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

Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 15-Month Trial of TRx0237 in Subjects With Mild to Moderate Alzheimer's Disease

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.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: Placebo; Drug: TRx0237 250 mg/day; Drug: TRx0237 150 mg/day

• Study Type: Interventional
• Enrollment (Actual): 891
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Hornsby, New South Wales, Australia, 2077
      • Division of Rehabilitation and Aged Care
    • Kogarah, New South Wales, Australia, 2217
      • Southern Neurology Pty Limited
    • Randwick, New South Wales, Australia, 2031
      • Academic Department for Old Age Psychiatry, Prince of Wales Hospital
  • Queensland
    • Herston, Queensland, Australia, 4006
      • Discipline of Psychiatry, University of Qld
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital Memory Trials Centre
    • Woodville South, South Australia, Australia, 5011
      • Memory Unit, Neurology, The Queen Elizabeth Hospital
  • Victoria
    • Heidelberg West, Victoria, Australia, 3081
      • Medical and Cognitive Research Unit, Austin Health Heidelberg Repatriation Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • McCusker Alzheimer's Research Foundation Inc
    • Perth, Western Australia, Australia, 6005
      • Neurodegenerative Disorders Research Pty Ltd
• Bulgaria
  • Sofia, Bulgaria, 1431
    • UMHAT "Alexandrovska" Clinic of Neurology Diseases Department of Neurodegenerative and Immune and Infectious Diseases of Central Nervous System with Sector for Treatment of Neuroinfections
  • Sofia, Bulgaria, 1431
    • UMHAT "Alexandrovska" Clinic of Psychiatry First Department of Psychiatry
• Canada
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 1Z9
      • Okanagan Clinical Trials
  • Nova Scotia
    • Kentville, Nova Scotia, Canada, B4N 4K9
      • True North Clinical Research Kentville Inc
  • Ontario
    • North York, Ontario, Canada, M3B 2S7
      • Toronto Memory Program
• Croatia
  • Zagreb, Croatia, 10000
    • University hospital centre Zagreb
  • Zagreb, Croatia, 10090
    • University Psychiatric Hospital Vrapce
• Germany
  • Achim, Germany, 28832
    • Neurozentrum Achim Dr. med. Andreas Mahler
  • Berlin, Germany, 12200
    • Charité, University Medicine Berlin, CBF, Neurology
  • Berlin, Germany, 13125
    • Memory Clinic, ECRC
• Italy
  • Milano, Italy, 20133
    • Istituto Neurologico Carlo Besta
  • Milano, Italy, 20122
    • Neurologia Ospedale Maggiore Policlinico
  • Pavia, Italy, 27100
    • IRCCS Istituto neurologico Casimiro Mondino
  • Perugia, Italy, 06156
    • Clinica Neurologica, Università di Perugia-Ospedale S. Maria della Misericordia
  • Roma, Italy, 00168
    • Universita' Cattolica del Sacro Cuore
  • Roma, Italy, 00189
    • Azienda Ospedaliera Universitaria Sant'Andrea di Roma- Unita' di Neurologia
  • Torino, Italy, 10126
    • Dipartimento di Neuroscienze Universita' di Torino
  • Udine, Italy, 33100
    • Azienda Ospedaliera S.maria Della Misericordia
  • Varese, Italy, 21100
    • U.O. Di Neurologia Ospedale di Circolo e Fondazione Macchi
• Korea, Republic of
  • Busan, Korea, Republic of, 602-715
    • Dong-A Medical Center
  • Incheon, Korea, Republic of, 400-711
    • Inha University Hospital
  • Incheon, Korea, Republic of, 405-760
    • Gachon University Gil Medical Center
  • Seongnam-si, Korea, Republic of, 463-707
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center
  • Seoul, Korea, Republic of, 110-744
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 143-729
    • Konkuk University Medical Center
  • Seoul, Korea, Republic of, 156-707
    • Seoul National University Boramae Medical Center
  • Seoul, Korea, Republic of, 139-707
    • Inje University Sanggye Paik Hospital
• Malaysia
  • Ipoh, Malaysia, 30450
    • University Kuala Lumpur Royal College of Medicine
  • Johor Bahru, Malaysia, 81100
    • Hospital Sultan Ismail
  • Kuala Lumpur, Malaysia, 50603
    • University Malaya Medical Centre
  • Taiping, Malaysia, 34000
    • Taiping Hospital
• Poland
  • Białystok, Poland, 15-756
    • Podlaskie Centrum Psychogeriatrii
  • Bydgoszcz, Poland, 85-796
    • Pallmed sp zoo prowadząca NZOZ Dom Sue Ryder; Centrum Psychoneurologii Wieku Podeszłego
  • Katowice, Poland, 40-123
    • NZOZ Wielospecjalistyczna Poradnia Lekarska Synapsis
  • Mosina, Poland, 62-050
    • Gabinet Neurologiczny, Indywidualna Specjalistyczna Praktyka Lekarska
  • Poznań, Poland, 61-853
    • NZOZ NEURO-KARD Ilkowski i Partnerzy Spółka Partnerska Lekarzy
  • Szczecin, Poland, 70-111
    • EUROMEDIS Sp. z o.o.
  • Warszawa, Poland, 02-106
    • MTZ Clinical Research Sp. z o.o.
  • Warszawa, Poland, 00-669
    • Usługi Lekarskie Sp.c Palasik, Żabierek
  • Warszawa, Poland, 01-697
    • mMED
• Romania
  • Arad, Romania, 310022
    • County Emergency Clinical Hospital Arad, Psychiatry Department
  • Brasov, Romania, 500283
    • CMDTA "Neomed"
  • Bucharest, Romania, 024072
    • Psychomedical Consult
  • Bucharest, Romania, 010816
    • University Emergency Central Military Hospital "Dr.Carol Davila", Psychiatry Department
  • Oradea, Romania, 410154
    • Clinical Municipal Hospital "Dr. Gavril Curteanu", Psychiatry Department
  • Sibiu, Romania, 550082
    • Psychiatry Hospital "Dr. Gheorghe Preda", Department of Psychiatry III
  • Sibiu, Romania, 550082
    • Psychiatry Hospital "Dr. Gheorghe Preda", Center of Mental Health
  • Sibiu, Romania, 550166
    • Emergency Clinical County Hospital Sibiu, Neurology Department
• Russian Federation
  • Ekaterinburg, Russian Federation, 620030
    • State Budgetary Healthcare Institution of Sverdlovsk region "Sverdlovsk Regional Clinical Psychiatric Hospital"
