In Protocol v2.1, the protocol for Study TRx-237-039 (Version 1.0 dated 23 Aug 2017) was revised to clarify the assessments that would be made at various visits as follows: the blood was to 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 was to be collected, a redundant paragraph was removed, specifications for procedure of blood collection were removed from the protocol, the Appendices were renumbered and the table of contents updated, and minor edits, such as expansion of abbreviations, were made.

In Protocol v3.0, the protocol for Study TRx-237-039 (Version 2.1 dated 25 October 2017), the study duration was increased from 6 months to 9 months and the procedures and assessments associated with Visit 6 (39 weeks) were added. The study sample size increased from 180 to 375 subjects and an HMTM 16-mg/day treatment arm added: HMTM 8 mg/day, HMTM 16 mg/day, and placebo (2:1:2); the number of planned study sites was increased from 60 to at least 100. 18F-FDG-PET SUVR of temporal lobe (normalized to pons) kept as primary endpoint but a Composite Scale, to be defined, was added as the secondary endpoint. The study population was expanded from mild AD with an MMSE of 20-25 to include MCI-AD with an MMSE of 20-27; CDR 0.5 (requiring a score of >0 in one of the functional domains: Community Affairs, Home and Hobbies, or Personal Care). The inclusion criteria were changed to require an amyloid-positive PET scan and include subjects who discontinued AChEI and/or memantine at Screening; this required an extension of Screening period extended up to 6 weeks (15 weeks in total) to allow for 60-day washout of AChEI and/or memantine. The exclusion criteria were changed to exclude subjects with moderate to severe sleep apnea or any physical disability that would prevent completion of study procedures and assessments, and taking Souvenaid® and carbamazepine, but allow olanzapine. Whole blood and plasma assessed for the concentration of HMT and its metabolites and urine assessed for color determination were added as were MMSE and CDR assessments after 39 weeks or upon early termination. Brain MRI hyperintensities were also quantified.

In Protocol v4.0, 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 (e.g., number of allowed screened subjects increased from 900 to 1500), informed consent, study assessments, documentation, data protection, and study administration.

In Protocol v5.0, 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 phase (now 12 months, extended from 9 months) with subjects randomized to HMTM 16 mg/day, HMTM 8 mg/day, or placebo, followed by an open-label, delayed-start treatment period with HMTM 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 phase now pertain to comparing HMTM 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 HMTM 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 HMTM 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. Minor revisions have also been incorporated for clarity.

In Protocol v6.0, 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. Additional revisions are editorial and are intended to correct typographical errors and editorial inconsistencies as well as to add clarification.

In Protocol v7.0, 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. Additional revisions are editorial and are intended to correct typographical errors and editorial inconsistencies as well as to add clarification.