To determine the dose proportionality of desmetramadol following oral single-dose administration 
of 10, 20 and 30 mg in fasted healthy subjects. 
 
To determine the food effect on 30 mg desmetramadol in healthy subjects following oral single-
dose administration. 
 
To determine the safety and tolerability of desmetramadol following oral single-dose 
administration in fasted and fed healthy subjects. 
 
 
 
Secondary Objectives: 
 
Determine PK parameters for each M5 enantiomer in blood following oral single-dose 
administration of 10, 20 and 30 mg desmetramadol in fasted healthy subjects and of 30 mg 
desmetramadol administered with food. 
 
Quantify total M1 and M5 excreted (unconjugated and de-conjungated) in the urine after the 30 
mg fasted dosings and compute clearance of each and in relation to 24 hr creatinine clearance. 
 
Study Population: 
 
Potential study subjects are screened and consented.  Subjects will be men and women aged 19 to 55 
years in general good health. 
 
 
Design: 
 
 
An open-label, randomized, balanced, single-dose, four-treatment, four-period, four-sequence (using a 
Williams’ square design) cross-over study with each dose separated by >3 days: 
 

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Period 
Sequence 
I 
II 
III 
IV 
1 
30 mg, food 
30 mg, fasted 
10 mg, fasted 
20 mg, fasted 
2 
10 mg, fasted 
30 mg, food 
20 mg, fasted 
30 mg, fasted 
3 
20 mg, fasted 
10 mg, fasted 
30 mg, fasted 
30 mg, food 
4 
30 mg, fasted 
20 mg, fasted 
30 mg, food 
10 mg, fasted 
 
 
To account for potential dropouts, up to 32 eligible subjects will be randomized to obtain a target 
sample of 24 subjects with PK responses at each of the four treatment periods (based on our completed 
phase 1 study in 43 subjects, dropouts are unlikely (~5%); see Section 1.2.2).  Before each oral dose, 
subjects will be fasted overnight for at least 10 hours.  Treatment sequences will include the following 
four unblinded single-dose oral treatments: 1) desmetramadol 1 x 10 mg tablet; 2) desmetramadol 2 x 10 
mg tablets; 3) desmetramadol 3 x 10 mg tablets; and 4) desmetramadol 3 x 10 mg tablets following a 
high-fat, high-calorie breakfast served approximately 30 minutes before dosing and entirely consumed 
within 20 minutes.  All subjects will fast for an additional four hours after desmetramadol administration.  
The fed treatment should be administered the desmetramadol dose approximately 30 minutes after the 
start of the meal.  Desmetramadol will be administered with approximately 240 ml of water.  No water is 
allowed one hour before and one hour after each desmetramadol administration.  
 
 
This will be an inpatient study.  Subjects will be admitted to the clinical pharmacology unit on Study 
Day -1, and administered a single oral dose treatment on Study Day 1, Study Day 4, Study Day 7 and 
Study Day 10.  After completing study procedures on Day 11 the subject will be discharged from the 
facility.    
 
 
Blood specimens for plasma preparation and PK analysis will be collected at the following times: pre-
dose (0 h), and post-dose 0.5, 1.0, 1.5, 2.0, 2.5, 3, 3.5, 4, 6, 8, 12, 16, 24, and 32 h. 
 
 
Urine will be collected as described in the Appendix A Auxiliary to determine the clearance of M1, 
M5 and creatinine and determine the fraction of the desmetramadol dose excreted as M1 and M5.   
 
 
 
Other salient aspects of the approach to evaluating the investigational agent are enumerated below: 
 
Sample Size and Randomization: 
 
 
Up to 32 subjects will be randomized to obtain a target sample of 24 subjects with PK responses at 
each of the four treatment periods.  Desmetramadol and tramadol are closely related chemicals and are 
therefore expected to have a similar intra-patient coefficient of variation and food-effect.  Published 
studies indicate a ~15% intra-subject coefficient of variation for immediate release tramadol (Najib 2009, 
ESP_Pharma_Limited 2010, Dhanure 2013), and the Ultram label indicates that “oral administration of 
Ultram with food does not significantly affect its rate or extent of absorption, therefore, Ultram can be 
administered without regard to food.” 
 
 
Dose-proportionality will be established according to the power-model Yi = α·Diβ, where Y is the 
pharmacokinetic response (e.g., AUC, Cmax), α is the coefficient, β the exponent, D the dose, and i the 
fasted dose levels to be explored (i.e.,  i = 1, 2 and 3 correspond to the 10, 20 and 30 mg doses, 
respectively).  The power-model is linearized by natural log transforming the equation to ln(Yi) = α + 
β·ln(Di). Strict dose linearity yields a slope β equal to 1.   

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Using a conservative estimate of 20% for the intra-subject coefficient of variation (CV) of 
desmetramadol, and a 5% level of significance, a sample size of 24 subjects is considered sufficient to 
provide 89.6% power (essentially 90% power) to establish dose-proportionality and absent food effect, 
assuming no multiplicity and a fed/fasting ratio of 0.95 and a 5% deviation from 1 for the slope β in dose 
proportionality.  Based on a study drop-out rate of ~30% in the Ultram label, up to 8 subjects (alternates) 
might be added to maintain a sample of 24 subjects with blood draws at each treatment period (based on 
our completed phase 1 study in 43 subjects, dropouts are unlikely to exceed 5%; see Section 1.2.2). 
 
 
Randomization of subjects will be balanced across the four treatment sequences in the 4x4 Williams’ 
design. 
 
Study Duration: 
 
 
Enrollment is estimated to take approximately 30 days.  Subjects will be on study for 11 Days.  It will 
take approximately 6 weeks to complete the study after enrollment of the first subject. 
 
Study Agent: 
 
 
Test desmetramadol tablets:  10 mg slow release tablet. 
 
Endpoints: 
 
 
The endpoints are pharmacokinetic (PK) responses for all measured blood analytes (i.e., each 
enantiomer of M1 and M5): T1/2, Tmax, Cmax, AUC0-t, AUC0-inf, and if present, Tlag).  The PK responses 
relevant to dose-proportionality and food effect are M1 AUC0-inf (AUC0-t when appropriate) and Cmax. 
 
 
The urine endpoints are CLM1, CLM5, CLCR, and the mass of M1 and M5 excreted.  Exploratory urine 
endpoints include calculating the rate constants for total elimination (kel), renal elimination (ke), and 
fraction excreted (fe) by plotting the rate of excretion (ΔU/Δt) vs. the midpoint time of each interval.  
 
 
Safety: Adverse events. 
 
Monitoring: 
 
 
Syntrix Biosystems and its representatives. 
 
Clinical Site: 
 
 
Celerion 
 
Bioanalytical Laboratory: 
 
 
Celerion 
 

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Schematic of Study Design 
Prior to  
Randomization 
 
 
 
 
 
 
 
 
 
 
Day 1- 
Day 3 
(Period I) 
 
 
 
Day 4- 
Day 6 
(Period II) 
 
 
 
Day 7- 
Day 9 
(Period III) 
 
 
 
 
Day 10- 
Day 11 
(Period IV) 
 
Obtain informed consent. Screen subjects by entry criteria. 
Admit subjects to CPU. 
On study day 1 randomize subjects to the four treatment sequences and administer a single 
dose of study drug (period 1 of treatment).  Before and after the dose PK blood and urine 
(urine only for 30 mg fasted subjects) specimens are collected.  The next dose of study drug 
is on study day 4.   
On study day 4 administer single dose of study drug (period 2 of treatment).  Before and after the dose 
PK blood and urine (urine only for 30 mg fasted subjects) specimens are collected. The next dose of 
study drug is on study day 7.  
On study day 7 administer single dose of study drug (period 3 of treatment).  Before and after the dose 
PK blood and urine (urine only for 30 mg fasted subjects) specimens are collected.  The next dose of 
study drug is on study day 10 
On study day 10 administer single dose of study drug (period 4 of treatment).  Before and after the dose 
PK blood and urine (urine only for 30 mg fasted subjects) specimens are collected.  Subjects are 
discharged from clinical pharmacology unit and study on Study Day 11.   

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1 
BACKGROUND AND SCIENTIFIC RATIONALE 
 
1.1 
Background Information 
 
1.1.1 
Tramadol and desmetramadol: Background and Pharmacology 
 
 
Tramadol is a synthetic atypical, centrally-acting opioid analgesic approved in the U.S. and elsewhere 
for treating moderate to severe pain with efficacy and potency between weak opioids and potent opioids 
such as morphine (Grond 2004).  Tramadol was developed by the German pharmaceutical company 
Grünenthal GmbH in the late 1970s under the trade name Tramal.  One of the advantages of tramadol 
over traditional opioids is its lower risk of opioid dependence (Raffa 2008).  Tramadol is a widely 
prescribed generic analgesic either alone, or together with acetaminophen, with over 25 million 
prescriptions in the U.S. in 2009 (http://drugtopics.modernmedicine.com). 
 
 
Tramadol is a racemate consisting of 1R, 2R-tramadol [(+)-tramadol], and 1S, 2S-tramadol [(−)-
tramadol].  After oral administration of the racemate, both the (−) and (+) forms of both tramadol and the 
O-desmethyltramadol metabolite (O-DMT or M1) are detected in the circulation (FIG. 1A).  
desmetramadol, the test study agent, is racemic O-desmethyltramadol, and thus provides (-) and (+) O-
DMT without requiring metabolism.   
 
(A)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(B) 
 
 
Ki (μM) 
Compound 
opioid receptor affinity 
 
uptake inhibition 
 
μ 
δ 
κ 
 
norepinephrine 
serotonin 
morphine 
0.00034 
0.092 
0.57 
 
inactive 
inactive 
(+)-tramadol 
1.3 
62.4 
54.0 
 
2.51 
0.53 
(-)-tramadol 
24.8 
213 
53.5 
 
0.43 
2.35 
(+)-O-DMT 
0.0034 
- 
- 
 
11-14.4 
2.98 
(-)-O-DMT 
0.240 
- 
- 
 
0.38-0.86 
17.7 
FIG. 1.  Structures of (A) tramadol and the active metabolite O-DMT; and (B) relative inhibition of opioid receptors and 
monoamine transporters.  Determined and estimated from (Grond 2004, Raffa 2012).  Highlighted values reflect dominant 
target of compound based on affinity. [7]. 
 
 
Each enantiomer of tramadol and O-DMT has a different dominant receptor or transporter target 
(FIG. 1B).  These targets include (+)-O-DMT enantiomer binding to the μ-opioid receptor, and (-)-
tramadol and (-)-O-DMT enantiomers binding to norepinephrine transporter (NET) (Kayser 1991, Kayser 
1992, Raffa 1992, Driessen 1993, Desmeules 1996).  The (-)-enantiomers of tramadol and O-DMT have 
substantially equivalent in vitro potency with respect to binding the NET and inhibiting NE reuptake. 
 
N
HO
OCH3
Tramadol
N
HO
OH
O-desmethyltramadol (M1)

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Two synergistic mechanisms are believed involved in tramadol and O-DMT mediated analgesia.  
First, supraspinal μ-opioid receptor agonism by (+)-O-DMT increases serotonin and NE in the dorsal horn 
of the spinal cord via descending pathways originating from the locus coeruleus and possibly other areas 
(Ide 2006).  Second, the released spinal NE is potentiated by the (-)-tramadol and (-)-O-DMT enantiomers 
blockade at the NET.  The accumulated NE exerts antinociceptive action by reducing neurotransmitter 
release from primary afferent nerves.  
 
 
In addition to the pharmacology of (+)-O-DMT, (-)-O-DMT, and (-)-tramadol, the (+)-enantiomer of 
tramadol directly inhibits serotonin reuptake (FIG. 1B) (Driessen 1992, Bamigbade 1997).  Studies 
conducted in the µ-opioid receptor knockout mouse demonstrated that serotonin reuptake inhibition is not 
involved in tramadol analgesia (Ide 2006).  Furthermore, the tramadol (+)-enantiomer inhibition of 
serotonin reuptake may trigger the serotonin syndrome, a rare potentially fatal known adverse reaction of 
tramadol.  The serotonin syndrome is observed more frequently when tramadol is taken with other 
serotonin reuptake inhibitors, e.g., antidepressants (Sansone 2009).  Thus, compared to tramadol, O-DMT 
has equivalent analgesia, but substantially less serotonin reuptake inhibition than tramadol (FIG. 1B) (Ide 
2006, Yanarates 2010).  Therefore O-DMT (desmetramadol), compared to tramadol, should offer equal 
analgesia and, through its decreased propensity to induce the serotonin syndrome, both improved safety 
and improved drug-drug compatibility.   
 
