Conditions: Psoriasis
Keywords: Anti-folate
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 19
Healthy volunteers: no

Brief summary:
This study evaluates the treatment of psoriasis with aminopterin. Participants will be treated for 14 weeks with either aminopterin or placebo followed. The participants will not know if they are being treated with aminopterin or placebo.

Detailed description:
A Phase 2, multi-center, randomized, double-blind, placebo-controlled study enrolling subjects with moderate-to-severe psoriasis to investigate the safety and efficacy of LD-aminopterin (AMT) (3 mg (six 0.5 mg tablets). Forty-six subjects will be randomized to one of two parallel treatment arms: LD-AMT (3 mg) or placebo, in a 1:1 ratio. The endpoint analysis will include efficacy and safety. Randomized subjects will initially enter a 14-week treatment phase, followed by a 6-week post-treatment phase.

Arms:
arm 1: LD-Aminopterin tablets (0.5 mg tablet) over-encapsulated, 3.0 mg (6 tablets) once orally each week for 14 weeks (14 doses). arm 2: Placebo capsules containing microcrystalline once orally each week for 14 weeks (14 doses).

Interventions: intervention 1: LD-Aminopterin oral capsule intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: anti-folate treatment intervention 2: Microcrystalline filled capsule to mimic capsule containing aminopterin tablets

Protocol document:
Prot_SAP_000.pdf: 
Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
1 
 
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. 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL TO 
ESTABLISH THE EFFICACY AND SAFETY OF ONCE WEEKLY ORAL 
AMINOPTERIN FOR THE TREATMENT OF SUBJECTS WITH MODERATE-TO-
SEVERE PSORIASIS  
 
 
Syntrix Protocol AMT-PSO-201 
 
Protocol Version: 1.8 
01 December 2018 
 
Study Agent:  
LD-Aminopterin 0.5 mg tablets 
 
Protocol Number: 
Syntrix-AMT-PSO-201 
 
IND Number: 
71,205 
 
 
Sponsor: 
Syntrix Biosystems, Inc.  
 
Personnel: 
 
Stuart Kahn, MD (Project Director, Sponsor’s Medical Monitor) 
James McNamara, MD (NIAID Medical Monitor and Independent Safety 
Monitor) 
 
 
 
 
John Zebala, MD, PhD (Regulatory Affairs) 
 
 
 
 
Matt Johnson, MS (Biostatistician) 
 
 
 
 
Sandi Tennyson (Data Manager) 
 
 
 
 
Aaron Schuler, PhD (Formulation Scientist) 
 
 
 
 
Kristi Garrett (CMO Representative) 
 
 
 
 
 
 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
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quoted without prior written authorization from Syntrix Biosystems, Inc. 
Contact Information 
Clinical Site 
Principal Investigator 
Menter Dermatology Research 
Institute 
Baylor Medical Pavilion 
3900 Junius Street, Suite 125 
Dallas, Texas 75246 
Tel: (972) 354-7993 
Alan Menter, M.D. 
Tel: 972-354-7993 
Email: alanmresearch@gmail.com 
Dermatology Associates 
1730 Minor Avenue, Suite 1000  
Seattle, WA 98101-1498  
Tel: (206) 267-2100  
Fax: (206) 267-2101 
Peter Jenkin, MD 
Tel: (206) 267-2100 
Email: pjenkin@daseattle.com 
Additional sites to be determined. 
 
 
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 
Email: skahn@syntrixbio.com 
John Zebala 
Tel: 253-833-8009 
Aaron Schuler 
Tel: 253-833-8009 
 Kristi Garrett 
Tel: 252-317-3996 
 
NIH-NIAID 
Autoimmunity and Mucosal 
Immunity Branch 
Division of Allergy, Immunology 
and Transplantation 
NIAID, NIH 
5601 Fishers Lane, 7D31 
Rockville, MD 20852 
James McNamara, MD 
Chief, Autoimmunity and Mucosal Immunity Branch 
Division of Allergy, Immunology and Transplantation 
Tel: (240) 627-3517 
Email: jmcnamara@niaid.nih.gov 
 
 
 
Statistician 
 
DF/Net Research Inc. 
140 Lakeside Avenue, Suite 310 
Seattle, WA  98122 
 
Matt Johnson 
Tel: (206) 322-5931 
Email: matt@dfnetresearch.com  
 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
3 
 
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quoted without prior written authorization from Syntrix Biosystems, Inc. 
Principal Investigator Agreement 
 
Protocol Number: Syntrix-AMT-PSO-201 
 
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 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
4 
 
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. 
Table of Contents 
Principal Investigator Agreement ........................................................................................................ 3 
Table of Contents ................................................................................................................................. 4 
Protocol Summary (Synopsis) ............................................................................................................. 9 
1 
OBJECTIVES ............................................................................................................................. 11 
1.1 
Primary Objective ............................................................................................................... 11 
1.2 
Secondary Objectives .......................................................................................................... 11 
2 
BACKGROUND AND SCIENTIFIC RATIONALE ................................................................ 11 
2.1 
Introduction ......................................................................................................................... 11 
2.2 
Description of the Study Agent ........................................................................................... 12 
2.3 
Relevant AMT Pre-clinical Studies..................................................................................... 13 
2.3.1 
Adenosine Release In Vitro ......................................................................................... 13 
2.3.2 
Mouse Anti-Inflammatory Studies .............................................................................. 13 
2.3.3 
L-AMT and D-AMT Pharmacokinetics and Toxicity in Dogs .................................... 14 
2.3.4 
Canine PK Study .......................................................................................................... 15 
2.3.5 
Canine Atopic Dermatitis (CAD) Pilot Study ............................................................. 16 
2.3.6 
CAD Dose Ranging Trial............................................................................................. 16 
2.4 
Relevant Human AMT Clinical Studies.............................................................................. 17 
2.4.1 
Psoriasis Subjects Exposed to Lederle’s L-AMT 0.5 mg Tablet ................................. 17 
2.4.2 
Oncology Subjects Exposed to AMT in Multi-Agent Therapy (CINJALL trial) ........ 17 
2.4.3 
CNS Sparing Relative to Systemic Compartments ...................................................... 18 
2.4.4 
Oncology Subjects Exposed to AMT Monotherapy .................................................... 19 
2.4.5 
AMT Efficacy Experience in Psoriasis ........................................................................ 19 
2.4.6 
Early (1951) AMT Efficacy Experience in RA ........................................................... 19 
2.4.7 
AMT Chronic (> 1 year) Toxicity Experience in Psoriasis and Oncology ................. 20 
2.4.8 
Bioavailability .............................................................................................................. 20 
2.4.9 
Syntrix LD-AMT Tablets in PK Study in Psoriasis Subjects ...................................... 20 
2.4.10 
Syntrix LD-AMT Tablets in Phase 2 Study in RA Subjects ....................................... 21 
2.5 
Potential Risks and Benefits ................................................................................................ 21 
2.6 
Rationale.............................................................................................................................. 22 
3 
OVERVIEW OF INVESTIGATIONAL PLAN ........................................................................ 23 
3.1 
Study Design ....................................................................................................................... 23 
3.2 
Primary and Secondary Endpoints ...................................................................................... 23 
3.2.1 
Co-Primary Efficacy Endpoints ................................................................................... 23 
3.2.2 
Secondary Efficacy Endpoints ..................................................................................... 23 
3.2.3 
Primary Safety Endpoints ............................................................................................ 24 
3.2.4 
Exploratory Endpoints ................................................................................................. 24 
3.3 
Study Sites ........................................................................................................................... 24 
3.4 
Number of Subjects ............................................................................................................. 24 
3.5 
Estimated Duration/Completion of the Study ..................................................................... 24 
3.6 
Randomization .................................................................................................................... 25 
3.7 
Administration of Study Drug ............................................................................................. 26 
3.8 
Identification of Source Data Recorded Directly on the CRF ............................................ 26 
4 
STUDY POPULATION ............................................................................................................. 26 
4.1 
Inclusion Criteria ................................................................................................................. 26 
4.2 
Exclusion Criteria ................................................................................................................ 27 
4.3 
Discontinuation of Study Drug ........................................................................................... 29 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
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quoted without prior written authorization from Syntrix Biosystems, Inc. 
4.4 
Subject Withdrawal from the Study .................................................................................... 29 
4.5 
Subject Replacement ........................................................................................................... 29 
5 
STUDY PROCEDURES ............................................................................................................ 29 
5.1 
Consent and Screening Procedures ..................................................................................... 29 
5.2 
Week 0 - Day 0 (Baseline) Evaluations .............................................................................. 31 
5.3 
Week 2 - Day 14 Evaluations (±2) ...................................................................................... 32 
5.4 
Week 6 - Day 42 Evaluations (±3) ...................................................................................... 34 
5.5 
Week 10 - Day 70 Evaluations (±3) .................................................................................... 35 
5.6 
Week 14 - Day 98 Evaluations (±3) .................................................................................... 36 
5.7 
Week 17 - Day 119 Evaluations (±4) .................................................................................. 37 
5.8 
Week 20 - Day 140 Evaluations (±4) .................................................................................. 37 
5.9 
Concomitant Medications ................................................................................................... 38 
5.10 Prohibited Medications and Procedures .............................................................................. 38 
5.11 Contraception Requirements for Men and Women............................................................. 39 
5.12 Unscheduled Visits .............................................................................................................. 39 
5.13 Missed Visits ....................................................................................................................... 39 
5.14 Subject Samples .................................................................................................................. 39 
6 
Evaluations of Folate Metabolism .............................................................................................. 39 
7 
STUDY DRUG........................................................................................................................... 40 
7.1 
Study Drug Supplies and Handling ..................................................................................... 40 
7.2 
Labeling ............................................................................................................................... 40 
7.3 
Storage ................................................................................................................................. 40 
7.4 
Preparation, Administration, and Dosage of Study Drug ................................................... 40 
7.5 
Accountability of Study Agent ............................................................................................ 40 
7.5.1 
Receipt of Study Agent ................................................................................................ 40 
7.5.2 
Record of Administration and Dispensing ................................................................... 41 
7.5.3 
Unused Study Drug ...................................................................................................... 41 
8 
ADVERSE EVENTS ................................................................................................................. 41 
8.1 
Specification of Safety Parameters ..................................................................................... 41 
8.2 
Definitions ........................................................................................................................... 41 
8.2.1 
Adverse Event .............................................................................................................. 41 
8.2.2 
Serious Adverse Event ................................................................................................. 41 
8.2.3 
Unexpected Adverse Event .......................................................................................... 42 
8.3 
Assessment of Adverse Events ........................................................................................... 42 
8.3.1 
Severity Grading .......................................................................................................... 42 
8.3.2 
Relationship of Adverse Event to Study Drug ............................................................. 42 
8.4 
Diaries (Memory Aids) ....................................................................................................... 43 
8.5 
Reporting Adverse Events ................................................................................................... 43 
8.6 
Follow-up of Subjects with Adverse Events ....................................................................... 44 
8.7 
Reporting of Pregnancy ....................................................................................................... 44 
8.8 
Oversight of Data and Safety .............................................................................................. 44 
9 
ASSESSMENT OF RISK .......................................................................................................... 45 
9.1 
Modification of Study Drug for a Subject ........................................................................... 45 
9.1.1 
Hematologic Adverse Events (Leukopenia, Thrombocytopenia, Anemia) ................. 45 
9.1.2 
Hepatic Adverse Events ............................................................................................... 45 
9.1.3 
Mucositis/Stomatitis Adverse Events .......................................................................... 46 
9.2 
Criteria for Interrupting the Trial Based on Dose-Limiting Toxicity (DLT) ...................... 46 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
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quoted without prior written authorization from Syntrix Biosystems, Inc. 
9.2.1 
Rules for Discontinuing Study Drug in an Individual Subject .................................... 46 
9.2.2 
Rules for Suspension of the Entire Study .................................................................... 46 
10 
STATISTICAL CONSIDERATIONS.................................................................................... 47 
10.1 Determination of Sample Size............................................................................................. 48 
10.2 Plan for Statistical Summaries and Analyses ...................................................................... 48 
10.2.1 
General Considerations ................................................................................................ 48 
10.2.2 
Disposition of Subjects ................................................................................................ 49 
10.2.3 
Demographic Characteristics ....................................................................................... 49 
10.2.4 
Safety Endpoints .......................................................................................................... 49 
10.3 Procedure for Deviations from Planned Statistical Analyses.............................................. 50 
11 
ADMINISTRATIVE PROCEDURES ................................................................................... 51 
11.1 Institutional Review Board Approval ................................................................................. 51 
11.2 Informed Consent ................................................................................................................ 51 
11.3 Direct Access to Source Data/Documents, Study Monitoring, Data Collection ................. 51 
11.4 Modification of the Protocol ............................................................................................... 52 
11.5 Protocol Deviation(s) .......................................................................................................... 52 
11.6 Departure from the Protocol ................................................................................................ 52 
11.7 Suspension of the Study ...................................................................................................... 53 
11.8 Study Termination by the Sponsor ...................................................................................... 53 
11.9 Use of Information and Publications ................................................................................... 53 
11.10 
Record Retention ............................................................................................................. 54 
11.11 
Exclusion of Women, Minorities, and Children (Special Populations) .......................... 54 
11.12 
Subject Confidentiality .................................................................................................... 54 
Appendix A: Schedule of Study Visits and Procedures..................................................................... 55 
Appendix B.  Calculation of Selected Inclusion and Exclusion Criteria ........................................... 56 
Appendix C.  Toxicity Grading Scale for Clinical Laboratory Value  .............................................. 57 
References .......................................................................................................................................... 58 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
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quoted without prior written authorization from Syntrix Biosystems, Inc. 
 List of Abbreviations 
 
AE  
 
 
Adverse Event 
ALT 
 
 
Alanine Aminotransferase 
ANOVA 
 
Analysis of Variance 
AST 
 
 
Aspartate Aminotransferase 
API 
 
 
Active Pharmaceutical Ingredient 
BBB  
 
Blood Brain Barrier 
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 
CRF 
 
 
Case Report Form 
CRO  
 
Contract Research Organization 
CRU  
 
Clinical Research Unit 
CRP 
 
 
C-Reactive Protein 
DAS  
 
Dermatology Associates 
DHFR  
 
Dihydrofolate reductase 
DSM  
 
Data and Safety Monitoring 
DSMB  
 
Data and Safety Monitoring Board 
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 
IB  
 
 
Investigator’s Brochure 
ICF 
 
 
Informed Consent Form 
ICH 
International Conference for the Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IND 
 
 
Investigational New Drug 
IRB 
 
 
Institutional Review Board 
ISM 
 
 
Independent Safety Monitor 
ITT 
 
 
Intent-To Treat 
LOCF  
 
Last Observation Carried Forward 
LOQ  
 
Limit of Quantification 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
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quoted without prior written authorization from Syntrix Biosystems, Inc. 
MDRI  
 
Menter Dermatology Research Institute 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MM 
 
 
Medical Monitor 
MOP  
 
Manual of Procedures 
N  
 
 
Number (typically refers to subjects) 
NDA  
 
New Drug Application 
NIAID  
 
National Institute Of Allergy and Infectious Diseases 
NIH 
 
 
National Institutes of Health 
OHRP  
 
Office for Human Research Protection 
OHSR  
 
Office for Human Subjects Research 
PASI  
 
Psoriasis Area and Severity Index  
PE  
 
 
Physical Exam 
PHI 
 
 
Protected Health Information 
PI  
 
 
Principal Investigator 
PID#  
 
Participant Identification Number 
QA 
 
 
Quality Assurance 
QC  
 
 
Quality Control 
RR  
 
 
Respiratory Rate 
SAE 
 
 
Serious Adverse Event 
SID#  
 
Screening Identification Number 
SMC  
 
Safety Monitoring Committee 
SOP 
 
 
Standard Operating Procedure 
sPGA  
 
Static Physician Global Assessment 
SSP 
 
 
Study Specific Procedure 
TBD  
 
To be determined 
TS  
 
 
Thymidylate Synthase 
WBC  
 
White Blood Cell 
 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
9 
 
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quoted without prior written authorization from Syntrix Biosystems, Inc. 
Protocol Summary (Synopsis) 
 
Protocol Number: Syntrix-AMT-PSO-201  
 
Objectives: 
 
The purpose of the study is to investigate the efficacy and safety of LD-AMT in adult subjects with 
moderate-to-severe psoriasis.  LD-AMT is manufactured as a 0.5 mg tablets.  
 
 
 
Primary Objective: 
 
To determine the efficacy of LD-AMT in the treatment of subjects with moderate-to-severe 
psoriasis. 
 
Secondary Objectives: 
 
To determine the safety of LD-AMT in the treatment of subjects with moderate-to-severe psoriasis  
 
Design: 
 
A Phase 2, multi-center, randomized, double-blind, placebo-controlled study enrolling subjects with 
moderate-to-severe psoriasis to investigate the safety and efficacy of LD-AMT (3 mg (six 0.5 mg 
tablets overencapsulated in a single capsule).  Forty-six subjects are randomized to one of two 
parallel treatment arms: LD-AMT (3 mg) or placebo, in a 1:1 ratio.  The endpoint analysis will 
include efficacy and safety.  Randomized subjects will initially enter a 14-week treatment phase, 
followed by a 6-week post-treatment phase. 
 
Study Population: 
 
Male and female subjects with moderate-to-severe psoriasis 18 years of age or older. 
 
Sample Size and Randomization: 
 
A total of 46 subjects will be enrolled, 23 in the LD-AMT treatment arm, and 23 in the placebo arm.  
Subjects will be randomly assigned to receive LD-AMT or placebo. 
 
Main Inclusion Criteria: 
 
Male or female subjects aged ≥18 years having a diagnosis of moderate-to-severe psoriasis for at 
least 6 months confirmed by a dermatologist, defined here as plaque-type psoriasis affecting a body 
surface area of >10% and a PASI of >10.   
 
Study Duration: 
 
Enrollment of 46 subjects is estimated to take approximately 18 months. Subjects will be on study 
for 20 weeks. It will take approximately 24 months to complete the study after enrollment of the 
first subject. 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
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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. 
 
Endpoints: 
 
Efficacy:  
 
1. Proportion of subjects achieving Psoriasis Area and Severity Index of 75% (PASI 75) at 
study Day 98 (14 weeks). 
2. Static Physician Global Assessment (sPGA) dichotomized to success or failure at study Day 
98 (14 weeks). 
3. Proportion of subjects achieving PASI 50 at study Day 98 (14 weeks). 
4. Mean reduction in the PASI at study Day 98 (14 weeks). 
5. Proportion of subjects achieving “success” in erythema at study Day 98 (14 weeks). 
6. Proportion of subjects achieving “success” in scaling at study Day 98 (14 weeks). 
7. Proportion of subjects achieving “success” in plaque induration at study Day 98 (14 weeks). 
 
Safety: Adverse events. 
 
Exploratory: 
 
1. Mean hematologic (e.g., hemoglobin, platelets, leukocytes) and hepatic laboratory (e.g., 
SGOT, SGPT) values over the treatment-phase. 
2. Fraction of abnormal hematologic and hepatic laboratory values over the treatment-phase.  
3. Cumulative incidence of abnormal hematologic and hepatic laboratory values as a function 
of time over the 14-week treatment-phase. 
4. Mitochondrial and cytoplasmic folate metabolism correlates with AMT efficacy and 
toxicity. 
 
Monitoring: 
 
Syntrix Biosystems and its representatives. 
 
Clinical Sites: 
 
Menter Dermatology Research Institute, Dallas, Texas 
Dermatology Associates, Seattle, WA 
Additional sites to be determined. 
 
Sponsor: 
 
Syntrix Biosystems, Inc. 
 
