Randomized, Double-Blind, Placebo-Controlled, Three-Arm, 12-Month, Safety and Efficacy Study of TRx0237 Monotherapy in Subjects With Alzheimer's Disease Followed by a 12-Month Open-Label Treatment
Phase: PHASE3
Conditions: Alzheimer Disease
Sponsor: TauRx Therapeutics Ltd

 
CLINICAL STUDY PROTOCOL: Randomized, Double-Blind, Placebo-Controlled, Three-
Arm, 12-Month, Safety and Efficacy Study of Hydromethylthionine Mesylate (LMTM) 
Monotherapy in Subjects with Alzheimer’s Disease Followed by a 12-Month Open-Label 
Treatment 
Study Number: NCT03446001 
Date: 16-Jun-2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol: TRx-237-039 
TauRx Therapeutics Ltd. 
16 June 2023 
EUDRACT # 2017-003558-17  
Protocol Version 7.1 
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Page 1 of 145 
  
 
CLINICAL STUDY PROTOCOL 
 
Randomized, Double-Blind, Placebo-Controlled, Three-Arm, 12-Month, Safety and 
Efficacy Study of Hydromethylthionine Mesylate (LMTM) Monotherapy in Subjects with 
Alzheimer’s Disease Followed by a 12-Month Open-Label Treatment 
 
STUDY CODE: TRx-237-039 
 
STUDY PHASE: 3 
 
VERSION 7.1 DATED 16 JUNE 2023 
 
 
Previous Versions: 
VERSION 7.0 DATED 28 JULY2021 
VERSION 6.0 DATED 09 OCT 2020 
VERSION 5.1 DATED 05 FEB 2020 
VERSION 5.0 DATED 09 JUL 2019 
VERSION 4.1 DATED 09 NOV 2018 
VERSION 4.0 DATED 24 AUG 2018 
VERSION 3.0 DATED 31 MAY 2018 
VERSION 2.1 DATED 25 OCT 2017 
VERSION 2.0 DATED 31 AUG 2017 
VERSION 1.0 DATED 23 AUG 2017 
 
 
 
 
TauRx Therapeutics Ltd. 
3 Shenton Way, #21-04 
Shenton House 
Singapore 068805 
Republic of Singapore  
Operational Location: 
395 King Street 
Aberdeen AB24 5RP 
Scotland, UK 
Tel: +44 (0) 1224 440905 
 
 
THIS PROTOCOL IS A CONFIDENTIAL DOCUMENT 
 
 
This protocol is the property of TauRx Therapeutics Limited. The information within it is 
confidential and is provided to you, for review by you, your staff and applicable Ethics 
Committees and Institutional Review Boards. The protocol must be kept in a confidential 
manner and must be returned to TauRx upon request. No part of this document may be 
reproduced in any form without permission from TauRx. By accepting this document, you 
agree that the information contained therein will not be disclosed to a third party without 
written authorization from TauRx. 

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1 
TABLE OF CONTENTS 
 
 
PAGE 
1 
TABLE OF CONTENTS ..................................................................................................2 
2 
GCP COMPLIANCE STATEMENT ..............................................................................7 
3 
PROTOCOL APPROVAL ...............................................................................................8 
4 
RESPONSIBLE PERSONNEL ........................................................................................9 
5 
INVESTIGATOR SIGNATURE SHEET .....................................................................11 
6 
SYNOPSIS ........................................................................................................................12 
7 
ABBREVIATIONS ..........................................................................................................22 
8 
BACKGROUND AND RATIONALE FOR THE STUDY ..........................................25 
8.1 
Background ............................................................................................................26 
8.1.1 
Investigational Product ........................................................................26 
8.1.2 
Nonclinical Data ..................................................................................26 
8.1.3 
Clinical Data ........................................................................................28 
8.2 
Rationale ................................................................................................................33 
9 
OBJECTIVES ..................................................................................................................34 
9.1 
Primary Objectives.................................................................................................34 
9.2 
Secondary Objectives ............................................................................................34 
9.2.1 
Double-Blind Treatment Period ...........................................................34 
9.2.2 
Open-Label, Delayed-Start Phase ........................................................35 
10 
STUDY DESIGN ..............................................................................................................35 
10.1 
General Description ...............................................................................................35 
10.2 
Changes Implemented Due to COVID-19 .............................................................37 
10.2.1 
Changes to Study Conduct ...................................................................38 
10.2.2 
Changes to Study Monitoring ..............................................................41 
10.2.3 
Changes to Statistical Analyses ...........................................................41 
10.3 
Study Population ....................................................................................................42 
10.4 
Duration .................................................................................................................43 
10.5 
Schedule of Assessments .......................................................................................43 
10.5.1 
Screening Assessments ........................................................................43 
10.5.2 
Baseline and Post-randomization Assessments in Double-Blind 
Treatment Period ..................................................................................47 
10.5.3 
Assessments in the Open-Label, Delayed-Start Phase ........................51 
10.6 
Data and Safety Monitoring Board ........................................................................54 
10.7 
Definition of End of Study .....................................................................................54 
11 
SUBJECT ENROLLMENT AND WITHDRAWAL ...................................................54 
11.1 
Inclusion Criteria ...................................................................................................54 
11.2 
Exclusion Criteria ..................................................................................................56 
11.3 
Re-screening ..........................................................................................................59 

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11.4 
Discontinuations / Withdrawals .............................................................................60 
11.4.1 
Handling of Subjects Who Discontinue Study Drug ...........................60 
11.4.2 
Handling of Study Discontinuation / Withdrawal ...............................60 
11.4.3 
Replacements .......................................................................................61 
12 
STUDY DRUG .................................................................................................................61 
12.1 
Treatments Administered: Form, Dosage and Administration ...............................61 
12.1.1 
Active Ingredient .................................................................................61 
12.1.2 
Inactive Ingredients ..............................................................................61 
12.2 
Study Regimens .....................................................................................................62 
12.2.1 
Maximum Anticipated Dosage ............................................................62 
12.2.2 
Dose Interruption .................................................................................63 
12.3 
Randomization .......................................................................................................63 
12.4 
Packaging, Labeling, and Storage ..........................................................................63 
12.5 
Dispensing..............................................................................................................64 
12.6 
Compliance ............................................................................................................64 
12.7 
Study Drug Accountability ....................................................................................65 
12.8 
Breaking the Blind for Double-Blind Treatment Period ........................................65 
13 
CONCOMITANT MEDICATIONS AND SUBJECT RESTRICTIONS ..................66 
13.1 
AChEI and/or Memantine ......................................................................................66 
13.2 
Drugs with Serotonergic Potential .........................................................................67 
13.3 
CYP and P-gp Substrates .......................................................................................67 
13.4 
Drugs Used to Manage Behavioral Disturbance ....................................................67 
13.5 
Other Medications ..................................................................................................68 
13.6 
Dietary Tyramine ...................................................................................................68 
13.7 
Contraceptive Measures .........................................................................................68 
13.8 
Folate and Vitamin B12 ...........................................................................................69 
14 
TERMINATION OF THE STUDY ...............................................................................70 
15 
STUDY ASSESSMENTS ................................................................................................70 
15.1 
Demographic Data/Medical History ......................................................................70 
15.2 
Assessment of Efficacy ..........................................................................................70 
15.2.1 
Raters ...................................................................................................70 
15.2.2 
Instruments ...........................................................................................72 
15.3 
Imaging Assessments and Procedures ...................................................................75 
15.3.1 
General Considerations ........................................................................75 
15.3.2 
Site Selection and Qualification...........................................................76 
15.3.3 
Imaging Methods for Efficacy .............................................................76 
15.4 
Safety Assessments and Procedures.......................................................................78 
15.5 
Other Assessments .................................................................................................79 
15.5.1 
MT Concentration ................................................................................79 
15.5.2 
Genotyping ...........................................................................................80 

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ADVERSE EVENTS AND SAFETY .............................................................................80 
16.1 
Definition of AEs, Period of Observation, and Recording of AEs ........................80 
16.2 
Eliciting Adverse Event Information .....................................................................81 
16.3 
Categorizing Intensity ............................................................................................81 
16.4 
Investigator’s Brochure ..........................................................................................82 
16.5 
Assessing Causality ...............................................................................................82 
16.6 
Categorizing the Outcome .....................................................................................82 
16.7 
Serious Adverse Event Reporting ..........................................................................82 
16.8 
Suspected, Unexpected Serious Adverse Reactions and Emerging Safety 
Information ............................................................................................................84 
16.9 
Malignancies ..........................................................................................................85 
16.10 Reporting of Pregnancy .........................................................................................85 
16.11 Guidance for the Handling of Adverse Events of Special Interest and 
Selected Test Abnormalities ...................................................................................86 
16.11.1 
Hemolytic Anemia ...............................................................................86 
16.11.2 
Lens Discoloration ...............................................................................86 
16.11.3 
Other Safety Reasons Requiring Discontinuation of Study 
Drug .....................................................................................................86 
16.12 Urgent Safety Measures .........................................................................................87 
17 
STATISTICAL ANALYSIS ...........................................................................................87 
17.1 
Efficacy Endpoints .................................................................................................88 
17.1.1 
Primary Efficacy Endpoints for Double-Blind Treatment 
Period ...................................................................................................88 
17.1.2 
Secondary Efficacy Endpoints for Double-Blind Treatment 
Period ...................................................................................................89 
17.1.3 
Secondary Endpoint for Open-Label, Delayed-Start Phase .................89 
17.2 
Number of Subjects and Sample Size Calculation ................................................89 
17.3 
Analysis Populations ..............................................................................................90 
17.4 
Clinical Efficacy and Imaging Analysis ................................................................91 
17.4.1 
Hypothesis............................................................................................91 
17.4.2 
MITT (FDA) Analysis .........................................................................92 
17.4.3 
ITT (EMA) Analysis ............................................................................93 
17.4.4 
Estimands .............................................................................................93 
17.4.5 
Handling of Missing and Incomplete Data ..........................................95 
17.4.6 
Open-Label, Delayed-Start Analysis ...................................................96 
17.4.7 
Dose Response Analyses .....................................................................96 
17.4.8 
Responder Analyses .............................................................................96 
17.4.9 
Time-to-Event Analyses ......................................................................97 
17.4.10 
Subgroup Analyses ..............................................................................98 
17.4.11 
Sensitivity Analyses .............................................................................98 
17.5 
Exploratory Analyses ...........................................................................................100 
17.6 
Demographic and Baseline Characteristics .........................................................102 
17.7 
Safety Analysis.....................................................................................................102 

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17.8 
Other Data ............................................................................................................103 
17.9 
Interim Analysis ...................................................................................................103 
18 
REGULATORY AND ETHICS ...................................................................................104 
18.1 
Approval of the Protocol and Amendments .........................................................104 
18.2 
Serious Breaches ..................................................................................................105 
18.3 
Informed Consent.................................................................................................105 
18.4 
Investigator Responsibilities ................................................................................106 
19 
CONFIDENTIALITY AND DATA PROTECTION .................................................107 
20 
STORED SAMPLES AND IMAGING DATA ...........................................................108 
20.1 
Biosamples ...........................................................................................................108 
20.2 
Imaging Data ........................................................................................................108 
21 
QUALITY ASSURANCE AND CLINICAL MONITORING ..................................108 
21.1 
Standard Procedures.............................................................................................108 
21.2 
COVID-19 Risk Assessment................................................................................109 
22 
DOCUMENTATION .....................................................................................................110 
23 
PUBLICATION .............................................................................................................111 
24 
INDEMNITY, INSURANCE, AND COMPENSATION ...........................................111 
25 
ADMINISTRATIVE AND FINANCIAL AGREEMENT .........................................111 
26 
STUDY ADMINISTRATION ......................................................................................111 
27 
REFERENCES ...............................................................................................................113 
28 
APPENDICES ................................................................................................................117 
28.1 
Disallowed Treatments and Windows .................................................................. 117 
28.1.1 
Disallowed Medical Food / Medications Beginning 90 Days 
Before Baseline and During the Study...............................................117 
28.1.2 
Disallowed Medications Beginning 60 Days Before Baseline 
and During the Study .........................................................................117 
28.1.3 
Disallowed Treatments Beginning 28 Days Before Baseline 
and During the Study .........................................................................117 
28.2 
Study Blood Assessments .................................................................................... 118 
28.3 
Education / Occupation ........................................................................................ 119 
28.3.1 
Education ...........................................................................................119 
28.3.2 
Occupation .........................................................................................119 
28.4 
Summary of Changes to the Protocol ..................................................................120 
28.4.1 
Protocol Version 2.0 ..........................................................................120 
28.4.2 
Protocol Version 2.1 ..........................................................................121 
28.4.3 
Protocol Version 3.0 ..........................................................................122 
28.4.4 
Protocol Version 4.0 ..........................................................................127 
28.4.5 
Protocol Version 4.1 ..........................................................................129 
28.4.6 
Protocol Version 5.0 ..........................................................................130 
28.4.7 
Protocol Version 5.1 ..........................................................................137 

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28.4.8 
Protocol Version 6.0 ..........................................................................138 
28.4.9 
Protocol Version 7.0 ..........................................................................142 

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2 
GCP COMPLIANCE STATEMENT 
This study will be conducted in compliance with the protocol, the principles contained in the 
Declaration of Helsinki, International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) Integrated Addendum to ICH E6(R1): Guideline 
for Good Clinical Practice (GCP) E6(R2) (or ICH E6(R1) in those jurisdictions where ICH 
E6(R2) is not yet implemented by the regulatory authorities), and the applicable regulatory 
requirement(s). 
 
 
 

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3 
PROTOCOL APPROVAL 
 
Sponsor Signatory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature Date 
TauRx Medical Oversight 
 
 
 
Signature Date 
Statistician 
 
 
 
 
 
Signature Date 
 
 
 
 

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4 
RESPONSIBLE PERSONNEL 
TauRx Global Project Lead(s) 
 
TauRx Therapeutics Ltd. 
395 King Street 
Aberdeen AB24 5RP 
Scotland, United Kingdom  
Global Project Manager 
Coordinating Investigator 
 
North America Medical Monitor 
Medical Management and Scientific Services 
Clinical Solutions 
Syneos Health  
Contact details for specific personnel are provided in 
the Site Contact List in the Investigator Site File 
Europe Medical Monitor 
Medical Management and Scientific Services 
Clinical Solutions 
 
Syneos Health 
Contact details for specific personnel are provided in the 
Site Contact List in the Investigator Site File 
24-hour Medical Contact:  
Emergency Scientific and Medical Services Global 
(ESMS Global) 
A current list of contact details is provided in the 
Site Contact List in the Investigator Site File  
Pharmacovigilance 
Syneos Health 
Safety/Pharmacovigilance Department 
Farnborough Business Park – 1 Pinehurst Road,  
Farnborough,  
Hampshire, GU14 7BF 
United Kingdom 
Fax: +1 877 464 7787 
Email: safetyreporting@syneoshealth.com 
Investigational Medicinal Product Manufacturer 
(including packaging, labelling and distribution) 
Piramal Healthcare UK Ltd. 
Piramal Pharma Solutions 
Whalton Road 
Morpeth, Northumberland NE61 3YA 
United Kingdom  
Tel: +44 1670 562 635 
Rater Training and Approval, Scale Management,  
Electronic Capture of Clinical Efficacy Data, Central 
Review of Assessments  
MedAvante-ProPhase Inc. 
100 American Metro Blvd, Suite 106 
Hamilton, New Jersey 08619 
United States 
Tel.: +1 609 528 9400 
 
Data Management  
Synteract, Inc. 
5909 Sea Otter Place 
Carlsbad, California 92010 
United States 
Tel: +1 760 268 8200 
Randomization and Trial Supply Management 
System 
Bioclinica, Inc. 
800 Adams Avenue 
Audubon, Pennsylvania 19403 
United States 
Tel: +1 484 928 6886 
 

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Central Laboratory 
Labcorp Central Laboratory Services 
 
Americas 
   Labcorp Central Laboratory Services LP 
8211 SciCor Drive 
Indianapolis, Indiana 46214 
United States 
Tel: +1 317 271 1200 
Fax: +1 317 273 4030 
 
Europe 
   Labcorp Central Laboratory Services S.à r.l.  
7 Rue Moïse-Marcinhès 
Meyrin, Geneva 1217 
Switzerland 
Tel: +41 58 822 7000 
Fax: +41 58 822 6999 
Magnetic Resonance Imaging (MRI) Imaging  
 
 
Suitably Qualified Vendor 
 
 
Positron Emission Tomography (PET) 
Invicro 
60 Temple Street, Suite 8A 
New Haven, Connecticut 06510 
United States 
Tel: +1 203 401 4393 
Fax: +1 203 401 4304 
Methylthioninium (MT) Concentrations 
Charles River Laboratories Edinburgh Ltd. 
(cross-validation purposes only) 
Elphinstone Research Centre 
Tranent, East Lothian, EH33 2NE 
United Kingdom 
Tel: +44 (0) 1875 614545 
Statistical Analysis of Pharmacokinetic Data 
Certara USA, Inc. 
100 Overlook Center, Suite 101 
Princeton, NJ 08540 
 
Amsterdam office, Tauro office building, 
Teleporboulevard 110, 104EJ Amsterdam,  
The Netherlands 
Tel: +31 (0)88 101 2450 
 
 
Statistics 
Cytel Inc  
Geneva Branch 
Route de Prebois 20 
1215 Geneva 
Switzerland 
Tel: +41 791021971 
 
 

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5 
INVESTIGATOR SIGNATURE SHEET 
By signing below, I agree to the conditions relating to this study as set out in this protocol 
(TRx-237-039 Version 7.1 dated XX June 2023). 
 
I agree to conduct this study according to the principles contained in the Declaration of 
Helsinki, International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Integrated Addendum to ICH E6(R1): Guideline for 
Good Clinical Practice (GCP) E6(R2) (or ICH E6(R1) in those jurisdictions where ICH 
E6(R2) is not yet implemented by the regulatory authorities), the National Institute on Aging 
(NIA), the Alzheimer’s Association (AA), and the applicable regulatory requirement(s). 
 
I fully understand that any changes instituted by me without previous discussion with TauRx 
Therapeutics Limited or their designated representative constitute a deviation from the 
protocol. 
 
I agree to adhere to the protocol in all circumstances other than where necessary to protect the 
well-being of the subject. 
 
I will ensure that the drugs supplied by TauRx will be used only for administration to subjects 
enrolled in this study and for no other purpose. 
 
 
Study Site Principal Investigator’s Name, Title, Address and Contact Information: 
 
___________________________________________________________ 
___________________________________________________________ 
___________________________________________________________ 
___________________________________________________________ 
___________________________________________________________ 
___________________________________________________________ 
___________________________________________________________ 
___________________________________________________________ 
___________________________________________________________ 
 
 
Signature: 
Date: 
 
 
 
 
 

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6 
SYNOPSIS 
Name of Sponsor / Company: TauRx Therapeutics Ltd (TauRx) 
Name of Finished Product: LMTM (TRx0237) Film-coated Tablets, 4 mg 
Name of Active Ingredient (Drug Substance): Hydromethylthionine Mesylate  
Number and Title of Study: TRx-237-039: Randomized, Double-Blind, Placebo-Controlled, Three-Arm, 
12-Month, Safety and Efficacy Study of Hydromethylthionine Mesylate (LMTM) Monotherapy in Subjects with 
Alzheimer’s Disease Followed by a 12-Month Open-Label Treatment  
Study Site(s): Sites in North America (United States and Canada) and Europe 
Study Duration: The total duration of participation for an individual 
subject will be up to 120 weeks, including a Screening period of up to 
16 weeks (112 days), a double-blind treatment period of 52 weeks, and 
a further open-label treatment period of 52 weeks. It is anticipated that 
the study will have an overall duration of at least 40 months, depending 
on recruitment rate. In addition, subjects who complete the study and 
receive treatment with LMTM up to and including the last open-label 
visit may be subsequently offered an opportunity to receive treatment 
with LMTM in a separate Expanded Access Program (EAP). 
Phase of Development: 
Phase 3 
Objectives 
The primary objectives of the study pertain to the randomized, double-blind treatment period, listed below. The 
secondary objectives are presented separately for the double-blind treatment period and the open-label, delayed-
start phase. 
 
Primary (double-blind treatment period): 
1. To compare the LMTM dose of 16 mg/day with the placebo group on the following co-primary 
endpoints: 
a. 
Alzheimer’s Disease Assessment Scale, 11-item version (ADAS-cog11) 
b. Alzheimer’s Disease Cooperative Study - Activities of Daily Living, 23-item version 
(ADCS-ADL23)  
2. To assess the safety and tolerability of LMTM 16 mg/day given for up to 52 weeks 
 
Secondary (double-blind treatment period): 
3. To compare the LMTM dose of 16 mg/day with the placebo group in annualized rate of whole brain 
atrophy over 52 weeks as measured by brain magnetic resonance imaging (MRI) and quantified using the 
Boundary Shift Integral (BSI) 
4. To compare the LMTM dose of 16 mg/day with the placebo group in temporal lobe 
18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) change in Standardized Uptake 
Value Ratio (SUVR) (normalized to pons) over 52 weeks, restricted to subjects with Clinical Dementia 
Rating (CDR) 0.5 at Screening, if a predefined threshold is reached for a sufficient number of subjects 
providing data 
5. To compare the LMTM dose of 8 mg/day with the placebo group in temporal lobe 18F-FDG-PET change 
in SUVR (normalized to pons) over 52 weeks, restricted to subjects with CDR 0.5 at Screening, if a 
predefined threshold is reached for a sufficient number of subjects providing data 
6. To compare the LMTM dose of 8 mg/day with the placebo group on the co-primary endpoints (ADAS-
cog11 and ADCS-ADL23)  
7. To compare the LMTM doses of 8 and 16 mg/day with the placebo group in annualized rate of temporal 
and parietal lobe atrophy over 52 weeks as measured by MRI and quantified using the BSI 
8. To assess the safety and tolerability of LMTM 8 mg/day given for up to 52 weeks 
 
Secondary (open-label, delayed-start phase): 
9. To determine if there is a difference in disease progression on the co-primary clinical endpoints and the 
MRI imaging endpoint for subjects who started treatment in the double-blind treatment phase and those 
who started treatment in the open-label, delayed-start phase (referred to as “early” and “late” LMTM 
starters, respectively) 
a. 
Only ADAS-cog11 will serve as a secondary endpoint; ADCS-ADL23 and other imaging 
endpoints are exploratory with the aim to be directionally supportive 

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Name of Sponsor / Company: TauRx Therapeutics Ltd (TauRx) 
Name of Finished Product: LMTM (TRx0237) Film-coated Tablets, 4 mg 
Name of Active Ingredient (Drug Substance): Hydromethylthionine Mesylate  
10. To evaluate safety and tolerability of LMTM given for up to 104 weeks 
 
Sensitivity analyses, including the evaluation of the secondary imaging endpoints to confirm the absence of 
treatment unblinding, are described in the protocol and Statistical Analysis Plan (SAP). 
 
Population Pharmacokinetic (PK) analyses will be performed to estimate PK exposure in each subject for use in 
the evaluation of exposure-response relationships; these will be defined in a separate Population PK SAP or a 
dedicated section of the main SAP. 
 
Additional exploratory analyses are described in the protocol and SAP. These include analyses of: 
1. ADAS-cog13 
2. A new composite endpoint/composite endpoints based on selected item of the Alzheimer’s Disease 
Assessment Scale, 13-item version (ADAS-cog13) and the ADCS-ADL23, analyzed at 9 months and 12 
months to evaluate its usefulness for future studies (for all subjects and also separately for subjects with 
CDR 0.5 and CDR 1-2 at Screening).  
3. MMSE 
4. CDR sum of boxes 
5. Influence of Apolipoprotein E (ApoE) genotype 
Study Design 
This is a two-phase outpatient study of LMTM administered as monotherapy in 500 subjects with early to mild-
moderate Alzheimer’s disease (AD): a randomized, double-blind, placebo-controlled, 52-week treatment period 
followed by a 52-week open-label phase that represents a modified delayed start of treatment. Subjects who are 
not receiving concomitant AChEI and/or memantine, for whom legally acceptable informed consent has been 
obtained and who are found eligible on the basis of screening evaluations, will be randomly assigned at Baseline 
to receive either LMTM 16 mg/day, LMTM 8 mg/day, or placebo; the drug supplies for the placebo group will 
include tablets containing a urinary discolorant, methylthioninium chloride (MTC), 4 mg. The primary treatment 
group comparisons during the double-blind treatment phase are of LMTM 16 mg/day and placebo. Following 
completion of the 52-week treatment period, all subjects (regardless of randomized treatment assignment or 
response) will continue open-label treatment with LMTM 16 mg/day for a further 52 weeks; prior treatment 
assignment will not be unblinded. 
 
The Screening period is to be up to 9 weeks for subjects who are not receiving an AChEI and/or memantine at 
the time of signing the consent (Initial Screening Visit, Visit 1). For subjects who are receiving an AChEI and/or 
memantine, the Screening period may be extended for up to a further 6 weeks, 15 weeks in total (+7 days at 
Sponsor discretion), to allow for the performance of the necessary screening tests prior to the discontinuation of 
an AChEI and/or memantine and to permit a washout of at least 60 days from the last dose prior to the baseline 
assessments (inclusive of the baseline 18F-FDG-PET scan in subjects who have a screening CDR of 0.5). 
 
A sufficient number of subjects will be recruited from sites in North America and Europe such that 
approximately 500 subjects are enrolled. Beginning with Protocol Version 5.0, approximately 450 subjects are to 
be enrolled and randomized at the Baseline/Randomization Visit (Visit 2) to the LMTM 16mg/day 
(200 subjects), LMTM 8mg/day (50 subjects), or placebo (200 subjects) groups. Randomization will be stratified 
by severity (Mini-Mental State Examination [MMSE] 16-19, 20-25, or 26-27 at study level for those randomized 
to Protocol Version 5.0 and above), by prior use of AChEIs and/or memantine, and by region (grouped into 
North America or Europe). Subjects will be assigned to the MMSE severity groups based on screening MMSE 
score with a target ratio of approximately 2:3:1 (MMSE 16-19, 20-25, 26-27, respectively) for those randomized 
to Protocol Version 5.0 and above; to achieve this target, enrollment will be monitored and controlled at the site 
level for high recruiting sites (i.e., sites projected to recruit more than 10% of the subjects) and capped as needed 
at the study level. 
 
Eight post-Baseline visits are scheduled: five during the double-blind treatment period (Visit 3: safety, and Visits 
4, 5, 6, and 7: imaging, efficacy, and safety) and three during the open-label, delayed-start phase (Visits 8 
[telephone contact only], 9, and 10). A summary of modifications to the post-Baseline visits that may be 
implemented in response to the Coronavirus Disease 2019 Public Health Emergency (hereafter referred to as 
COVID-19) is described in the body of the protocol. Unscheduled visits may occur as needed for assessment, or 

Protocol: TRx-237-039 
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upon early termination. In addition, subjects are to be followed as needed for the resolution or stabilization of an 
adverse event (AE), including following the last dose, consistent with the investigator’s medical judgement.   
 
Subjects who drop out after randomization will not be replaced (however, the study partner may be replaced if 
the current one withdraws/drops out); subjects will be encouraged to continue with study visits until the 
scheduled completion of the double-blind treatment period (Visit 7). Only subjects who continue in the study 
and receive LMTM treatment up to and including the last visit (Visit 10) without the addition of concomitant 
AChEIs and/or memantine may be eligible for a separate EAP. 
Sample Size 
Sample size estimations to achieve 90% power (two-sided alpha = 0.05) to detect a difference between LMTM 
16 mg/day and placebo, the primary treatment group comparison in the double-blind treatment period, have been 
performed for the two co-primary clinical endpoints. These assume a withdrawal rate of 20% to 25% over 
52 weeks. The study sample size of approximately 450 subjects enrolled under Protocol Version 5.0 and above 
(200 subjects in each treatment group, with a further 50 subjects for secondary analyses of an LMTM 8-mg/day 
group) is based on the ADCS-ADL23, since a larger sample size is required for this rating scale to achieve the 
target power.  
 
Based on an estimated decline in ADCS-ADL23 over 52 weeks in the control arm of 7.7 units with an estimated 
standard deviation (SD) of 8.5 units, the study will have >90% power to detect a reduction in decline of 3.4 units 
or more. The 3.4 units are motivated by an estimated treatment effect of 5.0 ± 1.6 (mean ± standard error) units 
in the pooled studies TRx-237-005/TRx-237-015.  
 
Based on an estimated decline in ADAS-cog11 over 52 weeks based on pooled information from studies 
TRx-237-005/TRx-237-015 in the control arm of 6.5 units with an estimated SD of 5.9 units, 200 subjects per 
treatment arm provide >90% power to detect a reduction in decline of 2.6 units or more. The 2.6 units represent 
a conservative value as the estimated treatment effect based on pooled studies TRx-237-005/TRx-237-015 is 
5.2 ± 1.3 (mean ± standard error) units.  
 
With 200 subjects randomized to the primary comparison in the double-blind treatment period under Protocol 
Version 5.0 and above, 160 to 170 subjects per arm will enter the open-label, delayed-start treatment phase 
assuming the 20-25% drop-out rates mentioned above. Assuming a further 10% drop out in the delayed-start 
phase, the key secondary analysis to demonstrate disease modification by comparing early to late starters using a 
non-inferiority margin of -2 ADAS-cog11 units has approximately 80% power. 
Subject Population 
Inclusion Criteria: 
1. AD, encompassing probable AD and mild cognitive impairment due to AD (MCI-AD) based on 2011 
National Institute on Aging (NIA) / Alzheimer’s Association (AA) criteria: 
• 
All cause dementia and probable AD (probable AD) 
In brief, subjects with probable AD dementia must have insidious onset, worsening impairment in 
at least two cognitive areas (learning and recall, language, executive function, visuospatial skills), 
sufficient to significantly interfere with work or usual activities, that is not explained by delirium, 
drugs, major psychiatric disorder, medical illness, cerebrovascular disease, other forms of 
dementia, or neurological disorder. The accuracy of the diagnosis will be confirmed independently 
by the diagnosing physician at site 
OR 
• 
MCI-AD 
In subjects with MCI-AD, there should be evidence of concern about a change in cognition, in 
comparison with the person’s previous level verified by a knowledgeable informant or clinician. 
Other mild cognitive deficits may also be present, but there must be preservation of independence 
in functional abilities. Subjects should not meet the criteria for dementia. The cognitive changes 
must be mild and there must be no evidence of a significant impairment in social or occupational 
functioning. Impairments must not be explained by delirium, drugs, major psychiatric disorder, 
medical illness, cerebrovascular disease, other forms of dementia, or neurological disorder. 
2. Documented PET scan that is positive for amyloid; if most recent PET scan was performed >3 years 
prior to Screening and was negative, it may be repeated (a negative amyloid PET scan within the 
3 years prior to Screening is exclusionary) 

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3. MMSE score of 16-27 (inclusive) at Screening, subject to stratification requirements 
4. Global CDR score of 0.5 to 2 at Screening (if 0.5, including a score of > 0 in one of the functional 
domains: Community Affairs, Home and Hobbies, or Personal Care) 
5. Age < 90 years at Screening 
6. Females must meet one of the following: 
• 
Surgically sterile (hysterectomy, bilateral salpingectomy / oophorectomy) for at least 6 months 
minimum 
• 
Have undergone bilateral tubal occlusion / ligation at least 6 months prior 
• 
Post-menopausal for at least 1 year 
• 
Using adequate contraception (a barrier method [such as condom, diaphragm or cervical/vault cap] 
with spermicidal foam, gel, film, cream, or suppository; intrauterine device [IUD] or system, or oral 
or long-acting injected or implanted hormonal contraceptives for at least 90 days prior to Baseline; 
or vasectomized partner [with the appropriate post-vasectomy documentation of the absence of 
spermatozoa in the ejaculate]) or true abstinence (when this is in line with the preferred and usual 
lifestyle of the subject); subjects must be competent to use adequate contraception and to agree to 
continue to maintain adequate contraception throughout participation in the study (including up to 
4 weeks after the last dose of study drug) 
7. Subject and/or, in the case of reduced decision-making capacity, legally acceptable representative(s) 
(LAR(s)), consistent with local and national law, is able to read, understand and provide written 
informed consent in the designated language of the study site 
8. Has one (or more) identified adult study partner (i.e., a caregiver or informant) who meets the following 
criteria: 
• 
Either lives with the subject, or in the investigator’s opinion, the extent of contact is sufficient to 
provide meaningful assessment of changes in subject behavior and function over time and provide 
information on safety and tolerability (e.g., sees the subject on average for ≥1 hour/day 
≥3 days/week) 
• 
Is willing to provide written informed consent for his/her own participation 
• 
Is able to read, understand, and speak the designated language at the study site 
• 
Agrees to accompany the subject to each study visit 
• 
Is able to verify compliance with study drug 
9. The subject must not have been taking either an AChEI, i.e., donepezil, galantamine, or rivastigmine, 
and/or memantine, for at least 60 days at the time of the baseline assessments 
• 
Subjects never previously treated with an AChEI and/or memantine may be enrolled if initiation of 
treatment with these medications is not planned for the time period during which the subject will be 
participating in this study 
10. Able to comply with the study procedures in the view of the investigator 
Exclusion Criteria: 
1. Significant central nervous system (CNS) disorder other than probable AD or MCI-AD, e.g., Lewy 
body dementia, Parkinson’s disease, multiple sclerosis, progressive supranuclear palsy, 
hydrocephalus, Huntington’s disease, any condition directly or indirectly caused by Transmissible 
Spongiform Encephalopathy (TSE), Creutzfeldt-Jakob Disease (CJD), variant Creutzfeldt-Jakob 
Disease (vCJD), or new variant Creutzfeldt-Jakob Disease (nvCJD) 
2. Significant intracranial focal or vascular pathology seen on brain MRI scan that would, based on the 
independent reviewer imaging evaluation, lead to a diagnosis other than probable AD or MCI-AD, 
including but not limited to: 
• 
Large confluent white matter hyperintense lesions (i.e., Fazekas score of 3) 
• 
Other focal brain lesions judged clinically relevant by the investigator 
• 
Evidence of a prior or current macrohemorrhage 
3. Clinical evidence or history of any of the following (within specified period prior to Baseline): 
• 
Cerebrovascular accident (2 years) 
• 
Transient ischemic attack (6 months) 
• 
Significant head injury, for example, associated loss of consciousness, skull fracture or persisting 
cognitive impairment (2 years) 

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• 
Other unexplained or recurrent loss of consciousness (2 years) 
4. Diagnosed with epilepsy (a single prior seizure >6 months prior to Screening, is considered acceptable) 
5. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria met (for any of the 
following within specified period): 
• 
Major depressive disorder (current) 
• 
Schizophrenia (lifetime) 
• 
Other psychotic disorders, bipolar disorder (within the past 5 years) 
• 
Substance (including alcohol) related disorders (within the past 2 years) 
6. Metal implants in the head (except dental), pacemaker, cochlear implants, or any other non-removable 
items that are contraindications to MRI. MRI compatible prosthetics, clips, stents, or any other device 
proven to be compatible are allowed 
7. Resides in hospital or moderate to high dependency continuous care facility (residence in low grade 
assisted living facility where there is sufficient autonomy to permit valid evaluation of activities of 
daily living is allowed so long as it is not mandated by an order issued either by the judicial or the 
administrative authorities) 
8. Any physical disability that would prevent completion of study procedures or assessments (e.g., 
blindness or significant uncorrected visual impairment, deafness or significant hearing loss not 
corrected by hearing aids, non-AD-related speech impairment) 
9. History of swallowing difficulties (note: study drug should be swallowed whole and MUST NOT be 
broken, crushed, chewed, or dissolved in fluids prior to ingestion) 
10. Pregnant or breastfeeding 
11. Glucose-6-phosphate dehydrogenase (G6PD) deficiency based on World Health Organization 
classification (<60% of normal, i.e., <6.1 U/g hemoglobin [Hgb]) 
12. History of significant hematological abnormality or current acute or chronic clinically significant 
abnormality, including: 
• 
History of hemoglobinopathy, myelodysplastic syndrome, hemolytic anemia, or splenectomy 
• 
Screening Hgb value (confirmed upon repeat) below age/sex appropriate lower limit of the central 
laboratory normal range 
Subjects in whom folate is <4.0 ng/mL may be entered into the study provided folate supplementation 
(approximately 1 mg/day) is initiated and maintained for the duration of the study. 
Subjects in whom vitamin B12 is <150 pg/mL can be allowed if the investigator confirms that it does 
not affect the cognitive state of the subject and that the subject is supplemented as appropriate prior to 
the initiation of study drug 
13. Abnormal serum chemistry laboratory value at Screening deemed to be clinically significant by the 
investigator. In addition, subjects with either of the following abnormalities must be excluded: 
• 
Creatinine clearance <30 mL/min, estimated by the central laboratory according to the Cockcroft 
and Gault equation 
• 
Thyroid stimulating hormone (TSH) above laboratory normal range (subject may be treated [if 
clinically indicated based on further laboratory testing] and re-screened after 90 days) 
14. Clinically significant cardiovascular disease or abnormal assessments (based on the investigator’s 
interpretation of the locally obtained electrocardiogram [ECG]) such as: 
• 
Hospitalization for acute coronary syndrome (acute myocardial infarction or unstable angina) or 
symptoms consistent with angina pectoris, within the 12 months preceding Baseline 
• 
Signs or symptoms of clinical heart failure within the 12 months preceding Baseline 
• 
Atrial fibrillation on screening ECG or history of atrial fibrillation that is not currently controlled 
(heart rate ≥ 85 bpm and/or inappropriate anticoagulation)  
• 
QTcF (QT corrected for heart rate using Fridericia’s formula) at Screening >460 msec in males or 
> 470 msec in females, or low or flat T waves making measurement of QT interval unreliable 
• 
Recent history of poorly controlled hypertension, systolic blood pressure >180 mmHg, or diastolic 
blood pressure >100 mmHg, after 5 minutes in a seated position at Screening 
• 
Hypotension: systolic blood pressure <100 mmHg after 5 minutes in a seated position at Screening 

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• 
Heart rate <48 bpm or >96 bpm by measurement of vital signs (after 5 minutes in a seated position) 
or by local ECG at Screening 
15. Pre-existing or current signs or symptoms of respiratory failure, e.g., caused by chronic obstructive 
pulmonary disease, bronchial asthma, lung fibrosis, or other disease 
• 
Subjects with currently diagnosed moderate to severe sleep apnea should be excluded; the 
definition of moderate to severe includes oxygen supplementation, e.g., nasal prongs or Continuous 
Positive Airway Pressure (CPAP) 
16. Concurrent acute or chronic clinically significant (in the opinion of the investigator) immunologic, 
hepatobiliary (such as presence of encephalopathy or ascites), or endocrine disease (not adequately 
treated), and/or other unstable or major disease other than probable AD or MCI-AD; the following are 
specifically excluded: 
• 
Active hepatitis or primary biliary cirrhosis  
• 
Active Human T-Cell Lymphocytic Virus Type III (HTLV-III), Lymphadenopathy Associated 
Virus (LAV), any mutants or derivatives of HLTV-III or LAV, any condition associated with 
active Acquired Immunodeficiency Syndrome or similar condition however named 
17. Diagnosis of cancer (excluding basal cell carcinoma, squamous cell carcinoma, or prostate carcinoma in 
situ [Stage 1]) meeting either of the following criteria: 
• 
Newly diagnosed within past 2 years 
• 
Previous (>2 years) diagnosis of cancer that has required any form of intervention or treatment 
within the past 2 years, e.g., chemotherapy, radiotherapy, hormonal therapy, or surgery 
18. Prior intolerance or hypersensitivity to MT-containing drug or methemoglobinemia induced by MT-
containing drug, similar organic dyes, or any of the excipients 
19. Treatment currently or within 90 days before Baseline with any of the following: 
• 
Souvenaid® 
• 
Antipsychotics 
o 
Clozapine (and there is no intent to initiate therapy during the course of the study) 
o 
Other antipsychotics are allowable provided they have not been initiated within 90 days before 
Baseline and preferably at a stable dose and regimen 
• 
Carbamazepine, primidone, valproate 
• 
Drugs for which there is a warning or precaution in the labeling about methemoglobinemia at 
approved doses (e.g., dapsone, local anesthetics such as benzocaine used chronically, primaquine 
and related antimalarials) 
20. Current or prior participation in a clinical trial as follows: 
• 
Any clinical trial of LMTM 
• 
Clinical trial of a product for cognition prior to Baseline in which the last dose was received within 
90 days prior to Baseline unless confirmed to have been randomized to placebo 
• 
A clinical trial of any other investigational drug, biologic, device, or medical food in which the last 
dose was received within 28 days prior to Baseline 
Dose/Route/Regimen 
Throughout the study, all subjects will receive four tablets orally per day (two in the morning and two in the 
evening), to be taken at the same time (and same meal condition) to the extent possible. Study drug should be 
swallowed whole and MUST NOT be broken, crushed, chewed, or dissolved in fluids prior to ingestion.  
 
For the 52-week, double-blind treatment period, subjects will be randomized 4:1:4 (beginning with Protocol 
Version 5.0) to one of the following treatment groups: 
• 
LMTM 16-mg/day group: Two 4-mg tablets in the morning and two 4-mg tablets in the evening 
• 
LMTM 8-mg/day group: One 4-mg tablet and one placebo tablet in the morning, and one 4-mg 
tablet and one placebo tablet in the evening 
• 
Placebo group: Two “dummy” tablets in the morning and two “dummy” tablets in the evening, one 
of which may be replaced by a 4-mg MTC tablet to maintain the treatment blind (the remainder 
being placebo tablets) 
 

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The first dose of study drug (Visit 2) and the morning dose at Visit 3 (after 4 weeks of study drug), Visit 7 (after 
52 weeks of study drug), and Visit 10 (after 104 weeks of study drug) will be administered in the clinic. These 
visits should be scheduled to occur in the morning and subjects will be required to remain at the site for at least 
4 hours post-dose on each occasion. Alternative arrangements for dosing and dispensing study drug supplies due 
to COVID-19 may be permitted and are further described in the body of the protocol. 
 
Interruption of dosing for up to a maximum of 14 consecutive days may be allowed if the investigator 
determines this is indicated (e.g., due to an AE or any other reported change in the subject’s physical condition 
in the judgment of the investigator) on a maximum of two occasions. Dose reduction is not permitted. The 
reason for dose interruption should be recorded in the source documentation. 
 
After the completion of the 52-week double-blind treatment period, beginning with supplies dispensed at Visit 7 
(Baseline/Day 1 for the open-label phase), all subjects will receive LMTM 16 mg/day (two 4-mg tablets in the 
morning and two 4-mg tablets in the evening) from a newly dispensed open-label study kit for an additional 
52 weeks during the open-label, delayed-start phase. The in-clinic dose of study drug at Visit 7 is to be taken 
after pre-dose assessments have been completed (refer to Table 10-3 for the pre-dose and post-dose assessments 
to be performed at Visit 7). 
Methodology 
All subjects should have a likely diagnosis of probable AD or MCI-AD prior to being offered the consent forms, 
on the basis of investigator interview and examination. Subjects currently using an AChEI and/or memantine 
must be willing to discontinue such medication before continuing with screening (for timing of withdrawal 
reference Table 10-1). 
 
Following provision of written informed consent by the subject (and/or legal representative[s]) and study 
partner(s), consistent with national and/or local law, eligibility for enrollment will be assessed initially during the 
Screening period which may require multiple visits (collectively designated Visit 1). These will occur no earlier 
than 63 days before Visit 2 for subjects not using an AChEI and/or memantine. For subjects using an AChEI 
and/or memantine at the time of signing the consent document or who have recently discontinued use, Screening 
visits can occur no earlier than 105 days before Visit 2. 
 
The diagnosis of probable AD or MCI-AD should be confirmed per the 2011 NIA/AA criteria, documented in 
the subject’s medical records and independently confirmed by site diagnosing physician. MMSE and CDR will 
then be completed at Screening for eligibility assessment. Note that MMSE should be conducted first, followed 
by the CDR assessment only if the subject meets the MMSE inclusion criteria. If the subject does not qualify 
with either of these scales, no further assessments should be performed and the subject should be considered a 
screen failure. If, however, the subject meets the MMSE and CDR inclusion criteria, a blood sample for clinical 
laboratory testing should be obtained and medical screening assessments performed. 
 
In subjects for whom it is appropriate to proceed with further screening, a PET scan that is positive for amyloid 
and an MRI scan that excludes other CNS pathology are required at Screening to confirm subject eligibility. The 
amyloid PET scan can have been documented previously as positive or, alternatively, be based on the local read  
(or central for those sites not able to read locally) of a PET scan using an approved amyloid ligand and according 
to criteria recommended as standard by the manufacturer of the ligand. All images (including prior images with 
subject consent) will be sent to an imaging core laboratory, either as a repository (amyloid PET) or for 
evaluation by a trained technologist for acceptable quality (MRI). MRIs will be reviewed by an independent 
neuroradiologist (reader) who is trained in the evaluations and is not involved in the clinical conduct of the study 
to confirm eligibility of the subject. The reader’s MRI assessment will be communicated to the site within 
5 business days of image transfer to the imaging core laboratory (or of resolution of any quality issues).  
 
Subjects willing to discontinue AChEI and/or memantine in order to take part in the study must be documented 
to be eligible according to clinical inclusion / exclusion criteria, screening MRI and amyloid positive PET scan, 
before these drugs are discontinued. 
 
Only subjects with a CDR 0.5 will undergo 18F-FDG-PET. 18F-DG-PET images are to be obtained prior to 
Visit 2 (and at least 60 days after the last dose of AChEI and/or memantine) for purposes of establishing the 
baseline assessment. Completion of this scan must be confirmed prior to randomization; other than confirmation 
of acceptable quality, the results per se are not considered for eligibility at the Screening visit. The baseline 

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18F-FDG-PET image will be sent to a core imaging laboratory and will be reviewed by an independent, 
appropriately trained nuclear medicine reader. Imaging receipts will be sent in all cases; only in those instances 
where the scan is deemed unacceptable will the site and imaging laboratory be further notified. 
 
At the Baseline/Randomization visit (Visit 2), eligibility will be confirmed, subjects will be randomized, and 
baseline safety and efficacy assessments will be completed. Subjects will be treated with study drug for 
52 weeks on an outpatient basis. During the double-blind, treatment period, on-treatment, post-Baseline study 
visits will occur at time points approximately 4, 13, 26, 39, and 52 weeks after Baseline. All subjects will receive 
a supply of study drug according to their randomization, to take home for use until Visit 4 (13 weeks after 
Baseline). Study drug will be resupplied at Visits 4, 5, and 6 (13, 26, and 39 weeks after Baseline). Visit 7 (the 
final visit in the double-blind treatment period) will serve as the open-label Baseline. During the open-label, 
delayed-start phase, study visits will occur at approximately 4 weeks (by telephone), 26 weeks, and 52 weeks 
after the open-label Baseline (Visits 8, 9, and 10), with a supply of open-label study drug from a newly 
dispensed study kit provided at Visits 7 and 9. Alternative arrangements for study procedures and assessments in 
response to COVID-19 are described in the body of the protocol.   
 
The study will be monitored for safety by a Data and Safety Monitoring Board (DSMB) throughout its duration. 
Assessments 
Efficacy: 
Imaging assessments will be made by central readers as follows: 
• 
Brain MRI will be evaluated for temporal, parietal, whole brain, lateral ventricular, hippocampal, 
putamen, nucleus accumbens, and nucleus basalis volumes at Screening and after 13, 26, 39, and 
52 weeks, or upon early termination. Change in MRI volumetric parameters will be quantified at the 
imaging core laboratory. The image hyperintensities will also be quantified. MRIs will also be obtained 
and evaluated after the additional 26 and 52 weeks of open-label treatment.  
• 
Brain 18F-FDG-PET will be evaluated in subjects with CDR 0.5 for normalized temporal, parietal, and 
frontal lobe SUVR at Baseline and after 52 weeks, or upon early termination. Other regions of interest 
will also be examined including, but not restricted to, inferior temporal gyrus, angular gyrus, anterior 
and posterior cingulate gyrus, and cerebellum. Change in SUVR parameters will be quantified by the 
imaging core laboratory. 
 