 
Tramadol has 75% oral bioavailability, with peak serum concentrations reached within 2 hours (Grond 
2004).  Tramadol elimination kinetics are two-compartmental; after a single 100 mg oral dose of 
tramadol, tramadol half-life is 5.1 hours and 9 hours for O-DMT.  The FDA approved dose of tramadol is 
50-100 mg every 4 to 6 hours, with a maximum dose of 400 mg/day; the duration of the analgesic effect 
after a single oral dose of tramadol 100 mg is about 6 hours. 
 
 
Tramadol is metabolized as follows, and desmetramadol is not expected to yield M2, but only M5: 
 
 
 
 

Protocol version 1.2 
 
 
 
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1.1.2 
Unmet Need: Absent Tramadol Efficacy in Patients with Low CYP2D6 
Activity 
 
 
Most individuals rapidly and extensively metabolize tramadol in the liver principally by the 
cytochrome P-450 (CYP) isoenzymes CYP2D6 and CYP2B6 (O-desmethylation), and CYP3A4 (N-
desmethylation).  Importantly, following tramadol administration O-DMT generation is dependent on 
CYP2D6.  Approximately 7-10% of Caucasians have two inactive CYP2D6 alleles, and no or severely 
reduced CYP2D6 activity.  These individuals are poor metabolizers (PMs) of tramadol, and following 
tramadol administration their M1 serum concentration is below the therapeutic range (50-100 ng/mL) 
after a 100 mg oral (Kirchheiner 2008) or iv dose (Enggaard 2006), being almost undetectable or below 
the limit of detection compared to extensive metabolizers (EMs) with two normal alleles, and confirming 
the dominant role of CYP2D6 in O-demethylation of tramadol in humans (FIG. 2A). 
 
 
In addition to genetic deficiency of CYP2D6, studies have shown that patients with one or two normal 
CYP2D6 may be functionally deficient as a result of concurrent use of a drug that inhibits CYP2D6.  
These patients are said to be “phenoconverted” to poor metabolizers.  Such findings are clinically 
important to the relevance of desmetramadol, because multiple medication use is common in clinical 
practice, and increases the risk of CYP2D6 phenoconversion and non-response to tramadol.  
Phenoconversion is unpredictable and is not detected by genetic testing.  In one study of a university 
hospital medication database in Finland, every fifth patient receiving tramadol was concomitantly taking 
another drug that had the potential to inhibit its activation to O-DMT (Tirkkonen 2004).  In another large-
scale study that assessed the incidence of phenoconversion to CYP2D6 poor metabolizer status in patients 
being treated for depression in clinical practice in the U.S. (Preskorn 2013), the rate of phenoconversion 
was 27%.  The incidence of CYP2D6 poor metabolizer status based on phenotype was ~7 times larger 
than that expected based on genotype.   
 
 
Consistent with O-DMT being critical to mediating tramadol analgesia, several human studies have 
shown that tramadol efficacy is significantly decreased or lacking in PM patients.  In the first study, using 
two parallel, randomized, double-blind, placebo-controlled crossover designs, the analgesic effect of 
tramadol was assessed in 27 volunteers (15 EMs and 12 PMs) using several experimental pain models 
(Poulsen 1996).  Sufficient differences were noted between the EMs and the PMs to indicate that O-DMT 
is critical for the analgesic effect of tramadol on experimental pain. 
 
 
In the second study, the effect of CYP2D6 polymorphism on tramadol analgesia was assessed in 300 
Caucasian patients undergoing major abdominal surgery (Stamer 2003).  Patients who had one or more 
functional alleles were classified as EMs.  Genotyping revealed that 35 patients were PMs.  Compared to 
the EMs, the PMs displayed a significantly higher incidence of non-response (P = 0.005) and frequently 
required rescue medication (P = 0.02). 
 

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FIG. 2  (A) Tramadol and O-DMT plasma concentrations over time in subjects with different CYP2D6 genotypes; PM vs. EM.  
All subjects received 100 mg dose of tramadol po.  (B) Non-responders to tramadol treatment allocated to genotypes. Grey 
columns: % of patients needing rescue medication in the post-anesthetic care unit (PACU); black columns: % of non-
responders after the 48-h study period. *P<0.001 for the PM group compared with the HZ/IM, EM, and UM groups.   
 
 
In the third study, the effect of CYP2D6 polymorphism (specifically CYP2D6*10, a SNP that results 
in a Pro34 to Ser substitution and reduced CYP2D6 activity) on tramadol-induced analgesia was assessed 
in 63 Chinese patients who underwent gastrectomy for gastric cancer (Wang 2006).  The patients were 
classified as EMs (N = 17), or heterozygous (N = 26) or homozygous (n = 20) for CYP2D6*10.  
Compared to the other groups, the homozygous group required more tramadol (P<0.05). 
 
 
Finally, a fourth study of patients (N=187) undergoing major abdominal surgery reported a 4-fold 
greater non-response rate to tramadol in PMs (Stamer 2007); (FIG. 2B).   
 
 
In summary, the analgesic effect of tramadol is decreased or absent in patients with low CYP2D6 
enzymatic activity (PMs) because their serum O-DMT concentration is considerably lower.   
 
1.1.3 
Significant Negative Impact on Patient Care and Safety 
 
 
Tramadol is widely prescribed, with over 25 million prescriptions in the U.S. in 2009 
(http://drugtopics.modernmedicine.com).  As such, 10-30% drug resistance in a target patient population 
due to CYP2D6 PM phenotype results in significant negative impact on patient care.  Based on an 
estimated 3:1 prescription-to-patient ratio, these data suggest that upwards of 1-2 million patients 
annually may receive inadequate analgesia from tramadol therapy.  Furthermore, the need to switch non-
responders to traditional opioids increases their risk of opioid dependence. 
 
 
Thus, there exists a need to develop an “improved tramadol” (desmetramadol (O-DMT)) that would 
be effective in all patients irrespective of their metabolic status, and safer.  desmetramadol could serve all 
patients being treated with tramadol, as well as a significant portion of patients who are being treated with 
conventional opioids that are plagued with similar issues of metabolic variability. 
 
(A) 
Plasma Tramadol 
Plasma M1 
Time (hours) 
Plasma Tramadol 
Time (hours) 
(B) 
(A) 
Plasma M1 
Plasma Tramadol 
Time (hours) 
(B) 

Protocol version 1.2 
 
 
 
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1.2 
Description of the Study Agent 
 
1.2.1 
Pilot Study of Desmetramadol in a Human Subject 
 
1.2.1.1 
Single Dose Pharmacokinetics 
 
 
Single-dose pharmacokinetics of tramadol and desmetramadol are shown in FIG. 3.  In the Hagelberg 
study, 12 healthy subjects were randomized in three segments to ingest 50 mg of tramadol after 4 days of 
pretreatment with either placebo, ticlopidine (250 mg twice daily) or ticlopidine plus itraconazole (200 
mg once daily).  Data for the M1 exposure in the placebo treated subjects is shown.  M1 exposure for a 
single 100 mg tramadol dose is from the Ultram label and the Grond review.  The pharmacokinetic 
parameters for M1 exposure from 20 mg desmetramadol approximates those for 50 mg tramadol. 
 
Drug 
 
tramadol 
tramadol 
desmetramadol (M1) 
Study 
 
(Hagelberg 2013) 
Ultram label, (Grond 2004) 
(SYN-PAIN-115 2011) 
n 
 
12 
12 
1 
population 
 
healthy adult 
healthy adult 
healthy adult 
Route 
 
oral 
oral 
oral 
Dose (mg) 
 
50 
100 
20 
Fasting 
 
Fasted then meal at 4 and 8 
hours 
“food does not significantly 
affect its rate” 
Fasted 30 min before and after 
dosing 
M1 Exposure 
 
 
 
 
 AUC (ng-h)/mL 
 
367 
722 
229 
 Cmax (ng/mL) 
 
34 
55.0 
28.8 
 Tmax 
 
2.7 
3.0 
3.6 
 Half-life (hr) 
 
6.6 
6.7 
6.0 
FIG. 3.  Single-dose PK parameters for M1 exposure in man from 50 and 100 mg tramadol and 20 mg desmetramadol. 
 
 
 

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1.2.1.2 
Steady-State Pharmacokinetics 
 
 
The approved oral dosage of tramadol is 50-100 mg q 6 hours, and the mean steady-state level of M1 
produced by this approved dosage is ~55-110 ng/mL (see Ultram label).  This is the same steady-state M1 
level produced by 20-30 mg oral desmetramadol q 6 hours (i.e., 2-3 10 mg desmetramadol tablets q 6 
hours) (FIG. 4).  Importantly however, desmetramadol achieves therapeutic M1 levels without requiring 
metabolism by CYP2D6, thus obviating the shortcomings of tramadol related to CYP2D6. 
 
(A) 
(B) 
 
 
FIG. 4.  Steady-state data for tramadol and desmetramadol in a healthy male human subject.  Black traces in (A) and (B) are 
dose 9 (48-54 hours) and 10 (54-60 hours) of tramadol q 6 hours: 25 mg (squares), 50 mg (circles), 75 mg (triangles), 100 mg 
(diamonds).  Purple traces represent dose 9 and 10 of desmetramadol (10 mg tablet) q 6 hours: 20 mg (A) and 30 mg (B). 
 
1.2.2 
Phase 1 PK and PD Study in Normal Healthy Volunteers 
 
 
In October 2014 the Sponsor completed a phase 1 trial entitled “A Phase 1 Randomized, Double-
Blind, Placebo-Controlled, Double Cross-Over Study Investigating the Safety, Oral Steady-State 
Pharmacokinetics, and Clinical Activity of 20 Mg desmetramadol and 50 Mg Tramadol in Normal Human 
Subjects”.  Briefly, 42 males in normal health, 21 to 55 years of age, were inpatients for 3 days at a 
clinical pharmacology unit and randomized to three parallel arms (N=14 each) to ingest a total of 9 
blinded doses of desmetramadol (two 10 mg tablets), tramadol (one 50 mg tablet), or placebo in a first 
treatment segment (one dose every 6 hours).  Immediately before the 9th dose, and at times (1.0, 1.5, 2.0, 
2.5 and 4.0 hours) after the 9th dose blood samples were collected to quantify plasma M1 and tramadol 
enantiomers to identify Cssmin and Cssmax.  Pain tolerance was assessed in the cold pressor test at three 
sequential time points (1.0, 2.0, and 3.0 hours) after the 9th dose and averaged to provide a single value for 
subsequent analyses.  The cold pressor test involved non-dominant hand immersion in ice-cold water (2 
°C ± 0.5°C) for up to 3 minutes, an established experimental pain measure used in previous studies of 
tramadol (Poulsen 1996, Hagelberg 2013).  Measurements included (a) time to first pain perception, (b) 
pain intensity at first pain perception, (c) pain at 30 seconds, (d) pain at 60 seconds, (e) total time 
immersed not to exceed 3 minutes.  Subjects were discharged from the clinical pharmacology unit after 
the last blood draw and washed out for 7 days (i.e., after the first and second treatment segments) before 
being readmitted. The endpoint analyses included the steady-state parameters Cssmin and Cssmax, pain 
tolerance, and safety. 
 
0
20
40
60
80
100
120
48
50
52
54
56
58
60
Plasma M1 (ng/mL)
Time (hours)
0
20
40
60
80
100
120
48
50
52
54
56
58
60
Plasma M1 (ng/mL)
Time (hours)

Protocol version 1.2 
 
 
 
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The PK equivalence of desmetramadol to tramadol was evaluated using the log-transformed Cssmin 
and Cssmax of M1 (note only two genetic CYP2D6 PMs were in the population).  Formal bioequivalence 
is claimed for a Css parameter when the 90% confidence interval of its desmetramadol-to-tramadol ratio 
falls within 0.8 and 1.25 (Rani 2007).  Pain tolerance for desmetramadol, tramadol and placebo were 
compared using a mixed effects linear model with treatment, period, and sequence as fixed effects and 
subject as a random effect nested within sequence. Period was added as a fixed effect to find any 
significant first-order crossover effects. If significant treatment effects were present, least squares means 
were compared between desmetramadol and placebo treating placebo as a control using the Dunnett’s 
procedure. 
 