 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
11 
 
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quoted without prior written authorization from Syntrix Biosystems, Inc. 
1 
OBJECTIVES 
 
The purpose of this study is to determine the efficacy and safety of a new drug to treat psoriasis, 
LD-AMT.   LD-AMT 3.0 mg is administered as a once weekly oral dose to adult subjects with 
moderate-to-severe psoriasis. 
 
1.1 
Primary Objective 
 
 
To evaluate the efficacy of once weekly 3.0 mg oral LD-AMT administered for 14 weeks in this 
double-blind, placebo-controlled, trial.    
 
1.2 
Secondary Objectives 
 
• To assess the safety of once weekly 3.0 mg oral LD-AMT administered for 14 weeks.   
 
• To assess the relationship of each subject’s level of expression of cytoplasmic and 
mitochondrial folate metabolism genes to the subject’s psoriasis treatment efficacy and 
safety outcomes. 
 
2 
BACKGROUND AND SCIENTIFIC RATIONALE 
 
2.1 
Introduction 
 
 
Psoriasis is a common papulosquamous skin disease that may be associated with a seronegative 
spondyloarthropathy.  Psoriasis affects 2% of the US population, and approximately 10% of these 
subjects have psoriatic arthritis.  Psoriasis has two peaks of onset, one in adolescents and young 
adults (at 16 to 22 years of age), and the other in older persons (at 57 to 60 years of age), but the 
range extends from newborn to 100 years.  Men and women are affected equally, but women may 
be affected earlier than men. 
 
 
US primary care physicians initially see 58% of the estimated 150,000 – 260,000 new cases of 
psoriasis per year, but dermatologists handle 80% of the 3 million office and hospital visits for 
psoriasis each year (Stem '96). 
 
 
Experts agree that psoriatic skin lesions are the result of inflammation in the dermis and 
epidermal hyperproliferation with abnormal differentiation.  The primary pathologic process is 
believed to arise in the immune system, specifically dysregulation of activated T-cell interactions 
with antigen-presenting cells and overproduction of proinflammatory cytokines.  Evidence for this 
theory derives from the dramatic improvement of severe psoriasis in subjects treated with 
immunosuppressive drugs used in organ transplantation, such as cyclosporine and tacrolimus. 
 
 
Although a single disease, psoriasis has several morphologic expressions and a full range of 
severity.  The form that psoriasis takes in a subject depends on a combination of genetic influences, 
environmental factors (e.g., trauma and climate), associated diseases (especially infections), and 
concomitant medications.  Certain drugs, including lithium, antimalarials, beta-adrenergic blockers, 
calcium channel blockers, angiotensin-converting enzyme inhibitors, and interferons, have been 
reported to induce psoriasis or aggravate preexisting disease in some subjects.  Emotional stress 


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01 December 2018 
 
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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. 
may also cause cutaneous nerve fibers to release peptides.  This can evoke inflammation or 
proliferation, thereby leading to a flare of psoriasis. 
 
 
Over the past 25 years, methotrexate (MTX) has become a reference standard in the treatment of 
psoriasis. When used for the treatment of psoriasis, MTX inhibits the enzymes involved in purine 
metabolism, which leads to an accumulation of extracellular adenosine, a powerful anti-
inflammatory autocoid, and the induction of T cell apoptosis (Cronstein '93; Genestier '98; Morabito 
'98; Paillot '98; Johnston '05). 
 
 
Despite the effectiveness of MTX in treating moderate-to-severe plaque psoriasis, a randomized 
observer-blinded study demonstrated that 15 mg/wk oral monotherapy for 16 weeks in 43 subjects 
(given in three divided doses with a 12 hour interval between doses) did not achieve PASI 50 in 
30% of subjects, and failed to achieve remission (i.e., > PASI 90) in 60% of subjects (Heydendael 
'03).  The limited response and large interindividual variability in anti-psoriatic effect of oral MTX 
has been attributed to marked differences in oral bioavailability between subjects, where a poor 
reduction in PASI score has been significantly correlated to poor oral bioavailability of MTX 
(Chladek '98; Chladek '02; Chladek '05).  While some of these subjects may still respond to 
subcutaneous MTX, development of alternative, more efficacious antifolates, with increased and 
less variable oral bioavailability, is urgently needed.   
 
 
Additionally, up to 30% of subjects with moderate-to-severe plaque psoriasis discontinue oral 
MTX primarily because of intolerance to the drug (Haustein '00).  Common side effects include GI 
toxicity (nausea, anorexia, stomatitis), marrow suppression and hepatotoxicity.  The latter is of 
particular concern in psoriatic subjects, who may develop life-threatening cirrhosis after chronic 
use.  Depending on the dosage of oral MTX, reports indicate that 10-47% of subjects with psoriasis 
also experience a variety of CNS effects including headache, fatigue, lethargy, disorientation, poor 
memory and agitation (Nyfors '78; Duller '85; Haustein '00; Wollina '01). 
  
 
Thus, an important goal is to develop newer antifolate agents that can increase the proportion of 
subjects that can be maintained at an orally efficacious dose level with less treatment-related 
toxicity. 
 
2.2 
Description of the Study Agent 
 
 
The study agent is the Sponsor’s scored biconvex 0.5 mg LD-aminopterin tablets.  Aminopterin 
(AMT; 4-amino-pteroylglutamic acid, aminopterin is the International Nonproprietary Name ‘INN’ 
for the sodium salt) is an antifolate in the same class as methotrexate (MTX; 4-amino-N10-methyl-
pteroylglutamic acid, also known as amethopterin, see FIG. 1).  Compared to other antifolates, 
AMT bears the closest structural similarity to folic acid, differing from the natural substrate by only 
two atoms. 
 
 
 
 
FIG. 1.  The structure of folic acid (FA), AMT, and MTX.  AMT, first synthesized in 1946 by Lederle Laboratories, 
was the first antifolate to exhibit efficacy in pediatric ALL reported in 1948 by Sydney Farber (Farber '48).  Structurally 
related antifolates, including MTX, were described by Lederle in the ensuing years from 1948 to 1955. 
Folic Acid (FA) 
Aminopterin (AMT) 
Methotrexate (MTX) 
N
HN
N
N
NH
NH
COOH
O
COOH
NH2
O
N
HN
N
N
NH
NH
COOH
O
COOH
NH2
NH2
N
HN
N
N
N
NH
COOH
O
COOH
NH2
NH2
CH3


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
13 
 
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. 
 
 
AMT was marketed by Lederle Laboratories between 1953 and 1964 as a 0.5 mg tablet for the 
indication of pediatric acute leukemia.  It was used off-label to treat over 3,500 psoriatic subjects 
over its 11 year marketed period, being preferred over MTX by dermatologists of the time (Rees 
'64).  Lederle discontinued marketing AMT for what appeared to have been manufacturing 
preferences for MTX.  During the period of their use, the relative toxicity of AMT and MTX were 
never carefully examined by modern clinical trial standards. 
 
 
Our more recent preclinical and clinical studies comparing AMT and MTX that are summarized 
in the sections that follow, indicate that AMT: (a) has improved mean oral bioavailability (>90%), 
(b) is more actively and completely taken up by cells, (c) accumulates less in the CSF, (d) spares 
erythropoiesis in the marrow, and (e) spares the liver as measured by liver transaminases. 
 
 
These features have spurred renewed interest in testing AMT in the treatment of psoriasis, as 
well as in a variety of other autoimmune conditions where MTX is used ubiquitously; for example, 
in rheumatoid arthritis, transplantation (solid organ, GVHD), polymyositis, and uveitis to name a 
few.  Thus, the results of clinical testing of AMT in psoriasis promise to have far reaching 
implications across clinical disciplines in addition to dermatology. 
 
2.3 
Relevant AMT Pre-clinical Studies 
 
2.3.1 
Adenosine Release In Vitro 
 
 
Interactions between T cells, antigen presenting cells and keratinocytes play a key role in the 
pathogenesis of psoriasis (Prinz '99; Gudjonsson '04), and a continuous recruitment of mononuclear 
leukocytes is probably required for maintaining active psoriatic lesions (Davison '01).  The 
inhibition of enzymes involved in purine metabolism by antifolates lead to the extracellular release 
of adenosine, a powerful anti-inflammatory autocoid that decreases the activation of antigen-
stimulated cells, decreases the expression of adhesion molecules, and possibly induces T cell 
apoptosis (Cronstein '93; Genestier '98; Morabito '98; Paillot '98; Johnston '05). 
 
 
Cronstein et al. reported that MTX induced adenosine release from fibroblasts in culture with an 
EC50 of 1 nM (Cronstein '91).  Similarly, L-AMT caused a dose-dependent release of adenosine in 
cultured ma104 cells with an EC50 of 0.5 nM (data not shown).  These data argue that the anti-
inflammatory mechanism of both AMT and MTX is adenosine release. 
 
2.3.2 
Mouse Anti-Inflammatory Studies 
 
 
L-AMT has been shown to be active in the murine air-pouch model of inflammation, and using 
this model we have quantified the dose-response relationship of L-AMT and L-MTX (Alcaraz '06).  
The activities of L-AMT and L-MTX were assessed by giving mice (5 CDI Swiss males per dose 
cohort) four weekly intraperitoneal injections of vehicle, or varying doses of L-AMT or L-MTX 
over the course of a month.  L-AMT and L-MTX diminished, in a dose-dependent fashion, the 
number of leukocytes (predominantly neutrophils) that accumulated in the carrageenan-treated air 
pouches with EC50 values of 0.0009 mg/kg/wk and 0.04 mg/kg/wk, respectively (p < 0.001) 
(Alcaraz '06).  Thus, using a once-weekly dosing regimen that mimics the clinical L-MTX regimen 


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quoted without prior written authorization from Syntrix Biosystems, Inc. 
employed in RA and psoriasis, L-AMT is a 43-fold more potent anti-inflammatory agent than L-
MTX.    
 
 
The dose of L-MTX required to achieve a 50% to 100% response in the air pouch model is 
similar to the dose required clinically for the treatment of RA or psoriasis (the equivalent of 7-25 
mg/week in a 70-kg individual), arguing that the model is a valid indicator of antifolate potency in 
humans.  Based on the dose-response in mice, we predict that the appropriate clinical dose range of 
L-AMT for treating humans with inflammatory disorders will range from 0.1-2.0 mg/week in a 70-
kg individual, which is encompassed by the doses used in this RA study (3.0 mg LD-AMT which 
contains 1.5 mg L-AMT), and is several-fold below the known human maximally tolerated weekly 
dose where mucositis becomes dose-limiting (i.e., ~3-7 mg/week L-AMT).  The weekly AMT 
dosing interval to be used in this study is by the MTX regimen employed in RA and psoriasis.  
Early human experience with the Lederle tablet further supports these conclusions, where relapse of 
psoriatic lesions after discontinuation of L-AMT was usually seen after 2 weeks (range 2-8 weeks); 
(Rees '55; Rees '59). 
 
 
The greater potency of AMT over MTX is mainly due to a greater efficiency of cell uptake of L-
AMT from plasma (Sirotnak '75; Fry '82; Fry '83).  Surprisingly, under these same dosage 
conditions, the brains of L-AMT-treated animals contained significantly less L-AMT than the brains 
of L-MTX-treated animals (P ≤ 0.0003), consistent with transport of antifolate across the blood-
brain barrier (BBB) being a concentration dependent phenomenon in mice (Cole '06).  These 
findings in mice paralleled our findings in humans, where weekly doses of 4.0 mg/m2 L-AMT and 
100 mg/m2 L-MTX produced equivalent levels of each drug in erythrocytes, but significantly less 
AMT in the CSF of human subjects (p < 0.0001, two-tailed t-test) (Cole '06).  This difference in the 
distribution of L-AMT and L-MTX into brain parenchyma and CSF is the basis for the clinical 
hypothesis that AMT may decrease the frequency or severity of antifolate-related neurotoxicity by 
sparing the brain, while providing equivalent systemic anti-inflammatory efficacy as MTX. 
 
2.3.3 
L-AMT and D-AMT Pharmacokinetics and Toxicity in Dogs 
 
 
The oral pharmacokinetics and toxicity of L-AMT and D-AMT were evaluated in 40 beagle 
dogs in escalating doses (Menter '12).  The L-enantiomer dose range was 0.02 to 2.4 mg/kg, and the 
D-enantiomer dose range was 0.8 to 82.5 mg/kg.  Doses of the L-enantiomer ranged from a dose 
having optimal anti-inflammatory activity at the low end of the range (data from canine model of 
inflammation), to the minimum lethal single dose at the upper end of the range (Thiersch '49; 
Rieselbach '63).  Doses of the D-enantiomer were at least 10-fold larger than the L-enantiomer 
doses to allow for possible poor intestinal absorption of the D-enantiomer.  The Cmax of L-AMT was 
11- and 6-fold larger than the Cmax of D-AMT at doses of 0.8 and 2.5 mg/kg, respectively (p < 
0.001).  The AUC(0-4 h) of L-AMT was 12- and 6-fold larger than the AUC(0-4 h) of D-AMT at doses 
of 0.8 and 2.5 mg/kg, respectively (p < 0.001).  There was no dose-dependent trend in Tmax for 
either L-AMT or D-AMT, and no significant difference between the Tmax values for L-AMT and D-
AMT.   
 
 
Maximum plasma concentration and observed area under the curve were dose-proportional over 
the L-AMT dose range of 0.02 to 0.2 mg/kg and the entire tested D-AMT dose range of 0.8 to 82.5 
mg/kg.  The same pharmacokinetic parameters responded non-linearly to L-AMT doses above 0.2 
mg/kg.  As reflected by the 6- to 12-fold larger maximum plasma concentration and observed area 


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quoted without prior written authorization from Syntrix Biosystems, Inc. 
under the curve of L-AMT compared to D-AMT at identical doses, the exposure is stereoselective 
for the L-enantiomer.  Non-linearity in pharmacokinetic parameters as a function of L-AMT dose, 
and stereoselectivity for L-AMT over D-AMT together indicate a transporter-mediated component 
in absorption. 
 
 
The toxicity of L-AMT and D-AMT was evaluated in each of the above 40 beagle dogs as 
function of dose through detailed daily clinical and physical observations, and terminal necropsy 
that included gross and histopathologic examinations (Menter '12).  An additional vehicle group of 
4 beagle dogs served as a negative control.  Beginning three days after the oral administration of L-
AMT, dogs in the 0.8 and 2.5 mg/kg dose groups exhibited severe lethargy, anorexia, vomiting, 
weight loss, and diarrhea (including bloody) characteristic of acute antifolate intoxication, with one 
dog found dead and another found moribund and euthanized.  Dogs in the 0.2 mg/kg L-AMT dose 
group exhibited diarrhea five days after dosing.  Dogs in the remaining 0.02 and 0.08 mg/kg L-
AMT dose groups exhibited no signs of clinical antifolate toxicity.  At necropsy, dogs in the 2.5 
mg/kg L-AMT dose group were found to have multiple red and pigmented lesions throughout the 
small and large intestines that consisted of epithelial necrosis and neutrophilic inflammation on 
histologic examination.  Other histopathologic changes in the 2.5 mg/kg L-AMT dose group 
consisted of mild to moderate bone marrow hypocellularity. Dogs in the remaining L-AMT dose 
groups (lower doses) had no significant gross lesions or histopathologic findings at necropsy.  
Although the largest D-AMT dose (82.5 mg/kg) was 100-fold greater than the minimum lethal L-
AMT dose (0.8 mg/kg) and yielded a 7-fold greater exposure in the plasma, none of the D-AMT 
dose groups exhibited any signs of clinical toxicity and there were no significant gross lesions or 
histopathologic changes at necropsy (Menter '12). 
 
 
In summary oral absorption was stereoselective for the L-enantiomer and D-AMT was not toxic 
at the maximum dose tested (82.5 mg/kg), which was 100-fold larger than the minimum lethal L-
AMT dose (0.8 mg/kg) (Menter '12).   
 
2.3.4 
Canine PK Study 
 
 
For treatment of inflammatory diseases the Sponsor had prepared a 0.25 mg tablet 
(investigational batch 157I0907) that contained racemic LD-AMT.  For oncology treatment and use 
in previous oncology studies, the Sponsor prepared a 1 mg tablet (investigational batch 116I0604) 
that contains > 99% L-AMT.  Therefore, the Sponsor performed a study in Beagle dogs to compare 
the toxicology and toxicokinetics of these two AMT formulations (Menter '12).  The study design 
was a randomized, single dose, two-period cross-over study to compare 0.25 mg LD-AMT tablet 
with a 1.0 mg reference AMT tablet (L-isomer).  Ten dogs were randomized to two parallel arms (5 
per arm) to ingest a 1.0 mg single dose of either the 0.25 mg tablets (4 x 0.25 mg tablets) or the 
reference 1.0 mg tablet (1 x 1.0 mg tablet), and blood specimens were obtained from each dog over 
12 hours.  Seven days later dogs of both arms were crossed-over and received a single oral 1.0 mg 
dose of the other formulation and again blood specimens were obtained over 12 hours.  The 
endpoint analysis included safety, and measurement of the L and D isomers in plasma by chiral 
LC/MS. 
 
 
There were no significant AEs, including an absence of gastrointestinal AEs which are the 
earliest symptom of antifolate intoxication.  The concentration profiles of L-AMT in the plasma 
samples following ingestion of the two test formulations (L-AMT formulation and LD-AMT 


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formulation) were indistinguishable.  Importantly, following ingestion of the LD-AMT formulation, 
no D-AMT was detected in any plasma sample.  Therefore, following ingestion of the LD-AMT 
formulation, D-AMT was not absorbed.  Combined, these findings demonstrate that LD-AMT is 
toxicologically and toxicokinetically indistinguishable from L-AMT, and that the oral 
administration of the LD-AMT does not result in detectable systemic exposure to D-AMT (Menter 
'12). 
 
2.3.5 
Canine Atopic Dermatitis (CAD) Pilot Study 
 
 
CAD is a chronic, progressive allergic skin disease that results in a profound impairment of 
quality of life due to persistent itching, spontaneous and self-induced skin lesions, secondary skin 
infections, and loss of sleep.  It is associated with IgE antibodies to environmental allergens (Olivry 
'01). 
 
 
In an initial 4-week open-label pilot trial, followed by an optional 1-year extension, AMT 
treatment of CAD was safe and effective (Olivry '07).  The Sponsor’s 1 mg L-AMT tablet 
(investigational batch 116I0604) was used to treat adult mongrel outpatient dogs with CAD at North 
Carolina State University.  Subjects were given L-AMT orally at 0.010 mg/kg/week for weeks 1-4 
(except for one subject who was given 0.015 mg/kg/week at week 4 because of lack of efficacy); 
and escalated as needed to 0.015 or 0.020 mg/kg/wk during the 1-year extension. 
 
 
All 8 dogs that completed the initial 4-week efficacy phase entered the extension phase.  Four 
(50%) completed 16 weeks or more of AMT therapy (mean 19.6 weeks, range 8-40 weeks).  Seven 
subjects were evaluable for efficacy during the extension phase.  The overall efficacy in CAD was 
impressive.  At week 20 for example, all dogs exhibited a greater than 50% reduction in their 
disease assessments, and 66% had greater than a 90% reduction in their disease assessments.  No 
adverse events were observed in any subjects treated for up to 40 weeks with doses up to 0.02 
mg/kg/week, a dose equivalent to 1.5 mg/week L-AMT in a 70-kg human. 
 
 
Together these data indicate that the potency of L-AMT anti-inflammatory activity is similar 
across these species (mice, rats, dogs and humans).  It is therefore reasonable to predict that 0.25-
2.0 mg/week L-AMT in a 70-kg individual will be the appropriate clinical dose range for treating 
human inflammatory disorders.  This is a dose range that is used in this psoriasis study and whose 
safety is supported by both animal and human studies. 
 