Two primary clinical efficacy scales will be used, ADAS-cog13 and ADCS-ADL23. Clinical assessments will be 
made by suitably trained Efficacy Raters who are not involved in safety assessments, using the instruments on an 
electronic tablet (and captured via an audio recording of the assessment for independent evaluation). The 
following will be assessed at Baseline; after 13, 26, 39, and 52 weeks during the double-blind treatment period; 
and after the additional 26 and 52 weeks of open-label treatment, or upon early termination: 
• 
ADAS-cog13  
o 
As the primary endpoint is ADAS-cog11, in order to be able to link the results of this study to the 
recently completed Phase 3 studies TRx-237-005 and TRx-237-015, an ADAS-cog11 will be 
derived from the ADAS-cog13. 
• 
ADCS-ADL23 
 
The MMSE and CDR will be repeated at the final double-blind treatment period visit (Visit 7) and the final 
open-label visit (Visit 10) or upon early termination.  
 
The clinical efficacy scale assessments should be performed at approximately the same time of day throughout 
the study for a given subject, to the greatest extent possible. 
 
Safety and Tolerability: 
Safety assessments will be performed during Screening to assess subject eligibility for enrollment. All safety 
assessments will be performed by an independent qualified assessor not involved in efficacy assessments; where 
specified below, the assessments must be made by a medical assessor (physician, doctor of medicine [MD], or 
doctor of osteopathic medicine [DO]). For enrolled subjects, safety assessments will be made at Baseline and at 
each clinic visit (i.e., after 4, 13, 26, 39, and 52 weeks during the double-blind treatment period as well as after 
26 and 52 weeks in the open-label, delayed-start phase); during a telephone contact after 4 weeks in the open-
label, delayed-start phase; when needed to follow up on an AE; and upon early termination. All AEs, vital signs, 

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ECG, clinical laboratory findings, physical and neurological examinations, and ophthalmological examinations 
(as applicable) will be assessed according to the following: 
• 
AEs will be recorded from the time informed consent is signed and recording will continue throughout 
the study and, if pertinent, until resolution of the event; AEs with an onset after the first dose of study 
drug or that worsen in intensity or treatment relationship after the first dose will be considered 
treatment-emergent (and must be reviewed by a medical assessor). 
• 
Blood pressure and pulse will be obtained at Screening, on Day 1 (pre-dose and approximately 2 hours 
post-dose), and at each clinic visit thereafter or upon early termination. Blood pressure and pulse will be 
measured after the subject has been in a seated position for at least 5 minutes. 
• 
Height will be measured at Screening only. Body weight will be measured at Screening and at each 
clinic visit thereafter or upon early termination. 
• 
A 12-lead ECG will be obtained at Screening, with the site assessing eligibility based on the local 
clinical interpretation by a medical assessor. 
• 
TSH, vitamin B12, folate, haptoglobin, and G6PD will be measured at Screening; a thyroid panel may be 
obtained in response to an elevated TSH. Standard clinical laboratory testing, including hematology and 
blood chemistry, will be performed at Screening and each subsequent clinic visit (or upon early 
termination). Testing may also be performed as needed in response to an AE. All laboratory testing 
results must be reviewed by a medical assessor. 
• 
A blood sample for a serum pregnancy test will be collected from all women of childbearing potential at 
Screening and at each subsequent clinic visit (or upon early termination). 
• 
Complete physical and neurological assessments will be performed at Screening. Targeted 
examinations will be performed pre-dose and approximately 3 hours after administration of the first 
dose of study drug (Visit 2). Thereafter, targeted examinations are to be performed at each subsequent 
clinic visit (or upon early termination). At a minimum, targeted examinations should include heart and 
lung auscultation and brief neurological assessment guided by any reported signs/symptoms/AEs (e.g., 
evaluating subjects for potential serotonin toxicity). These examinations are to be performed by a 
medical assessor. 
• 
Ophthalmological examination (slit lamp) of subjects with history of lens implants will be performed by 
a licensed optometrist, ophthalmologist, or other suitably qualified medical assessor prior to the first 
dose of study drug (during the Screening procedures or as part of the baseline assessments), at Visit 7, 
and at Visit 10 / early termination (after completion of efficacy assessments), to assess whether the lens 
has been discolored during the trial. A slit lamp examination should also be performed if a subject has 
cataract surgery/lens implantation at any point during his or her study participation (as soon as possible 
after the surgery), as well as in response to visual complaints if suggestive of lens discoloration. 
• 
At Screening, medications administered within the last 90 days will be recorded; the exception is for 
anti-dementia medications, where lifetime use (as far as possible) is to be recorded. Changes in 
concomitant medications and any new medications will be recorded at all subsequent visits, including 
the telephone contact, and reviewed by a medical assessor.  
Other Assessments: 
• 
At Visit 2, Visit 3, Visit 7, and Visit 10, blood will be collected on the same day on three occasions for 
determination of plasma MT and whole blood concentrations (parent MT/LMT, N-desmethyl MT, and 
total MT, to the extent possible); these visits should be scheduled to occur in the morning. Samples will 
be collected prior to dosing (in the clinic) and again approximately 1 to 2 hours post-dose; a third 
sample will be collected approximately 4 hours after the dose. Times of dose and blood sampling (and 
at Visits 3, 7, and 10, times of the prior dose taken on the preceding day) will be recorded. At any early 
termination visit, if the subject has not yet discontinued study drug and is willing to take a final in-clinic 
dose, three blood samples will be collected as described above. If, however, the subject has already 
discontinued study drug or is unwilling to take a final in-clinic dose, a single blood sample only for 
determination of MT concentrations will be collected, irrespective of the date or time of the last dose of 
study drug. The date and time of the last dose will be collected and recorded. For subjects who continue 
in the study off-treatment (the off-treatment-on-study [TOTOS] group), blood samples will not continue 
to be collected for the determination of MT concentrations. 
• 
A single blood sample for ApoE will be obtained from subjects who provide legally acceptable 
informed consent; the blood sample may be collected any time after eligibility for randomization and 
continued participation in the study has been confirmed but prior to Visit 7 (end of the double-blind 
treatment period). 

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Name of Sponsor / Company: TauRx Therapeutics Ltd (TauRx) 
Name of Finished Product: LMTM (TRx0237) Film-coated Tablets, 4 mg 
Name of Active Ingredient (Drug Substance): Hydromethylthionine Mesylate  
Statistical Analyses 
Double-blind Treatment Period: 
The primary target of estimation is the difference in ADAS-cog11 and ADCS-ADL23 over 52 weeks in subjects 
receiving LMTM in a dose of 16 mg/day as compared to placebo. 
 
The primary efficacy analyses for FDA will be performed on the Efficacy Modified Intent-to-Treat (E-MITT) 
which will include all randomized subjects who took at least one dose of study drug and have a baseline and a 
valid post-baseline efficacy assessment, and for EMA on the Intent-to-Treat (ITT) population with conservative 
assumptions about disease progression made for subjects who have missing post-baseline assessments. Subjects 
will be analyzed in the treatment group and according to the stratification variables to which they were 
randomized. 
 
Changes from baseline to Week 52 on the co-primary efficacy endpoints and other modalities with repeated 
measures such as MRI will be analyzed using a linear mixed model for repeated measures with unstructured 
covariance matrix. The linear mixed model will contain fixed effects for time, treatment, and a treatment-by-
time interaction; additionally, the baseline value of the corresponding endpoint will be included as a covariate 
and the randomization stratification variables of prior usage of AChEIs and/or memantine, severity based on 
MMSE (16-19, 20-25, or 26-27) as determined at Screening, and region will be included as fixed effects in the 
model. 18F-FDG-PET and other modalities with only one planned post-baseline assessment will be analyzed 
using an ANCOVA; the covariates for this model will be adjusted accordingly by removing terms with time.  
 
More details about the exact contrast statements used for these tests as well as further sensitivity analyses, 
additional analyses of the primary variables (such as responder analyses and subgroup analyses), analyses of the 
secondary and exploratory endpoints, and modifications to be implemented regarding sensitivity analyses due to 
COVID-19 are described in the body of the protocol and SAP.  
 
Open-Label, Delayed-Start Phase: 
“Late” starters, i.e., subjects originally randomized to placebo, will be compared to “early” starters, i.e., those 
originally randomized to LMTM 16 mg/day or 8 mg/day (pooled, and individually for both groups as a 
sensitivity analysis). The last assessment prior to start of open-label treatment (Visit 7) will serve as the baseline 
assessment for these comparisons. The analyses will be based on a similar linear mixed model for repeated 
measures with the aim to investigate whether there is a difference in change in primary and MRI imaging 
endpoints dependent on LMTM treatment history. The comparison will be implemented through a non-
inferiority test. The non-inferiority margin for the primary endpoint of ADAS-cog11 will be 2 units, motivated by 
the fact that these 2 units are small compared to the estimated treatment effect of > 5 units (~40% of this effect 
size). Margins for other endpoints which are exploratory to support a disease modifying argument will be 
defined in the SAP. The results will also be presented with the Visit 2 Baseline as baseline and treatment visits 
Week 26 and Week 52 in the open-label, delayed-start phase as Week 78 and Week 104.  

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7 
ABBREVIATIONS 
 
Abbreviations 
Definitions 
AA 
Alzheimer’s Association 
AChEI 
acetylcholinesterase inhibitor 
AD 
Alzheimer’s Disease 
ADAS-cog11 
Alzheimer's Disease Assessment Scale – Cognitive Subscale (11-item) 
ADAS-cog13 
Alzheimer's Disease Assessment Scale – Cognitive Subscale (13-item) 
ADCS-ADL23 
Alzheimer's Disease Cooperative Study – Activities of Daily Living 
(23-item) 
ADNI 
Alzheimer's Disease Neuroimaging Initiative 
ADR 
Adverse Drug Reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
ApoE 
Apolipoprotein E gene 
ATC 
Anatomical Therapeutic Classification 
AUC 
area under the plasma concentration versus time curve 
BCRP 
breast cancer resistance protein 
bid 
twice daily 
BSI 
Boundary Shift Integral 
BSA 
body surface area 
bvFTD 
behavioral variant frontotemporal dementia 
CDR 
Clinical Dementia Rating 
CJD 
Creutzfeldt-Jakob Disease 
CL/F 
apparent plasma clearance 
Cmax 
peak plasma concentration 
Cmax, ss 
peak steady-state plasma concentration 
CMP 
Clinical Monitoring Plan 
CNS 
central nervous system 
COVID-19 
Coronavirus Disease 2019 Public Health Emergency 
CT 
computerized tomography 
CYP 
Cytochrome P450 isoenzyme 
DO 
Doctor of Osteopathic Medicine 
DSMB 
Data and Safety Monitoring Board 
EAP 
Expanded Access Program 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EMA 
European Medicines Agency 
E-MITT 
Efficacy Modified Intent-to-Treat  
eTMF 
electronic Trial Master File 
EU 
European Union 
FDA 
Food and Drug Administration (United States) 
18F-FDG-PET 
18F-fluorodeoxyglucose positron emission tomography 
g, kg, mg, pg 
gram, kilogram, milligram, picogram 
G6PD 
glucose-6-phosphate dehydrogenase 
GCP 
Good Clinical Practice 
GI 
gastrointestinal  

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Abbreviations 
Definitions 
GMP 
Good Manufacturing Practice 
Hgb 
hemoglobin 
HTLV-III 
human T-cell lymphocyte virus Type III 
ICE 
intercurrent events 
ICF 
informed consent form 
 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
INN 
International Nonproprietary Name 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
IUD 
intrauterine device 
L, mL, dL 
liter, milliliter, deciliter 
LAR  
Legally Acceptable Representative 
LAV 
Lymphadenopathy Associated Virus 
LDH 
lactate dehydrogenase 
LMT 
hydromethylthionine, leuco-methylthioninium 
LMTB 
leuco-methylthioninium bis(hydrobromide) 
LMTM 
hydromethylthionine mesylate, leuco-methylthioninium 
bis(hydromethanesulfonate) 
LSM 
Least Squares Mean 
LVV 
lateral ventricular volume  
MAO 
monoamine oxidase 
MATE 
Multidrug And Toxin Extrusion (protein) 
MCI-AD 
mild cognitive impairment due to AD 
MD 
Doctor of Medicine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
min, msec 
minutes, millisecond 
MI-MITT 
MRI Imaging Intent-to-Treat 
MMSE 
Mini-Mental State Examination 
MRI 
magnetic resonance imaging 
MT 
Methylthioninium 
MTC 
methylthioninium chloride 
NIA 
National Institute on Aging 
NMDA 
N-methyl-D-aspartate 
NOAEL 
no-observed-adverse effect-level 
nvCJD 
new variant Creutzfeldt-Jakob Disease 
OAT 
Organic Anion Transporter 
OCT 
Organic Cation Transporter 
PET 
Positron Emission Tomography 
P-gp 
P-glycoprotein 
PHF 
paired helical filament 
PI 
principal investigator 
PI-MITT 
Imaging Modified Intent-to-Treat  
PK 
Pharmacokinetic 
PP 
Per Protocol 

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Abbreviations 
Definitions 
QA 
Quality Assurance 
RBC 
red blood cell 
ROI 
region of interest 
RTSM 
Randomization and Trial Supply Management 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SI 
Sub-Investigator 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure  
SPM 
statistical parametric mapping  
SUSAR 
suspected unexpected serious adverse event 
SUVR 
Standardized Uptake Value Ratio 
T½ 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
tid 
three times daily 
TOTOS 
The-Off-Treatment-On-Study (subjects) 
TSE 
Transmissible Spongiform Encephalopathy 
TSH 
thyroid stimulating hormone 
UGT 
UDP-glucuronosyltransferase 
USAN 
United States Abbreviated Name 
USP 
United States Pharmacopeia 
vCJD 
variant Creutzfeldt-Jakob Disease 
WBC 
white blood cell 
WHO 
World Health Organization 
 
 
 
 

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8 
BACKGROUND AND RATIONALE FOR THE STUDY 
Hydromethylthionine (International Nonproprietary Name [INN] and United States 
Abbreviated Name [USAN]), the reduced form of methylthioninium (MT) that is also known 
as leuco-methylthioninium (LMT), is proposed for treatment of tauopathies and other protein 
misfolding disorders. Tauopathies are a class of neurodegenerative diseases associated with 
pathological aggregation of tau protein in the human brain. The tauopathies include diseases 
that primarily affect cognition such as Alzheimer’s disease (AD). AD is a severe irreversible 
neurodegenerative disease resulting in complete loss of mental faculties. In AD, the 
microtubule associated protein tau is redistributed exponentially into paired helical filaments 
(PHF) forming neurofibrillary tangles that correlate with pyramidal cell destruction (Wischik 
et al., 1997). There is a robust clinico-pathological correlation between tau pathology, tau 
aggregation, and clinical measures of dementia (Bierer et al., 1995; Mukaetova-Ladinska et 
al., 2000). These relationships are maintained from the earliest detectable stages of dementia 
and progress in parallel with clinical deterioration and are also seen by imaging using 
recently developed tau ligands (Lockhart et al., 2016; Xia et al., 2017; Pontecorvo et al., 
2017. 
 
The repeat-domain tau fragment originally identified biochemically as a structural constituent 
of the tangle PHF core (Wischik et al., 1988a,b) has recently been confirmed using cryo-
electron microscopy (Fitzpatrick et al., 2017). This fragment assembles spontaneously in 
vitro to form PHF-like filaments (Al-Hilaly et al., 2017). The active moiety required both to 
block filament assembly and to disassemble formed filaments is the reduced LMT form of 
MT (Al-Hilaly et al., 2018).  
 
As of 2020, drugs currently available to treat AD, such as acetylcholinesterase inhibitors 
(AChEIs) or memantine, are symptomatic treatments that address certain central neuronal 
dysfunctions associated with AD, but are not known to directly affect the neurofibrillary 
tangles in the brain that represent a core pathological component of AD. Controlled studies 
with the AChEIs donepezil, rivastigmine, and galantamine have demonstrated small 
improvements in cognitive tests and global measures of change in selected subjects with mild 
to moderate AD over 3 to 12 months (Birks and Harvey, 2003; Olin and Schneider, 2002). 
However, improvements in function and behavior have been demonstrated less reliably with 
AChEIs. Furthermore, although these medications provide benefits for some subjects, their 
effectiveness often is limited in duration and they do not affect the rate of progression of the 
disease (Courtney et al., 2004). 
 
Memantine is a noncompetitive, low-affinity, N-methyl-D-aspartate (NMDA) receptor 
antagonist that might prevent calcium-mediated glutamate excitatory toxicity in AD. Studies 
with memantine over 6 months in subjects with moderate to severe AD have shown small 
benefits on cognition, global measures, daily living activities, and behavior (Reisberg et al., 
2003), but evidence for a benefit is lacking in mild AD (Schneider et al., 2011). 
 
Aduhelm™ (aducanumab), an amyloid beta-directed antibody, was recently granted 
accelerated approval by FDA in June 2021 for early AD based on a biomarker (reduction of 
amyloid plaque). One particularly significant limitation in the widespread use of such drugs is 
the requirement for monthly intravenous infusions of the monoclonal antibody preparations 
that target aggregated forms of amyloid, which has a substantial impact on the costs of 
production, distribution, and administration of such treatments. Based on the clinical trials to 
date, there are uncertainties regarding the effectiveness of aducanumab on clinical outcomes.  

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In addition, there is a significant risk of triggering amyloid-related imaging abnormalities, 
requiring regular monitoring by magnetic resonance imaging (MRI) scans (summarized in the 
Aduhelm FDA Drug Approval Package, June 2021). 
 
Therefore, an unmet need exists to develop new medications for AD that more directly 
modify the underlying disease pathology and offer longer-term and greater efficacy. LMTM, 
the investigational product, is believed to have the potential to confer benefits over existing 
treatments for AD due to its ability to affect the process of tau aggregation responsible for the 
underlying neurofibrillary pathology of AD. Available nonclinical and clinical evidence 
supports the clinical evaluation of LMTM in AD. 
 
8.1 
Background 
8.1.1 
Investigational Product 
The investigational product is LMTM (USAN hydromethylthionine mesylate, also referred to 
as leuco-methylthioninium bis(hydromethanesulfonate), hydromethylthionine 
bis(hydromesylate), leucomethylene blue dimesylate, and its code name, TRx0237). As a 
dihydromethanesulfonate salt (also known as mesylate), LMTM stabilizes the reduced 
crystalline form of the MT moiety in the solid state.  
 
LMTM is provided as 4-mg, immediate-release tablets, to be taken twice daily; the 
pharmacokinetics (PK) of LMTM 4 mg as a single dose and given twice daily at steady state 
(8 mg/day) are described in Section 8.1.3.1. Following dissociation of the counter ions, the 
uncharged (reduced) LMT form, i.e., the active moiety, is absorbed passively. The charged 
(MT+) form does not have the conformation necessary to block filament assembly and to 
disassemble formed filaments (Al-Hilaly et al., 2018). When dosed as the charged (MT+) 
form (as in methylthioninium chloride [MTC], also known as methylene blue), it is 
postulated that MT+ requires an additional reduction step (to LMT) to be distributed to the 
brain. Within cells, MT exists in equilibrium between the reduced (LMT) and oxidized (MT+) 
forms, the predominant form present depending on the cellular milieu, i.e., pH and reductive 
capacity within that cell, with the LMT form predominating intracellularly (May et al. 2004).  
 
Matching placebo tablets are provided. The drug supplies for the placebo group will include 
tablets containing a urinary discolorant, MTC, 4 mg, in order to provide urinary discoloration 
and maintain the treatment blind. 
 
8.1.2 
Nonclinical Data 
In cell models, LMT (including as LMTM) has been shown to prevent aggregation and 
facilitate disaggregation of pre-existing oligomers and fibers. In transgenic mouse models, 
facilitation of clearance of tau aggregates and associated improvements in cognitive and 
motor learning abilities have been demonstrated. Tau pathology in these transgenic mouse 
models has been shown to be ameliorated in certain brain regions (e.g., entorhinal cortex, 
hippocampus, and neocortex) following treatment with LMTM. 
 
The primary toxicity of MT is hematological, manifesting as methemoglobinemia and a 
regenerative hemolytic anemia. Depending on the species, Heinz body formation also occurs. 
A no-observed-adverse effect-level (NOAEL) of 3 to 5 mg MT/kg/day was established in 
rats, regardless of salt or duration, depending on the low dose in a given study; the parent 

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MT/LMT plasma levels (exposure) at these doses are comparable to human exposure at an 
LMTM dose of 8 mg/day. In monkeys, the NOAEL for hematological toxicity was 0.9 mg 
MT/kg/day in the 6-month MTC phase (toxicokinetic data at this dose are not available); the 
NOAEL in the subsequent 9-month LMTB phase in which higher doses were given was 
<20 mg MT/kg/day (the lowest dose studied). Hematological toxicity was seen in minipigs 
even at the lowest dose studied; therefore, the NOAEL is considered to be <3 mg MT/kg/day. 
The hematological effects in rats occur at exposures that are 2.1-fold higher than in humans at 
an LMTM dose of 16 mg/day and in minipigs at exposures that are 1.2-fold higher. In rats 
and minipigs (but not monkeys) at the hematologically toxic doses, myeloid generation is 
also affected, and extramedullary hematopoiesis is seen. Pigment (hemosiderin) deposition 
becomes evident in liver and renal cortical tubules (some lipofuscin is also present in 
minipigs) with no adverse effect on either liver or kidney function evident. At relatively high 
doses, effects on white blood cells (WBCs) are seen, but not consistently across species (seen 
only in rats, not monkeys or minipigs). Decreases in circulating neutrophils occurred with an 
exposure-based safety margin of 8.9. 
 
The other potential significant toxicities observed include effects on the heart, described as 
myocardial necrosis, generally occurring at rapidly lethal doses that exceed the maximum 
tolerated doses for chronic administration. In the minipig, no cardiac toxicity was observed at 
the highest dose administered chronically, providing safety margins of >7.5-fold relative to 
an LMTM dose of 16 mg/day in humans. Gastric irritation is seen in rodents and urinary 
bladder irritation is seen in mice and minipigs (with single cell necrosis in the latter species). 
 
MT is genotoxic in vitro and damages DNA in vitro, but is not genotoxic in vivo. There is no 
evidence of an interaction with or damage to DNA in vivo, a difference which may be due to 
differences in the predominant redox state of MT in vitro and in vivo. In addition, MT+, as a 
photosensitizer, is activated in vitro by visible light to form reactive hydroxyl and superoxide 
radicals and has been found to be mutagenic in vitro only in the presence of light; there is no 
evidence that MT administered orally undergoes photo-oxidation. According to the 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH)1, “When a positive result occurs in an in vitro mammalian cell assay, 
clearly negative results in two well-controlled in vivo assays, in appropriate tissues and with 
demonstrated adequate exposure, are considered sufficient evidence for lack of genotoxic 
potential in vivo.” Thus, MT (and by extension its active metabolite N-desmethyl MT) is 
considered to have no clinically relevant genotoxic potential. 
 
As reviewed by the U.S. National Toxicology Program, there is “some evidence of 
carcinogenic activity”2 of MTC in male rats based on increased incidences of pancreatic islet 
cell adenoma and adenoma or carcinoma (combined) and in male mice based on increased 
incidences of carcinoma and of adenoma or carcinoma (combined) in the small intestine. 
When data are evaluated using the U.S. Food and Drug Administration (FDA) criteria for a 
positive response3, there were no statistically significant neoplastic findings in either species. 
However, FDA concluded that the combined incidence of pancreatic islet cell adenomas and 
carcinomas in male rats was higher than in historical controls, particularly at the mid-dose of 
 
1 ICH S2(R1): Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use 
(2012) 
2 Text in quotation marks refers to the interpretation of results provided by the U.S. National Toxicology 
Program, the sponsoring organization. These analyses were not consistent with FDA statistical guidelines. 
3 FDA Guidance for Industry: Statistical aspects of the design, analysis, and interpretation of chronic rodent 
carcinogenicity studies of pharmaceuticals (draft, May 2001). 

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19 mg MT/kg/day, and thus caused by MT. At this dose, the exposure-based safety margin 
relative to a human LMTM dose of 16 mg/day is 3.0-fold. 
 
MT has no effect on mating performance or pregnancy rate in rats when administered orally. 
The exposure-based safety margin is >8.3-fold and >10.1-fold in males and females, 
respectively, for an LMTM dose of 16 mg/day. 
 
Two embryo-fetal development studies have been performed by NTP wherein MT was dosed 
orally during organogenesis. There was no evidence of teratogenicity in rats (NOAEL safety 
margin of 92-fold relative to a human LMTM dose of 16 mg/day, adjusted for differences in 
body surface area [BSA]); evaluation of fetotoxicity was confounded by maternal toxicity at 
all doses. In rabbits, the NOAEL for teratogenicity was the lowest dose studied, a 46-fold 
safety margin; fetotoxicity (abortions) occurred at the lowest dose (a dose that was maternally 
toxic). The observed malformations in rabbits, umbilical hernia, are of unclear relevance to 
humans. Thus, the nonclinical reproductive toxicity studies do not raise a strong suspicion of 
human teratogenicity/fetotoxicity at clinical doses of LMTM to be studied. Results of studies 
in other species and by other routes of administration are presented in the Investigator’s 
Brochure. There have been no reports of human teratogenicity in early pregnancy. Thus, MT 
is considered to have “unlikely human terotogenicity/fetotoxicity in early pregnancy”4.  
 
In a standard study performed in male Long-Evans pigmented rats, MT does not cause 
phototoxicity. 
 
Additional details regarding findings from nonclinical studies with various salt forms of MT 
(LMTM, leuco-methylthioninium bis(hydrobromide) [LMTB], and MTC) are described in 
the Investigator’s Brochure. 
 
8.1.3 
Clinical Data 
8.1.3.1 
Pharmacokinetics 
A single- and multiple-dose pharmacokinetic study has been completed in older (≥50 years), 
healthy, male and female volunteers (TRx-237-036). Following a single 4-mg dose, the mean 
peak (Cmax) plasma parent MT/LMT concentration is 0.1 ng/mL, occurring approximately 1 
to 1.5 hours post dose. From review of individual concentration versus time profiles, split 
peaks and one or more secondary peaks are evident within the first 12 hours following dosing 
in the majority of subjects, consistent with a possible biliary recirculation.  
 
Following a single 125-mg dose of LMTM, the presence of food delays absorption by about 
1 hour. Cmax of parent MT/LMT increases, but not to a clinically meaningful extent; there is 
no difference in area under the plasma concentration versus time curve (AUC). 
 
There is evidence of a possible saturation of absorption with increasing doses. With single-
dose administration beginning with a dose of 75 mg, plasma concentrations increase 
proportionally until a dose of 500 mg. At higher doses up to 1000 mg, there is a delay in Cmax 
and plateau in AUC. 
 
MT is not highly protein bound: 69.1% to 74.9% in human blood. 
 
4 Clinical Trials Facilitation Group: Recommendations related to contraception and pregnancy testing in clinical 
trials (Version 1.1, September 2020) 

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Hepatic metabolism to N-desmethyl MT, an active metabolite, occurs, mediated primarily by 
cytochrome P450 isoenzyme (CYP) 1A2 and, to a minor extent, by CYP3A4. Plasma levels 
of this metabolite are approximately 10% to 30% of parent MT/LMT based on Cmax and AUC 
following single or multiple doses (however, plasma concentrations could not be reliably 
measured).  
 
Conjugation to the inactive N-glucuronide is the primary route of metabolism of LMTM. The 
primary UDP-glucuronosyltransferase (UGT) isoform responsible is UGT1A4; UGT1A7 and 
UGT1A9 may contribute, as well as UGT1A8 and UGT1A10 to a lesser extent. “Total” MT, 
i.e., predominantly LMT-glucuronide(s), is present in concentrations that are >1000-fold 
higher than those of parent MT/LMT in plasma, whether based on Cmax or AUC following a 
single 4-mg dose or 8 mg/day. This is consistent with extensive first pass metabolism 
(particularly glucuronidation) and rapid distribution of MT from the central compartment, as 
MT is absorbed and passed through the intestine and liver to the systemic circulation and 
deep compartments.  
 
Steady-state plasma concentrations of parent MT/LMT are achieved within 10 days of dosing 
(the first timepoint at which trough plasma concentrations were measured in TRx-237-036). 
At an LMTM dose of 8 mg/day (given daily as two divided doses), plasma parent MT/LMT 
Cmax is 0.3 ng/mL. Based on Cmax and AUC, there is no unexpected accumulation with 
multiple dosing. At steady state, the mean terminal elimination half-life (T½) of parent 
MT/LMT is 35.6 hours; mean T½ of total MT is shorter (19.1 hours). 
 
At the higher doses (150 and 250 mg/day dosed to steady state), there is a linear but greater 
than proportional increase in parent MT/LMT exposure and a less than proportional increase 
in total MT. As a result, at steady state, total MT-to-parent MT/LMT ratios are 243- to 388-
fold for Cmax and 249- to 291-fold for AUC 0-τ over the dosing interval, suggesting either a 
saturation in formation of the glucuronide conjugate or proportionately more extensive 
distribution into deep compartments at high doses.  
 
LMT is not a substrate of either P-glycoprotein (P-gp) or breast cancer resistance protein 
(BCRP) transporters. MT+ (but not LMT) is a substrate of the hepatic uptake transporter, 
organic cation transporter 1 (OCT1); the renal uptake transporter, organic cation transporter 2 
(OCT2); and the renal/hepatic efflux transporters, multidrug and toxin extrusion proteins 1 
and 2K (MATE1 and MATE2K). Neither LMT nor MT+ is a substrate of the other 
transporters tested (organic anion transporters 1 and 3 [OAT1 and OAT3], or organic anion 
transporting polypeptides 1B1and 1B3 [OATP1B1 and OATP1B3]). 
 
There are no clinically meaningful differences in apparent clearance (CL/F) between men and 
women (adjusted for differences in body weight) or between Caucasians and non-Caucasians.  
 
In cross study comparisons, the CL/F of parent MT/LMT is lower in older subjects, possibly 
attributable to renal and/or hepatic impairment of varying degrees. The mean T½ of parent 
MT/LMT after a single oral dose in healthy older subjects is 20.7 hours as compared to 
approximately 15.8 hours in younger healthy volunteers5.  
 
 
5 Average based on Studies TRx-237-019, TRx-237-021, and TRx-237-024. 

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Renal clearance of parent MT/LMT in healthy volunteers represents 13% of CL/F. Most of a 
radiolabeled dose (72%) is recovered in the urine, with 24% as unchanged drug and the 
remainder as metabolites, primarily LMT-glucuronide (28% of the dose). Apparent clearance 
of parent MT/LMT and total MT is decreased in subjects with renal impairment; 
correspondingly, AUC increases and T½ is prolonged. AUC for parent MT/LMT increases by 
1.5-fold in subjects with mild impairment to 4.8-fold in subjects with severe impairment; in 
subjects with severe impairment, Cmax is also affected (1.7-fold increase). T½ of parent 
MT/LMT after a single dose increases with worsening degree of impairment (mean 
24.4 hours, 29.3 hours, and 46.2 hours in mildly, moderately, and severely impaired subjects, 
respectively), relative to a mean T½ of 15.7 hours in generally younger healthy controls [and 
in a cross-study comparison, 21.3 hours in older healthy volunteers]); the longest T½ was 
81.9 hours in a subject with severe impairment. 
 
Apparent clearance of parent MT/LMT (but not total MT) is decreased in subjects with mild 
to moderate hepatic impairment; some of the subjects with mild to moderate hepatic 
impairment also had markedly elevated bilirubin (including due to Gilbert’s syndrome) 
and/or history of cholecystectomy. When compared to control subjects with normal hepatic 
function, Cmax was 2.1- to 3.2-fold higher with mild and moderate impairment, respectively; 
AUC was 1.4- to 2.1-fold higher, respectively. Mean T½ was prolonged 54% to 87% relative 
to a mean T½ of 15.2 hours in generally younger healthy controls (and in a cross-study 
comparison, 21.3 hours in older healthy volunteers as noted above); the longest T½ was 50.1 
hours in a subject with mild impairment. 
 
Approximately 23% of an orally administered dose is recovered from the feces (primarily as 
parent MT/LMT). The observation of secondary peaks in plasma concentrations (and the 
demonstrated excretion into bile of bile duct-cannulated rats) is consistent with biliary 
recirculation, indicating that the fecal excretion cannot be attributed solely to unabsorbed 
drug. 
 
Results of a drug-drug interaction study in healthy volunteers given LMTM (225 mg twice 
daily [bid]) for 3 days or 10 days indicate that MT is a weak inhibitor of CYP3A4, CYP2C8, 
and CYP2C19. LMTM is also a weak inducer of CYP2B6 and P-gp. These data indicate that 
MT may also increase exposure to other co-administered drugs that are substrates of 
CYP3A4, CYP2C8, or CYP2C19, and decrease exposure to substrates of CYP2B6 or P-gp. 
However, the extent to which this occurs at the lower LMTM doses of 8 or 16 mg/day is not 
known. LMTM is not an inducer or inhibitor of CYP1A2, CYP2C9, CYP2D6, or CYP2E1. 
 
When evaluated in vitro, neither the reduced form (LMT) nor the oxidized form (MT+) 
inhibits UGT enzyme activity or the OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3, 
MATE1, MATE2k, or the bile salt export pump (BSEP) transporters at clinically relevant test 
concentrations. LMT (but not MT+) inhibits BCRP at clinically relevant test concentrations. 
 
8.1.3.2 
Cardiac Pharmacodynamics 
LMTM given in single, supra-therapeutic doses of 250 and 875 mg (62.5- and 218.8-fold 
higher than an LMTM 4-mg dose administered at one time) does not prolong the QT interval 
and is not associated with any other abnormalities of cardiac repolarization. 
 

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8.1.3.3 
Efficacy 
In a double-blind, placebo-controlled Phase 2 study (TRx-014-001) of male and female 
subjects with mild or moderate AD (AChEIs and memantine excluded), MTC was 
administered orally at doses of 30 mg three times daily (tid), 60 mg tid, and 100 mg tid (total 
doses of 69 mg/day, 138 mg/day, and 228 mg/day MT base equivalents, respectively). 
MT 138 mg MT/day appeared to slow the clinical rate of decline on the Alzheimer’s Disease 
Assessment Scale – cognitive subscale (ADAS-cog) and the Mini-Mental State Examination 
(MMSE) measured over 1 year. These effects and the benefit on the ADAS-cog, Alzheimer’s 
Disease Cooperative Study-Clinical Global Impression of Change, and MMSE scales were 
already evident in subjects with moderate disease at Baseline within the first 6 months in an 
analysis of the entire population with severity as an interaction term. The 6-month analysis 
and methodology were pre-specified as part of the primary analysis. The result in subjects 
with moderate disease severity at 6 months remained significant after correction for multiple 
comparisons. Longer term efficacy was confirmed in mixed mild/moderate subjects by post 
hoc analyses at 50 weeks and 102 weeks, and efficacy was also confirmed in analyses of a 
variety of secondary endpoints (Wischik et al., 2015). The lower dose (69 mg MT/day) was 
below the minimally effective dose. The capsule formulation used limited the absorption of 
MT at the 228 mg MT/day dose due to a combination of dose-dependent delay in dissolution 
of the 100-mg MTC capsules used in the study and a formulation-independent limitation in 
the ability to absorb MT at the highest dose in the presence of food when administered as 
MTC. When both of these factors were taken into account, the clinically effective dose 
available for release within 60 minutes in subjects receiving a nominal dose of 228 mg 
MT/day was equivalent to approximately 69 mg MT/day (Baddeley et al., 2015), and the 
total available dose was equivalent to 109 mg MT/day (Wischik et al., 2015). 
 
Evidence of clinical efficacy was supported by neuroimaging in 138 mild and moderate AD 
subjects imaged at Baseline and at 24 weeks. Despite lack of decline over this time detected 
by neuropsychological measures such as ADAS-cog in subjects with mild disease at 
Baseline, statistically significant decline in neuronal function as measured by regional 
cerebral blood flow was detected using hexamethylpropylamine oxime-single photon 
emission computed tomography in all predefined lobes in the region-of-interest analysis and 
was particularly marked in the inferior medial temporal and temporo-parietal regions of the 
neocortex on the statistical parametric mapping (SPM) analysis, areas characteristically 
affected by the tau aggregation pathology of AD and the regions primarily affected in the 
Braak staging system (Braak and Braak, 1991). MTC at a dose of 138 mg MT/day was found 
to eliminate this decline entirely (Wischik et al., 2015). A similar effect was seen in a smaller 
group of 20 subjects imaged by 18F-fluorodeoxyglucose positron emission tomography (18F-
FDG-PET) to measure neuronal function by glucose uptake. The effect on functional 
neuroimaging markers at 24 weeks in subjects with mild AD was found to be predictive of a 
clinical response at 50 weeks (Wischik et al., 2015). The reduced efficacy of the 100-mg 
capsule dose (228 mg MT/day) relative to the 60-mg capsule dose (138 mg MT/day) was also 
confirmed by neuroimaging. 
 
Two Phase 3 studies of LMTM in AD subjects have recently been completed (Gauthier et al., 
2016; Wilcock et al. 2018); final study reports are in preparation. These were a 15-month 
study in subjects with mild to moderate AD comparing doses of 150 mg/day and 250 mg/day 
with a control arm of 8 mg/day (TRx-237-015), and an 18-month study in subjects with mild 
AD comparing a dose of 200 mg/day and the 8-mg/day control (TRx-237-005). AChEIs 
and/or memantine were used concomitantly by approximately 80% to 85% of the subjects 

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depending on study. Briefly, there was no statistically significant difference between LMTM 
in the higher doses of 150 to 250 mg/day in either of the two co-primary clinical efficacy 
endpoints or lateral ventricular volume (LVV) when compared with the dose of LMTM 
8 mg/day, intended as a control. Based on the results of the Phase 2 study, it was assumed 
that a dose of 8 mg/day of LMTM would be without activity and could thus be used to 
control for urinary discoloration because of concerns about blinding. Further analyses of 
results from both studies suggest that LMTM 8 mg/day given as monotherapy may be 
effective in delaying progression of mild to moderate AD on co-primary clinical efficacy 
endpoints, the 11-item version of the ADAS-cog (ADAS-cog11) or the Alzheimer’s Disease 
Cooperative Study - Activities of Daily Living scale, 23-item version (ADCS-ADL23), and 
also on imaging measures of progression of brain atrophy (MRI and 18F-FDG-PET), and that 
there is no added benefit to using approximately ≥20-fold higher doses than 8 mg/day.  
 
Recent population PK studies suggest that there are concentration-response relationships for 
cognitive and neuroimaging outcomes at the 8-mg/day dose. This is seen whether LMTM is 
taken alone or as add-on to symptomatic treatments (Schelter et al., 2019). In a within-cohort 
meta-analysis of both studies, LMTM at a dose of 8 mg/day as monotherapy was found to 
produce significant deceleration in the annualized rate of whole brain atrophy after 9 months 
of treatment. The magnitude of the concentration-dependent treatment effects was reduced by 
approximately half when LMTM was given to subjects who were concurrently using AChEIs 
and/or memantine. The reduction in treatment effects of LMTM by treatment with an AChEI 
or memantine has been reproduced in a tau transgenic mouse model, and appears to reflect a 
generalized homeostatic downregulation that is induced in multiple brain systems to 
compensate for the activating effects of symptomatic treatments (Riedel et al., 2020). 
 
8.1.3.4 
Safety 
As of 17 December 2020, 2678 subjects have received at least a single dose of MT (as 
LMTM, MTC, or an earlier reduced salt studied previously). With respect to LMTM, a total 
of 2283 subjects (337 healthy volunteers, 40 hepatically or renally impaired subjects, 1688 
subjects with AD and 218 subjects with bvFTD) have received at least one dose (ranging 
from 8 to 1000 mg/day) in completed TauRx-sponsored studies. A total of 321 subjects with 
AD participated in the 2-year Phase 2 study, TRx-014-001, of whom 307 were exposed to at 
least one dose of MTC.  
 
The most common adverse events (AEs) associated with MT are anemia and gastrointestinal 
(GI), genitourinary, and central nervous system (CNS) effects; these are also the most 
common reasons for discontinuing treatment. These were seen in both the Phase 2 study 
performed with MTC (given in MT doses up to 228 mg/day) as well as in the Phase 3 studies 
with LMTM given in MT doses up to 250 mg/day. When all treatment-emergent adverse 
events (TEAEs) reflective of anemia are grouped, the overall incidence is 13% in subjects 
randomized to LMTM 8 mg/day. The GI and genitourinary TEAEs are less common at 
LMTM 8 mg/day than at higher doses. Overall, GI events occurred in 21% of subjects 
randomized to LMTM 8 mg/day; diarrhea and nausea were amongst the most common 
individual treatment-related TEAEs, occurring in 7% and 2% of subjects, respectively. The 
most common urinary TEAEs were frequency, urgency, and incontinence, each treatment 
related in 1 to 2%. Other less likely TEAEs were agitation, dizziness, fatigue, headache (each 
with an incidence of 2%), and confusional state (with an incidence of 1%). 
 

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Additional details regarding clinical findings from studies are described in the Investigator’s 
Brochure. 
8.2 
Rationale 
The two recently completed Phase 3 studies conducted in subjects with mild to moderate AD 
(TRx-237-015) and mild AD (TRx-237-005) were designed on the basis of results from the 
earlier Phase 2 study of MTC as monotherapy in mild to moderate AD. In that study, the 
minimum dose required for benefit on clinical and imaging endpoints was found to be 
138 mg/day. Both of the Phase 3 studies were therefore designed on the assumption that a 
dose of 8 mg/day of LMTM could be used to control for urinary discoloration because of 
concerns about blinding. As noted earlier, results from both Phase 3 studies in subjects with 
mild to moderate AD suggest that LMTM 8 mg/day given as monotherapy may be effective 
in delaying progression of AD and that there is no added benefit to using doses of 150 to 
250 mg/day. 
 
The results of the first of the studies to become available (TRx-237-015) showed that there 
was no statistically significant difference between LMTM in doses of 150 mg/day or 
250 mg/day in either of the two co-primary clinical efficacy endpoints or LVV when 
compared with the dose of LMTM 8 mg/day intended as a control. However, of the pre-
specified terms in the analysis model used in the primary analysis, use of approved AD 
co-medications (AChEIs and/or memantine) at Baseline was a highly significant term. 
Further pre-specified analyses in which monotherapy and add-on subjects in the higher dose 
treatment arms were compared separately with the control group as randomized suggested 
that LMTM may be effective when given as monotherapy, but not when taken as add-on to 
approved treatments for AD. LMTM 8 mg/day as monotherapy was also found to differ 
significantly from 8 mg/day as add-on to existing AD treatments. In light of these results 
from TRx-237-015, the Statistical Analysis Plan (SAP) of TRx-237-005 was modified prior 
to database lock and unblinding to specify as primary two similar parallel analyses, each at a 
statistical threshold of 0.025, to examine 200 mg/day as monotherapy compared with the 
8 mg/day control group as randomly assigned, and also 8 mg/day as monotherapy compared 
with 8 mg/day as add-on to approved AD treatments. Both of these sets of comparisons were 
statistically significant at the 0.025 threshold for both of the co-primary clinical efficacy 
endpoints, as well as LVV. No difference in baseline characteristics has been identified in 
either of the two Phase 3 studies that accounts for the discrepant responses between subjects 
taking and not taking approved AD treatments, nor is a pharmacokinetic basis for an 
interaction evident. As indicated above, a within-cohort meta-analysis of both studies showed 
that LMTM at a dose of 8 mg/day as monotherapy was associated with significant 
deceleration in the annualized rate of whole brain atrophy after 9 months of treatment.  
 
In the continued development of LMTM, the efficacy of LMTM is to be confirmed in a 
placebo-controlled study at a dose of 16 mg/day. A population PK model was developed 
based on Study TRx-237-036 and applied to plasma concentrations from the Phase 3 studies. 
Using per-patient peak steady-state plasma concentration (Cmax,ss) estimates, concentration-
response analyses for ADAS-cog11 decline over 65 weeks were performed and a Cmax,ss 
threshold of 0.373 ng/mL was identified. The clearance of parent MT/LMT is most 
significantly associated with renal function, suggesting that the most important predictor of 
whether or not a subject achieves a parent MT/LMT Cmax,ss above the threshold is creatinine 
clearance. At a dose of 8 mg/day, approximately 60% of subjects with normal renal function 

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would be expected to have plasma concentrations above the threshold, whereas at a dose of 
16 mg/day, all subjects would. 
 
The co-primary endpoints are ADAS-cog11 and ADCS-ADL23, consistent with trials in 
subjects with mild to moderate AD. Based on the prior studies, a 12-month duration is 
deemed sufficient to demonstrate superiority to placebo. To address concerns regarding 
inadvertent unblinding due to urinary discoloration, subjects randomized to placebo may 
receive a 4-mg MTC tablet as one of the four tablets to be taken daily. As subjects with early 
AD (also referred to as prodromal AD/mild cognitive impairment due to AD [MCI-AD]) are 
also included in the study, 18F-FDG-PET and clinical composite scales are included as 
sensitive endpoints for this subset of subjects. 
 
An open-label, “delayed-start” phase is also included to demonstrate a disease-modifying 
drug effect. During the delayed-start phase, placebo subjects are switched to receive the 
active treatment and thus become delayed-start subjects or “late” starters. Active-treatment 
subjects continue to receive active treatment (all at a dose of 16 mg/day) during the delayed-
start phase and are labeled as “early” starters. The rationale of a delayed-start design is that 
under the null hypothesis, when the active drug has a purely symptomatic effect and has no 
effect on neuropathologic process, a delay in administration should have no lasting effect on 
subjects. An effect that slows the progression of disease by modifying the underlying 
biological pathology, rather than only attenuating symptoms, would be evident if late starters 
fail to “catch up” to early starters. Demonstrating a disease-modifying effect would imply a 
sustained benefit of starting such drugs early. Throughout (that is, both the placebo-controlled 
and delayed-start phases), all subjects and study personnel are blinded to each subject’s 
randomization to the early-start or late-start treatment group. 
 
9 
OBJECTIVES 
The primary objectives of the study pertain to the randomized, double-blind treatment period. 
The secondary objectives are presented separately for the double-blind treatment period and 
the open-label, delayed-start phase. Further exploratory analyses and exploratory analyses 
compared to external data are described in Section 17.5. 
9.1 
Primary Objectives 
1. 
To compare the LMTM dose of 16 mg/day with the placebo group on the following 
co-primary endpoints: 
a. ADAS-cog11  
b. ADCS-ADL23 
2. 
To assess the safety and tolerability of LMTM 16 mg/day given for up to 52 weeks 
9.2 
Secondary Objectives 
9.2.1 
Double-Blind Treatment Period 
3. 
To compare the LMTM dose of 16 mg/day with the placebo group in annualized rate 
of whole brain atrophy over 52 weeks as measured by brain magnetic resonance 
imaging (MRI) and quantified using the Boundary Shift Integral (BSI) 

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4. 
To compare the LMTM dose of 16 mg/day with the placebo group in temporal lobe 
18F-FDG-PET change in Standardized Uptake Value Ratio (SUVR) (normalized to 
pons) over 52 weeks, restricted to subjects with Clinical Dementia Rating (CDR) 
0.5 at Screening, if a predefined threshold is reached for a sufficient number of 
subjects providing data 
5. 
To compare the LMTM dose of 8 mg/day with the placebo group in temporal lobe 
18F-FDG-PET change in SUVR (normalized to pons) over 52 weeks, restricted to 
subjects with CDR 0.5 at Screening, if a predefined threshold is reached for a 
sufficient number of subjects providing data 
6. 
To compare the LMTM dose of 8 mg/day with the placebo group on the co-primary 
endpoints (ADAS-cog11 and ADCS-ADL23)  
7. 
To compare the LMTM doses of 8 and 16 mg/day with the placebo group in 
annualized rate of temporal and parietal lobe atrophy over 52 weeks as measured 
by MRI and quantified using the BSI 
8. 
To assess the safety and tolerability of LMTM 8 mg/day given for up to 52 weeks 
 
9.2.2 
Open-Label, Delayed-Start Phase  
9. 
To determine if there is a difference in disease progression on the co-primary clinical 
endpoints and the MRI imaging endpoint for subjects who started treatment in the 
double-blind treatment phase and those who started treatment in the open-label, 
delayed-start phase (referred to as “early” and “late” LMTM starters, respectively) 
a. Only ADAS-cog11 will serve as a secondary endpoint; ADCS-ADL23 and other 
imaging endpoints are exploratory with the aim to be directionally supportive 
10. 
To assess the safety and tolerability of LMTM given for up to 104 weeks 
 
Population PK analyses will be performed to estimate PK exposure in each subject for use in 
the evaluation of exposure-response relationships. These will be defined in a separate 
Population PK SAP or a dedicated section of the SAP. 
 