 
Steady-state dosing of 20 mg desmetramadol was formally bioequivalent to 50 mg tramadol with 
respect to plasma (+)-O-desmethyltramadol (FIG. 5A).  desmetramadol was nearly formally 
bioequivalent with respect to (-)-O-desmethyltramadol: Cssmin (21+5 v. 30+6 ng/mL) and Cssmax (30+9 v. 
42+9 ng/mL). This Phase 1b trial confirmed the earlier pilot data, and showed desmetramadol indeed 
successfully “flattened” the steady-state blood levels of M1 between doses in a manner equivalent to that 
obtained with tramadol (FIG. 5B).  Twenty mg desmetramadol is therefore a therapeutic substitute for 50 
mg tramadol with respect to the steady-state delivery of M1, a finding that informed the desmetramadol 
dose selected for this phase 1 trial to examine the effect phenoconversion of CYP2D6 on desmetramadol 
and tramadol analgesia in normal subjects. 
 
 
Evaluation of total time immersed in the cold pressor test revealed a significant difference between 
desmetramadol vs. placebo (P = 0.0060) and tramadol vs. placebo (P = 0.0076) (FIG. 5C).  A significant 
difference was also found between desmetramadol and placebo for time to first pain perception (P = 
0.0057), and pain at 30 seconds (P = 0.0019).  Data was lacking for pain at 60 seconds due to hand 
withdrawal before 60 seconds.  The adverse events after desmetramadol and tramadol were similar (FIG. 
5D). 
 
 
 

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without prior written authorization from Syntrix Biosystems, Inc. 
(A) 
(C) 
 
 
Treatment 
Cssmin 
Cssmax 
Cssmean 
 
ng/mL 
ng/mL 
ng/mL 
20 mg 
desmetramadol 
(test) 
26 + 6 
36 + 10 
31 + 7 
50 mg Ultram IR 
(reference) 
28 + 7 
37 + 10 
33 + 8 
90% CI of ratio 
0.85-1.08* 
0.88-1.13* 
- 
*90% CI within 0.80-1.25; formally bioequivalent.  Mean+SD. 
 
(B) 
 
 
(D) 
 
Preferred Term 
desmetramad
ol 
(n=43) 
tramadol 
(n=41) 
placebo 
(n=41) 
Dizziness 
 5 ( 12%) 
 5 ( 12%) 
 1 (  2%) 
Headache 
 3 (  7%) 
 6 ( 15%) 
 0 (  0%) 
Nausea 
 8 ( 19%) 
 5 ( 12%) 
 3 (  7%) 
Pruritus 
 0 (  0%) 
 1 (  2%) 
 0 (  0%) 
Pruritus generalized 
 3 (  7%) 
 3 (  7%) 
 0 (  0%) 
Somnolence 
 3 (  7%) 
 2 (  5%) 
 0 (  0%) 
Urinary hesitation 
 1 (  2%) 
 2 (  5%) 
 0 (  0%) 
Vomiting 
 1 (  2%) 
 1 (  2%) 
 0 (  0%) 
 
 
 
FIG. 5.  Summary of results from Phase 1b trial.  (A) tabular and (B) graphical summary (mean+SD) of steady-state plasma 
+M1 due to 20 mg desmetramadol q6 hr and 50 mg tramadol q6 hr.  (C) Graphical summary total immersion time in cold 
pressor test as a function of treatment with placebo, tramadol and desmetramadol (horizontal bar is median). The mixed effects 
linear model was applied to the data. The Type III tests of fixed effects showed a significant treatment effect (P = 0.0036) and 
no significant sequence or period effects.  Least square means for each treatment showed that desmetramadol had the highest 
mean (62.8) with placebo having the lowest mean (50.0).  After observing a significant treatment effect, Dunnett’s procedure 
was run to find which study treatments were significantly different than the control (placebo).  Dunnett’s procedure indicated a 
significant difference between both desmetramadol vs. placebo (P = 0.0060) and tramadol vs. placebo (P = 0.0076). (D) 
Tabular summary of adverse events.   
 
1.3 
Rationale 
 
1.3.1 
Overall Study Design 
 
 
For this study, Syntrix Biosystems, through its CMO, has manufactured desmetramadol 10 mg SR 
tablets (10 mg SR O-DMT) to be the test drug.  This study will investigate in male and female subjects 
single-dose oral PK responses of desmetramadol (test drug) following administration: in a fasted state of 
10 mg (1x10 mg tablet); 20 mg (2x10 mg tablets); and 30 mg (3x10 mg tablets); and in a fed state: 30 mg 
(3x10 mg tablets).   
 
 
This protocol is designed to perform a randomized, open-label, four sequence, four period, cross-over 
study to analyze the fasted-state oral dose proportionality of desmetramadol, and the effect of food on 
desmetramadol. 
T o ta l tim e  (s e c )
P la c e b o
T r a m a d o l
O m n itr a m
0
2 0
4 0
6 0
8 0
1 0 0
1 0 0
1 5 0
2 0 0
0
20
40
60
80
100
120
0
1
2
3
4
Plasma (+)-O-Desmethyltramadol 
(ng/mL)
Time After 9th Dose (hours)
50 mg Tramadol
20 mg Omnitram

Protocol version 1.2 
 
 
 
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1.3.2 
Dosage 
 
 
The rationale for the efficacy and safety of the 10 mg, 20 mg, and 30 mg single dose desmetramadol 
SR is based on 20 mg desmetramadol providing a similar M1 Cmax as does the FDA-approved single dose 
of 50 mg tramadol, and 20 mg desmetramadol providing the same steady-state M1 exposure as does the 
FDA-approved dosing of 50 mg tramadol every 6 hours.  The extensive public database on the safety and 
adverse events associated with the use of tramadol at the approved dosing of 50-100 mg q 6 hours defines 
the safety profile of 10 mg, 20 mg, and 30 mg of desmetramadol SR. 
 
1.3.2.1 
 
Nonclinical Toxicology Data 
 
 
See the Investigator’s Brochure.  
 
1.3.2.2 
 
Clinical Data   
 
 
See the Investigator’s Brochure. 
 
1.3.3 
Study Population 
 
 
For this phase 1 study, the study population is male and female volunteers in normal health 19 to 55 
years of age.   
 
1.3.4 
Study Endpoints  
 
 
The endpoints are pharmacokinetic (PK) responses for all measured blood analytes (i.e., each 
enantiomer of M1 and M5): T1/2, Tmax, Cmax, AUC0-t, AUC0-inf, and if present, Tlag).  The PK responses 
relevant to dose-proportionality and food effect are M1 AUC0-inf (AUC0-t when appropriate) and Cmax. 
 
 
The urine endpoints are CLM1, CLM5, CLCR, and the mass of M1 and M5 excreted.  Exploratory urine 
endpoints include calculating the rate constants for total elimination (kel), renal elimination (ke), and 
fraction excreted (fe) by plotting the rate of excretion (ΔU/Δt) vs. the midpoint time of each interval. 
 
 
Safety endpoints are adverse events. 
 
1.4 
Potential Risks and Benefits 
 
 
Significant risks or benefits are not expected.  Formally, however, potential physical risks include 
side-effects commonly known to be associated with tramadol.  The side-effects from the test drug 
desmetramadol are not expected to be qualitatively or quantitatively worse than the side-effects arising 
from tramadol.  Additional risks associated with any pharmacokinetic study are also possible including 
minor bruising and hematoma at the site of vein puncture.  
 
 
The eventual availability of desmetramadol for pain will be beneficial as an alternative to tramadol as 
it will result in fewer analgesic non-responders.   
 

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2 
STUDY OBJECTIVES 
 
 
The purpose of the study is to investigate in healthy human subjects desmetramadol dose-
proportionality and food effect (desmetramadol is the M1 metabolite of tramadol).  Dose proportionality 
will be assessed for 10, 20, and 30 mg single oral doses, and food effect will be assessed for the 30 mg 
single oral dose.  The primary objectives are to: 
 
• Determine the dose proportionality of desmetramadol following oral single-dose administration of 10, 
20, and 30 mg in fasted healthy subjects.  
 
• Determine the food effect on 30 mg desmetramadol in healthy subjects following oral single-dose 
administration. 
 
• Determine the safety and tolerability of desmetramadol following oral single-dose administration in 
fasted and fed healthy subjects. 
 
• Determine PK parameters for each M5 enantiomer in blood following oral single-dose administration 
of 10, 20 and 30 mg desmetramadol in fasted healthy subjects and of 30 mg desmetramadol 
administered with food. 
 
• Quantify total M1 and M5 excreted (unconjugated and de-conjungated) in the urine after the 30 mg 
fasted dosings and compute clearance of each and in relation to 24 hr creatinine clearance. 
 
3 
STUDY DESIGN 
 
3.1 
Description of the Study Design 
 
 
An open-label, randomized, balanced, oral single-dose, four-treatment, four-period, four-sequence 
(using a Williams’ square design) cross-over study as follows:   
 
 
Period 
Sequence 
I 
II 
III 
IV 
1 
30 mg, food 
30 mg, fasted 
10 mg, fasted 
20 mg, fasted 
2 
10 mg, fasted 
30 mg, food 
20 mg, fasted 
30 mg, fasted 
3 
20 mg, fasted 
10 mg, fasted 
30 mg, fasted 
30 mg, food 
4 
30 mg, fasted 
20 mg, fasted 
30 mg, food 
10 mg, fasted 
 
 
To account for potential dropouts, up to 32 male and female subjects, 19 to 55 years of age, could be 
randomized to obtain a target sample of 24 subjects with PK responses at each of the four treatment 
periods (based on our completed phase 1 study in 43 subjects, dropouts are unlikely; see Section 1.2.2).  
Before each oral dose, subjects will be fasted overnight for at least 10 hours. Treatment sequences will 
include the following 4 unblinded single-dose oral treatments: 1) desmetramadol 1 x 10 mg tablet; 2) 
desmetramadol 2 x 10 mg tablets; 3) desmetramadol 3 x 10 mg tablets; and 4) desmetramadol 3 x 10 mg 
tablets following a high-fat, high-calorie breakfast served approximately 30 minutes before dosing and 
that is to be entirely consumed within 30 minutes.  Each dose will be separated by 3 days.  All subjects 
will fast for an additional four hours after desmetramadol administration.  The fed treatment should be 

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administered and the desmetramadol dose administered approximately 30 minutes after the start of the 
meal.  Desmetramadol will be administered with approximately 240 ml of water.  Only water is allowed 
one hour before and one hour after each desmetramadol administration.  
 
 
This will be an in-patient study.  Subjects will be admitted to the clinical pharmacology unit on Study 
Day -1, and administered a single oral dose treatment on Study Day 1, Study Day 4, Study Day 7 and 
Study Day 10.  After completing study procedures on Day 11 the subject will be discharged from the 
facility.    
 
 
Blood specimens for plasma preparation and PK analysis will be collected at the following times: pre-
dose (0 h), and post-dose 0.5, 1.0, 1.5, 2.0, 2.5, 3, 3.5, 4, 6, 8, 12, 16, 24, and 32 h. 
 
 
Urine will be collected as described in the Appendix A Auxiliary to determine the clearance of M1, 
M5 and creatinine and determine the fraction of the desmetramadol dose excreted as M1 and M5. 
 
 
Safety will be assessed while subjects are inpatients for each of the four treatment segments.   
 
 
After the study drug dosing and evaluations are completed the subjects will be discharged from the 
clinical pharmacology unit.  
 
 
Blood will be obtained for: 1) safety assessment at screening and on Day 11; and 2) for 
desmetramadol PK assessment on Days 1, 2, 4, 5, 7, 8, 10, and 11.   
 
3.2 
Study Endpoints 
 
3.2.1 
Primary Endpoint-Pharmacokinetic Responses 
 
 
The primary endpoints are pharmacokinetic (PK) responses for all measure blood analytes (i.e., each 
enantiomer of M1 and M5): T1/2, Tmax, Cmax, AUC0-t, AUC0-inf, and if present, Tlag).  The PK responses 
relevant to dose-proportionality and food effect are M1 AUC0-inf (AUC0-t when appropriate) and Cmax.   
 