2.3.6 
CAD Dose Ranging Trial 
 
 
Following the successful CAD pilot study, Syntrix sponsored (with support from NIH, National 
Institute of Arthritis and Musculoskeletal Diseases) a multi-center double-blinded, placebo-
controlled, dose-ranging study randomizing 75 dogs to 5 parallel arms (15 subjects per arm).  All 5 
arms receive twice weekly oral dosing (one of the two weekly doses in 3 of the 5 arms is a dummy 
placebo dose).  Thus, three arms receive once weekly LD-AMT at 0.01 mg/kg, 0.02 mg/kg or 0.03 
mg/kg, and once weekly placebo.  One arm receives twice weekly LD-AMT at 0.01 mg/kg, and one 
arm receives twice weekly placebo.  Primary outcome efficacy was assessed at study Day 84 (end 
of 12 weeks).  The Sponsor’s 0.25 mg LD-AMT tablet (investigational batch 157I0907) was used.  
 


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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. 
 
Measures of toxicity were physical examination, and CBC and blood chemistry tests at Days 14, 
35, 56 and 84.  Seventy-five subjects completed the study; no safety concerns occurred.  Efficacy 
was demonstrated in the 0.02 mg/kg/week dose arm (published in Zebala JA, Mundell A, Messinger 
L, Griffin CE, Schuler AD, Kahn SJ.  LD-aminopterin in the canine homologue of human atopic 
dermatitis: a randomized, controlled trial reveals dosing factors affecting optimal therapy.  PLoS 
One. 2014 Sep 25;9(9):e108303).   
 
2.4 
Relevant Human AMT Clinical Studies 
 
2.4.1 
Psoriasis Subjects Exposed to Lederle’s L-AMT 0.5 mg Tablet 
 
 
In the 1950s Lederle produced a 0.5 mg L-AMT tablet.  Safety data were available on 579 
human subjects with psoriasis treated with this Lederle tablet.  The extent of L-AMT exposure was 
under 1 year in 472 subjects (81.5%), 1-5 years in 87 subjects (15.0%), and 10 years in 20 subjects 
(3.5%).  An additional 3,738 psoriasis subjects were exposed to AMT monotherapy with the 
Lederle L-AMT tablet for periods not specified in the primary literature reports, indicating a total of 
4,317 psoriasis subjects were exposed to at least one course of Lederle’s L-AMT tablet. 
 
2.4.2 
Oncology Subjects Exposed to AMT in Multi-Agent Therapy 
(CINJALL trial) 
 
 
Between March 2001 and September 2005, 58 children or young adults with acute 
lymphoblastic leukemia (ALL) enrolled in CINJALL: A Phase IIB Trial Of AMT In Multiagent 
Therapy For Children With Newly Diagnosed Acute Lymphoblastic Leukemia at High Risk of 
Relapse.  The CINJALL trial used the Sponsor’s 1 mg L-AMT tablet (investigational batch 
116I0604).  The extent of exposure was a median of 98 weeks (range 12 to 140 weeks, N=32 
subjects) or 2,800 subject-weeks. 
 
 
The CINJALL trial employed adult-equivalent doses of AMT (3.6-7.2 mg per week) and MTX 
(77-180 mg per week).  Once-weekly MTX doses in RA and psoriasis range from 7.5-30 mg (15-20 
mg usually), but may extend in some select subjects to 50 mg per week.  The upper MTX range 
employed in RA and psoriasis subjects thus approaches the lowest MTX dose employed in 
CINJALL.   
 
 
 
AMT was found to be 20- to 25-fold more potent than MTX in CINJALL based on a variety of 
toxicity measures.  Using this potency ratio, the equipotent anti-inflammatory dose range for AMT 
can be extrapolated from the known anti-inflammatory MTX dose range.  This extrapolation results 
in a predicted once-weekly range of 0.3-1.5 mg for L-AMT, and 2.0 mg occasionally. 
 
 
As CINJALL AMT and MTX doses were up to 6-fold greater than one would typically use for 
anti-inflammatory indications, the rate and severity of toxicities related to AMT and MTX were 
accelerated, and this study afforded the opportunity to compare AMT and MTX toxicity over 2-
years of subject exposure and demonstrated the potential advantages of AMT over MTX when used 
at lower anti-inflammatory doses. 
 
2.4.2.1 
Hematologic Sparing 
 


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Treatment for over 50 weeks with L-AMT 2 mg/m2 (3.6 mg/week in an average adult) caused 
equal suppression of granulopoiesis to L-MTX 40 mg/m2 (72 mg/week in an average adult), but 
resulted in significantly less suppression of erythropoiesis as measured by mean hemoglobin levels 
(p <0.001).   
 
 
Contemporary experience with MTX in psoriasis provides a useful benchmark for comparison 
with AMT.  In 2001, Wollina et al. reported the chronic toxicities of MTX in 81 subjects with 
psoriasis and psoriatic arthritis treated with 6.5-40 mg MTX once per week for about 100 weeks 
(Wollina '01).  There were 32 anemic events, the CTC grades were as follows: 4 were grade 1, 24 
were grade 2 (most common), 3 were grade 3, and 1 was grade 4.  AMT therefore offers the 
potential to make an important clinical improvement in the incidence or severity of anemia AEs. 
 
2.4.2.2 
Hepatic Sparing 
 
 
The potential for MTX to cause hepatotoxicity and cirrhosis in psoriasis (Roenigk '98) and RA 
(Kremer '94) subjects has been recognized for decades, and has been extensively discussed and 
studied in the literature.  Both dermatologists and rheumatologists monitor for liver toxicity by 
performing regular liver blood tests (ALT and AST).  The presumed mechanistic model of MTX-
mediated liver injury and corresponding changes in liver blood tests is through intermittent episodes 
of hepatocellular necrosis, which in turn result in intermittent rises in serum AST above the normal 
range.  The greater the frequency of the necrosis, the greater probability that liver fibrosis, and 
uncommonly cirrhosis, will occur.  In a study by Kremer et al. of 354 baseline and annual 
sequential liver biopsies in 94 RA subjects administered oral L-MTX 15 mg per week, it was shown 
that the mean AST and the frequency of abnormal AST values significantly increased in subjects as 
a function of the Roenigk grade, consistent with the mechanistic model (Kremer '96).  The 
maximum magnitude of abnormal AST values did not correlate with histologic grade. The 
difference in the frequency of abnormal AST elevations between Roenigk Grade I and IIIA was 
8.7% vs. 18.6%, respectively. 
 
 
In CINJALL, oral L-AMT 3.6 mg/week in an average adult and L-MTX 72 mg/week in an 
average adult both resulted in elevations of AST:  this happened in 24.4% of the AMT arm, and 
56.6% of the MTX arm (p = 0.0001, Fisher’s exact test).  The AMT arm also had a significantly 
lower mean value for all AST measurements over the same period (p = 0.0001).  AMT thus appears 
to exhibit clinically relevant sparing of the liver compared to MTX, both in terms of the frequency 
and the mean value of AST elevations. 
 
2.4.3 
CNS Sparing Relative to Systemic Compartments 
 
 
Neurotoxicity arising during weekly administration of MTX in RA and other autoimmune 
diseases manifests as headache, fatigue, somnolence, vertigo and uncomfortable dissociative-type 
experiences (i.e., the “post-dosing reaction”).  This neurotoxicity is presumed to be mediated by 
binding of MTX within the CNS to high-affinity intracellular targets such as DHFR.  Penetration of 
AMT and MTX across the blood-brain barrier is thought to be concentration dependent.  Indeed, of 
41 psoriatic subjects treated with MTX, the 9 subjects who experienced headache on the day of 
MTX administration had plasma MTX Cmax of 0.76 ± 0.28 µM, whereas those subjects without 
headache had plasma MTX Cmax of 0.24 ± 0.15 µM (Chladek '05). 
 
 


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During CINJALL CSF was collected for analysis of antifolate concentrations.  These date 
demonstrated that CSF MTX concentrations (mean ± SE =  26.3 ± 5.0 nM; n = 45) were 
significantly greater than CSF AMT concentrations (3.56 ± 0.83 nM; n = 64; P<0.0001, two-tailed 
t-test) (Cole '06).  These data indicate that the penetration of the blood-brain barrier by AMT and 
MTX are concentration dependent.  Because AMT is 20- to 25-fold more potent than MTX in the 
periphery, lower plasma concentrations of AMT result in lower CSF concentrations, and thus lower 
CNS intracellular AMT.  As a result of these differences in CNS intracellular concentrations of 
AMT and MTX, AMT may cause less neurotoxicity when used in autoimmune indications (Cole 
'06). 
 
2.4.4 
Oncology Subjects Exposed to AMT Monotherapy 
 
 
AMT monotherapy (Lederle’s L-AMT) exposure was reported in 218 subjects.  The exposure 
periods reported were 0-12 weeks in 178 subjects (81.73%), 13-28 weeks in 24 subjects (11.0%), 
29-44 weeks in 13 subjects (5.9%), 45-60 weeks in 1 subject (0.45%) and 61-76 weeks in 2 subjects 
(0.92%).  An additional 277 oncology subjects were exposed to L-AMT monotherapy (using 
Lederle’s L-AMT) for periods not specified in the primary literature reports, providing for a total of 
495 oncology subjects exposed to L-AMT monotherapy. 
 
2.4.5 
AMT Efficacy Experience in Psoriasis 
 
 
Two studies with the Lederle L-AMT tablet compared L-AMT and L-MTX (active control) 
using each drug in an equivalent dosing regimen (Rees '61; Strakosch '63).  The Rees et al. study 
used a crossover design (n=37 in AMT and MTX arms), and the Strakosch study used a parallel 
dose group design (N=84 AMT, N=36 MTX).  Both studies found that 3.0-6.0 mg/wk L-AMT 
produced significantly (P < 0.001 both studies, Fisher’s, two-tailed) more successes than L-MTX at 
a 5-fold greater dose.  Analyses of these studies revealed the important observation that increasing 
dose intensity in L-AMT monotherapy beyond about 1.5 mg/wk (given in 3 divided doses over 3 
days) was associated with an increased incidence of AEs, but no increase in therapeutic successes. 
 
2.4.6 
Early (1951) AMT Efficacy Experience in RA 
 
 
As was the case in cancer, the first reported use of an antifolate to treat RA employed L-AMT, 
not L-MTX (Ward '85).  In 1951, Gubner et al. described the use of L-AMT to treat RA in six 
patients (Gubner '51).  They noted a rapid improvement in arthritis in 5 patients, with exacerbation 
1-6 weeks after stopping treatment.  Patients were given 1-2 mg of L-AMT daily, and stomatitis 
developed in 5 of the patients within 1 to 2 weeks.  Other adverse effects were nausea, diarrhea, and 
alopecia. 
 
 
 
It is now appreciated that the dose employed by Gubner et al. was 2- to 4-fold above the MTD 
for L-AMT, and at least 7- to 14-fold above the dose predicted to be efficacious in a patient with 
RA.  This study provides evidence that L-AMT is active in RA.  To facilitate comparing the the 
efficacy of L-AMT and L-MTX, we retrospectively evaluated the degree of Gubner’s reported 
improvement using modern ACR criteria.  We found significant improvements in tender joints, 
swollen joints, and physician’s global score of a magnitude similar to those reported for L-MTX 
(Hoffmeister '72; Wilke '80; Wilkens '80; Hoffmeister '83; Thompson '84; Weinblatt '85; Kremer 
'86; Weinblatt '88; Weinblatt '90; Choi '00; Sokka '02; Ruperto '08).  Gubner et al. is the only report 


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in the literature of the use of L-AMT to treat RA, and represents a historical landmark often cited in 
reviews describing the development of L-MTX for RA.  A review by Ward notes that the 
observation by Gubner et al. went unnoticed for 20 years for a variety of reasons until it was 
rediscovered in 1972 when the first clinical use of L-MTX in RA patients was reported (Ward '85).  
As L-AMT manufacturing by Lederle was discontinued in 1965, L-MTX became the inevitable 
antifolate of choice for a variety of diseases including RA. 
 
2.4.7 
AMT Chronic (> 1 year) Toxicity Experience in Psoriasis and 
Oncology 
 
 
The most common AEs associated with chronic AMT therapy include mucositis, bone marrow 
suppression (usually manifesting as leukopenia and thrombocytopenia), nausea, and abdominal 
discomfort.  These can arise at any time during therapy.  The incidence and severity of AEs 
generally exhibits a dose-response relationship.  However, the schedule of administration can also 
influence toxicity, with divided weekly regimens, compared to once weekly regimens, increasing 
toxicity, presumably due to prolongation of DHFR suppression in normal tissues.  There is no 
evidence that the incidence of toxicity is related to the duration of treatment, cumulative dose or 
efficacy outcomes. 
 
 
In all pooled data from clinical trials in psoriasis (N=427) employing 3-6 mg/week L-AMT 
given in divided daily doses, leukopenia (defined as WBC <3500/mm3) was seen in 4 subjects, but 
this was never greater than grade 2.  No leukopenia was seen in 21 patients treated chronically with 
1.5 mg/wk L-AMT in a divided dose regimen.  In this protocol all doses are being given as a single 
weekly dose (i.e., less intense than divided doses), and therefore no grade 3 or 4 hematologic 
toxicities are anticipated.  It is possible that grade 1 or grade 2 hematologic toxicities may occur 
uncommonly to rarely at the dose of 1.5 mg/wk L-AMT (3.0 mg LD-AMT). 
 
2.4.8 
Bioavailability 
 
 
In psoriasis poor responses to MTX have been correlated to poor oral bioavailability (Chladek 
'98; Chladek '02; Chladek '05).  Furthermore, the oral bioavailability of L-MTX in adults has been 
reported to be limited by intestinal absorption at doses above about 15 mg (Bannwarth '96).  Thus, 
MTX non-responders cannot simply increase the MTX dose.  In contrast to MTX, AMT oral 
absorption does not appear to be limited.  If bioavailability is a limiting variable for oral MTX 
efficacy, then oral AMT may offer a greater response rate than oral MTX. 
 
2.4.9 
Syntrix LD-AMT Tablets in PK Study in Psoriasis Subjects 
 
 
Syntrix sponsored a PK study in human subjects with psoriasis (ClinicalTrials.gov Identifier: 
NCT00937027) (Menter '12).  The study was performed at the Dermatology Research Clinic of the 
Baylor Research Institute (Dallas, Texas, USA) and used Syntrix’s 0.25 mg tablet (composed of 
LD-AMT; investigational batch 157I0907) and 1.0 mg tablet (composed of L-AMT; investigational 
batch 116I0604).  The objective of the study was to compare the toxicology and toxicokinetics of 
these two AMT formulations.  The study design was a randomized, single oral dose, two-period 
cross-over study to compare 0.25 mg AMT tablet (LD-AMT) with a 1.0 mg reference AMT tablet 
(L-isomer).  Twenty-two subjects were randomized to two parallel arms (11 per arm) ) to ingest a 
1.0 mg single dose of either the new LD-AMT 0.25 mg tablets (4 x 0.25 mg tablets) or the reference 


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quoted without prior written authorization from Syntrix Biosystems, Inc. 
tablet L-AMT (1 x 1.0 mg tablet), and blood specimens were collected from each subject for 12 
hours.  Seven days later subjects of both arms crossed-over and received a single oral 1.0 mg dose 
of the other formulation and again blood specimens were collected over 12 hours.  The endpoint 
analysis included safety and the AUC, Cmax and Tmax of L-AMT based on adverse events and L-
AMT concentration in the blood following administration of either formulation.   In addition, PK 
bioequivalence of the LD-AMT and L-AMT was analyzed.  
 
 
The PK results demonstrated that the LD-AMT and L-AMT formulations were bioequivalent.  
Furthermore, absorption of LD-AMT was stereoselective for the L-isomer.  The safety evaluation 
demonstrated that all AEs were grade 1 or grade 2.  All adverse events related to the test study drug 
were expected.  The study conclusions are that the LD-AMT was bioequivalent to the L-AMT.  
Absorption of aminopterin enantiomers was stereoselective for the L-isomer.  The safety database 
for L-AMT tablets can be extrapolated to LD-AMT tablets (Menter '12). 
 
2.4.10 
Syntrix LD-AMT Tablets in Phase 2 Study in RA Subjects  
 
 
The Sponsor completed a phase 2 trial (ClinicalTrials.gov Identifier: NCT01724931) that 
enrolled 175 MTX-naïve subjects with RA into a 12-week double-blind placebo-controlled LD-
AMT dose ranging study.  Subjects with active RA (≥ 6 tender and ≥ 6 swollen joints (28 joint 
count)) were randomized to one of three treatments: placebo, LD-AMT (1 mg), or LD-AMT (3 mg) 
in a 1:1:1 ratio.  The primary efficacy endpoints were ACR20 and HAQ at Study Day 84 evaluated 
for each cohort in a sequential gate-keeping/step-down approach.  Secondary endpoints included 
ACR20 (at Study Day 28), ACR50, ACR70, ACR-N, DAS28, DAS28 <3.2, DAS28 <2.6.  Safety 
endpoints were all AEs, SAEs and treatment-emergent AEs (TEAEs), including laboratory 
measurements of serum chemistry and hematology, and the occurrence of dose limiting toxicity 
(i.e., interruption of dosing due to AEs as defined in protocol Section 8.7).   PK analysis was 
performed on 90 of the enrolled subjects.   
 
 
The 3.0 mg L/D-aminopterin significantly reduced disease activity by 12 weeks as measured by 
ACR20 (P=0.021), ACR-N (P=0.030) and DAS28 (P=0.009).  The 1.0 mg dose did not reach 
significance.  Blinded placebo-controlled safety data were obtained and confirm the safety of 
investigating 3 mg L/D-aminopterin according to this protocol (see IB).  
 
2.5 
Potential Risks and Benefits 
 
 
Potential risks at the dose of LD-AMT to be used include those side-effects commonly known to 
be associated with antifolate use, such as stomatitis, hepatotoxicity, marrow toxicity, and more 
rarely pulmonary toxicity.  The side-effects from LD-AMT are qualitatively equivalent to the side-
effects arising from oral L-MTX therapy, which is the standard-of-care, that enrolled subjects might 
be offered. 
 
 
The value of the information to be gained outweighs the potential risks involved.  The ultimate 
availability of LD-AMT to subjects with psoriasis will be beneficial, as an alternative to L-MTX, 
with fewer anticipated toxicities.  LD-AMT will also provide a low cost oral medication compared 
to the more expensive anti-cytokine therapies (e.g., etanercept, infliximab, adalimumab). 
 


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The subjects enrolled in the study can also expect greater LD-AMT bioavailability and thus a 
greater proportion of subjects experiencing clinical improvement.  In addition, subjects enrolled in 
the study may also benefit from more careful monitoring of their disease status than what is 
provided under standard-of-care.  Subjects enrolled may also benefit from greater fewer treatment 
emergent toxicities than might occur with MTX. 
 
2.6 
Rationale 
 
 
Lederle marketed L-AMT tablets from 1953 to 1964, and L-MTX tablets from 1955 to the late 
1990s.  The major published studies conducted to evaluate the efficacy of AMT in psoriasis were 
open-label.  These studies showed a significantly greater number of treatment successes with AMT 
than MTX and showed that approximately 55-65% of a population will reach success after AMT 
treatment.  This protocol is designed to conduct a placebo-controlled double-blinded trial to 
determine if LD-AMT is efficacious and safe in the treatment of subjects with moderate-to-severe 
psoriasis who are naïve to prior MTX treatment.  
 