Additional analyses including exploratory and sensitivity analyses are described in Section 17 
and further detailed in the SAP.  
 
10 
STUDY DESIGN 
10.1 
General Description 
This is a two-phase outpatient study of LMTM administered as monotherapy in subjects with 
early to mild-moderate AD: a randomized, double-blind, placebo-controlled, 52-week 
treatment period followed by a 52-week open-label, delayed-start phase. In the latter, all 
subjects are to continue with open-label treatment, such that subjects originally randomized 
to placebo are “late” starters of LMTM and subjects originally randomized to LMTM 
8 mg/day or 16 mg/day are “early” starters. The total duration of participation for an 
individual subject will be up to 120 weeks, including a Screening period of up to 16 weeks. 
Subjects are to have pathophysiological changes as confirmed by positive amyloid PET and 
severity determined by a Mini-Mental State Examination (MMSE) score of 16-27 / Global 
Clinical Dementia Rating (CDR) score of 0.5 to 2 at Screening. Subjects must not have used 
an AChEI and/or memantine within the 60 days prior to the baseline assessments (inclusive 

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of the baseline 18F-FDG-PET scan in subjects who have a screening CDR of 0.5). The 
primary treatment group comparisons are of LMTM 16 mg/day and placebo; secondary 
comparisons will be done for subjects receiving LMTM 8 mg/day versus placebo. Following 
completion of the 52-week treatment period, subjects will continue open-label treatment with 
LMTM 16 mg/day for a further 52 weeks; prior treatment assignment will not be unblinded. 
(However, upon completion of the initial 52-week, double-blind, placebo-controlled 
treatment period, the database will be locked and unblinded for analysis; individual subject 
prior treatment assignment will not be divulged to subjects or individuals involved in the 
operational conduct of the ongoing open-label, treatment phase). A description of the study is 
provided below; see Section 10.2 for a summary of the alternate arrangements that may be 
implemented due to the Coronavirus Disease 2019 Public Health Emergency (hereafter 
referred to as COVID-19). 
 
Following provision of written informed consent by the subject (and/or LAR, consistent with 
national and/or local law) and study partner(s), eligibility will be assessed initially during the 
Screening period which may require multiple visits (collectively designated as Visit 1).  
 
A sufficient number of subjects will be recruited from sites in North America (United States 
and Canada) and Europe such that approximately 500 subjects are enrolled. Beginning with 
Protocol Version 5.0, approximately 450 are to be enrolled and randomized in a 4:1:4 ratio 
(at the study level) to the LMTM 16-mg/day (200 subjects), LMTM 8-mg/day (50 subjects), 
and placebo (200 subjects) groups. The randomization will be stratified by severity (three 
levels: MMSE 16-19, 20-25, or 26-27, with a target ratio of approximately 2:3:1 for those 
randomized to Protocol Version 5.0 and above), prior use of AChEIs and/or memantine (two 
levels: prior use of either any AChEIs and/or memantine or none), and region (two levels: 
North America or Europe).  
 
Eligibility will be confirmed during the Screening period, with the duration of screening 
depending on whether or not the subject enters the study using an approved AD medication, 
described as follows (and illustrated in Table 10-1): 
• 
The Screening period will be up to 9 weeks for subjects who are not receiving an 
AChEI and/or memantine at the time of signing the Informed Consent (Initial 
Screening Visit, Visit 1). 
• 
The Screening period will be extended for up to a further 6 weeks, 15 weeks in total 
(+7 days at Sponsor discretion), for subjects who are receiving an AChEI and/or 
memantine at the time of signing the Informed Consent to allow for the performance 
of necessary screening tests to confirm eligibility prior to the discontinuation of 
AChEI and/or memantine and to permit a washout of at least 60 days from the last 
dose prior to the baseline assessments (inclusive of the baseline 18F-FDG-PET scan in 
subjects who have a screening CDR of 0.5). 
• 
The Screening visit window may be further extended at the discretion of the Sponsor 
when justification is provided. 
 
For eligible subjects, one Baseline/Randomization (Visit 2: imaging, efficacy, and safety), 
and five post-Baseline double-blind visits (Visit 3: safety, and Visits 4, 5, 6, and 7: efficacy, 
imaging, and safety), and three open-label treatment visits (Visits 8 [telephone contact only], 
9, and 10) are scheduled. Unscheduled visits may occur as needed for assessment, or upon 
early termination. In addition, subjects are to be followed as needed to monitor for the 
resolution or acceptable stabilization of AEs (including after the last dose), consistent with 
the investigator’s medical judgement. For women of childbearing potential this includes a 

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return visit to the clinic for pregnancy testing within 3 months of last exposure to study drug 
in the event of delayed menstruation.   
 
Visit 2 (Baseline/Randomization) must be scheduled to occur in the morning when the first 
dose of study drug will be administered in the clinic. Visit 3 (after 4 weeks of study drug), 
Visit 7 (after 52 weeks of study drug), and Visit 10 (after 104 weeks of study drug) should 
also be scheduled to occur in the morning; subjects are to be instructed not to take the 
morning dose of study drug as it will be administered in the clinic. Subjects will be required 
to remain at the clinic for at least 4 hours post-dose on each occasion to allow for safety 
assessments and PK blood sample collection.  
 
Cognitive and functional assessments using two standard scales, ADAS-cog13 and ACDS-
ADL23, will be performed at Baseline, approximately every 3 months during the double-blind 
treatment period (Visits 4, 5, 6, and 7), and after the additional 26 and 52 weeks of open-label 
treatment (Visits 9 and 10), or upon early termination. These will be captured electronically 
on tablets and subject to independent review. The MMSE and CDR will be repeated after 52 
weeks of double-blind treatment (Visit 7) and at the final open-label visit (Visit 10) or upon 
early termination. To the greatest extent practicable, a consistent rater(s) for a given subject is 
to be maintained throughout the study.  
 
The MRI obtained during Screening will also be the basis for the baseline volumetric MRI; 
volumetric MRI will be repeated approximately every 13 weeks (Visits 4, 5, 6, and 7). The 
imaging endpoints will be quantified by independent core laboratories. MRI will also be done 
after the additional 26 and 52 weeks of open-label treatment (Visits 9 and 10).18F-FDG-PET 
imaging will be performed at Baseline and Visit 7 (after 52 weeks), or upon early 
termination, only in subjects with CDR 0.5. 
 
Safety assessments (AE and concomitant medication review, vital sign review, targeted 
physical and neurological examinations, and review of clinical laboratory results) will be 
performed by an independent qualified assessor not involved in efficacy assessments; where 
specified, the assessments must be made by a medical assessor (physician, doctor of medicine 
[MD], or doctor of osteopathic medicine [DO]). These will be performed at each clinic visit 
during the double-blind treatment period (Visits 2 to 7) and after 26 and 52 weeks of open-
label treatment (Visits 9 and 10), and when needed to follow up on an AE. Selected safety 
assessments will also be performed during a telephone contact after 4 weeks in the open-
label, delayed-start phase (Visit 8). An ophthalmological examination (only to be conducted 
in subjects with lens implants) will be performed prior to the first dose of study drug (during 
the screening procedures or as part of the baseline assessments) and at the final visits in each 
of the study phases (Visits 7 and 10), or upon early termination, to assess for potential 
discoloration of the lens. See Table 10-2, Table 10-3 and Section 15.4 for more details on 
these assessments and the qualifications required to perform them.  
 
Other assessments include collection of blood for plasma and whole blood MT concentration 
determination and (optionally) collection of a blood sample for Apolipoprotein E (ApoE) 
genotyping. 
10.2 
Changes Implemented Due to COVID-19 
Based on ongoing risk assessment regarding the impact of COVID-19 on this study as 
described in Section 21.2, selected changes to the performance of study conduct and 

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monitoring are to be implemented as deemed necessary to protect subjects due to COVID-19 
as described in Sections 10.2.1 and 10.2.2, respectively. For subjects already enrolled under 
earlier versions of the protocol (prior to Protocol Version 6.0), subjects will be re-consented 
at their next in-clinic visit; in the interim, verbal consent will be obtained as needed for 
changes to study procedures. Changes to the statistical analyses, including sensitivity 
analyses to address any impact of COVID-19 on study outcomes, are described in Section 
10.2.3. 
 
10.2.1 
Changes to Study Conduct 
If a subject is undergoing screening assessments, but cannot have protocol-required 
assessments performed due to COVID-19, the subject should be put on screening pause until 
such time as COVID-19 impacts have ceased and abstention from treatment with an AChEI 
and/or memantine should be retained. Screening MMSE/CDR/DV, brain scans, and G6PD 
blood sample collection do not require repetition if already confirmed. The approach for 
individual assessments is described further below. Re-screening is addressed in Section 11.3. 
 
Both the Screening visit (including informed consent and all screening assessments) and the 
Baseline/Randomization visit must continue to occur in the clinic at the study site. The first 
dose of study drug (Visit 2) will be administered in the clinic. This visit should be scheduled 
to occur in the morning and subjects will be required to remain at the site for at least 4 hours 
post-dose.   
 
The intervening post-Baseline visits, i.e., Visits 3, 4, 5, 6 and 7 (after 4, 13, 26, 29, and 
52 weeks of double-blind study drug), for clinical safety assessments (adverse event and 
concomitant medication recording/review), safety and PK blood sample collection (inclusive 
of the optional genotyping blood sample collected any time after Baseline but prior to 
Visit 7), as well as efficacy assessments, may be completed in-clinic at the site, in the 
subject’s home by visiting study personnel, or at other safe, suitable alternative location, if 
deemed necessary to protect a subject due to COVID-19. Similarly, Visits 9 and 10 (after 26 
and 52 weeks of open-label treatment) may also be completed in the clinic at the site, in the 
subject’s home by visiting study personnel, or at other safe, suitable alternative location. 
Efficacy scales may also be performed remotely, if approved by the Sponsor in advance on a 
case-by-case basis, as further described below. The principal investigators (PIs) retain 
unilateral decision-making and discretion regarding ongoing subject participation dependent 
on local circumstance and authority recommendations. Travel to the investigational site is the 
subject’s decision. The following procedures are also to be implemented as necessary: 
• Consideration may be given on an individual site basis to expand the allowable time 
windows for study visits if a site closure is anticipated to be short-term. 
• Alternative arrangements for dispensing study drug supplies (e.g., home delivery that 
would not raise new safety risks) may be permitted if deemed necessary to protect 
subjects due to COVID-19. If a trial site is not able to deliver study drug to subjects, 
the study drug may, as an exception, be shipped directly to the subjects by a 
distributor independent from and acting on behalf of the Sponsor, in line with national 
law or temporary emergency measures. Requirements for obtaining subject consent 
consistent with local and national requirements, maintaining the specified study drug 
storage conditions and handling, accountability, and compliance monitoring will be 
addressed and documented. In the event that a given subject cannot attend a visit at 
the study site, the study personnel will make reasonable attempts to assess study drug 

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compliance with the subject or study partner(s) and document the assessment in the 
source until it can be verified. 
• The ADAS-cog13 may be performed in the clinic at the site or, if deemed necessary to 
protect subjects due to COVID-19, in the subject’s home or at other safe, suitable 
alternatives, in person or remotely via videoconference. For remote administrations to 
avoid loss of data, MedAvante ProPhase will provide clinical sites with electronic 
tablets provisioned with Zoom (or equivalent) videoconferencing software only6. The 
electronic tablets will be shipped by the clinical sites directly to subjects, and 
guidance will be provided to subjects and study partners regarding the use of the 
electronic tablets for remote scale administration as well as instructions for returning 
the electronic tablets to the sites. When assessments are performed remotely, the rater 
will confirm the identity of the subject and study partner before proceeding. The 
approved site raters will administer the scales through the videoconferencing software 
and will document the assessment as they would if performing the assessment in 
person; source data and audio recordings will still be captured via the Virgil system.  
o In the remote administration of the ADAS-cog13 (if applicable at that visit), the 
standard (i.e., validated) mode of administration has been adapted to enable data 
to be captured by videoconference, with the exception of Commands (only 
partially supported, and thus a total score cannot be calculated for this subset), 
Ideational Praxis, and Number Cancellation. Due to these missing data (not all 
subtests can be administered remotely), total scores will not be calculated directly 
for the remote administration of the ADAS-cog13 but a derived upscaled score will 
be used for analysis as defined in the SAP. 
• The MMSE, CDR, and ADCS-ADL23 may be performed either in the clinic at the site 
or, if deemed necessary to protect subjects due to COVID-19, in the subject’s home or 
at other safe, suitable alternatives in person or remotely by speakerphone. If 
assessments are performed remotely, the rater will confirm the identity of the subject 
and study partner before proceeding. The approved site raters will document the 
assessment as they would if performing the assessment in person; source data and 
audio recordings will still be captured via the Virgil system.  
o In the remote administration of the MMSE (if applicable at that visit), the 
approved site rater will administer as much of the MMSE as possible. For those 
elements that cannot be administered remotely, the rater will confirm that these 
were omitted before submitting the data to MedAvante-ProPhase per usual 
practice. Due to missing data, total MMSE scores for remote assessments will not 
be directly calculated but upscaled as per the SAP. 
o In the remote administration of an ADCS-ADL23 or CDR (if applicable at that 
visit), all items will be scored. 
• All MRI scans are to be performed at approved MRI centers using approved scanners; 
no alternative scanners will be accepted and there is to be no change in scanner for a 
given subject over the course of the study.  
o Guidance will be provided for scheduled MRI visits at approved imaging 
centers that may be closed due to COVID-19, including acceptable windows 
outside the scheduled visit window during which MRI scans can still be 
performed at approved imaging centers and would be accepted for analysis. 
 
6 While remote administration of the ADAS-cog13, MMSE, CDR, and ADCS-ADL23 has not been validated, 
MedAvante ProPhase will prepare written instructions for the rater that detail how to alter administration of 
each of the scales in order to minimize any impact on the data collected, and to minimize loss of data. 

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• In subjects with CDR 0.5 at Screening, 18F-FDG-PET imaging will be performed at 
Baseline (unless the Sponsor approves subject randomization without a brain 
18F-FDG-PET scan, if the scan cannot be performed due to COVID-19). All 
18F-FDG-PET scans are to be performed at approved PET centers using approved 
scanners; no alternative scanners will be accepted and there is to be no change in 
scanner for a given subject over the course of the study. 
o If a Baseline 18F-FDG-PET scan cannot be done due to lack of imaging 
facility, a follow-up 18F-FDG-PET scan will not be required 
• Blood samples for safety laboratory assessments and PK as well as optional 
genotyping may be collected from subjects in the clinic at the site, in the subject’s 
home, or at other safe, suitable alternative location, using the central laboratory 
(Labcorp) kits for sample collection; samples are to be shipped to Labcorp for 
analysis using a designated courier service, and the shipment parameters as per the 
laboratory manual must be adhered to during transfer (e.g., between the subject’s 
home, primary care provider, or clinical site).  
o If blood samples for safety laboratory assessments cannot be shipped to Labcorp, 
sample analysis for hematology testing will be performed at a local laboratory. As 
the first post-Baseline (Visit 3) hematology sample analysis is key in monitoring 
the adverse event of special interest (AESI) of hemolytic anemia, clinical sites 
will not be permitted to randomize a subject if the Visit 3 blood collection plan is 
not in place. Blood chemistry and genotyping samples can also be analyzed at a 
local laboratory or may be stored at -20 °C at the clinical site until shipment to the 
central laboratory.  
o If blood samples for PK laboratory assessments cannot be shipped to Labcorp, 
plasma PK samples should be stored at -20 °C at the clinical site; whole blood PK 
data may be compromised as the samples are stable for a limited period. The 
University of Aberdeen GLP Test Facility must analyze the PK whole blood 
sample within 22 days after the sample is taken to confirm it is acceptable for 
analysis. Results are to be entered into the eCRF by the site. 
o For serum pregnancy testing performed in women of childbearing potential, such 
women should be encouraged to return to the clinic or request serum pregnancy 
testing (to be performed at the subject’s home or at other suitable, safe 
alternatives) in the event of a delayed menstrual period to rule out possible 
pregnancy, during study conduct and for up to 3 months after the last dose of 
study drug. Site follow up on such subjects should be recorded in the source 
documentation. 
o For PK blood sample collection at Visit 2, Visit 3, Visit 7, and Visit 10, the third 
sample to be collected approximately 4 hours after the dose is not required if the 
visit occurs in the subject’s home (although timing of previous dose should be 
ascertained as accurately as possible). 
• Multiple study partners participating only as caregivers will be permitted for a given 
subject, either simultaneously or as replacements for previous study partners, with no 
specified maximum. For study partners participating as informants providing data 
from assessments of the subject, a maximum total of two study partners (i.e., one 
replacement) would normally be permitted for a given subject; however, up to a total 
of four study partners (i.e., three replacements) are permitted if circumstances change 
due to COVID-19 and provided they have sufficient contact with the subject to act as 
a reliable informant. Information obtained from study partners participating as 
informants will be appropriately identified to distinguish each informant in the event 
that a given subject has more than one study partner providing data for analysis. 

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10.2.2 
Changes to Study Monitoring 
As part of ongoing risk assessment regarding the impact of COVID-19, the Sponsor has 
assessed the risk associated with the collection of post-baseline data for this study. All study 
subjects should continue to attend clinic visits as defined in the protocol as long as it is safe 
and feasible to do so. However, in the event that subjects and/or study partners are unable to 
attend post-Baseline visits at the clinic in person, guidance for continued data collection to be 
completed in the subject’s home or at other safe, suitable alternatives is described in 
Section 10.2.1. Any impact of COVID-19 on subject participation in the study will be 
recorded in the eCRFs. 
 
Due to the unpredictable nature of COVID-19, remote monitoring may be conducted in lieu 
of onsite monitoring, including the targeting of critical data and source (for example to 
include consent, eligibility, subject safety and drug accountability) for periods where a source 
data verification backlog exists due to inaccessibility of the site to the clinical monitor. Any 
change to monitoring of the study as a direct result of COVID-19, such as remote monitoring 
policies and procedures, will be captured through an addendum/amendment to the Clinical 
Monitoring Plan (CMP). Every effort will be made to complete the same monitoring tasks 
remotely as would be conducted onsite while accommodating site-specific policies and 
limitations. Every effort will also be made to ensure the continued protection of subject 
safety, subject rights, and data integrity. Any deviations from the CMP will be clearly 
documented.  
 
There is the possibility of increased amounts of missing data and protocol deviations due to 
limitations on protocol implementation imposed by COVID-19. Clinical sites are expected to 
maintain documentation of missing data and protocol deviations in source documents with 
data entered accordingly in the eCRFs.  
 
As the study continues, there will be a need to address other new and challenging scenarios in 
real time as they arise at different clinical sites during COVID-19. The Sponsor will continue 
to assess any limitations imposed on protocol implementation that may pose safety risks to 
study subjects, and whether it is feasible to mitigate these risks by amending study processes 
and/or procedures such that subject safety, trial integrity, and compliance with regulations are 
assured. 
 
10.2.3 
Changes to Statistical Analyses 
Changes to the Statistical Analyses will be outlined in the SAP and will follow the most 
recent regulatory guidelines. This section describes briefly the general approach followed and 
addresses particular challenges related to this study. A detailed list of analyses will be 
provided in the SAP including the conditions that need to be met in order to trigger these 
analyses. At a minimum, the number of missing or likely impacted assessments and data 
points will be provided.  
 
Sites projected to recruit more than 10% of the subjects will be closely monitored to ensure 
that the MMSE balance is met as closely as possible. It is acknowledged that COVID-19 will 
have an impact on certain MMSE groups as they are more likely to be asked to take social 
distancing precautions; corresponding sensitivity analyses will be implemented to assess the 
impact as briefly described below and summarized further in the SAP.  

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As COVID-19 can impact specific assessments and lead to missing data due to missed visits, 
various sensitivity analyses will be provided assessing the impact of COVID-19 on the 
results. Dependent on the actual number of assessments impacted by COVID-19, a more or 
less exhaustive set of analyses will be provided taking account of regulatory guidelines and as 
specified in the SAP.  
 
Among these additional analyses, some will focus on the impact on primary endpoints. If 
more than 5% of all the assessments (over all subjects and visits) of a given primary endpoint 
are impacted by COVID-19 (based on the eCRF Covid-19 Impact Assessment), the 
assessments impacted by COVID-19 will be excluded and upscaled when the respective 
primary endpoint is analyzed. 
 
Other sensitivity analyses include: 
• Subgroup analysis by the way of endpoint ascertainment (in-clinic, remote). A subject 
is assigned to the subgroup with the most visits done with respect to in-clinic or 
remotely (excluding Baseline and Week 52, which must be performed in-clinic). 
• ADAS-cog11: Include only the subset of items (for all visits), which can be 
administered remotely by telephone or video call. 
• ADCS-ADL23: Exclude items which are affected by COVID-19 restrictions. 
• A composite scale designed as a COVID-19 impact free joint score (“COVID-19 
Composite Scale”) will be analyzed. It will include items, selected from ADAS-Cog11 
and ADCS-ADL23, that are not expected to be impacted by COVID-19. 
 
Details and further analysis will be specified in the SAP.  
 
If a significant number of assessments is impacted by COVID-19, a sample size increase may 
be applied. The conditions for this to happen will be outlined and specified before any 
analyses/assessments are conducted. 
 
As indicated above, a more exhaustive list will be provided accounting for regulatory 
guidelines in the SAP. 
10.3 
Study Population 
To be eligible for randomization, subjects are to have AD based on a diagnosis of probable 
AD or MCI-AD according to the criteria of the 2011 National Institute on Aging [NIA] / 
Alzheimer’s Association [AA] with documented pathological changes as confirmed by 
positive amyloid PET (McKhann et al., 2011; Albert et al., 2011). The allowable severity 
will be a MMSE score of 16 to 27 (inclusive) and Global CDR score of 0.5 to 2 (if 0.5, 
including a score of >0 in one of the functional domains). Inclusion and exclusion criteria are 
given in Section 11.  
 
The study will be conducted in approximately 150 study sites in North America and Europe. 
 
Approximately 2000 subjects may be screened to have approximately 500 subjects who will 
be enrolled, of whom approximately 450 are to be enrolled and randomized under Protocol 
Version 5.0 and above. Randomization will be such that subjects will be assigned to the 
MMSE severity groups at study level based on screening MMSE score with a target ratio of 
approximately 2:3:1 (MMSE 16-19, MMSE 20-25, MMSE of 26-27, respectively) for those 

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randomized to Protocol Version 5.0 and above. To achieve this target, enrollment will be 
monitored and controlled at the site level for high recruiting sites (i.e., sites projected to 
recruit more than 10% of the subjects) as per Section 10.2.3 and capped as needed at the 
study level via the Randomization and Trial Supply Management (RTSM) system. Subjects 
who drop out after randomization will not be replaced; subjects will be encouraged to 
continue with study visits until the scheduled completion of the double-blind treatment period 
(Visit 7). Only subjects who continue in the study and receive LMTM until and including the 
last open-label visit (Visit 10) may be eligible for a separate EAP.  
10.4 
Duration 
The total duration of participation for an individual subject will be up to 120 weeks, including 
a Screening period of up to 16 weeks (112 days, with further extension permitted at the 
discretion of the Sponsor when justification is provided), a double-blind treatment period of 
52 weeks, and a further open-label, delayed-start phase of 52 weeks. It is anticipated that the 
study will have an overall duration of at least 40 months, depending on recruitment rate. The 
current study will be concluded after the last visit for the last subject under this protocol. 
10.5 
Schedule of Assessments 
10.5.1 
Screening Assessments 
All subjects should have a likely diagnosis of probable AD or MCI-AD prior to being offered 
the consent forms on the basis of investigator interview and examination. Subjects for whom 
legally acceptable informed consent has been obtained will be screened at trial sites for 
determination of eligibility to enter the study on the basis of further diagnostic evaluations, 
cognitive assessments, and safety assessments (clinical laboratory testing, vital signs, 
complete physical and neurological examinations, and a local 12-lead electrocardiogram 
[ECG]). An overview of the screening assessments is provided in Table 10-1 below; 
assessments must be performed in the sequence presented. Where required and indicated, 
eligibility should be confirmed prior to progressing to the next screening assessment. 
18F-FDG-PET, to be evaluated only in subjects with CDR 0.5 at Screening, is not an 
eligibility assessment; however, a valid baseline scan is required prior to randomization, 
hence it is included on this table. See Section 10.2 for a summary of alternate arrangements 
that may be implemented due to COVID-19. 
 

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Table 10-1: Schedule of Screening Assessments  
(Over Multiple Visits, Collectively Designated Visit 1) 
Required Sequence of Assessments 
Time Frame 
On AChMem  
at Start of Screening 
Not on AChMem  
at Start of Screening 
1. Likely diagnosis of probable AD or MCI-AD (M) 
9 to 16 weeks before 
Baseline,  
Days -112 to -63  
(+7 days at Sponsor 
discretion)d 
≤9 weeks before 
Baseline,  
Days -63 to -1d  
 
2. Informed consent by Subject (and/or LAR) and Study 
Partner(s) (Ma) 
3. Demographics  
4. Medical history and concomitant medication review (M) 
5. NIA/AA probable AD or MCI-AD clinical diagnosis 
confirmed (M) 
6. MMSE 
7. CDR 
8. Diagnostic Verification Form (M) 
9. Medical assessments (M): 
Vital sign measurementb 
Physical/neurological examinationsc 
12-lead electrocardiogram 
Laboratory testing: 
Serum chemistry 
Hematology 
Haptoglobin 
Folate / vitamin B12 
Thyroid stimulating hormone 
Glucose-6-phosphate dehydrogenase 
Serum pregnancy test (women of childbearing 
potential only) 
10. Wait for Confirmation of Eligibility email received from 
MedAvante-ProPhase and laboratory testing 
confirmation of compliance by Labcorp Central 
Laboratory Services before moving to step 11 
11. Amyloid PET scan 
• 
Documentation of prior positive scan  
OR 
• 
If no negative scan within prior 3 years, perform 
using approved amyloid ligand 
12. Wait for Amyloid PET scan confirmation of compliance 
by local / central imaging center (if scan required) 
13. MRI scan 
14. Wait for MRI confirmation of compliance by Bioclinica 
15. Withdraw AChEI/memantine 
≥ 60 days before  
baseline assessments 
Not applicable 
16. Medical history and concomitant medication review, 
serum chemistry, hematology, serum pregnancy test (M) 
Repeat within 42 days 
of Baseline 
Repeat if not 
performed within 
42 days of Baseline 
17. 18F-FDG-PET only in subjects with CDR 0.5  
(Not an eligibility assessment, but independent 
confirmation of a valid baseline 18F-FDG-PET) 
Within 42 days before 
randomization, but 
at least 60 days after 
the last dose of AChEI 
and/or memantine 
Within 42 days before 
randomization 
18. Wait for 18F-FDG-PET confirmation of scan quality by 
Invicro for subjects with CDR 0.5 
Before randomization 
Abbreviations: AChEI = anticholinesterase inhibitor; ACh/Mem = AChEI and/or memantine; AD = Alzheimer’s disease; 
CDR = Clinical Dementia Rating; 18F-FDG = 18F-fluorodeoxyglucose positron emission tomography; LAR = Legally 
Acceptable Representative; MCI-AD = mild cognitive impairment due to Alzheimer’s disease; MMSE = Mini-Mental State 
Examination; MRI = magnetic resonance imaging; PET = positron emission tomography 
Note: (M) requires medical assessor (physician / MD / DO); study partner = caregiver or informant 

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a At all study sites, the PI or SI who obtains informed consent must be a physician (such as a neurologist, psychiatrist) or 
other medically qualified assessor (physician/MD/DO); in the case of subjects with reduced decision-making capacity, 
LARs, consistent with national and/or local law, may provide written informed consent 
b Vital signs include seated blood pressure and pulse, height, and body weight 
c Based on medical history, subjects with a history of lens implantation should be scheduled for an ophthalmological 
examination by a licensed ophthalmologist, optometrist, or other suitably qualified medical assessor (physician/MD/DO) 
to occur prior to the first dose of study drug (once eligibility has been confirmed), during the screening procedures or as 
part of the baseline assessments 
d The Screening visit window may be further extended at the discretion of the Sponsor when justification is provided. 
 
 
10.5.1.1 
Diagnostic and Cognitive Eligibility Assessments 
After consent is obtained, the principal investigator (PI) (or sub-investigator [SI]) is required 
to review medical records and confirm the accuracy of the diagnosis during the examination 
of each subject. The NIA/AA diagnostic interview must be conducted with the subject, and 
the designated study partner (i.e., a caregiver or informant) providing data from assessments 
of the subject, by the PI (or SI). In brief: 
• 
Subjects with probable AD dementia must have insidious onset, worsening 
impairment in at least two cognitive areas (learning and recall, language, executive 
function, visuospatial skills), sufficient to significantly interfere with work or usual 
activities, that is not explained by delirium, drugs, major psychiatric disorder, medical 
illness, cerebrovascular disease, other forms of dementia, or neurological disorder.  
• 
In subjects with MCI-AD, there should be evidence of concern about a change in 
cognition in comparison with the person’s previous level verified by a knowledgeable 
informant or clinician. There should also be evidence of lower performance in 
episodic memory than would be expected for the subject’s age and educational 
background (typically 1 to 1.5 standard deviations below the mean). Other mild 
cognitive deficits may also be present, but there must be preservation of independence 
in functional abilities. Subjects should not meet the criteria for dementia. The 
cognitive changes must be mild and there must be no evidence of a significant 
impairment in social or occupational functioning. Impairments must not be explained 
by delirium, drugs, major psychiatric disorder, medical illness, cerebrovascular 
disease, other forms of dementia, or neurological disorder. 
 
The diagnostic interview should be completed and documented in the subject’s medical 
records prior to administering the MMSE and CDR. The MMSE will be the first evaluation at 
Screening (Visit 1), followed by the CDR, to obtain Severity Ratings. These will be assessed 
on a Virgil tablet. Note that the CDR assessment should only be performed if the subject 
meets the MMSE inclusion criterion. If the subject does not qualify with either of these 
scales, no further assessments should be made and the subject should be considered a screen 
failure. If eligible, a Diagnostic Verification Form will be completed by the PI/SI and 
submitted to independent reviewers at MedAvante-ProPhase Inc., who will confirm the 
accuracy of the diagnosis and Severity Ratings and will provide confirmation (by e-mail) that 
the subject is eligible to proceed to the remaining screening assessments. The PI must 
acknowledge receipt of this independent confirmation prior to subject randomization. In the 
event that MedAvante-ProPhase central reviewers identify issues that cannot be resolved, the 
subject will be deemed not eligible. The subject may be re-screened (after a wait of 90 days 
from last MMSE), inclusive of repeat of MMSE and CDR which will again be subject to the 
independent review to confirm eligibility. 
 

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Eligibility assessments include documentation of a previous PET scan that was positive for 
amyloid. If such documentation is absent, or if the subject has a negative amyloid PET scan 
that is dated >3 years prior to Screening, an amyloid PET scan must be conducted as part of 
screening. A negative amyloid PET scan within 3 years prior to Screening is exclusionary 
and no amyloid PET scan should be performed. If a new amyloid PET scan is performed as 
part of screening, local determination (or central for those sites not able to read locally) of 
positivity using criteria routinely applied at the local imaging facility and using an amyloid 
PET ligand that is approved in the country of participation will be accepted. With subject 
(and/or LAR) consent, these and previous amyloid PET scans will be sent to a core imaging 
laboratory for storage and later exploratory analysis.  
 
The screening assessments should be performed so that MRI is the last of the key eligibility 
assessments to be scheduled. The screening MRI scan(s) results (of sufficient quality) must 
be available for the purpose of inclusion/exclusion review and confirmation of compliance 
with inclusion and exclusion criteria by an independent neuroradiologist. If the initial 
screening MRI is not of sufficient quality, then a repeat screening scan may be performed. If 
the repeat scan cannot be accomplished within the pertinent window (see Table 10-1), then 
the subject must be re-consented and re-screened. For subjects who are re-screened for other 
reasons and an acceptable MRI scan was already completed during the original Screening 
window, the scan does not require repetition. See Section 10.2 for a summary of alternate 
arrangements that may be implemented due to COVID-19.  
 
In subjects receiving an AChEI and/or memantine at Screening, documentation of amyloid 
positive PET imaging (either by prior history or in the sequence of screening tests) and 
confirmation of compliance with inclusion and exclusion criteria by the independent 
neuroradiologist (inclusive of screening MRI), must be available prior to the discontinuation 
of such medication.  
 
At any step, should any of the assessments indicate the subject’s ineligibility, the screening 
process should be stopped immediately (no further assessments performed) and the subject 
considered a screen failure. The reason(s) for screen failure is (are) to be documented. 
 
10.5.1.2 
Other Medical Screening Assessments 
Medical screening assessments will include a review of medical history and concomitant 
medications. Physical and neurological examinations will be conducted by a qualified 
medical assessor (physician/MD/DO) at Screening. The complete physical examination is to 
consist of an evaluation of the skin, head, eyes, ears, nose, throat, neck, thyroid, lungs, heart, 
lymph nodes, abdomen, and extremities. The complete neurological examination is to consist 
of an evaluation of appearance and behavior (including observation for tremor and abnormal 
movements) and an evaluation of the following: speech, cranial nerves (2-12), motor (muscle 
strength), muscle tone, sensory abnormalities, coordination, gait, and tendon reflexes. At 
Screening, the primary aim of this assessment is to exclude neurological disorders other than 
the condition of interest. Any abnormalities noted on either the physical or neurological 
examination should be described.  
 
An ophthalmological examination will be performed by a licensed optometrist, 
ophthalmologist, or other suitably qualified medical assessor (physician/MD/DO) prior to the 
first dose of study drug (during the screening procedures or as part of the baseline 
assessments) in subjects with a history of lens implantation.  

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At Screening, vital signs will be measured (seated blood pressure and pulse, body weight, and 
height), blood obtained for clinical laboratory testing, and a 12-lead ECG performed. Clinical 
laboratory testing at Screening will include hematology, serum chemistry panels, glucose-6-
phosphate-dehydrogenase (G6PD) activity, haptoglobin, vitamin B12, and folate. A serum 
pregnancy test will be performed in women of childbearing potential only. Thyroid 
stimulating hormone (TSH) will be measured during screening, with a thyroid hormone panel 
obtained only in the event of an elevated TSH, if clinically warranted, to determine further 
treatment before re-screening. Clinical laboratory testing (serum chemistry, hematology, and 
serum pregnancy test) and medical history and concomitant medication review should be 
repeated within 42 days of Baseline if the initial screening assessments were performed 
earlier. Review of the clinical laboratory and ECG results should be performed by a medical 
assessor (physician/MD/DO). 
 
Should a subject be found to have met one or more of the exclusion criteria, he/she will be 
considered a screen failure; the reason(s) will be documented. For eligible subjects, findings 
will be documented in the subject's medical record and in the electronic Case Report Form 
(eCRF). 
 
10.5.2 
Baseline and Post-randomization Assessments in Double-
Blind Treatment Period 
The baseline and post-randomization assessments during the double-blind treatment period 
are presented below in Table 10-2. The procedures are further described, briefly, in the 
subsections that follow (with reference to more detailed discussions). See Section 10.2 for a 
summary of alternate arrangements that may be implemented related to COVID-19. 
 

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Table 10-2: Schedule of Post-Screening Assessments (Double-Blind Treatment Period) 
Visit Name
Baselinea 
Double-Blind Treatment Period 
Visit Number
2 
3 
4 
5 
6 
7 (or ET) 
Also 
Baseline/ 
Day 1 for 
Open-
Label 
Phase 
Weeks Relative to Baseline
- 
4 weeks 13 weeks 26 weeks 39 weeks 52 weeks 
Allowable Time Window in Days
Pre-
Dose 
Post-
Dose 
(±3) 
(±14) 
(±14) 
(±14) 
(±14) 
18F-FDG-PET (see Table 10-1) b 
 
 
 
 
 
 
X 
Randomization 
X 
 
 
 
 
 
 
MRI c 
 
 
 
X 
X 
X 
X 
ADAS-cog13 and ADCS-ADL23 d, o 
X 
 
 
X 
X 
X 
X 
AE/Concomitant Medication 
Recording/Review e (M) 
X 
X 
X 
X 
X 
X 
X 
Targeted Physical/Neurological 
Examinations f (M) 
X 
X 
X 
X 
X 
X 
X 
Ophthalmological Examination g (M/O) 
X 
 
 
 
 
 
X 
Clinical Laboratory Testing h (M) 
X 
 
X 
X 
X 
X 
X 
Pregnancy Testing i 
X 
 
X 
X 
X 
X 
X 
Blood Pressure, Pulse, Body Weight j 
X 
X 
X 
X 
X 
X 
X 
Study Drug Dispensing 
X 
 
 
X 
X 
X 
Xp 
Study Drug Compliance Assessment k 
 
 
X 
X 
X 
X 
X 
Blood Sample for MT Concentration l 
X 
X 
X 
 
 
 
X 
Blood Sample for Genotyping (optional) m 
X 
 
 
 
 
 
 
MMSE n, o 
 
 
 
 
 
 
X 
CDR n, o 
 
 
 
 
 
 
X 
Abbreviations: ADAS-cog13 = Alzheimer’s Disease Assessment Scale – cognitive subscale (13-item); ADCS-ADL23 = 
Alzheimer’s Disease Cooperative Study – Activities of Daily Living (23-item); AE = adverse event; CDR = Clinical 
Dementia Rating; EOT/ET = end of treatment/early termination; 18F-FDG-PET = 18F-fluorodeoxyglucose positron emission 
tomography; MMSE = Mini-Mental State Examination; MRI = magnetic resonance imaging; MT = methylthioninium. 
Note: Screening assessments, which include a PET scan for amyloid and a 12-lead ECG, are described in Table 10-1 
Note: (M) = assessment of the result requires medical assessor (physician / doctor of medicine [MD] / doctor of osteopathic 
medicine [DO]); M/O = licensed optometrist/ophthalmologist or other suitably qualified medical assessor 
(physician/MD/DO)  
a 
The Baseline visit (Visit 2) may span over 2-3 days if necessary; Day 1 will commence with the administration of the 
first in-clinic dose of study drug. 
b 
18F-FDG-PET should be performed only in subjects confirmed to meet all inclusion and exclusion criteria and a 
screening CDR 0.5. The Baseline 18F-FDG-PET should be performed within a 42-day window prior to Baseline 
(Visit 2), at least 60 days after the last dose of AChEI and/or memantine, and as described in Table 10-1. A valid scan 
must be confirmed by the independent neuroradiologist prior to randomization at Visit 2. 
If the subject’s last 18F-FDG-PET scan was performed ≥30 days prior to the early termination date, the 18F-FDG-PET 
scan must be repeated as part of the ET visit assessments within the time window of the EOT/ET visit (i.e., ± 14 days of 
the EOT/ET visit).  
Note: Use of sedatives is not permitted within 24-hours prior to 18F-FDG-PET scans and the subject’s fasting (for at 
least 4 to 6 hours) blood glucose should be <180 mg/dL (<9.9 mmol) for the injection to take place.  
c 
Volumetric MRI scans will be obtained at Screening (which also will be the baseline scan) and approximately every 
13 weeks after randomization; the screening MRI will also be used for purposes of confirmation of compliance with 
inclusion and exclusion criteria by an independent neuroradiologist. Subjects may or may not be receiving concomitant 
treatment with AChEI and/or memantine at the time of the screening MRI; the screening MRI will be used as the 
baseline. For subjects who terminate early, if the subject’s last MRI scan was performed <90 days prior to the ET date, 
no additional scan is required.  
d 
At each applicable time point, clinical efficacy assessments should be administered before vital signs measurement and 
blood sample collection. All ADAS-cog13 and ADCS-ADL23 assessments will be subject to central review by 
MedAvante-ProPhase clinicians in the native language. 
e 
AEs and concomitant medication use will be evaluated by a medical assessor (M) and recorded on an ongoing basis 
starting after signing of informed consent, including at each scheduled visit; unscheduled visits should occur as needed 
to follow up an AE (including after the last dose of study drug), consistent with the physician/MD/DO judgment. 

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f 
Targeted examinations will be performed by a medical assessor (M) pre-dose and approximately 3 hours after 
administration of the first dose of study drug (Visit 2). Thereafter, targeted examinations are to be performed at each 
subsequent clinic visit (or upon ET). At a minimum, targeted examinations should include heart and lung auscultation 
and brief neurological assessment guided by any reported signs/symptoms/AEs (e.g., evaluating subjects for potential 
serotonin toxicity).  
g 
Ophthalmological examination (slit lamp) is to be performed only in those subjects with history of lens implant to 
evaluate discoloration of lens. The initial examination will be performed prior to the first dose of study drug (during the 
screening procedures or as part of the baseline assessments); performance of this examination is not restricted to the 
2 to 3 days before the first dose of study drug. The final evaluation (EOT/ET) should be done after completion of the 
efficacy assessments. 
h 
At each identified time point, blood samples will be obtained for chemistry and hematology panels; results are to be 
reviewed by a medical assessor (M). Testing is also to be performed as needed to follow-up on an AE. 
i 
Serum pregnancy testing is to be performed at each identified time point in women of childbearing potential only. 
j 
Within 1 hour prior to dosing on Day 1, blood pressure and pulse will be measured with subjects in a seated position 
(for at least 5 minutes). The post-dose measurement on Day 1 is to be made approximately 2 hours post-dose (after the 
1-2 hour PK sample is taken). Body weight will be measured at each visit (pre-dose at Visit 2). 
k 
Compliance with study drug will be assessed by counting returned tablets (see Section 12.6). 
l 
At Visits 2, 3, and 7, blood will be collected on the same day on three occasions, pre-dose and again approximately 1 to 
2 hours post-dose (these should be morning appointments); and a third sample with time of dose and sample at 
approximately 4 hours after the dose. Note: The time of the dose from the previous day must be collected and recorded 
at Visits 3 and 7, in addition to the time of the dose given in the clinic. For any ET visit, if the subject has not yet 
discontinued study drug and is willing to take a final in-clinic dose, three blood samples will be collected as described 
above. If, however, the subject has already discontinued study drug or is unwilling to take a final in-clinic dose, a single 
blood sample only for determination of MT concentrations will be collected, irrespective of the date or time of the last 
dose of study drug. The date and time of last dose must be collected and recorded. If a subject has discontinued study 
drug but wants to continue to attend study visits off-treatment (the off treatment on study [TOTOS] group), then MT 
concentration blood samples will not continue to be collected. 
m 
A single blood sample for ApoE can be collected any time after eligibility for randomization and continued participation 
in the study has been confirmed (but prior to Visit 7, the end of the double-blind treatment period) for subjects who 
provide legally acceptable consent. 
n 
These are to be rated by the same rater, where possible, as at Screening, after all other efficacy assessments have been 
completed. MMSE and CDR assessments will be subject to central review by MedAvante-ProPhase clinicians in the 
native language. 
o 
The clinical efficacy scale assessments should be performed at approximately the same time of day throughout the 
study for a given subject, to the greatest extent possible. 
p 
In-clinic dose at Visit 7 to be taken after pre-dose assessments, from newly dispensed Visit 7 open-label study drug kit 
(see Table 10-3 for the pre-dose and post-dose assessments to be performed at Visit 7). 
 
10.5.2.1 
Imaging Efficacy Assessments in Double-Blind 
Treatment Period 
Only in subjects with CDR 0.5 at Screening, 18F-FDG-PET will be performed within the 
42 days before Baseline (but not earlier) and after 52 weeks of double-blind treatment or 
upon early termination. The purpose is to assess reduction in decline of glucose uptake in 
regions of interest. If the subject’s last 18F-FDG-PET scan was performed ≥30 days prior to 
the early termination date, the 18F-FDG-PET scan must be repeated as part of the early 
termination visit assessments within the time window of the early termination visit (i.e., 
± 14 days of the last dose of study drug). 18F-FDG-PET data will be evaluated by an 
independent, nuclear medicine staff physician experienced in neuro 18F-FDG-PET, not 
involved in the clinical conduct of the study, and trained on the study endpoints. Note: The 
use of sedatives is not permitted within 24 hours prior to 18F-FDG-PET scans and the subject 
should have a fasting (at least 4 to 6 hours) blood glucose level <180 mg/dL (<9.9 mmol/L) 
in order for the injection to take place. 
 
Brain MRI (obtained at Screening and approximately every 13 weeks during the double-blind 
treatment period after randomization or upon early termination) will be evaluated for change 
in various parameters to determine whether there is reduction of temporal, parietal, whole 
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atrophy rates over the period of the study. Changes in the brain volumes above will be 
quantified at the imaging core laboratory. 
 
For subjects who terminate early, if the subject’s last MRI scan was performed <90 days 
prior to the early termination date, no additional MRI scan is required. 
 
The obtainment and assessment of imaging data are further described in Section 15.3. 
 
10.5.2.2 
Clinical Efficacy Assessments in Double-Blind 
Treatment Period 
The ADAS-cog13 and ADCS-ADL23 will be performed at Baseline and every 13 weeks after 
randomization (or upon early termination) during the double-blind treatment period by an 
approved Efficacy Rater using electronic tablets. Assessments will be recorded and reviewed 
independently as further described in Section 15.2.  
 
As exploratory clinical efficacy assessments, the MMSE and CDR sum of boxes will be 
performed after 52 weeks of double-blind treatment (or upon early termination). For a given 
subject, these are to be performed by the same rater, where possible, who made the screening 
assessments and recorded on electronic tablets, as further described in Section 15.2. These are 
to be the last assessments performed, i.e., after all other efficacy assessments have been 
completed. 
 
All clinical efficacy assessments will be subject to independent review (all subjects, all 
applicable time points). 
 
10.5.2.3 
Safety Assessments in Double-Blind Treatment Period 
Safety assessments (described in Section 15.4) will be performed throughout study 
participation, including at Baseline (prior to dosing and during the 4-hour post-dose 
evaluation at Visit 2) and during the balance of the double-blind treatment period (Visits 3, 4, 
5, 6, and 7, or upon early termination). Safety assessments will be performed by an 
independent qualified assessor not involved in efficacy assessments; where specified, the 
assessments must be made by a medical assessor (physician/MD/DO). Study visits during the 
double-blind treatment period will occur at time points approximately 4, 13, 26, 39, and 
52 weeks after Baseline.  
 
At each in-clinic visit, AEs and changes in concomitant medications will be recorded. These 
must be reviewed by a medical assessor (physician/MD/DO). 
 
Other post-screening assessments include measuring vital signs, performing targeted physical 
and neurological examinations, clinical laboratory testing (e.g., hematology, serum chemistry 
panels), and serum pregnancy testing (women of childbearing potential only). The targeted 
physical and neurological examinations and review of the clinical laboratory results should be 
performed by a medical assessor (physician/MD/DO). 
 
Subjects with a history of lens implant will undergo an ophthalmologic examination by a 
licensed optometrist, ophthalmologist, or other suitably qualified medical assessor 
(physician/MD/DO) prior to the first dose of study drug (during the screening procedures or 
as part of the baseline assessments) and at Visit 7 of the double-blind treatment period or 

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upon early termination (after completion of the efficacy assessments), to evaluate whether the 
lens has become discolored.  Sites that do not have access to a licensed optometrist, 
ophthalmologist, or other suitably qualified medical assessor (physician/MD/DO) are not 
permitted to screen subjects with a history of lens implant. 
 
10.5.2.4 
Other Assessments in Double-Blind Treatment Period 
At Visits 2, 3, and 7, blood will be collected for determination of MT concentrations. 
Samples will be collected pre-dose, approximately 1 to 2 hours post-dose, and approximately 
4 hours post-dose. To achieve this sample collection schedule, these should be morning 
appointments (and for Visits 3 and 7, subjects instructed not to take their morning dose at 
home). See Section 15.5.1 for further details. 
 
For any early termination visit during the double-blind treatment period, also refer to 
Section 15.5.1 for blood sampling requirements for determination of MT concentrations. 
 