The urine endpoints are CLM1, CLM5, CLCR, and the mass of M1 and M5 excreted.  Exploratory urine 
endpoints include calculating the rate constants for total elimination (kel), renal elimination (ke), and 
fraction excreted (fe) by plotting the rate of excretion (ΔU/Δt) vs. the midpoint time of each interval. 
 
The PK parameters will be determined from the desmetramadol concentrations in the blood and urine 
samples collected before and after each study drug dose. To determine dose proportionality, results will 
be compared between the three fasted treatment groups (fasted desmetramadol: 10 mg, 20 mg, and 30 
mg).  To determine food effect, results will be compared between the two 30 mg dose treatment groups 
(fasted and fed).   
 
3.2.2 
Secondary Endpoint-Safety 
 
 
Any abnormal laboratory values, abnormal vital signs, reported symptoms, or abnormal physical 
examination findings determined to be clinically significant by the Investigator/designee will be 
documented as adverse events. The safety assessments will be based on all reported adverse events, and 
changes in laboratory values from baseline.  The severity and relationship to desmetramadol treatment 

Protocol version 1.2 
 
 
 
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will be recorded for all adverse events. Adverse events will be coded for summary and analysis using 
standardized preferred terms and system organ class.   
 
3.3 
Study Site 
 
 
This trial will be conducted at a clinical pharmacology unit.  Study products will be stored at the site 
under controlled conditions. 
 
4 
STUDY POPULATION 
 
 
The study population is male and female subjects in normal health to be evaluated at the clinical 
pharmacology unit.  A subject is considered enrolled in the study once they have completed the informed 
consent, completed the screening assessments, found to be eligible, and have been randomized.  The goal 
is to enroll sufficient subjects so that 24 subjects complete the study with PK specimens collected for each 
period.  The subjects will be randomized on Day 1 to one of four sequences, with each sequence having 
four treatments (e.g., after fasting either 10 mg, 20 mg, 30 mg desmetramadol; or after a high fat meal, 30 
mg desmetramadol).  The study population is defined by all randomized subjects. 
 
   
 
Children and subjects less than 19 years of age will be excluded from this phase 1 study.  The study 
will not enroll children, pregnant women, prisoners, or other vulnerable populations.  The study is 
therefore exempt from 45 CFR 46 Subparts B, C, and D. 
 
 
The study population will include all subjects who have been randomized.  The safety population will 
include all subjects who have been randomized and have received study drug.  The pharmacokinetic 
population will be defined in the SAP. 
 
4.1 
Subject Inclusion Criteria 
 
 
During screening, subjects must meet all of the following inclusion criteria to participate in this study: 
 
1. Healthy males and females with vital signs as follows at screening: systolic blood pressure > 90 mm 
Hg and < 140 mm Hg; diastolic blood pressure > 40 mm Hg and < 90 mm Hg; pulse 40 to 99 beats 
per minute; respiratory rate 12 to 24 breathes per minute. 
 
2. Age 19 to 55 years. 
 
3. Able and willing to give informed consent 
 
4. Able to comply with all study procedures. 
 
5. If female, must not be of childbearing potential or must agree to use one or more of the following 
forms of contraception from screening, throughout the study and for 30 days following study drug 
administration: hormonal (e.g., oral, transdermal, intravaginal, implant or injection for 3 months); 
double barrier (e.g., condom or diaphragm with spermicide); intrauterine device (IUD) or system 
(IUS) (for 3 months); vasectomized partner (6 months minimum); or abstinence. 
 
Screening laboratory results must be within normal range, or judged by the PI to be not clinically 
significant: serum sodium, potassium, calcium, BUN, creatinine, ALT, AST, total bilirubin, alkaline 

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phosphatase, glucose (random), albumin, total protein, WBC and differential, hemoglobin, and 
platelets. In addition PT and PTT must be < 1.2 ULN.  Urinalysis demonstrating < +1 glucose, and +1 
protein. 
 
6. Electrocardiogram (ECG) without clinically significant abnormalities. 
 
7. If female, must have a negative pregnancy test at screening and when performed on Day -1 
(Appendix A). 
 
8. Negative urine test for substances of abuse, including opiates, per clinical pharmacology unit 
standards at screening and clinic check-in. 
 
9. Negative serology tests for HIV, hepatitis B surface antigen, and hepatitis C virus antibody. 
 
10. Weight > 50 Kg and a body mass index (BMI) of 18.0 to 32.0 kg/m (inclusive). 
 
11. Non-smoker of tobacco for a minimum of the past 3 months, and negative urine continine test. 
 
4.2 
Subject Exclusion Criteria 
 
 
During screening, subjects meeting any of the following exclusion criteria will be excluded from 
study participation: 
 
1. Oral temperature > 38°C or current illness. 
 
2. History of seizures, epilepsy, or recognized increase risk of seizure (e.g., head trauma, metabolic 
disorders, alcohol or drug withdrawal). 
 
3. History of cirrhosis or laboratory evidence of liver disease. 
 
4. Having undergone gall bladder removal. 
 
5. Use of alcohol within 24 hours of day -1 until the end of the study; and grapefruit, grapefruit-related 
citrus fruits (e.g., Seville oranges, pomelos), or grapefruit juice or grapefruit-related juices within 7 
days of study drug administration and until the end of the study. 
 
6. History of previous anaphylaxis, severe allergic reaction to tramadol, codeine, or other opioid drugs.   
 
7. Any other unstable acute or chronic disease that could interfere with the evaluation of the safety of the 
study drug as determined by the principal Investigator. If the appropriateness of a participants 
enrollment is unclear the the Sponsor’s Medical Monitor can be consulted. 
 
8. Females must not be currently pregnant or breast feeding. 
 
9. Unlikely to comply with the study protocol. 
 
10. Known or suspected alcohol or drug abuse within the past 6 months. 
 

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11. Received another investigational agent within 4 weeks of Day -1, or within five half-lives of Day -1, 
whichever is longer; or receiving any other investigational agent during this study. 
 
12. Any concurrent disease or condition that in the opinion of the investigator impairs the subject’s ability 
to complete the trial.  Psychological, familial, sociological, geographical or medical conditions which, 
in the Investigator’s opinion, could compromise compliance with the objectives and procedures of this 
protocol, or obscure interpretation of the trial data. 
 
5 
STUDY AGENT/INTERVENTIONS 
 
5.1 
Study Drug (Desmetramadol) 
 
 
Desmetramadol is an analgesic in the same class as tramadol (see FIG. 1 for chemical structures).  For 
comprehensive safety information on the study drug please refer to the Investigator’s Brochure. 
 
5.1.1 
Formulation, Packaging, and Labeling 
 
 
Syntrix will provide desmetramadol 10 mg SR tablets.  For shipment to the clinical pharmacology 
unit, desmetramadol tablets will be packaged in bulk in bottles labeled as follows: 
 
 
5.1.2 
Study Drug Storage and Stability 
 
 
Study drug will be stored at 15-30°C.  The supplies should only be accessible to person(s) authorized 
to dispense them.  As soon as the pharmacist or clinical team member receives the study drug, the clinical 
study supply shipping form must be completed and returned to Syntrix or its designate.  The clinical team 
member should retain a copy of this form for the Investigator’s file. 
 
5.1.3 
Preparation, Administration, and Dosage of Study Drug 
 
 
At the time of dosing on Day 1 the subject will be randomized to one of four treatment sequences.  
Subject treatment randomization will be performed by a pharmacist, investigator, or investigator designee 
at the clinical pharmacology unit using a treatment randomization list provided by Syntrix Biosystems or 
designee. The randomization list will: 1) assign a PID#; and 2) indicate the subject’s treatment sequence.   
 
 
The study drug will be administered orally after all protocol specified pre-dose study procedures are 
completed (see Appendix A).  Only water is allowed one hour before and one hour after each 
desmetramadol administration. The study drug will be administered at time 0 hour to each subject in a 

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sitting posture with approximately 240 mL of water at ambient temperature by trained study personnel in 
each period. Subjects will be instructed not to chew or crush the tablet(s) but to consume it/them as a 
whole. Compliance with dosing will be assessed by a thorough check of the oral cavity immediately after 
dosing. Subjects will remain seated for two hours after dosing in each period except when clinically 
indicated to change posture or in case of any natural exigency. Thereafter, the subjects will be allowed to 
engage in normal activities, including eating solid food, but while avoiding severe physical exertion.    
 
5.1.4 
Study Drug Shipping and Accountability Procedures 
 
 
Desmetramadol drug bottles will be shipped protected from moisture and insulated enabling 
appropriate temperature control with a temperature recording device.  The temperature recording device 
will be returned by the recipient to the shipper or designate for extraction of the shipment temperature 
data.  Syntrix, or its designee, will keep a record of each shipment, along with the temperature data, for 
future reference. 
 
 
All used canisters will be retained by the clinical pharmacology unit until the study monitor performs 
a complete drug accountability audit.  Following this accounting, used canisters may be discarded 
according to clinical pharmacology unit policy, or returned to Syntrix. 
 
5.2 
Assessment of Subject Compliance with Study Drug  
 
 
Assessment of compliance with administration of study drug in this trial is at the level of the 
Investigator.  All study drug will be administered to subjects as inpatients at the clinical pharmacology 
unit. 
 
5.3 
Concomitant Medications and Procedures 
 
 
Concomitant medication use will be queried from Study Day -1 through Study Day 11, and any 
reported medications will be recorded on the concomitant medications CRF.  
 
5.4 
Precautionary and Prohibited Medications and Procedures 
 
5.4.1 
Prohibited Medications and Procedures  
 
• Use of alcohol within 24 hours of day -1 until the end of the study; and grapefruit, grapefruit-related 
citrus fruits (e.g., Seville oranges, pomelos), or grapefruit juice or grapefruit-related juices within 7 
days of study drug administration and until the end of the study. 
 
• MAO Inhibitors (including linezolid), Serotonin-Reuptake Inhibitors, Serotonin-Norepinephrine 
Reuptake Inhibitors, drugs known to induces or inhibit drug metabolism, including CYP2D6, and 
other drugs that may affect the serotonergic neurotransmitter systems including, but not limited to, 
triptans, dextromethorphan, tricyclic antidepressants, bupropion, lithium, tramadol, dietary 
supplements such as tryptophan and St. John’s Wort, and antipsychotics or other dopamine 
antagonists are prohibited from 14 days before Study Day -1, or 5 half-lives, whichever is longer, until 
the end of the study (Study Day 11). 
 

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• Prescription medications (excluding contraceptive medications or hormone replacement therapy) and 
nonprescription medications, including dietary supplements and herbal remedies, are prohibited from 
14 days before Study Day -1, or 5 half-lives, whichever is longer, until the end of the study (Study 
Day 11).   
 
• At any time while on study, elective surgical procedures. 
 
6 
STUDY PROCEDURES and EVALUATIONS 
 
 
The information outlined in this Procedures and Evaluations section will be more readily followed if 
read in conjunction with the tabular listing of this information in the Schedule of Procedures and 
Evaluations in Appendix A.  All assessments, unless otherwise specified, should be performed within 
approximately 15 minutes of the indicated time. 
 
6.1 
Screening (≤ 30 days Before Day-1) and Check-In (Day -1) 
 
 
Perform informed consent and obtain signed informed consent form. 
 
 
Assign a Screening Identification number (SID #) and record it in the Screening Enrollment Log. 
 
 
Review contraception requirements with female subjects (section 4.1) 
 
 
Perform and record medical history including current medications and those taken within the past 
6 weeks, any signs and symptoms being experienced, i.e., adverse events, vital signs, collection of 
safety lab test specimens, including viral serologies, sample for serum pregnancy test (beta-HCG) 
if subject is female, urine test for substances of abuse, and ECG.  Calculate BMI.   
 
 
Determine if subject meets eligibility criteria.  Volunteers who meet all entry criteria can be 
scheduled for check-in on Day -1. 
 
 
At check-in, assess continued eligibility with respect to the inclusion criteria (including normal 
vital signs), and exclusion criteria (including oral temperature >38°C or current illness).  Obtain 
interim medical history, perform symptom driven physical examination, and obtain vital signs.  
Record concomitant medications (including alternative and complementary treatments) and 
determine if they are within the prohibited drugs (section 5.4). 
 