 
The 14 week duration was selected as subjects treated with MTX reach maximum improvement 
in PASI score by 14 weeks (Heydendael '03).  Similarly, the time to onset of psoriasis lesion 
“clearing” or “almost clearing” in early pilot trials with AMT support 14 weeks as sufficient to 
observe the majority of the maximum efficacy.  Hence a 14-week treatment duration was chosen.  
Thus 14 weeks will allow responders to declare themselves, and non-responders to be treated within 
the ethical limits established in previous trials for placebo treatment.    
 
 
The weekly dose of LD-AMT for this study is 3.0 mg (1.5 mg of L-AMT).  The selection of this 
dose for efficacy purposes is based on preclinical studies, human studies, and the known relative 
potencies of AMT and MTX.  AMT is an antimetabolite that is associated with a variety of dose-
dependent toxicities qualitatively similar to those seen with MTX.  In 1998 our phase I oncology 
trial determined the MTD, the dose at which the mildest symptoms first appear, of AMT to be 0.13 
mg/kg/week (with no folic acid supplementation) (Ratliff '98).  For a 45 kg subject the MTD of an 
L-AMT single weekly dose is 5.85 mg.  Hence 3.0 mg LD-AMT (1.5 mg/wk L-AMT), the 
maximum dose in this study, is for all subjects approximately 4-fold below the MTD.  Mucositis 
and stomatitis were the dose-limiting toxicity and the earliest and most sensitive indicator of 
toxicity.  Other common toxic manifestations, at or just beyond the MTD, included GI disturbances, 
abdominal cramps, diarrhea, hemorrhage, leukopenia, skin changes and alopecia.  In our phase 1 
and 2 oncology studies weekly L-AMT was used to safely treat over 100 adult and pediatric 
subjects, including 20 subjects who were treated for over two years (Ratliff '98; Cole '05; Cole '07).  
 
 
In addition, in our 2010 bioequivalence study in subjects with psoriasis (AMT-PSO-101) LD-
AMT was shown to be bioequivalent to L-AMT.   These results are further supported by our trial 
(AMT-RA-202) in adult subjects with rheumatoid arthritis that has demonstrated the safety of a 
dose of 3.0 mg LD-AMT, without folic acid supplementation, for 12 weeks.  It is expected that the 
3.0 mg LD-AMT to be used in this clinical trial will not cause detectable toxicities.   
 
 
Finally, AMT is known to cause congenital malformations in animals and humans (Thiersch '50; 
Warkany '59; Shaw '68).  As a result, AMT is handled as an FDA Pregnancy Category X agent, 
requiring effective birth control during treatment and for 90 days after the cessation of treatment.  If 
an oral hormonal birth control is used, then it should be in use at least 30 days prior to the first study 


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quoted without prior written authorization from Syntrix Biosystems, Inc. 
treatment.  The agent is not used in patients who are pregnant, or until pregnancy can be ruled out in 
women of child-bearing potential. 
 
3 
OVERVIEW OF INVESTIGATIONAL PLAN 
 
3.1 
Study Design 
 
 
This is a phase 2, multi-center, randomized, double-blind, placebo-controlled, clinical trial to 
investigate the efficacy, safety, of LD-AMT in the treatment of subjects with moderate-to-severe 
psoriasis.  Folate metabolism biomarkers will be study to determine their correlation with efficacy 
and safety.  Forty-six subjects will be randomized to one of two parallel treatment arms: LD-AMT 
(3 mg) or placebo, in a 1:1 ratio.  LD-AMT tablets (overencapsulated) or placebo 
(overencapsulated) will be administered once weekly for 14 weeks.  Randomized subjects will 
initially enter a 14-week treatment phase, followed by a 6-week post-treatment phase.  The first 
study drug administration will be on Day 0.   
 
 
Subjects in both treatment groups will receive 14 once weekly oral treatments.   
 
Group Treatment Assignment 
Route 
Schedule 
N=46 
1 
3.0 mg AMT 
oral 
Once weekly x 14 
23 
2 
placebo 
oral 
Once weekly x 14 
23 
 
 
General safety will be evaluated for each subject on Days 0, 14, 42, 70, 98, 119, and 140.  
Subjects will be evaluated for signs and symptoms of study drug intolerance.  Subjects will 
complete weekly diaries to record study drug administration, and signs and symptoms of AEs.  
Blood will be obtained at screening and on Days 0, 14, 42, 70, and 98. 
 
3.2 
Primary and Secondary Endpoints  
 
3.2.1 
Co-Primary Efficacy Endpoints 
 
 
The co-primary endpoints are:  
 
• The proportion of subjects achieving Psoriasis Area and Severity Index of 75% (PASI 
75) at study Day 98 (14 weeks). 
 
• Static Physician Global Assessment (sPGA) dichotomized to success or failure at study 
Day 98 (14 weeks). 
 
3.2.2 
Secondary Efficacy Endpoints 
 
• Proportion of subjects achieving PASI 50 at study Day 98 (14 weeks). 
 
• Mean reduction in the PASI at study Day 98 (14 weeks). 
 
• Proportion of subjects achieving “success” in erythema at study Day 98 (14 weeks). 


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• Proportion of subjects achieving “success” in scaling at study Day 98 (14 weeks). 
 
• Proportion of subjects achieving “success” in plaque induration at study Day 98 (14 
weeks). 
 
3.2.3 
Primary Safety Endpoints 
 
 
Any abnormal laboratory values, abnormal vital signs, reported symptoms, or physical 
examination findings will be documented by the Investigator 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 treatment will be recorded for all adverse events. Adverse 
events will be coded for summary and analysis using standardized preferred terms and system organ 
class.   
 
3.2.4 
Exploratory Endpoints 
 
• Mean hematologic (e.g., hemoglobin, platelets, leukocytes) and hepatic laboratory (e.g., 
SGOT, SGPT) values over the treatment-phase 
 
• Folate Metabolism: The evaluation will be based on the comparative analysis of 
mitochondrial localizing and cytoplasmic localizing folate metabolism enzymes by 
analysis of gene expression levels determined by RNA sequencing, e.g., DHFRL1 
(mitochondrial) and DHFR (cytoplasmic).  These analyses will be performed on subject 
RNA isolated from whole blood obtained at baseline.   
 
3.3 
Study Sites 
 
 
This trial will be conducted at two study sites (Menter Dermatology Research Institute (MDRI), 
Dallas, TX, and Dermatology Associates (DAS), Seattle, WA). All study products will be stored at 
each site under controlled conditions. 
 
3.4 
Number of Subjects  
 
 
At the end of this trial, if safety concerns have not been observed, a total of 46 subjects will 
have been enrolled (i.e., will have received at least one study drug dose). Of these, 23 will have 
received oral LD-AMT 3.0 mg, and 23 will have received oral placebo. It is anticipated that 
approximately 50 subjects will be screened to enroll the 46 subjects into the study. 
 
3.5 
Estimated Duration/Completion of the Study  
 
 
Each subject will be on study for 140 days (20 weeks). It will take approximately 18 months 
from enrollment of the first subject to complete the study. Completion of the Day 140 assessment 
for the last enrolled subject is estimated to occur 18 months after initial enrollment. 
 


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3.6 
Randomization 
 
 
The principal investigator (or qualified designees) will be responsible for all study drug 
accounting and distribution.  A randomization list will be generated by the Syntrix Pharmaceutical 
Division in blocks of appropriate size resulting in a treatment ratio of 1:1 for 3.0 mg LD-AMT and 
placebo.  The randomization list will indicate treatment (3.0 mg LD-AMT or placebo) by 
consecutive Participant ID number (PID#) (a unique three-digit PID#). The randomization list will 
remain under control of the Syntrix Pharmaceutical Division.  The Syntrix Pharmaceutical Division 
will ship participant study drug kits to the study sites.  Each participant’s study drug kit will be 
composed of a bottle containing 14 study drug doses (14 capsules), and each bottle will be labeled 
with a PID# that corresponds to the study drug treatment assigned by the randomization list.  The 
label will not indicate the treatment.  Study drug kits will be assigned to participants by sequentially 
increasing PID# as indicated on the bottle label.  The PID# on the study drug kit assigned to a 
participant becomes the participant’s assigned PID#.  The assigned PID# will be recorded in the 
Screening Log with the corresponding participant. Each subject PID# will be given a site-specific 
two-digit prefix that identifies the site (01 = MDRI; 02 = DAS).   
 
 
 
All subjects who sign consent and who meet all inclusion/exclusion criteria are eligible to 
receive study drug. When eligible subjects present for the Day 0 (baseline) visit, they are assigned a 
study drug kit.  Study drug kits are assigned to participants by sequentially increasing PID# as 
indicated on the bottle label.  The PID# on the study drug kit assigned to a participant becomes the 
participant’s assigned PID#.   
 
 
A total of 46 subjects will be randomized into this study. The randomization list will be 
generated by the Syntrix Pharmaceutical Division such that subjects will be randomly assigned in 
blocks of appropriate size resulting in a 1:1 ratio of subjects assigned to LD-AMT 3.0 mg once per 
week or placebo once per week.  The randomization list will indicate treatment assignment and 
corresponding PID #.  
 
 
 
Once a subject is found to be eligible and has completed the baseline assessments, they will be 
considered enrolled in the study.  At study Day 0 they will be randomized to treatment assignment 
and will be provided with masked study drug.   
 
 
The Syntrix Pharmaceutical Division will keep the randomization lists in a secure location.  If 
the Investigators request unblinding of a participant’s treatment assignment, provided it is not a life-
threatening event, the Investigator will provide the NIAID and Syntrix MMs with sufficient 
information to decide if unblinding should occur.  If the event is life threatening and the MMs are 
not immediately available to review the request, the investigator can contact the Syntrix Medical 
Monitor and that subject’s treatment assignment will be revealed by the Syntrix Pharmaceutical 
Division to the Syntrix Medical Monitor.  All unblinding of participants will be reported to the 
MMs, the ISM, SCG, the study statistician by the close of the next business day.  It is expected that 
given the stopping algorithms and availability of the antidote leucovorin, treatment assignments will 
not need to be unmasked to adequately respond to possible drug-related toxicities.   
 
 
Syntrix Pharmaceutical Division will not release participant treatment assignments to anyone 
during the study, except as may be required for safety.  The final unmasking of all subject 


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quoted without prior written authorization from Syntrix Biosystems, Inc. 
assignments may only be made at the direction of the Sponsor.  This is planned to occur after all 
subjects have completed the study and the study database has been locked. 
 
3.7 
Administration of Study Drug 
 
 
Study drug administration is scheduled for the first Day of each Study Week (Day 0, Day 7, Day 
14, etc.).   All efforts should be made to maintain an exact weekly administration cycle of study 
drug.  Accuracy to within 12 hours should be sought by the Investigator and the subject.  If the 
exact weekly administration of study drug is missed, then study drug should be administered as 
soon as possible within two days (e.g., the weekly study drug administration is on Wednesday and 
is missed, then the study drug should be administered as soon as possible on Thursday or Friday).  
If the study drug administration is missed for more than two days, then that week’s administration 
should be skipped, and study drug administration should resume on the next weekly cycle day.  This 
is to avoid a temporal spacing of dosings that might precipitate toxicity (i.e., < 4 day interval 
between doses).   Actual dates of all study drug administration should be noted in the CRFs.  All 
subsequent study drug administrations should proceed according to the ideal weekly cycle 
referenced back to the date of randomization (Study Day 0), and should not be adjusted to the 
deviated study drug administration date.  At each study visit, subjects will be given diaries to record 
study drug administration dates. 
 
3.8 
Identification of Source Data Recorded Directly on the CRF 
 
 
All data entered in the CRFs must have a valid source document, either written or electronic. 
Data may not be recorded directly in the CRF without a source document unless specified in study 
specific procedures. 
 
4 
STUDY POPULATION 
 
4.1 
Inclusion Criteria 
 
 
Be 18 years of age or older.   
 
 
Have a diagnosis of moderate-to-severe psoriasis for at least 6 months confirmed by a 
dermatologist, defined here as plaque-type psoriasis affecting a body surface area of >10% 
and a PASI of >10. 
 
 
Agree to avoid prolonged sun exposure and avoid use of tanning booths or other ultraviolet 
light sources during the study. 
 
 
Ability to understand and sign written informed consent. 
 
 
Heterosexually active men and women of childbearing potential must use two methods of 
contraception during the study (20 weeks) and for 90 days after study completion.  The two 
methods of birth control may be used simultaneously in the same subject or simultaneously 
in both partners. The two birth control methods can be (a) 2 barrier methods or (b) a barrier 
method plus a hormonal method to prevent pregnancy.   
 


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quoted without prior written authorization from Syntrix Biosystems, Inc. 
Barrier methods include: condom (female or male), copper intrauterine device, sponge, or 
spermicide. 
 
If an oral hormonal birth control is being used, then it should be in use at least 30 days prior 
to the first study drug administration.  Hormonal Methods include: any registered and 
marketed contraceptive agent that contains an estrogen and/or a progestational agent, 
including oral, subcutaneous, intrauterine, or intramuscular agents. 
 
 
For pre-menopausal women, a negative pregnancy test, obtained at screening visit and at 
study visits Week 0, Week 6, Week10, Week 14, and Week 20.  If at any visit during the 
Treatment Phase (see Appendix A) a positive pregnancy test is returned, the subject will be 
discontinued from any further study drug. 
 
 
Negative serology for HIV1/2, hepatitis B and hepatitis C. 
 
 
The following screening laboratory blood tests must have the following values, or not 
clinically significant as determined by the PI and Medical Monitor: WBC WNL; absolute 
neutrophil count > lower limit of normal; platelet count WNL; hemoglobin >10.0 g/dL; AST 
< 2.5 x the upper limit of normal. 
 
 
Adequate renal function: Creatinine clearance estimated by Cockcroft-Gault formula >60 
ml/min 
 
4.2 
Exclusion Criteria 
 
Subjects who meet ANY of the following criteria will be excluded from the study (ineligible): 
 
 
Known history of hepatitis, HIV infection, interstitial lung disease. 
 
 
Greater than moderate alcohol consumption on a regular basis (moderate consumption for 
females is 1 drink or 1 glass of wine a day; for males is 2 drinks or 2 glasses of wine a day) 
and unwilling, or unable, to control consumption during the study period. 
 
 
Prior use of AMT.  
 
 
Use of these biologic treatments in the timeframes specified: 
 
• Within 9 months of first study drug dose: ustekinumab (Stelara). 
 
• Within 12 weeks of first study drug dose: any experimental therapy for psoriasis or 
rheumatoid arthritis. 
 
• Within 8 weeks of first study drug dose: infliximab (Remicade), adalimumab (Humira). 
 
• Within 4 weeks of first study drug dose: etanercept (Enbrel). 
 


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• Other biologic therapies will have discontinuation periods determined by 5x their half-
life. 
 
 
Within 90 days prior to Day 0 and at any time while on study, the use of MTX. 
 
 
Within 4 weeks prior to randomization and at any time while on study, use of phototherapy 
(e.g., UVB, narrow band UVB, Goeckerman regimen, Ingram regimen, PUVA), systemic 
medications (e.g. acitretin, mycophenolate mofetil, tacrolimus/FK506, cyclosporine A, 
azathioprine, 6-thiogaunine, sulfasalazine, hydroyurea, calcitriol, apremilast, any systemic 
immunosuppressants), lithium, or any treatments that could affect psoriasis or sPGA 
evaluations.  Subjects are eligible 4 weeks after the last dose of any of the aforementioned 
treatments was received. 
 
 
Within 2 weeks prior to randomization and at any time while on study, use of any topical 
medications or treatments that could affect psoriasis evaluations (e.g., corticosteroids, 
anthralin, vitamin D3/calcitriol and analogues such calcipotriene and tacalcitol, synthetic 
retinoids such as tazarotene, coal tar, and keratolytics such as salicylic acid, lactic acid and 
urea including those contained in over-the-counter medicated shampoos). Subjects are 
eligible 2 weeks after the last dose of any of the aforementioned treatments was received. 
 
 
 
Note:  Over-the-counter topical steroids will be permitted for use limited to the face, axilla, 
and/or genitalia, as needed.  These topical medications should not be used within 
approximately 24 hours prior to study visits Day 0 and Day 98. Over-the-counter shampoos 
for the treatment of psoriasis of the scalp are also permitted. 
 
 
Use of emollients on the morning of the first (Week 0) study visit. 
 
 
Within 2 weeks prior to Study Day 0, or on Study Day 0, or at any time during the study, use 
of any of the following medications that may result in drug/drug interactions with AMT: 
trimethoprim with or without sulfamethoxazole; sulfonamides; sulfonylureas; 
pyrimethamine; triamethamine; salicylates; non-steroidal anti-inflammatory (NSAID) drugs 
including ibuprofen; dipyridamole; colchicine; probenecid; aminoglycosides; theophylline; 
phenytoin; and folinic acid (i.e., leucovorin).   
 
 
Known concurrent malignancy except basal or squamous cell skin carcinoma, or cervical 
carcinoma in situ. 
 
 
Concurrent participation in another clinical trial involving experimental treatment within 30 
days of Study Day 0. 
 
 
Current and uncontrolled infection, cardiovascular, renal, pulmonary, hepatic or GI 
conditions that will interfere with the conduct of the trial or pose a morbid risk. 
 
 
Investigator’s opinion that a concurrent disease or condition impairs the subject’s ability to 
complete the trial: includes psychological, familial, sociological, geographical or medical 
conditions. 
 


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Breast-feeding. 
 
4.3 
Discontinuation of Study Drug 
 
 
Subjects with any of the following conditions will be discontinued from additional study drug: 
 
• Pregnancy 
 
• Adverse events or concomitant medication that in the opinion of the Principal 
Investigator (or designated sub-investigator) would preclude further drug 
 
• Dose limiting toxicity  
 
• Malignancy 
 
 
All subjects who have study drug discontinued will be followed until resolution or stabilization 
of the event and will remain on study for follow-up visits and safety evaluations. 
 
4.4 
Subject Withdrawal from the Study 
 
 
Subjects will be free to withdraw from the study at any time, for any reason, and without 
prejudice to further treatment.  Any subject who withdraws from the study, regardless of reason, 
will not be allowed to re-enroll in this study.  Reasons for withdrawal will be recorded on the 
appropriate CRF.   The final report will include reasons, if available, for withdrawal and any 
necessary treatment. 
 
 
Anytime a subject withdraws from the study, for whatever reason, including voluntary 
withdrawal, every attempt should be made to evaluate all procedures planned for the Study Day 98 
visit. 
 
4.5 
Subject Replacement 
 
 
Subjects will not be replaced. 
 
5 
STUDY PROCEDURES 
 
 
A summary of study procedures is provided in Appendix A. 
 
5.1 
Consent and Screening Procedures 
 
 
Screening evaluations will occur during the 30-day period prior to Day 0 (i.e., Day -30 to Day -
1).  More than one clinic visit may be required in order to complete all screening evaluations for a 
subject.  Screening labs may be repeated if necessary for parameters with out of range results (e.g., 
a subject with low hemoglobin may be tested again within 14 days or more after the initial test, as 
long as it is within the 30-day window).  The purpose of the screening period is to assure that the 


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quoted without prior written authorization from Syntrix Biosystems, Inc. 
subjects meet the study entry criteria and that they adequately comprehend the protocol and its 
requirements. 
 
 
Prior to the start of screening, the investigator (or study personnel) obtains a signed study 
consent form from each potential study participant. The Screening procedure includes the following 
assessments: 
 
 
Explain the study and screening procedures to the subject. 
 
 
Review the informed consent form with the subject and obtain his/her signature and date of 
signature on the informed consent document. Provide the subject with a copy of the signed 
consent form. 
 