ApoE genotype will be determined for subjects who provide legally acceptable consent. A 
single blood sample may be collected any time after eligibility for randomization and 
continued participation in the study has been confirmed at Baseline (Visit 2), but prior to 
Visit 7 (end of the double-blind treatment period). Sample collection is further described in 
Section 15.5.2. 
 
10.5.3 Assessments in the Open-Label, Delayed-Start Phase 
The assessments during the open-label, delayed-start phase are presented below in Table 
10-3. The procedures are further described, briefly, in the subsections that follow (with 
reference to more detailed discussions in Section 15). See Section 10.2 for a summary of 
alternate arrangements that may be implemented due to COVID-19. 
 

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Table 10-3: Schedule of Assessments (Open-Label, Delayed-Start Phase) 
Visit Name
Baseline/Day 1 for 
Open-Label Phase 
Continued Open-Label Treatment 
Visit Number
7 
8 (TC) 
9 
10 
(OL-EOT or 
OL-ET) 
Weeks Relative to Visit 2 Baseline
52 weeks 
56 weeks 
78 weeks 
104 weeks 
Allowable Time Window in Days
(±14 days) 
(±3 days) 
(±14 days) 
(±14 days) 
Pre-Dose 
Post-Dose 
18F-FDG-PET (see Table 10-1 and Table 10-2) 
X 
 
 
 
 
MRI a 
X 
 
 
X 
X 
ADAS-cog13 and ADCS-ADL23 b, l 
X 
 
 
X 
X 
AE/Concomitant Medication Recording/Review c (M) 
X 
X 
X 
X 
X 
Targeted Physical/Neurological Examinations d (M) 
X 
 
 
X 
X 
Ophthalmological Examinatione (M/O) 
X 
 
 
 
X 
Clinical Laboratory testing f (M) 
X 
 
 
X 
X 
Pregnancy Testing g 
X 
 
 
X 
X 
Blood Pressure, Pulse, Body Weight h 
X 
 
 
X 
X 
Study Drug Dispensing 
Xm  
 
 
X 
 
Study Drug Compliance Assessment i 
X 
 
X 
X 
X 
Blood Sample for MT Concentration j 
X 
X 
 
 
X 
MMSE k, l 
X 
 
 
 
X 
CDR k, l 
X 
 
 
 
X 
 
Abbreviations: ADAS-cog13 = Alzheimer’s Disease Assessment Scale – cognitive subscale (13-item); ADCS-ADL23 = 
Alzheimer’s Disease Cooperative Study – Activities of Daily Living (23-item); AE = adverse event; CDR = Clinical 
Dementia Rating; MMSE = Mini-Mental State Examination; MRI = magnetic resonance imaging; OL-EOT = open-label end 
of treatment; OL-ET = open-label early termination; TC = telephone contact. 
Note:  Visit 7 results from Table 10-2 provide baseline values for the open-label, delayed-start phase. 
Note:  (M) = requires medical assessor (physician/doctor of medicine [MD]/doctor of osteopathy [DO]); M/O = licensed 
optometrist/ophthalmologist or other suitably qualified medical assessor (physician/MD/DO) is also acceptable 
a 
For subjects who terminate early, if the subject’s last MRI scan was performed <90 days prior to the ET date, no 
additional scan is required.  
b 
At each applicable time point, clinical efficacy assessments should be administered before vital signs measurement and 
blood sample collection. All ADAS-cog13 and ADCS-ADL23 assessments will be subject to central review by 
MedAvante-ProPhase clinicians in the native language. 
c 
AEs and concomitant medication use will be evaluated by a medical assessor and recorded on an ongoing basis starting 
after signing of informed consent, including at each scheduled visit; unscheduled visits should occur as needed to 
follow up an AE (including after the last dose of study drug), consistent with the physician/MD/DO judgment. 
d 
Targeted examinations are to be performed by a medical assessor at each clinic visit (or upon ET). At a minimum, 
targeted examinations should include heart and lung auscultation and brief neurological assessment guided by any 
reported signs/symptoms/AEs (e.g., evaluating subjects for potential serotonin toxicity).  
e 
Ophthalmological examination (slit lamp) is to be performed only in those subjects with history of lens implant to 
evaluate discoloration of lens. The final evaluation (OL-EOT or OL-ET) should be done after completion of the 
efficacy assessments. 
f 
At each identified time point, blood samples will be obtained for chemistry and hematology panels; results are to be 
medically reviewed by a medical assessor. Testing is also to be performed as needed to follow-up on an AE. 
g 
Serum pregnancy testing is to be performed at each identified time point in women of childbearing potential only. 
h 
Blood pressure and pulse will be measured with subjects in a seated position (for at least 5 minutes).  
i 
Compliance with study drug will be assessed by counting returned tablets (see Section 12.6); compliance will also be 
queried in the TC. 
j 
At Visits 7 and 10, blood will be collected on the same day on three occasions, pre-dose and again approximately 1 to 
2 hours post-dose (these should be morning appointments); and a third sample with time of dose and sample at 
approximately 4 hours after the dose. Note: The time of the dose from the previous day must be collected and recorded 
at Visits 7 and 10, in addition to the time of the dose given in the clinic. For any ET visit, if the subject has not yet 
discontinued study drug and is willing to take a final in-clinic dose, three blood samples will be collected as described 
above. If, however, the subject has already discontinued study drug or is unwilling to take a final in-clinic dose, a single 
blood sample only for determination of MT concentrations will be collected, irrespective of the date or time of the last 
dose of study drug. The date and time of last dose must be collected and recorded. If a subject has discontinued study 
drug but wants to continue to attend study visits off-treatment (TOTOS group), then MT concentration blood samples 
will not continue to be collected. 

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k 
These are to be rated by the same rater, where possible, as at Screening, after all other efficacy assessments have been 
completed. MMSE and CDR assessments will be subject to central review by MedAvante-ProPhase clinicians in the 
native language. 
l 
The clinical efficacy scale assessments should be performed at approximately the same time of day throughout the 
study for a given subject, to the greatest extent possible. 
m 
In-clinic dose at Visit 7 to be taken after pre-dose assessments, from newly dispensed Visit 7 open-label study drug kit. 
 
 
10.5.3.1 
Imaging Efficacy Assessments in the Open-Label, 
Delayed-Start Phase 
Brain MRI will be obtained after the additional 26 and 52 weeks of open-label treatment 
(Visit 9/Week 78 and Visit 10/Week 104) and will be evaluated and quantified as briefly 
described in Section 10.5.2.1 for the double-blind treatment period. The obtainment and 
assessment of imaging data are further described in Section 15.3. 
 
For subjects who terminate early, if the subject’s last MRI scan was performed <90 days 
prior to the early termination date, no additional MRI scan is required. 
 
10.5.3.2 
Clinical Efficacy Assessments in the Open-Label, 
Delayed-Start Phase 
The ADAS-cog13 and ADCS-ADL23 will be performed after the additional 26 and 52 weeks 
of open-label treatment (Visit 9/Week 78 and Visit 10/Week 104) by an approved Efficacy 
Rater using electronic tablets. Assessments will be recorded and reviewed independently as 
further described in Section 15.2. 
 
As exploratory clinical efficacy assessments, the MMSE and CDR sum of boxes will be 
performed after the additional 52 weeks of open-label treatment (Visit 10/Week 104 or upon 
early termination). These are to be performed by the same rater, where possible, who made 
the screening assessments and recorded on electronic tablets, as further described in 
Section 15.2. These are to be the last assessments performed, i.e., after all other efficacy 
assessments have been completed. 
 
All clinical efficacy assessments will be subject to independent review (all subjects, all 
applicable time points). 
 
10.5.3.3 
Safety Assessments in the Open-Label, Delayed-Start 
Phase 
Safety assessments (described in Section 15.3) will be performed after 26 and 52 weeks 
(Visit 9/Week 78 and Visit 10/Week 104) of open-label treatment and will include AE 
review, concomitant medication recording and review, targeted physical and neurological 
examinations, clinical laboratory testing (e.g., hematology and serum chemistry panels), 
serum pregnancy testing (women of childbearing potential only), and vital sign 
measurements. In addition, AEs and changes in concomitant medications will be recorded 
during a telephone contact after 4 weeks of open-label treatment (Visit 8/Week 56). The 
targeted physical and neurological examinations along with review of any AEs, changes in 
concomitant medications, and clinical laboratory results should be performed by a medical 
assessor (physician/MD/DO). 
 

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Subjects with a history of lens implant will undergo an ophthalmologic examination by a 
licensed optometrist, ophthalmologist, or other suitably qualified medical assessor 
(physician/MD/DO) at the final visit of the open-label treatment period (Visit 10/Week 104), 
or upon early termination (after completion of the efficacy assessments), to evaluate whether 
the lens has become discolored. 
 
10.5.3.4 
Other Assessments in Open-Label, Delayed-Start Phase 
At Visit 10/Week 104, blood will be collected for determination of MT concentrations. 
Samples will be collected pre-dose, approximately 1 to 2 hours post-dose, and approximately 
4 hours post-dose. To achieve this sample collection schedule, this should be a morning 
appointment and subjects instructed not to take their morning dose at home. See 
Section 15.5.1 for further details. 
 
For any early termination visit during the open-label phase, also refer to Section 15.5.1 for 
blood sampling requirements for determination of MT concentrations. 
10.6 
Data and Safety Monitoring Board 
Safety will be overseen by a Data and Safety Monitoring Board (DSMB) throughout the 
duration of study conduct. At any time, the DSMB may recommend that dosing be modified 
or enrollment stopped due to safety concerns. The DSMB may also request to receive 
additional data unblinded to the subject level in response to identified safety concerns. 
 
Routine meetings are to be scheduled as determined by the DSMB. Ad hoc meetings will be 
convened if needed in response to safety concerns. The DSMB Charter will describe the 
composition of the DSMB and safety monitoring details, as well as the frequency of meetings 
needed as the study progresses. 
10.7 
Definition of End of Study 
The end of study will occur when the last subject has completed the final study visit in the 
open-label, delayed-start phase (whether or not the visit occurs as scheduled). As noted in 
Section 17.9, an analysis will be performed after the last subject completes the last visit in the 
double-blind treatment period. 
 
Subjects who complete the study and receive treatment with LMTM up to and including the 
last open-label visit may be offered an opportunity to subsequently receive treatment with 
LMTM in a separate EAP. 
 
11 
SUBJECT ENROLLMENT AND WITHDRAWAL 
11.1 
Inclusion Criteria 
To be eligible for enrollment in this study, a subject must meet all of the following inclusion 
criteria: 
 
1. 
AD, encompassing probable AD and MCI-AD based on 2011 NIA/AA criteria: 
• 
All cause dementia and probable AD (probable AD) 
In brief, subjects with probable AD dementia must have insidious onset, 

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worsening impairment in at least two cognitive areas (learning and recall, 
language, executive function, visuospatial skills), sufficient to significantly 
interfere with work or usual activities, that is not explained by delirium, drugs, 
major psychiatric disorder, medical illness, cerebrovascular disease, other 
forms of dementia, or neurological disorder. The accuracy of the diagnosis 
will be confirmed independently by the diagnosing physician at site. 
OR 
• 
MCI-AD 
In subjects with MCI-AD, there should be evidence of concern about a change 
in cognition, in comparison with the person’s previous level verified by a 
knowledgeable informant or clinician. Other mild cognitive deficits may also 
be present, but there must be preservation of independence in functional 
abilities. Subjects should not meet the criteria for dementia. The cognitive 
changes must be mild and there must be no evidence of a significant 
impairment in social or occupational functioning. Impairments must not be 
explained by delirium, drugs, major psychiatric disorder, medical illness, 
cerebrovascular disease, other forms of dementia, or neurological disorder. 
2. 
Documented PET scan that is positive for amyloid; if most recent PET scan was 
performed >3 years prior to Screening and was negative, it may be repeated (a 
negative amyloid PET scan within the 3 years prior to Screening is exclusionary) 
3. 
MMSE score of 16-27 (inclusive) at Screening, subject to stratification requirements 
4. 
Global CDR score of 0.5 to 2 at Screening (if 0.5, including a score of >0 in one of the 
functional domains: Community Affairs, Home and Hobbies, or Personal Care)  
5. 
Age <90 years at Screening 
6. 
Females must meet one of the following: 
• 
Surgically sterile (hysterectomy, bilateral salpingectomy / oophorectomy) for 
at least 6 months minimum 
• 
Have undergone bilateral tubal occlusion / ligation at least 6 months prior 
• 
Post-menopausal for at least 1 year 
• 
Using adequate contraception (a barrier method [such as condom, diaphragm 
or cervical/vault cap] with spermicidal foam, gel, film, cream, or suppository; 
intrauterine device [IUD] or system, or oral or long-acting injected or 
implanted hormonal contraceptives for at least 90 days prior to Baseline; or 
vasectomized partner [with the appropriate post-vasectomy documentation of 
the absence of spermatozoa in the ejaculate]) or true abstinence (when this is 
in line with the preferred and usual lifestyle of the subject); subjects must be 
competent to use adequate contraception and to agree to continue to maintain 
adequate contraception throughout participation in the study (including up to 
4 weeks after the last dose of study drug) 
7. 
Subject and/or, in the case of reduced decision-making capacity, legally acceptable 
representative(s) (LAR(s)), consistent with local and national law, is able to read, 
understand, and provide written informed consent in the designated language of the 
study site 
8. 
Has one (or more) identified adult study partner (i.e., a caregiver or informant) who 
meets the following criteria: 
• 
Either lives with the subject, or in the investigator’s opinion, the extent of 
contact is sufficient to provide meaningful assessment of changes in subject 

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behavior and function over time and provide information on safety and 
tolerability (e.g., sees the subject on average for ≥1 hour/day ≥3 days/week) 
• 
Is willing to provide written informed consent for his/her own participation 
• 
Is able to read, understand, and speak the designated language(s) at the study 
site 
• 
Agrees to accompany the subject to each study visit 
• 
Is able to verify compliance with study drug 
9. 
The subject must not have been taking either an AChEI, i.e., donepezil, galantamine, 
or rivastigmine, and/or memantine, for at least 60 days at the time of the baseline 
assessments 
• 
Subjects never previously treated with an AChEI and/or memantine may be 
enrolled if initiation of treatment with these medications is not planned for the 
time period during which the subject will be participating in this study 
10. 
Able to comply with the study procedures in the view of the investigator 
11.2 
Exclusion Criteria 
The exclusion criteria are: 
 
1. 
Significant central nervous system (CNS) disorder other than probable AD or MCI-
AD, e.g., Lewy body dementia, Parkinson’s disease, multiple sclerosis, progressive 
supranuclear palsy, hydrocephalus, Huntington’s disease, any condition directly or 
indirectly caused by Transmissible Spongiform Encephalopathy (TSE), Creutzfeldt-
Jakob Disease (CJD), variant Creutzfeldt-Jakob Disease (vCJD), or new variant 
Creutzfeldt-Jakob Disease (nvCJD) 
2. 
Significant intracranial focal or vascular pathology seen on brain MRI scan that would, 
based on the independent reviewer imaging evaluation, lead to a diagnosis other than 
probable AD or MCI-AD, including but not limited to: 
• 
Large confluent white matter hyperintense lesions (i.e., Fazekas score of 3) 
• 
Other focal brain lesions judged clinically relevant by the investigator 
• 
Evidence of a prior or current macrohemorrhage 
3. 
Clinical evidence or history of any of the following (within specified period prior to 
Baseline): 
• 
Cerebrovascular accident (2 years) 
• 
Transient ischemic attack (6 months) 
• 
Significant head injury, for example, associated loss of consciousness, skull 
fracture or persisting cognitive impairment (2 years) 
• 
Other unexplained or recurrent loss of consciousness ≥15 minutes (2 years) 
4. 
Diagnosed with epilepsy (a single prior seizure >6 months prior to Screening is 
considered acceptable) 
5. 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria met (for 
any of the following within specified period): 
• 
Major depressive disorder (current) 
• 
Schizophrenia (lifetime) 
• 
Other psychotic disorders, bipolar disorder (within the past 5 years) 
• 
Substance (including alcohol) related disorders (within the past 2 years) 

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6. 
Metal implants in the head (except dental), pacemaker, cochlear implants, or any 
other non-removable items that are contraindications to MRI. MRI compatible 
prosthetics, clips, stents, or any other device proven to be compatible are allowed 
7. 
Resides in hospital or moderate to high dependency continuous care facility 
(residence in low grade assisted living facility where there is sufficient autonomy to 
permit valid evaluation of activities of daily living is allowed so long as it is not 
mandated by an order issued either by the judicial or the administrative authorities) 
8. 
Any physical disability that would prevent completion of study procedures or 
assessments (e.g., blindness or significant uncorrected visual impairment, deafness or 
significant hearing loss not corrected by hearing aids, non-AD-related speech 
impairment) 
9. 
History of swallowing difficulties (note: study drug should be swallowed whole and 
MUST NOT be broken, crushed, chewed, or dissolved in fluids prior to ingestion) 
10. 
Pregnant or breastfeeding 
11. 
G6PD deficiency based on World Health Organization (WHO) classification (<60% 
of normal, i.e., <6.1 U/g hemoglobin [Hgb]) 
12. 
History of significant hematological abnormality or current acute or chronic clinically 
significant abnormality, including: 
• 
History of hemoglobinopathy, myelodysplastic syndrome, hemolytic anemia, 
or splenectomy 
• 
Screening Hgb value (confirmed upon repeat) below age/sex appropriate 
lower limit of the central laboratory normal range 
Subjects in whom folate is <4.0 ng/mL may be entered into the study provided folate 
supplementation (approximately 1 mg/day) is initiated and maintained for the duration 
of the study; subjects in whom vitamin B12 is <150 pg/mL can be allowed if the 
investigator confirms that it does not affect the cognitive state of the subject and that 
the subject is supplemented as appropriate prior to the initiation of study drug 
13. 
Abnormal serum chemistry laboratory value at Screening deemed to be clinically 
significant by the investigator. In addition, subjects with either of the following 
abnormalities must be excluded: 
• 
Creatinine clearance <30 mL/min, estimated by the central laboratory 
according to the Cockcroft and Gault equation 
• 
TSH above laboratory normal range (subject may be treated [if clinically 
indicated based on further laboratory testing] and re-screened after 90 days) 
14. 
Clinically significant cardiovascular disease or abnormal assessments (based on the 
investigator’s interpretation of the locally obtained ECG) such as: 
• 
Hospitalization for acute coronary syndrome (acute myocardial infarction or 
unstable angina) or symptoms consistent with angina pectoris, within the 
12 months preceding Baseline 
• 
Signs or symptoms of clinical heart failure within the 12 months preceding 
Baseline 
• 
Atrial fibrillation on screening ECG or history of atrial fibrillation that is not 
currently controlled (heart rate ≥85 bpm and/or inappropriate anticoagulation)  
• 
QTcF (QT corrected for heart rate using Fridericia’s formula) at Screening 
>460 msec in males or >470 msec in females, or low or flat T waves making 
measurement of QT interval unreliable 

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• 
Recent history of poorly controlled hypertension, systolic blood pressure 
>180 mmHg, or diastolic blood pressure >100 mmHg, after 5 minutes in a 
seated position at Screening 
• 
Hypotension: systolic blood pressure <100 mmHg after 5 minutes in a seated 
position at Screening 
• 
Heart rate <48 bpm or >96 bpm by measurement of vital signs (after 5 minutes 
in a seated position) or by local ECG at Screening 
15. 
Pre-existing or current signs or symptoms of respiratory failure, e.g., caused by 
chronic obstructive pulmonary disease, bronchial asthma, lung fibrosis, or other 
disease 
• 
Subjects with currently diagnosed moderate to severe sleep apnea should be 
excluded; the definition of moderate to severe includes oxygen 
supplementation, e.g., nasal prongs or Continuous Positive Airway Pressure 
(CPAP) 
16. 
Concurrent acute or chronic clinically significant (in the opinion of the investigator) 
immunologic, hepatobiliary (such as presence of encephalopathy or ascites), or 
endocrine disease (not adequately treated), and/or other unstable or major disease 
other than probable AD or MCI-AD; the following are specifically excluded: 
• 
Active hepatitis or primary biliary cirrhosis 
• 
Active Human T-Cell Lymphocytic Virus Type III (HTLV-III), 
Lymphadenopathy Associated Virus (LAV), any mutants or derivatives of 
HLTV-III or LAV, any condition associated with active Acquired 
Immunodeficiency Syndrome or similar condition however named 
17. 
Diagnosis of cancer (excluding basal cell carcinoma, squamous cell carcinoma, or 
prostate carcinoma in situ [Stage 1]) meeting either of the following criteria:  
• 
Newly diagnosed within past 2 years 
• 
Previous (>2 years) diagnosis of cancer that has required any form of 
intervention or treatment within the past 2 years, e.g., chemotherapy, 
radiotherapy, hormonal therapy, or surgery  
18. 
Prior intolerance or hypersensitivity to MT-containing drug or methemoglobinemia 
induced by MT-containing drug, similar organic dyes, or any of the excipients 
19. 
Treatment currently or within 90 days before Baseline with any of the following: 
• 
Souvenaid® 
• 
Antipsychotics 
o Clozapine (and there is no intent to initiate therapy during the course of the 
study) 
o Other antipsychotics are allowable provided they have not been initiated 
within 90 days before Baseline and preferably at a stable dose and regimen 
• 
Carbamazepine, primidone, valproate 
• 
Drugs for which there is a warning or precaution in the labeling about 
methemoglobinemia at approved doses (e.g., dapsone, local anesthetics such 
as benzocaine used chronically, primaquine, and related antimalarials) 
20. 
Current or prior participation in a clinical trial as follows: 
• 
Any clinical trial of LMTM 
• 
Clinical trial of a product for cognition prior to Baseline in which the last dose 
was received within 90 days prior to Baseline unless confirmed to have been 
randomized to placebo 

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• 
A clinical trial of any other investigational drug, biologic, device, or medical 
food in which the last dose was received within 28 days prior to Baseline 
11.3 
Re-screening 
Re-screening of a subject is allowed in selected instances, as listed below (to a maximum of 
two re-screening occasions). Upon re-consent and re-screening, the subject must continue to 
meet all of the inclusion and exclusion criteria described in Section 11.1 and Section 11.2, 
respectively. Prior to re-consent, the PI (or SI) should confirm that the subject continues to 
meet the diagnosis of AD, encompassing probable AD and MCI-AD, of the acceptable 
severity (MMSE 16-27 and CDR score of 0.5 to 2 [if 0.5, including a score of >0 in one of 
the functional domains]), and has not used an AChEI and/or memantine for at least 60 days 
prior to the baseline assessments (inclusive of the baseline 18F-FDG-PET scan in subjects 
who have a screening CDR of 0.5). Screening may also be paused at a given site due to 
COVID-19 as described in Section 10.2.1; such subjects do not require re-consent but 
otherwise, the principles listed below with respect to repeat testing apply. 
 
1. 
At the initial Screening, MMSE score will be obtained first to determine eligibility. 
CDR scores will also be obtained for eligibility. A Diagnostic Verification Form will 
be completed to confirm diagnosis of probable AD or MCI-AD. These assessments 
will be subject to independent review. If scoring discrepancies are found that cannot 
be resolved, the subject will be deemed not eligible. The subject may be re-screened 
(after a wait of 90 days from last MMSE), inclusive of repeat of MMSE and CDR 
which will again be subject to the independent review to confirm eligibility. For the 
avoidance of doubt, re-screening is not allowed if a valid MMSE or CDR score falls 
outside the acceptable criteria. 
2. 
If the initial screening MRI scan is not of sufficient quality as determined by the core 
imaging laboratory, a repeat scan may be performed. If the repeat scan cannot be 
accomplished within the time window specified in Table 10-1, the subject must be re-
consented and re-screened. For subjects who are re-screened for other reasons and an 
acceptable MRI scan was already completed during the original Screening window, 
the scan does not require repetition. 
3. 
Evidence of atrial fibrillation on initial screening ECG or history of atrial fibrillation 
that is not currently controlled (heart rate ≥85 bpm and/or inappropriate 
anticoagulation) is not allowed. If better control of the heart rate and/or of 
anticoagulation can be achieved after adequate treatment, the subject may be entered 
into the study if still within the 42-day window; otherwise the subject must be re-
consented and re-screened. A cardiology consult should be sought for further ECG 
evaluation if deemed necessary by the investigator. 
4. 
Subjects with vitamin B12 levels <150 pg/mL at initial screening which cannot be 
corrected during the Screening period may be reconsented and re-screened after the 
deficit has been corrected (see Section 13.8 for further details). 
5. 
Subjects with a TSH above laboratory normal range at the initial screening may be 
treated (if clinically indicated) and re-consented and re-screened after 90 days. 
 
Any other criterion not listed above would require justification and approval by TauRx. 
 
No other minimum time is required for re-screening unless specifically stated above or 
elsewhere in the protocol. 

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11.4 
Discontinuations / Withdrawals 
11.4.1 
Handling of Subjects Who Discontinue Study Drug 
For a discussion of reasons for permanent discontinuation of study medication on the basis of 
safety, see Section 16.11. These include, but are not limited to, clinically evident hemolytic 
anemia (Section 16.11.1) and decrease in renal function when it raises renal concerns 
(Section 16.11.3). 
 
Subjects may discontinue study drug at any time for any reason. Furthermore, the investigator 
also has the right to discontinue study medication if he or she judges that treatment is no 
longer appropriate, if the subject’s clinical condition is worsening, or for an AE. 
 
If study drug is discontinued, the reason and the last date of study drug should be recorded on 
the eCRF. 
 
For subjects who cease taking study drug but who wish to continue in the study, the planned 
schedule of assessments should be followed, except for the collection of blood samples for 
MT concentrations. These subjects will be classified as “the off-treatment-on-study” 
(TOTOS) group. Subjects who continue in the study off-treatment will not be eligible for a 
separate EAP. The handling of data for these subjects is discussed in Section 17.4.11.4. 
 
As discussed in Section 13.1, study drug must be discontinued in subjects who initiate 
treatment with an AChEI and/or memantine. The handling of data for these subjects is 
discussed in Section 17.4.11.3. 
 
11.4.2 
Handling of Study Discontinuation / Withdrawal 
Subjects may withdraw (drop out) from the study at any time for any reason. A study partner 
(who is functioning as an informant) may also withdraw his or her consent from study 
participation at any time for any reason. If a study partner withdraws his or her consent, the 
subject must then also be withdrawn if alternative arrangements are not available (e.g., an 
alternate study partner). (See Section 11.4.3 for replacement of study partners.) 
 
If the subject withdraws from study participation, the reason should be recorded on the eCRF 
as one of the following: 
• 
Adverse event 
• 
Death 
• 
Lack of efficacy (including progressive disease or worsening of cognitive capacity) 
• 
Lost to follow-up 
• 
Withdrawal by subject or legally acceptable representative (or study partner), 
including specific reason(s), wherever possible 
• 
Protocol deviation 
• 
Non-compliance with study drug 
• 
Pregnancy 
• 
Study terminated by Sponsor 
• 
Physician decision, including specific reason(s), wherever possible 
• 
COVID-19 
• 
Other (specify) 
 

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If the reason for discontinuation of study is an AE, the principal event associated with 
discontinuation must be specified and recorded. In this case, reasonable effort must be made 
to clearly document the outcome. If the reason for premature discontinuation is a serious 
adverse event (SAE), this must be documented and an SAE form completed. 
 
For subjects who withdraw from the study for reasons other than death or subject/LAR or 
study partner consent withdrawn, a visit should be scheduled as soon as possible after the last 
dose of study drug and the End-of-Treatment safety evaluations for the current treatment 
period performed. For subjects or legally acceptable representatives who withdraw consent or 
when a study partner withdraws consent without available alternate study partner, the 
investigator should request that the reason be specified and the subject have any clinically 
indicated safety assessments performed.  
 
11.4.3 
Replacements 
Subjects who are withdrawn from the study will not be replaced nor can they be re-enrolled 
or enter the EAP. 
 
In the event a study partner participating as an informant withdraws, one replacement is 
normally permitted. However, as noted in Section 10.2.1, up to a total of three replacements 
may be allowed if necessitated by COVID-19, and the replacement study partner has 
sufficient contact with the subject to permit informed responses regarding their ADL 
functioning. Multiple study partners participating only as caregivers will be permitted for a 
given subject, either simultaneously or as replacements for previous study partners, with no 
specified maximum. 
 
12 
STUDY DRUG 
12.1 
Treatments Administered: Form, Dosage and Administration 
Study drug is available as blue, round, film-coated, immediate-release tablets (5-mm 
diameter, approximately 55-mg core weight) manufactured and packed for TauRx in 
accordance with Good Manufacturing Practice (GMP), as detailed in the European Union 
(EU) Guide to GMP. These and visually matching placebo tablets are debossed on one side 
with the Greek “Tau” symbol. 
 
12.1.1 
Active Ingredient 
The active ingredient (drug substance) is LMTM (USAN hydromethylthionine mesylate, also 
known as leuco-methylthioninium bis(hydromethanesulfonate) or the code name, TRx0237). 
It is included in the tablets as 4 mg LMT (expressed as MT base equivalent). 
 
12.1.2 
Inactive Ingredients 
Tablets also contain the following inactive compendial excipients: mannitol, crospovidone, 
microcrystalline cellulose, and magnesium stearate. 
 
The film coat of study drug tablets contains polyvinyl alcohol-part hydrolyzed, talc, titanium 
dioxide, Macrogol PEG 3350, lecithin (soya), as well as non-compendial FD&C blue #2 
(indigo carmine aluminum lake). 

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12.2 
Study Regimens 
All subjects will receive four tablets orally per day (two in the morning and two in the 
evening) in a double-blind fashion for 52 weeks in one of the following three study regimens, 
in a 4:1:4 ratio for Protocol Version 5.0 and above:  
• LMTM 16-mg/day group: Two 4-mg tablets in the morning, and two 4-mg tablets 
in the evening 
• LMTM 8-mg/day group: One placebo tablet and one 4-mg tablet in the morning, 
and one placebo tablet and one 4-mg tablet in the evening 
• Placebo group: Two “dummy” tablets in the morning, and two “dummy” tablets in 
the evening; one of which may be replaced by a 4-mg MTC tablet to maintain the 
treatment blind (the remainder being placebo tablets) 
 
After the completion of the 52-week double-blind treatment period, beginning with supplies 
dispensed at Visit 7, all subjects will receive open-label LMTM 16 mg/day (two 4-mg tablets 
in the morning and two 4-mg tablets in the evening) for an additional 52 weeks in the 
open-label, delayed-start phase of the study. 
 
Tablets may be taken with or without meals. Subjects will be instructed to take each dose of 
study medication with a full glass of water. Study drug should be swallowed whole and 
MUST NOT be broken, crushed, chewed, or dissolved in fluids prior to ingestion.  
 
The first dose of study drug (Visit 2) and the morning dose at Visit 3 (after 4 weeks of study 
drug), Visit 7 (after 52 weeks of study drug), and Visit 10 (after 104 weeks of study drug) 
will be administered in the clinic. These visits should be scheduled to occur in the morning, 
with subjects instructed not to take their morning dose at home; subjects will be required to 
remain in the clinic for at least 4 hours post-dose on each occasion. The time of the dose (and 
at Visits 3, 7 and 10, also the time of the prior dose taken on the preceding day) will be 
recorded. Note: the Visit 7 dose must be taken from a newly dispensed Visit 7 open-label 
treatment study drug kit, after pre-dose assessments have been completed (see Table 10-3 for 
the pre-dose and post-dose assessments to be performed at Visit 7). 
 
All other doses will be taken on an outpatient basis. The subject/study partner will be asked 
to establish the times of day that the subject will take the study medication (twice daily), with 
further inquiry as to whether this will be before or after a meal. They will be asked to adhere, 
to the best of their capability, to the same administration schedule throughout the study. 
 
Alternative arrangements for dosing and dispensing study drug supplies due to COVID-19 
may be permitted and are further described in Section 10.2. Requirements for obtaining 
subject consent consistent with local and national requirements, maintaining the specified 
study drug storage conditions, accountability, and compliance monitoring will be addressed 
and documented. 
 
12.2.1 
Maximum Anticipated Dosage 
The maximum dosage of study drug will be LMTM 16 mg/day. 
 
Note: Dose reduction is not permitted. 
 

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12.2.2 
Dose Interruption 
Interruption of dosing for up to a maximum of 14 consecutive days may be allowed if the 
investigator determines this is indicated (e.g., due to an AE or any other reported change in 
the subject’s physical condition in the judgment of the investigator) on a maximum of two 
occasions. The reason for dose interruption should be recorded in the source documentation. 
If this is exceeded, study drug would need to be discontinued; however, the subject will be 
encouraged to continue study participation off-treatment. Subjects who continue in the study 
off-treatment will not be eligible for a separate EAP. 
12.3 
Randomization 
Subjects will be randomized to one of three study regimens described in Section 12.2: 
LMTM 16 mg/day, LMTM 8 mg/day, or placebo (4:1:4, at the study level). Randomization 
will be stratified according to severity (three levels: MMSE 16-19, 20-25, or 26-27) at study 
level for those randomized to Protocol Version 5.0 and above, prior use of standard AD 
treatment (two levels: AChEI/memantine or none), and region (two levels: North America or 
Europe).  
 
Enrollment will be such that subjects are assigned to the MMSE severity groups based on 
screening MMSE score with a target of approximately 2:3:1 (MMSE 16-19, MMSE 20-25, 
and MMSE 26-27, respectively) for those randomized to Protocol Version 5.0 and above; to 
achieve this target, enrollment will be monitored and controlled at the site level for high 
recruiting sites and capped as needed at the study level. 
 
Randomization, stratification, and enrollment cap requirements will be controlled by a web-
based RTSM system. 
12.4 
Packaging, Labeling, and Storage 
Study drug will be packaged, labeled, and distributed to study sites by a designated vendor. 
 
Study drug supplied to subjects will be in individual aluminum blister wallets containing 
28 tablets. An appropriate number of blister wallets will be contained within cardboard 
cartons with sufficient supplies until the next scheduled study visit at which dispensing is 
planned (see Section 12.5, Dispensing). Additional 28-tablet blister wallets will be included 
in cartons as needed to allow for delays in visit scheduling (or if original medication is lost or 
damaged). 
 
Study drug package labels will be compliant with applicable regulatory requirements and will 
include the statement “Keep out of reach of children,” the cautionary statement “Caution: 
New Drug – Limited by Federal (United States) law to investigational use” and/or “For 
clinical trial use only” as appropriate, as well as any other locally mandated statements. 
Labels will also be translated into the local language as required. 
 
At a minimum, labels will also include the following information: the name and address of 
the Sponsor, the study code, a unique identifier, and appropriate contact information. In those 
jurisdictions where required, an expiry date will be included. 
 
At the study site, study drug must be stored securely (e.g., locked area, pharmacy) and at a 
temperature not more than 25C. The temperature at which study drug is stored at the study 

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site will be recorded daily using a centralized temperature monitoring system if this is 
available. If not, study drug storage temperature will be recorded each working day using a 
maximum-minimum thermometer. The packaging protects the study drug from light and 
moisture. 
 
Subjects and study partners should also be provided with information about required storage 
conditions. Study drug should be ingested immediately after removal from the blister wallet. 
12.5 
Dispensing 
At the Baseline/Randomization visit (Visit 2), all subjects/study partners will receive a supply 
of study drug according to their randomization to take home for use until Visit 4 (13 weeks 
after Baseline). At subsequent drug-dispensing visits, Visits 4, 5, 6, and 7 (13, 26, 39, and 52 
weeks after Baseline, respectively) of the double-blind treatment period, as well as Visit 9 
(78 weeks after Baseline) of the open-label delayed-start phase, all subjects/study partners 
will be required to return the complete study drug kit, including all unused study drug and 
empty packaging, dispensed at the preceding drug-dispensing visit (Visits 2, 4, 5, 6, and 7) 
before receiving a re-supply of either randomized study drug or open-label treatment, to take 
home for use until the next scheduled visit. Visit 7 is Baseline/Day 1 of the open-label 
treatment phase, at which study drug from a newly dispensed Visit 7 open-label study drug 
kit should be administered after pre-dose assessments (see Table 10-3 for the pre-dose and 
post-dose assessments to be performed at Visit 7). 
 
Subjects and study partners will be provided with information about storage conditions and 
taking study drug, including instructions indicating that study drug must be used only as 
described in this protocol. They will also be informed that tablets should be swallowed whole 
and MUST NOT be broken, crushed, chewed, or dissolved in fluids prior to ingestion. If 
there are swallowing difficulties which prevent taking the medication as instructed, subjects 
should not be entered into the study. Subjects and study partners should be warned that if the 
product is not swallowed immediately and is allowed to dissolve in the mouth, it may cause 
discoloration of teeth and oral mucosa.  
 
In the event of a dose interruption, the subjects and study partners will be provided with 
updated dosing instructions. 
 
See Section 10.2 for a summary of alternate arrangements that may be implemented due to 
COVID-19. 
12.6 
Compliance 
At Visits 2, 4, 5, 6, and 7 during the double-blind treatment period and at Visit 9 during the 
open-label, delayed-start phase, the number of tablets dispensed to the subject/study partner 
will be recorded.  
 
At the Week 4 visit (Visit 3) and at each clinic visit thereafter (Visits 4 to 7 during the 
double-blind treatment period, and Visits 9 and 10 during the open-label, delayed-start 
phase), the subject/study partner will bring the complete study drug kit, including unused 
study drug and empty packaging, to the study site. The number of tablets (all tablets 
remaining in unopened blister wallets plus any tablets that have been removed from the 
blister wallets) will be counted and recorded by study site staff. Following the compliance 
check, the complete study drug kit, including unused study drug and empty packaging, should 

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be retained by the study site, except at Visit 3, when the drug kit should be returned to the 
subject/study partner. 
 
Subject compliance with prescribed study drug will also be assessed at each clinic visit 
(Visits 4 to 7 during the double-blind treatment period, and Visits 9 and 10 during the open-
label, delayed-start phase) as well as during the telephone contact (Visit 8) by questioning the 
subject and study partner. Any apparent discrepancies between the number of tablets taken 
and the number of tablets which should have been taken since the last visit will be discussed 
with the subject and study partner. 
 
Any dose interruptions will also be recorded in the source documentation and will be 
captured in the eCRF. 
 
If during participation in the study, a subject’s compliance is determined to be <80% or 
>120% (taking into consideration any dose interruptions), the subject and study partner 
should be re-educated about taking study drug properly and the clinical research associate 
should be informed promptly. If compliance problems are recurrent, the investigator should 
inform the clinical research associate and contact the Medical Monitor to determine the 
course of action. 
12.7 
Study Drug Accountability 
The investigator or designee will keep a record of all study drug received, and of all study 
drug dispensed to and returned by subjects. Drug accountability will be recorded in the 
RTSM system. 
 
The investigator will ensure that the supplied study drug will be used only for administration 
to subjects enrolled in this study and for no other purpose. 
 
The study drug accountability record will be checked by a study monitor at monitoring visits. 
 
All unused and returned study drug will be returned to the Sponsor or designee after study 
completion according to provided instructions. 
12.8 
Breaking the Blind for Double-Blind Treatment Period 
The randomization list for the double-blind treatment period will be maintained within the 
RTSM system and in secure locations by individuals who are not directly involved in the 
conduct of the study. This is limited to the unblinded statistician and unblinded programmer 
at the statistics vendor, the project management personnel at the drug product manufacturer, 
and project management/system build personnel at the RTSM system vendor.  
 
The blind for an individual subject should not be broken during conduct of the study except 
in the case of a medical situation for which it is deemed essential to know which treatment 
the subject has received during the double-blind treatment period to provide appropriate care. 
If possible, discussion with the Sponsor should be sought before the blind is broken. In an 
emergency, the investigator may unblind a specific subject and determine the identity of 
treatment using the RTSM System. Instructions regarding treatment identification using the 
RTSM System will be available in separate guidance documents. In such circumstances, the 
Medical Monitor must be contacted and informed of any unblinding as soon as possible. The 
date, time, and reason for unblinding must be documented. In case of after-hours emergency 

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unblinding or in circumstances when the investigator is not available, a 24/7 emergency 
number (provided on patient cards) will be available to determine the identity of the 
treatment. This will be achieved via a “peek blind” function within the RTSM system, 
whereby an end user with appropriate access can view the unblinded treatment group on 
screen. Completion of the peek blind transaction will reinstate the blinded status of the 
subject. 
 
If a subject is unblinded, study drug will be discontinued and the subject will be followed 
until resolution or stabilization of the event. He/she will then be discontinued from the study. 
 
Information about any subject for whom an unblinding occurs will be provided to the DSMB 
by the Sponsor or designee within 15 days (within 7 days in the event of a fatal event). For 
requirements and unblinding procedures for suspected unexpected serious adverse 
event (SUSAR) reporting, refer to Section 16.8. 
 
After the last subject completes the 52-week, double-blind, treatment period, that portion of 
the database will be locked and subject populations determined by blinded data review. The 
database will then be unblinded for purposes of performing primary and secondary efficacy 
analyses, and a report will be prepared (see Section 17.9); individual subject treatment 
assignment will not be revealed either to the subjects or personnel involved in the ongoing 
management and assessment of subjects in the open-label treatment phase. 
 
13 
CONCOMITANT MEDICATIONS AND SUBJECT RESTRICTIONS 
All concomitant medications and medications administered within the past 90 days from 
Screening, as well as a lifetime history (as far as possible) of AChEI and/or memantine use 
will be recorded at the Screening visit (Visit 1). While in the clinic at Baseline (Visit 2; 
before and after the first dose of study drug is administered), any medications administered 
will be recorded. “Medication” is used to encompass prescription and over-the-counter drugs 
or biologics, vitamins used in supra-pharmacologic doses, alternative pharmacotherapies for 
dementia, medical foods, and for women, forms of contraception. At each subsequent 
scheduled visit (i.e., Visits 3 to 7 during the double-blind treatment period, and Visits 8 to 10 
during the open-label, delayed-start phase) or upon early termination, any changes to existing 
concomitant medication and any new concomitant medication will be reviewed and recorded. 
These must be reviewed by a medical assessor (physician/MD/DO). 
 
Concomitant medications identified at Screening generally should be maintained at a constant 
dose for the duration of the study if clinically indicated. The investigator should evaluate any 
changes in the doses of existing concomitant medications and/or initiation of new 
concomitant medications, and the Medical Monitor should be contacted to discuss any 
concerns as needed. The date of commencement, dose, and date of any change of dose of 
concomitant medications are to be recorded in the eCRF. 
 
Disallowed treatments and the time windows are listed in Section 28.1. 
13.1 
AChEI and/or Memantine 
Subjects are not to be treated with an AChEI and/or memantine within the 60 days prior to 
the baseline assessments (inclusive of the baseline 18F-FDG-PET scan in subjects who have a 
screening CDR of 0.5). If a subject decides to discontinue AD medication in order to enter 

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the study, a letter will be sent to his/her primary care physician informing him/her of the 
subject’s decision. The withdrawal / discontinuation of AD medication for study inclusion 
should not occur until the subject has been confirmed eligible for the study. 
 
If a subject begins an AChEI and/or memantine during the study, LMTM will be 
discontinued and LMTM will not be made available via the EAP. Subjects will be 
encouraged to continue with scheduled assessments if willing to do so without LMTM. 
Handling of data for such subjects is described in Section 17.4.11.3.  
13.2 
Drugs with Serotonergic Potential 
Methylene blue (MTC) has been shown to be an inhibitor of monoamine oxidase (MAO) and 
to be associated with serotonin toxicity in conjunction with other serotonergic drugs 
(discussed in the Investigator’s Brochure). Most cases have followed intravenous 
administration. Two cases have also been reported, one each following enteral and oral 
administration; however, neither case provides compelling evidence of MT-induced serotonin 
toxicity via these routes. There is a theoretical potential for serotonin toxicity following 
administration of oral LMTM alone, as well as a theoretical possibility of clinically 
significant drug interaction following co-administration of LMTM with a serotonergic 
medication. There have been four potential cases in the Phase 3 studies of LMTM; it is 
difficult to determine from the available information whether any represents a true case of 
serotonin toxicity.  
 
There is no proscription against the use of serotonergic drugs; however, investigators should 
evaluate subjects for potential serotonin toxicity. For additional details regarding clinical 
findings from studies, refer to the Investigator’s Brochure. A list of drugs with serotonergic 
potential will be provided separately.  
13.3 
CYP and P-gp Substrates 
Results of a completed drug-drug interaction study using LMTM 450 mg/day indicate that 
LMTM is generally a weak inhibitor of CYP3A4, CYP2C8, and CYP2C19 enzymes (see the 
Investigator’s Brochure for examples of drugs metabolized by these enzymes). The extent to 
which this occurs within an individual or with a given drug is not known, especially for those 
drugs with multiple metabolic pathways. Therefore, subjects on drugs known to be 
metabolized by one or more of these enzymes (especially those that have a narrow 
therapeutic index) should be closely monitored for AEs that could suggest an increase in 
systemic exposure. Dose adjustment of the concomitant medication may be warranted. 
 
LMTM is also a weak inducer of CYP2B6 and P-gp transporter at concentrations relevant to 
higher doses (see the Investigator’s Brochure for examples of substrates); the extent to which 
this might occur at LMTM doses of up to 16 mg/day is not known. Co-administration of 
LMTM with digoxin, a P-gp substrate, was shown to result in decreased concentrations of 
digoxin. Therefore, it is advisable to obtain a baseline digoxin level in subjects on this drug 
and to monitor digoxin levels while on study. Any such results obtained from the local 
laboratory should be entered into the eCRF. 
13.4 
Drugs Used to Manage Behavioral Disturbance 
Subjects may be treated with antipsychotics (other than clozapine) provided they have been 
used in a stable dose and regimen for at least 90 days prior to Baseline. There should be no 

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intent to initiate such therapy during the course of the study. Should treatment be initiated, 
the reason(s) should be clearly documented by indicating one or more of the following 
reasons: delusions, hallucinations, agitation/aggression, depression, anxiety, elation/euphoria, 
apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, nighttime 
behavior, or appetite/eating change. 
 
“As-needed” use of antipsychotics is to be avoided if possible, but such use does not preclude 
further participation. Similarly, regular or occasional use of benzodiazepines to manage 
distress, agitation, etc. does not preclude further participation, with the exception of prior to 
18F-FDG-PET scans to be obtained in subjects with CDR 0.5 at Screening only (the use of 
sedatives is not permitted within 24 hours prior to 18F-FDG-PET scans). These must not be 
used within the 12 hours prior to cognitive testing. 
13.5 
Other Medications 
The medical food and other medications listed in Exclusion Criterion No. 19 (see Section 
11.2) are specifically prohibited during participation in this study. 
 
Anxiolytics and/or sedatives/hypnotics may be used as sedation for claustrophobia or 
agitation or to manage excessive movement during MRI scans; however, use of sedatives is 
not permitted within 24 hours prior to 18F-FDG-PET scans in subjects with CDR 0.5. Regular 
or occasional benzodiazepines, chloral hydrate, low dose trazodone (50 mg), or zolpidem 
may be used as needed at bedtime for sleep. 
 