Review contraception requirements with female subjects (section 4.1) 
 
 
Perform urine test for: substances of abuse; and pregnancy (female subjects only). 
 
6.2 
Randomization and Study Drug Treatment Period 1 (Day 1 Through Day 3). 
 
 
Randomization: review Syntrix randomization list to obtain participant identification number 
(PID#) and treatment sequence.  Randomized subject PID# is to be used on all CRFs. 
 
 
On Day 1 determine if subject to be fasted (subject’s diet limited to clear liquids for a minimum of 
10 hours pre-dose and a minimum of 4 hours after dosing; and diet limited to water only one hour 

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pre-dose and one hour post-dose), or served a high-fat, high-calorie breakfast approximately to 30 
minutes before dosing that is to be consumed within 20 minutes. 
 
 
On Day 1 obtain study drug, provide proper diet (record if fasted or time of high-fat, high-calorie 
meal consumption), and administer the oral dose according to Section 5.1.3 and record the time of 
dosing and the absence of tablets in the oral cavity.   
 
 
Record adverse events and concomitant medications. 
 
 
Collect PK blood and urine (urine only for 30 mg fasted subjects) specimens and process to 
specimens as indicated in the validated method or PK specimen preparation procedure. 
 
 
Approximately 35 minutes before the dose obtain PK baseline level blood specimen, and at 0.5, 1.0, 
1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 8.0, 12, 16, 24, and 32 hours after the dose, obtain a blood specimen as 
close to the nominal time point for sample collection as possible but in no event not outside the window 
specified in the Appendix A Auxiliary.  Collect urine as described in the Appendix A Auxiliary.  Time 
of collection of each sample will be recorded in source documents and CRF.  The specimens will be 
stored at the method validated temperature (e.g., -20°C or -80°C) until analysis is performed.  If 
specimens require shipping for analysis, then it will be by overnight courier (split 1 and split 2 must be 
sent in separate shipments) to the Celerion designated bioanalytical laboratory on dry ice with sufficient 
dry ice to keep samples at -80°C for 48 hours.   
 
6.3 
Study Drug Treatment Period 2 (Day 4 through Day 6) 
 
 
On Day 4 determine if subject to be fasted (subject’s diet limited to clear liquids for a minimum of 
10 hours pre-dose and a minimum of 4 hours after dosing; and diet limited to water only one hour 
pre-dose and one hour post-dose), or served a high-fat, high-calorie breakfast approximately 30 
minutes before dosing that is to be consumed within 20 minutes. 
 
 
On Day 4 obtain study drug, provide proper diet (record if fasted or times of consumption), and 
administer the oral dose according to Section 5.1.3 and record the time of dosing and the absence 
of tablets in the oral cavity.   
 
 
Record adverse events and concomitant medications. 
 
 
Collect PK blood and urine (urine only for 30 mg fasted subjects) specimens and process to frozen 
plasma specimens as described in protocol section 6.2, item #5.  
 
 
Obtain vital signs. 
 
6.4 
Study Drug Treatment Period 3 (Day 7 through Day 9) 
 
 
On Day 7 determine if subject to be fasted (subject’s diet limited to clear liquids for a minimum of 
10 hours pre-dose and a minimum of 4 hours after dosing; and diet limited to water only one hour 
pre-dose and one hour post-dose), or served a high-fat, high-calorie breakfast approximately 30 
minutes before dosing and that is to be consumed within 20 minutes. 
 

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 On Day 7 obtain study drug, provide proper diet (record if fasted or times of consumption), and 
administer the oral dose according to Section 5.1.3 and record the time of dosing and the absence 
of tablets in the oral cavity.   
 
 
Record adverse events and concomitant medications. 
 
 
Collect PK blood and urine (urine only for 30 mg fasted subjects) specimens and process to frozen 
plasma specimens as described in protocol section 6.2, item #5.  
 
 
Obtain vital signs. 
 
6.5 
Study Drug Treatment Period 4 (Day 10 through Day 11) 
 
 
On Day 10 determine if subject to be fasted (subject’s diet limited to clear liquids for a minimum 
of 10 hours pre-dose and a minimum of 4 hours after dosing; and diet limited to water only one 
hour pre-dose and one hour post-dose ), or served a high-fat, high-calorie breakfast approximately 
30 minutes before dosing that is to be consumed within 20 minutes. 
 
 
 On Day 10 obtain study drug, provide proper diet (record if fasted or times of consumption), and 
administer the oral dose according to Section 5.1.3 and record the time of dosing and the absence 
of tablets in the oral cavity.   
 
 
Record adverse events and concomitant medications. 
 
 
Collect PK blood and urine (urine only for 30 mg fasted subjects) specimens and process to frozen 
plasma specimens as described in protocol section 6.2, item #5.  
 
 
Obtain vital signs.   
 
 
On Day 11, with 24.0 h PK blood collection, collect blood specimen for safety lab tests.  
 
 
Before discharge from the clinical pharmacology unit, review the contraception requirements with 
female subjects (section 4.1).   
 
6.6 
Subject Samples 
 
 
PK samples will be stored frozen for analysis.  Safety lab blood collections will be processed by the 
clinical pharmacology unit laboratory, or designated laboratory. 
 
7 
ADVERSE EVENTS 
 
7.1 
Specification of Safety Parameters 
 
 
The safety assessments will be based on clinical AEs reported by the subject or observed by the 
investigator (or appropriate designee) and laboratory abnornmalities considered to be clinically significant 
by the investigoator (or designee).  AEs will be recorded on the AE CRF.  Clinical AE relationship to 
study drug will be determined by the investigator (or appropriate designee) and recorded on the AE CRF.  
Laboratory AE relationship to study drug will be determined or recorded on the AE CRFs. 

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7.2 
Definitions 
 
7.2.1 
Adverse Event 
 
 
An AE is any untoward medical occurrence in a subject administered the study drug that does not 
necessarily have a causal relationship with this treatment.  An AE can be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease, whether or not related to the study 
drug. 
 
7.2.2 
Serious Adverse Event 
 
 
A Serious Adverse Event is defined as an AE occurring while subject is on study resulting in one of 
the following conditions: 
 
• Death, 
• Life Threatening* (defined as a subject at immediate risk of death at the time of the event), 
• Inpatient hospitalization or prolongation of existing hospitalization, 
• Congenital anomaly or birth defect, 
• A persistent or significant disability/incapacity. 
 
 
*Any other important medical event that may not result in death, be life threatening, or require 
hospitalization, may be considered a SAE when, based upon medical judgment, the event may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the outcomes listed above.  
Examples of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
7.2.3 
Unexpected Adverse Event 
 
 
An adverse event is considered “unexpected” if it is not listed in the investigator brochure or is not 
listed at the specificity or severity that has been observed. 
 
7.2.4 
Life-Threatening Event 
 
 
An adverse event is considered “life-threatening” if, in the view of either the investigator or sponsor, 
its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event 
that, had it occurred in a more severe form, might have caused death. 
 
7.3 
Assessment of Adverse Events 
 
 
Assessment of clinical AE/SAE must be by the Investigator or appropriate designee, and should 
include the intensity (severity) of the event and the relationship to study drug. 
 
7.3.1 
Severity Grading 
 
 
 
Assessment of an AE/SAE severity must be made by the Investigator, whether clinical or laboratory.  
Severity of clinical and laboratory adverse events will be assessed by the study clinician using a protocol-

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defined grading system as represented in Appendix C and Appendix D, adapted from similar toxicity 
grading tables used for healthy adult volunteers in vaccine clinical trials (CBER September 2007).     
 
7.3.2 
Definition of Relationship of Adverse Events to Study Drug 
 
 
All AEs will be recorded, and assessment of their relationship to study drug will be based on the 
clinical judgment of the study clinician according to the definitions set out below. For every AE, the study 
clinician will evaluate its relationship to the study drug administration based on the temporal relationship 
to administrations and the toxicity profile of any concomitant medication.  (NOTE: relationship is not a 
factor in determining whether an AE is or is not reported). 
 
 
Relationship of AE to study drug: 
 
• Definitely related: The event: 
 
➢ follows a reasonable temporal sequence from the time of administration; and/or 
➢ follows a known response pattern to the administration; and 
➢ could not have been produced by other factors such as the subject’s clinical state, therapeutic 
intervention, or concomitant therapy; and 
➢ either occurs immediately following administration, oIr improves on stopping administration. 
 
• Probably related: The event: 
 
➢ follows a reasonable temporal sequence from the time of administration; and/or 
➢ follows a known response pattern to the administration; and 
➢ could not have been produced by other factors such as the subject’s clinical status, therapeutic 
intervention, or concomitant therapy. 
 
• Possibly related: The event could have been produced by other factors (such as a clinical illness), but 
it either: 
 
➢ follows a reasonable temporal sequence from the time of administration; or 
➢ follows a known response pattern to the administration 
 
 
There is some evidence to suggest a causal relationship (e.g., the event occurred within a reasonable 
time after administration of the trial medication).  However, the influence of other factors may have 
contributed to the event (e.g., the subject’s clinical condition, other concomitant events). Although an 
adverse drug event may rate only as “possible” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to probable or certain as appropriate. 
 
• Not related: The event is clearly related to other factors such as the subject’s clinical state, or other 
concomitant therapy.  The alternative, definitive etiology must be documented.  
 
7.4 
Reporting Adverse Events 
 
 
All AEs, regardless of severity or presumed relationship to study drug, will be documented on the AE 
CRF.  All SAEs, Grade 3 and Grade 4 AEs, must be reported by the Principal Investigator (or designee) 

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directly to Syntrix Pharmacovigilance within 24 hours by e-mail or telephone. The reporting sequence for 
all SAEs, Grade 3 AEs, and Grade 4 AEs will be as follows: 
 
 
The Principal Investigator (or designee) must report the event immediately (within 24 hours) to 
Syntrix Pharmacovigilance. 
 
 
Syntrix Pharmacovigilance will then complete and forward an incident report by e-mail, 
containing all relevant information about the subject to the Syntrix Medical Monitor (MM) within 
48 hours of receipt of the report of the event. 
 
 
The MM must provide a written report by e-mail to Syntrix Pharmacovigilance within 2 working 
days of receipt of the initial incident report. This report must provide a recommendation as to 
whether the individual subject may continue to receive study drug (if more drug is scheduled). 
 
 
Syntrix Pharmacovigilance will forward the MM’s written report and recommendation by e-mail 
to the Principal Investigator within 2 working days of receipt. 
 
 
The Principal Investigator will meet the IRB reporting requirements. 
 
 
All SAEs, Grade 3 AEs, and Grade 4 AEs judged to be probably or definitely related to study drug 
will be reported by Syntrix to the FDA within 15 days of receipt of the report of the event. 
 
7.5 
Follow-up of Subjects with Adverse Events 
 
 
All AEs must be followed to resolution or stabilization. 
 
8 
Assessment of Risk 
 
8.1 
Criteria for Interrupting the Study Based on Dose-Limiting Toxicity  
 
8.1.1 
Rules for Discontinuing Study Drug in an Individual Subject 
 
 
The following are individual stopping rules, as determined by the principal investigator, that would 
result in a subject being withdrawn from further study drug administration.  The expected toxicity profile 
of desmetramadol, the metabolic product of tramadol, should be very similar to the tramadol toxicity 
profile, which is well described (see IB). 
 
1. Occurrence of a seizure. 
 
2. Signs or symptoms indicating serotonin syndrome, which may include mental status changes (e.g., 
agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, 
hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal 
symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can 
resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic 
instability with possible rapid fluctuation of vital signs, and mental status changes.  
 

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3. Inability to tolerate study drug (e.g., excessive nausea, repeated vomiting, excessive diarrhea, 
respiratory depression, excessive agitation or anxiety).  Respiratory depression is defined as 
respiratory rate of < 10 breathes/minute. 
 
4. Any clinical significant condition (e.g., a condition for which continued study drug administration 
may pose additional risk), including but not limited to the following: 
 
• Pregnancy 
• Any Grade 4 systemic symptom, clinical or laboratory abnormality, or AE regardless of 
relationship to study drug. 
 
5. Any change in health status during the study period that would affect eligibility status of the subject as 
defined by all of the study entry criteria.  
 
8.1.2 
Suspension of the Study 
 
 
If safety concerns arise during the study, the Sponsor may suspend, amend or terminate the study. 
Furthermore, if the study is suspended, the Sponsor may resume the study once the safety concern is 
resolved. 
 
