Safety and Efficacy of TRx0237 in Subjects With Alzheimer's Disease Followed by Open-Label Treatment

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and efficacy of TRx0237 16 mg/day and 8 mg/day in the treatment of subjects with Alzheimer's Disease compared to placebo. In addition, an open-label, delayed-start phase is included to demonstrate a disease-modifying effect of TRx0237.

Official Title
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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

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: TRx0237 16 mg/day
* Drug: Placebo
* Drug: TRx0237 8 mg/day


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Alzheimer's Disease (AD), encompassing probable AD and mild cognitive impairment due to AD (MCI-AD) based on the 2011 National Institute on Aging and Alzheimer's Association (NIA/AA) criteria Documented PET scan that is positive for amyloid Mini-Mental State Examination (MMSE) score of 16-27 (inclusive), subject to stratification requirements Global Clinical Dementia Rating (CDR) of 0.5 to 2 (if 0.5, including a score of >0 in one of the functional domains: Community Affairs, Home and Hobbies, or Personal Care) Age <90 years Females must be surgically sterile, have undergone bilateral tubal occlusion / ligation, be post-menopausal, or use adequate contraception Subject, and/or, in the case of reduced decision-making capacity, legally acceptable representative(s) consistent with local and national law is/are able to read, understand, and provide written informed consent in the designated language of the study site Has one or more identified adult study partner who either lives with the subject or has sufficient contact to provide assessment of changes in subject behavior and function over time and information on safety and tolerability; 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; and is able to verify daily compliance with study drug Must not be taking an acetylcholinesterase inhibitor and/or memantine for at least 60 days at the time of the Baseline assessments Able to comply with the study procedures in the view of the Investigator Exclusion Criteria: Significant central nervous system disorder other than probable AD or MCI-AD Significant intracranial focal or vascular pathology seen on brain MRI scan that would lead to a diagnosis other than probable AD or MCI-AD Clinical evidence or history of cerebrovascular accident; transient ischemic attack; significant head injury, for example, associated loss of consciousness, skull fracture or persisting cognitive impairment; other unexplained or recurrent loss of consciousness for ≥15 minutes Epilepsy (a single prior seizure >6 months prior to Screening is considered acceptable) Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria met for major depressive disorder; schizophrenia; other psychotic disorders, bipolar disorder; substance (including alcohol) related disorders Metal implants in the head, pacemaker, cochlear implants, or any other non-removable items that are contraindications to MRI Resides in hospital or moderate to high dependency continuous care facility Any physical disability that would prevent completion of study procedures or assessments History of swallowing difficulties Pregnant or breastfeeding Glucose-6-phosphate dehydrogenase (G6PD) deficiency History of significant hematological abnormality or current acute or chronic clinically significant abnormality Abnormal serum chemistry laboratory value at Screening deemed to be clinically significant by the Investigator Clinically significant cardiovascular disease or abnormal electrocardiogram assessments Pre-existing or current signs or symptoms of respiratory failure Concurrent acute or chronic clinically significant immunologic, hepatobiliary, or endocrine disease and/or other unstable or major disease other than probable AD or MCI-AD Diagnosis of cancer (excluding basal cell carcinoma, squamous cell carcinoma, or prostate carcinoma in situ [Stage 1]) within the past 2 years or a previous (>2 years) diagnosis of cancer that has required any form of intervention or treatment within the past 2 years Prior intolerance or hypersensitivity to methylthioninium (MT)-containing drug or methemoglobinemia induced by MT-containing drug, similar organic dyes, or any of the excipients Treatment currently or within 90 days before Baseline with Souvenaid®, clozapine, carbamazepine, primidone, valproate, or drugs for which there is a warning or precaution in the labeling about methemoglobinemia at approved doses Current or prior participation in any clinical trial of TRx0237; a 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; or 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

Ages Eligible for Study
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Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TRx0237 16 mg/day<br> | Drug: TRx0237 16 mg/day<br>* Oral TRx0237 4-mg tablets administered twice daily<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Oral placebo tablets (some of which contain a urinary discolorant) administered twice daily<br>|
| Experimental: TRx0237 8 mg/day<br> | Drug: TRx0237 8 mg/day<br>* Oral TRx0237 4-mg tablet administered twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline on Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog11) | This primary outcome measure will be assessed in the TRx0237 16 mg/day group compared to the placebo group. The scores on this scale range from 0 to 70, with higher numbers indicating a worse outcome (greater impairment). | Baseline and 52 weeks | 
| Change from Baseline on Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23) | This primary outcome measure will be assessed in the TRx0237 16 mg/day group compared to the placebo group. The scores on this scale range from 0 to 78, with higher numbers indicating a better outcome (lower impairment). | Baseline and 52 weeks | 
| Number of study participants with serious and non-serious adverse events | This primary outcome measure will be assessed in the TRx0237 16 mg/day group compared to the placebo group. All laboratory test or vital sign parameter abnormalities deemed clinically significant by the Investigator are to be reported as adverse events. | Up to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in annualized rate of whole brain atrophy | This secondary outcome measure will be assessed in the TRx0237 16 mg/day group compared to the placebo group. | Baseline and 52 weeks | 
| Change in Standardized Uptake Value Ratio (SUVR) based on temporal lobe 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) | This secondary outcome measure will be assessed in each of the TRx0237 dose groups compared to the placebo group, and restricted to subjects with Clinical Dementia Rating (CDR) 0.5 at Screening. | Baseline and 52 weeks | 
| Change in annualized rate of temporal and parietal lobe atrophy | This secondary outcome measure will be assessed in each of the TRx0237 dose groups compared to the placebo group. | Baseline and 52 weeks | 
| Change from Baseline on Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog11) | This secondary outcome measure will be assessed in the TRx0237 8 mg/day group compared to the placebo group. The scores on this scale range from 0 to 70, with higher numbers indicating a worse outcome (greater impairment). | Baseline and 52 weeks | 
| Change from Baseline on Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23) | This secondary outcome measure will be assessed in the TRx0237 8 mg/day group compared to the placebo group. The scores on this scale range from 0 to 78, with higher numbers indicating a better outcome (lower impairment). | Baseline and 52 weeks | 
| Change from Open-Label Baseline on Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog11) | This secondary outcome measure will be assessed for the open-label period of the study comparing subjects originally randomized to placebo to subjects originally randomized to either dose of TRx0237. The scores on this scale range from 0 to 70, with higher numbers indicating a worse outcome (greater impairment). | 52 weeks and 104 weeks | 
| Number of study participants with serious and non-serious adverse events | This secondary outcome measure will be assessed in the TRx0237 8 mg/day group compared to the placebo group over 52 weeks and for all subjects receiving TRx0237 up to 104 weeks. All laboratory test or vital sign parameter abnormalities deemed clinically significant by the Investigator are to be reported as adverse events. | Up to 104 weeks |