Alzheimer’s Disease MedDRA version: 18.0 Level: LLT Classification code 10001896 Term: Alzheimer's disease System Organ Class: 100000004852
Conditions
Interventions
Product Name: Leuco-methylthioninium bis(hydromethanesulfonate)
Product Code: TRx0237
Pharmaceutical Form: Tablet
INN or Proposed INN: Not yet establish
Sponsors
TauRx Therapeutics Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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 1 (mild) to 2 (moderate) and Mini-Mental State Examination (MMSE) score of 14-26 (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 salpingectomy / oophorectomy) for at least 6 months minimum • Have undergone bilateral tubal occlusion / ligation at least 6 months prior Post-menopausal for at least 1 year • Using adequate contraception (a barrier methor [such as condom, diaphragm or cervical/vault cap] with spermicidal foam, gel, film, cream or suppository; intrauterine device [IUD] or system; or oral or longacting injected or implanted hormonal contraceptives for at least 3 months prior to Baseline; or vasectomized partner [with the appropriate postvasectomy documentation of the absence of spermatozoa in the ejaculate]); or true abstinence (when this is in line with the preferred and usual lifestyle of the subject); subjects must be competent to use adequate contraception and to agree to continue to maintain adequate contraception throughout participation in the study OR In Italy, have avoided a pregnancy for at least 3 months prior to Baseline and accept to avoid a pregnancy 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 • In Germany, subjects must be able to provide their own written informed consent 7. Has one or more identified adult caregivers who meet the followingcriteria: • Either lives with the subject or sees the subject on average for = 2 hours/day = 3 days/week, or 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 at the time of the Screening: • The subject must have been taking such medication(s) for = 3 months • The current dosage regim
Exclusion criteria
Exclusion criteria: 1.CNS disorder other than AD 2.intracranial focal or vascular pathology seen on brain MRI scan within a max of 42 days before Baseline that would lead to a diagnosis other than probable AD or that puts the subject at risk of ARIA, incl: large confluent white matter hyperintense lesions, other focal brain lesion(s), 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 before Baseline: •Cerebrovascular accident (2 yrs) •Transient ischemic attack (6 mnts) •Significant head injury with associated loss of consciousness, skull fracture or persisting cognitive impairment (2 yrs) •Other unexplained or recurrent loss of consciousness =15 mins (2 yrs) 4.Epilepsy (single prior seizure is acceptable) 5.DSM IV-TR criteria met for any of the following: •Major depressive disorder (current) •Schizophrenia (lifetime) •Other psychotic disorders, bipolar disorder (in past 5yrs), or substance (including alcohol) related disorders (in 2yrs) 6.Metal implants in the head (except dental), pacemaker, cochlear implants, or any non-removable items that are contraindications to MR imaging; MR compatible prosthetics, clips, stents, or any device proven to be compatible will be allowed. 7.Resides in hospital or moderate to high dependency on care facility. 8.History of swallowing difficulties 9.Pregnant/breastfeeding 10.G6PD deficiency 11.History of significant hematological abnormality or current acute or chronic clinically significant abnormality, inc: •History of hereditary or acquired methemoglobinemia or baseline measurement of MetHb >2.0% •History of hemoglobinopathy, myelodysplastic hemolytic anemia, or splenectomy •Screening hemoglobin value below age/sex appropriate lower limit of the central lab normal range for any of the following: hemoglobin &vitamin B12 or folate (subject may be treated and re-screened after 3 mths) 12.Abnormal serum chemistry value at Screening. Subjects with either : creatinine clearance 460 msec 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 •Hypotension: systolic blood pressure <100 mmHg at Screening •Heart rate <48 bpm o
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): Primary efficacy endpoints: ADAS-cog11, ADCS-CGIC.;Timepoint(s) of evaluation of this end point: Assessments will be made at Baseline (Visit 2, pre-dose), after 13, 26, 39, and 65 weeks of treatment, and at the 4 week off-treatment follow-up visit.; Main Objective: 1.To demonstrate clinical efficacy of at least one dose level of leuco-methylthioninium bis(hydromethanesulfonate) (also known as LMTM, TRx0237) in mild to moderate Alzheimer’s disease based on change from baseline on the following co-primary endpoints: •Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-cog11) and •Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL23) 2.To assess the safety and tolerability of LMTM 150 and 250 mg/day given for up to 65 weeks ; Secondary Objective: Secondary: 3.To demonstrate disease modification based: •Reduction in decline in whole brain volume using change from Baseline as measured by the BBS Integral by MRI imaging 4.evaluate the effect of LMTM on a global measure, ADCS-CGIC – independently rated 5.To evaluate the effects of LMTM on other aspects of AD including cognition (MMSE) Exploratory: 6.To determine the effects of LMTM on AD by showing retardation of the rate of brain atrophy by reducing the expected increase in ventricular volume and decline in hippocampal volume as evaluated by MRI 7.evaluate the effect of LMTM on AD modification by reduction in decline in glucose uptake in the temporal lobe on FDG-PET imaging in sites with appropriate capability 8.To determine the effects of LMTM on resource utilization using the RUD Lite 9.explore changes in CSF biomarkers of AD in subjects who are mentally capable of providing their own separate | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary efficacy endpoints: ADCS-ADL23, MMSE, FDG-PET/CT, CDR Secondary safety and tolerability endpoints: adverse events (AEs), vital sign and methemoglobin measurements, 12-lead ECGs, clinical laboratory findings, physical and neurological examinations, potential for serotonin toxicity, brain MRI, and potential for suicide or self-harm ; Timepoint(s) of evaluation of this end point: •ADCS-ADL23: at Baseline, after 13, 26, 39, 52 and 65 weeks of treatment, at follow-up visit. •MMSE: at Screening, after 26 52 and 65 weeks of treatment, at follow-up visit. •FDG-PET/CT: at Screening/Baseline and after 26 and 52 weeks of treatment. •CDR: at Screening. •AEs: from the ICF signature and throughout the study. •Lab testing:at Screening,Baseline,Visits 3 - 10 •Serotonin toxicity:at Baseline &at each subsequent visit •Brain MRI:at Screening & at Weeks 13,26,39,52,65 •At screening & each visit: oral T°, respiratory rate, ECG, BP &pulse (+within 1 hour before & approx. 2 hours after administration of the first dose), MetHB (+approx. 1 hour before &approx. 2.5 hrs after administration of the first dose of study drug). | — |
Countries
Australia, Bulgaria, Canada, Croatia, Germany, Italy, Korea, Republic of, Malaysia, Poland, Romania, Russian Federation, Singapore, Spain, Taiwan, United Kingdom, United States
Contacts
Public ContactInformation Desk
TauRx Therapeutics Ltd
Outcome results
None listed