Unless otherwise prohibited, concomitant medications (preferably at stable doses) considered 
appropriate by the subject’s physician are allowable but should be kept to the minimum 
possible as clinically indicated. If there are questions about whether or not a medication is 
permitted in the study, the Medical Monitor should be consulted. 
13.6 
Dietary Tyramine 
Historically, MAO inhibitors as a class have been reported to be associated with hypertensive 
crises caused by ingestion of foods containing high amounts of tyramine (known as a 
tyramine or “cheese” reaction). While there is a theoretical potential for a tyramine reaction 
with MT, there have been no reports to date in subjects taking part in TauRx-sponsored 
studies, even though there have been no dietary restrictions in these studies. There have also 
been no effects on blood pressure. Nonetheless, as a precaution, subjects and their study 
partners (caregivers/informants) should be advised about this potential while taking LMTM 
(see the Investigator´s Brochure for examples of tyramine-rich foods and beverages, such as 
air-dried, aged or fermented meats, sausages and salamis; aged cheeses; fava bean pods; non-
pasteurized beers; sauerkraut; and most soybean products). They should also be advised to 
seek medical care immediately in the event of signs or symptoms of hypertensive crisis 
(sudden onset of severe headache, nausea, stiff neck, tachycardia or palpitations, profuse 
sweating, and/or confusion) or other sudden or unusual symptoms following ingestion of 
tyramine-rich foods or beverages. 
13.7 
Contraceptive Measures 
As a precautionary measure, women of childbearing potential (i.e., not documented to be 
post-menopausal for at least 1 year or not having undergone hysterectomy or bilateral 
salpingectomy/oophorectomy for at least 6 months minimum), either must have undergone 

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bilateral tubal ligation or occlusion at least 6 months prior to Baseline or must use adequate 
contraception. Subjects must be competent to use adequate contraception and must agree to 
continue to maintain adequate contraceptive measures throughout study participation and for 
at least 4 weeks after the last dose of study drug. Examples of adequate contraception 
include: 
• 
Use of a barrier method (condom, diaphragm or cervical/vault cap) with spermicidal 
foam, gel, film, cream, or suppository 
• 
IUD or system 
• 
Oral or long-acting injected or implanted hormonal contraceptives for at least 90 days 
prior to Baseline 
• 
Sexual activity restricted to a vasectomized partner (with the appropriate post-
vasectomy documentation of the absence of spermatozoa in the ejaculate).  
• 
Abstinence is only acceptable as true abstinence when this is in line with the subject’s 
preferred and usual lifestyle; periodic abstinence (e.g., calendar, ovulation, 
symptothermal, and post-ovulation methods) and withdrawal are not acceptable 
methods of birth control.  
 
Serum pregnancy testing will be performed at each scheduled study visit in women of 
childbearing potential. Such women should be encouraged to return to the clinic in the event 
of a delayed menstrual period to rule out possible pregnancy, during study conduct and for up 
to 3 months after the last dose of study drug. Alternative arrangements related to COVID-19 
for pregnancy monitoring may be permitted and are described in Section 10.2.   
 
The risk of drug secretion through the ejaculate is not fully studied. To ensure that the fetus is 
not exposed to MT through vaginal absorption, male subjects (including men who have had 
vasectomies) whose partners are pregnant should use condoms for the duration of the study 
and for an additional 10 days after cessation of study treatment. The investigator must 
provide appropriate counsel to male subjects regarding this issue. 
13.8 
Folate and Vitamin B12 
The manufacturer of the test kits used by the central laboratory for measuring folate and 
vitamin B12 has established the following normal ranges (healthy U.S. males and females 
aged 18 years and older): 5.9-24.8 ng/mL for folate and 180-914 pg/mL for vitamin B12. 
However, these values are not applicable for all geographical areas as food in the United 
States is supplemented with these vitamins. Prior to initiating study drug, subjects with folate 
levels <4.0 ng/mL or vitamin B12 levels <150 pg/mL (i.e., deficient according to WHO 
Technical Consultation, 2008, 2012), should be supplemented for the duration of the study. 
Subjects with folate levels <4.0 ng/mL may be entered into the study provided they are 
supplemented (approximately 1 mg/day folate). Subjects with vitamin B12 levels <150 pg/mL 
should be referred to their primary care physician for evaluation and treatment or the Medical 
Monitor consulted. There must be a treatment plan in place for any applicable chronic 
condition. If a condition is diagnosed that the primary care physician believes cannot be 
reliably or continuously corrected, the subject should be excluded from the study. If review 
and correction can be achieved within the Screening window, the subject may be entered into 
the study; otherwise the subject must be re-consented and re-screened after the deficit has 
been corrected. 
 

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14 
TERMINATION OF THE STUDY 
The Sponsor reserves the right to terminate the study for duly justified reasons in accordance 
with the national laws. These reasons include in particular: 
• 
Administrative reasons: e.g., financial reasons 
• 
Interest of subject welfare: e.g., new information or events that result in an 
unfavorable risk-benefit profile 
 
Continued access to investigational study drug may be available as detailed in separate 
EAP Protocols or by other legally acceptable means. 
 
15 
STUDY ASSESSMENTS 
15.1 
Demographic Data/Medical History 
The PI (or SI) must complete the NIA/AA diagnostic interview with the subject and study 
partner. The NIA/AA criteria should be used as a guide and the information recorded in the 
subject’s medical records. The accuracy of the diagnosis will be confirmed independently by 
MedAvante-ProPhase (Section 10.5.1.1). 
 
The investigator should collect the following demographic data: age of the subject at 
informed consent, gender, ethnicity, race, and geographic region. 
 
General baseline characteristics that should be collected are height, weight, creatinine 
clearance, smoking history, and age at leaving full-time education. Further information 
indicating years spent in full-time education and its type before the age of 26 years is to be 
collected (see Section 28.3); also, main occupation during working life is to be provided as 
indicated. 
 
Disease-specific baseline characteristics that should be collected are time from diagnosis of 
AD to informed consent (years); amyloid biomarker confirmation; MMSE; CDR; use of an 
AChEI and/or memantine (previous use or never used and if previous use, drug[s], how long 
used, when stopped, and reason for stopping); and use of other anti-dementia treatments or 
medical foods other than AChEIs or memantine. Medical history (including history of lens 
implantation) will be recorded. 
 
Recently used medications (lifetime use of antidementia medications and within 90 days prior 
to Screening for other medications) will be recorded at Screening. Concomitantly used 
medications will be recorded throughout study participation. 
15.2 
Assessment of Efficacy 
15.2.1 
Raters 
Efficacy instruments (ADAS-cog13, ADCS-ADL23, MMSE, and CDR) will be completed by 
assessors/raters who are not involved in the assessment of safety parameters that could result 
in unblinding. These will be administered using Virgil tablets in the local language. Efficacy 
assessments should be performed at approximately the same time of day throughout the study 
for a given subject, to the greatest extent possible. For a given subject, raters should remain 
constant throughout the study. Investigators and other raters will be trained and approved by 

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MedAvante-ProPhase; only individuals approved to complete each assessment will receive 
access via the Virgil System. Rater performance and consistency will be subject to 
surveillance throughout the study. One to two efficacy raters are required at each site (with 
back-ups as needed).  
 
Information obtained from study partners providing data from assessments of the subject (i.e., 
informants) will be appropriately identified to distinguish each informant in the event that a 
given subject has more than one study partner providing data for analysis (see Section 10.2 
for a summary of alternate arrangements that may be implemented due to COVID-19). 
 
A summary of the efficacy rater allocation and the order of efficacy assessments by visit is 
provided in Table 15-1. 
 

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Table 15-1: 
Efficacy Rater Allocation and Order of Assessments by Visit  
Section 1. Rater Allocation 
Assessments are made by suitably trained efficacy raters who are NOT involved in safety assessment. 
It is expected that the SAME rater completes the efficacy assessments for a given subject throughout the study. 
Raters should carry out assessments according to a specific allocation: 
Rater Allocation 1 (Preferred) 
Rater Allocation 2 
Rater Allocation 3 
Rater 1 
MMSE  
Rater 1 
MMSE 
Rater 1 
MMSE 
CDR 
Rater 2 
CDR 
CDR 
Rater 2 
ADAS-cog13 
ADAS-cog13 
ADAS-cog13 
ADCS-ADL23 
ADCS-ADL23 
ADCS-ADL23 
Section 2. Order of Assessments 
Assessments are to be carried out in the order specified. The order of assessment depends on the visit type. 
Visit 
Order 
Assessment 
Visit 1 Screening 
1. 
MMSE (Eligibility) 
2. 
CDR (Eligibility) 
 
Visit 2 Baseline 
1. 
ADAS-cog13 
2. 
ADCS-ADL23 
 
Visit 4, 5, 6 
1. 
ADAS-cog13 
2. 
ADCS-ADL23 
 
Visit 7 or Double-Blind ET  
(Also Baseline/Day 1 for 
Open-Label Phase) 
1. 
ADAS-cog13 
2. 
ADCS-ADL23 
3. 
CDR 
4. 
MMSE 
 
Visit 9 Open-Label, Delayed-Start 
1. 
ADAS-cog13 
2. 
ADCS-ADL23 
 
 
 
Visit 10 OL-EOT or OL-ET 
1. 
ADAS-cog13 
2. 
ADCS-ADL23 
3. 
CDR 
4. 
MMSE 
Abbreviations: ADAS-cog13 = Alzheimer’s Disease Assessment Scale – cognitive subscale (13-item); ADCS-ADL23 = 
Alzheimer’s Disease Cooperative Study – Activities of Daily Living (23-item); CDR = Clinical Dementia Rating; ET = early 
termination; MMSE = Mini-Mental State Examination; OL-EOT = open label end of treatment; OL-ET = open-label early 
termination 
 
 
15.2.2 
Instruments 
The main efficacy instruments include the following: ADAS-cog13 (cognition) and 
ADCS-ADL23 (activities of daily living).  From these, Composite Scores will be derived as 
an exploratory endpoint: at least one that is designed to be sensitive to early stages of the 
disease as well as one that is less/not impacted by COVID-19 (all Composite Scores will be 
defined in the SAP prior to sign off and database lock/unblinding). The MMSE and CDR 
(total and sums of boxes) are rated as secondary instruments. All are described briefly below.  
 
For a given subject, the ADAS-cog13 and ADCS-ADL23 will be completed by Efficacy 
Raters, in the local language. The Efficacy Raters must not also elicit, record, or enter data 

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relating to subject safety. The instruments will be administered via an electronic Virgil tablet 
provided by MedAvante-ProPhase, which will also capture an audio recording of the 
assessment. Alternative arrangements that may be implemented for conducting these 
instruments for post-Baseline visits directly impacted by COVID-19 are summarized in 
Section 10.2. 
 
Each time an efficacy instrument is administered, the person administering it will be 
documented within the electronic form. Efficacy Raters will be trained and their proficiency 
in administering applicable efficacy instruments will be confirmed. Raters must be approved 
by MedAvante-ProPhase prior to administering assessments. A unique identifier and 
password will be provided to each rater that completes and passes the rater training for 
applicable assessments. Raters must enter their unique password to commence a subject 
assessment, and again when they upload the data to verify the identity of the rater.  
 
The MMSE and CDR questionnaires and the ADAS-cog13 and ADCS-ADL23 will be 
assessed in the native language by an independent Clinical Reviewer at MedAvante-ProPhase 
by reference to audio recordings of the assessments. The objective of these independent 
reviews is to ensure raters adhere to the administration and scoring conventions detailed in 
rater training. Where necessary, raters will be requested to review their performance and 
confirm the scoring. For eligibility assessments (screening MMSE and CDR), adjudication 
will occur for any subject where assessments fall outside of the inclusion criteria. Once 
efficacy assessments are completed and uploaded, raters should review and discuss with 
MedAvante-ProPhase and receive approval prior to making any proposed change in scoring. 
A Diagnostic Verification Form (on the Virgil Tablet) completed by the PI (or SI) at 
Screening will be reviewed by an independent Clinical Reviewer at MedAvante-ProPhase 
prior to subjects proceeding to imaging assessments to ensure that subjects meet those 
elements of the inclusion criteria that relate to clinical diagnosis of probable AD or MCI-AD.  
 
Efficacy assessments should be performed at approximately the same time of day throughout 
the study for a given subject, to the greatest extent possible. The clinical efficacy assessments 
should be administered before vital signs measurement and blood sample collection. All 
attempts should be made to have the same rater collect efficacy outcome data at all visits. The 
key efficacy scales are described below. 
 
15.2.2.1 
ADAS-cog 
The ADAS was designed to evaluate the severity of cognitive and non-cognitive or 
behavioral symptoms of AD (Rosen et al., 1984). The ADAS-cog is the cognitive subscale of 
the ADAS, originally proposed with 11 items. The ADAS-cog11 consists of tasks that 
measure memory, orientation, language, and praxis resulting in scores that range from 0 to 
70, with higher numbers indicating greater impairment. Two additional items have been 
added in the ADAS-cog13 to provide additional sensitivity to change in cognition at earlier 
stages of the disease (Mohs et al., 1997); these are Delayed Word Recall and Number 
Cancellation.  
 
As the original ADAS-cog11 was used in the earlier Phase 3 studies, that score will be derived 
from the assessment of the ADAS-cog13 for the primary analyses. The Composite Scale 
described in Section 15.2.2.3 will be based on items selected from the ADAS-cog13. 
 

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15.2.2.2 
ADCS-ADL23 
The ADCS-ADL23 includes 23 items that were derived from a larger set of items describing 
performance of activities of daily living (ADL) by AD patients (Galasko et al., 1997). Of 45 
ADL items originally evaluated during the creation of this instrument, the 23 items showed 
good test-retest reliability over 1 to 2 months (Galasko et al., 2005). Scores of these items 
(ADCS-ADL23) were also shown to correlate with MMSE scores of AD patients and to 
decline over 12 months in at least 20% of AD patients.  The Composite Scale described in 
Section 15.2.2.3 will also be based on selected items from the ADCS-ADL23. 
 
15.2.2.3 
Composite Scale(s) 
The new Composite Scale based on selected items of the ADAS-cog13 and the ADCS-ADL23 
will be analyzed at 9 months and 12 months during the double-blind treatment period to 
evaluate its usefulness for future studies. It consists of cognitive subdomains (orientation [8], 
constructional praxis [5], word recall, third trial [10], assessor rating of subject speech [5], 
and assessor rating of subject comprehension [5]) from the standard ADAS-cog11, and 
functional items (use of telephone [5], keeping appointments [3], cooking and preparation of 
meals [4], and cleaning dishes [3]) from the standard ADCS-ADL23. The selected cognitive 
items are based on a non-interventional study (Study TRx-GTD-025) examining performance 
of a range of psychometric tools which decline over 12 months in discriminating subjects 
with mild AD from age-matched healthy controls, supplemented with functional items 
identified as declining over 9 months in add-on treatment arms in Study TRx-237-005, 
independently confirmed by similar data from TRx-237-015, and supported by ADNI data. 
The items listed provide a maximum possible score of 48 (higher score indicates less 
impairment).  
 
Additional Composite Endpoints (if any) such as one that is less/not impacted by COVID-19 
will be defined in the SAP and signed off prior to database lock and unblinding.  
 
15.2.2.4 
Mini-Mental State Examination (MMSE) 
The MMSE (Folstein et al., 1975) was originally developed to differentiate between 
psychiatric patients with functional and organic conditions, to quantify the level of cognitive 
impairment, and to monitor changes over time. The MMSE subsequently has become a 
widely used and extensively validated cognitive test demonstrating satisfactory reliability, 
validity, and change sensitivity under a wide variety of conditions (Tombaugh and McIntyre, 
1992). A modified version of the form, supplied by Psychological Assessment Resources, is 
used in this study. 
 
The utility of the MMSE as a means of assessing treatment response in AD has been 
questioned (Bowie et al., 1999), but its status as a clinical outcome measure has been 
supported by the UK National Institute for Clinical Excellence guidance (NICE, 2001). 
Furthermore, the MMSE has demonstrated an ability to detect change in clinical studies with 
AChEIs (Birks and Harvey, 2004). Further, in an epidemiological study (Mukaetova-
Ladinska et al., 2000), pre-mortem MMSE scores have been correlated with post-mortem 
Braak stage (based on the spread of tau pathology through the brain). 
 

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15.2.2.5 
Clinical Dementia Rating (CDR) 
The CDR rates overall severity of dementia (Hughes et al., 1982). The CDR has been shown 
to have good reliability (Morris et al., 1997) and validity (Fillenbaum et al., 1996) and to 
correlate with neuropathological status (Morris et al., 1988). The scale is sensitive to change 
over longer time periods (Berg et al., 1988). 
 
The CDR is administered using a worksheet and semi-structured interview of a reliable 
informant (e.g., caregiver) followed by an interview of the subject to assess the following six 
domains: memory, orientation, judgment and problem solving, community affairs, home and 
hobbies, and personal care. Each domain is scored on a 5-point scale, where 0 = normal, 
0.5 = questionable impairment, 1 = mild impairment, 2 = moderate impairment, and 
3 = severe impairment. The CDR total score (also sometimes referred to as the CDR global 
score) is derived from individual (“box”) scores for each of the six domains, in accordance 
with published scoring rules.  
 
15.3 
Imaging Assessments and Procedures 
15.3.1 
General Considerations 
PET imaging using an amyloid ligand and brain MRI play a role in this protocol for 
eligibility determination of the subjects; brain MRI is also used as a secondary efficacy 
endpoint as well as to confirm a lack of treatment unblinding. 18F-FDG-PET will be 
performed in subjects with CDR 0.5 at Screening as a secondary efficacy endpoint at all 
study sites, and will be assessed by an independent nuclear physician who is trained and not 
otherwise involved in the clinical conduct of the study. The independent central imaging core 
laboratories will be responsible for image collection and storing, including, with the subject’s 
(and/or LAR’s) consent, collection of amyloid PET scan performed either in the course of the 
study or previously. The total radiation exposure to subjects from the amyloid PET scan 
procedure (if not performed previously) is estimated to be 9 mSv for a single scan; the limits 
for radiation exposure from the 18F-FDG-PET scans are discussed in Section 15.3.3.1. 
 
With respect to 18F-FDG-PET and MRI, the core laboratories will be responsible for checking 
the quality of imaging data, verifying that site anonymization of the images is maintained, 
pre-processing of images, presenting data to the reader(s) (for MRI eligibility and volumetric 
evaluations and 18F-FDG-PET), and analyzing the data. Each core laboratory will provide 
SAS datasets to the data management and statistics facilities for analysis. All systems and 
processes used for independent and central reads of this trial will be 21 CFR Part 11 
compliant.  
 
Before commencement of central evaluations, vendor study-specific documents such as 
charters and manuals will be developed that will describe in detail the imaging acquisition 
protocols, image collection procedures, quality check procedures, site training procedures, 
reader training, image evaluation procedures (central determination of subjects’ eligibility, 
efficacy, and safety), and communication plans. 
 
All sites will be prospectively trained about imaging requirements including scanner 
requirements, image acquisition, image transfer to the core laboratories, and timelines that are 
critical for this trial. 
 

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See Section 10.2 for a summary of alternate arrangements that may be implemented due to 
COVID-19. 
 
15.3.2 
Site Selection and Qualification  
A site imaging technical evaluation questionnaire will be distributed to potential clinical sites 
to evaluate their technical and personnel capabilities that will include machine description, 
availability of phantoms (if applicable), onsite availability of modality-specific technologist 
or physicist (depending on 18F-FDG-PET or MRI facility), site experience in evaluating brain 
18F-FDG-PET and/or MRI, experience in AD and other dementia trials, etc. The site’s 
capability of producing quality data that are necessary for this trial will also be evaluated by 
appropriate phantom imaging and/or review of imaging data of the site’s first subject. 
Continuous monitoring of the quality of imaging data will be performed throughout the trial. 
Technical details of imaging and quality check procedures will be described in a separate 
imaging manual. 
 
15.3.3 
Imaging Methods for Efficacy 
A separate imaging manual will be developed that will outline imaging methods for both 
18F-FDG-PET and brain MRI to harmonize image acquisition across the sites. 18F-FDG-PET 
should be obtained with computerized tomography (CT); brain-dedicated high-resolution 
PET devices, such as the Siemens High Resolution Research Tomograph system, that use a 
transmission source for attenuation correction will also be considered from expert sites.  
 
15.3.3.1 
18F-FDG-PET 
An 18F-FDG-PET scan will be performed in subjects with CDR 0.5 at Screening using 
PET/CT or a brain-dedicated high-resolution PET device.   
 
Use of sedatives is not permitted for a period of 24 hours prior to 18F-FDG-PET scans. The 
subject’s fasting (at least 4 to 6 hours) blood glucose level, carried out by the imaging 
center’s standard operating procedures, should be <180 mg/dL (<9.9 mmol/L) in order for the 
injection to take place. If a screening amyloid scan is acquired under the study, there must be 
a minimum of 16 hours between the amyloid scan and the 18F-FDG-PET scan due to the half-
life of fluorine. 
 
The baseline 18F-FDG-PET scan is to be performed within 42 days before Baseline (Visit 2) 
only in subjects confirmed to meet all inclusion and exclusion criteria and who have a 
screening CDR of 0.5. Subjects who were previously treated with an AChEI and/or 
memantine must have received the last dose at least 60 days prior to this scan. If the initial 
screening/baseline 18F-FDG-PET is not of sufficient quality to serve as an adequate baseline 
as determined by the PET Imaging Core Lab, then the scan must be repeated within 42 days 
before Visit 2 as long as the repeat PET does not cause radiation exposure to the subject that 
exceeds the limits for the clinical trial (approximately 4.7 mSv for a single scan and 14.1 mSv 
in total, if a repeat scan is deemed necessary). If the repeat scan cannot be accomplished 
within the 42-day window before Baseline, the subject must be re-consented and re-screened. 
For subjects who are re-screened for other reasons and an acceptable 18F-FDG-PET scan was 
already completed during the original Screening window, the scan does not require repetition. 
 

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The Week 52 (end of double-blind treatment) 18F-FDG-PET scan should be performed within 
± 14 days of the designated visit. In the event of early termination, if the subject’s last 
18F-FDG-PET scan was performed ≥30 days prior to that date, the 18F-FDG-PET scan must 
be done as part of the early termination visit assessments within the time window of the early 
termination visit (i.e., ± 14 days of the last dose of study drug). The allowable time window 
for the early termination 18F-FDG-PET scan can be extended to up to 28 days after the last 
dose of study drug in the double-blind treatment period only with the permission of the 
Sponsor/Medical Monitor. 
 
Imaging assessments will be made by central readers as follows: 
• 
Brain 18F-FDG-PET will be evaluated for temporal, parietal, and frontal lobe SUVR 
(normalized with respect to pons and cerebellum) at Baseline and after 52 weeks of 
double-blind treatment, or upon early termination. Other SUVR ROIs will also be 
examined including, but not restricted to, inferior temporal gyrus, angular gyrus, 
anterior and posterior cingulate gyrus, and cerebellum. Change in SUVR parameters 
will be quantified by the imaging core laboratory. 
• 
SPM preprocessing may be performed, which involves realignment of the dynamic 
18F-FDG-PET images, the summation of those images, registration to the MR images 
in native space, normalization to atlas space, count normalization to a reference 
region, and smoothing for statistical purposes. After database lock, the voxelwise 
change in the SUVR maps may be quantified using an SPM approach (models to be 
characterized in the SAP). Details of analysis conducted will be reported in a separate 
report.  
15.3.3.2 
MRI 
The screening MRI (to be obtained within the 9-week Screening period [Days -63 to -1] in 
subjects not receiving an AChEI and/or memantine, or Days -112 to -63 in subjects who 
begin Screening on an AChEI and/or memantine) will also be used as the baseline for 
volumetric measurements. The volumetric MRI will be repeated approximately every 
13 weeks in the double-blind treatment period after randomization (i.e., after 13, 26, 39, and 
52 weeks) as well as after the additional 26 and 52 weeks of open-label treatment. For 
subjects who terminate early (in either the double-blind treatment or open-label treatment 
periods), if the subject’s last MRI scan was performed <90 days prior to the early termination 
date, no additional MRI scan is required. 
 
Imaging assessments will be made by central readers as follows: 
• 
Brain MRI will be evaluated for temporal and parietal, whole brain, lateral 
ventricular, hippocampal, putamen, nucleus accumbens, and nucleus basalis ROI 
volumes. Change in MRI volumetric parameters will be quantified by the imaging 
core laboratory. 
• 
T2*-weighted gradient-recalled echo is to be included to enable the detection and 
quantification of the image hyperintensities. 
• 
SPM preprocessingmay be performed, which involves registration of the MR images 
to atlas space, segmentation into tissue types (grey, white, cerebral spinal fluid). After 
database lock, the voxelwise change may be quantified in the segmented MR maps 
using an SPM approach (models to be characterized in the SAP). Details of analysis 
conducted will be reported in a separate report. 

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15.4 
Safety Assessments and Procedures 
Safety assessments will be performed during Screening to assess subject eligibility for 
enrollment. All safety assessments will be performed by an independent qualified assessor 
not involved in efficacy assessments; where specified below, the assessments must be made 
by a medical assessor (physician/MD/DO). For enrolled subjects, safety assessments will be 
made at Baseline and at each clinic visit (i.e., after 4, 13, 26, 39, and 52 weeks during the 
double-blind treatment period as well as after 26 and 52 weeks in the open-label, delayed-
start phase); during a telephone contact after 4 weeks in the open-label, delayed-start phase; 
when needed to follow up on an AE; and upon early termination. See Section 10.2 for a 
summary of alternate arrangements that may be implemented due to COVID-19. All AEs, 
vital signs, ECG, clinical laboratory findings, physical and neurological examinations, and 
ophthalmological examinations (as applicable) will be assessed according to the following: 
• 
AEs will be recorded from the time informed consent is signed and recording will 
continue throughout the study. The recording and assessment of AEs will be 
performed by a medical assessor (physician/MD/DO) separate from those 
administering the efficacy outcome scales (ADAS-cog13 and ADCS-ADL23 as well as 
the CDR and MMSE). AEs with an onset after the first dose of study drug or that 
worsen in intensity or treatment relationship after the first dose will be considered 
treatment-emergent (and must be reviewed by a medical assessor 
[physician/MD/DO]). Assessment should continue as needed to follow up an AE to its 
resolution or acceptable stabilization (including after the last dose of study drug), 
consistent with the medical judgment of the investigator.  
• 
Blood pressure and pulse will be obtained at Screening, on Day 1 (within 1 hour pre-
dose and approximately 2 hours post-dose), and at each clinic visit thereafter or upon 
early termination. Blood pressure and pulse will be measured after the subject has 
been in a seated position for at least 5 minutes.  
• 
Height will be measured at Screening only. Body weight will be measured at 
Screening and at each clinic visit thereafter or upon early termination. 
• 
A 12-lead ECG will be obtained at Screening, with the site judging eligibility based 
on the local interpretation by a medical assessor (physician/MD/DO). 
• 
TSH, vitamin B12, folate, haptoglobin, and G6PD will be measured at Screening; a 
thyroid panel may be obtained in response to an elevated TSH. Standard clinical 
laboratory testing, including hematology and blood chemistry, will be performed at 
Screening and each subsequent clinic visit (or upon early termination). Testing may 
also be performed at unscheduled visits as necessary to follow-up an AE (see 
Section 16.11.1 for testing in response to possible hemolytic anemia). All laboratory 
results are to be reviewed by a medical assessor (physician/MD/DO). Any abnormal 
laboratory test result from Screening assessments (prior to treatment) is to be added to 
the subject’s medical history, unless deemed clinically significant by the medical 
assessor (MD/DO) in which case it will be recorded as an AE. 
• 
A blood sample for a serum pregnancy test will be collected from all women of 
childbearing potential at Screening and at each subsequent clinic visit (or upon early 
termination). 
• 
Complete physical and neurological assessments will be performed at Screening (see 
Section 10.5.1.2). Targeted examinations will be performed pre-dose and 
approximately 3 hours after administration of the first dose of study drug (Visit 2). 
Thereafter, targeted examinations are to be performed at each subsequent clinic visit 
(upon early termination). At a minimum, targeted examinations should include heart 
and lung auscultation and brief neurological assessment guided by any reported 

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signs/symptoms/AEs (e.g., evaluating subjects for potential serotonin toxicity). These 
examinations are to be performed by a medical assessor (physician/MD/DO). 
• Slit lamp ophthalmological examination of subjects with history of lens implants will 
be performed by a licensed optometrist, ophthalmologist, or other suitably qualified 
medical assessor (physician/MD/DO) prior to the first dose of study drug (during the 
screening procedures or as part of the baseline assessments), at Visit 7, and at Visit 10 
/ early termination (after completion of efficacy assessments), to assess whether the 
lens has been discolored during the trial. The slit lamp examination should also be 
performed if a subject has cataract surgery / lens implantation at any point during his 
or her study participation (as soon as possible after the surgery), as well as in response 
to visual complaints if suggestive of lens discoloration. 
• 
At Screening, medications administered within the last 90 days will be recorded, with 
the exception of anti-dementia medications, where lifetime use (as far as possible) is 
to be recorded. Changes in concomitant medications and any new concomitant 
medications will be recorded at all visits, including the telephone contact during the 
open-label, delayed-start phase, and reviewed by a medical assessor 
(physician/MD/DO). For antipsychotics, the reason for use should be documented 
(see Section 13.4). 
 
Further details regarding alternate arrangements for sample collection and shipment that may 
be implemented due to COVID-19 are described in Section 10.2.   
 
15.5 
Other Assessments 
15.5.1 
MT Concentration 
At Visits 2, 3, 7, and 10, blood will be collected on the same day on three occasions for 
determination of plasma and whole blood MT concentrations (to the extent possible, parent 
MT/LMT and N-desmethyl MT, and after the sample has had acid and heat treatment, total 
MT); these visits should be scheduled to occur in the morning. Samples will be collected 
prior to dosing (in the clinic), approximately 1 to 2 hours post-dose, and approximately 4 
hours post-dose. The time of the dose given in the clinic and the time of the blood sample 
will be recorded. In addition, at Visits 3, 7, and 10, the time of the prior dose taken on the 
preceding day at home will be recorded.  
 
At any early termination visit, if the subject has not yet discontinued study drug and is willing 
to take a final in-clinic dose, three blood samples will be collected as described above. If, 
however, the subject has already discontinued study drug or is unwilling to take a final 
in-clinic dose, a single blood sample only for determination of MT concentrations will be 
collected, irrespective of the date or time of the last dose of study drug. The date and time of 
the last dose must be collected and recorded.   
 
For subjects who continue in the study off-treatment (TOTOS group), blood samples will not 
continue to be collected for the determination of MT concentrations. 
 
Concentration results will not be made available to the study sites during the conduct of the 
study. However, results for a given subject (if available) may be provided to the DSMB if 
requested to aid in interpretation of a significant subject safety issue.  
 

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The collection, handling, and shipping of blood samples are described below. These are to be 
analyzed using validated analytical methods. 
 
See Section 10.2 for a summary of alternate arrangements that may be implemented due to 
COVID-19. 
 
15.5.1.1 
Procedure for Blood Sample Collection  
Blood samples (9 mL) will be collected into a suitable vacutainer (9.0 mL), as defined in the 
laboratory manual. A portion of the whole blood will be centrifuged under refrigeration; the 
separated plasma will be transferred as defined in the laboratory manual. Both the whole 
blood aliquot and separated plasma will be stored at ca -20°C until shipment to the central 
laboratory for storage. The complete sample collection and handling procedures to be 
followed can be found in the laboratory manual.  
 
15.5.1.2 
Packaging, Labeling, and Shipping of Blood Samples  
The samples must be labeled with unique identification numbers; other labeling information 
will be detailed in the laboratory manual. Labels must remain intact and indelible throughout 
processing and frozen storage. Samples will be clearly distinguished from the other 
bioanalytical samples. Samples are to be transported in insulated containers filled with dry 
ice. They will be shipped to the central laboratory where they will be stored frozen and 
shipped in batches to the analytical laboratory. 
 
15.5.2 
Genotyping 
A single blood sample will be obtained only from subjects who provide legally acceptable 
informed consent for genotyping evaluation of ApoE. The blood sample may be collected any 
time after eligibility for randomization and continued participation in the study has been 
confirmed but prior to Visit 7 (end of double-blind treatment period). A volume of 
approximately 2 mL is to be collected and shipped ambient to the central laboratory 
(Labcorp) on the day of collection. See Section 10.2 for a summary of alternate arrangements 
that may be implemented due to COVID-19. 
 
Genotyping results will not be provided to the study sites or to subjects. 
 
16 
ADVERSE EVENTS AND SAFETY 
16.1 
Definition of AEs, Period of Observation, and Recording of AEs 
An AE is any unfavorable or unintended sign, symptom, or disease, whether or not 
considered related to the study treatment. This also includes events resulting from medication 
error or inappropriate use. AE recording will begin at the time the informed consent form 
(ICF) is signed. Thereafter, AEs will be ascertained by asking the subject (and study partner) 
how the subject has been since the last visit. A clinical abnormality, laboratory test value 
abnormality, or imaging abnormality that the investigator deems to be clinically significant 
should be recorded as an AE.  Any abnormal laboratory test result from Screening 
assessments (prior to treatment) is to be added to the subject’s medical history, unless 
deemed clinically significant by the medical assessor (MD/DO) in which case it will be 
reported as an AE. 

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Every attempt should be made to describe the AE in terms of a diagnosis. Once a clear 
diagnosis has been made, individual signs and symptoms shall not be recorded unless they 
represent atypical or extreme manifestations of the diagnosis, in which case they should be 
reported as separate events. Events leading up to a diagnosis should be retained. If a clear 
diagnosis cannot be established, each sign and symptom must be recorded individually. 
 
All AEs must be fully recorded in the source documents and in the eCRF, regardless of 
whether or not the event is considered related to study drug. 
 
New AEs reported by a subject after screen failure will not be recorded for the study. 
Emergent AEs up to the point of screen failure will be followed up to resolution at the 
discretion of the PI. 
16.2 
Eliciting Adverse Event Information 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets one or more of the criteria for 
classification as an SAE or pregnancy requiring immediate notification. 
 
As a part of evaluating subjects for potential AEs, investigators should ask one or more 
questions directed to evaluating suicidal ideation and behavior. Such questions are to be part 
of the routine evaluation of AEs at each in-clinic visit, addressed both to subjects and to their 
study partners. 
 
Follow-up of an AE, even after the final dose of study drug, is required if the AE or its 
sequelae persist. Follow-up should be continued beyond the scheduled final visit if needed, 
until the AE or its sequelae resolve or stabilize at a level acceptable to the investigator in his / 
her medical judgement. 
 
For each AE, information recorded will include the following: the date when the AE started, 
the date when the AE stopped (or whether it remained ongoing), the intensity of the AE, the 
relationship of the AE to study drug, action taken with regard to study drug (none, 
interrupted, or discontinued), other drug therapy (no change, new medication, altered 
medication, or both of the latter), outcome, and whether or not the AE was considered an 
SAE. 
16.3 
Categorizing Intensity 
The intensity (severity) of each AE will be assessed by the investigator and graded as mild, 
moderate, or severe, as follows: 
• 
Mild: An AE that is easily tolerated by the subject, causes minimal discomfort and 
does not interfere with everyday activities 
• 
Moderate: An AE that is sufficiently discomforting to interfere with normal everyday 
activities 
• 
Severe: An AE that prevents normal everyday activities 
An AE that is assessed as severe should not be confused with an SAE. Severity is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe. 

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16.4 
Investigator’s Brochure 
The Investigator’s Brochure will be used as a guide to assess causality. 
16.5 
Assessing Causality 
The investigator will make a judgement considering whether or not, in his or her opinion, 
each AE is related to the study drug according to classifications described here. However, 
even if the investigator feels that there is no relationship to the study drug, the AE should be 
reported nevertheless. For each AE, the relationship or association (causality) of the AE to 
study drug will be assessed by the investigator and characterized as not related, unlikely 
related, possibly related, or related as follows: 
• 
Not related: If there is a confirmed cause of the AE (other medical condition, other 
therapy) which does not involve the study drug 
• 
Unlikely related: If the temporal association between the AE and the study drug is 
such that the AE is not likely to be related to the study drug 
• 
Possibly related: If the AE shows a reasonable temporal association to study drug 
administration but could be due to the subject’s clinical state or other therapies 
administered 
• 
Related: If the AE shows a reasonable temporal association to study drug 
administration and cannot be explained by the known characteristics of the subject’s 
clinical state 
16.6 
Categorizing the Outcome 
Outcome describes the status of the AE. The investigator will provide information regarding 
the subject outcome of each AE. 
 
Note: While negligible to slight coloration of urine or feces may occur as a result of study 
drug, these manifestations should not be recorded as AEs. 
 
Definitions for possible results of an AE outcome are: 
• 
Recovered/resolved: the event has improved or the subject recuperated 
• 
Recovering/resolving: the event is improving 
• 
Not recovered/not resolved: the event has not improved or the subject has not 
recuperated 
• 
Recovered/resolved with sequelae: the subject recuperated but retained pathological 
conditions directly resulting from the disease or injury 
• 
Fatal: termination of life as a result of an AE 
• 
Unknown: not known, not observed, not recorded, or refused 
16.7 
Serious Adverse Event Reporting 
An SAE is defined as any event that: 
• 
Results in death (including suicide) 
• 
Is life-threatening 
• 
Results in hospitalization or prolongation of existing inpatient hospitalization 
o 
Planned admissions for respite care are not to be considered an SAE (the 
Medical Monitor should be contacted for confirmation regarding whether or 
not an admission for respite care should be considered planned or unplanned). 

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Unplanned admissions for respite care will constitute an SAE unless it is as a 
result of study partner needs that are independent of the subject's condition. 
o 
An admission or prolongation of existing hospitalization because the subject 
does not want to be discharged, or because the study partner is unable or 
unwilling to care for the subject, is not to be considered an SAE. 
o 
Admissions to a hospital that were planned or anticipated before the start of 
the study for an unrelated pre-existing medical condition are not to be 
considered an SAE. 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Important medical events that might not be immediately life-threatening or result in 
death or hospitalization but might jeopardize the subject or might require intervention 
to prevent one of the other outcomes listed above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or development 
of dependency or abuse 
 
Medical and scientific judgment should be exercised in deciding whether an event is serious 
and whether expedited reporting is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the subject or may require intervention to prevent one of the outcomes listed 
in the definitions above. 
 
All SAEs must be reported on the eCRF. An assessment should be made by the investigator 
as to whether the event is study drug-related, i.e., is ‘causally’ related to the study drug. 
 
All SAEs (including any SAEs associated with COVID-19 that occur during study 
participation) should be reported to the Sponsor designee, Syneos Health, immediately (and 
not exceeding 24 hours following knowledge of the event). These should be followed by 
follow-up reports as soon as possible, whether or not the events are deemed study drug-
related. 
 
SAEs must be reported by entering the SAE information in the AE/SAE Section of the eCRF 
system. The information provided in the eCRF system should be as complete as possible, but 
must contain the following minimum fields: 
• 
Subject number 
• 
Brief description of the SAE (diagnosis or signs/symptoms) 
• 
Serious criteria 
• 
Causality assessment 
• 
Assessment of the intensity of the event 
Syneos Health Drug Safety will receive notification of the initial SAE via an e-mail alert 
generated from the eCRF system. In the event of any temporary disruption of the electronic 
system, an alternative SAE reporting mechanism will be available to site personnel; in this 
instance, a paper SAE report form will be available. Site personnel will complete the paper 
SAE report form, scan, and e-mail it within 24 hours to the following e-mail address:  
safetyreporting@syneoshealth.com 
Fax: +1 877 464 7787 
Address:  

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Syneos Health 
Safety/Pharmacovigilance Department 
Farnborough Business Park – 1 Pinehurst Road,  
Farnborough,  
Hampshire, GU14 7BF 
United Kingdom 
 
SAEs that are ongoing should be followed until resolved or stabilized to a level acceptable to 
the investigator. 
 
SAEs reported after screen failure will not be recorded for the study. Emergent SAEs up to 
the point of screen failure will be followed up to resolution at the discretion of the PI. 
 
The investigator is obliged to provide additional information as requested by the Medical 
Monitor. In general, this will include a description of the event in sufficient detail to allow for 
a complete medical assessment of the case and independent determination of possible 
causality. In the case of a subject death, a summary of available autopsy findings, if 
performed, must be submitted as soon as possible to Syneos Health. However, any supporting 
information provided should not reveal a subject’s identity beyond the agreed study 
identifier. The investigator should ensure that information reported is accurate and consistent. 
 
Information not available at the time of the initial report (e.g., an end date for the AE, 
laboratory values received after the report, or hospital discharge summary) must be 
documented on a follow-up form. All follow-up information must be reported in the same 
timelines as initial information. 
 
Any SAEs considered related to the study drug and discovered by the investigator after the 
study should be communicated in writing to the Sponsor within 24 hours following 
knowledge of the event. 
16.8 
Suspected, Unexpected Serious Adverse Reactions and Emerging Safety 
Information 
Suspected, unexpected serious adverse reactions are AEs that are believed to be related to an 
investigational medicinal product and are both unexpected (i.e., the nature or severity is not 
expected from the information provided in the Investigator's Brochure) and serious. As stated 
in the EU ‘CT-3’ Communication from the Commission (2011/C 172/01) and the US Code of 
Federal Regulations (21 CFR 312.32), for there to be a reasonable possibility of a causal 
relationship between the event and study drug there must be facts (evidence) or arguments to 
suggest a causal relationship. Final assessment of expectedness for purposes of regulatory 
reporting is the responsibility of the Sponsor. 
 
It is the responsibility of the Sponsor to determine whether a reported SAE fits the 
classification of a SUSAR and to notify the investigator of the decision as soon as possible. 
 
All SUSAR reporting, whether determined following unblinding during study conduct or 
apparent only after the study has ended, will adhere to European Directives 2001/20/EC, 
21 CFR 312.32 of the U.S. Code of Federal Regulations, Health Canada Food and Drug 
Regulation C.05.014, and other regions as applicable. 

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16.9 
Malignancies 
All cases of malignancies, other than non-melanoma skin cancers, are to be reported to the 
Sponsor designee, Syneos Health, as outlined above in Section 16.7. Adverse events of 
malignancies other than non-melanoma skin cancers are to be reported regardless of causality 
or whether they meet the criteria for serious. These will be reported to Health Canada as 
Adverse Drug Reactions (ADRs). Expedited reporting in other countries will be consistent 
with the handling of SUSARs.   
16.10 Reporting of Pregnancy 
Pregnancy is to be considered an immediately reportable event. This includes pregnancy of a 
female subject or a female sexual partner of a male subject. An event of a pregnancy will be 
reported to the Sponsor designee, Syneos Health, immediately (and not exceeding 24 hours 
following knowledge of the event), and followed by follow-up reports as soon as possible. 
 
Subjects who become pregnant during the clinical study should discontinue study drug 
immediately and contact the investigator. Subjects should be instructed to notify the 
investigator of a pregnancy either during the Treatment period of the study or within 90 days 
after the last dose of study drug. Whenever possible, a pregnancy should be followed to term, 
any premature terminations reported, and the status of the mother and child reported to the 
Sponsor after delivery. 
 
Although the pregnancy is not considered to be an AE or SAE, any pregnancy complications 
should be recorded as AEs or SAEs (if applicable). Any pregnancy should be followed 
through delivery for observation of any SAE, if possible. Therefore, regardless of whether or 
not a pregnancy is actually considered an SAE, a pregnancy form should be completed for all 
pregnancies. 
 
The information provided in the eCRF should be as complete as possible, but must contain 
the following minimum fields: 
• 
Subject number 
• 
Confirmation that the subject’s contact information is on file at the site 
• 
Date of report of pregnancy 
• 
Expected delivery date 
 
All data related to pregnancy, pregnancy outcome, and SAEs associated with pregnancy 
should be recorded in a safety database maintained by personnel responsible for 
pharmacovigilance at Syneos Health. Pregnancies should initially be reported in the 
Pregnancy Notification Form, Part I and sent by e-mail to the e-mail address provided below. 
When the outcome of the pregnancy is known, site personnel will complete the Pregnancy 
Notification Form, Part II and e-mail it to the same e-mail address noted below. 
 
Syneos Health Drug Safety will receive notification of the pregnancy via an e-mail alert 
generated from the eCRF system. In the event of any temporary disruption of the electronic 
system, site personnel will scan and e-mail a written report within 24 hours to the following 
e-mail address:  
safetyreporting@syneoshealth.com 
Fax: +1 877 464 7787 
Address:  

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Syneos Health 
Safety/Pharmacovigilance Department 
Farnborough Business Park – 1 Pinehurst Road,  
Farnborough,  
Hampshire, GU14 7BF 
United Kingdom 
 
16.11 Guidance for the Handling of Adverse Events of Special Interest and 
Selected Test Abnormalities  
The pre-specified AESIs in this study are hemolytic anemia and lens discoloration. 
Guidelines for the monitoring and management of the AESIs are given below along with 
selected test abnormalities. Clinical circumstances requiring additional evaluation of a subject 
and/or potential interruption or discontinuation of study drug are presented. 
 
16.11.1 
Hemolytic Anemia 
When there are signs and/or symptoms of clinically evident hemolytic anemia, dosing should 
be interrupted. A hemolysis panel should be considered (including complete blood count with 
differential, reticulocyte count [including absolute reticulocyte number], lactate 
dehydrogenase (LDH), direct and indirect bilirubin, and haptoglobin). See Section 13.8 for 
guidance on vitamin B12. If confirmed as related to study drug, dosing should be 
discontinued. 
 
Signs of possible treatment-emergent hemolytic anemia include: 
• 
Decrease by 20% from screening in red blood cell (RBC) count and/or hemoglobin 
• 
Abnormal RBCs in peripheral blood smear 
• 
Elevation of reticulocyte count to above laboratory normal range 
• 
Increase in LDH or indirect bilirubin, or lower haptoglobin than screening 
 
16.11.2 
Lens Discoloration 
For subjects with a history of lens implants, ophthalmological examinations (slit lamp 
examinations) will be performed prior to the first dose of study drug (during Screening or as 
part of Baseline assessments), at Visit 7, and at Visit 10 / early termination as scheduled 
procedures. Subjects and investigators are informed of the potential for lens discoloration in 
the Informed Consent Form and Investigator’s Brochure, respectively. If a lens discoloration 
is identified by slit lamp examination, this is to be recorded as an AESI in the AE eCRF; 
however, no specific action is required for the study drug. Slit lamp examination should also 
be performed if a subject has cataract surgery / lens implantation at any point during his or 
her study participation (as soon as possible after the surgery), as well as in response to visual 
complaints if suggestive of lens discoloration. 
 
16.11.3 
Other Safety Reasons Requiring Discontinuation of Study 
Drug 
If the calculated creatinine clearance is <30 mL/min and renal concerns arise, study drug 
should be discontinued.  
 

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For any other safety concerns that may arise during treatment, the Medical Monitor or 
24-hour medical contact number (see Section 4) should be contacted to discuss possible 
discontinuation of study drug. 
16.12 Urgent Safety Measures 
The Sponsor and investigator may take appropriate urgent safety measures in order to protect 
the subjects of the clinical study against any immediate hazard to their health or safety. 
 
The Sponsor and the Medical Monitor or designated deputy will be notified of any urgent 
safety measures taken by the investigator or qualified designee and advised of their 
responsibility to notify the licensing authority. The investigator or qualified designee will 
notify the Independent Ethics Committee/Institutional Review Board (IEC/IRB). 
 
If these measures are taken, the Sponsor or investigator shall immediately give written notice 
to the pertinent regulatory authorities consistent with the regional/national requirements, 
IEC/IRB, and DSMB of the measures taken and the circumstances giving rise to those 
measures. In any event, the written notice shall be no later than 7 days from the date the 
measures are taken. 
 
17 
STATISTICAL ANALYSIS 
A SAP will be finalized and signed off prior to database lock and unblinding. The SAP will 
provide details about the planned analysis. A brief overview of the plans for the primary 
analysis and selected secondary and exploratory analyses is given in the following sections. 
Specific ROI and SPM techniques and comparisons to previous Phase 3 data or external 
databases as well as Population PK analyses will be described in the SAP or a corresponding 
additional SAP where necessary; the SAP will provide details.  
 
Changes to the planned analysis will be documented in the SAP prior to database lock and 
unblinding. Deviations from the SAP (if any) will be noted in the clinical study report. 
 
The primary target of estimation is the difference in ADAS-cog11 and ADCS-ADL23 over 
52 weeks in subjects receiving the LMTM dose of 16 mg/day as compared to placebo. 
 
The primary efficacy analyses for FDA will be performed on the Efficacy Modified Intent-to-
Treat (E-MITT) which will include all randomized subjects who took at least one dose of 
study drug and have a baseline and a valid post-baseline efficacy assessment, and for EMA 
on the Intent-to-Treat (ITT) population with conservative assumptions about disease 
progression made for subjects who have missing post-baseline assessments. Subjects will be 
analyzed in the treatment group and according to the stratification variables to which they 
were randomized. 
 
Changes from baseline to Week 52 on the co-primary efficacy endpoints and other modalities 
with repeated measures such as MRI will be analyzed using a linear mixed model for 
repeated measures with unstructured covariance matrix (this assumption about the covariance 
matrix might be relaxed if the model does not converge; the SAP will provide details). The 
linear mixed model will contain fixed effects for time, treatment, and a treatment-by-time 
interaction; additionally, the baseline value of the corresponding endpoint will be included as 
a covariate and the randomization stratification variables of prior usage of AChEIs and/or 

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memantine, MMSE split (16-19, 20-25 or 26-27) as determined at Screening, and region will 
be included as fixed effects in the model. 18F-FDG-PET and other modalities with only one 
planned post-baseline assessment will be analyzed using an ANCOVA; the covariates for this 
model will be adjusted accordingly by removing terms with time.  
 