8.1.3 
Confirmatory Testing of Significant (grade 3 and 4) Laboratory 
Abnormalities 
 
 
Any laboratory abnormality, obtained after study drug administration, of grade 3 or higher should be 
repeated before declaring the abnormality legitimate for the purpose of following the algorithms in this 
section.  Grade 1 and grade 2 abnormalities are not subject to repeat testing.  To declare the initial grade 3 
or higher laboratory abnormality legitimate, confirmatory testing must (1) be completed as soon as 
possible following the initial abnormality, and (2) exhibit at least some abnormality consistent with the 
original finding (albeit perhaps not of the same severity).  If confirmed in this fashion, the initial finding 
is declared legitimate and the finding acted upon per protocol.  If repeat testing demonstrates a laboratory 
value completely within normal range, the initial value is declared illegitimate for management purposes 
and treatment and reporting is continued per protocol as if the first finding was normal. 
 
8.2 
Subject Withdrawal from the Study 
 
 
Subjects will be free to withdraw from the study at any time and for any reason. Any subject who 
withdraws from the study, regardless of reason, will not be re-enrolled in this study. Reasons for 
withdrawal will be recorded on the appropriate CRF. The final report will include reasons for withdrawal. 
 
8.3 
Replacement of a Subject Who Withdraws from Study Treatment 
 
 
If subjects withdraw from study before study Day 11, additional subjects may be screened and 
enrolled at the discretion of the Sponsor (see Section 9.7 Sample Size Considerations).  The Syntrix Study 
Director or designee will provide instructions on replacement treatment assignments.  
 
 

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9 
STATISTICAL CONSIDERATIONS 
 
 
Descriptive statistics for continuous variables will consist of the mean, median, geometric mean 
(where appropriate), standard deviation, CV, minimum, and maximum values. For categorical variables, 
the number and percentage of each category will be displayed for each treatment group. An alpha level of 
5% will be used. All statistical tests will be two-tailed unless otherwise stated. 
 
 
Calculations and statistical analyses will be described in further detail as part of a statistical analysis 
plan (SAP). 
 
9.1 
Randomization Procedures 
 
 
All subjects who meet all entry criteria are eligible to be randomized and receive study drug 
treatments.  On Day 1 subjects are randomized.  The PID # is then conveyed to study staff for treatment 
assignment.   
 
 
A minimum of 24 subjects will be enrolled and randomized.  The randomization list will be provided 
by Syntrix Biosystems or designee.  Randomization of subjects will be balanced across the four treatment 
sequences in the 4x4 Williams’ design.  Balanced randomization requires N be evenly divisible by four. 
The treatment assignments will be made using a computer-generated random list.  The randomization list 
will be provided to the pharmacist or designee responsible for study drug diet and study drug 
disbursement.  This randomization list will match treatment assignment to PID #.  As subjects are 
assigned a PID # on Day1, the pharmacist or designee will link that number to the treatment sequence 
assigned. 
 
9.2 
Plan for Statistical Summaries and Analyses  
 
9.2.1 
General Considerations  
 
 
The safety and intent-to-treat (ITT) populations are defined as all subjects who receive at least one 
dose of study drug.  The per-protocol (PP) population  is defined as subjects who meet the 
inclusion/exclusion criteria, complete Study Day 11, receive all four doses of study drug, and have 
provided for each study drug dose, at least 13 of the 15 PK blood samples. The evaluable population are 
those subjects with calculable values for one or more of AUC0-inf  (AUC0-t when appropriate) and/or Cmax. 
 
9.2.2 
Disposition of Subjects 
 
 
The following information will be summarized: 
 
• Number of subjects randomized. 
 
• Number (%) of subjects receiving all four study drug doses. 
 
• Number (%) of subjects who discontinued the study and reasons for discontinuation. 
 
• Number (%) of subjects in the per-protocol population and reasons for those excluded. 
 

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• Number (%) of subjects with at least one protocol violation and the protocol violation. 
 
• Additional as may be defined in the SAP. 
 
 
Protocol violations will be identified by the Syntrix Medical Monitor (or designee) for the trial. 
 
9.2.3 
Demographic Characteristics 
 
 
The summaries and statistical analyses of demographic characteristics will be provided for the safety 
population as defined in the SAP. 
 
9.2.4 
Safety Endpoints 
AEs will be coded using the most current version of Medical Dictionary for Regulatory Activities 
(MedDRA®) available at Celerion and summarized by treatment for the number of subjects reporting the 
treatment emergent adverse event (TEAE) and the number of TEAEs reported. A by-subject AE data 
listing including verbatim term, coded term, treatment, severity, and relationship to treatment will be 
provided.  
Safety data including ECGs, vital signs assessments, clinical laboratory results, will be summarized by 
treatment and point of time of collection. 
Descriptive statistics using appropriate summary statistics will be calculated for quantitative safety data as 
well as for the difference to baseline, when appropriate.  
Concomitant medications will be listed by subject and coded using the most current version of the World 
Health Organization (WHO) drug dictionary available at Celerion. Medical history will be listed by 
subject. 
9.2.4.1 
Dropouts Due to AEs 
 
 
The number (%) of subjects who dropped out due to AEs will be summarized for each treatment 
group. 
 
9.2.4.2 
Laboratory Data 
 
 
Summaries of the actual value and change from baseline for all laboratory tests will be provided.  A 
tabulated summary of laboratory abnormalities by toxicity grade will also be provided. 
 
9.2.4.3 
Vital Signs 
 
 
Summaries by treatment group for all vital signs will be provided for each treatment. 
 
9.2.4.4 
Interim Safety Analyses 
 
 
There will be no interim safety analyses for this study. 
 
 
 

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9.2.4.5 
Missing Data 
 
 
Subjects with missing data will be included in the analyses.  There will be no imputation of missing 
values. 
 
9.2.5 
PK Analysis  
 
 
The specified endpoints (PK responses) will be computed from the plasma analyte levels and urine 
volume and analyte levels (urine only for 30 mg fasted subjects), and summarized for each subject by 
treatment, and for each treatment cohort.   
 
 
9.3 
Planned Interim Analysis 
 
 
There will be no interim analysis for this study. 
 
9.4 
Procedures for Deviations from Planned Statistical Analyses  
 
 
The planned statistical analyses for this study will be described in detail in a statistical analysis plan 
(SAP). Modifications or additions to the analyses of study data described herein will be described in the 
SAP. Any decisions to deviate from the planned analyses described in the protocol will be documented in 
the clinical study report and an explanation provided. 
 
9.5 
Appropriate Method and Timing for Analyzing Outcome Measures 
 
9.5.1 
Methods and Timing for the Primary End-Point 
 
 
Endpoints.  The endpoints are PK responses for all measured blood analytes (i.e., each enantiomer of 
M1 and M5): Cmax, Tmax, T1/2, AUC0-t, AUC0-inf and if present, Tlag) derived from blood specimens 
obtained before and after each single dose study drug treatment.  The urine endpoints are CLM1, CLM5, 
CLCR, and the mass of M1 and M5 excreted(urine only for 30 mg fasted subjects).  Exploratory urine 
endpoints include calculating the rate constants for total elimination (kel), renal elimination (ke), and 
fraction excreted (fe) by plotting the rate of excretion (ΔU/Δt) vs. the midpoint time of each interval  They 
will be reported for the ITT, evaluable and PP populations.  The PK responses relevant to dose-
proportionality and food effect are M1 AUC0-inf (AUC0-t when appropriate) and Cmax.  Dose-
proportionality and food-effect will be established using the evaluable population.   
 
 
Methods.  Dose-proportionality will be established according to the power-model Yi = α·Diβ (Smith 
2000), where Y is the pharmacokinetic response (e.g., AUC, Cmax), α is the coefficient, β the exponent, D 
the dose, and i the fasted dose levels to be explored (i.e.,  i = 1, 2 and 3 correspond to the 10, 20 and 30 
mg doses, respectively).  The power-model is linearized by natural log transforming the equation to: 
 
 
ln(Yi) = α + β·ln(Di) 
(Equation 1) 
 
 
Strict dose linearity yields a slope β equal to 1. 
 
 
The common acceptance range of 0.8–1.25 for dose proportionality is modified to account for the 
ratio of dose levels employed in this study as follows: [1+ln(0.8)/ln(3), 1+ln(1.25)/ln(3)], which yields an 

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acceptance range of [0.7969, 1.2031].  A mixed-effects statistical model based on Equation 1 can be used 
to account for correlation between repeated measurements in a given subject (Smith 2000).  The random 
effects, as well as the fixed effects (α and β) and their 90% CI, can be estimated with MIXED procedure 
of SAS and other statistical packages. 
 
 
If the 90% CI of β lies entirely within [0.7969, 1.2031], dose-proportionality will be said to be proven 
for the PK response. 
 
 
If at least one of the limits of the 90% CI of β lies outside [0.7969, 1.2031], dose proportionality will 
be said to not be proven for the PK response (inconclusive: e.g., higher variability and/or higher deviation 
from dose-proportionality than expected). 
 
 
If the 90% CI of β lies entirely outside [0.7969, 1.2031], dosing is disproportionate for the PK 
response. 
 
 
Absent food effect will be established if the 90 percent CI for the ratio of population geometric means 
between fed and fasted 30 mg desmetramadol doses, based on log-transformed data, is contained in the 
equivalence limits of 0.80-1.25 for AUC0-inf (AUC0-t when appropriate) and Cmax (FDA Guidance for 
Industry.  Assessing the Effects of Food on Drugs in INDs and NDAs-Clinical Pharmacology 
Considerations.  (Draft) CDER. February 2019). 
 
 
The above dose-proportionality and food effect analyses will be carried out using PK responses 
derived from the sum of (+) and (-) O-desmethyltramadol.  Exploratory dose-proportionality and food 
effect analyses may optionally be carried out for PK responses derived from individual enantiomers.  
 
9.6 
Study Hypotheses 
 
 
Desmetramadol is (1) dose-proportional for the desmetramadol doses of 10 mg, 20 mg and 30 mg, and 
(2) oral administration of desmetramadol with food does not significantly affect its rate or extent of 
absorption, and therefore, desmetramadol can be administered without regard to food. 
 
9.7 
Sample Size Considerations 
 
 
Sample Size.  A minimum of 24 subjects will be randomized.  Desmetramadol and tramadol are 
closely related chemicals and are therefore expected to have a similar intra-patient coefficient of variation 
and food-effect.  Published studies indicate a ~15% intra-subject coefficient of variation for immediate 
release tramadol (Najib 2009, ESP_Pharma_Limited 2010, Dhanure 2013), and the Ultram label indicates 
that “oral administration of Ultram with food does not significantly affect its rate or extent of absorption, 
therefore, Ultram can be administered without regard to food.” 
 
 
 
Intra-Subject CV 
 
 
Najib 2009 
(N=24) 
ESP Pharma Limited 2010 
(N=18) 
Dhanure 2013 
(N=35) 
AUC (0-t) 
12% 
12% 
5.6 
AUC (inf) 
12% 
11% 
6.3 
Cmax 
12% 
15% 
15.0 
 

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Using a conservative estimate of 20% for the intra-subject coefficient of variation (CV) of 
desmetramadol, and a 5% level of significance, a sample size of 24 subjects is considered sufficient to 
provide 89.6% power (essentially 90% power) to establish dose-proportionality and absent food effect, 
assuming no multiplicity and a fed/fasting ratio of 0.95 and a 5% deviation from 1 for the slope β in dose 
proportionality.  Based on a study drop-out rate of ~30% in the Ultram label, up to 8 additional subjects 
(alternates) might be randomized to enable a per protocol population of 24 subjects with blood draws at 
each treatment period (based on our completed phase 1 study in 43 subjects, dropouts are unlikely to 
exceed 5%; see Section 1.2.2). 
 
 
Sensitivity Analysis.  ICH E9, “It is important to investigate the sensitivity of the sample size estimate 
to a variety of deviations from these assumptions and this may be facilitated by providing a range of 
sample sizes appropriate for a reasonable range of deviations from assumptions.”  Generally power is set 
to at least 80% in BE studies, and a minimum of 12 evaluable subjects should be included in any BE 
study (FDA 2001).  However, even with a power of 80%, 1 in 5 studies will fail by mere chance alone, 
and thus higher power is preferable.  Based on the assumptions above of a 5% deviation from 1 for the 
slope β in dose proportionality and a 20% intra-subject CV, 20 subjects provide at least 80% power and 
24 subjects provide nearly 90% power (table below). 
 