  • Moscow, Russian Federation, 109388
    • Non-governmental Healthcare Institution "Central Clinical Hospital #6 of the JSC "Russian Railways"
  • Moscow, Russian Federation, 115522
    • Mental Health Research Center of the Russian Academy of Medical Sciences, Gerontopsychiatry department
  • Moscow, Russian Federation, 115522
    • Mental Health Research Center of the Russian Academy of Medical Sciences
  • Novosibirsk, Russian Federation, 630054
    • CityClinical Hospital #34, City Scientific Practical Neurological Center
  • Saint Petersburg, Russian Federation, 190103
    • City Geriatric Medical and Social Center
  • Saint Petersburg, Russian Federation, 192019
    • Saint Petersburg Psychoneurological Research Institute n. a. V.M. Bekhterev
  • Saint Petersburg, Russian Federation, 190121
    • Saint Nicholas Psychiatric Hospital
• Singapore
  • Singapore, Singapore, 529889
    • Changi General Hospital
  • Singapore, Singapore, 308433
    • Tan Tock Seng Hospital (TTSH)
  • Singapore, Singapore, 308433
    • National Neuroscience Institute (NNI)
  • Singapore, Singapore, 119223
    • National University Hospital (NUH)
• Spain
  • Ceuta, Spain, 51003
    • Hospital Universitario de Ceuta
  • Córdoba, Spain, 14011
    • Hospital Reina Sofia
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Zaragoza, Spain, 50006
    • Hospital Viamed Montecanal
• Taiwan
  • Changhua, Taiwan
    • Changhua Christian Hospital
  • Kaohsiung, Taiwan
    • Chang Gung Memorial Hospital, Kaohsiung
  • Taichung, Taiwan
    • China Medical University Hospital
  • Taipei, Taiwan
    • National Taiwan University Hospital
  • Taipei, Taiwan
    • En Chu Kong Hospital
  • Taipei, Taiwan
    • National Yang-Ming University School of Medicine
  • Taoyuan, Taiwan
    • Chang Gung Memorial Hospital, Linkou
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZH
    • NHS Grampian, Department of Old Age Psychiatry Royal Cornhill Hospital
  • Bath, United Kingdom, BA1 3NG
    • RICE - The Research Institute for the Care of Older People
  • Belfast, United Kingdom, BT12 6BA
    • Belfast Health and Social Care Trust (BHSCT)
  • Birmingham, United Kingdom, B15 2SG
    • The Barberry Centre
  • Blackpool, United Kingdom, FY2 0JH
    • MAC Clinical Research Ltd
  • Bradford, United Kingdom, BD3 0DQ
    • MAC Clinical Research Ltd
  • Cannock, United Kingdom, WS11 0BN
    • MAC Clinical Research Ltd
  • Leeds, United Kingdom, LS10 1DU
    • MAC Clinical Research Ltd
  • London, United Kingdom, W6 8RF
    • Charing Cross Hospital
  • London, United Kingdom, W1G 9JF
    • Re: Cognition Health Ltd.
  • London, United Kingdom, WC1N 3BG
    • Dementia Research Centre
  • Manchester, United Kingdom, M13 9NQ
    • MAC Clinical Research Ltd
  • Southampton, United Kingdom, SO16 6YD
    • Southampton General Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85004
      • Xenoscience, Inc/ 21st Century Neurology
  • California
    • Laguna Hills, California, United States, 92653
      • Feldman, Robert MD
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • Newport Beach, California, United States, 92658
      • Shankle Clinic and Hoag Memorial Hospital Presbyterian
    • San Diego, California, United States, 92103
      • Pacific Research Network
    • San Francisco, California, United States, 94118
      • San Francisco Clinical Research Center
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University School of Medicine
  • Florida
    • Atlantis, Florida, United States, 33462
      • JEM Research
    • Delray Beach, Florida, United States, 33445
      • Brain Matters Research
    • Jacksonville, Florida, United States, 32256
      • CNS Healthcare, Inc
    • Leesburg, Florida, United States, 34748
      • Compass Research, LLC-North Clinic
    • Miami, Florida, United States, 33143
      • Miami Research Associates
    • Orlando, Florida, United States, 32806
      • Compass Research, LLC
  • Georgia
    • Decatur, Georgia, United States, 30030
      • iResearch Atlanta
  • Illinois
    • Elk Grove, Illinois, United States, 60007
      • Alexian Brothers Neurosciences Institute
  • Massachusetts
    • Methuen, Massachusetts, United States, 01844
      • ActivMed Practices & Research
  • Mississippi
    • Olive Branch, Mississippi, United States, 38654
      • Olive Branch Family Medical
  • New Jersey
    • Eatontown, New Jersey, United States, 07724
      • Memory Enhancement Centers of America, Inc
    • Marlton, New Jersey, United States, 08053
      • CRI Worldwide
    • Springfield, New Jersey, United States, 07801
      • The Cognitive Research Center of New Jersey
    • Toms River, New Jersey, United States, 08757
      • Advanced Memory Research Institute of NJ PC
  • New York
    • Albany, New York, United States, 12208
      • Neurological Associates of Albany, P. C.
    • Brooklyn, New York, United States, 11235
      • SPRI
  • Ohio
    • Canton, Ohio, United States, 44718
      • Neurobehavioral Clinical Research
  • Pennsylvania
    • Jenkintown, Pennsylvania, United States, 19046
      • The Clinical Trial Center, LLC
  • Texas
    • Austin, Texas, United States, 78731
      • FutureSearch Trials of Neurology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 89 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of all cause dementia and probable Alzheimer's disease
• Clinical Dementia Rating (CDR) total score of 1 (mild) to 2 (moderate) and MMSE score of 14-26 (inclusive)
• Age < 90 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 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, or 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 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:

  • Tacrine
  • Clozapine, olanzapine (and there is no intent to initiate therapy during the course of the study)
  • Carbamazepine, primidone
  • Drugs with 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, therapeutic 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
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	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	Drug: TRx0237 250 mg/day; TRx0237 125 mg tablets will be administered twice daily.
EXPERIMENTAL: TRx0237 150 mg/day	Drug: TRx0237 150 mg/day; TRx0237 75 mg tablets will be administered twice daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline on Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23)		65 weeks
Change from Baseline on Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog11)		65 weeks
Number of study participants who tolerate oral doses of TRx0237 as determined by safety parameter changes	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	65 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Change from Baseline on Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC)	65 weeks
Change from Baseline on Mini-Mental Status Examination (MMSE)	65 weeks
Change in expected decline of whole brain volume as measured by brain MRI	39 weeks and 65 weeks

Other Outcome Measures

Outcome Measure	Time Frame
Reduction in glucose uptake decline in the temporal lobe on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging	39 weeks and 65 weeks
Change in expected increase in ventricular volume and decline in hippocampal volume as evaluated by MRI	39 weeks and 65 weeks
Change in resource utilization using the Resource Utilization in Dementia (RUD) Lite	65 weeks
Change from Baseline on cerebrospinal fluid biomarkers of Alzheimer's Disease in subjects who separately consent to lumbar puncture	65 weeks
Compare the influence of Apolipoprotein E genotype on the primary and selected secondary outcomes in subjects by or for whom legally acceptable consent is separately provided	65 weeks

Collaborators and Investigators

• Sponsor: TauRx Therapeutics Ltd

Publications and helpful links

General Publications

• Gauthier S, Feldman HH, Schneider LS, Wilcock GK, Frisoni GB, Hardlund JH, Moebius HJ, Bentham P, Kook KA, Wischik DJ, Schelter BO, Davis CS, Staff RT, Bracoud L, Shamsi K, Storey JM, Harrington CR, Wischik CM. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet. 2016 Dec 10;388(10062):2873-2884. doi: 10.1016/S0140-6736(16)31275-2. Epub 2016 Nov 16.

Helpful Links

• Alzheimer's Survey

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (ACTUAL): November 1, 2015
• Study Completion (ACTUAL): November 1, 2015

Study Registration Dates

• First Submitted: September 14, 2012
• First Submitted That Met QC Criteria: September 20, 2012
• First Posted (ESTIMATE): September 21, 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: Alzheimer's Disease; Dementia; Alzheimer Disease; Neurodegenerative Diseases; AD; Brain Diseases; TRx0237
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Methylene Blue
• Other Study ID Numbers: TRx-237-015