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

• Change from Baseline in Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• Change from Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog11) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• Number of study participants who tolerate oral doses of TRx0237 as determined by safety parameter changes [ Time Frame: 52 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 suicide and self-harm, brain magnetic resonance imaging (MRI), and potential for serotonin toxicity

• Change from Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• Change from Baseline in Mini-Mental Status Examination (MMSE) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]

• Reduction in glucose uptake decline by 18F-fluorodeoxyglucose positron emission tomography/computerized tomography (FDG-PET/CT) of the temporal lobes [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• Change in expected decline of whole brain volume as measured by brain MRI [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]

• Reduction in glucose uptake decline by FDG-PET/CT of the temporal lobes [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
• Change in expected decline of whole brain volume as measured by brain MRI [ Time Frame: 52 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 to moderate Alzheimer's Disease.

• Drug: TRx0237 150 mg/day
  TRx0237 75 mg tablets will be administered twice daily.
• Drug: TRx0237 250 mg/day
  TRx0237 125 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 250 mg/day
  Intervention: Drug: TRx0237 250 mg/day
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo
• Experimental: TRx0237 150 mg/day
  Intervention: Drug: TRx0237 150 mg/day

Inclusion Criteria:

• Diagnosis of all cause dementia and probable Alzheimer's disease
• Clinical dementia rating (CDR) total score of 1 to 2 and MMSE score of 14-26 (inclusive)
• Age < 90 years
• Modified Hachinski ischemic score of ≤ 4
• Females, if of child-bearing potential, must be using adequate contraception or practice true abstinence 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 an identified 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; magnetic resonance compatible prosthetics, clips, stents, or any other device proven to be compatible will be allowed
• 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
  • Anxiolytics and/or sedatives/hypnotics taken prior to cognitive testing (exceptions: sedation for imaging or occasional short-acting benzodiazepines, chloral hydrate, or zolpidem as needed at bedtime)
  • Clozapine, olanzapine (and there is no intent to initiate therapy during the course of the study)
  • Carbamazepine, primidone
  • Drugs associated with methemoglobinemia

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

  • Phase 3 clinical trial of a product for cognition within 3 months (unless confirmed to have been randomized to placebo)
  • A clinical trial of a drug, biologic, therapeutic device, or medical food in which the last dose/administration was received within 28 days prior to Baseline