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

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

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).

Study Overview

• Status: Completed
• Conditions: Behavioral Variant Frontotemporal Dementia (bvFTD)
• Intervention / Treatment: Drug: TRx0237; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 220
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • Neuroscience Research Australia
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Box Hill Hospital
  • Western Australia
    • West Perth, Western Australia, Australia, 6005
      • Neurodegenerative Disorders Research Pty Ltd
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • Heritage Medical Research Clinic-University of Calgary
  • British Columbia
    • Vancouver, British Columbia, Canada, V6T 2B5
      • University of British Columbia Hospital, Clinic for Alzheimer Disease and Related Disorders
    • Victoria, British Columbia, Canada, V8R 1J8
      • Vancouver Island Health Authority
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3S 1M7
      • True North Clinical Research
  • Ontario
    • London, Ontario, Canada, N6C 0A7
      • Geriatric Clinical Trials Group, Parkwood Institute
    • Toronto, Ontario, Canada, M3B 2S7
      • Toronto Memory Program
    • Toronto, Ontario, Canada, M5T 2S8
      • University Health Network, Toronto Western Hospital, Memory Clinic
  • Quebec
    • Verdun, Quebec, Canada, H4H 1R3
      • McGill Centre for Studies in Aging, Alzheimer Disease Research Unit
• Croatia
  • Zagreb, Croatia, 10000
    • University hospital centre Zagreb
  • Zagreb, Croatia, 10090
    • University Psychiatric Hospital Vrapce
• Germany
  • Berlin, Germany, 10117
    • Charité-Universitätsmedizin Berlin Klinik für Psychiatrie und Psychotherapie
  • Berlin, Germany, 13125
    • Memory Clinic, ECRC
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf Klinik für Psychiatrie und Psychotherapie
  • München, Germany, 81675
    • Klinik und Poliklinik für Psychiatrie und Psychotherapie der Technischen Universität München
  • Ulm, Germany, 89081
    • Universitäts - und Rehabilitationskliniken Ulm, Neurologie
• Italy
  • Brescia, Italy, 25125
    • Unità di Neuroimmagine e Epidemiologia Alzheimer
  • Chieti Scalo, Italy, 66100
    • Fondazione Universita' Gabriele D'Annunzio di Chieti
  • Milano, Italy, 20133
    • Fondazione IRCCS Istituto Neurologico "Carlo Besta"
  • Torino, Italy, 10126
    • Neurology I, Department of Neuroscience, University of Torino
• Netherlands
  • Amsterdam, Netherlands, 1081
    • Alzheimer Research Center Amsterdam
  • Den Bosch, Netherlands, 5223
    • Jeroen Bosch Ziekenhuis, afdeling geriatrie
  • Rotterdam, Netherlands, 3015
    • Erasmus University Medical Center
• Poland
  • Poznań, Poland, 61-853
    • NZOZ Neuro-Kard Ilkowski i Partnerzy Spółka Partnerska
  • Szczecin, Poland, 70-111
    • EUROMEDIS Sp. z o.o.
• Romania
  • Bucharest, Romania, 024072
    • Psychomedical Consult
• Singapore
  • Singapore, Singapore, 308433
    • National Neuroscience Institute Department of Neurology
• Spain
  • Barcelona, Spain, 08028
    • Fundació ACE. Institut Català de Neurociències Aplicades
  • Ceuta, Spain, 51003
    • Ceuta University Hospital; Neurology
  • Zaragoza, Spain, 50012
    • Hospital Viamed Montecanal, Neurology Department
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZH
    • NHS Grampian, OAP Directorate
  • Birmingham, United Kingdom, B15 2FG
    • The Barberry Out-Patients Department
  • Cheltenham, United Kingdom, GL53 9DZ
    • 2gether NHS foundation trust
  • Derby, United Kingdom, DE22 3LZ
    • Kingsway Hospital
  • Epping, United Kingdom, CM16 6TN
    • St Margaret's Hospital Mental Health Unit
  • London, United Kingdom, W1G 9JF
    • Cognition Health Ltd.
  • London, United Kingdom, W6 8RF
    • Imperial College Healthcare NHS Trust - Charing Cross Hospital
  • London, United Kingdom, WC1N 3BG
    • Dementia Research Center at Queens Square
  • Oxford, United Kingdom, OX3 9DU
    • Nuffield Department of Clinical Neurosciences
  • Shrewsbury, United Kingdom, SY3 5DS
    • Redwoods Centre
