Safety and Efficacy Study Evaluating TRx0237 in Subjects With Behavioral Variant Frontotemporal Dementia (bvFTD)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to demonstrate the safety and efficacy of TRx0237 in the treatment of patients with behavioral variant frontotemporal dementia (bvFTD).

Official Title
-----------------
A Double-Blind, Placebo-Controlled, Randomized, Parallel Group, 12-Month Safety and Efficacy Trial of TRx0237 in Subjects With Behavioral Variant Frontotemporal Dementia (bvFTD)

Conditions
-----------------
Behavioral Variant Frontotemporal Dementia (bvFTD)

Intervention / Treatment
-----------------
* Drug: TRx0237
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of probable bvFTD Centrally rated frontotemporal atrophy score of 2 or greater on brain MRI MMSE ≥20 Age <80 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, 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 bvFTD Significant intracranial pathology seen on brain MRI scan Biomarker evidence of underlying Alzheimer's disease pathology Expressive language deficits Meets research criteria for Amyotrophic Lateral Sclerosis or motor neuron disease Meets diagnostic criteria for probable bvFTD but has a proven mutation producing non-tau, non-TDP-43 pathology Clinical evidence or history of stroke, transient ischemic attack, significant head injury or other unexplained or recurrent loss of consciousness ≥15 minutes Epilepsy Rapid eye movement sleep behavior disorder 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 bvFTD 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 90 days before Baseline with any of the following medications (unless otherwise noted): Tacrine Amphetamine or dexamphetamine Clozapine, olanzapine (and there is no intent to initiate therapy during the course of the study) Carbamazepine, primidone Drugs for which there is a warning or precaution in the labeling about methemoglobinemia at approved doses Current or prior participation in a clinical trial as follows: Clinical trial of a product for cognition within 3 months of 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

Ages Eligible for Study
-----------------
Maximum Age: 79 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TRx0237 200 mg/day group<br> | Drug: TRx0237<br>* TRx0237 100 mg tablet will be administered twice daily.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo tablets will be administered twice daily. The 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline on Addenbrooke's Cognitive Examination - Revised (ACE-R) |  | 52 weeks | 
| Change from Baseline on Functional Activities Questionnaire (FAQ) |  | 52 weeks | 
| Change from Baseline on whole brain volume (assessed by brain MRI) |  | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline on Unified Parkinson's Disease Rating Scale (UPDRS Parts II and III) |  | 52 weeks | 
| Change from Baseline on Frontotemporal Dementia Rating Scale (FRS) |  | 52 weeks | 
| Change from Baseline on Modified Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (modified ADCS-CGIC) |  | 52 weeks | 
| Number of study participants who tolerate oral doses of TRx0237 as determined by safety parameter changes | Safety parameters included adverse events, vital signs, methemoglobin and oxygen saturation, physical and neurological examinations, laboratory tests (hematology, serum chemistry, and urinalysis), electrocardiograms, assessment of serotonin syndrome, brain magnetic resonance imaging (MRI) and potential for suicidal behavior and thoughts | 52 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Behavioral Variant Frontotemporal Dementia, bvFTD, Frontotemporal Dementia