 
Assign the subject a screening identification number (SID#).  This number will be assigned 
sequentially and must be recorded on the sites screening log.  The first two digits of the 
SID# identify the site (e.g., 01 = Clinic X).  The next three digits identify the subject.  For 
example, the first subject screened, if at the center designated “01”, will be assigned the 
SID# 01-001, the second subject if at the same site, 01-002.  If a subject is re-screened they 
will be assigned a new SID#. 
 
 
Document medical history including smoking history, chronic obstructive pulmonary 
disease, sleep apnea, and drug and alcohol consumption. Rule out any allergies, acute or 
chronic illness that could interfere with study evaluations, cancer or treatment for cancer 
within 3 years, participation in experimental protocols within past 30 days, psychiatric 
illness, alcohol or drug abuse. 
 
 
Record any signs and symptoms the subject is experiencing at the screening visit on the 
appropriate baseline source document and CRF. 
 
 
Record any current use of medications, including any taken within the past 6 weeks.  
Concomitant medications will include contraception that is being used during the trial. 
 
 
Assess vital signs: blood pressure, heart rate and temperature. 
 
 
Assess psoriasis body surface area involvement and PASI. 
 
 
Perform physical examination.   Measure weight and height of the subject.  BSA can be 
calculated.  Rule out tattoos or any other dermatological condition that could adversely 
affect the psoriasis evaluations. 
 
 
Obtain a urine specimen for urinalysis. 
 
 
If subject is female of child-bearing potential, perform a urine pregnancy test (beta-HCG). 
 
 
Collect approximately 15 ml blood as follows: 
 
• 5 mL anti-coagulated whole blood for CBC, white cell differential and platelet count. 


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• 5 mL whole blood for serum chemistry testing. Chemistries to include: BUN, creatinine, 
ALT, AST, total bilirubin, alkaline phosphatase, albumin, and total protein. 
 
• 5 mL whole blood for serology testing. Serology tests to include: HIV1/2, hepatitis B 
surface antigen (HBsAg), and hepatitis C antibody (HCV AB). 
 
 
Obtain a chest X-ray (CXR) (a CXR within the previous 6 months (to date of screening 
visit) may be used instead of performing a new CXR).   
 
 
Review CXR and lab results.  Lab results must meet the listed inclusion criteria.  If they do 
not, then the subject is ineligible. 
 
 
If subject meets eligibility criteria, then: 
 
• Schedule Study Day 0 visit. When scheduling this Week 0 visit, be sure to inform 
subjects not to eat for at least 1 hour before their visit as that visit will be one where 
study drug is given. 
 
• Review subject randomization procedure.  Notify central randomization or appropriate 
sponsor designee of new subject to be randomized. 
 
 
Complete all CRFs for the visit. 
 
5.2 
Week 0 - Day 0 (Baseline) Evaluations 
 
 
Subjects who meet all screening evaluation criteria will be asked to return to the clinic for the 
baseline visit.  The clinical site coordinator or designee will confirm that appropriate study drug is 
available.   As the subject is randomized and assigned to a study drug treatment, the study drug 
bottle label PID# will be recorded on appropriate CRFs and logs as required.  The PID# will be 
composed of the two-digit site number, e.g., 01=Clinic X, followed by the subject-specific three-
digit number that links the study drug provided to the masked study drug treatment assigned, e.g., 
01-101.  This PID# must be recorded and linked to the corresponding SID# in the screening log. 
 
Upon arrival, the following evaluations will be completed: 
 
 
Perform physical exam as directed by subject history. 
 
 
Assess vital signs: blood pressure, heart rate, and temperature. 
 
 
Review and record concomitant medications (including alternative and complementary 
treatments) and determine if they are within the prohibited drugs. 
 
 
Verify that the subject is compliant with the contraception requirement.   
 


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If subject is a woman of child-bearing potential, then perform a urine pregnancy test (beta-
HCG).  A negative result must be confirmed before subject is randomized and study drug is 
administered.  
 
 
Perform psoriasis assessments (PASI, sPGA, Dermatology Life Quality Index).   
 
 
Collect 5 mL or less blood prior to study drug administration for folate metabolism 
evaluations.  The blood sample will be processed as described in the study specific 
procedure manual. 
 
 
Subjects who continue to meet entry criteria, who have completed baseline evaluations, and 
have provided signed informed consent will be provided their first dose of study drug.   
 
 
Randomize subject to appropriate treatment assignment.  Provide subject with the study 
drug. 
 
 
Instruct subject they may eat 1.0 hr after the study drug administration.  Clear liquids are 
permitted. 
 
 
Record any adverse events that occur after study drug administration. 
 
 
Instruct subject to not ingest solid food at least 1 hour before, and 1 hours after, the next 
study drug administration (clear liquids are okay). 
 
 
Instruct subject on the completion of the study drug diary which will document the AMT 
doses for home administration.  The diary will be used to capture the dosing of the AMT as 
well as to note any signs or symptoms that may occur in between the site visits.  Provide the 
subject with sufficient blank diaries to last until their next clinic visit.  Ask subject to bring 
their completed diary to their next clinic visit. The Diary shall be reviewed with the subject 
prior to leaving the study site; clear understanding of how to complete the diary shall be 
documented by the research staff, with contact information for the subject in the event that 
there are questions afterwards. 
 
 
Remind subject to bring study drug bottle to next (and all) study clinic visits to enable study 
drug accounting. 
 
 
The completed diary will be collected by the study site and retained in the subject source 
document binder on Day 14 and a new diary will be provided, to be collected at the next 
study visit. 
 
 
Complete all CRFs for the visit. 
 
5.3 
Week 2 - Day 14 Evaluations (±2) 
 
Upon arrival, the following evaluations will be completed: 
 
 
Review subject diary and record: 


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• Concomitant medications (including alternative and complementary treatments) and 
determine if they are within the prohibited drugs. 
 
• Adverse events. 
 
• Study drug dosing compliance.  
 
 
Verify that the subject is compliant with the contraception requirement.   
 
 
Collect blood for CBC and chemistries.  Results must be reviewed before administration of 
study drug on Day 21 so that appropriate study drug dose adjustments (Section 9.1) can be 
made. 
 
 
If subject is a woman of child-bearing potential, then obtain a urine sample and perform a 
pregnancy test (beta-HCG).  A negative result must be confirmed before additional study 
drug is administered. 
 
 
If subject remains eligible study drug can be administered. Subject will be given sufficient 
study drug for home administration until subject returns to the clinic for the next scheduled 
visit in 4 weeks. 
 
 
Record any adverse events that occur after study drug administration. 
 
 
Instruct subject to not ingest solid food at least 1 hour before and 1 hour after study drug 
administration (clear liquids are okay). 
 
 
Remind subject to bring study drug bottle to next (and all) study clinic visits to enable study 
drug accounting. 
 
 
File the completed diaries in the subject source document binder and provide the subject 
with sufficient blank diaries to last until their next clinic visit. 
 
 
Instruct subject on the completion of the study drug diary which will document the AMT 
doses for home administration.  The diary will be used to capture the dosing of the AMT as 
well as to note any signs or symptoms that may occur in between the site visits. Ask the 
subject to bring their completed diary to their next clinic visit. The Diary shall be reviewed 
with the subject prior to leaving the study site; clear understanding of how to complete the 
diary shall be documented by the research staff, with contact information for the subject in 
the event that there are questions afterwards. 
 
 
Instruct subject on home administration of study drug on Study Day 21, 28, and 35. 
 
 
Complete all CRFs for the visit. 
 


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quoted without prior written authorization from Syntrix Biosystems, Inc. 
5.4 
Week 6 - Day 42 Evaluations (±3) 
 
Upon arrival, the following evaluations will be completed: 
 
 
Review subject diary and record: 
 
• Concomitant medications (including alternative and complementary treatments) and 
determine if they are within the prohibited drugs. 
 
• Adverse events. 
 
• Study drug dosing compliance.  
 
 
Verify that the subject is compliant with the contraception requirement.   
 
 
If subject is a woman of child-bearing potential, then obtain a urine sample and perform a 
pregnancy test (beta-HCG).  A negative result must be confirmed before additional study 
drug is administered. 
 
 
Perform physical exam as directed by subject history. 
 
 
Collect blood for CBC and chemistries.  Results must be reviewed before administration of 
study drug on Day 49 so that appropriate study drug dose adjustments (Section 9.1) can be 
made. 
 
 
If subject remains eligible study drug can be administered. Subject will be given sufficient 
study drug for home administration until subject returns to the clinic for the next scheduled 
visit in 4 weeks. 
 
 
Record any adverse events that occur after study drug administration. 
 
 
Instruct subject to not ingest solid food at least 1 hour before and 1 hour after study drug 
administration (clear liquids are okay). 
 
 
Remind subject to bring study drug bottle to next (and all) study clinic visits to enable study 
drug accounting. 
 
 
File the completed diaries in the subject source document binder and provide the subject 
with sufficient blank diaries to last until their next clinic visit. 
 
 
Instruct subject on the completion of the study drug diary which will document the AMT 
doses for home administration.  The diary will be used to capture the dosing of the AMT as 
well as to note any signs or symptoms that may occur in between the site visits. Ask the 
subject to bring their completed diary to their next clinic visit. The Diary shall be reviewed 
with the subject prior to leaving the study site; clear understanding of how to complete the 


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quoted without prior written authorization from Syntrix Biosystems, Inc. 
diary shall be documented by the research staff, with contact information for the subject in 
the event that there are questions afterwards. 
 
 
Instruct subject on home administration of study drug on Study Day 49, 56, and 63. 
 
 
Complete all CRFs for the visit. 
 
5.5 
Week 10 - Day 70 Evaluations (±3) 
 
Upon arrival, the following evaluations will be completed: 
 
 
Review subject diary and record: 
 
• Concomitant medications (including alternative and complementary treatments) and 
determine if they are within the prohibited drugs. 
 
• Adverse events. 
 
• Study drug dosing compliance.  
 
 
Verify that the subject is compliant with the contraception requirement.   
 
 
If subject is a woman of child-bearing potential, then obtain a urine sample and perform a 
pregnancy test (beta-HCG).  A negative result must be confirmed before additional study 
drug is administered. 
 
 
Perform physical exam as directed by subject history. 
 
 
Collect blood for CBC and chemistries.  Results must be reviewed before administration of 
study drug on Day 77 so that appropriate study drug dose adjustments (Section 9.1) can be 
made. 
 
 
If subject remains eligible study drug can be administered. Subject will be given sufficient 
study drug for home administration until subject returns to the clinic for the next scheduled 
visit in 4 weeks. 
 
 
Record any adverse events that occur after study drug administration. 
 
 
Instruct subject to not ingest solid food at least 1 hour before and 1 hour after study drug 
administration (clear liquids are okay). 
 
 
Remind subject to bring study drug bottle to next (and all) study clinic visits to enable study 
drug accounting. 
 
 
File the completed diaries in the subject source document binder and provide the subject 
with sufficient blank diaries to last until their next clinic visit. 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
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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. 
 
 
Instruct subject on the completion of the study drug diary which will document the AMT 
doses for home administration.  The diary will be used to capture the dosing of the AMT as 
well as to note any signs or symptoms that may occur in between the site visits. Ask the 
subject to bring their completed diary to their next clinic visit. The Diary shall be reviewed 
with the subject prior to leaving the study site; clear understanding of how to complete the 
diary shall be documented by the research staff, with contact information for the subject in 
the event that there are questions afterwards. 
 
 
Instruct subject on home administration of study drug on Study Day 77, 84, and 91.  Inform 
subject that this will be the last visit where they will be receiving drug. Subjects will need to 
bring back study drug bottle and all other study related materials at their next visit. 
 
 
Complete all CRFs for the visit. 
 
5.6 
Week 14 - Day 98 Evaluations (±3) 
 
Upon arrival, the following evaluations will be completed: 
 
 
Review subject diary and record: 
 
• Concomitant medications (including alternative and complementary treatments) and 
determine if they are within the prohibited drugs. 
 
• Adverse events. 
 
• Study drug dosing compliance.  
 
 
Verify that the subject is compliant with the contraception requirement.  Remind subject to 
refrain from donating sperm as well as to continue their birth control methods for the next 
90 days (3 months). 
 
 
If subject is a woman of child-bearing potential, then obtain a urine sample and perform a 
pregnancy test (beta-HCG).   
 
 
Perform physical exam as directed by subject history. 
 
 
Assess vital signs: blood pressure, heart rate and temperature. 
 
 
Collect blood for CBC and chemistries.  
 
 
 Obtain a urine specimen for urinalysis. 
 
 
Perform psoriasis assessments (PASI, sPGA, Dermatology Life Quality Index).   
 


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quoted without prior written authorization from Syntrix Biosystems, Inc. 
 
File the completed diaries in the subject source document binder and provide the subject 
with sufficient blank diaries to last until their next clinic visit. 
 
 
Instruct the subject on the completion of the diary which will be used to capture any signs or 
symptoms that may occur in between the site visits.  Ask subject to bring their completed 
diary to their next clinic visit. The Diary shall be reviewed with the subject prior to leaving 
the study site; clear understanding of how to complete the diary shall be documented by the 
research staff, with contact information for the subject in the event that there are questions 
afterwards.   
 
 
Complete all CRFs for the visit. 
 
5.7 
Week 17 - Day 119 Evaluations (±4) 
 
The following evaluations will be performed by telephone: 
 
 
Review subject diary and record: 
 
• Concomitant medications (including alternative and complementary treatments) and 
determine if they are within the prohibited drugs. 
 
• Adverse events. 
 
 
File the completed diaries in the subject source document binder and provide the subject 
with sufficient blank diaries to last until their next clinic visit.  Instruct the subject on the 
completion of the diary which will be used to capture any signs or symptoms that may occur 
in between the site visits.  Ask subject to bring their completed diary to their next clinic 
visit. The Diary shall be reviewed with the subject prior to leaving the study site; clear 
understanding of how to complete the diary shall be documented by the research staff, with 
contact information for the subject in the event that there are questions afterwards.   
 
 
Verify that the subject is compliant with the contraception requirement.   
 
 
Complete all CRFs for the visit. 
 
5.8 
Week 20 - Day 140 Evaluations (±4) 
 
Upon arrival the following evaluations will be completed: 
 
 
Review subject diary (file the completed diaries in the subject source document binder) and 
record: 
 
• Concomitant medications (including alternative and complementary treatments) and 
determine if they are within the prohibited drugs. 
 
• Adverse events. 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
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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. 
 
 
Verify that the subject is compliant with the contraception requirement. 
 
 
If subject is a woman of child-bearing potential, then obtain a urine sample and perform a 
pregnancy test (beta-HCG). 
 
 
Complete all CRFs for the visit. 
 
5.9 
Concomitant Medications 
 
 
Subjects may use concomitant medications as permitted by the protocol.  All medications and 
immunizations, prescription or non-prescription (including over the counter, alternative, and 
traditional preparations), including any medication used in the treatment of an AE, taken at any time 
from the day of screening evaluation, through the end of post drug surveillance, must be recorded 
on the Concomitant Medication CRF.  
 
 
Over-the-counter topical steroids will be permitted for use limited to the face, axilla, and/or 
genitalia, as needed.  These topical medications should not be used within approximately 24 hours 
prior to study visits Day 0 and Day 98. Over-the-counter shampoos for the treatment of psoriasis of 
the scalp are also permitted.  
 
5.10 
Prohibited Medications and Procedures 
 
 
At any time while on study, use of phototherapy (e.g., UVB, narrow band UVB, 
Goeckerman regimen, Ingram regimen, PUVA), systemic medications (e.g., MTX, 
cyclosporine, biologic therapies, interleukin-2-diptheria-toxin, acitretin, mycophenolate 
mofetil, tacrolimus/FK506, azathioprine, 6-thiogaunine, sulfasalazine, hydroyurea, calcitriol, 
apremilast, any systemic immunosuppressants), lithium, or any treatments that could affect 
psoriasis evaluations are prohibited. 
 
 
At any time while on study, any topical medications or treatments that could affect psoriasis 
evaluations (e.g. corticosteroids, anthralin, vitamin D3/calcitriol and analogues such 
calcipotriene and tacalcitol, synthetic retinoids such as tazarotene, coal tar, and keratolytics 
such as salicylic acid, lactic acid and urea including those contained in over-the-counter 
medicated shampoos) are prohibited. Subjects are eligible 2 weeks after the last dose of any 
of the aforementioned treatments was received. 
 
 
Within 2 weeks prior to Study Day 0, or on Study Day 0, or at any time during the study, use 
of any of the following medications that may result in drug/drug interactions with AMT: 
trimethoprim with or without sulfamethoxazole; sulfonamides; sulfonylureas; 
pyrimethamine; triamethamine; salicylates; non-steroidal anti-inflammatory (NSAID) drugs 
including ibuprofen; dipyridamole; colchicine; probenecid; aminoglycosides; theophylline; 
phenytoin; and folinic acid (i.e., leucovorin) unless prescribed by the investigator to treat 
study drug related toxicity.   
 
 
At any time while on study elective surgical procedures are prohibited. 
 


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5.11 
Contraception Requirements for Men and Women 
 
 
Aminopterin is embryo-toxic and teratogenic in animals (Bellairs '54; Johnson '64) and humans 
(Thiersch '50; Meltzer '56; Warkany '59; Shaw '68), and is reported to have transient effects on 
human sperm.   
Men and non-pregnant, nonbreast-feeding women may be enrolled if they are 
considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically 
sterilized (e.g., vasectomy, hysterectomy, tubal ligation), or 2) postmenopausal (a woman who is 
≥45 years of age and has not had menses for greater than 2 years), or 3) amenorrheic for <2 years 
without a hysterectomy and oophorectomy and with a documented FSH value in the 
postmenopausal range, or 4) not heterosexually active for the duration of the study, or 5) 
heterosexually active and willing to use two methods of birth control throughout the study starting 
with Day 0 through 90 days after the last dose of study medication.  The 2 methods of birth control 
may be used simultaneously in the same subject or simultaneously in both partners. 
 
 
The two birth control methods can be (a) 2 barrier methods or (b) a barrier method plus a 
hormonal method to prevent pregnancy. 
 
Barrier Methods.  The following are adequate barrier methods of contraception: diaphragm, 
condom (female or male), copper intrauterine device, sponge, or spermicide. 
 
 
Hormonal Methods.  Appropriate hormonal contraceptives will include any registered and 
marketed contraceptive agent that contains an estrogen and/or a progestational agent, including oral, 
subcutaneous, intrauterine, or intramuscular agents. If an oral hormonal birth control is used, then it 
should be in use at least 30 days prior to the first study treatment.  The agent is not used in patients 
who are pregnant, or until pregnancy can be ruled out in women of child-bearing potential. 
 
5.12 
Unscheduled Visits 
 
 
If the subject attends the clinic for an unscheduled visit, all information must be recorded in the 
source document, AEs must be reported on the AE form, and the history, physical exam, 
procedures, treatments, interventions, or outcomes will be reported on the appropriate unscheduled 
visit CRF. 
 
5.13 
Missed Visits  
 
 
Any missed study-specified visit will be documented on the appropriate CRF. 
 
5.14 
Subject Samples 
 
 
Folate metabolism samples will not be used for additional analyses without subject consent.  If 
not used within 10 years from the time of the study’s last subject clinic visit, the samples will be 
destroyed by the Sponsor.   
 
6 
Evaluations of Folate Metabolism 
 
 
Analysis of the role of the cytoplasmic and mitochondrial compartments in folate metabolism 
will be performed.    Assessment of folate metabolism will be performed with blood specimens 


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quoted without prior written authorization from Syntrix Biosystems, Inc. 
obtained at baseline.  Endpoints of interest include the ratio of mitochondrial to cytoplasmic gene 
expression levels of DHFR and thymidylate synthase.  These results will be correlated with study 
trial efficacy and safety outcomes. 
 