  • Southampton, United Kingdom, SO16 6YD
    • Wessex Neurological Centre, Southampton General Hospital
• United States
  • California
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine at UCLA, UCLA Neurological Services
    • Newport Beach, California, United States, 92663
      • The Shankle Clinic
    • San Francisco, California, United States, 94158
      • Memory and Aging Centre
  • Florida
    • Brooksville, Florida, United States, 34601
      • Meridien Research
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
    • Orlando, Florida, United States, 32806
      • Compass Research, LLC
    • Tampa, Florida, United States, 33613
      • University of South Florida
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Department of Neurology, Emory University
  • Illinois
    • Elk Grove Village, Illinois, United States, 60007
      • Alexian Brothers Neurosciences Institute Clinical Research
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Department of Neurology
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Neurological Clinical Research Institute (NCRI) Massachusetts General Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic, Department of Neurology
  • New Jersey
    • Eatontown, New Jersey, United States, 07724
      • Memory Enhancement Center of America, Inc.
  • New York
    • Albany, New York, United States, 12208
      • Neurological Associates of Albany, P. C.
    • Brooklyn, New York, United States, 11229
      • Integrative Clinical Trials LLC
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Department of Neurology, Physicians Office Building
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center, Neurology Clinical Trials Unit
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Rivers Wellness and Research Institute
  • Pennsylvania
    • Jenkintown, Pennsylvania, United States, 19046
      • The Clinical Trial Center, LLC
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania, Department of Neurology
  • Utah
    • Salt Lake City, Utah, United States, 84106
      • PRA Health Sciences, Phase 2/3 Outpatient and CNS Clinic
  • Vermont
    • Bennington, Vermont, United States, 05201
      • The Memory Clinic
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 79 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; 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.
Experimental: TRx0237 200 mg/day group	Drug: TRx0237; TRx0237 100 mg tablet will be administered twice daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	Time Frame
Early effect on modified ADCS-CGIC (change from Baseline)	8 weeks
Change from Baseline on the rate of atrophy in frontal and temporal lobes as well as ventricular volume (assessed by brain MRI)	52 weeks
Change from Baseline on Mini-Mental Status Examination (MMSE)	52 weeks
Change from Baseline on Addenbrooke's Cognitive Examination-III (ACE-III)	52 weeks
Determine the effect of TRx0237 in subjects with known genetic mutations associated with bvFTD	52 weeks

Collaborators and Investigators

• Sponsor: TauRx Therapeutics Ltd

Publications and helpful links

General Publications

• Pletnikova O, Sloane KL, Renton AE, Traynor BJ, Crain BJ, Reid T, Zu T, Ranum LP, Troncoso JC, Rabins PV, Onyike CU. Hippocampal sclerosis dementia with the C9ORF72 hexanucleotide repeat expansion. Neurobiol Aging. 2014 Oct;35(10):2419.e17-21. doi: 10.1016/j.neurobiolaging.2014.04.009. Epub 2014 Apr 18.

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: June 20, 2012
• First Submitted That Met QC Criteria: June 20, 2012
• First Posted (Estimate): June 22, 2012

Study Record Updates

• Last Update Posted (Actual): March 14, 2018
• Last Update Submitted That Met QC Criteria: March 12, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Frontotemporal Dementia; bvFTD; Behavioral Variant Frontotemporal Dementia
• Additional Relevant MeSH Terms: Mental Disorders; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Language Disorders; Communication Disorders; Speech Disorders; Frontotemporal Lobar Degeneration; Aphasia; Dementia; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain
• Other Study ID Numbers: TRx-237-007