 
 

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N* 
 
 
 
 
 
12 
14 
16 
18 
20 
22 
24 
26 
28 
5% β deviation 
 
 
 
 
 
 
 
 
 
 
CV 
 
 
 
 
 
 
 
 
 
 
15% 
80.0% 
 
90+% 
 
 
 
 
 
 
 
20% 
 
 
73.5% 
79.1% 
83.5% 
 
89.6% 
90+% 
 
 
25% 
 
 
 
 
 
 
 
78.0% 
80.0% 
 
 
 
 
 
 
 
 
 
 
10% β deviation 
 
 
 
 
 
 
 
 
 
 
CV 
 
 
 
 
 
 
 
 
 
 
15% 
 
 
 
 
80+% 
 
 
 
 
 
20% 
 
 
 
 
 
 
70.0% 
 
<80% 
 
25% 
 
 
 
 
 
 
 
 
<<80% 
*Note that a balanced four-sequence Williams’ design requires an N evenly divisible by 4. 
 
 
If the intra-subject CV is actually closer to the published value for tramadol of 15%, then as few as 12 
subjects provide at least 80% power and 16 subjects provide at least 90% power (see table).  On the other 
hand, if the intra-subject CV is much worse at 25%, then the planned enrollment of 24 subjects fails to 
provide the minimum threshold of 80% power.  Likewise, if the deviation from 1 in the slope β is 10% 
instead of 5%, then only a 15% intra-subject CV and 20 enrolled subjects will provide the minimum 
desired power of 80%.  Higher intra-subject CVs of 20% and 25% both fail to provide at least 80% power 
with this degree of deviation in β, even with as many as 28 subjects.  Based on this sensitivity analysis 
and the small (6-15%) actual intra-subject CV for the closely related molecule tramadol, the planned 
enrollment of 24 subjects provides a comfortable margin of power should the already conservative 
estimates of 20% intra-subject CV and 5% β deviation prove correct or even slightly larger.   
 
9.8 
Maintenance of Trial Randomization List 
 
 
Syntrix and the site pharmacist, investigator or investigator designee will maintain the randomization 
list. 
 
9.9 
Subject Enrollment and Follow-Up 
 
 
The total number of subjects who complete the PK analysis in all 4 Periods is targeted to be 24.  The 
total duration of accrual is 4 months, and duration from first patient enrolled until final subject contact is 
about 6 weeks.   
 
9.10 
Safety Review 
 
 
No formal interim statistical analyses will be performed for safety.   
 
9.11 
Final Analysis Plan 
 
 
A formal statistical analysis plan will be developed and finalized prior to data analysis. 
 
 

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10 
ADMINISTRATIVE PROCEDURES 
 
10.1 
Institutional Review Board Approval 
 
 
The protocol for this study has been designed in accordance with Good Clinical Practice and ICH E6. 
The review of this protocol by the Institutional Review Board (IRB) and the performance of all aspects of 
the study, including the methods used for obtaining informed consent, must also be in accordance with 
principles codified in Title 21 Code of Federal Regulations (CFR) Part 50 Protection of Human Subjects 
and Part 56 Institutional Review Boards. 
 
 
The Investigator will be responsible for preparing and submitting documents to the relevant IRB, and 
obtaining written IRB approval for this study.  The approval will be obtained prior to study initiation. 
 
10.2 
Informed Consent 
 
 
A study informed consent will be obtained from each subject.  The Investigator or designee will 
explain the nature of the investigation and the risks involved to each subject prior to enrollment, and will 
obtain written informed consent. The subject will also be informed that he/she is free to voluntarily 
withdraw from the study at any time. 
 
10.3 
Direct Access to Source Data/Documents, Study Monitoring, Data Collection 
 
 
The Investigator will allow representatives of Syntrix (or their designee) to periodically monitor, at 
mutually convenient times during and after the study, all CRFs and corresponding source documents for 
each subject. It is important that the Investigator or staff is available at these visits. The monitoring visits 
provide Syntrix with the opportunity to evaluate the progress of the study, to verify the accuracy and 
completeness of CRFs, to resolve any inconsistencies in the study records, as well as assuring that all 
protocol requirements, applicable regulations, and Investigator's obligations are being fulfilled. The 
Investigator must maintain all source documents, i.e., all information, original records of clinical findings, 
observations, or other activities necessary for the reconstruction and evaluation of the trial.  Examples of 
these original documents and data records include, but are not limited to clinical charts, laboratory notes, 
pharmacy dispensing records, and subject files and records kept at the pharmacy, at the laboratories, and 
other medico-technical departments involved in the clinical trial), for possible review.  The investigational 
site will provide direct access to all trial-related source documents, other documents, and reports for the 
purpose of monitoring and auditing by Syntrix and regulatory authorities.   
 
 
The Syntrix representative will record the date of each monitoring visit together with a summary of 
the status and progress of the study. Proposed actions will be confirmed with the Investigator in writing.  
Telephone contact will be made as necessary during the data collection period and during the data and 
report writing periods. 
 
 
Celerion standard CRFs will be supplied. CRFs are produced, stored electronically, and are 
available to the designated study team members. Each CRF is reviewed and signed by the PI. The final 
signed CRFs are provided to the Sponsor in the format as decided upon between Celerion and the Sponsor 
(e.g., CD, flashdrive, SFTP). This will be documented in the DMP (if applicable).  
 
  
 

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If CRF entries are modified, the initials of the associate making the change as well as the date and 
reason for the change will be captured in an electronic audit trail.  The clinical monitors will verify that 
the clinical trial is conducted and data are generated, documented (recorded), and reported in compliance 
with the protocol and the applicable regulatory requirements. 
 
Standard operating procedures are available for all activities performed at Celerion relevant to the quality 
of this study. Designated personnel of Celerion will be responsible for implementing and maintaining 
quality assurance (QA) and quality control systems to ensure that the study is conducted, and that data are 
generated, documented and reported in compliance with the study protocol, and GCP requirements as well 
as applicable regulatory requirements and local laws, rules and regulations relating to the conduct of the 
clinical study. 
All clinical data will undergo a 100% quality control check prior to clinical database lock. Edit checks are 
then performed for appropriate databases as a validation routine using SAS® or comparable statistical 
program to check for missing data, data inconsistencies, data ranges, etc. Corrections are made prior to 
database lock. 
The Clinical Study Report will be audited by the QA department and the QA audit certificate will be 
included in the study report. 
10.4 
DATA ANALYSIS 
 
Data will be handled and processed according to Celerion SOPs, which are written based on 
the principles of GCP. A brief description of the statistical analysis is included below, 
detailed methodology for all summary and statistical analyses of the data collected in this 
trial will be documented in a statistical analysis plan (SAP) prepared by Celerion and agreed 
upon by the Sponsor. The SAP may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoints and/or their analysis will also be reflected in a 
protocol amendment. If deemed appropriate, additional statistical analyses other than those 
described in this section may be performed and included in the plan. 
 
10.5 
Modification of the Protocol 
 
 
No deviations from the protocol are permitted. Syntrix may approve minor exceptions on a case-by-
case basis. If modification of the protocol is necessary, the modification must be initiated and confirmed 
in writing by Syntrix, and the Investigator will inform the IRB and not institute the modification until 
approved by the IRB. 
 
10.6 
Protocol Deviation(s) 
 
 
A protocol deviation is any noncompliance with the clinical trial protocol or Good Clinical Practice.  
Syntrix’s Medical Director should be consulted if there is uncertainty as to whether a protocol deviation 
has occurred.  The noncompliance may be either on the part of the subject, the investigator, or the study 
site staff.  As a result of deviations, corrective actions are to be developed by the site and implemented 
promptly.  Protocol deviations will be recorded by the site and included in the final study report.  It is the 
responsibility of the site to use continuous vigilance to identify and report deviations.  Protocol deviations 
must be sent to the IRB per their guidelines.   
 

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10.7 
Departure from the Protocol 
 
 
When an emergency involving an individual occurs a departure from the protocol may be required.  
This protocol departure will be limited to this individual emergency.  The Investigator, or other physicians 
in attendance, in such an emergency will, if circumstances and time permit, contact Syntrix immediately 
by telephone. The protocol deviation forms will completely describe the departure from the protocol and 
state the reasons for such departure. The IRB must be notified immediately if the departure from the 
protocol affects the safety or rights of the subject.   
 
10.8 
Suspension of the Study 
 
 
If safety concerns arise during the study, the Sponsor may suspend, amend or terminate the study.  
Furthermore, if the study is suspended, the Sponsor may resume the study once the safety concern is 
resolved. 
 
10.9 
Study Termination by the Sponsor 
 
 
Syntrix retains the right to terminate the study for any cause, suspending subject enrollment and 
removing all investigational products and related study materials from the study site at any time. Specific 
instances, which may precipitate such termination at a site, are as follows: 
 
• Deviation from protocol requirements. 
 
• Inaccurate or incomplete data recording on a recurrent basis. 
 
• Unauthorized use of investigational products. 
 
• Delinquent fulfillment of obligation on the part of the Investigator with regard to adverse 
reaction reporting, unacceptable subject enrollment, or other responsibilities as outlined in this 
protocol. 
 
10.10 
Use of Information and Publications 
 
 
Publication of the results of this study is encouraged subsequent to full data analysis.  No part of the 
results of the study, or any of the information provided by the Sponsor to the Investigator for the purposes 
of performing the study, will be published, or passed on to a third party, without prior review by the 
Sponsor.  The Investigator, or anyone else working on the study, will submit all proposed publications, 
papers, abstracts or other written materials related to the Study, or an outline of any proposed oral 
presentation with respect thereto, to the Sponsor at least one month prior to (i) submission of such written 
materials for publication, or (ii) any proposed oral disclosure to a third party. 
 
 
The Sponsor shall have the right to comment on such written material or outline; such comments shall 
be considered in good faith by the Investigator in determining the final form of disclosure.  In the event 
patentable material is identified in the data, the Sponsor may delay publication for up to six months to 
submit the appropriate patent applications.  Notwithstanding any of the above, the Investigator or anyone 
else working on the Study may not include any confidential information in any such publication or 
disclosure. 

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The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a 
trials-registration policy as a condition for publication.  This policy requires that clinical trials be 
registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the National Library 
of Medicine.  The ICMJE defines a clinical trial as any research project that prospectively assigns human 
subjects to intervention or comparison groups to study the cause-and-effect relationship between a 
medical intervention and a health outcome.  Studies designed for other purposes, such as to study 
pharmacokinetics or major toxicity (e.g., Phase 1 trials), would be exempt from this policy.  Syntrix will 
register this trial in a public trials registry.     
 
 
The Investigator is obliged to provide the Sponsor with complete test results and all data derived from 
the study.  Only the Sponsor may make information obtained during and from the study available to 
regulatory agencies, except as required by regulation. 
 
10.11 
Record Retention  
 
 
The Investigator or Investigative site must retain the clinical study until a minimum of two years 
following the last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least two years have elapsed since the formal 
discontinuation of clinical development of the study agent.  Syntrix Biosystems will notify sites when 
records can be destroyed.  In the event this information is not communicated to the sites, permission must 
be obtained from Syntrix Biosystems before records can be destroyed. 
 
10.12 
Exclusion of Minorities, and Children (Special Populations) 
 
 
Children and subjects less than 19 years of age are excluded from this phase 1 study.  Thus, the study 
will not enroll children, prisoners, or other vulnerable populations.  The study is therefore exempt from 45 
CFR 46 Subparts B, C and D.   
 
 
Minorities and underinsured persons are encouraged to participate.  Since the sponsor pays for the 
study medication, lab tests and examination costs, there are no impediments to anyone’s participation in 
the study.   
 
 
10.13 
Subject Confidentiality 
 
 
Subject confidentiality will be maintained, and neither full names nor social security numbers will be 
entered into the database.  Subject confidentiality will be strictly held in trust by the participating 
Investigators and their staff, and the Sponsor and their representatives.   
 
 
The study protocol, documentation, data and all other information generated will be held in strict 
confidence.  No information concerning the study or the data will be released to any unauthorized third 
party, without prior written approval of the Sponsor. 