Several of the analyses described below will be performed separately for the comparisons of 
LMTM 16 mg/day with placebo and 8 mg/day with placebo. As only the LMTM 16 mg/day 
and placebo comparison is a primary endpoint, the models will use two treatment levels 
dependent on the comparison of interest. Several analyses provided for the comparisons of 
LMTM 16 mg/day and placebo will be repeated for the LMTM 8 mg/day versus placebo 
group as secondary or exploratory/sensitivity endpoints. The SAP will detail which analyses 
are performed for which treatment groups, and in which cases the LMTM 8 mg/day with 
placebo comparisons will be provided for which sensitivity, subgroup, and exploratory 
analyses.  
 
Further analysis on selected primary and secondary endpoints will be provided for pooled 
LMTM 16 mg/day and 8 mg/day arms compared to placebo. The analysis models will be 
identical to the 16 mg/day versus placebo with the exception of pooled treatment arms. The 
SAP will detail which analyses are repeated for the pooled 16 mg/day and 8 mg/day arms. 
 
More details about the exact contrast statements used for these tests as well as further 
sensitivity analyses, additional analyses of the primary variables (such as responder analyses 
and subgroup analyses), and the analyses of the secondary and exploratory endpoints are 
described in the subsections below as well as in the SAP.  
 
“Late” starters, i.e., subjects originally randomized to placebo, will be compared to “early” 
starters, i.e., those originally randomized to LMTM 16 mg/day or 8 mg/day (pooled, and 
individually for both groups as a sensitivity analysis). The last assessment prior to start of 
open-label treatment (pre-dose at Visit 7) will serve as the baseline assessment for these 
comparisons. The analyses will be based on a similar linear mixed model for repeated 
measures with the aim to investigate whether there is a difference in change in primary and 
MRI imaging endpoints dependent on LMTM treatment history. The comparison will be 
implemented through a non-inferiority test.  
 
The non-inferiority margin for the primary endpoint of ADAS-cog11 will be 2 units, 
motivated by the fact that these 2 units are small compared to the estimated treatment effect 
of > 5 units (~40% of this effect size). Margins for other endpoints which are exploratory to 
support a disease modifying argument will be defined in the SAP. The results will also be 
presented with the Visit 2 Baseline as baseline and treatment visits Week 26 and Week 52 in 
the open-label, delayed-start phase as Week 78 and Week 104. 
17.1 
Efficacy Endpoints 
17.1.1 
Primary Efficacy Endpoints for Double-Blind Treatment 
Period 
• 
ADAS-cog11 (LMTM 16 mg/day versus placebo) 
• 
ADCS-ADL23 (LMTM 16 mg/day versus placebo) 
 

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17.1.2 
Secondary Efficacy Endpoints for Double-Blind Treatment 
Period 
• 
Annualized rate of whole brain atrophy on brain MRI using BSI (LMTM 16 mg/day 
versus placebo) 
• 
Difference in temporal lobe 18F-FDG-PET change in SUVR normalized to pons in 
subjects with CDR 0.5 at Screening (LMTM 16 mg/day versus placebo, and LMTM 
8 mg/day versus placebo), if a sufficient number of subjects have provided data as 
specified in the SAP 
• 
ADAS-cog11 and ADCS-ADL23 (LMTM 8 mg/day versus placebo) 
• 
Annualized rate of temporal and parietal lobe atrophy on brain MRI using BSI 
(LMTM 16 mg/day versus placebo, and LMTM 8 mg/day versus placebo) 
 
17.1.3 
Secondary Endpoint for Open-Label, Delayed-Start Phase  
• 
Difference in disease progression on the co-primary clinical endpoints and the MRI 
imaging endpoint for subjects who started treatment in the double-blind treatment 
phase and those who started treatment in the open-label, delayed-start phase (referred 
to as “early” and “late” LMTM starters, respectively) 
o Only ADAS-cog11 will serve as a secondary endpoint; ADCS-ADL23 and 
other imaging endpoints are exploratory with the aim to be directionally 
supportive 
 
17.2 
Number of Subjects and Sample Size Calculation 
The target number of subjects is approximately 450 subjects enrolled in Protocol Version 5.0 
and above, randomized in a ratio of 4:1:4 (at the study level) to the LMTM 16 mg/day (200 
subjects), LMTM 8 mg/day (50 subjects) and placebo (200 subjects) groups; total enrollment 
is approximately 500 subjects. Subjects will be assigned to the MMSE severity groups based 
on screening MMSE score with a target of approximately 2:3:1 (MMSE 16-19, 
MMSE 20-25, MMSE 26-27 respectively) for those randomized to Protocol Version 5.0 and 
above. Subjects who drop out after randomization will not be replaced.  
 
Sample size estimations to achieve 90% power (two-sided alpha = 0.05) to detect a difference 
between LMTM 16 mg/day and placebo (containing intermittent MTC as a urinary 
discolorant), the primary treatment group comparison in the double-blind treatment period, 
have been performed for the two co-primary clinical endpoints. These assume a withdrawal 
rate of 20% to 25% over 52 weeks. The study sample size of approximately 450 subjects 
(approximately 200 subjects in each treatment group, with a further 50 subjects for secondary 
analyses of an LMTM 8-mg/day group) is based on the ADCS-ADL23 as a larger sample size 
is required to achieve the target power. 
 
Based on an estimated decline in ADCS-ADL23 over 52 weeks in the control arm of 7.7 units 
with an estimated SD of 8.5 units, the study will have >90% power (two-sided alpha=0.05) to 
detect a reduction in decline of 3.4 units or more. The 3.4 units are motivated by an estimated 
treatment effect of 5.0 ± 1.6 (mean ± standard error) units in the pooled studies TRx-237-005/ 
TRx-237-015.  
 

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Based on an estimated decline in ADAS-cog11 over 52 weeks based on pooled information 
from Studies TRx-237-005 / TRx-237-015 in the control arm of 6.5 units with an estimated 
SD of 5.9 units, 200 subjects per treatment arm provide >90% power (two-sided alpha=0.05) 
to detect a reduction in decline of 2.6 units or more. The 2.6 units represent a conservative 
value as the estimated treatment effect based on pooled Studies TRx-237-005 / TRx-237-015 
is 5.2 ± 1.3 (mean ± standard error) units.  
 
With 200 subjects randomized to the primary comparison in the double-blind treatment 
period under Protocol Version 5.0 and above, 160 to 170 subjects per arm will enter the open-
label, delayed-start phase assuming the drop-out rates mentioned above. Assuming a further 
10% drop out in the delayed-start phase, the key secondary analysis to demonstrate disease 
modification by comparing early to late starters with a noninferiority margin of -2 ADAS-
cog11 units has approximately 80% power. 
 
Subjects who withdraw from treatment will be encouraged to stay in the study and continue 
their assessments off-treatment. Subjects’ withdrawal rates will be closely monitored in a 
blinded fashion, to monitor if sample size calculations remain correct.  
17.3 
Analysis Populations 
The following subject populations will be used for the statistical analyses; all definitions 
reply on the treatment period in the double-blind phase excluding open-label assessments 
(population definitions will be used for the delayed-start analyses without any modifications): 
• 
Intent-to-Treat (ITT) population will include all randomized subjects. Three subsets 
are defined as follows: 
o The Efficacy Modified Intent-to-Treat (E-MITT) population will include all 
randomized subjects who take at least one dose of the study drug and have a 
baseline and at least one valid post-baseline efficacy assessment in the 
treatment period (prior to any potential follow-up assessment).  
o An MRI Imaging Modified Intent-to-Treat (MI-MITT) population will include 
all randomized subjects who took at least one dose of study drug and have at 
least one valid baseline and at least one valid post-baseline volumetric MRI. 
o The Imaging Modified Intent-to-Treat population (PI-MITT) for 18F-FDG-
PET will include all randomized subjects with screening CDR 0.5 who took at 
least one dose of study drug and have a baseline and a valid post-baseline 
SUVR assessment. 
• 
The Per Protocol (PP) population will include all subjects who are in the E-MITT and 
MI-MITT populations and who do not have any PP exclusionary protocol deviations 
or intercurrent medical events that could confound the interpretations. PP 
exclusionary deviations, irrespective of their classification as minor/major, and 
intercurrent medical events will be determined prior to treatment unblinding. 
• 
The Safety population will include all randomized subjects who take at least one dose 
of study drug.  
 
Due to the introduction of MTC spiking in the placebo arm with Protocol Version 5.0, the 
respective MITT populations will be restricted to subjects randomized to Protocol Versions 
5.0 and above for the primary and key secondary analyses as per the SAP. The full MITT 
populations will be analyzed for these as a sensitivity analysis. Details will be provided in the 
SAP. For the ITT, respective restrictions will be applied as part of the first step in the EMA 
analysis (see Section 17.4.3). 

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17.4 
Clinical Efficacy and Imaging Analysis 
The various analyses planned in the study are outlined below. The SAP will be more specific 
and clearly state which analysis and which model will be applied to what type of data.  
 
Subjects will be analyzed in the treatment group and stratification to which they were 
randomized unless stated otherwise in potential sensitivity analyses. For safety analyses, 
treatment assignment will be based on the treatment actually received. If a subject receives an 
incorrect treatment transiently, he/she will be assigned to the predominant treatment group 
(i.e., the treatment group for which he/she received the greatest number of doses). 
 
For E-MITT, MI-MITT, and PI-MITT analyses, only valid data will be included in the 
primary and secondary analyses. In subjects who have initiated treatment with an AChEI 
and/or memantine, assessments made after initiation of such treatment are not considered 
valid as they could confound the interpretation of the results and will be excluded. Such 
subjects and affected assessments will be identified prior to unblinding. Sensitivity analyses 
will be provided for the primary and selected secondary analyses including all data. 
 
The primary and key secondary analyses will be further restricted by excluding subjects who 
were randomized under protocols prior to Protocol Version 5.0; this is due to the spiking with 
MTC in the placebo arm. Sensitivity analyses not applying this restriction will be provided.  
 
Various imaging and clinical efficacy analyses will be handled differently for the FDA and 
European Medicines Agency (EMA). Summary statistics will be tabulated by visit and 
treatment group using observed data. ITT, E-MITT, MI-MITT, and PI-MITT 
population-weighted least squares means (LSM), unless otherwise stated, treatment 
differences, and 95% confidence intervals will also be included; the population will be 
determined by the corresponding model, dependent on whether the endpoint is an imaging 
endpoint or an efficacy endpoint. Where requested, annualized rates will be estimated based 
on the population-weighted LSM. 
 
All models will include the randomization stratification variables as covariates unless 
otherwise stated. If the models do not converge because of too few observations for a given 
randomization stratification variable, the corresponding variable/variables will be removed 
from the model. 
 
Various 8 mg/day analyses might be omitted if not promising based on the secondary or other 
analyses. These and corresponding thresholds will be defined in the SAP. In the specification 
of various analyses below, they are included for sake of completeness and as they might be 
performed.  
 
Data listings will include all observed data for the primary and secondary endpoints.  
 
17.4.1 
Hypothesis 
There are two co-primary efficacy endpoints for this trial: Baseline adjusted decline in 
ADAS-cog11 and Baseline adjusted decline in ADCS-ADL23 from Baseline at Week 52. Both 

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co-primary endpoints must reach significance based on the use of a two-sided test at the 
alpha=0.05 level of significance for LMTM to be designated as superior to placebo. 
 
The primary analysis will be performed using the E-MITT/ITT populations as defined in 
Section 17.3, with the additional exclusions mentioned in Sections 17.3 and 17.4.  
 
The global null hypotheses are as follows: 
H01:   There is no difference between the LMTM 16 mg/day and placebo groups 
change in ADAS-cog11 from baseline to Week 52  
 
and 
 
H02:   There is no difference between the LMTM 16 mg/day and placebo groups 
change in ADCS-ADL23 from baseline to Week 52  
 
The global null versus alternative primary efficacy hypotheses is a Union-Intersection Test 
which requires both co-primary endpoints to meet statistical significance at the 5% two-sided 
level of significance for the global null hypothesis to be rejected.  Additional details will be 
provided in the SAP. 
 
All secondary analyses have the same underlying null hypothesis that there is no difference in 
change from baseline in the quantity of interest between the LMTM 16-mg/day group, or the 
LMTM 8-mg/day group, and the placebo group. For association analyses, the null hypothesis 
is that there is no association between the variables of interest. 
 
17.4.2 
MITT (FDA) Analysis 
The FDA analyses will be based on the E-MITT, MI-MITT, or PI-MITT population, with the 
additional restriction as per Sections 17.3 and 17.4, depending on endpoint, and will include 
all available valid data for each subject. No data will be imputed (unless specified in selected 
sensitivity/exploratory analyses). Sensitivity analyses for selected endpoints will be provided 
where all assessments are included. 
 
Change from baseline in the respective efficacy/imaging parameter will be analyzed using a 
restricted maximum likelihood-based repeated measures linear mixed model. The model will 
include fixed effects for treatment group (two levels dependent on the comparison, three 
levels for sensitivity); nominal time; the treatment group-by-time interaction; and covariates 
for categorical severity, region, and prior use of AChEIs and/or memantine. The 
corresponding baseline parameter will be included as a covariate (continuous) as well (certain 
covariates in the model might be dropped if the model does not converge; see SAP for 
details). An unstructured covariance model will be used. The Kenward and Roger method of 
calculating the denominator degrees of freedom will be used for the tests of fixed effects. 
Treatment comparisons will be based on the modeled change from baseline at Week 52. 
 
If there is only one scheduled post-baseline imaging or efficacy assessment, the model will be 
replaced by a simple linear model with fixed effects for treatment group and the 
randomization stratification variables and with the baseline value of the corresponding 
endpoint as a covariate. 
 
For annualized rate of atrophy or decline, time will be used as a continuous variable 
supported by corresponding contrast analyses of time as a nominal variable. 

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17.4.3 
ITT (EMA) Analysis 
The EMA analyses will be based on the ITT population, regardless of endpoint.  
 
Change from baseline in the respective efficacy/imaging parameter will be analyzed using a 
restricted maximum likelihood-based repeated measures linear mixed model or, in the case of 
only one scheduled post-baseline imaging or efficacy assessment, using a simple linear model 
(the models used are described above in Section 17.4.2). This analysis will be restricted to 
scheduled, on-treatment visits for subjects randomized under Protocol Version 5.0 and above 
(a sensitivity will be provided including data from subjects of all protocol versions). An on-
treatment visit is a visit where a subject was on investigational product and not on any AChEI 
and/or memantine. 
 
This provides the on-treatment effect, E, at the final time point. For each subject who 
withdrew from the study, the decision will be made as part of the blinded data review 
meeting as to whether the withdrawal was potentially treatment-related. For potentially 
treatment-related drop-outs, the fraction of subjects randomized to active treatment who 
withdrew at a given time point will be calculated. If a subject is determined to have 
withdrawn for non-treatment-related reasons, no further adjustment will be made as the 
mixed effects model correctly accounts for subjects who are missing at random.  
 
In this intervention effect analysis, subjects who withdraw for potential treatment-related 
reasons are assumed to retain 100% of the treatment effect they had attained up to the point 
of withdrawal but do not continue to benefit from treatment afterwards. This corresponds to 
the estimate I = (E0*w0 + E13*w13 + E26*w26 + E39*w39) + E52*(1-w0-w13-w26-w39), 
where E13 is the treatment effect at week 13. W13 is defined as the fraction of subjects who 
withdrew for potentially treatment-related reasons, have a non-missing imaging/efficacy 
parameter at Week 13, and do not have any on-treatment assessments at any scheduled visit 
subsequent to Week 13. The other wxx are defined likewise. Wxx is calculated for the active 
treatment group only. W0 refers to subjects who had no measurement taken after the baseline 
measurement and thus E0 is zero. This analysis will be implemented as a contrast statement 
and the estimate I will be reported as the intervention effect. 
 
Annualized rate of atrophy or decline will also be analyzed in a similar fashion.  
 
17.4.4 
Estimands 
In general, definition of estimands in the analysis of clinical trials become increasingly 
important. The SAP will specify estimands to provide a more comprehensive assessment of 
the performance and efficacy of the drug accounting for various factors (importantly, 
drop-outs). 
 
In line with the ITT analysis of Section 17.4.3, the primary estimand therefore is designed to 
answer the question on the treatment effect of the LMTM dose of 16 mg/day as monotherapy 
versus placebo (occasional 4 mg/day MTC) in the targeted population of subjects with 
probable AD and MCI-AD at Week 52, regardless of study drug discontinuation, based on 
the two co-primary endpoints. 
This estimand is constructed in line with ICH E9 (R1) addendum. The five components 
defining the estimand of interest are listed below: 

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A. Treatment: 
52 weeks of LMTM 16 mg/day or matching placebo (4 mg/day MTC) as 
monotherapy, regardless of adherence. 
B. Population: 
Subjects with probable AD or MCI-AD as described by the inclusion and exclusion 
criteria, randomized under Protocol Version 5.0 or higher. 
C. Patient-level 
outcomes / variables: 
Change from Baseline of the ADAS-cog11 and ADCS-ADL23 at Week 52 as 
co-primary outcomes. 
D. Population-level 
summary: 
Population-weighted least squares mean difference. 
E. Intercurrent 
Events (ICE): 
The following ICE have been identified which could prevent measurement of the 
primary outcome or change the interpretation of the measured primary outcome: 
1. Withdrawal from study before completion of 52-week treatment period for non-treatment 
related reason   
2. Withdrawal from study before completion of 52-week treatment period for treatment-
related reason   
3. Initiation of AChEI and/or memantine  
4. Study treatment discontinuation for any reason other than initiation of AChEI and/or 
memantine (including discontinuation by the investigator if he/she judges that treatment is 
no longer appropriate, if the subject’s clinical condition is worsening or for an AE, or due 
to study drug dose interruption that is longer / more frequent than specified in ICE #5 
below) (see Section 17.4.11.4 regarding analysis of the TOTOS group)  
5. A dose interruption for more than 14 consecutive days or more than two occasions of dose 
interruptions up to a maximum of 14 consecutive days  
6. Intercurrent illnesses, or initiation of medical food or medications not allowed by protocol 
(which will be identified during the blinded data review meeting) 
7. Study treatment non-compliance, defined as <80% or >120% taking into consideration any 
dose interruptions (if this cannot be estimated, it does not result automatically in a non-
compliance) 
8. Death before completion of 52-week treatment period 
9. COVID-19 infection 
10. Death due to COVID-19 
 
The handling of ICEs is described as follows: 
• 
Events 1 will be handled according to a hypothetical strategy as if subjects have stayed on treatment; in 
a sensitivity analysis, all these subject withdrawals are assumed to be potentially treatment-related, 
which are then handled using the treatment policy approach from ICE #2. 
• 
Events 2 will be handled using a treatment policy approach reflecting Copy Incremental from 
Reference strategy (using data after occurrence of the ICE). Subjects who withdraw for treatment-
related reasons are assumed to retain 100% of the treatment effect they had attained up to the point of 
withdrawal but do not continue to benefit from treatment afterwards, i.e., assuming that the clinical 
course post ICE for either treatment group follows the placebo group. This corresponds to the estimate 
I = (E0*w0 + E13*w13 + E26*w26 + E39*w39) + E52*(1-w0-w13-w26-w39), where, for instance, 
E13 is the treatment effect at Week 13 and W13 is defined as the fraction of subjects who withdrew for 
a potential treatment-related reason, have a non-missing efficacy parameter at Week 13, and do not 

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have any on-treatment assessments at any scheduled visit subsequent to Week 13. The fractions are 
calculated within the active treatment group. W0 refers to subjects who had no measurement taken after 
the baseline measurement and thus E0 is zero. The estimate I will be reported as the intervention effect 
and will be calculated using a contrast on the LSM (see Section 17.4.3). 
o 
Two sensitivity analyses will be run using hypothetical strategies (not using data after 
occurrence of the ICE), one by imputing missing data for both treatment groups based on data 
seen in the placebo group, and one by imputing missing data for each treatment group based 
on data seen in their own group. 
o 
In another sensitivity analysis, the alternative assumption will be investigated, that the 
subjects withdrawing from treatment for treatment-related reasons do not retain any treatment 
effect after Baseline; the intervention effect I in this case is I=E*(1-w), where E is the 
treatment effect at Week 52 and w is the fraction of subjects within the active treatment group 
who withdraw for a potential treatment-related reason up to Week 52. 
• 
Events 3 will be handled according to the original randomized treatment group assuming they stopped 
treatment and did not start AChEI and/or memantine (analyzed same as ICE #2), not using data after 
occurrence of the ICE. 
• 
Events 4 will be handled according to a treatment policy strategy, using data after occurrence of the 
ICE. In addition, for EMA, the analysis will be carried out using the strategy as described for ICE #2 
(not using data after occurrence of the ICE). 
• 
Events 5, 6, and 7 will be handled according to a treatment policy approach, using all data (also after 
occurrence of respective ICE). 
• 
Events 8 will be handled as treatment failure. If the subject dies prior to Week 52, the population 
average in decline within the placebo arm will be imputed. 
• 
Events 9 and 10 will be handled with a hypothetical strategy assuming COVID-19 disease would not 
have happened, not using data after occurrence of the ICE. 
 
17.4.5 
Handling of Missing and Incomplete Data  
Missing imaging data will not be imputed; it will be assumed that the data are close to 
missing at random after accounting for the terms in the model for all analyses other than 
those described for the EMA ITT-based analyses. The EMA ITT-based analyses treat 
subjects for whom assessments are missing from a certain point onwards as having no 
treatment benefit thereafter; while the primary analysis assumes that they retained the 
treatment effect that they had at the point of drop-out, a sensitivity analysis treats them as 
having lost all treatment effect. While the primary analysis assumes that some of subjects’ 
data might be missing at random for drop-outs, a sensitivity analysis assumes all withdrawals 
were treatment related. Various other sensitivity analyses, including multiple imputation, 
time to event, and responder analyses, will be provided to investigate the robustness of the 
primary and secondary analyses (see respective sections below for more detail; drop-outs are 
treated as non-responders or having an event of decline in these models). 
 
Efficacy data missing for an entire outcome scale or for the majority of the scale will not be 
imputed unless stated otherwise. Instead, it will be assumed that the data are close to missing 
at random after accounting for the terms in the model. However, missing items within a 
subdomain or scale may be upscaled if some items of the subdomain or scale are present; the 
SAP will provide details of the handling of partial data for the efficacy endpoints for each 
scale. As automated data capturing devices are used for all efficacy assessments, the risk of 
missing data of this type is low. For imaging data, this type of missing data is impossible and 
consequently they are not subject to upscaling either. 

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17.4.6 
Open-Label, Delayed-Start Analysis  
“Late” starters, i.e., subjects originally randomized to placebo, will be compared to “early” 
starters, i.e., those originally randomized to LMTM 16 mg/day or 8 mg/day (pooled, and 
individually for both groups as a sensitivity analysis). The last assessment prior to start of 
open-label treatment (pre-dose at Visit 7) will serve as the baseline assessment for these 
comparisons. The analyses will be based on a similar linear mixed model for repeated 
measures as outlined for the FDA/EMA primary analysis (see model specification in Sections 
17.4.2 and 17.4.3) with the aim to investigate whether there is a difference in change in 
primary and MRI imaging endpoints dependent on LMTM treatment history (certain 
covariates in the model might be dropped if the model does not converge; see SAP for 
details).  
 
The comparison will be implemented through a non-inferiority test. The non-inferiority 
margin for the primary endpoint of ADAS-cog11 will be 2 units, motivated by the fact that 
these 2 units are small compared to the estimated treatment effect of > 5 units (~40% of this 
effect size). Margins for other endpoints which are exploratory to support a disease 
modifying argument will be defined in the SAP.  
 
The results will also be presented with the Visit 2 Baseline as baseline, and treatment visits 
Week 26 and Week 52 in the open-label, delayed-start phase as Week 78 and Week 104. 
 
17.4.7 
Dose Response Analyses 
Various dose response analyses will be performed. The primary endpoints and key secondary 
endpoints will be analyzed using FDA/EMA primary analyses (see model specification in 
Sections 17.4.2 and 17.4.3) to show the functional relationship of dose and response on the 
various endpoints as change from baseline to Week 52. This analysis will also be provided 
split by MMSE groups as randomized. For CDR 0.5 subjects, the listed secondary analysis of 
18F-FDG-PET will be translated into a dose response curve as well.  
 
Several of these dose response analyses are contingent on primary analyses and key 
secondary analyses showing a significant effect as outlined in the SAP.  
 
17.4.8 
Responder Analyses 
Responder analyses will be conducted for the primary and selected secondary endpoints by 
dichotomizing each endpoint.  
 
For the corresponding imaging/efficacy parameter, a responder will be defined as a subject 
whose change from baseline is less than or equal to a threshold “T” defined as follows (these 
analyses will be done separately for the LMTM 16-mg/day versus placebo and LMTM 
8-mg/day versus placebo groups): 
 
• 
Let LSM1 be the LSM of change from baseline for the placebo group from the 
respective endpoint analysis 
• 
Let LSM2 be the LSM of change from baseline for the LMTM group from the 
respective endpoint analysis 
• 
Then T = (LSM1 + LSM2)/2 

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Thresholds will be chosen based on the E-MITT, MI-MITT, or PI-MITT population-
weighted LSMs from the respective model. Subjects who do not have a final assessment will 
be classified as non-responders. 
 
For each separate LMTM group comparison versus placebo, the proportions of responders 
will be compared using the Cochran-Mantel-Haenszel test, adjusting for the randomization 
strata. Odds ratios and 95% confidence intervals will be presented.  
 
For each of these analyses, if there is a significant effect of treatment on an imaging as well 
as another imaging or clinical efficacy parameter, the association between responders across 
these parameters at Week 52 will be assessed by using Pearson’s chi-square test to analyze 
the resulting 2 × 2 table. The number and percent of subjects in each cell of the 2 × 2 table 
will be tabulated along with the p-value from the Pearson’s chi-square test. 
 
Responder analyses will be used to investigate associations between various endpoints. 
Correlation analyses will complement or replace responder-based analyses of associations in 
some cases. 
 
17.4.9 
Time-to-Event Analyses 
Time-to-Event/Time-to-Decline analyses will be performed for a selected subset of endpoints 
as repeated measurements over time are needed. The distributions of time-to-decline in the 
key parameters will be summarized using the Kaplan-Meier method, with onset of decline 
defined as the first of two consecutive measurements that are worse than the baseline score, 
allowing for a certain margin which will be predefined in the SAP prior to database lock and 
unblinding; typical margins for the two primary endpoints are 1 unit. If there is no onset of 
decline prior to Week 52 and if Week 52 has a marked worsening as specified in the SAP for 
a given subject, an onset of decline will be triggered at Week 52 for that subject. 
Time-to-decline will be calculated as date of onset of decline – date of randomization + 1.  
 
The time-to-decline analyses are based on visit window. One measurement per visit window 
is selected, including off-treatment measurements. Subjects without any decline will be 
censored at the date of last assessment, but if a subject missed the scheduled visit, the subject 
is censored at the target day of the scheduled visit. The analysis will be run for the ITT 
population. 
 
Any missing efficacy/imaging value for a scheduled visit will be treated as a worsening from 
baseline, for that visit. Because of this convention for missing values, it is possible that the 
first of two consecutive measurements that are worse than the baseline score by the defined 
amount occurs at a missed visit. In that case, since there is no date associated with the missed 
visit, the time-to-decline will be calculated based on the scheduled date of the missing visit. 
 
The Cox proportional hazards regression model with effects for treatment group (two or three 
levels depending on whether primary or sensitivity comparison) and the randomization 
stratification variables will be used to compare LMTM 8 mg/day versus placebo (and LMTM 
16 mg/day versus placebo, respectively) by way of Hazard Ratio, 95% confidence interval, 
and p-value (for alpha 0.05). A graph of the Kaplan-Meier estimates will be provided. 
 
There will also be versions of this analysis using actual dates.  

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17.4.10 
Subgroup Analyses 
For selected endpoints and treatment groups, subgroup analyses will be provided. These are 
implemented by restricting a given analysis to the corresponding subgroup or by adding 
interaction terms in the model with appropriate contrast statements as described in the SAP.  
 
Subgroup analyses will be performed for the primary endpoints and selected secondary 
endpoints based on the E-MITT/MI-MITT/PI-MITT populations (FDA analysis) by repeating 
the analysis as described for the primary and secondary endpoints restricted to the subgroup. 
If the subgroup consists of less than 10% of subjects in observed cases, only summary 
statistics will be presented. The subject characteristics that will be included in this type of 
analysis are the following:  
• 
Baseline diagnosis (probable AD and MCI-AD) 
• 
MMSE (16-19, 20-25, and 26-27) 
• 
CDR (0.5 and CDR 1 or 2 pooled) 
• 
AChEI/memantine use (prior use and never used) 
• 
Age group (<75 years and ≥75 years) 
• 
Gender (male and female) 
• 
Race (white and non-white) 
• 
Geographic region (North America and Europe) 
 
17.4.11 
Sensitivity Analyses 
Sensitivity analyses for key primary as well as secondary parameters will be conducted to 
assess the impact of missing data and to assess alternative models. 
 
See Section 10.2.3 for a summary of the modifications regarding sensitivity analyses to be 
implemented due to COVID-19. The SAP will be more specific about the analyses 
conducted, including those related to COVID-19 impact assessment and will follow available 
regulatory guidelines.      
 
17.4.11.1 Mis-stratification Analysis 
If there are more than 5% of subjects who have been mis-stratified, then the primary analyses 
will be repeated using the actual status at randomization. 
 
17.4.11.2 All Protocol Version Analysis 
As outlined in Sections 17.3 and 17.4, the MITT and on-treatment populations will be 
restricted further in the primary analysis. A sensitivity will be provided for the respective 
analysis with all data from subjects or all protocol versions included (unrestricted MITT/on-
treatment definitions).  
 
17.4.11.3 Analysis of Subjects Who Started AChEI and/or 
Memantine  
For the FDA analyses, in subjects who initiated treatment with AChEI and/or memantine at 
any time during the study, data after initiation of such treatment are excluded from the 
primary analyses as they could confound the results. Such subjects will be identified prior to 

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unblinding. For EMA analyses, such subjects are treated as subjects who terminated the study 
at the time of starting AChEI and/or memantine; a conservative post-withdrawal course is 
assumed for these subjects. 
 
Data for these excluded subjects will be tabulated separately with their observed means, 
standard deviations, standard errors, and minimum and maximum values of selected changes 
in imaging and efficacy assessments. Primary reasons for initiating antidementia therapy will 
be provided. Furthermore, tables will be provided quantifying the number of assessments as 
well as time points that are impacted by these exclusions. 
 
Sensitivity analyses will be performed including all data for these subjects. Time to event 
(i.e., time to withdrawal in order to start AChEI and/or memantine) may also be performed if 
more than 10% meet this criterion; if not, the information will be tabulated. 
 
17.4.11.4 Analysis of the Off-Treatment-On-Study (TOTOS) 
Subjects  
Data for the TOTOS subjects will be handled in a similar fashion as described in Section 
17.4.11.3. For the FDA analyses, the TOTOS subjects are included in the analyses (unless 
they initiated AChEI and/or memantine, in which case data after the initiation of such therapy 
will be excluded). For the EMA analysis, all TOTOS subjects are treated as subjects who 
terminated the study; a conservative post-withdrawal course is assumed for these subjects. 
 
Data for these subjects will be tabulated separately with their observed means, standard 
deviations, standard errors, and minimum and maximum values of selected changes in 
imaging and efficacy assessments; primary reasons for withdrawal of study drug will be 
provided. Furthermore, tables will be provided quantifying the number of assessments as well 
as time points that are impacted by these exclusions. 
 
Sensitivity analyses will be performed including all data for these subjects.  
 
17.4.11.5 Imputation Methods 
No data will be imputed in the primary and secondary analysis models unless stated 
otherwise. As sensitivity analyses, two methods for imputation will be explored, as described 
below. 
 
17.4.11.5.1 
Multiple Imputation 
A multiple imputation analysis will be carried out using SAP-specified endpoints and 
analysis models, but will include the primary and selected secondary endpoints. The missing 
values will be imputed with multiple imputation methodology using PROC MI in SAS. A 
multivariate normal imputation model will be used by treatment group with a seed of 237039. 
The imputation model will have exactly the same covariates as the respective models. A total 
of 50 imputed datasets will be generated for this analysis. Each of the imputed datasets will 
be analyzed using the respective model with the same covariates. The MIANALYZE 
procedure in SAS will be used to combine results. 
 

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For endpoints that do not have planned multiple post-baseline assessments, additional 
variables such as sex, age, and other baseline values will be employed to allow appropriate 
multiple imputation.  
 
17.4.11.6 Baseline Severity Rate-correction Analysis 
The FDA model will include baseline value as an additive covariate. In order to determine 
whether baseline value influences future assessments, i.e., the rate of progression, a further 
sensitivity analysis which includes the additional term baseline*visit instead of just baseline 
will be conducted. 
 
17.4.11.7 Sensitivities for Intervention Effect Analyses 
Further sensitivity analyses are planned to determine the effect of withdrawals on estimation 
of intervention effect (as required by the EMA). These include the alternative assumption that 
the subjects withdrawing from treatment do not retain any treatment effect; the intervention 
effect I in this case is I=E*(1-w), where w is the fraction of subjects who withdraw for 
potential treatment-related reasons. This is implemented as a contrast statement as well. This 
analysis is only needed if there are more than two scheduled visits with imaging/efficacy 
assessments, as otherwise this analysis is identical to the EMA analysis model specified in 
Section 17.4.3.  
 
An additional sensitivity analysis will assume that all subjects withdrew due to a potential 
treatment-related reason.  
 
17.4.11.8 Polynomial Models 
For the key efficacy/imaging assessments with more than one scheduled post-Baseline visit, 
maximum likelihood (rather than restricted maximum likelihood) based repeated measures 
models with polynomial time effects with time treated as a continuous variable (number of 
nominal weeks as well as actual study week defined by study day divided by 7) will be 
assessed. Tests of the significance of the linear, quadratic, and cubic time effects will be 
carried out in each treatment group. The estimated annualized change in mean values and 
standard errors from baseline to Week 52 will be presented. 
 
17.4.11.9 Other Population Analyses 
As a sensitivity analysis, the FDA primary analyses and potentially other pre-specified 
endpoints will be repeated for: 
• 
The PP population 
• 
The set of completers (i.e., all subjects who were on-treatment at Week 52) 
• 
All visits that are not potentially confounded by intercurrent illnesses, COVID-19, 
and concomitant medications as identified during the blinded data review meeting 
17.5 
Exploratory Analyses 
A number of exploratory analyses will be undertaken, to be specified in the SAP. These could 
include the following (details will be provided in the SAP): 
• 
To compare the treatment groups on the ADAS-cog13 
• 
To compare the treatment groups on a new composite endpoint/composite endpoints 
based on selected item of the Alzheimer’s Disease Assessment Scale, 13-item version 

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(ADAS-cog13) and the ADCS-ADL23, analyzed at 9 months and 12 months to 
evaluate its usefulness for future studies (for all subjects and also separately for 
subjects with CDR 0.5 and CDR 1-2 at screening)  
• 
To compare the treatment groups on the MMSE 
• 
To compare the treatment groups on the CDR sum of boxes 
• 
Comparison of atrophy in MRI parameters (including putamen, nucleus accumbens, 
and nucleus basalis) according to treatment assignment, as well as the combination of 
treatment assignment with previous treatment status of AChEIs and/or memantine 
(prior use or never used) in a subgroup analysis; the influence of the baseline volumes 
of putamen, nucleus accumbens, and nucleus basalis will also be investigated for 
selected MRI parameters. Further SPM analyses may be conducted using all available 
MRI volumetric data to determine regions of significant difference associated with 
treatment 
• 
Comparison of decline in 18F-FDG-PET SUVR normalized with respect to pons and 
cerebellum in temporal, parietal, and frontal lobes according to treatment assignment, 
as well as the combination of treatment assignment with previous treatment status of 
AChEIs and/or memantine (prior use or never used) in subgroup analyses 
• 
Determination of decline in SUVR in cerebellum normalized with respect to pons 
according to treatment assignment, as well as the combination of treatment 
assignment with previous treatment status of AChEIs and/or memantine (prior use or 
never used) in a subgroup analysis 
• 
Other SUVR regions of interest will also be examined including, but not restricted to, 
inferior temporal gyrus, angular gyrus, anterior and posterior cingulate gyrus, and 
cerebellum  
• 
SPM analyses (Friston et al., 2007) may be conducted using all available normalized 
cortical 18F-FDG-PET SUVR data and MRI data to determine regions of significant 
difference associated with treatment without assuming the location and extent of any 
differences  
• 
To examine the associations of SPM approaches using all available normalized 
18F-FDG-PET SUVR data and volumetric MRI data with the following clinical 
measures: 
o 
ADAS-cog13 
o 
ADCS-ADL23 
o 
Composite Scales (selected) 
• 
Comparisons of measures of brain MRI hyperintensities by treatment group; subgroup 
analyses by previous treatment status of AChEIs and/memantine (prior use or never 
used) will also be performed, including for the combined LMTM 8-mg/day and 
placebo groups 
• 
Population pharmacokinetics (to be subject to a section in the SAP or a separate SAP 
and report) 
• 
To evaluate the influence of ApoE genotype (in subjects who provide legally 
acceptable consent) on the primary and selected secondary endpoints 
 
A number of exploratory comparisons with external data may also be performed, to be 
specified in the SAP. These include comparisons of LMTM 16 mg/day or LMTM 8 mg/day 
on the following: 
• 
Comparison of annualized rates of atrophy in a range of brain regions (including 
temporal lobe and whole brain) with the estimated decline for subjects with MCI-AD 
and mild AD with MMSE in the range of 20-27 not receiving either of the standard 

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treatments for AD (AChEIs and/or memantine) from the ADNI; this will be repeated 
for the entire MMSE range used in this study 
• 
To compare the primary and selected secondary imaging and efficacy endpoints at 
52 weeks with pooled mild AD subjects in control groups (subjects receiving LMTM 
at any dose in combination with an AChEI and/or memantine) from the LMTM 
Phase 3 trials (Studies TRx-237-005 and TRx-237-015) with baseline MMSE in the 
range of 20-26; this will be repeated for the entire MMSE range used in this study 
• 
Comparison of decline in temporal lobe 18F-FDG-PET SUVR with the estimated 
decline for subjects with mild AD (CDR 0.5 at Screening) not receiving either of the 
standard treatments for AD (AChEIs and/or memantine) from the ADNI 
• 
Accounting for and using historic data more generally such as placebo decline or 
treatment effects as priors to inform the analyses of this study.   
17.6 
Demographic and Baseline Characteristics 
Demographic variables, baseline characteristics and medical history will be summarized in 
tables. Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 20.1. The tabular summaries will present the numbers and percentages of 
subjects with abnormalities in a given MedDRA System Organ Classification (SOC).  
 
Recently used medications and concomitant medications will be coded using the 01March 
2017 version of the WHO drug dictionary. Tabulations will be prepared of all drugs used 
concomitantly (relative to the first dose of study drug) based on WHO Anatomical 
Therapeutic Classification (ATC) level 1 term, ATC level 3 term, and Preferred Term 
(generic name) with frequency and percentage of subjects in each treatment group using each 
concomitant medication. Separate tabulation will be made of on-treatment changes in 
antipsychotic medications (to be identified by blinded review), together with the reason(s) for 
such change. 
 
Further information indicating years spent in full-time education and its level before the age 
of 26 years is to be collected. In addition, main occupation during working life is to be 
provided (see Section 28.3); main occupation will be coded using the Standard Occupational 
Classification, 2010, Volume 2 The Coding Index, UK Office for National Statistics. These 
have been found to be useful proxies for cognitive reserve (Staff et al., 2004). Exploratory 
analyses will be described in the SAP. 
 
All data, including study eligibility and screening data (including reason for exclusion), will 
be listed. 
 
Subjects who are mis-stratified at the time of randomization will be flagged in the listing. 
17.7 
Safety Analysis  
Various safety analyses will be conducted for this study. Details will be provided in the SAP. 
The planned safety analyses, including tabulations by treatment group, include: 
• 
A quantification of the extent of drug exposure 
• 
Various analyses of AEs (using MedDRA Version 20.1) 
o 
TEAEs, including by relationship and intensity 
o 
TEAEs that result in interruption or discontinuation of study drug 
o 
Selected subsets of TEAEs (referred to as TauRx AE Groupings) 

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o 
Subgroup analyses 
o 
Time-to-event analyses of TEAEs 
o 
SAEs and serious adverse reactions 
o 
Malignancies other than non-melanoma skin cancers 
• 
Clinical laboratory evaluations  
• 
Vital sign analysis  
• 
Physical and neurological examinations 
 
All safety data will be listed. 
17.8 
Other Data 
Total duration of exposure and mean and modal daily dose per subject (including “dose 
equivalent” for subjects randomized to placebo), will be summarized descriptively by 
treatment group. Mean, modal, and maximum dose will also be summarized over selected 
exposure intervals. In addition, tabular summaries of the proportions of subjects with dose 
interruptions will be prepared for each treatment group. Listings will encompass dosing, drug 
accountability, and compliance (percentage of tablets taken relative to intended number); any 
doses that are other than that randomized will be flagged. 
 
The plasma MT and whole blood concentrations (parent MT/LMT, N-desmethyl MT, and 
total MT concentrations, as available) will be listed. The results of population PK and 
exposure-response analyses will be provided in a separate report. 
 
ApoE genotype will be listed for each subject who consents to this determination. Use of 
these data in exploratory analyses will be described in the SAP. 
17.9 
Interim Analysis 
No interim futility or efficacy analysis is planned prior to the completion of the double-blind 
treatment period in which treatment groups will be compared. 
 
Recruitment and discontinuations will, however, be continuously monitored in a blinded 
fashion to ensure that the sample size calculations remain appropriate. The sample sizes may 
be increased but not decreased; thresholds will be defined in an interim monitoring SAP. 
Specifically: 
• Should the overall dropout for the duration of the study be projected to exceed 25%, 
then the number of subjects to be enrolled may be increased in order to power an 
analysis at 52 weeks. 
• The assumed SD for the change from baseline to Week 52 in the primary endpoints 
may be re-estimated at some point during the study’s recruitment period and the 
sample size required to provide 90% power for the primary endpoints will be re-
estimated. 
• The balance between the three different MMSE stratification groups is determined to 
be approximately 2:3:1 (MMSE 16-19, 20-25, and 26-27) for those randomized to 
Protocol Version 5.0 and above. This value will be closely monitored and controlled 
at study level. Should the balance be deviating from the desired balance, then the 
number of subjects to be enrolled may be increased in order to rebalance the design 
enriching the MMSE groups that are underrepresented. 

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• As indicated in Section 10.2, COVID-19 can have a significant effect on the number 
of assessments available for analysis. Quality and subitems of assessments can also be 
impacted, leaving the primary analysis underpowered. The interim monitoring SAP 
will provide details regarding how this will be assessed prior to any analysis being 
conducted and will also outline approaches that are to be followed given pre-
determined thresholds.  
 
As noted in Section 10.7, an analysis of the primary efficacy endpoints will be undertaken 
when the last subject completes the final visit in the double-blind treatment period.. If the null 
hypotheses presented in Section 17.4.1 are rejected, complete safety and efficacy analysis of 
the data from the double-blind treatment period will be undertaken and an interim study 
report prepared. The complete Clinical Study Report will be prepared upon completion of the 
entire study as defined in Section 10.7. 
 
18 
REGULATORY AND ETHICS 
Investigators and all other parties involved in the conduct of the study are responsible for 
ensuring that the study is conducted at their sites in accordance with the approved protocol 
and with the principles contained in the Declaration of Helsinki, the ICH Guidelines for Good 
Clinical Practice (GCP)7 and with applicable country and local regulatory requirements and 
laws. All deviations identified at or by the site will be reported to the study monitor. See 
Section 10.2 regarding the Sponsor’s ongoing consideration of updates to guidances and 
requirements due to COVID-19 to ensure continued protection of subject safety, subject 
rights, trial integrity, and compliance. 
 
The Sponsor’s designee(s) will be responsible for ensuring that the relevant approval is 
obtained from the local regulatory authority prior to the start of the study. The relevant 
documents will be provided to the investigator. The Sponsor’s designee(s) will forward any 
protocol amendments to the regulatory authority and will ensure that SAEs are reported, and 
that progress reports and details of any serious protocol violations are provided as required. 
 
Each regulatory authority will be informed should the study be terminated early consistent 
with local requirements. 
18.1 
Approval of the Protocol and Amendments 
Following authorization by the Sponsor, the final protocol and all related documents (e.g., 
information sheets and ICFs) will be submitted to the IEC/IRB. 
 
The Sponsor’s designee, Syneos Health, will be responsible for ensuring that regulatory and 
IEC/IRB approvals are obtained prior to the start of the study. The relevant documents will be 
provided to the investigator. 
 
Neither the investigator nor the Sponsor will modify this protocol. If modification is 
necessary, either party must first obtain the concurrence of the other. The party initiating a 
 
7 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
[homepage on the Internet].  E6(R2):  Good Clinical Practice:  Consolidated Guideline (or ICH E6(R1) in 
those jurisdictions where ICH E6(R2) is not yet implemented by the regulatory authorities)  

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modification will confirm it in writing and the investigator will be responsible for informing 
the IEC/IRB. In case of a substantial amendment, prior approval of the IEC/IRB is required. 
 
The Sponsor or designee is responsible for the submission of a protocol amendment to the 
regulatory authority. In the event of a substantial amendment, prior regulatory approval is 
required for implementation. 
18.2 
Serious Breaches 
It is the responsibility of the Sponsor to notify the licensing authority of any serious breach 
which is likely to affect, to a significant degree, the safety or mental integrity of the subjects 
of the study or the scientific value of the study. 
 
All serious breaches will be notified to the pertinent regulatory authorities according to the 
relevant national regulatory requirement. The reporting will be via the Sponsor or delegated 
party in accordance with TauRx Standard Operating Procedures (SOPs). 
18.3 
Informed Consent 
It is the responsibility of the PI or SI to obtain informed consent from each subject (or his/her 
LAR who is permitted to provide consent in accordance with local legislation) and study 
partner(s) participating in this study. At all study sites, the PI or SI who obtains informed 
consent must be a physician (such as a neurologist, psychiatrist) or other medically qualified 
person (MD/DO). 
 
Subjects and/or their LAR(s) must give written (signed and personally dated) informed 
consent prior to study entry and before any study specific procedures are undertaken. The 
identified study partner(s) for each subject also must provide written consent to his/her own 
participation as outlined below. Where there is a change of study partner, the new study 
partner must provide written informed consent. 
 
Potential subjects will be assessed for whether they have capacity to understand the ICF and 
give consent. 
 
Where possible, fully informed consent will be obtained from the subject. However, subjects 
entering this study may lack the necessary mental capacity to give fully informed consent. If 
the potential subject is unable to comprehend the ICF, then one or more LARs will be 
required to sign the ICF as required by national and/or local law. In this situation, and 
provided that it is permitted by local legislation, the subject’s agreement to participate in the 
study will still be obtained to his/her best level of understanding and recruitment will not 
proceed if the subject refuses or shows signs of significant distress. 
 
Informed consent can be obtained only after it is confirmed that the subject has a likely 
diagnosis of probable AD or MCI-AD and the aims, methods, anticipated benefits, and 
known potential hazards of the study have been explained to and discussed with the potential 
subject and study partner(s) by the investigator. As subjects are not allowed to receive 
approved AD medication while in the study, they will be informed of the benefits and risks of 
discontinuing and/or not initiating such therapy, as pertinent. If a subject decides to 
discontinue AD medication in order to enter the study, a letter will be sent to his/her primary 
care physician informing him/her of the subject’s decision. 
 

