Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 18-Month Safety and Efficacy Study of Leuco-methylthioninium bis(hydromethanesulfonate) in Subjects with Mild Alzheimer*s Disease

1. Diagnosis according to the National Institute on Aging (NIA) and Alzheimer*s Association (AA) criteria of:;• All cause dementia;and;• Probable Alzheimer*s disease;2. Clinical Dementia Rating (CDR) total score of 0.5 or 1 (mild) and MMSE score of 22-26 (inclusive) at Screening;3. Age <=90 years at Screening;4. Modified Hachinski ischemic score of <=4 at Screening;5. Females must meet one of the following: ;• Surgically sterile (hysterectomy, bilateral oophorectomy) for at least 6 months minimum;• Have undergone bilateral tubal ligation at least 6 months prior ;• Post-menopausal for at least 1 year ;• Using adequate contraception (such as condoms, foams, jellies, diaphragm, intrauterine device [IUD], oral or long-acting injected contraceptives for at least 3 months prior to Baseline or vasectomized partner) or true abstinence (when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception); subjects must agree to continue to maintain adequate contraception throughout participation in the study;6. 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 in the designated language of the study site ;7. Has an identified caregiver who meets the following criteria:;• Either lives with the subject or sees the subject on average for >= 2 hours/day >= 3 days/week, and 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;• 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 daily compliance with study drug;8. If currently taking an acetylcholinesterase inhibitor (AChEI), i.e., donepezil, galantamine, or rivastigmine, and/or memantine:;• The subject must have been taking such medication(s) for >= 3 months ;• The current dosage regimen and dosage form must be within the locally approved dose range and must have remained stable for >= 6 weeks before Baseline (Visit 2) ;• It must be planned that the dosage regimen will remain stable throughout participation in the study;Subjects not being treated with an AChEI or memantine (for >= 6 weeks before Baseline) may also be enrolled if initiation of an AChEI or memantine is not planned for the time period during which the subject will be participating in this study;9. Able to comply with the study procedures in the view of the investigator

1.Significant CNS disorder other than Alzheimer*s disease;2.Significant intracranial focal or vascular pathology seen on brain MRI scan within a maximum of 28 days before Baseline that would lead to a diagnosis other than probable Alzheimer*s disease or that puts the subject at risk of ARIA, including: other focal brain lesions, a single area of superficial siderosis, > 4 cerebral microhemorrhages, evidence of a prior 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 with associated loss of consciousness, skull fracture or persisting cognitive impairment (2 years);•Other unexplained or recurrent loss of consciousness >=15 minutes (2 years);4.Epilepsy (a single prior seizure is considered acceptable);5.DSM IV-TR criteria met for any of the following within specified period:;•Major depressive disorder (current) ;•Schizophrenia (lifetime);•Other psychotic disorders, bipolar disorder, substance (including alcohol) related disorders (within the past 5 years);6.Metal implants in the head (except dental), pacemaker, cochlear implants, or any other non-removable items that are contraindications to MR imaging; MR compatible prosthetics, clips, stents, or any other device proven to be compatible will be allowed. ;7.Resides in hospital or moderate to high dependency continuous care facility;8.History of swallowing difficulties;9.Pregnant or breastfeeding;10.History of significant hematological abnormality or current acute or chronic clinically significant abnormality, including: ;•History of hereditary or acquired methemoglobinemia or baseline measurement of MetHb >2.0%;•History of hemoglobinopathy, myelodysplastic syndrome, hemolytic anemia, or splenectomy;•G6PD deficiency ;•Baseline value below age/sex appropriate lower limit of the central laboratory normal range for any of the following:;oHemoglobin (subject may be treated and re-screened after 3 months);oVitamin B12 or folate (subject may be treated and re-screened after 3 months);11.Abnormal serum chemistry laboratory value at Screening. In addition, subjects with either of the following abnormalities must be excluded: creatinine clearance <30 mL/min at Screening, TSH above laboratory normal range (subject may be treated and re-screened after 3 months);12.Clinically significant cardiovascular disease or abnormal assessments such as:;•Hospitalization for acute coronary syndrome 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;•Evidence of atrial fibrillation on ECG or history of atrial fibrillation that is not currently controlled;•QTcB at Screening or Baseline >450 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 >160 mmHg, or diastolic blood pressure >100 mmHg, at Screening or at Baseline;•Hypotension: systolic blood pressure <100 mmHg at Screening or at Baseline;•Heart rate <48 bpm or >96 bpm by measurement of vital signs or by ECG at Screening or at Baseline;13.Preexisting or current signs or symptoms of respiratory failure; in addition, subjects should be excluded if they have: previously diagnosed moderate to severe sleep apnea not adequately controlled;14.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. Subjects with primary biliary cirrhosis should be excluded.;15.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;16.Prior intolerance or hypersensitivity to MT-containing drug, similar organic dyes, or any of the excipients;17.Treatment currently or within 3 months before Baseline with any of the following medications:;•Moderate to strong inhibitors of CYP1A2 (e.g., ciprofloxacin, fluvoxamine) ;•Tacrine ;•Anxiolytics and/or sedatives/hypnotics before cognitive testing (exceptions: sedation for MRI or short-acting benzodiazepines, chloral hydrate, or zolpidem as needed at bedtime);•Antipsychotics: clozapine, olanzapine. Other antipsychotics are allowable, preferably at a stable dose and regimen.;•Carbamazepine, primidone;•Drugs associated with methemoglobinemia;18.Prior participation in a clinical trial as follows:;•Phase 3 clinical trial of a product for cognition within the 3 months prior to Screening (unless confirmed to have been randomized to placebo);•A clinical trial of a drug, biologic, or device in which the last dose was received within 28 days prior to Baseline