7 
STUDY DRUG 
 
7.1 
Study Drug Supplies and Handling 
 
 
Syntrix or CRO designee will supply identical appearing capsules containing placebo or 3 mg 
LD-AMT.  The capsules will be supplied in a coded bottle.  The Sponsor designee will maintain the 
blinded treatment assignment list and will send coded study drug bottles to the clinical sites for each 
subject.  The clinical investigator or designee will provide subjects with sufficient study drug at the 
clinic visits.  The Study drug will be shipped under controlled conditions.  A second bottle can be 
used by the subjects to take home sufficient study drug for the weekly doses to be administered at 
home in between clinic visits. 
 
7.2 
Labeling 
 
 
Study drug will be distributed in bottles with labels that indicate that they contain study drug, 
and with the caution statement “Caution: New Drug – Limited by United States Law to 
Investigational Use.” 
 
7.3 
Storage 
 
Study drug will be stored at 15-30°C, protected from light.  The supplies will be accessible 
to authorized personnel only.   
 
7.4 
Preparation, Administration, and Dosage of Study Drug 
 
 
Study drug or matching placebo will be provided to the site; the treatment period is 1 capsule 
weekly, a total dose of 14 capsules.  An additional bottle can be used by the subjects to take home 
sufficient study drug for the weekly doses to be administered at home in between clinic visits. 
During the clinic visits at Week 0, 2, 6, and 10, the study drug can be taken by the subject in the 
clinic after all study procedures have been completed for that visit. 
 
 
Study subjects will be instructed to take their study drug on a designated day each week in 
between the clinic visits; they will be instructed that this drug schedule is to be kept unless 
otherwise instructed by the research staff.  If the dosing schedule is changed or altered in any way 
for any reason, the subject will be asked to discuss this with the investigative team at the clinic. 
 
7.5 
Accountability of Study Agent 
 
7.5.1 
Receipt of Study Agent 
 
 
As soon as the clinical team member receives study drug from Syntrix or designee, the accuracy 
of the clinical supply shipping form will be verified and the appropriate shipment accounting form 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
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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. 
must be completed and returned to Syntrix or its designee.  The clinical team member should retain 
a copy of this form for the Investigator’s file. 
 
7.5.2 
Record of Administration and Dispensing 
 
 
Accurate recording of all administration and dispensing of study drug will be made on the 
appropriate logs and CRFs.  All used containers, study drug not dispensed, and accountability 
records must be retained for eventual accountability by the Sponsor or designee. 
 
7.5.3 
Unused Study Drug 
 
 
At the end of the study the Investigator or designee will be responsible for retaining 
investigational supplies at the sites pending instructions from Syntrix or designee for returning all 
unused study drug to Syntrix or designee as instructed. Following final accounting, as instructed by 
Syntrix or designee, used canisters will be discarded according to hospital or clinic policy or 
returned to Syntrix or designee. 
 
8 
ADVERSE EVENTS 
 
8.1 
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 AEs reported as test results.  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.  Laboratory AEs considered not 
clinically significant will not be recorded on the AE CRF. 
 
8.2 
Definitions 
 
8.2.1 
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. 
 
8.2.2 
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, 


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• 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. 
 
8.2.3 
Unexpected Adverse Event 
 
 
Unexpected AEs are those not described in the Investigator’s Brochure.  Expected AEs are those 
described in the IB.  Expected treatment related AEs include, but are not limited to, grade 1-2: 
stomatitis, mucositis, nausea, vomiting, gastrointestinal cramping, anemia, leukopenia, 
thrombocytopenia and elevations in liver transaminases.  The IB should be consulted for a 
comprehensive listing.  The duration of such AEs will typically be less than 1 week. 
 
8.3 
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. 
 
8.3.1 
Severity Grading 
 
 
The NCI Common Terminology Criteria for Adverse Events v4.0 (NCI CTCAE v4.0) will be 
used to categorize AEs and SAEs and to score severity (online at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf ). 
 
8.3.2 
Relationship of Adverse Event to Study Drug 
 
 
Clinical AE/SAEs must have their relationship to study drug assessed using the following terms 
(NOTE: relationship is not a factor in determining what is or is not reported in the study): 
 
• Definitely Related (5) 
 
 
There is clear evidence to suggest a causal relationship, and other possible contributing factors 
can be ruled out. The clinical event, including an abnormal laboratory test result, occurs in a 
plausible time relationship to drug administration and cannot be explained by concurrent disease or 
other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be clinically 
plausible. The event must be pharmacologically or phenomenologically definitive, with use of a 
satisfactory rechallenge procedure if necessary. 
 
• Probably Related (4) 
 
 
There is evidence to suggest a causal relationship, and the influence of other factors is unlikely. 
The clinical event, including an abnormal laboratory test result, occurs within a reasonable time 


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quoted without prior written authorization from Syntrix Biosystems, Inc. 
sequence to administration of the drug, is unlikely to be attributed to concurrent disease or other 
drugs or chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfill this definition.  
 
• Possibly Related (3) 
 
 
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 “possibly” soon after discovery, it can be 
flagged as requiring more information and later be upgraded to “probably” or “definitely” as 
appropriate. 
 
• Unlikely (2) 
 
 
A clinical event, including an abnormal laboratory test result, whose temporal relationship to 
drug administration makes a causal relationship improbable (e.g., the event did not occur within a 
reasonable time after administration of the trial medication) and in which other drugs or chemicals 
or underlying disease provides plausible explanations (e.g., the subject’s clinical condition, other 
concomitant treatments).  
 
• Not related (1) 
 
 
The AE is completely independent of study drug administration, or evidence exists that the 
event is definitely related to another etiology.  The alternative, definitive etiology must be 
documented. 
 
 
Adverse events that are related to psoriasis or common syndromes will be considered related to 
the underlying disease and not to the study agent.  
 
8.4 
Diaries (Memory Aids) 
 
 
Diaries will be distributed to subjects to aid in documentation of study drug administration, and 
to aid in collection of signs and symptoms of AEs.  Subjects will be instructed to record the date or 
day of study drug administration.  Subjects will also be instructed to record signs and symptoms of 
AEs. 
 
8.5 
Reporting Adverse Events 
 
 
All AEs, regardless of severity or presumed relationship to study drug, will be documented on 
the AE CRF.  All SAEs, and grade 3 and grade 4 hematologic AEs, and grade 4 hepatic AEs must 
be reported by the Principal Investigator (or designee) directly to Syntrix Pharmacovigilance within 
24 hours by email or telephone.  The reporting sequence for all SAEs, grade 3 and grade 4 
hematologic AEs, and grade 4 hepatic AEs will be as follows: 
 


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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 MM, NIAID MM, and 
ISM within 48 hours of receipt of the report of the event. 
 
 
The Syntrix MM must provide a written report by e-mail to Syntrix Pharmacovigilance, the 
NIAID MM, and the ISM 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 study drug is scheduled). 
 
 
Syntrix Pharmacovigilance will forward the Syntrix and NIAID MM’s written report and 
recommendation by e-mail to the Principal Investigator within 2 working days of receipt. 
 
 
The Principal Investigator will meet his IRB reporting requirements. 
 
 
All SAEs, grade 3 and grade 4 hematologic AEs, and grade 4 hepatic AEs (increased ALT, 
AST, alkaline phosphatase, total bilirubin) 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.  
 
8.6 
Follow-up of Subjects with Adverse Events 
 
 
All AEs must be followed to resolution or stabilization of the event. 
 
8.7 
Reporting of Pregnancy 
 
 
Pregnant women are not eligible to participate in the study. Women are counseled regarding 
prevention of pregnancy and are required to avoid pregnancy during study participation by adhering 
to the contraception requirements of the study.  If a subject becomes pregnant, no further doses of 
study drug will be given.  The blind will be broken for this subject only, and the event recorded as a 
protocol deviation.  The investigator should be informed immediately of any pregnancy in a 
participant or pregnancy of a female partner of a male participant occurring from randomization 
through 30 days after the participant completes the trial.  Events surrounding the pregnancy should 
be recorded and reported to Syntrix following the instructions provided in the Sponsors 
Pharmacovigilance Instructions. 
 
 
 
If there are complications during the pregnancy, the complications will be recorded as AEs 
in the usual way.  The subject will be asked to report the outcome of the pregnancy.  If there is a 
congenital anomaly in the infant, this will be recorded and reported as a SAE for the mother (i.e., 
the study subject). 
 
8.8 
Oversight of Data and Safety 
 
 
As described in the study DSMP the Syntrix Clinical Group (SCG) in collaboration with NIAID 
medical officers will monitor AMT-PSO-201 ensure the safety of the subjects and the integrity of 
the data.  Stuart Kahn, M.D., Medical Director of Syntrix will act as the Sponsors Medical Monitor.  


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
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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. 
Dr. Kahn will work closely with the NIAID Medical Monitor.  Study accrual and Patient Status 
reports generated by the SCG that include delinquency, adverse event summaries, and a listing of 
enrollees will be provided to the MMs and the ISM.   
 
9 
ASSESSMENT OF RISK 
 
9.1 
Modification of Study Drug for a Subject 
 
 
The NCI Common Terminology Criteria for Adverse Events v4.0 (NCI CTCAE v4.0) will be 
used to score severity grade (online at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf or this protocol Appendix C) 
 
9.1.1 
Hematologic Adverse Events (Leukopenia, Thrombocytopenia, 
Anemia) 
 
 
For grade 2 leukopenia, grade 2 thrombocytopenia, and grade 3 anemia: study drug is held for a 
maximum of 3 weeks.  Monitoring is performed weekly until the grade 2 leukopenia, grade 2 
thrombocytopenia, or grade 3 anemia AE resolves.  Then study drug is resumed and the normal 
monitoring schedule is resumed.  If grade 2 leukopenia, grade 2 thrombocytopenia, or grade 3 
anemia continues for > 3 weeks, study drug is withdrawn permanently and leucovorin treatment 
considered. 
 
 
For grades 3 and 4 leukopenia and thrombocytopenia, and grade 4 anemia: study drug is 
withdrawn permanently.  Hematologic labs are retested until normal.  Leucovorin treatment is 
considered for grade 3, and administered for grade 4 AEs 
 
Hematologic AE Algorithm 
Grade 
Monitoring Schedule 
Study Drug Dosing 
Leucovorin Treatment * 
2 ** 
Weekly until AE improves  
Hold until AE improves (3 weeks 
maximum). 
Consider for AEs > 3 weeks 
3*** 
PI judgment until AE improves. 
Permanent hold. 
Consider 
4 
PI judgment until AE improves. 
Permanent hold. 
Yes 
* 10 mg tablet orally once daily 
** Excluding grade 2 anemia 
*** Excluding grade 3 anemia 
 
9.1.2 
Hepatic Adverse Events 
 
 
As recommended by the ACR for MTX monitoring, only AST (SGOT) is used to guide study 
drug dose modifications for hepatoxicity, unless other blood tests are grade 3 or 4. 
 
 
If a subject experiences three grade 3 AST AEs then study drug is permanently withdrawn and 
weekly evaluations performed until the AE resolves.  Leucovorin rescue is considered.     
 
 
If a subject experiences a grade 4 AE, then study drug is permanently withdrawn and weekly 
evaluations performed until AE resolves.  Leucovorin treatment is considered.   
 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
46 
 
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. 
 
For grade 4 changes in ALT, alkaline phosphatase, total bilirubin and albumin, study drug is 
permanently held and the subject monitored weekly until the AE resolves.   
 
Hepatic AE Algorithm 
Grade 
Monitoring Schedule 
Study Drug Dosing 
Leucovorin Treatment * 
1 
No change.   
No change 
No 
2 
No change 
No change 
No 
3 
Weekly until AE becomes grade 2, 
(then resume regular schedule). 
After three grade 3 AEs, then 
study drug is withdrawn. 
Consider 
4 
Change to weekly until AE resolves. 
Study drug is withdrawn. 
Consider 
* 10 mg tablet orally once daily 
 
9.1.3 
Mucositis/Stomatitis Adverse Events 
 
 
For oral mucositis grade 1 a dose suspension is not required.  For mucositis grade 2 that persists 
for ≥ 3 weeks, study drug is held.  For grade 3 or grade 4 mucositis study drug is held until grade 2 
or lower are observed, and then study drug is resumed and the subject is re-examined in a week.  If 
after two weeks lesions have not improved to grade 1, then study drug is withdrawn permanently.  
For persistent lesions of grade 2, or lesions > grade 2, leucovorin treatment (10 mg tablet orally 
once daily) can be given. 
 
9.2 
Criteria for Interrupting the Trial Based on Dose-Limiting Toxicity 
(DLT) 
 
9.2.1 
Rules for Discontinuing Study Drug in an Individual Subject 
 
 
Possible reasons for discontinuing a subject from receiving study drug include: 
 
 
Excessive toxicity as delineated by AE algorithms. 
 
 
Any clinical adverse event, laboratory abnormality, intercurrent illness, other medical 
condition or situation that, in the opinion of the Sponsor’s Medical Monitor or clinical site 
Investigator, continued participation in the study would not be in the best interest of the 
subject. 
 
 
Study closure due to a decision by the regulatory authorities or Sponsor. 
 
 
Subjects who discontinue study drug because of adverse events should be encouraged to 
complete visits through Day 98 and to complete the 6-week post-drug surveillance phase of the 
study.   
 
9.2.2 
Rules for Suspension of the Entire Study 
 
 
Interim rules to halt enrollment until an ad hoc safety review is convened are based on simple 
proportionality, and are therefore: 
 
Hematologic SAEs:  
Grade 3: >2 in 20 enrolled subjects, 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
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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. 
 
 
 
 
 
Grade 3: >3 in 30 enrolled subjects, 
 
 
 
 
 
Grade 4: Any. 
 
 
Based on the known toxicity profile of the study drug, non-hematologic SAEs related to study 
drug are not likely to occur.  Halting-rules for non-hematologic SAEs related to study drug are 
therefore not specified in this protocol.  Instead, non-hematologic SAEs related to study drug will 
be reported to the Medical Monitor.  The Medical Monitor will assess whether to convene an ad hoc 
review.  The following are provided to the Medical Monitor as guideline thresholds to convene an 
ad hoc review, but they are not to be binding:   
 
 
Non-Hematologic SAEs related to study drug:  
Grade 3: >1 in 30 enrolled subjects, 
 
 
 
 
 
 
 
 
 
Grade 4: Any. 
 
 
The objective of an ad hoc review would be to render a decision as to whether the study should 
continue per protocol, proceed with caution, be further investigated, be discontinued, or the trial be 
modified and then proceed.  Suspension of enrollment for the entire study is a potential outcome of 
a safety review. 
 
 
The review of serious, unexpected and related adverse events by the Medical Monitor, IRB, the 
Sponsor, and regulatory authorities may also result in suspension of further study drug 
administration. The regulatory authorities and the study sponsor retain the authority to suspend 
additional enrollment and study drug administration for the entire study as applicable. 
 
10 
STATISTICAL CONSIDERATIONS 
 
 
This study is a 14 week double-blind, placebo-controlled, study to establish the efficacy of once 
weekly oral LD-AMT in the treatment of moderate-to-severe psoriasis.  The co-primary endpoints 
are 1) the PASI 75, a composite measure; and 2) the Static Physician Global Assessment (sPGA) 
dichotomized to success or failure.  The efficacy of LD-AMT will be established by comparing: 1) 
the proportion of subjects attaining a PASI 75 in the placebo arm and active LD-AMT arm; and 2) 
the proportion of subjects attaining a sPGA success (a score of 0 or 1) in the placebo arm and active 
LD-AMT arm.  These comparisons will be made using the Fisher’s exact test. The null hypothesis 
is no treatment effect or equality of proportions, and the alternative hypothesis is that 3 mg LD-
AMT/week is effective at providing a greater proportion of PASI 75 than placebo, or that 3 mg LD-
AMT/week is effective at providing a greater proportion of sPGA success than placebo. 
 
 
All descriptive and inferential statistical analyses will be performed using SAS® version 9.3, R 
version 3.01, or Strata version 13 or higher. Descriptive statistics for continuous variables will 
consist of the mean, median, geometric mean (where appropriate), standard deviation, minimum, 
and maximum values. For categorical variables, the number and percentage of each category will be 
displayed for each treatment group. For the analysis of safety and immunogenicity endpoints, a two-
sided alpha level of 5% will be used. All statistical tests will be two-tailed unless otherwise stated. 
 
 
Demographics will be compared among treatment groups using Fisher’s exact test for 
categorical variables and either a two-sided t-test or the Wilcoxon sum-rank test for continuous 
variables depending on the distribution of the underlying data. Calculations and statistical analyses 
will be described in further detail as part of a statistical analysis plan. 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
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48 
 
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. 
 
10.1 
Determination of Sample Size 
 
 
For the purpose of determining the sample size for this study, the sPGA results indicating the 
success and failure endpoint for placebo and antifolate treatment of psoriasis was not available.  In 
contrast, PASI 75 endpoint results were available.  Based on these results the proportion of PASI 75 
achieved in subjects treated with placebo is assumed to be 15%, the proportion of PASI 75 achieved 
in subjects treated with 3.0 mg/week LD-AMT dose is assumed to be 60%, and using a significance 
level (2-sided alpha) of 0.05, giving a final sample size of 46 subjects.  This sample size provides 
approximately 85% power to detect a statistically significant efficacy-response. The sample size 
was calculated assuming that a two-sided Fisher’s exact test will be used to analyze the primary 
endpoint.  Moderate loss to follow-up will still result in adequate power – the power would be 
approximately 80% assuming 10% loss to follow-up. 
 
 
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.”  The 
table below shows the sample size sensitivity analysis for a range of deviations in sample size, 
power and treatment effect size assuming a 2-sided alpha of 0.05 and a placebo PASI75 of 15% 
(power computed using http://hedwig.mgh.harvard.edu/sample_size/fisher/js/fisher.html). 
 
 
N 
PASI75 
46 
50 
54 
58 
62 
60% 
0.85 
0.89 
0.91 
0.93 
0.95 
55% 
0.76 
0.80 
0.84 
0.86 
0.89 
50% 
0.64 
0.68 
0.73 
0.76 
0.80 
 
 
Considering a power of 0.80 a minimum, the above sensitivity analysis supports a sample size 
expansion of up to 16 subjects based on a reasonable range of deviations in treatment PASI75 from 
assumptions. 
 
10.2 
Plan for Statistical Summaries and Analyses  
 
10.2.1 
General Considerations  
 
 
Statistical summaries and analyses of baseline and safety data will be provided for the ITT and 
safety population, defined as all subjects who receive at least one dose of study drug. Statistical 
summaries and analyses of folate metabolism data will be provided for the ITT and per-protocol 
population, defined as subjects who meet the inclusion/exclusion criteria, receive all 14 study drug 
doses, and complete the Day 98 visit. 
 
 
Comparisons will be made using a two sided 0.05 level of significance (α = 0.05). The null 
hypothesis for the comparison is that there is no difference between the treatment groups. Pairwise 
comparison of 3.0 mg LD-AMT and placebo will be analyzed by Fisher’s exact test for discrete 
binary comparisons. The primary efficacy analyses for the co-primary endpoints will be analyzed 
utilizing a step-down procedure, which determines statistical significance for the co-primary 
endpoints, while protecting the rate of type I error.  The order of sPGA and PASI75 analysis in the 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
49 
 
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quoted without prior written authorization from Syntrix Biosystems, Inc. 
step-down procedure will be determined in the final statistical analysis plan prepared prior to 
unblinding.  Continuous and categorical data will be analyzed according to t-test and Wilcoxon rank 
sum, respectively.   
 