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A subject information sheet, providing a written summary of all relevant information, will be 
given to the potential subject and study partner(s) prior to written informed consent being 
obtained. The study partner(s) will also be given an information sheet. The information sheets 
will make clear that access to the subject’s medical records will be required. It is the 
responsibility of the investigator to ensure that the potential subject and study partner(s) are 
aware of this. The investigator will explain to the potential subject and study partner(s) that 
they are at liberty to refuse to take part in the study or, should they decide to participate, they 
may withdraw from the study at any time. Such a decision will not impinge on the future 
management of the subject. The potential subject and study partner(s) will be allowed as 
much time as they need to decide whether or not to participate in the study and will be 
provided with a contact point where further information about the study may be obtained. 
 
The study includes sites in North America and Europe, two geographic regions that maintain 
descriptions of clinical studies on the internet. As required by the FDA, the ICF must contain 
the following text: “A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include 
information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.” Consistent with European Union law, the 
ICF also indicates that information will be on https://www.clinicaltrialsregister.eu. 
Information regarding other national registries will also be included in the ICF, where 
applicable. 
 
Separate consent may be required by the previous imaging center for transfer of prior 
amyloid PET scan data to the imaging core laboratory for later confirmation of positive 
amyloid status. 
18.4 
Investigator Responsibilities 
The primary responsibility of all investigators participating in the study is for the well-being 
and interests of their subjects, including subjects enrolled in this study. The PI has overall 
responsibility for the conduct of the trial at his/her study site and may delegate specific duties 
to appropriately trained members of his/her research team or to other hospital staff, e.g., the 
pharmacy. Any delegation must be clearly documented in a study site specific delegation list. 
The PI is responsible for the following: 
• 
Performing the study in accordance with ICH GCP 
• 
Ensuring that adequate time and appropriate resources are available to perform the 
study as described in this protocol 
• 
Ensuring that all persons assisting with the trial are adequately qualified, trained, and 
informed about the protocol, trial-related duties, and functions 
• 
Maintaining a list of SIs and other appropriately qualified persons to whom duties 
have been delegated 
• 
Supervising any individual or party to whom the investigator delegates trial-related 
duties and functions conducted at the trial site 
• 
Signing an Investigator Agreement to confirm acceptance and willingness to comply 
with the study protocol 
• 
Maintaining adequate control of study drug and appropriate records of drug 
disposition 
• 
Maintaining adequate records of each subject's participation 
 

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TauRx and the appointed DSMB will constantly evaluate the risk threshold of this particular 
study by assessing the safety profile as well as assessing the safety profile of other ongoing 
studies with the same active moiety. Any changes in the risk profile during the course of the 
study will be communicated to the investigators. In addition, the investigators will review 
AEs at each visit in accordance with the schedule of assessments, and have the right to 
interrupt or discontinue study drug for safety reasons as described in Section 11.4. 
 
The burden/distress associated with participation in this study is addressed in the subject 
information sheet. During the study, the investigators should obtain information from the 
subjects in order to adequately monitor the degree of burden/distress. Subjects are advised 
that they have the right to discontinue study drug and withdraw from the study at any time for 
any reason and should inform the investigators accordingly in order to assist the investigators 
with monitoring activities. 
 
19 
CONFIDENTIALITY AND DATA PROTECTION 
All study-related documentation is confidential, whether obtained by the investigator or 
provided by TauRx or their representative. 
 
The investigator must strictly maintain the confidentiality of subjects in the trial. For all 
documents and materials submitted to TauRx, its designee, or any electronic system (for 
example, eCRFs, samples, specimens, and other documents), the investigator must refer to 
subjects by an identification code. The investigator must keep a separate local log of subject 
codes, names, and addresses for all subjects, including those that were screened but not 
enrolled. This local log must never be uploaded to the electronic Trial Master File (eTMF).  
 
Collecting, processing of, and / or transferring data outside the European Economic Area will 
meet the requirements of EU Directive 2016/679 (General Data Protection Regulation), with 
appropriate transparency notices included in informed consent documentation. In the United 
States, data will be protected consistent with Health Insurance Portability and Accountability 
Act. 
 
Confidentiality of the records identifying each subject shall be maintained. Representatives of 
the Sponsor, such as monitor(s) or auditor(s), IRB/IEC, and pertinent regulatory authorities 
will be permitted direct access to these records and other source data/documents as 
appropriate. 
 
Details of access to the subjects’ data will be fully described within the subject information 
sheet. The consequence of the subject's withdrawal of consent with regards to the use of data 
will also be described. 
 
For the avoidance of doubt, this protocol does not define or describe any data protection 
obligations. These will be dealt with in relevant vendor contracts and subject-facing 
documentation in compliance with relevant local law. 
 

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20 
STORED SAMPLES AND IMAGING DATA 
20.1 
Biosamples 
TauRx is interested in identifying biomarkers that correlate to a drug’s mechanism of action 
or the disease state under study. Finding appropriate biomarkers can give clinicians a clearer 
understanding of the most appropriate patients for a particular drug and the most appropriate 
dose for those patients, offering the potential for improved clinical outcomes. 
 
Storage of samples of plasma and whole blood for possible future research related to 
determination of potential biomarker predictors of LMTM response or surrogates of 
treatment response is a mandatory part of this study, unless country-specific laws and 
regulations prohibit this storage. The samples obtained for genetic testing and the remainder 
of the samples not used for MT concentration determination as described in Section 15.5 will 
be stored. Stored samples will retain the subject identifier and, therefore, will not be stored 
indefinitely. Samples will be stored for a maximum of 8 years after the last subject visit for 
the study; any sample remaining at that time will be destroyed. Because of the exploratory 
nature of these analyses and because the results should not change medical management, 
neither subjects nor investigators will receive the test results. 
 
TauRx’s research procedures dictate that a research plan be prepared before conducting any 
secondary (future) research on stored samples. The research plan would include objectives of 
the research, scientific rationale for the research, a clear indication that the research is being 
conducted as secondary research, how alternative authorization to use and disclose the data 
from secondary research is to be obtained, and how the results are intended to be used. For 
this study, future research could include, but need not be limited to, measurement of plasma 
markers of tau and other protein species, genetic and epigenetic markers which might be 
predictors of LMTM response, or potential surrogate markers of treatment response. Analysis 
of these data could provide an important, minimally invasive biomarker that would guide 
future decisions by clinicians and researchers.  
20.2 
Imaging Data 
Additional exploratory analyses are to be undertaken of the blinded 18F-FDG-PET and MRI 
data generated as part of this study. The analyses will be for scientific research and quality 
control purposes which are separate from the study objectives. A separate plan will capture 
standard procedures and a data transfer agreement will detail the requirements for data to be 
transferred to the imaging center performing the analyses. Data analyses will be conducted in 
line with required data protection requirements, will not reveal potentially sensitive 
information about the study or its participants, and will not lead to potential unblinding of 
study data. The transfer and use of these data will be described in the informed consent form.  
 
21 
QUALITY ASSURANCE AND CLINICAL MONITORING 
21.1 
Standard Procedures 
SOPs will be adhered to for all activities relevant to the quality of the study, including 
protocol compliance, data collection, quality control, and data analyses and reporting. 
 

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QA audits will be conducted on critical phases during the clinical and reporting phases of the 
study. These audits will be carried out by QA personnel, independent of the staff involved in 
the study, according to relevant SOPs. 
 
Clinical monitoring, both primary and secondary, will be performed by trained clinical 
research personnel. Clinical monitoring is an integral part of controlling and securing of data 
integrity and subject safety. The first monitoring visit will be scheduled appropriately after 
the first subject is screened at a site depending on factors that could impact on data reliability, 
some of which are mentioned below. The average monitoring frequency will be described in 
a CMP and will depend on a number of factors, including subject screening and recruitment 
rates, site performance, and quality adherence. Regulatory recommendations and guidelines 
will be followed. Detailed expected monitoring activity will be described in the CMP, which 
will be modified on an ongoing basis to ensure subject safety and data integrity. 
 
The monitor will ensure compliance with the protocol, adherence to regulatory and ICH 
obligations, accurate reporting of AEs, maintenance of trial records including drug 
accountability records, and correct administration of study procedures including supply and 
storage of study materials. ICFs will be reviewed to verify that they are correctly signed and 
dated by the subject and study partner and the medically qualified PI or SI. At each 
monitoring visit, subject data will be reviewed and verified against the medical records. 
 
The monitor will require direct access to laboratory test results and other records needed to 
verify entries on the eCRF. 
 
The investigator (or his/her designated deputy) agrees to cooperate with the monitor and 
other clinical research personnel to ensure that any problems detected in the course of these 
monitoring visits are quickly resolved. 
 
Quality review of data and/or trial documentation may be carried out by or on behalf of the 
Sponsor at any stage. Audits of study sites and/or trial processes may be carried out at any 
stage. 
21.2 
COVID-19 Risk Assessment 
Due to the impact of COVID-19 on this study, the Sponsor has conducted risk assessments to 
identify the potential risk levels and impacts of COVID-19, as well as associated mitigating 
actions for a number of clinical study aspects, including:  direct-to-subject study drug 
shipments, missed study visits and/or clinical assessments, handling of missed post-baseline 
study data, remote site initiation visits, remote monitoring visits, and remote clinical 
assessments (e.g., remote ADAS-cog13). Vendors have also conducted risk assessments 
associated with their services to this study. Risk assessment and management are ongoing 
processes for this study; all risks and mitigations are regularly reviewed and managed, and 
the Sponsor will continue to ensure that additional risk assessments are carried out and 
documented, in particular for any potential impact due to COVID-19, as the situation 
develops and as regulatory guidances are updated. 
 
A summary of alternate arrangements to clinical monitoring that may be implemented due to 
COVID-19 is provided in Section 10.2.2. 
 

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22 
DOCUMENTATION 
The following documents must be provided before or at site initiation: 
• 
Protocol and amendments (if applicable) signed and dated by applicable Sponsor 
representatives, as well as by the investigator 
• 
Regulatory approval (or in absence of document, evidence that study may proceed) 
• 
Signed and dated IEC/IRB approval 
• 
Approved subject and study partner information sheets, ICF, and advertisement for 
recruitment (if any) 
• 
eCRFs 
• 
Confidentiality agreement(s) 
• 
Financial disclosure 
• 
Signed curricula vitae for personnel who have signed the authorized delegation log 
(including PI, all SIs, and designated assistants) 
• 
Authorized signature log/delegation list 
• 
Investigator’s Brochure with signed and dated Investigator’s Brochure receipt 
• 
Signed and dated clinical trial agreement 
• 
Research and development (or institution) approval, if applicable 
• 
Signed and dated indemnity/insurance statement (if applicable) 
• 
Laboratory reference ranges and accreditation for all applicable laboratories (central 
and local, as applicable) 
• 
Pharmacy agreement (if any) 
• 
Imaging center agreement (if any) 
• 
SAE forms 
 
The protocol, its amendments, and any other required documents must be submitted for 
appropriate regulatory review and approval. 
 
The investigator at each study site must generate and maintain adequate records (medical 
records, source documents, and eCRFs) to enable the conduct of this study to be fully 
documented. The eCRF may serve as the primary collection medium for any data (to be 
agreed with the investigator and documented in the Source Document Agreement). Each 
enrolled subject must have an eCRF completed and this must be reviewed and approved by 
the investigator. 
 
A record must be kept of all subjects consenting for the study and subsequently excluded. 
The reason for non-participation in the study should be recorded.  
 
The documents specified by ICH GCP (e.g., copies of protocols, CRF pages, original copies 
of test results, reports, drug dispensing logs, correspondence, records of informed consent, 
and other documents pertaining to the conduct of the study) must be kept on file by the 
investigator for a minimum of 25 years after the end of the clinical trial or for the period of 
time specified by local law for the preservation of hospital subject documents, whichever is 
the longest. No study documents should be destroyed without prior written agreement 
between TauRx and the investigator. Should the site wish to assign the study records to 
another party, or move them to another location, TauRx must be informed. 
 

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The study eTMF will be maintained as specified by ICH GCP. The eTMF shall be archived 
for a minimum of 25 years after the end of the clinical trial in a way that ensures that it is 
readily available, upon request, to the regulatory authorities. 
 
23 
PUBLICATION 
Since this is a multicenter study, the community of investigators and delegated individual 
investigators shall not publish any partial results before the end of the study or before the 
analysis and publication of the results of the entire study. 
 
The investigator and/or institution shall have the right to publish, display, or otherwise 
communicate orally, in writing, or electronically (hereafter a “publication”) the results of 
his/her work conducted under this protocol after 12 months from a New Drug Application or 
equivalent filing, or earlier only with explicit consent of the Sponsor in advance and in 
writing. 
 
Sites and/or investigators must provide the Sponsor with the opportunity to review the 
contents of any proposed abstract or publication concerning the work, including any results of 
the study, in advance of publication, and agree to delay the publication if, in the Sponsor’s 
reasonable view, the publication may prejudice the Sponsor’s intellectual property. The 
Sponsor will make every reasonable effort to consider and release each proposed abstract or 
publication within 60 days of submission. The investigator and/or site will include, where 
possible, comments made by the Sponsor. Authorship will be determined by mutual 
agreement. Access to data will be in accordance with authorship. 
 
24 
INDEMNITY, INSURANCE, AND COMPENSATION 
A clinical trials insurance and product liability insurance policy will be in place to cover the 
conduct of this study. 
 
25 
ADMINISTRATIVE AND FINANCIAL AGREEMENT 
Agreed costs for each participating study site will be met by TauRx. For each study site, an 
agreement will be prepared and signed off by the relevant authority on behalf of the 
institution (e.g., National Health Service Trust, University) and by TauRx or its designee 
before the initiation of the trial. Each PI and SI must also sign a Form FDA 3455 or its 
equivalent to disclose any financial arrangements or interests. 
 
Subjects will be reimbursed by TauRx, through the investigator, for reasonable travel costs to 
and from the study site and accommodation in certain circumstances by prior agreement with 
the Sponsor. 
 
26 
STUDY ADMINISTRATION 
This trial will be conducted in compliance with ICH GCP and other applicable regulatory 
requirements. 
 

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Vendors and/or independent contract personnel will be contracted to manage and monitor the 
trial; to provide services for data management and statistical analysis; to provide regulatory 
advice and services; to handle the reporting of SAEs; to provide services for laboratory, 
imaging, and PK analysis; to package and distribute the clinical trial supplies; and to provide 
QA support and services. 
 
Calibration certification for the following equipment maintained by the site and used to 
generate study data will be confirmed: ECG machines, refrigerated centrifuges, and 
pharmacy temperature loggers. 
 
 

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27 
REFERENCES 
Aduhelm FDA Drug Approval Package, Office of Neurology’s Summary Review 
Memorandum. June 2021. 
 
Al-Hilaly YK, Pollack SJ, Vadukul D, et al.: Alzheimer's disease-like paired helical filament 
assembly from truncated tau protein is independent of disulphide cross-linking. J Mol Biol 
2017;429:3650-65. 
 
Al-Hilaly YK, Pollack SJ, Rickard JE, et al.: Cysteine-independent inhibition of Alzheimer's 
disease-like paired helical filament assembly by leuco-methylthioninium (LMT). J Mol Biol 
2018; https://doi.org/10.1016/j.jmb.2018.08.010. 
 
Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due 
to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s 
Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers 
Dement 2011; 7(3):270-9. 
 
Baddeley TC, McCaffrey JM, Storey JM, et al. Complex disposition of methylthioninium 
redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer's disease. 
J Pharmacol Exp Ther 2015; 352(1):110-18. 
 
Berg L, Miller JP, Storandt M, et al. Mild senile dementia of the Alzheimer type: 2. 
Longitudinal assessment. Ann Neurol 1988; 23(5):477-84. 
 
Bierer LM, Hof PR, Purohit DP, et al. Neocortical neurofibrillary tangles correlate with 
dementia severity in Alzheimer's disease. Arch Neurol 1995; 52(1):81-8. 
 
Birks JS, Harvey R. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database 
of Systematic Reviews, Issue 3, 2004. Article No. CD001190. 
 
Bowie P, Branton T, Holmes J. Should the Mini Mental State Examination be used to 
monitor dementia treatments? Lancet 1999; 354(9189):1527-8. 
 
Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta 
Neuropathol 1991; 82(4): 239-59. 
 
Courtney C, Farrell D, Gray R, et al.  AD2000 Collaborative Group.  Long-term donepezil 
treatment in 565 patients with Alzheimer’s disease (AD2000): Randomised double-blind 
trial.  Lancet. 2004;363:2105-15 
 
Fillenbaum GG, Peterson B, Morris JC. Estimating the validity of the Clinical Dementia 
Rating Scale: the CERAD experience. Aging (Milano) 1996; 8(6):379-85. 
 
Fitzpatrick AWP, Falcon B, He S, et al.: Cryo-EM structures of tau filaments from 
Alzheimer’s disease. Nature 2017; 547:185-90. 
 

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Folstein MF, Folstein SE, McHugh PR. “Mini-mental State”: A practical method for grading 
the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12(3):189-98. 
 
Friston K, Ashburner J, Kiebel S, et al. (eds) Statistical Parametric Mapping: The analysis of 
functional brain images. 1st ed. Amsterdam: Academic Press; 2007. 
 
Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for 
clinical trials in Alzheimer's disease. The Alzheimer's Disease Cooperative Study. Alzheimer 
Dis Assoc Disord 1997; 11(Suppl 2):S33-9.  
 
Galasko D, Schmitt F, Thomas R, et al. Detailed assessment of activities of daily living in 
moderate to severe Alzheimer's disease. J Int Neuropsychol Soc 2005; 11(4):446-53. 
 
Gauthier S, Feldman HH, Schneider LS, et al. Efficacy and safety of tau-aggregation 
inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, 
controlled, double-blind, parallel-arm, phase 3 trial. Lancet 2016; 388:2873-84. 
 
Hughes CP, Berg L, Danziger WL, et al. A new clinical scale for the staging of dementia. Br 
J Psychiatry 1982; 140:566-72.  
 
Lockhart SN, Baker SL, Okamura N, et al. Dynamic PET measures of tau accumulation in 
cognitively normal older adults and Alzheimer’s disease patients measured using 
18F THK-5351. PLoS One 2016; 11(6):e0158460. 
 
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to 
Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s 
Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers 
Dement 2011; 7(3):263-9. 
 
Mohs RC, Knopman D, Petersen RC, et al. Development of cognitive instruments for use in 
clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale 
that broaden its scope. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc 
Disord 1997;11(Suppl 2):S13–21. 
 
Morris JC, McKeel DW Jr, Fulling K, et al. Validation of clinical diagnostic criteria for 
Alzheimer's disease. Ann Neurol 1988; 24(1):17-22. 
 
Morris JC, Ernesto C, Schafer K, et al. Clinical Dementia Rating training and reliability in 
multicenter studies: the Alzheimer's Disease Cooperative Study experience. Neurology 1997; 
48(6):1508-10. 
 
Mukaetova-Ladinska EB, Garcia-Siera F, Hurt J, et al. Staging of cytoskeletal and β-amyloid 
changes in human isocortex reveals biphasic synaptic protein response during progression of 
Alzheimer's disease. Am J Pathol 2000; 157(2):623-36. 
 
National Institute for Clinical Excellence (NICE) Technology Appraisal Guidance No 19. 
Guidance for the use of donepezil, rivastigmine and galantamine for the treatment of 
Alzheimer’s disease 2001, London: NICE. 
 

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Olin J, Schneider L. Galantamine for dementia due to Alzheimer’s disease. Cochrane 
Database of Systematic Reviews, Issue 3, 2002, article No. CD001747. 
 
Pontecorvo MJ, Devous MD, Sr., Navitsky M, et al. Relationships between flortaucipir PET 
tau binding and amyloid burden, clinical diagnosis, age and cognition. Brain 2017; 140:748-
63. 
 
Reisberg B, Doody R, Stöffler A, et al. Memantine in moderate-to-severe Alzheimer's 
disease. N Engl J Med 2003; 348(14):1333-41. 
 
Riedel G, Klein J, Niewiadomska G, et al.  Mechanisms of anticholinesterase interference 
with tau aggregation inhibitor activity in tau-transgenic mouse model.  Curr Alzheimer Res.  
2020;17(3):285-296. 
 
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J 
Psychiatry 1984; 141(11):1356-64. 
 
Schelter BO, Shiells H, Baddeley TC, et al. Concentration-dependent activity of 
hydromethylthionine on cognitive decline and brain atrophy in mild to moderate Alzheimer's 
disease. J Alzheimers Dis 2019;72(3):931-46 
 
Schneider LS, Dagerman KS, Higgins JP, et al. Lack of evidence for the efficacy of 
memantine in mild Alzheimer disease. Arch Neurol 2011; 68(8):991-8. 
 
Staff RT1, Murray AD, Deary IJ, et al. What provides cerebral reserve? Brain 2004; 127(Pt 
5):1191-9. 
 
Tombaugh TN, McIntyre NJ. The Mini-Mental State Examination: A comprehensive review. 
J Am Geriatr Soc 1992; 40(9):922-35. 
 
Wilcock GK, Gauthier S, Frisoni GB, et al. Potential of low dose leuco-methylthioninium 
bis(hydromethanesulphonate) (LMTM) monotherapy for treatment of mild Alzheimer’s 
disease: Cohort analysis as modified primary outcome in a Phase III clinical trial. J 
Alzheimer’s dis 2018; 61:435-57. 
 
Wischik CM, Lai RY, Harrington CR. Modelling prion-like processing of tau protein in 
Alzheimer’s disease for pharmaceutical development. In: Brain Microtubule Associated 
Proteins: Modifications in Disease. Eds. Avila J, Brandt R, Kosik KS 1997. Amsterdam: 
Harwood Academic Publishers, 185-241. 
 
Wischik CM, Novak M, Edwards PC, et al.: Structural characterization of the core of the 
paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 1988a; 85:4884-8. 
 
Wischik CM, Novak M, Thøgersen HC, et al.: Isolation of a fragment of tau derived from the 
core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 1988b; 
85:4506-10. 
 
Wischik CM, Staff RT, Wischik DJ, et al. Tau aggregation inhibition therapy: an exploratory 
Phase 2 study in mild or moderate Alzheimer’s disease. J Alzheimer’s Dis 2015; 44(2):705-
20. 

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Xia CJ, Makaretz SJ, Caso C, et al. Association of in vivo [18F] tau PET imaging results with 
cortical atrophy and symptoms in typical and atypical Alzheimer disease. JAM Neurol 2017; 
74:427-36. 
 

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28 
APPENDICES 
28.1 
Disallowed Treatments and Windows  
28.1.1 
Disallowed Medical Food / Medications Beginning 90 Days 
Before Baseline and During the Study 
Medical food 
Souvenaid® 
 
Antipsychotic 
Clozapine 
 
Antiepileptic drugs 
Carbamazepine 
Primidone 
Valproate 
 
Anti-malarial drugs 
Dapsone 
Primaquine and related antimalarials 
 
Anesthetics 
Benzocaine or other local anesthetics used chronically 
 
Investigational product for cognition (unless confirmed to have been randomized to placebo) 
 
 
28.1.2 
Disallowed Medications Beginning 60 Days Before Baseline 
and During the Study 
Alzheimer’s disease drugs 
Donepezil 
Galantamine 
Rivastigmine 
Memantine 
 
 
28.1.3 
Disallowed Treatments Beginning 28 Days Before Baseline 
and During the Study 
Investigational drug (other than for cognition), biologic, device, or medical food  
 
 
 

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28.2 
Study Blood Assessments 
 
Please see schedule of assessments for timing of blood sample collections. 
 
Clinical Chemistry 
Hematology 
Sodium 
Red blood cell (RBC) count 
Potassium 
Hemoglobin 
Chloride 
Hematocrit 
Bicarbonate 
MCV, MCH, MCHC 
Total protein 
RBC distribution width 
Albumin 
Platelet count 
Calcium 
White blood cell (WBC) count 
Phosphorus 
WBC Differential (% and absolute) 
Glucose 
• Neutrophils 
Blood urea nitrogen 
• Eosinophils 
Creatinine 
• Basophils 
Indirect bilirubin 
• Lymphocytes 
Direct bilirubin 
• Monocytes 
Total bilirubin 
Reticulocytes (absolute and relative) 
Alkaline phosphatase 
 
Alanine aminotransferase 
 
Aspartate aminotransferase 
 
Gamma-glutamyl transferase 
 
Lactate dehydrogenase 
 
 
 
Other Tests 
 
Serum Pregnancy test 
 
Vitamin B12 / Folate 
 
Haptoglobin 
 
Thyroid Stimulating Hormone (TSH) 
 
Glucose-6-Phosphate Dehydrogenase (G6PD) 
ApoE (in subjects who consent for this) 
 
Blood sample for MT concentration  
 
 
 
 

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28.3 
Education / Occupation 
28.3.1 
Education 
Q: How many years did you spend in full time education before the age of 26?  
 
(integer)_ years 
 
Q: How would you best describe your level of education? 
1. 
Elementary 
2. 
Some high school / secondary 
3. 
Completed high school / secondary 
4. 
Some post high school / secondary education 
5. 
College education graduate 
6. 
Post graduate education (including high professional qualification) 
 
28.3.2 
Occupation 
 
Q: What was your main occupation during your working life? 
(text)
 
 
(Responses will be coded using The Standard Operational Classification, 2010, 
Volume 2 The Coding Index, UK Office for National Statistics)  
 

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28.4 
Summary of Changes to the Protocol 
28.4.1 
Protocol Version 2.0 
The protocol for study TRx-237-039 (Version 1.0 dated 23 Aug 2017) has been revised 
(Version 2.0) to clarify the assessments that will be made at various visits as follows: 
• The blood will be collected during Visit 2 and Visit 3 (not at Visit 2 or Visit 3). 
• A spelling error was corrected (dimethyl to desmethyl). 
• Clarification was made that the time of dose from the previous day will be collected. 
• A redundant paragraph was removed. 
• Specifications for procedure of blood collection were removed from the protocol as 
these details will be presented in the laboratory manual. 
• The Appendices were renumbered and the table of contents updated. 
• Minor edits, such as expansion of abbreviations, were made. 
 
The sections affected by these changes are detailed below. 
 
Summary of Changes 
Affected Section(s) in Revised Protocol 
(Version 2.0) 
Targeted examinations will be performed 
pre-dose and approximately 3 hours after 
administration of first dose of study drug 
(Visit 2); these are to be repeated as needed 
for subjects who remain in the clinic longer 
than 4 hours. Thereafter, targeted 
examinations are to be performed at each 
subsequent visit or upon early termination. 
• Synopsis, Safety and tolerability  
• Table 10-1 Schedule of Assessments,  
foot note ‘f’ 
• Section 15.2, Bullet #7 
Added the following missing bullet to the 
Synopsis: 
TSH, vitamin B12, folate, haptoglobin and 
G6PD will be measured at Screening only. 
Standard clinical laboratory testing, 
including hematology, blood chemistry, 
will be performed at Screening and each 
visit thereafter including an early 
termination, if applicable. A blood sample 
for a serum pregnancy test will be collected 
for all women of childbearing potential at 
Screening and at each subsequent visit, or 
upon early termination. 
• Synopsis, Safety and tolerability 
Several updates were made to the various 
statistical analyses planned  
• Section 17.8 including subsections 
The blood will be collected during Visit 2 
and Visit 3 (not at Visit 2 or Visit 3) 
• Table 10-1 Schedule of Assessments,  
foot note ‘q’ 
A redundant bullet was removed 
• Synopsis, Safety and Tolerability 
• Section 15.2 
Spelling changed from dimethyl to 
desmethyl 
• Synopsis, safety and tolerability, Bullet #5 
• Section 15.2 Bullet #5 
• Section 15.5.2, line 2 

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Summary of Changes 
Affected Section(s) in Revised Protocol 
(Version 2.0) 
The time of dose from the previous day will 
be collected 
• Table 10-1 Schedule of Assessments,  
foot note ‘q’ 
• Section 15.4.1 Paragraph 1 
The volume of whole blood, centrifuge 
speed and the number and type of blood 
collection tubes were removed 
• Section 15.4.1.1 
The Appendices were renumbered and the 
Table of contents updated 
• Table of Contents 
• Appendices 30.3 and 30.3.1 
 
28.4.2 
Protocol Version 2.1 
The protocol for study TRx-237-039 (Version 2.0 dated 31 Aug 2017) was updated to make 
administrative changes to provide the latest contact details of the Sponsor and the Sponsor’s 
personnel, and the details of the Central Laboratory. 
 
Summary of Changes 
Affected Section(s) in Revised Protocol 
(Version 2.1) 
The address and phone numbers of the 
Sponsor and the Sponsor’s personnel was 
updated.  
 
• Cover page 
• Section 3 Protocol Approval 
• Section 4 Responsible Personnel 
 
Version number was changed from 2.0 to 
2.1 and date of the protocol was changed 
from 31 Aug 2017 to 25 Oct 2017.  
• Cover page 
• Headers 
• Footers 
• Section 5 Investigator Signature Sheet 
The Central Laboratory name, address and 
phone numbers were added. 
• Section 4 Responsible Personnel 
 

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28.4.3 
Protocol Version 3.0 
The protocol for Study TRx-237-039 (Version 2.1 dated 25 October 2017) was updated to 
modify the study design to a 39-week treatment period (from 26 weeks) in subjects with early 
AD (i.e., by the inclusion of subjects with MCI-AD in addition to mild AD). As a result of 
the addition of a cognitive/functional Composite Scale (to be finalized prior to database lock 
and unblinding) and a third treatment arm (LMTM 16 mg/day), the sample size has been 
increased to approximately 375 subjects (from 180 subjects). Numerous changes have been 
made to the protocol to clarify and/or specify the timing and sequence of assessments.  
 
A summary of the key changes and primary affected sections is provided below (as the 
Synopsis is affected by the majority of the changes, it is not listed).   
 
Administrative changes have also been made, such as adding the EudraCT number issued for 
this study (2017-003558-17); updating references to the 2013 (current) version of the 
Declaration of Helsinki, the ICH Integrated Addendum to ICH E6(R2) Guidelines for GCP, 
and GDPR; and updating parties and contact information for responsible parties in Section 4. 
Additional statistical analyses, including of derived endpoints (such as the Composite Scale) 
and the higher treatment group, are now described. While a brief summary of planned 
statistical analyses of primary and secondary endpoints is described and a list of possible 
exploratory analyses is included, these will be finalized in a Statistical Analysis Plan prior to 
database lock and unblinding. These are not described below but are enumerated in a separate 
detailed summary of changes document. 
 
Summary of Changes 
Primary Affected Sections in Revised Protocol 
(Version 3.0) 
Background 
The recently adopted United States Abbreviated 
Names of hydromethylthionine (LMT) and 
hydromethylthionine mesylate (LMTM, drug 
substance) have been added 
Section 8.1.1 Investigational Product 
Section 12.1.1 Active Ingredient 
Nonclinical and clinical data have been updated to be 
reflective of most current version of Investigator’s 
Brochure (v. 20.0); references have been updated as 
pertinent 
Section 8.1.2 Nonclinical Data  
Section 8.1.3 Clinical Data 
Objectives 
A new clinical efficacy scale has been added as a 
gated primary objective; this Composite Scale is to 
be derived from cognitive/functional items selected 
from the ADAS-cog11 and ADCS-ADL23  
Section 8.2 Rationale 
Section 9.1 Primary Objectives 
Section 15.3.3 Composite Scale 
Section 17 Statistical Analysis 
Section 17.1.2 Primary Efficacy Endpoint 
Section 17.2 Number of Subjects and Sample Size 
Calculation 
Section 17.4.1 Hypothesis 
Section 17.4.7 Subgroup Analyses 
Section 17.4.8.4.1 Multiple Imputation 
Section 17.5 Exploratory Analyses 
The secondary clinical endpoint has been changed 
from the ADAS-cog11 to the ADAS-cog13 as 
potentially more sensitive to change in subjects with 
milder disease 
Section 9.2 Secondary Objectives 
10.4.2.2 Clinical Efficacy Assessments 
15.3.1 ADAS-cog 
17.1.4 Other Secondary Endpoints 
17.5 Exploratory Analyses 

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Summary of Changes 
Primary Affected Sections in Revised Protocol 
(Version 3.0) 
The sequence of the secondary objectives has been 
modified and the examination of associations 
between the 18F-FDG-PET regions of interest and the 
Composite Scale and the examination of associations 
between brain MRI endpoints and ADAS-cog13, 
ADCS-ADL23, and the Composite Scale have been 
added. Comparison of the LMTM 16 mg/day and 
placebo groups has also been added. 
Section 9.2 Secondary Objectives 
Section 17.1.3 Secondary Imaging Endpoints 
Section 17.1.4 Other Secondary Endpoints 
Exploratory analyses and exploratory analyses that 
are comparisons with external data are now listed 
only in the Statistical Analysis section. 
Section 9.3 (Section removed) 
Section 9.4 (Section removed) 
Section 17.5 Exploratory Analyses 
Study Design 
The duration of the study has been increased from 6 
to 9 months; the numbers of visits, schedules of 
safety and efficacy assessments, and statistical 
analyses have also been updated accordingly.   
Section 10.1 General Description 
Section 10.3 Duration 
Section 10.4.2 Baseline and Post-randomization 
Assessments 
Section 10.4.2.1 Imaging Efficacy Assessments 
Section 10.4.2.2 Clinical Efficacy Assessments 
Section 10.4.2.3 Safety Assessments 
Section 12.2 Study Regimens 
Section 15.2.3 Imaging Methods for Efficacy 
Section 15.3 Clinical Assessments and Raters 
Section 15.4 Safety Assessment and Procedures 
Section 17 Statistical Analysis 
Total study duration for an individual subject has 
been increased from 36 weeks to up to 54 weeks, 
including a Screening period of up to 15 weeks 
(105 days) and a Treatment period of 39 weeks, 
which is updated throughout the protocol. As a result, 
the total duration of the overall study has been 
increased to at least 24 months, depending on 
recruitment rate.   
Section 10.1 General Description 
Section 10.3 Duration 
A third treatment arm, LMTM 16 mg/day, has been 
added and the total sample size increased from 180 
subjects (90 each randomized to placebo and LMTM 
8 mg/day) to 375 subjects (150 each randomized to 
placebo and LMTM 8 mg/day and 75 randomized to 
LMTM 16 mg/day). As many as 900 subjects may be 
screened (increased from 360). 
Section 10.1 General Description 
10.2 Study Population 
17.2 Number of Subjects and Sample Size 
Calculation 
The follow-up telephone contact, previously 
scheduled to occur 4 weeks after the last dose of 
study drug, has been deleted; the protocol clarifies 
that investigators are to follow any unresolved 
adverse events to resolution or acceptable 
stabilization consistent with their medical judgment. 
Section 10.1 General Description 
Section 10.4.2 Baseline and Post-randomization 
Assessments 
Section 10.4.2.3 Safety Assessments 
Section 11.4 Discontinuations / Withdrawals 
Section 15.4 Safety Assessment and Procedures 
Section 16.2 Eliciting Adverse Event Information 
Section 16.7 Serious Adverse Event Reporting 
Patient Population (Inclusion and Exclusion Criteria) 
The patient population has been expanded to include 
subjects with mild cognitive impairment due to 
Alzheimer’s disease (MCI-AD), such that the study 
is now being performed in subjects with early 
Alzheimer’s disease (AD) (inclusive of both mild AD 
and MCI-AD) 
Section 8.2 Rationale 
Section 9 Objectives 
Section 10.1 General Description 
Section 10.2 Study Population 
Section 10.4.1.1 Diagnostic and Cognitive Eligibility 
Assessments 
Section 11.1 Inclusion Criteria 

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Subjects must be able to give their own consent; 
consent by a caregiver on behalf of the subject is no 
longer allowed 
Section 9.2 Secondary Objectives 
Section 10.4.1 Screening Assessments 
Section 10.4.2 Baseline and Post-randomization 
Assessments 
Section 10.4.3 Other Assessments 
Section 11.1 Inclusion Criteria 
Section 15.5.3 Genotyping 
Section 18.3 Informed Consent 
A PET scan positive for amyloid is now required for 
eligibility (either by prior documentation or 
undertaken for the study)  
Section 10.1 General Description 
Section 10.2 Study Population 
Section 10.4.1 Screening Assessments 
Section 10.4.1.1 Diagnostic and Cognitive Eligibility 
Assessments 
Section 11.1 Inclusion Criteria 
Section 10.4.1 Screening Assessments 
Section 15.1 Demographic Data/Medical History 
Section 15.2.1 General Considerations 
Section 15.2.3.1 18F-FDG-PET 
Section 18.3 Informed Consent 
The acceptable disease severity based on MMSE has 
been expanded from 20-25 to 20-27; randomization 
will now be stratified based on a MMSE of 20-25 
and 26-27 (in a 2:1 ratio, monitored and controlled at 
the site level and capped as needed at the study level) 
Section 10.1 General Description 
Section 10.2 Study Population 
Section 11.1 Inclusion Criteria 
Section 11.3 Re-screening 
Section 12.3 Randomization 
Section 17.4.7 Subgroup Analyses 
Screening Global CDR score of 0.5 now has a further 
requirement that subjects have a score of >0 in one of 
the functional domains (Community Affairs, Home 
and Hobbies, or Personal Care)  
Section 10.2 Study Population 
Section 11.1 Inclusion Criteria 
Section 11.3 Re-screening 
Subjects taking an AChEI and/or memantine at 
Screening may now be enrolled, provided they are 
willing to discontinue such medication; the screening 
period in such subjects has been expanded to 15 
weeks to allow for the requisite eligibility 
assessments prior to the discontinuation of such 
medication (at least 60 days before Baseline 
18F-FDG-PET); if subjects discontinue these 
medications, a letter is to be sent to the primary care 
physicians to inform them of this decision 
Section 10.1 General Description 
Section 10.4.1 Screening Assessments 
Section 10.4.1.1 Diagnostic and Cognitive Eligibility 
Assessments 
Section 10.4.2 Baseline and Post-randomization 
Assessments 
Section 11.1 Inclusion Criteria 
Section 13.1 AChEI and/or Memantine 
As a result of the increased sample size, at least 100 
sites may be required (increased from 60) and sites 
from geographical regions outside of North America 
and Europe may also be sought 
Section 10.1 General Description 
Section 10.2 Study Population 
Section 12.3 Randomization 
Section 17.4.7 Subgroup Analyses 
Additional exclusion criteria: 
• Any physical disability that would prevent 
completion of study procedures or assessments 
(with examples provided) 
• Use of Souvenaid® within the 90 days prior to 
Baseline 
Section 11.2 Exclusion Criteria 

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Modifications of exclusion criteria include: 
• Moderate to severe sleep apnea, even if 
adequately controlled (previously, subjects who 
were controlled were accepted) 
• Carbamazepine is not allowed (previously, use for 
treatment of restless legs was permitted) 
• G6PD deficiency has been defined based on 
WHO classification (<60% of normal, i.e., 
<6.1 U/g Hgb) 
• Use of olanzapine is no longer exclusionary (the 
only disallowed antipsychotic is clozapine) 
• Need for a cardiology consult in subjects with left 
bundle branch block has been removed 
• The acceptable window for prior use of an 
investigational product for cognition has been 
reduced to 90 days (from 120 days) prior to 
Baseline (rather than Screening) 
Section 11.2 Exclusion Criteria 
Appendix 28.1 
Study Drug 
With the addition of a third treatment arm, all 
subjects will now receive four tablets daily, two in 
the morning and two in the evening, to maintain the 
study blind. 
12.2 Study Regimens 
The study drug wallet now contains 28 tablets (rather 
than 14 tablets) 
12.4 Packaging, Labeling, and Storage 
Assessments 
Information regarding education and main 
occupation will now be collected at Screening 
Section 15.1 Demographic Data / Medical History 
Section 17.6 Demographic and Baseline 
Characteristics 
Appendix 28.3 Education / Occupation 
In subjects with extended Screening, medical 
assessments for eligibility may need to be repeated if 
initial assessments were more than 42 days prior to 
Baseline 
Section 10.4.1 Screening Assessments 
Section 10.4.1.2 Other Medical Screening 
Assessments 
Brain MRI hyperintensities will now be quantified 
Section 10.4.2.1 Imaging Efficacy Assessments 
Section 15.2.3.2 MRI 
Section 17.5 Exploratory Analyses 
MMSE and CDR sum of boxes (which are obtained 
at Screening) will now also be assessed after 
39 weeks, or upon early completion of the study  
Section 10.1 General Description 
Section 10.4.2 Baseline and Post-randomization 
Assessments 
Section 10.4.2.2 Clinical Efficacy Assessments 
Section 15.3 Clinical Assessments and Raters 
Section 17.5 Exploratory Analyses 
Whole blood will also be assessed for MT, 
N-desmethyl MT, and total MT concentrations (in 
addition to plasma)  
Section 10.1 General Description 
Section 10.4.2 Baseline and Post-randomization 
Assessments 
Section 15.5.1 MT Concentration 
Section 15.5.1.1 Procedure for Blood Sample 
Collection 
Section 17.8 Other Data 
A urine sample will be collected at the final visit 
(following all safety and efficacy assessments) for 
determination of color by the central laboratory; 
results will not be reported to the site  
Section 10.1 General Description 
Section 10.4.3 Other Assessments 
Section 15.5.2 Urine Color 
Section 17.8 Other Data 
Other 
Malignancies (with the exception of non-melanoma 
skin cancers) are to be to be reported as ADRs to 
Health Canada   
Section 16.9 Malignancies 
Section 17.7 Safety Analysis 

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Stored samples may be kept for up to 8 years for 
future, as yet unspecified, analyses; consent to such 
storage is mandatory for participation in the study   
Section 20 Stored Samples 
 
 
 

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28.4.4 
Protocol Version 4.0 
The protocol for Study TRx-237-039 (Version 3.0 dated 31 May 2018) has been updated to 
include administrative changes, as the responsible party for study management, monitoring, 
and pharmacovigilance has changed (previously PAREXEL International, now Syneos 
Health). Additional modifications and clarifications have been incorporated with respect to 
the Sponsor contact details, objectives and statistical analyses, background, study population, 
informed consent, study assessments, documentation, data protection, and study 
administration. 
 
A summary of the key changes and affected sections is provided below.   
 
Summary of Changes 
Affected Sections in Revised Protocol  
(Version 4.0) 
Sponsor Information 
The contact details for the Sponsor have been clarified to 
indicate that the company headquarters are in Singapore, 
while the operational location is in the United Kingdom. 
Cover page 
Compliance Statement 
Compliance statement regarding ICH GCP further 
clarified to include ICH E6(R1) in those jurisdictions 
where ICH E6(R2) is not yet implemented by the 
regulatory authorities. Reference to the Declaration of 
Helsinki has been clarified to refer to the current 
applicable version. 
Section 2 GCP Compliance Statement 
Section 5 Investigator Signature Sheet 
Section 18 Regulatory and Ethics 
Responsible Personnel 
Changes have been made to include updated contact 
information for the Global Project Manager, North 
America Medical Monitor, Europe Medical Monitor, and 
Pharmacovigilance, as the responsible party is now 
Syneos Health (previously PAREXEL International); the 
procedures for safety and regulatory/ethics reporting have 
been updated accordingly.  Additional telephone numbers 
have been added to the list of DSSL 24-hour Medical 
Contacts, as the study will also be conducted in Italy and 
Spain.  The vendor for recruitment services (ThreeWire) 
has been removed. 
Section 4 Responsible Personnel 
Section 16.7 Serious Adverse Event Reporting 
Section 16.9 Malignancies 
Section 16.10 Reporting of Pregnancy 
Section 18 Regulatory and Ethics 
Section 18.1 Approval of the Protocol and 
Amendments 
Objectives and Statistical Analyses 
The evaluation of the outcomes described in the Primary 
and Secondary Objectives for LMTM 16 mg/day and 
placebo has been clarified in Objective Nos. 6 and 12, 
and an evaluation of the outcomes of selected endpoints 
for pooled doses of LMTM 8 mg/day and 16 mg/day 
compared to placebo has been added as Objective No. 13. 
The various LMTM 8 mg/day as well as LMTM 
16 mg/day and pooled comparisons to placebo are 
described in the SAP. 
Synopsis 
Section 9.2 Secondary Objectives 
Section 17 Statistical Analysis 
Background 
A new reference has been added regarding cysteine-
independent inhibition of Alzheimer's disease-like paired 
helical filament assembly by leuco-methylthioninium 
(Al-Hilaly et al., 2018). 
Section 8.1.1 Investigational Product 
Section 27 References 
The summary of PK data from studies in subjects with 
renal and hepatic impairment has been clarified; results 
have been added from a completed study in healthy older 
volunteers. 
Section 8.1.3.1 Pharmacokinetics 

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Study Population 
Up to approximately 1500 subjects may be screened for 
the study (increased from 900). 
Section 10.2 Study Population 
Informed Consent 
Clarification that at all study sites, the PI or SI who  
obtains informed consent must be a physician (such as a 
neurologist, psychiatrist) or other medically qualified 
person.  
Section 10.4.1 Screening Assessments 
Section 18.3 Informed Consent 
Section 21 Quality Assurance and Clinical 
Monitoring 
Study Assessments 
Clarification that the initial ophthalmological examination 
for subjects with lens implants will be performed prior to 
the first dose of study drug (during the Screening 
procedures or as part of the Baseline assessments), rather 
than being limited to Screening. 
Synopsis 
Section 10.1 General Description 
Section 10.4.1 Screening Assessments 
Section 10.4.1.2 Other Medical Screening 
Assessments 
Section 10.4.2 Baseline and Post-randomization 
Assessments 
Section 10.4.2.3 Safety Assessments 
Section 15.4 Safety Assessments and Procedures 
Baseline characteristics to be collected include smoking 
history and history of lens implantation.  
Section 15.1 Demographic Data/Medical History 
 
Additional instruction for investigators assessing AEs 
during the study includes asking one or more questions to 
evaluate suicidal ideation and behavior at each in-clinic 
visit, as recommended by the U.S. FDA. Questions are to 
be addressed to both subjects and their study partners.  
Section 16.2 Eliciting Adverse Event Information 
Clarification provided that lens discoloration reported 
during ophthalmological examination is to be reported as 
an SAE. 
Section 16.7 Serious Adverse Event Reporting 
Medical history and adverse events will be coded using 
MedDRA Version 20.1. 
Section 17.6 Demographic and Baseline 
Characteristics 
Direct bilirubin and alkaline phosphatase have been 
added to clinical chemistry laboratory assessments. 
Section 28.2 Study Blood Assessments 
Documentation 
Further details regarding archiving and management of 
the eTMF are provided. The requirements for document 
retention and archiving have been clarified to refer to a 
minimum of 25 years after the end of the clinical trial. 
Section 7 Abbreviations 
Section 22 Documentation 
Clarification that all deviations identified at or by the site 
will be reported to the study monitor, and deviations from 
the SAP (if any) will be noted in the clinical study report. 
Section 17 Statistical Analysis 
Section 18 Regulatory and Ethics 
Data Protection 
Clarification that data protection obligations are not 
defined in the protocol, but rather are to be described in 
vendor contracts and subject-facing documentation (e.g., 
in appropriate transparency notices included in informed 
consent documentation) in compliance with relevant local 
laws. 
Section 19 Confidentiality and Data Protection 
Study Administration 
Reference to pipettes has been removed from calibration 
certification, as the pipettes provided in the laboratory 
kits are disposable. 
Section 26 Study Administration 
 

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28.4.5 
Protocol Version 4.1 
The protocol for Study TRx-237-039 (Version 4.0 dated 24 August 2018) has been revised in 
this administrative amendment to include an additional Sponsor signatory for Medical 
Oversight, and to remove references to specific personnel for Medical Monitoring 
representation in North America and Europe.  The most current Medical Monitoring contact 
information is now provided by cross-reference to the Site Contact List in the Investigator 
Site File. 
 
A summary of the changes and affected sections is provided below.   
 
