Safety and Efficacy Study Evaluating TRx0237 in Subjects With Mild Alzheimer's Disease

• Change from Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog11) [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]
• Change from Baseline in Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC) [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]
• Reduction in glucose uptake decline in the temporal lobe on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]
• Number of study participants who tolerate oral doses of TRx0237 as determined by safety parameter changes [ Time Frame: 78 weeks ] [ Designated as safety issue: Yes ]
  Safety parameters include adverse events, vital signs, methemoglobin and oxygen saturation, physical and neurological examinations, laboratory tests (hematology, serum chemistry, and urinalysis), electrocardiograms, potential for serotonin toxicity, brain magnetic resonance imaging (MRI), and potential for suicide or self-harm.

• Change from Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23) [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]
• Change from Baseline in Mini-Mental Status Examination (MMSE) [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]
• Change from Baseline in Neuropsychiatric Inventory (NPI) [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]
• Change from Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]

• Change from Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23) [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]
• Change from Baseline in Mini-Mental Status Examination (MMSE) [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]
• Change from Baseline in Neuropsychiatric Inventory (NPI) [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]
• Change from Baseline in Montgomery-Ashberg Depression Rating Scale (MADRS) [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]

• Change in expected decline of whole brain volume as measured by brain MRI [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]
• Change in resource utilization using the Resource Utilization in Dementia (RUD) Lite [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]
• Change in cerebrospinal fluid biomarkers of Alzheimer's Disease in subjects who separately consent to lumbar puncture [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]
• Compare the influence of Apolipoprotein E genotype on the primary and selected secondary outcomes in subjects by or for whom legally acceptable consent is separately provided [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]

• Change in expected decline of whole brain volume as measured by brain MRI [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]
• Change in resource utilization using the Resource Utilization in Dementia (RUD) Lite [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]
• Change in cerebrospinal fluid biomarkers of Alzheimer's Disease in subjects who consent to lumbar puncture [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]
• Compare the influence of Apolipoprotein E genotype on the primary and selected secondary outcomes [ Time Frame: 78 weeks ] [ Designated as safety issue: No ]

The purpose of this study is to determine the safety and efficacy of TRx0237 in the treatment of subjects with mild Alzheimer's Disease.

• Drug: TRx0237 200 mg/day
  TRx0237 100 mg tablets will be administered twice daily.
• Drug: Placebo
  Placebo tablets will be administered twice daily. The active placebo tablets include 4 mg of TRx0237 as a urinary and fecal colorant to maintain blinding; hence the placebo group will receive a total of 8 mg/day of TRx0237.

• Experimental: TRx0237 200 mg/day
  Intervention: Drug: TRx0237 200 mg/day
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

Inclusion Criteria:

• Diagnosis of all cause dementia and probable Alzheimer's disease
• Clinical Dementia Rating (CDR) total score of 0.5 or 1 (mild) and MMSE score of 20-26 (inclusive)
• Age <90 years
• Modified Hachinski ischemic score of ≤4
• Females, if of child-bearing potential, must practice true abstinence or be competent to use adequate contraception and agree to maintain this throughout the study
• Subject, and/or, in the case of reduced decision-making capacity, legally acceptable representative(s) consistent with national law is/are able to read, understand, and provide written informed consent
• Has one (or more) identified adult caregiver who 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; either lives with the subject or sees the subject for ≥2 hours/day ≥3 days/week; agrees to accompany the subject to each study visit; and is able to verify daily compliance with study drug
• If currently taking an acetylcholinesterase inhibitor and/or memantine at the time of Screening, the subject must have been taking such medication(s) for ≥3 months. The dosage regimen must have remained stable for ≥6 weeks and it must be planned to remain stable throughout participation in the study.
• Able to comply with the study procedures

Exclusion Criteria:

• Significant central nervous system (CNS) disorder other than Alzheimer's disease
• Significant focal or vascular intracranial pathology seen on brain MRI scan
• Clinical evidence or history of stroke, transient ischemic attack, significant head injury or other unexplained or recurrent loss of consciousness ≥15 minutes
• Epilepsy
• Major depressive disorder, schizophrenia, or other psychotic disorders, bipolar disorder, substance (including alcohol) related disorders
• Metal implants in the head (except dental), 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
• History of swallowing difficulties
• Pregnant or breastfeeding
• Glucose-6-phosphate dehydrogenase 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 relevant by the investigator
• Clinically significant cardiovascular disease or abnormal assessments
• Preexisting or current signs or symptoms of respiratory failure
• Concurrent acute or chronic clinically significant immunologic, hepatic, or endocrine disease (not adequately treated) and/or other unstable or major disease other than Alzheimer's disease
• Diagnosis of cancer within the past 2 years prior to Baseline (other than basal cell or squamous cell skin cancer or Stage 1 prostate cancer) unless treatment has resulted in complete freedom from disease for at least 2 years
• Prior intolerance or hypersensitivity to methylthioninium-containing drug, similar organic dyes, or any of the excipients

• Treatment currently or within 3 months before Baseline with any of the following medications (unless otherwise noted):

  • Tacrine
  • Clozapine, olanzapine (and there is no intent to initiate therapy during the course of the study)
  • Carbamazepine, primidone
  • Drugs known to pose more than a very rare risk (1/10,000 cases) of methemoglobinemia at approved doses

• Current or prior participation in a clinical trial as follows:

  • Clinical trial of a product for cognition in which the last dose was received within 90 days prior to Screening (unless confirmed to have been randomized to placebo)
  • A clinical trial of a drug, biologic, device, or medical food in which the last dose/administration was received within 28 days prior to Baseline