 
All individual subject data listings for safety endpoints and the primary metabolism endpoint 
will be provided in separate appendices to the clinical study report. Separate listings will be 
provided for each of the treatment groups. All statistical analyses will be performed using SAS® 
version 9.3, R version 3.01, or Stata version 131 or higher. 
 
10.2.2 
Disposition of Subjects 
 
 
The following information will be summarized for each treatment group: 
 
• Number of subjects randomized 
 
• Number (%) of subjects receiving all 14 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 
 
• Number (%) of subjects with at least one protocol deviation 
 
 
Protocol deviations will be identified by the Syntrix Medical Monitor (or designee) for the trial. 
 
10.2.3 
Demographic Characteristics 
 
 
The summaries and statistical analyses of demographic characteristics will be provided for the 
safety population. 
 
10.2.4 
Safety Endpoints 
 
 
The summaries and statistical analyses of the safety endpoints will be completed for the safety 
population. Safety endpoints include AEs, any occurrence of dose-limiting toxicity, and changes in 
laboratory values. All AEs will be recorded by the Investigator in the AE CRF, and all AE terms 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
 
10.2.4.1 
Adverse Events 
 
All AE terms will be coded using MedDRA version 15 or higher. Summaries of the number (%) of 
subjects in each treatment group with at least one AE, classified according to MedDRA preferred 
term and system organ class, will be provided for: 
 
• All AEs 
• Related AEs 
• SAEs 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
50 
 
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. 
 
 
Related AEs are defined as AEs that are possibly, probably, or definitely related to study drug, 
as assessed by the study Investigator. The treatment groups will be compared with respect to the 
percentage of subjects with at least one AE using Fisher’s exact test. 
 
 
Comparisons of the treatment groups with respect to the incidence of AEs, classified according 
to preferred term and system organ class, will also be performed for all events reported by at least 5 
subjects overall. 
 
 
The following additional summaries of AEs will also be provided: 
 
• Incidence of AEs by severity of event (mild, moderate, severe, potentially life-
threatening) 
 
• Incidence of AEs by relationship to study drug (unrelated, related) 
 
10.2.4.2 
Incidence of Dose-limiting Toxicity 
 
 
The number (%) of subjects with at least one event of dose-limiting toxicity will be summarized 
for each treatment group. 
 
10.2.4.3 
Laboratory Data 
 
 
Summaries of the actual value and change from baseline for all laboratory tests will be provided 
for each study visit. A tabulated summary of laboratory abnormalities by toxicity grade will also be 
provided. 
 
10.2.4.4 
Interim Safety Analyses 
 
 
Interim safety reports will be produced during the study. 
 
10.2.4.5 
Missing Data 
 
 
Missing efficacy data, safety data, and folate metabolism data will be recorded as they are 
without imputation of missing values.  
 
10.3 
Procedure for Deviations from Planned Statistical Analyses 
 
 
The planned statistical analyses for this study will be described in detail in a statistical analysis 
plan. Modifications or additions to the analyses of study data will be described in the statistical 
analysis plan. Any decisions to deviate from the planned analyses described in the protocol will be 
documented in the clinical study report. The clinical study report will also provide a detailed 
explanation for any deviations from the planned analyses.  The final statistical analysis plan 
prepared prior to unblinding is controlling in all respects, including for any differences between the 
final statistical analysis plan and any plan in any protocol. 
 
 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
51 
 
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quoted without prior written authorization from Syntrix Biosystems, Inc. 
11 
ADMINISTRATIVE PROCEDURES 
 
11.1 
Institutional Review Board Approval 
 
 
The experimental protocol for this study has been designed in accordance with principles of 
GCP and ICH E6. The review of this protocol by the 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 CFR Part 50 Protection of Human Subjects and Part 56 Institutional 
Review Boards. 
 
 
The Investigator will be responsible for preparing documents for submission to the relevant IRB 
and obtaining written approval for this study. The approval will be obtained prior to the initiation of 
the study. 
 
11.2 
Informed Consent 
 
 
An IRB-approved study informed consent will be obtained from each subject that includes a 
description of: the investigational plan, including study procedures that include analysis of gene 
expression levels; specimen storage; risks and benefits; any study-related costs; and available 
alternative treatment options. The Investigator or his/her staff 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. 
 
11.3 
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. The Principal Investigator is required to ensure that all CRFs are 
completed for every participant entered in the trial.  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, NIH, 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. 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
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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. 
 
 
Syntrix and representatives will develop study CRFs to ensure that: (1) all information needed 
for the primary and secondary analyses are being collected in a way that will allow accurate and 
complete analysis; (2) minimal extraneous information is being collected; and (3) the format is 
efficient for recording, entering and analyzing the data. 
 
 
Syntrix or representatives will log and track CRFs to make sure that each CRF page received is 
processed in a timely manner.  Each table in the database will be carefully checked to make sure 
that all the variables specified on the CRF have been appropriately entered into the database.  Data 
will be cleaned using manual and automated data checks.  Data cleaning queries will be sent to 
investigators, appropriate ancillary staff, and clinical research monitors.  The status of data queries 
will be monitored.  Syntrix or representatives will ensure that queries are promptly addressed.  
Syntrix or representatives will work collaboratively with clinical monitors to follow-up on data 
clarification, initiating communication with the clinical site when necessary to make sure that data 
problems are promptly addressed.  This process will be used to generate clean data.   
 
 
If CRF entries are modified the clinical site staff will annotate the working copy of the CRF 
with who made the change and the date the change was made.  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. 
 
 
Syntrix is responsible for regular inspection of the conduct of the trial, for verifying adherence 
to the protocol, and for confirming the completeness, consistency, and accuracy of all documented 
data. 
 
11.4 
Modification of the Protocol 
 
 
No deviations from the protocol are permitted except in the event to avoid an immediate hazard 
to a study subject. 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 Syntrix will inform the IRB and the modification will not be implemented until approved by the 
IRB. 
 
11.5 
Protocol Deviation(s) 
 
 
A protocol deviation is any noncompliance with the clinical trial protocol.  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 on CRFs and included in the study 
database and 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. 
 
11.6 
Departure from the Protocol 
 
 
A departure the protocol may be required if an emergency involving a subject occurs as 
permitted by ICH/GCP Guidelines 4.5.2, 4.5.4.  The Investigator, or other physicians in attendance, 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
53 
 
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. 
in such an emergency will, if circumstances and time permit, contact Syntrix immediately by 
telephone. The CRFs 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. 
 
11.7 
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. 
 
11.8 
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. 
 
11.9 
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. 
 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
01 December 2018 
 
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quoted without prior written authorization from Syntrix Biosystems, Inc. 
 
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. 
 
11.10 
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. 
 
11.11 
Exclusion of Women, Minorities, and Children (Special Populations) 
 
 
Women comprise roughly half of all subjects with moderate-to-severe psoriasis although there 
tends to be a slightly greater female prevalence in the third decade of life.  This is reflected in the 
subject population at this study’s clinical sites.  Thus, women are expected to make up roughly half 
of the study population. 
 
 
Children and subjects less than 18 years of age are excluded from this phase 2 study.   Thus, 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.   
 
11.12 
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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quoted without prior written authorization from Syntrix Biosystems, Inc. 
Appendix A: Schedule of Study Visits and Procedures 
 1 At each visit study drug is counted and a single dose can be taken if it maintains the exact weekly administration cycle 
of study drug.  
2 Contraception is to be used while on study and for 90 days after the last study drug dose. 
3 Physical exam performed as directed and required by interim history. 
4 Chemistries include BUN, creatinine, AST, ALT, alkaline phosphatase, total bilirubin, albumin and total protein. 
5 Urine pregnancy tests for women of child-bearing potential only.  Tests will be performed during subject’s visit, prior 
to dosing. 
6 The specific amount of blood will be indicated and processed as described in study specific procedures. 
Procedure 
Screen 
Treatment 
 Phase 
Post-Treatment 
Phase 
Days 
-30 
to 
0 
Day 
 0 
Day 
 14(±2) 
Day 
42(±3) 
Day 
 70(±3) 
Day 
98(±3) 
Day 
119(±4) 
Day 
140(±4) 
Week 
0 
Week 
2 
Week 
6 
Week 
10 
Week 
14 
Week 
17 
Week 
20 
Randomization 
 
X 
 
 
 
 
 
 
Study Drug Dispensed  
 
X 
 
 
 
 
 
 
Study Drug Administer1 
 
X 
X 
X 
X 
 
 
 
Clinical 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Contraception Requirements2 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medical History & Physical Exam 
X 
X3 
 
X3 
X3 
X3 
 
 
 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
X 
 
 
 
Assess Psoriasis BSA involvement 
X 
 
 
 
 
 
 
 
 
 PASI 
X 
X 
 
 
 
X 
 
 
 
sPGA 
 
X 
 
 
 
X 
 
 
 
Dermatology Life Quality Index 
 
X 
 
 
 
X 
 
 
 
Review Patient Diary 
 
 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
Safety Lab Tests 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
 
X 
X 
X 
X 
 
 
 
Chemistries4 
X 
 
X 
X 
X 
X 
 
 
 
HIV1/2, Hepatitis B & C Serology 
X 
 
 
 
 
 
 
 
 
UA 
X 
 
 
 
 
X 
 
 
 
Pregnancy Test5 
X 
X 
X 
X 
X 
X 
 
X 
Folate Metabolism Studies 
 
 
 
 
 
 
 
 
 
Collect Blood6  
 
X 
 
 
 
 
 
 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
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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 B.  Calculation of Selected Inclusion and Exclusion Criteria 
 
1.  Inclusion Criteria:  Creatinine Clearance Estimate by Cockcroft-Gault Formula 
 
 
 
 
 
 
creatinine clearance = [(140 – age) x weight] 
 
 
 
 
 
 
72 x SCR 
 
where,  
age is in years 
 
 
 
weight is in kg 
 
 
 
serum creatinine (SCR) is in mg/dL. 
 
 
 
creatinine clearance is ml/min 
 
in females, the result is multiplied by 0.85 (Cockcroft '76).  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 . 
 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
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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 Value 1 
 
Grade 
Adverse Event 
1 
2 
3 
4 
WBC decreased 
< LLN – 3,000/mm3 
<3,000 – 2,000/mm3 
<2,000 – 1,000/mm3 
<1,000/mm3 
Anemia 
Hemoglobin (Hgb) <LLN – 
10.0 g/dL 
Hgb <10.0 – 8.0 g/dL 
Hgb <8.0 g/dL 
Life-threatening 
consequences; urgent 
intervention indicated 
Platelet count decreased < LLN – 75,000/mm3 
<75,000 – 50,000/mm3 
<50,000 – 25,000/mm3 
< 25,000/mm3 
AST (SGOT) increased 
> ULN – 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20 x ULN 
> 20 x ULN 
ALT (SGPT) increased 
> ULN – 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20 x ULN 
> 20 x ULN 
Alkaline phosphatase 
increased 
> ULN - 2.5 x ULN 
> 2.5 - 5.0 x ULN 
>5.0 - 20 x ULN 
> 20 x ULN 
Total bilirubin increased > ULN - 1.5 x ULN 
> 1.5 - 3.0 x ULN 
>3.0 - 10 x ULN 
> 10 x ULN 
Hypoalbuminemia 
<LLN – 3 g/dL 
<3 – 2 g/dL 
<2 g/dL 
Life-threatening 
consequences; urgent 
intervention indicated 
 
 
 
 
 
1 US Dept. of Health and Human Services, NIH, NCI, Common Terminology Criteria for Adverse Events, Version 4.0 28 May 2009 (v4.03, 14 June 2010). ULN=upper limit of normal; 
LLN=lower limit of 
normal; Hgb=hemoglobin; 


Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
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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. 
References 
 
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Syntrix-AMT-PSO-201, Protocol version 1.8 
 
 
 
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quoted without prior written authorization from Syntrix Biosystems, Inc. 
Wollina, U., K. Stander, et al. (2001). "Toxicity of methotrexate treatment in psoriasis and psoriatic 
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SAP_001.pdf: 
Version 0.4 (2020-10-21) 
Syntrix AMT-PSO-201 
Protocol Version 1.8 (2018-12-01) 
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 Template Version Date: 2019-02-15 
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DF/Net Research Inc. 
Building Relationships  
With People And Their Data 
140 Lakeside Avenue, Suite 310 
Seattle, WA 98122 USA 
1-206-322-5931 / phone 
1-206-322-5932 / fax 
www.dfnetresearch.com 
 
 
CLINICAL STATISTICAL ANALYSIS PLAN 
Syntrix Biosystems Inc. 
 
 
A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL TO ESTABLISH THE 
EFFICACY AND SAFETY OF ONCE WEEKLY ORAL AMINOPTERIN FOR THE TREATMENT OF 
SUBJECTS WITH MODERATE-TO-SEVERE PSORIASIS 
Client: Syntrix Biosystems Inc. 
 
Protocol: Syntrix-AMT-PSO-201 Version 1.8, 01DEC2018 
 
 
SAP Version: 0.4 
Date of Version: 2020-10-21 
 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or institutional 
review boards.  The contents of this document shall not be disclosed to others without written 
authorization from Themis (or others, as applicable), unless it is necessary to obtain informed consent 
from potential study subjects. 
 
 
 
 
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SPONSOR APPROVAL 
By signing below, I certify that I approve of the Statistical Analysis Plan for this project. 
Printed Name and Title: 
Stuart Kahn, Medical Director, Syntrix Biosystems, Inc. 
Signature and Approval Date: 
 
 
 
 
 
DF/NET APPROVAL 
By signing below, I certify that I approve of the Statistical Analysis Plan for this project. I also certify that 
the analyses will be performed in accordance with this Statistical Analysis Plan. 
Printed Name and Title: 
Joe Jiang, DF/Net Research Inc. 
Signature and Approval Date: 
 
 
 
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2/13/2023
2/13/2023


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Revision History 
 
Version 
Date 
Author(s) 
Organization(s) 
Purpose 
0.1 
27MAR2017 
Matt Johnson 
DF/Net Research, Inc. 
New document 
0.2 
25MAR2019 
Matt Johnson 
DF/Net Research, Inc. 
Revised version based on 
updated protocol 
0.3 
28MAY2019 
Matt Johnson 
DF/Net Research, Inc. 
Edits based on DF/Net review 
0.4 
21OCT2022 
John Zebala 
Syntrix Biosystems, Inc. 
Early termination by LOCF 
 
 
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS  
1-INTRODUCTION ................................................................................................ 5 
2-STUDY OBJECTIVES ........................................................................................... 5 
2.1 
Primary Objective .............................................................................................. 5 
2.2 
Secondary Objectives ......................................................................................... 5 
2.3 
Exploratory Objectives ....................................................................................... 5 
3-STUDY ENDPOINTS ........................................................................................... 6 
3.1 
Primary Endpoint ............................................................................................... 6 
3.2 
Secondary Endpoints ......................................................................................... 6 
3.3 
Safety Endpoints ................................................................................................ 6 
3.3 
Exploratory Endpoints ....................................................................................... 6 
4-DEFINITIONS ..................................................................................................... 6 
5-STUDY DESIGN .................................................................................................. 7 
5.1 
Study Schedule .................................................................................................. 8 
6-STUDY POPULATION ......................................................................................... 9 
6.1 
Inclusion Criteria ................................................................................................ 9 
6.2 
Exclusion Criteria ............................................................................................... 9 
6.3 
Withdrawal of Study Subject ............................................................................ 10 
6.4 
Randomization and Blinding ............................................................................ 10 
7-SAMPLE SIZE ................................................................................................... 10 
7.1 
Determination of Sample Size .......................................................................... 10 
8-STATISTICAL CONSIDERATIONS ....................................................................... 11 
8.1 
Primary Efficacy Analyses ................................................................................. 11 
8.2 
Secondary Efficacy Analyses ............................................................................. 11 
8.3 
Safety Analyses ................................................................................................ 12 
8.3.1 Safety Assessments .........................................................................................12 
8.3.2 Adverse Events ................................................................................................12 
8.3.3 Incidence of Dose-limiting Toxicity ...................................................................13 
8.3.4 Safety Laboratory Tests ....................................................................................13 
8.4 
Exploratory Analyses ....................................................................................... 13 
8.5 
Demographic and Other Baseline Characteristics.............................................. 13 
8.6 
Subject Disposition .......................................................................................... 13 
8.6 
Vital Signs ........................................................................................................ 14 
8.7 
Concomitant Medications ................................................................................ 14 
8.8 
Physical Exam Findings .................................................................................... 14 
8.9 
Missing Values ................................................................................................. 14 
10-SUGGESTED TABLES/LISTINGS/FIGURES ....................................................... 15 
APPENDIX I: ABBREVIATIONS ............................................................................ 17 
 
 
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1-INTRODUCTION 
The purpose of this document is to describe the reporting and statistical analyses that will guide 
the preparation of the clinical portion of the final study report for Syntrix Biosystems Inc study 
AMT-PSO-201.  
The study report will be prepared after all study subjects have completed the follow-up, all data 
in the database through the follow-up have been reviewed, all data queries have been resolved, 
and the database has been locked. 
All individual subject listings, summary tables, and statistical analyses described below will be 
provided in separate appendices to the study report. Unless other indicated, all listings and 
summary tables will be provided by treatment group. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials [ICH 1998] and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports [ICH 1995].  
2-STUDY OBJECTIVES 
The purpose of this study is to determine the efficacy and safety of LD-AMT in adult subjects with 
moderate-to-severe psoriasis who have not been treated with MTX  
2.1 Primary Objective 
To determine the efficacy of 3 mg oral LD-AMT in the treatment of moderate-to-severe psoriasis 
compared to a placebo. 
2.2 Secondary Objectives 
To determine the safety of 3 mg oral LD-AMT in the treatment of moderate-to-severe psoriasis 
compared to a placebo. 
2.3 Exploratory Objectives 
To assess the relationship of each subjects’ cytoplasmic and mitochondrial folate metabolism to 
the subjects’ efficacy and safety outcomes. 
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3-STUDY ENDPOINTS 
3.1 Primary Endpoint 
The co-primary endpoints are: 
1. Proportion of subjects achieving Psoriasis Activity and Severity Index of 75% (PASI 75) at 
study Day 98 (14 weeks).  
2. Static Physician Global Assessment (sPGA) dichotomized to success or failure at study Day 
98 (14 weeks). 
3.2 Secondary Endpoints 
1. Proportion of subjects achieving PASI 50 at study Day 98 (14 weeks).  
2. Mean reduction in the PASI at study Day 98 (14 weeks).  
3. Proportion of subjects achieving “success” in erythema at study Day 98 (14 weeks).  
4. Proportion of subjects achieving “success” in scaling at study Day 98 (14 weeks).  
5. Proportion of subjects achieving “success” in plaque induration at study Day 98 (14 
weeks). 
3.3 Safety Endpoints 
Safety endpoints are adverse events, including changes in laboratory values and the occurrence of dose 
limiting toxicity. Safety endpoints will be evaluated throughout the study and for an additional 42 days 
after a subject completes the treatment period of the study at Study Day 98. 
3.3 Exploratory Endpoints 
1. Mean hematologic (e.g., hemoglobin, platelets, leukocytes) and hepatic laboratory (e.g., 
SGOT, SGPT) values over the treatment-phase.  
2. Fraction of abnormal hematologic and hepatic laboratory values over the treatment-
phase.  
3. Cumulative incidence of abnormal hematologic and hepatic laboratory values as a 
function of time over the 12-week treatment-phase.  
4. Mitochondrial and cytoplasmic folate metabolism correlates with AMT efficacy and 
toxicity. 
4-DEFINITIONS 
The following definitions apply to the summary tables and statistical analyses planned for the study 
report: 
Screened population: All subjects who were screened. 
Intent-to-treat (ITT) population: All subjects who were randomized to treatment. 
Safety population: All subjects who received at least one study dose.  
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Per-protocol (PP) population: All subjects who received all 14 study drug doses and completed the 
Day 98 visit. 
Baseline value: Most recent value recorded prior to the first study drug administration.  
Treatment group: One of the two treatment assignments (3 mg LD-AMT and placebo). 
Visit Day: The scheduled Visit Day, for example Day 14.  
Study Day: The day on study that a visit actually took place (date of visit minus the date of 
enrollment, Day 0). For example an adverse event onset might be on Study Day 5; or a scheduled 
Visit Day 42 evaluation could take place on Study Day 44.  
Protocol deviation: Any noncompliance with the clinical trials protocol, Good Clinical Practice 
(GCP), or SOP requirements. Noncompliance may be either on the part of the subject, the 
investigator , or the study site staff.  
5-STUDY DESIGN 
This is a phase 2, multi-center, randomized, double-blind, placebo-controlled, clinical trial to 
investigate the efficacy, safety, of LD-AMT in the treatment of subjects with moderate psoriasis 
who have not been treated with MTX. Folate metabolism biomarkers will be studied to determine 
their correlation with efficacy and safety. Forty-six subjects will be randomized to one of two 
parallel treatment arms: LD-AMT (3 mg) or placebo, in a 1:1 ratio. LD-AMT tablets or placebo 
tablets will be administered once weekly for 14 weeks. Randomized subjects will initially enter a 
14-week treatment phase, followed by a 6-week post-treatment phase. The first study drug 
administration will be on Day 0. 
Subjects in both treatment groups will receive 14 once weekly oral treatments (6 tablets).  
 