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Appendix A: Schedule of Procedures/Evaluations 
1 Interim history and symptom drivenphysical examinations.  Do not include height or BMI calculation. 
2 Vital signs (blood pressure, pulse, respiratory rate, and temperature) will be obtained in the sitting position at screening, on 
clinical pharmacology unit admission day, before each study drug dose, 30-60 minutes after study drug administration, and before 
discharge. If the initial RR assessment indicates <10/min, then the RR assessment will be repeated with the rate determeined over 
60 seconds. 
3 Complete blood count includes: WBCs, platelets, RBCs, hemoglobin, hematocrit.  Differential includes % and absolute number 
of: neutrophils (all phases of development), lymphocytes (typical and atypical), monocytes, eosinophils, and basophils.  Urinalysis 
includes: appearance, and by dipstick pH, specific gravity, protein, sugar (glucose), keytones, bilirubin, leukocyte esterase or 
nitrites, blood, urobilinogen. If on the dipstick protein, leukocyte esterase or nitrites, or blood is positive, then a microscopic 
analysis of the urine will be performed. 
4 Substances to be tested inclue: amphetamines, barbituates, benzodiazepines, opiates, cocaine, cannabinoids, and ethanol. 
5 Female subjects only. At screening obtain a serum pregnancy test.  At check-in (Day -1) obtain a urine pregnancy test. 
6 See Appendix A Auxilliary that follows this page for collection details.  
7 On day 11 safety lab blood collections may be done at time of 24 hour PK blood specimen collection; other procedures should be 
done around the time of the final PK blood specimen collection prior to discharge.   
8 If a subject terminates early, then Day 11 procedures, as noted in Appendix A, should be completed before subject terminates 
from the study.   
 
 
Procedure 
Screen  
Days 
Day Of Study 
-31 
to 
-1 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 117,8 
In-CPU Stay 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Clinical 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Contraception Requirements with 
 
female subjects 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Medical History 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam include height, weight, BMI 
 
calculation. 
X 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs2 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Lab Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential3 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
BUN, creatinine, AST, ALT,  alkaline 
 
phosphatase,  total bilirubin,  albumin, total 
 
protein, sodium, potassium, chloride, 
 
bicarbonate, calcium, glucose (random),  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PT, PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B & C Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
UA3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Test for Substances of Abuse4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test5 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Samples for Pharmacokinetic Analysis6 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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Appendix A Auxiliary: Detailed Pharmacokinetic Sampling Schedule 
 
Days 1-2, 4-5, 7-8 and 10-11 (urine only for 30 mg fasted subjects). 
 
Blood collection1 
(+)-M1, (-)-M1, (+)-M5, (-)-M5 
Urine collection2 
M1 and M5 achiral, 24 hr creatinine 
Blood collection3 
Creatinine for 24 hr CLCR 
pre-dose 
collect pre-dose void (negative control) 
 
0.5 hr (+/- 5 minutes) 
 
 
1.0 hr (+/- 10 minutes) 
 
 
1.5 hr (+/- 10 minutes) 
 
 
2.0 hr (+/- 10 minutes) 
0.0 to 2.0 hour interval 
 
2.5 hr (+/- 10 minutes) 
 
 
3.0 hr (+/- 10 minutes) 
 
 
3.5 hr (+/- 10 minutes) 
 
 
4.0 hr (+/- 15 minutes) 
2.0 to 4.0 hour interval 
 
6.0 hr (+/- 15 minutes) 
4.0 to 6.0 hour interval 
 
8.0 hr (+/- 15 minutes) 
6.0 to 8.0 hour interval 
 
12.0 hr (+/- 15 minutes) 
8.0 to 12.0 hour interval 
12.0 hr (+/- 15 minutes) 
16.0 hr (+/- 15 minutes) 
12.0 to 16.0 hour interval 
 
24.0 hr (+/- 15 minutes) 
16.0 to 24.0 hour interval 
 
32.0 hr (+/- 15 minutes) 
24.0 to 36.0 hour interval 
 
 
Footnotes: 
 
1.  Collect in K2 EDTA tubes.  Centrifuge, split and freeze two duplicate 1 mL aliquots for each time point. 
2.  Record urine volume collected in each interval.  Freeze two duplicate 1 mL aliquots from each interval. 
3.  Collect blood at 12 hours (mid-point of 24 hour urine collection) in order to compute 24 hour creatinine 
clearance. 
4.  After all urine aliquots are obtained from the intervals in the first 24 hours, pool urine collected between 0.0 
and 24.0 hours and mix.  Take two duplicate 1 mL aliquots and use one to quantitate urine creatinine, and freeze 
the other one as a backup.  Creatinine clearance (CLCR) may be computed with the urine level of creatinine in 
24 hours of urine and the blood level of creatinine measured at the time midpoint (i.e., at 12 hours).1  The 
clearance mechanism of M1 and M5 is less likely to involve only glomerular filtration and no renal tubular 
secretion or absorption if CLM1 and CLM5 resemble CLCR across doses.  
 
 
 
 
 
1 One online calculator is at: 
 
http://www-users.med.cornell.edu/~spon/picu/calc/crclcalc.htm 
pool4 

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quoted without prior written authorization from Syntrix Biosystems, Inc. 
Appendix B.  Calculation of Selected Inclusion Criteria 
 
1.  Inclusion Criteria:  GFR Estimate by Cockcroft-Gault Formula 
 
 
 
 
 
 
GFR = [(140 – age) x weight] 
 
 
 
 
 
 
72 x SCR 
 
where,  
age is in years 
 
 
 
weight is in kg 
 
 
 
serum creatinine (SCR) is in mg/dL. 
 
 
 
GFR is ml/min 
                                
in females, the result is multiplied by 0.85 (Cockcroft 1976).  The Cockcroft-Gault value is not 
adjusted for body surface area (BSA), and in this protocol must be equal to or greater than 60 
ml/min.  An online Cockcroft-Gault calculator is available at: http://nephron.com/cgi-
bin/CGSI.cgi . 
 
 
2.  Inclusion Criteria:  Body Mass Index (BMI) 
 
 
 
 
 
BMI = (Weight in Pounds x 703)/(Square of Height in Inches) 
 
Examples: 
 
Weight = 188 lbs 
 
 
Weight = 258 lbs 
Height = 72 inches (6 feet) 
 
Height = 72 inches (6 feet) 
BMI = 25.5 
 
 
 
BMI = 35.0 
 
Online  BMI calculators are also available (e.g. http://www.nhlbisupport.com/bmi/bmicalc.htm ). 
 
Clinically accepted guidelines note that a BMI from 18.5-24.9 is normal; 25.0 to 29.9 is 
overweight; a BMI of greater than or equal to 30.0 is obese; and a BMI of greater than or equal 
to 35.0 is morbidly obese.   
 

Protocol version 1.2 
 
 
 
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This document is proprietary and is to be used only as authorized. No part is to be reproduced, disclosed to others, or quoted without prior written authorization from Syntrix 
Biosystems, Inc. 
 
Appendix C: Toxicity Grading Scale for Clinical Laboratory Values1 
 
1 = FDA Guidance for Industry Toxicity Grading Scale for Healthy Adults Enrolled in Preventive Vaccine Clinical Trials, 2007. ULN=upper limit of normal; LLN=lower limit of 
normal. 
Parameter 
Normal Range (Grade 0) 
Grade for Abnormal Results (Value or Change from Reference) 1 
 
Normal Values 
Mild (Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life- 
threatening (Grade 4) 
BUN (mg/dL) 
 
23-26 
27-31 
>31 
Requires dialysis 
Creatinine (mg/dL) 
 
> ULN - 1.7 
1.8 - 2.0 
2.1 - 2.5 
> 2.5 or requires dialysis 
ALT (SGPT) (U/L) 
 
> ULN - 2.5 x ULN 
> 2.6 - 5.0 x ULN 
> 5.1 - 10 x ULN 
> 10 x ULN 
AST (SGOT) (U/L) 
 
> ULN - 2.5 x ULN 
2.6 - 5.0 x ULN 
5.1 - 10 x ULN 
> 10 x ULN 
PT (prothrombin time) 
>ULN – 1.2 x ULN 
1.11 – 1.20 x ULN 
1.21 – 1.25 x ULN 
> 1.25 ULN 
PTT (partial 
tthromboplastin time) 
 
>ULN – 1.2 x ULN 
1.21 – 1.4 x ULN 
1.41 -1.5 x ULN 
> 1.5 x ULN 
WBC (K/µL or 109/L) 
 
> ULN - 15.0 
2.5 - < LLN 
> 15.0 - 20.0 
≥ 1.5 - < 2.5 
> 20.0 - 25.0 
≥ 1.0 - < 1.5 
> 25.0 
< 1.0 
Hemoglobin (g/dL) 
 
M: 12.5 - < LLN 
F: 11 - < LLN 
M: 10.5 - 12.4 
F: 9.5 - 10.9 
M: 8.5 - 10.4 
F: 8.0 - 9.4 
< 8.5 
< 8.0 
Platelet count (K/µL 
or 109/L) 
 
100 - < LLN 
50 - 99 
< 50 

Protocol version 1.2 
 
 
 
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37 
This document is proprietary and is to be used only as authorized. No part is to be reproduced, disclosed to others, or 
quoted without prior written authorization from Syntrix Biosystems, Inc. 
Appendix D: Toxicity Grading Scale for Clinical AEs¹ 
VITAL SIGNS 
 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially Life-threatening 
Fever: oral (˚C) 
(˚F) 
38.0 - 38.4 
100.4 - 101.1 
38.5 - 38.9 
101.2 - 102.1 
39.0 - 40.0 
102.2 - 104 
> 40.0 
> 104 
Tachycardia - bpm 
101 - 115 
116 - 130 
>130 
ER visit or hospitalization for 
arrhythmia 
Hypertension 
(systolic) mm Hg 
141 - 150 
151 - 155 
>155 
ER visit or hospitalization for 
malignant hypertension 
Hypertension 
(diastolic) mm Hg 
91 – 95 
96 - 100 
>100 
ER visit or hospitalization for 
malignant hypertension 
Hypotension 
(systolic) mm Hg 
85 – 89 
80 - 84 
<80 
ER visit or hospitalization for 
hypotensive shock 
SYSTEMIC (GENERAL) 
Nausea/Vomiting 
No interference with 
activity or 1 - 2 episode in 
24 hours 
Some interference with 
activity or >2 episodes in 
24 hours 
Prevents daily activity or 
requires outpatient IV 
hydration 
ER visit or hospitalization for 
hypotensive shock 
Diarrhea 
2-3 loose stools in 24 
hours 
4-5 loose stools in 24 
hours 
> 5 watery stools in 24 
hours or outpatient IV 
hydration 
Requiring significant/urgent 
medical care or hospitalization 
Headache 
No interference with 
activity 
Repeated use of 
non-narcotic pain reliever 
> 24 hours or some 
interference with activity 
Significant; use of 
narcotic pain reliever or 
prevents daily activity 
Requiring significant/urgent 
medical care or hospitalization 
Malaise/fatigue, 
muscle pain, chills, 
anorexia (loss of 
appetite), self- 
reported symptoms of 
‘fever’ (no 
temperature taken) 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents 
daily activity 
Requiring significant/urgent 
medical care or hospitalization 
Allergic reaction 
Pruritus without rash 
Localized urticaria (rash) 
Generalized urticaria; 
angioedema 
Requiring significant/urgent 
medical care or hospitalization 
Hives (urticaria) 
Urticarial lesions covering 
<10% BSA; topical 
intervention indicated 
Urticarial lesions covering 
10 -30% BSA; oral 
intervention indicated 
Urticarial lesions 
covering >30% BSA; IV 
intervention indicated 
Illness or clinical 
adverse event 
No interference with 
activity. 
Some interference with 
activity but does not 
require medical 
intervention 
Prevents daily activity 
and requires medical 
intervention 
Requiring significant/urgent 
medical care or hospitalization 
1 = FDA Guidance for Industry Toxicity Grading Scale for Healthy Adults Enrolled in Preventive Vaccine Clinical Trials, 2007. 
 
 
 

Protocol version 1.2 
 
 
 
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This document is proprietary and is to be used only as authorized. No part is to be reproduced, disclosed to others, or 
quoted without prior written authorization from Syntrix Biosystems, Inc. 
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