Summary of Changes 
Affected Sections in Revised Protocol  
(Version 4.1) 
Protocol Signatories 
An additional Sponsor signatory has been added for 
TauRx Medical Oversight. 
Section 3 Protocol Approval 
Responsible Personnel 
Specific names and contact information have been 
removed for personnel responsible for medical 
monitoring (i.e., the North America Medical Monitor and 
Europe Medical Monitor).  The most current contact 
information is now provided by cross-reference to the 
Site Contact List in the Investigator Site File. 
Section 4 Responsible Personnel 
 

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28.4.6 
Protocol Version 5.0 
The protocol for study TRx-237-039 (Version 4.1 dated 9 November 2018) has been revised 
primarily to include the following modifications: 
 
• The study design now includes two phases, including the double-blind treatment 
period (now 12 months, extended from 9 months) with subjects randomized to 
LMTM 16 mg/day, LMTM 8 mg/day, or placebo, followed by an open-label, 
delayed-start treatment period with LMTM 16 mg/day for an additional 52 weeks; 
study visits and schedules of assessments have been modified accordingly 
 
• The study population now includes subjects with early to mild-moderate AD 
(previously only early AD), and the number of randomized subjects has been 
increased to approximately 450 subjects (previously 375 subjects) 
 
• The primary objectives for the double-blind treatment period now pertain to 
comparing LMTM 16 mg/day with placebo for the co-primary endpoints of 
ADAS-cog11 and ADCS-ADL23 (difference in temporal lobe 18F-FDG-PET change in 
SUVR and the Composite Scale are no longer primary objectives), and for assessing 
safety and tolerability; secondary objectives have been modified to include 
comparisons of LMTM 16 mg/day with placebo in whole brain atrophy as measured 
by MRI, to restrict the 18F-FDG-PET endpoints to subjects with CDR 0.5 at 
Screening, and to compare the LMTM dose of 8 mg/day for selected endpoints 
 
Modifications have also been made to administrative information, criteria for subject 
enrollment and eligibility for the EAP, study drug supplies for the placebo group (now 
including a urinary discolorant to maintain blinding during the double-blind treatment 
period), and study assessments. A summary of the key changes and primary affected sections 
is provided below (as the Synopsis is affected by the majority of the changes, it is not listed).   
 
Minor revisions have also been incorporated for clarity; these are not described below but are 
enumerated in a separate detailed summary of changes document. 
 
Summary of Changes 
Affected Sections in Revised Protocol  
(Version 5.0) 
Administrative 
The GCP compliance statement has been modified to 
indicate that the study will be conducted in compliance with 
the principles contained in the Declaration of Helsinki, 
rather than include reference to a specific version. 
Section 2 GCP Compliance Statement 
Section 5 Investigator Signature Sheet 
Section 18 Regulatory and Ethics 
The statistician for the study has been changed to Bjoern 
Schelter, PhD (Data Analytics and Biostatistics Lead for 
TauRx). 
Section 3 Protocol Approval 
The TauRx Global Project Leads for this study are now 
Sotereos Gates and Alison Walker (previously Sean 
Neville). 
Section 4 Responsible Personnel 
A Coordinating Investigator, Serge Gauthier, C.M., C.Q., 
MD, FRCPC, is now identified. 
Section 4 Responsible Personnel 
The current 24-hour medical contact (DSSL) information is 
also provided by cross-reference to the Site Contact List in 
the Investigator Site File. 
Section 4 Responsible Personnel 

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For image hypersensitivities, Aberdeen Biomedical Imaging 
Centre has been removed as the data output will be 
provided by BioClinica, Inc. 
Section 4 Responsible Personnel 
Study Population 
The protocol now includes subjects with early to mild-
moderate AD rather than only those with early AD.  MMSE 
and CDR severity scores at Screening have been modified 
to reflect this change (i.e., MMSE 16 to 27 [inclusive] and 
Global CDR 0.5 to 2 [if 0.5, including a score of >0 in one 
of the functional domains]).  An additional stratification 
level for MMSE severity (i.e., 16-19) has been added, with 
a target of approximately 2:3:1 for MMSE scores of 16-19, 
20-25, and 26-27, respectively. 
Cover Page 
Section 10.1 General Description 
Section 10.2 Study Population 
Section 11.1 Inclusion Criteria 
Section 11.3 Re-screening  
Section 12.3 Randomization 
Section 17 Statistical Analysis 
Section 17.2 Number of Subjects and Sample Size 
Calculation 
The study will be conducted in approximately 150 study 
sites in North America and Europe (previously planned to 
be at least 100 study sites in North America, Europe, and 
Rest of World).  Approximately 2000 subjects (previously 
up to 1500 subjects) may be screened. 
Section 10.2 Study Population 
Section 12.3 Randomization 
Section 17.4.9 Subgroup Analyses 
Clarification provided that, at Screening, an interview and 
examination by the investigator are required to ensure 
subjects have a likely diagnosis of AD or MCI-AD prior to 
being offered consent forms.  It is further specified that the 
accuracy of the diagnosis is to be confirmed independently 
by the diagnosing physician at the site. 
Section 10.4.1 Screening Assessments 
Section 11.1 Inclusion Criteria 
Treatment Groups 
The primary treatment group comparison is now LMTM 
16 mg/day versus placebo, with secondary comparison of 
subjects receiving 8 mg/day versus placebo.  The rationale 
for revising primary LMTM dosing to 16 mg/day (using 
plasma concentration thresholds based upon a population 
PK model) and for adding the open-label, delayed-start 
treatment phase is described.  Safety margins for nonclinical 
data were updated to reflect the 16 mg/day dose.  
Supportive data regarding reduction in treatment effects of 
LMTM by pretreatment with an AChEI or memantine are 
also described. 
Section 8.1.2 Nonclinical Data 
Section 8.2 Rationale 
Section 9.1 Primary Objectives 
Section 9.2.1 Double-blind Treatment Period 
Section 10.1 General Description 
Section 12.2 Study Regimens 
The number of randomized subjects has been increased to 
approximately 450 subjects (previously 375 subjects), with 
a ratio of 4:1:4 (at the study level) to LMTM 16 mg/day 
(200 subjects), LMTM 8 mg/day (50 subjects), and placebo 
(200 subjects).  
Section 10.1 General Description 
Section 10.2 Study Population 
Section 12.2 Study Regimens 
Section 12.3 Randomization 
Section 17.2 Number of Subjects and Sample Size 
Calculation 
Study Design 
The study design has been modified to occur in two phases.  
The randomized, double-blind, placebo-controlled portion is 
now a 12-month (extended from 9-month) study, including 
five (rather than four) post-randomization visits (Visits 3 
through 7).  Following completion of the double-blind 
treatment period, subjects will continue open-label 
treatment with LMTM 16 mg/day for an additional 
52 weeks, representing a modified delayed start of 
treatment; the open-label, delayed-start phase will include 
three treatment visits (Visit 8 [telephone contact], Visit 9, 
and Visit 10).   
 
Prior treatment assignment will not be unblinded; however, 
upon completion of the initial 52-week, double-blind, 
placebo-controlled treatment period, the database will be 
Cover Page 
Section 8.2 Rationale 
Section 9 Objectives 
Section 10.1 General Description 
Section 10.3 Duration 
Section 10.4.2 Baseline and Post-randomization 
Assessments in Double-Blind Treatment Period 
Section 10.4.3 Assessments in the Open-Label, 
Delayed-Start Phase 
Section 12.2 Study Regimens 
Section 12.5 Dispensing 
Section 12.6 Compliance 
Section 12.8 Breaking the Blind for the Double-
Blind Treatment Period 

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locked and unblinded for analysis.  Individual subject 
treatment assignment will not be divulged to subjects or 
individuals involved in the conduct of the ongoing open-
label, treatment phase (except in cases of medical situations 
where it is deemed essential in order to provide appropriate 
care).  Access to the randomization list has also been 
clarified. 
Section 13 Concomitant Medications and Subject 
Restrictions 
Section 17.1.3 Secondary Endpoint for Open-Label, 
Delayed-Start Phase 
Section 17.4.1 Hypothesis 
Section 17.4.5 Open-Label, Delayed-Start Analysis 
Total duration of participation for an individual subject is 
now up to 120 weeks (rather than 54 weeks), including a 
Screening period of up to 16 weeks, a double-blind 
treatment period of 52 weeks, and a further open-label, 
delayed-start phase of 52 weeks.  Overall study duration is 
now anticipated to be at least 40 months (rather than 
24 months), depending on recruitment. 
Section 10.1 General Description 
Section 10.3 Duration 
Subject Enrollment and Withdrawal 
The protocol now states that, in the case of subjects with 
reduced decision-making capacity, legally acceptable 
representative(s), consistent with national law, may provide 
(and withdraw) written informed consent.   
Section 7 Abbreviations 
Section 10.4.1 Screening Assessments 
Section 11.1 Inclusion Criteria 
Section 11.4.2 Handling of Study Discontinuation / 
Withdrawal 
Section 18.3 Informed Consent 
Clarification that subjects are not to be treated with an 
AChEI and/or memantine within the 60 days prior to 
Baseline assessments, rather than only Baseline 
18F-FDG-PET as previously stated. 
Section 10.1 General Description 
Section 10.4.1 Screening Assessments 
Section 11.1 Inclusion Criteria 
Section 13.1 AChEI and/or Memantine 
Re-screening of a subject is allowed to a newly specified 
maximum of two re-screening occasions.  An additional 
acceptable instance for re-screening has been added for 
subjects with Hgb below the lower limit of laboratory 
normal; such subjects may be re-consented and re-screened 
after appropriate management at the discretion of the TauRx 
Medical lead.  Any other criterion not included the list 
would require approval by TauRx.  
Section 11.3 Re-Screening 
Criteria for significant head injury no longer specifies a 
specific duration of associated loss of consciousness. 
Section 11.2 Exclusion Criterion #3 
Criteria for epilepsy now specifies that a single prior seizure 
>6 months prior to Screening is considered acceptable. 
Section 11.2 Exclusion Criterion #4 
Determination of whether or not a Screening Hgb value 
below age/sex appropriate lower limit of normal is 
exclusionary now includes discussion with the Medical 
Monitor, with final decision at the discretion of the Medical 
Oversight Lead. 
Section 11.2 Exclusion Criterion #12 
Subjects with moderate to severe sleep apnea are to be 
excluded if the apnea is currently, rather than previously, 
diagnosed; the definition of moderate to severe apnea is 
now included (e.g., requiring oxygen supplementation). 
Section 11.2 Exclusion Criterion #15 
Clarified that active hepatitis or primary biliary cirrhosis; or 
active HTLV-III, LAV, mutants/derivatives of such, or 
conditions associated with AIDS or similar, are 
exclusionary. 
Section 11.2 Exclusion Criterion #16 
Further definitions have been added for exclusions 
regarding cancer diagnosis (e.g., new diagnosis within past 
2 years, or previous [>2 years] diagnosis requiring any 
intervention or treatment within past 2 years).  
Section 11.2 Exclusion Criterion #17 
Subjects who complete the study and receive treatment with 
LMTM up to and including the last open-label visit may be 
eligible for the EAP (and once entered into the EAP, are 
required to remain off AChEIs and/or memantine).  Patients 
Section 10.2 Study Population 
Section 10.6 Definition of End of Study 
Section 11.4.1 Handling of Subjects who 
Discontinue Study Drug 

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who discontinue treatment permanently in this study will 
not be eligible for the EAP. 
Section 12.2.2 Dose Interruption 
Study Drug 
The study title now refers to the investigational study drug 
by its USAN.  In addition to hydromethylthionine mesylate 
being the USAN, clarification is provided that it is also the 
INN.  
Cover Page 
Section 8 Background and Rationale for the Study 
Section 8.1.1 Investigational Product 
Section 12.1.1 Active Ingredient 
The drug supplies for the placebo group will include tablets 
containing a urinary discolorant, MTC, 4 mg.  To prevent 
inadvertent unblinding due to urinary discoloration, subjects 
randomized to placebo may receive a 4-mg tablet of MTC 
as one of the four tablets to be taken daily (the remainder 
being placebo tablets), in order to maintain the treatment 
blind. 
Section 8.1.1 Investigational Product 
Section 8.2 Rationale 
Section 12.2 Study Regimens 
Additional drug dispensing visits now include Visits 6 and 7 
during double-blind treatment, as well as Visit 9 of the 
open-label, delayed-start phase, at which time the number 
of tablets dispensed will be recorded and the complete study 
drug kit will be returned.  Subject compliance with study 
drug now will also occur at Visits 6 and 7 during the 
double-blind treatment period, at Visits 9 and 10 during the 
open-label, delayed-start phase, and during the telephone 
contact (Visit 8).   
Section 10.4.2 Baseline and Post-randomization 
Assessments in Double-Blind Treatment Period 
Section 10.4.3 Assessments in the Open-Label, 
Delayed-Start Phase 
Section 12.2 Study Regimens 
Section 12.5 Dispensing 
Section 12.6 Compliance 
Imaging Assessments 
18F-FDG-PET imaging is now to be performed only in AD 
subjects with CDR 0.5; imaging is to occur at Baseline and 
at end of double-blind treatment, i.e., Visit 7/Week 52 (or 
early termination).  For purposes of establishing the 
Baseline assessment, 18F-FDG-PET images are to be 
obtained prior to Visit 2 and at least 60 days after the last 
dose of AChEI and/or memantine. 
Section 9.2.1 Double-blind Treatment Period 
Section 10.1 General Description 
Section 10.4.1 Screening Assessments 
Section 10.4.2 Baseline and Post-randomization 
Assessments in Double-Blind Treatment Period 
Section 10.4.2.1 Imaging Efficacy Assessments in 
Double-Blind Treatment Period 
Section 13.4 Drugs Used to Manage Behavioral 
Disturbance 
Section 13.5 Other Medications 
Section 15.3.1 General Considerations 
Section 15.3.3.1 18F-FDG-PET 
Section 17.1.2 Secondary Efficacy Endpoints for 
Double-Blind Treatment Period 
Section 17.3 Analysis Populations 
Section 17.4.6 Dose Response Analyses 
Additional volumetric brain MRIs and cognitive / functional 
assessments (ADAS-cog13 and ADCS-ADL23) are to be 
conducted at Visit 7/Week 52, as well as after the additional  
26 and 52 weeks of open-label treatment (Visit 9/Week 78 
and Visit 10/Week 104), or upon early termination in the 
case of the ADAS-cog13 and ADCS-ADL23.  As pertains to 
early termination and MRI scans, no additional scan is 
required if the subject’s last scan was performed < 90 days 
prior to the early termination date for either the double-
blind treatment period or open-label treatment period.   
Section 10.1 General Description 
Section 10.4.2 Baseline and Post-randomization 
Assessments in Double-Blind Treatment Period 
Section 10.4.2.1 Imaging Efficacy Assessments in 
Double-Blind Treatment Period 
Section 10.4.2.2 Clinical Efficacy Assessments in 
Double-Blind Treatment Period 
Section 10.4.3 Assessments in the Open-Label, 
Delayed-Start Phase 
Section 10.4.3.1 Imaging Efficacy Assessments in 
the Open-Label, Delayed-Start Phase 
Section 15.3.3.2 MRI 
The estimated total radiation exposure to subjects from the 
amyloid PET scan procedure (if not performed previously) is 
now provided. 
Section 15.3.1 General Considerations 
Clinical Efficacy Assessments 
At Screening, the CDR assessment is only to be performed 
if the subject meets the MMSE inclusion criteria, and if the 
Section 10.1 General Description 

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subject does not qualify with either of these scales, no 
further assessments are to be made and the subject will be 
considered a screen failure.  For enrolled and randomized 
subjects, the MMSE and CDR sum of boxes (as exploratory 
clinical efficacy assessments) are to be administered at 
Visit 7 and at the final open-label, delayed-start visit 
(Visit 10), or upon early termination. 
Section 10.4.1.1 Diagnostic and Cognitive Eligibility 
Assessments 
Section 10.4.2 Baseline and Post-randomization 
Assessments in Double-Blind Treatment Period 
Section 10.4.2.2 Clinical Efficacy Assessments in 
Double-Blind Treatment Period 
Section 10.4.3 Assessments in the Open-Label, 
Delayed-Start Phase 
Section 10.4.3.2 Clinical Efficacy Assessments in the 
Open-Label, Delayed-Start Phase 
Section 15.2.2 Instruments 
Section 17.5 Exploratory Analyses 
Efficacy rater requirements, allocation, and the order of 
assessments by visit have been clarified.  The CDR and 
MMSE are now further described in the protocol with 
additional references included. 
Section 15.2 Assessment of Efficacy (and all 
subsections) 
Section 27 References 
Safety Assessments 
Safety assessments are to occur at each clinic visit during 
double-blind treatment, with additional assessments after 26 
and 52 weeks of open-label treatment (Visit 9/Week 78 and 
Visit 10/Week 104), and as needed to follow up on an AE.  
A telephone contact has been added to record AEs and 
changes in concomitant medications after 4 weeks in the 
open-label, delayed-start phase (Visit 8/Week 56).  All 
safety assessments are to be performed by an independent 
qualified assessor not involved in efficacy measures, with 
certain assessments now specified to be conducted and/or 
reviewed by a medical assessor (physician/MD/DO), 
including targeted physical and neurological examinations, 
clinical laboratory and ECG results, and AEs and 
concomitant medications.   
Section 10.1 General Description 
Section 10.4.1.2 Other Medical Screening 
Assessments 
Section 10.4.2 Baseline and Post-randomization 
Assessments in Double-Blind Treatment Period 
Section 10.4.2.3 Safety Assessments in Double-
Blind Treatment Period 
Section 10.4.3 Assessments in the Open-Label, 
Delayed-Start Phase 
Section 10.4.3.3 Safety Assessments in the Open-
Label, Delayed-Start Phase 
Section 13 Concomitant Medications and Subject 
Restrictions 
Section 15.4 Safety Assessments and Procedures 
Additional ophthalmological examinations in subjects with 
lens implants are to occur at Visits 7 and 10 (or early 
termination) to assess for potential lens discoloration.  It is 
now specified that the examinations are to be conducted by 
an ophthalmologist, optometrist, or other suitably qualified 
medical assessor (physician/MD/DO). 
Section 10.1 General Description 
Section 10.4.1 Screening Assessments 
Section 10.4.1.2 Other Medical Screening 
Assessments 
Section 10.4.2 Baseline and Post-randomization 
Assessments in Double-Blind Treatment Period 
Section 10.4.2.3 Safety Assessments in Double-
Blind Treatment Period 
Section 10.4.3 Assessments in the Open-Label, 
Delayed-Start Phase 
Section 10.4.3.3 Safety Assessments in the Open-
Label, Delayed-Start Phase 
Section 15.4 Safety Assessments and Procedures 
Targeted physical examinations, to be performed by a 
medical assessor, are now specified to include, at a 
minimum, heart and lung auscultation and brief 
neurological assessment guided by any reported 
signs/symptoms/AEs (e.g., evaluating for potential 
serotonin toxicity). 
Section 10.4.2 Baseline and Post-randomization 
Assessments in Double-Blind Treatment Period 
Section 10.4.3 Assessments in the Open-Label, 
Delayed-Start Phase 
Section 15.4 Safety Assessments and Procedures 
For women of childbearing potential, it is now specified that 
the return visit to the clinic for pregnancy testing is to occur 
within 3 months of last exposure to study drug in the event 
of delayed menstruation. 
Section 10.1 General Description 
Section 13.7 Contraceptive Measures 
Section 16.10 Reporting of Pregnancy 
New AEs and SAEs reported by a subject after screen 
failure will not be recorded for the study.  Emergent AEs 
and SAEs up to the point of screen failure will be followed 
up to resolution at the discretion of the PI. 
Section 16.1 Definition of AEs, Period of 
Observation, and Recording of AEs 
Section 16.7 Serious Adverse Event Reporting 

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Other Assessments 
In addition to study visits that are to occur in the morning 
for Visits 2 and 3 to allow for in-clinic dosing and PK blood 
sampling, the protocol now specifies that in-clinic dosing 
and PK sampling are also to occur at morning appointments 
for Visit 7 (after 52 weeks on study drug) and Visit 10 (after 
104 weeks of study drug).  Subjects are to be instructed not 
to take their morning dose at home. 
Section 10.1 General Description 
Section 10.4.2 Baseline and Post-randomization 
Assessments in Double-Blind Treatment Period 
Section 10.4.2.4 Other Assessments in Double-Blind 
Treatment Period 
Section 10.4.3 Assessments in the Open-Label, 
Delayed-Start Phase 
Section 10.4.3.4 Other Assessments in Open-Label, 
Delayed-Start Phase 
Section 12.2 Study Regimens 
Section 15.5.1 MT Concentration 
A urine sample will no longer be collected for color 
determination by the central laboratory. 
Section 10.1 General Description 
Section 10.4.2 Baseline and Post-randomization 
Assessments in Double-Blind Treatment Period 
Section 10.4.2.4 Other Assessments in Double-Blind 
Treatment Period 
Section 15.5.2 Urine Color (deleted) 
Blood samples for determination of plasma and whole 
blood MT concentrations will now be 9-mL blood samples  
collected in 9-mL vacutainers (previously 8-mL). 
Section 15.5.1.1 Procedure for Blood Sample 
Collection 
Objectives and Endpoints / Statistical Analyses 
The primary objectives now pertain to the double-blind 
treatment period only, comparing LMTM 16 mg/day with 
placebo for the co-primary endpoints of ADAS-cog11 and 
ADCS-ADL23 (difference in temporal lobe 18F-FDG-PET 
change in SUVR and the Composite Scale are no longer 
primary objectives), and for assessing safety and 
tolerability.  Secondary objectives have been modified for 
the double-blind treatment phase to include comparisons of 
LMTM 16 mg/day with placebo in whole brain atrophy as 
measured by MRI, to restrict the 18F-FDG-PET endpoints to 
subjects with CDR 0.5 at Screening, and to compare the 
LMTM dose of 8 mg/day for selected endpoints.  Brain 
MRI remains as a secondary efficacy endpoint, with 
clarification that it will also be used to confirm a lack of 
treatment unblinding. 
Section 9.1 Primary Objectives 
Section 9.2 Secondary Objectives 
Section 9.2.1 Double-blind Treatment Period 
Section 9.2.2 Open-Label, Delayed-Start Phase 
Section 15.3.1 General Considerations 
Section 17 Statistical Analysis 
Section 17.1.1 Primary Efficacy Endpoints for 
Double-Blind Treatment Period 
Section 17.1.2 Secondary Efficacy Endpoints for 
Double-Blind Treatment Period 
Section 17.4.1 Hypothesis 
 
The Composite Scale will now be based on items selected 
from the ADAS-cog13, rather than the ADAS-cog11, and on 
selected items from the ADCS-ADL23, with analysis at 
9 months and 12 months during double-blind treatment to 
evaluate usefulness for future studies and is included in the 
exploratory analyses. 
Section 15.2.2.1 ADAS-cog 
Section 15.2.2.2 ADCS-ADL23 
Section 15.2.2.3 Composite Scale 
Two open-label, delayed-start phase objectives have been 
added:  determination if there is a difference in disease 
progression on the co-primary clinical endpoints and MRI 
imaging endpoint for subjects who started treatment in the 
double-blind phase and those who started in the open-label, 
delayed-start phase (i.e., “early” and “late” LMTM starters, 
respectively), and assessment of safety and tolerability of 
LMTM given for up to 104 weeks.  Additional statistical 
analysis for the open-label phase has been defined. 
Section 9.2.2 Open-Label, Delayed-Start Phase 
Section 17 Statistical Analysis 
Section 17.1.3 Secondary Endpoint for Open-Label, 
Delayed-Start Phase 
Sample size estimations and study power to determine 
treatment effect have been revised based upon changes to 
primary treatment group, study population, co-primary 
clinical endpoints, and length of the double-blind treatment 
period of the study.  Sample size estimations have also been 
Section 17.2 Number of Subjects and Sample Size 
Calculation 

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added for the open-label, delayed-start treatment period of 
the study. 
Clarification is provided that the primary efficacy analyses 
for FDA will be based on the E-MITT, MI-MITT, or 
I-MITT population (depending on endpoint), and for EMA 
on the ITT population.  The co-primary efficacy endpoints 
and MRI will be analyzed using a linear mixed model for 
repeated measures with unstructured covariance matrix, and 
18F-FDG-PET analyzed using an ANCOVA, with covariates 
for this model adjusted accordingly.  
Section 17 Statistical Analysis 
Section 17.4 Clinical Efficacy and Imaging Analysis 
Section 17.4.2 FDA Analysis 
Evaluation of the influence of ApoE genotype (in subjects 
who provide legally acceptable consent) on the primary and 
selected secondary endpoints is now an exploratory 
endpoint (previously a secondary endpoint). 
Section 9.2 Secondary Objectives 
Section 17.1.2 Secondary Efficacy Endpoints for 
Double-Blind Treatment Period 
Section 17.5 Exploratory Analyses 
 
No interim futility or efficacy analysis is planned in which 
treatment groups will be compared.  Recruitment and 
discontinuations will, however, be continuously monitored 
in a blinded fashion and projections on future dropouts 
calculated.  In addition, a blinded interim analysis to re-
estimate the assumed SD for the change from Baseline to 
Week 52 in the primary endpoints may be carried out at 
some point during the study’s recruitment period. 
Section 17.9 Interim Analysis 

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28.4.7 
Protocol Version 5.1 
The protocol for Study TRx-237-039 (Version 5.0 dated 9 July 2019) has been revised 
primarily to include modifications to the exclusion criterion regarding hematological 
abnormalities (reverting to the original criterion), clarifications to background information for 
the study drug and the efficacy objectives/statistical analyses, as well as updates to 
responsible personnel.  A summary of the key changes and affected sections is provided 
below.   
 
Additional revisions are editorial and are intended to correct typographical errors or add 
further clarification. 
 
Summary of Changes 
Affected Sections in Revised Protocol  
(Version 5.1) 
Responsible Personnel 
Charles River Laboratories Edinburgh Ltd has been added 
to responsible personnel for analysis of MT concentrations 
(cross-validation purposes only). 
Section 4 Responsible Personnel 
Subject Enrollment and Withdrawal 
The provision for discussion of potentially exclusionary low 
screening Hgb values with the Medical Monitor has been 
removed; Hgb values below age/sex appropriate lower limit 
of the central laboratory normal range are once again 
exclusionary regardless of etiology. 
Synopsis 
Section 11.2 Exclusion Criterion #12 
Section 11.3 Re-screening 
Study Drug 
Clarification has been added that the increased incidences of 
pancreatic islet cell adenoma and adenoma or carcinoma 
(combined) in male rats, reported in a 2-year carcinogenicity 
study performed by the National Toxicology Program, were 
attributed to MTC by FDA (as interpreted by the FDA 
Executive Carcinogenicity Assessment Committee). 
Section 8.1.2 Nonclinical Data 
Clarification has been added that the magnitude of 
concentration-dependent treatment effects was reduced when 
LMTM was given to subjects who were concurrently using 
(rather than prior use of) AChEIs and/or memantine. 
Section 8.1.3.3 Efficacy 
Objectives and Endpoints / Statistical Analyses 
To correct a typographical error in the synopsis regarding 
the first secondary endpoint (the comparison of the LMTM 
dose of 16 mg/day with the placebo group in annualized 
rate of whole brain atrophy, rather than temporal and 
parietal lobe atrophy). 
Synopsis 
 
To clarify the exploratory analysis for comparison of 
decline in temporal lobe 18F-FDG-PET SUVR with the 
estimated decline for subjects with mild AD (CDR 0.5); 
reference to the MMSE range has been removed.  The 
analyses will be further described and clarified in the SAP. 
Section 17.5 Exploratory Analyses 
 
 
 

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28.4.8 
Protocol Version 6.0 
The protocol for Study TRx-237-039 (Version 5.1 dated 05 February 2020) has been revised 
to incorporate modifications to the study conduct and monitoring, guidance for continued 
data collection and analysis, and ongoing risk assessment due to the COVID-19 Public Health 
Emergency. In addition, the total number of subjects to be randomized has increased, and 
updates have been incorporated for contact information for responsible personnel, as well as 
modifications and/or clarifications to investigator responsibilities, study assessments, and 
statistical analyses. Reference to a separate plan has been included for additional analyses to 
be undertaken of the blinded 18F-FDG-PET and MRI data for scientific research and quality 
control purposes. A summary of the key changes and affected sections is provided below.   
 
Additional revisions are editorial and are intended to correct typographical errors and 
editorial inconsistencies as well as to add clarification. 
 
Summary of Changes 
Affected Sections in Revised Protocol  
(Version 6.0) 
Changes due to COVID-19 Public Health Emergency 
The post-Baseline visits for safety, PK, and genotyping 
blood sample collection as well as efficacy assessments 
may be completed in-clinic at the site, in the home, or at 
other safe, suitable alternative location if deemed necessary 
to protect subjects due to COVID-19. Acceptable 
procedures for safety and efficacy assessments, blood 
sample collection, shipment, and analysis are described.  
Study visit windows may be further extended at the 
discretion of the Sponsor when justification is provided. 
Synopsis 
Section 10.1 General Description 
Section 10.2.1 Changes to Study Conduct 
Section 10.5.3 Assessments in the Open-Label, 
Delayed-Start Phase 
Section 13.7 Contraceptive Measures 
Section 15.4 Safety Assessments and Procedures 
Section 15.5.1 MT Concentration 
Section 16.7 Serious Adverse Event Reporting 
Alternative arrangements for dispensing study drug supplies 
may be permitted if deemed necessary to protect subjects 
due to COVID-19. Requirements for obtaining subject 
consent consistent with local and national requirements, 
maintaining the specified study drug storage conditions, and 
handling, accountability, and compliance monitoring will be 
addressed and documented. 
Synopsis 
Section 10.1 General Description 
Section 10.2.1 Changes to Study Conduct 
Section 12.2 Study Regimens 
Section 12.5 Dispensing 
If a subject is undergoing screening assessments and cannot 
have assessments performed due to COVID-19, the subject 
should be put on screening pause until such times as 
COVID-19 impacts have ceased.  
Synopsis 
Section 10.2.1 Changes to Study Conduct 
Section 10.5.1.1 Diagnostic and Cognitive Eligibility 
Assessments 
Section 11.3 Re-screening 
The Sponsor may approve subject randomization without a 
brain 18F-FDG-PET scan if the scan cannot be performed 
due to COVID-19. 
Synopsis 
Section 10.1 General Description 
Section 10.2.1 Changes to Study Conduct 
Section 10.5.1 Screening Assessments 
Section 10.5.2 Baseline and Post-randomization 
Assessments in Double-Blind Treatment Period 
All MRI scans are to be performed at approved MRI centers 
using approved scanners; no alternative scanners will be 
accepted; there is to be no change in scanner for a given 
subject over the course of the study. Guidance will be 
provided for scheduled MRI visits at approved imaging 
centers that may be closed due to COVID-19, including 
acceptable windows outside of the scheduled visit window 
during which MRI scans can still be performed and would 
be accepted for analysis. 
Synopsis 
Section 10.1 General Description 
Section 10.2.1 Changes to Study Conduct 
Section 15.3.1 General Considerations 
Section 15.3.3.2 MRI 
All 18F-FDG-PET scans are to be performed at approved 
PET centers using approved scanners; there is to be no 
Synopsis 
Section 10.1 General Description 
Section 10.2.1 Changes to Study Conduct 

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change in scanner for a given subject over the course of the 
study. 
Section 15.3.1 General Considerations 
The ADAS-cog13 may also be performed by 
videoconference and the MMSE, ADCS-ADL23, and CDR 
may be performed by speakerphone. The remote efficacy 
scale assessments are now described in the protocol. 
Synopsis 
Section 10.1 General Description 
Section 10.2.1 Changes to Study Conduct 
Section 15.2.2 Instruments 
Clarification is now provided that multiple study partners 
participating only as caregivers will be permitted for a given 
subject, either simultaneously or as replacements for 
previous study partners, with no specified maximum. A 
maximum total of two study partners participating as 
informants (i.e., one replacement) would normally be 
permitted for a given subject; however, up to a total of four 
study partners (i.e., three replacements) are permitted if 
circumstances change due to COVID-19. Information 
obtained from study partners participating as informants 
will be appropriately identified to distinguish each 
informant in the event that a given subject has more than 
one study partner providing data for analysis. 
Synopsis 
Section 10.1 General Description 
Section 10.2.1 Changes to Study Conduct 
Section 10.5.1 Screening Assessments 
Section 10.5.1.1 Diagnostic and Cognitive Eligibility 
Assessments 
Section 11.4.2 Handling of Study Discontinuation / 
Withdrawal 
Section 11.4.3 Replacements 
Section 15.2.1 Raters 
For PK blood sample collection at Visit 2, Visit 3, Visit 7, 
and Visit 10, the third sample to be collected approximately 
4 hours after the dose is not required if the visit occurs in 
the home. 
Synopsis 
Section 10.2.1 Changes to Study Conduct 
Section 10.5.2 Baseline and Post-randomization 
Assessments in Double-Blind Treatment Period 
Section 10.5.2.4 Other Assessments in Double-Blind 
Treatment Period 
Section 10.5.3 Assessments in the Open-Label, 
Delayed-Start Phase 
Section 10.5.3.4 Other Assessments in Open-Label, 
Delayed-Start Phase 
Section 15.5.1 MT Concentration 
Sections have been added describing the Sponsor’s ongoing 
risk assessment regarding the impact of COVID-19 on this 
study, including guidance for continued data collection and 
potential changes in site and remote monitoring procedures, 
as well as changes to statistical analyses. 
Synopsis 
Section 10.2 Changes Implemented Due to 
COVID-19 
Section 10.2.1 Changes to Study Conduct 
Section 10.2.2 Changes to Study Monitoring 
Section 10.2.3 Changes to Statistical Analyses 
Section 17.4.11 Sensitivity Analyses 
Section 17.9 Interim Analysis 
Section 18 Regulatory and Ethics 
Section 21.2 COVID-19 Risk Assessment (new) 
Responsible Personnel 
A DSSL 24-hour medical contact telephone number has 
been added for France. 
Section 4 Responsible Personnel 
Investigator responsibilities include supervising any 
individual or party to whom the investigator delegates trial-
related duties and functions conducted at the trial site. 
Section 18.4 Investigator Responsibilities 
Study Population 
The number of randomized subjects has been increased: a 
sufficient number of subjects will be recruited such that 
approximately 500 subjects are enrolled; beginning with 
Version 5.0, approximately 450 subjects are to be enrolled 
and randomized in a 4:1:4 ratio (at the study level) to the 
LMTM 16-mg/day, LMTM 8-mg/day, and placebo groups.  
The inclusion criterion for an MMSE score of 16-27 
(inclusive) at Screening will be subject to stratification 
requirements. 
Synopsis 
Section 10.1 General Description 
Section 10.3 Study Population 
Section 11.1 Inclusion Criteria 
Section 12.2 Study Regimens 
Section 12.3 Randomization 
Section 17.2 Number of Subjects and Sample Size 
Calculation 

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Imaging 
If subjects have an acceptable MRI scan or PET scan (the 
latter only in subjects who have a screening CDR of 0.5) 
already completed during the original Screening window, the 
scan does not require repetition. 
Section 10.2.1 Changes to Study Conduct 
Section 10.5.1.1 Diagnostic and Cognitive Eligibility 
Assessments 
Section 11.3 Re-screening 
Section 15.3.3.1 18F-FDG-PET 
Reference is included to a separate plan and data transfer 
agreement that will capture standard procedures for 
additional exploratory analyses to be undertaken to 
characterize the blinded 18F-FDG-PET and MRI data for 
scientific research and quality control purposes, which are 
separate from the study objectives.  
 
 
Section 20.2 Imaging Data (new) 
 
Added consistent wording regarding baseline 18F-FDG-PET 
scan in subjects who have a screening CDR of 0.5. 
Synopsis 
Section 10.1 General Description 
Section 10.5.2.1 Imaging Efficacy Assessments in 
Double-Blind Treatment Period 
Section 11.3 Re-screening 
Section 13.1 AChEI and/or Memantine 
Section 15.3.3.1 18F-FDG-PET 
 
Safety 
Permanent discontinuation due to decreased creatinine 
clearance is only required in subjects if renal concerns arise. 
Section 11.4.1 Handling of Subjects Who Discontinue 
Study Drug 
Section 16.11.2 Other Safety Reasons Requiring 
Discontinuation of Study Drug 
Any abnormal laboratory test result from Screening 
assessments (prior to treatment) is to be added to the 
subject’s medical history, unless deemed clinically 
significant by the medical assessor (MD/DO) in which case 
it will be recorded as an AE. 
Section 15.4 Safety Assessments and Procedures 
Section 16.1 Definition of AEs, Period of 
Observation, and Recording of AEs 
Other Assessments 
Guidance is now provided regarding collection of blood 
samples at early termination visits for determination of MT 
concentrations. 
Synopsis 
Section 10.5.2 Baseline and Post-randomization 
Assessments in Double-Blind Treatment Period 
Section 10.5.2.4 Other Assessments in Double-Blind 
Treatment Period 
Section 10.5.3 Assessments in the Open-Label, 
Delayed-Start Phase 
Section 10.5.3.4 Other Assessments in Open-Label, 
Delayed-Start Phase 
Section 15.5.1 MT Concentration 
Statistical Analyses 
The secondary efficacy endpoints to compare the difference 
in temporal lobe 18F-FDG-PET change in SUVR normalized 
to pons in subjects with CDR 0.5 at Screening (LMTM 
16 mg/day versus placebo, and LMTM 8 mg/day versus 
placebo) will now only be analyzed if a predefined threshold 
is reached for a sufficient number of subjects providing data 
as specified in the SAP. 
Synopsis 
Section 9.2.1 Double-Blind Treatment Period 
Section 17.1.2 Secondary Efficacy Endpoints for 
Double-Blind Treatment Period 

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Upon completion of the initial 52-week, double-blind, 
placebo-controlled treatment period, the database will be 
locked and unblinded for analysis, and an interim report will 
be prepared describing the complete efficacy and safety 
analyses of the double-blind phase; individual subject prior 
treatment assignment will not be divulged to subjects or 
individuals involved in the operational conduct of the 
ongoing open-label, treatment phase. 
Section 10.1 General Description 
Section 10.7 Definition of End of Study 
Section 12.8 Breaking the Blind for Double-Blind 
Treatment Period 
Section 17.9 Interim Analysis 
Due to the introduction of MTC spiking in the placebo arm 
with Protocol Version 5.0, the respective MITT populations 
will be restricted to subjects randomized to Protocol 
Versions 5.0 and above for the primary and key secondary 
analyses as per the SAP. The full MITT populations will be 
analyzed for these as a sensitivity analysis. Details will be 
provided in the SAP. 
Section 17.3 Analysis Populations 
Section 17.4 Clinical Efficacy and Imaging Analysis 
It is now indicated that the SAP will specify estimands to 
provide a more comprehensive assessment of the 
performance and efficacy of the drug accounting for various 
factors (importantly, drop-outs). 
Section 17.4.4 Estimands 
The last observation carried forward (LOCF) imputation has 
been removed from the statistical analyses. 
Section 17.4.11.6 Last Observation Carried Forward 
(LOCF) Imputation (deleted) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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28.4.9 
Protocol Version 7.0 
The protocol for Study TRx-237-039 (Version 6.0 dated 09 October 2020) has been revised 
to incorporate changes to responsible personnel; updates to the background information to 
reflect the most current version of the Investigator’s Brochure; clarification of assessments 
and drug dispensing for Visit 7 of double-blind treatment (also Baseline/Day 1 of open-label 
phase); addition of lens discoloration as an AESI and further instruction regarding timing of 
slit lamp examinations; clarification that MT concentration sampling will not continue for the 
off-treatment on-study (TOTOS) group; and further description of composite scores and 
endpoints. Additional statistical analysis updates include sensitivity and subgroup analyses, 
and further detail provided for primary endpoints, all in response to potential impacts of 
COVID-19; the primary efficacy hypotheses have been clarified; and the primary estimand 
and five components of interest are now described.   
 
A summary of the key changes and affected sections is provided below. 
 
Additional revisions are editorial and are intended to correct typographical errors and 
editorial inconsistencies as well as to add clarification. 
 
Summary of Changes 
Affected Sections in Revised Protocol  
(Version 7.0) 
Signatories / Responsible Personnel 
Modified address for Sponsor Medical Oversight signatory. 
Section 3 Protocol Approval 
The Global Project Manager has been changed to Marty 
Perry, with corresponding telephone numbers and email 
address added. 
Section 4 Responsible Personnel 
The 24-hour Medical Contact has been changed from DSSL 
to Emergency Scientific and Medical Services Global 
(ESMS Global). 
Section 4 Responsible Personnel 
The Central Laboratory has been changed from Covance, 
Inc. to Labcorp Central Laboratory Services (e.g., Labcorp 
Central Laboratory Services LP in the Americas and 
Labcorp Central Laboratory Services S.à r.l in Europe). 
Section 4 Responsible Personnel 
Section 10.2.1 Changes to Study Conduct 
Section 10.5.1 Screening Assessments 
Section 15.5.2 Genotyping 
Certara USA, Inc. is now responsible for Statistical 
Analysis of Pharmacokinetic Data rather than the Institute 
for Clinical Pharmacodynamics, with corresponding 
addresses and telephone number added for Certara’s New 
Jersey and Amsterdam locations.    
Section 4 Responsible Personnel 
The data management and statistics responsible personnel 
have now been divided, with Synteract, Inc. continuing to 
be responsible for data management and Cytel Inc. now 
responsible for statistics (corresponding address and 
telephone number added for Cytel Inc.).   
Section 4 Responsible Personnel 
Section 12.8 Breaking the Blind for Double-Blind 
Treatment Period 
Background 
The background information has been updated to be 
reflective of the most current version of the Investigator’s 
Brochure (Version 23.0), including updates to nonclinical 
and clinical data as well as the study drug terminology. The 
discussion of drugs currently available to treat AD has been 
updated to include the recent FDA accelerated approval of 
Aduhelm (aducanumab). 
Synopsis 
Section 8 Background and Rationale for the Study 
Section 8.1.1 Investigational Product 
Section 8.1.2 Nonclinical Data 
Section 8.1.3.1 Pharmacokinetics 
Section 8.1.3.3 Efficacy 
Section 8.1.3.4 Safety 
Section 8.2 Rationale 
Section 12.1.1 Active Ingredient 
Section 13.2 Drugs with Serotonergic Potential 

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Section 13.3 CYP and P-gp Substrates 
Section 13.6 Dietary Tyramine 
Section 13.8 Folate and Vitamin B12 
Section 15.5.1 MT Concentration 
Section 17.8 Other Data 
Section 27 References 
Study Visits and Drug Dispensing 
Clarification provided that Visit 7 of the double-blind 
treatment period is also Baseline/Day 1 of the open-label 
phase. The in-clinic dose of study drug at Visit 7 is to be 
taken from a newly dispensed open-label study drug kit, 
after pre-dose assessments have been completed. The pre-
dose and post-dose assessments to be performed at Visit 7 
have also been clarified.   
Synopsis 
Section 10.5.2 Baseline and Post-randomization 
Assessments in Double-Blind Treatment Period 
Section 10.5.3 Assessments in the Open-Label, 
Delayed-Start Phase 
Section 12.2 Study Regimens 
Section 12.5 Dispensing 
Section 15.2.1 Raters 
Section 17 Statistical Analyses 
Section 17.4.6 Open-Label, Delayed-Start Analysis 
Efficacy 
Composite Scores (and additional Composite Endpoints [if 
any]) derived from the ADAS-cog13 and the ADCS-ADL23 
will be defined in the SAP prior to sign off and database 
lock/unblinding, with at least one designed to be sensitive to 
early stages of the disease as well as one that is less/not 
impacted by COVID-19. 
Synopsis 
Section 15.2.2 Instruments 
Section 15.2.2.3 Composite Scale(s) 
Section 17.5 Exploratory Analyses 
Safety 
Clarification that slit lamp ophthalmological examinations 
in subjects with history of lens implants are to be performed 
prior to the first dose of study drug (Screening/Baseline), at 
Visit 7, and at Visit 10/early termination to check for lens 
discoloration. In addition, this examination is now to be 
performed if subjects have cataract surgery/lens 
implantation at any point during study participation (as soon 
as possible after the surgery), as well as in response to 
visual complaints if suggestive of lens discoloration. 
Synopsis 
Section 15.4 Safety Assessments and Procedures 
Section 16.11.2 Lens Discoloration 
A new section added for lens discoloration, which is now a 
pre-specified AESI (in addition to hemolytic anemia). If a 
lens discoloration is identified by slit lamp examination, it 
is to be recorded as an AESI in the AE eCRF; however, no 
specific action is required for study drug. Lens discoloration 
has been removed from the list of examples of SAEs that 
are not life-threatening, as it should be reported as an AESI 
unless SAE reporting criteria are later met. 
Section 16.7 Serious Adverse Event Reporting 
Section 16.11 Guidance for the Handling of Adverse 
Events of Special Interest and Selected Test 
Abnormalities 
Section 16.11.2 Lens Discoloration 
Clarification that adverse events of malignancies other than 
non-melanoma skin cancers are to be reported to Syneos 
Health (regardless of causality or whether they meet the 
criteria for serious). 
Section 16.9 Malignancies 
Section 17.7 Safety Analysis 
Other Assessments 
For MT concentration sampling, if a subject has 
discontinued study drug but continues to attend study visits 
off-treatment (the TOTOS group), blood samples will not 
continue to be collected for measurement of MT 
concentrations. 
Synopsis 
Section 10.5.2 Baseline and Post-randomization 
Assessments in Double-Blind Treatment Period 
Section 10.5.3 Assessments in the Open-Label, 
Delayed-Start Phase 
Section 11.4.1 Handling of Subjects Who Discontinue 
Study Drug 

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Protocol Version 7.1 
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Summary of Changes 
Affected Sections in Revised Protocol  
(Version 7.0) 
Section 15.5.1 MT Concentration 
Statistical Analyses 
Further detail provided that if >5% of all assessments (over 
all subjects and visits) of a given primary endpoint are 
impacted by COVID-19 (based on the eCRF COVID-19 
Impact Assessment), the impacted assessment will be 
excluded and upscaled when the respective primary 
endpoint is analyzed. 
Section 10.2.3 Changes to Statistical Analyses 
Other sensitivity analyses were added and include:  
subgroup analysis of endpoint ascertainment (in-clinic, 
remote) with subjects assigned to the subgroup with most 
visits done, excluding (in-clinic) Baseline and Week 52 
visits; analysis of ADAS-cog11 to include only subset of 
items (for all visits) which are administered remotely by 
telephone or video call; analysis of ADCS-ADL23 to 
exclude items affected by COVID-19 restrictions; and 
analysis of composite scale designed as COVID-19 impact 
free joint score, to include items selected from ADAS-cog11 
and ADCS-ADL23 that are not expected to be impacted by 
COVID-19. 
Section 10.2.3 Changes to Statistical Analyses 
Clarification provided that the two co-primary endpoints are 
Baseline adjusted decline in ADAS-cog11 and Baseline 
adjusted decline in ADCS-ADL23 from Baseline at 
Week 52.   
Section 17.4.1 Hypothesis 
The primary efficacy hypotheses have been clarified, with 
the global null versus alternative as a Union-Intersection 
Test requiring both co-primary endpoints to meet statistical 
significance at the 5% two-sided level of significance for 
the global null hypothesis to be rejected.   
Section 17.4.1 Hypothesis 
For the ITT (EMA) analysis, no data will be imputed, 
unless specified in selected sensitivity/exploratory 
endpoints.    
Section 17.4.3 ITT (EMA) Analysis 
The Estimands section has been expanded, with the primary 
estimand now defined and constructed in line with ICH E9 
(R1) addendum. The five components for the estimand of 
interest are as follows:  treatment, population, patient-level 
outcomes/variables, population-level summary, and 
intercurrent events (ICE).   
Section 17.4.4 Estimands 
 
 
 

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CONFIDENTIAL 
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28.4.10 
Protocol Version 7.1 
 
Summary of Changes 
Affected Sections in Revised Protocol  
(Version 7.1) 
Signatories / Responsible Personnel 
The Global Project Manager has been changed to Marta 
Medina, with corresponding telephone numbers and email 
address added. 
Section 4 Responsible Personnel 
Bjoern Schelter job title has been updated from Data 
analytics and Biostatistic lead to Chief Analytics Officer 
Section 3 Protocol Approval 
Vendor Bioclinica removed for Magnetic Resonance 
Imaging (MRI); suitably qualified vendor added 
Section 4 Responsible Personnel 
Study Design 
Removed sentence- an interim report will be prepared 
describing the complete efficacy and safety analyses of the 
double blind phase. 
Section 10.1 General Description 
Study Assessments 
Aberdeen Biomedical Imaging centre removed as vendor. 
Removed sentence any further processing by central reader 
will be documented in SAP and replaced with Details of 
analysis conducted will be reported in a separate report. 
Section 15.3.3.1 18F-FDG-PET 
Section 15.3.3.2 MRI