General safety will be evaluated for each subject on Days 0, 14, 42, 70, 98, 119, and 140. Subjects 
will be evaluated for signs and symptoms of study drug intolerance. Subjects will complete weekly 
diaries to record study drug administration, and signs and symptoms of AEs. Blood will be obtained 
at baseline and on Days 14, 42, 70, and 98. 
 
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5.1 Study Schedule 
 
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6-STUDY POPULATION 
The study population is MTX-naïve subjects with moderate psoriasis 21 years of age or older.  A 
subject is considered enrolled or randomized in the study once they have completed the 
informed consent, completed the baseline assessments indicating that they are eligible, and have 
been assigned a participant identification number (PID#).   
6.1 Inclusion Criteria 
1. Be 21 years of age or older. 
2. Have a diagnosis of moderate psoriasis for at least 6 months confirmed by a 
dermatologist, defined here as plaque-type psoriasis affecting a body surface area of 3% 
to 10%. 
3. Agree to avoid prolonged sun exposure and avoid use of tanning booths or other 
ultraviolet light sources during the study. 
4. Ability to understand and sign written informed consent. 
5. For sexually active men and for women of childbearing potential, an adequate form of 
contraception. 
6. For pre-menopausal women, a negative pregnancy test, obtained within 1 week prior to 
first study drug dose. 
7. Negative serology for HIV1/2, hepatitis B and hepatitis C. 
8. The following screening laboratory blood tests must have the following values, or not 
clinically significant as determined by the PI and Medical Monitor: WBC WNL; absolute 
neutrophil count > lower limit of normal; platelet count WNL; hemoglobin >10.0 g/dL; AST 
< 2.5 x the upper limit of normal. 
9. Adequate renal function: GFR estimated by Cockcroft-Gault formula >60 ml/min   
6.2 Exclusion Criteria  
Subjects who meet ANY of the following criteria will be excluded from the study (ineligible):  
1. Known history of hepatitis, HIV infection, interstitial lung disease.  
2. Greater than moderate alcohol consumption on a regular basis (moderate consumption 
for females is 1 drink or 1 glass of wine a day; for males is 2 drinks or 2 glasses of wine a 
day) and unwilling, or unable, to control consumption during the study period.  
3. Prior use of MTX, AMT, cyclosporine, biologic drug therapy (e.g., etanercept, adalimumab, 
infliximab), or interleukin-2-diptheria-toxin.  
4. Within 4 weeks prior to randomization and at any time while on study, use of 
phototherapy (e.g., UVB, narrow band UVB, Goeckerman regimen, Ingram regimen, 
PUVA), systemic medications (e.g. acitretin, mycophenolate mofetil, tacrolimus/FK506, 
azathioprine, 6-thiogaunine, sulfasalazine, hydroyurea, calcitriol, any systemic 
immunosuppressants), lithium, or any treatments that could affect psoriasis or sPGA 
evaluations. Subjects are eligible 4 weeks after the last dose of any of the aforementioned 
treatments was received.  
5. Within 2 weeks prior to randomization and at any time while on study, use of any topical 
medications or treatments that could affect psoriasis evaluations (e.g., corticosteroids, 
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anthralin, vitamin D3/calcitriol and analogues such calcipotriene and tacalcitol, synthetic 
retinoids such as tazarotene, coal tar, and keratolytics such as salicylic acid, lactic acid and 
urea including those contained in over-the-counter medicated shampoos). Subjects are 
eligible 2 weeks after the last dose of any of the aforementioned treatments was 
received.  
6. Use of emollients on the morning of the first (Week 0) study visit.  
7. Within 2 weeks prior to Study Day 0, or on Study Day 0, or at any time during the study, 
use of any of the following medications that may result in drug/drug interactions with 
AMT: trimethoprim with or without sulfamethoxazole; sulfonamides; sulfonylureas; 
pyrimethamine; triamethamine; salicylates; non-steroidal anti-inflammatory (NSAID) 
drugs including ibuprofen; dipyridamole; colchicine; probenecid; aminoglycosides; 
theophylline; phenytoin; and folinic acid (i.e., leucovorin).  
8. Known concurrent malignancy except basal or squamous cell skin carcinoma, or cervical 
carcinoma in situ.  
9. Concurrent participation in another clinical trial involving experimental treatment within 
30 days of Study Day 0.  
10. Current and uncontrolled infection, cardiovascular, renal, pulmonary, hepatic or GI 
conditions that will interfere with the conduct of the trial or pose a morbid risk.  
11. Investigator’s opinion that a concurrent disease or condition impairs the subject’s ability 
to complete the trial: includes psychological, familial, sociological, geographical or medical 
conditions. 
6.3 Withdrawal of Study Subject  
Subjects will be free to withdraw from the study at any time, for any reason, and without 
prejudice to further treatment.  Any subject who withdraws from the study, regardless of reason, 
will not be allowed to re-enroll in this study.  Reasons for withdrawal will be recorded on the 
appropriate CRF.   The final report will include reasons, if available, for withdrawal and any 
necessary treatment. 
Anytime a subject withdraws from the study, for whatever reason, including voluntary 
withdrawal, every attempt should be made to evaluate all procedures planned for the Study Day 
98 visit. 
6.4 Randomization and Blinding 
A total of 46 subjects will be enrolled, 23 in the LD-AMT treatment arm, and 23 in the placebo 
arm. Subjects will be randomly assigned to receive LD-AMT or placebo. 
7-SAMPLE SIZE 
7.1 Determination of Sample Size 
Using a Fisher’s exact test and assuming the proportion of PASI 75 achieved in subjects treated 
with placebo is 15% and those treated with 3.0 mg/week LD-AMT dose is 60%, then at a 
significance level (1-sided alpha) of 0.05 we expect the study to be sufficiently powered with 46 
subjects. This sample size provides approximately 91.25% power to detect a statistically 
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significant efficacy-response. Moderate loss to follow-up will still result in high power – the 
power would be approximately 87.5% assuming 10% loss to follow-up. 
8-STATISTICAL CONSIDERATIONS 
Statistical summaries and analyses of baseline and safety data will be provided for the ITT and 
safety population. Statistical summaries and analyses of folate metabolism data will be provided 
for the ITT and per-protocol population. 
SAS® version 9.3 will be used for statistical analyses and the production of tables, listings, and 
figures (TLFs). 
Categorical variables will be summarized using the number frequency and percentage by 
treatment and overall of subjects falling into each category. Continuous variables will be 
summarized using mean, standard deviation, median, geometric median (where appropriate) 
minimum and maximum by treatment and overall. Statistical tests will use a significance level of 
5% and will be two-tailed unless otherwise stated. 
8.1 Primary Efficacy Analyses 
The efficacy of LD-AMT established using a step-down analysis approach with one-sided Fisher’s 
exact tests. First, the analysis for subjects attaining PASI 75 will be performed, then, if that 
analysis shows a significant treatment effect, analysis for subjects attaining a sPGA success will be 
performed. The following are the first and second step-down efficacy analyses:  
1. The proportion of subjects attaining a PASI 75 in the placebo arm vs. active LD-AMT arm. 
- 
The null hypothesis is no treatment effect or equality of proportions. 
- 
The alternative hypothesis is that 3 mg LD-AMT/week is effective at providing a 
greater proportion of PASI 75 than placebo. 
2. The proportion of subjects attaining a sPGA success (a score of 0 or 1) in the placebo arm 
vs. active LD-AMT arm. 
- 
The null hypothesis is no treatment effect or equality of proportions. 
- 
The alternative hypothesis is that 3 mg LD-AMT/week is effective at providing a 
greater proportion of sPGA success than placebo. 
8.2 Secondary Efficacy Analyses 
The efficacy of LD-AMT established using one-sided Fisher’s exact tests:  
1. Proportion of subjects achieving PASI 50 at study Day 98 (14 weeks). 
- 
The null hypothesis is no treatment effect or equality of proportions. 
- 
The alternative hypothesis is that 3 mg LD-AMT/week is effective at providing a 
greater proportion of PASI 50 than placebo. 
2. Proportion of subjects achieving “success” in erythema at study Day 98 (14 weeks).  
- 
The null hypothesis is no treatment effect or equality of proportions. 
- 
The alternative hypothesis is that 3 mg LD-AMT/week is effective at providing a 
greater proportion of erythema success than placebo. 
3. Proportion of subjects achieving “success” in scaling at study Day 98 (14 weeks).  
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- 
The null hypothesis is no treatment effect or equality of proportions. 
- 
The alternative hypothesis is that 3 mg LD-AMT/week is effective at providing a 
greater proportion of scaling success than placebo. 
4. Proportion of subjects achieving “success” in plaque induration at study Day 98 (14 
weeks). 
- 
The null hypothesis is no treatment effect or equality of proportions. 
- 
The alternative hypothesis is that 3 mg LD-AMT/week is effective at providing a 
greater proportion of plaque induration success than placebo. 
The efficacy of LD-AMT established using a one-sided Wilcoxon rank-sum test:  
5. Mean reduction in the PASI at study Day 98 (14 weeks).  
- 
The null hypothesis is no treatment effect or equality of means. 
- 
The alternative hypothesis is that 3 mg LD-AMT/week is effective at providing a 
greater reduction in mean PASI than placebo. 
8.3 Safety Analyses 
8.3.1 Safety Assessments 
The safety assessments will be based on clinical AEs reported by the subject or observed by the 
investigator (or appropriate designee) and laboratory AEs reported as test results. 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. Laboratory AEs considered not clinically significant will not be recorded on the 
AE CRF. The summaries and statistical analyses of the safety endpoints will be completed for the safety 
population. 
8.3.2 Adverse Events 
All AE terms will be coded using MedDRA 21.1 and classified according to preferred term (PT) and system 
organ class (SOC). Summaries by PT and SOC of the number (%) of subjects in each treatment group and 
overall with at least one AE, will be provided for: 
1. All AEs 
2. Related AEs 
3. SAEs 
Related AEs are defined as AEs that are possibly, probably, or definitely related to study injection. The 
treatment groups will be compared using Fisher’s exact test. 
Comparisons of the treatment groups with respect to the incidence of AEs by PT and SOC will also be 
performed for all events reported by at least 5 subjects overall. 
The following additional summaries of AEs will also be provided: 
1. Incidence of AEs by severity of event (mild, moderate, severe, potentially life-threatening) 
2. Incidence of AEs by relationship to study drug (unrelated, related) 
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8.3.3 Incidence of Dose-limiting Toxicity 
The number (%) of subjects with at least one event of dose-limiting toxicity will be summarized for each 
treatment group and overall. 
8.3.4 Safety Laboratory Tests 
Summaries of the actual value and change from baseline for all laboratory tests will be provided for each 
study visit. A tabulated summary of laboratory abnormalities by toxicity grade will also be provided. 
8.4 Exploratory Analyses 
Descriptive statistics including mean, standard deviation and range will be presented for the hematologic 
and hepatic laboratory variables of each of these treatments and overall over by visit day. Furthermore, 
the fraction and cumulative incidence of abnormal hematologic and hepatic laboratory values will be 
summarized by treatment and visit day.  
Analysis of the role of the cytoplasmic and mitochondrial compartments in folate metabolism will be 
performed. Assessment of folate metabolism will be performed with blood specimens obtained at 
baseline. Endpoints of interest include the ratio of mitochondrial to cytoplasmic DNA and the expression 
levels of DHFR and thymidylate synthase. These results will be correlated with study trial efficacy and 
safety outcomes. The evaluation of folate metabolism will be performed on subject leukocytes obtained at 
baseline and on Day 98 and based on measurements of:  
1. cytoplasmic and mitochondrial DHFR quantification 
2. cytoplasmic and mitochondrial thymidylate synthase quantification 
3. nuclear DNA uracil quantification 
4. polyglutamated AMT types and quantity. 
8.5 Demographic and Other Baseline Characteristics 
A table will summarize each treatment group and overall demographics characteristics of 
subjects in the safety population. Age, gender and race will be compared among treatment 
groups using Fisher’s exact test for categorical variables and either a two-sided t-test or the 
Wilcoxon rank-sum test for continuous variables depending on the distribution of the underlying 
data. 
8.6 Subject Disposition 
A table will summarize each treatment group and overall for: 
1. Number of subjects randomized 
2. Number (%) of subjects receiving all 14 study drug doses 
3. Number (%) of subjects who discontinued the study and reasons for discontinuation 
4. Number (%) of subjects in the per-protocol population and reasons for those excluded 
5. Number (%) of subjects with at least one protocol violation 
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8.6 Vital Signs 
A table will summarize each treatment group and overall vital sign values for subjects in the 
safety population. 
8.7 Concomitant Medications 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (WHODrug Global B3 September 1, 2017 dictionary). Concomitant medications will be 
summarized by dose level using descriptive statistics.  Tabulation will be made with respect to the 
proportion of subjects taking at least 1 concomitant medication for each preferred term during 
the study. 
8.8 Physical Exam Findings 
Abnormal findings in physical examinations will be summarized by dose level using descriptive 
statistics. 
8.9 Missing Values 
The investigators of this study will assume that any data is missing completely at random (MCAR). 
As such, a complete case analysis will be performed and any missing efficacy data, safety data, 
and/or folate metabolism data will be excluded without imputation.  Early drop-outs will be 
handled by LOCF. 
 
 
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10-SUGGESTED TABLES/LISTINGS/FIGURES 
Type 
Title 
Population 
Listing 
L16.2.1-Disposition 
Screened 
Listing 
L16.2.2-Protocol Deviations 
Screened 
Listing 
L16.2.3-Patients Excluded from PP Population 
Safety 
Listing 
L16.2.4-Demographics 
Safety 
Listing 
L16.2.5.1-Study Drug Accounting 
Safety 
Listing 
L16.2.5.2-Concomitant Medications 
Safety 
Listing 
L16.2.6.1-PASI 
PP 
Listing 
L16.2.6.3-sPGA 
PP 
Listing 
L16.2.7.1-Adverse Events (AE) 
Safety 
Listing 
L16.2.7.2-Serious Adverse Events (SAE) 
Safety 
Listing 
L16.2.7.3-Related Adverse Events (TRAE) 
Safety 
Listing 
L16.2.7.4-Dose-Limiting Toxicity (DLT) 
Safety 
Listing 
L16.2.8.1-Abnormal Laboratory Results 
Safety 
Listing 
L16.2.8.2-Laboratory Results (Hemogram, Differential, Serum Chemistry, Urinalysis) 
Safety 
Listing 
L16.2.8.3-Folate Metabolism 
Safety 
Listing 
L16.2.9-Vital Signs 
Safety 
Listing 
L16.2.10-Physical Exam Findings 
Safety 
Listing 
L16.2.11- Medical History 
Safety 
Listing 
L16.4-Patient Profile 
Safety 
Table 
T14.1.1-Disposition Summary 
Screened 
Table 
T14.1.2-Demographics Summary 
Safety 
Table 
T14.2.1-Primary-PASI 75 Analysis 
PP 
Table 
T14.2.2-Primary-sPGA Analysis 
PP 
Table 
T14.2.3-Secondary-PASI 50 Analysis 
PP 
Table 
T14.2.4-Secondary-Erythema Analysis 
PP 
Table 
T14.2.5-Secondary-Scaling Analysis 
PP 
Table 
T14.2.6-Secondary-Plaque Induration Analysis 
PP 
Table 
T14.2.7-Secondary-PASI Reduction Analysis 
PP 
Table 
T14.2.8-Exploratory-Folate Metabolism Summary 
PP 
Table 
T14.3.1.1-Adverse Events (AE) Summary 
Safety 
Table 
T14.3.1.2-Adverse Events (AE) by SOC/PT Summary 
Safety 
Table 
T14.3.2.1-Serious Adverse Events (SAE) Summary 
Safety 
Table 
T14.3.2.2-Serious Adverse Events (SAE) by SOC/PT Summary 
Safety 
Table 
T14.3.3.1-Related Adverse Events (RAE) Summary 
Safety 
Table 
T14.3.3.2-Related Adverse Events (RAE) by SOC/PT Summary 
Safety 
Table 
T14.3.3.3-Incidence of AEs by Severity 
Safety 
Table 
T14.3.3.4-Incidence of AEs by Relationship 
Safety 
Table 
T14.3.3.5-Dose-Limiting Toxicity (DLT) Summary 
Safety 
Table 
T14.4-Concomitant Medication Summary 
Safety 
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Table 
T14.5-Laboratory Results Summary (Hemogram, Differential, Serum Chemistry, Urinalysis) 
Safety 
Table 
T14.6-Vital Signs Summary 
Safety 
Table 
T14.7-Physical Exam Findings Summary 
Safety 
 
 
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APPENDIX I: ABBREVIATIONS 
 Abbreviation 
Meaning 
ACPA 
Anti-citrullinated protein antibody 
ACR 
American College of Rheumatology 
ACR20 
American College of Rheumatology 20% Improvement Criteria 
AE 
Adverse Event 
AMT 
Aminopterin 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
CRO 
Contract Research Organization 
DAS 
Disease Activity Score 
DLT 
Dose Limiting Toxicity 
DMARD 
Disease Modifying Anti-Rheumatic Drug 
ESR 
Erythrocyte Sedimentation Rate 
EULAR 
European League Against Rheumatism 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Assurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IND 
Investigational New Drug 
IRB 
Institutional Review Board  
ITT 
Intention-To-Treat 
LD-AMT 
LD-aminopterin 
LOCF 
Last Observation Carried Forward 
MTD 
Maximum Tolerated Dose 
MedDRA © 
Medical Dictionary for Regulatory Activities 
MTX 
Methotrexate 
N 
Number (typically refers to subjects) 
NDA 
New Drug Application 
PG 
Polyglutamate 
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PI 
Principal Investigator 
PK 
Pharmacokinetics 
QA 
Quality Assurance 
QC 
Quality Control 
RA 
Rheumatoid Arthritis 
RF 
Rheumatoid Factor 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
WNL 
Within Normal Limits 
 
 
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