A comparison study of LMTM and placebo in patients with behavioral variant frontotemporal dementia

• Register: EUCTR
• Last refreshed on: 27 July 2020
• Main ID: EUCTR2011-005529-34-GB
• Date of registration: 08/08/2012
• Prospective Registration: Yes
• Primary sponsor: TauRx Therapeutics Ltd
• Public title: A comparison study of LMTM and placebo in patients with behavioral variant frontotemporal dementia
• Scientific title: A Double-Blind, Placebo-Controlled, Randomized, Parallel Group, 12-Month Safety and Efficacy Trial of Leuco-methylthioninium bis(hydromethanesulfonate) in Subjects with Behavioral Variant Frontotemporal Dementia (bvFTD) - TRx-237-007
• Date of first enrolment: 17/01/2013
• Target sample size: 180
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-005529-34
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Canada, Croatia, Finland, Germany, Italy, Netherlands, Poland, Romania, Singapore, Spain, United Kingdom, United States

Contacts

• Name: Information Desk
• Affiliation: TauRx Therapeutics Ltd

• Name: Information Desk
• Affiliation: TauRx Therapeutics Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
1. Diagnosis of probable bvFTD according to the International Consensus Criteria for bvFTD
2. Centrally rated frontotemporal atrophy score of 2 or greater, taken as the maximum of right or left frontal or anterior temporal lobes on brain MRI of sufficient quality obtained at Screening or within a maximum of 42 days before Baseline, irrespective of pre-existing structural or functional imaging evidence supporting a diagnosis of bvFTD
3. MMSE =20 at the Screening visit
4. Age <80 years at the Screening visit
5. Modified Hachinski ischemic score of =4 at the Screening visit
6. 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 method [such as condom, diaphragm, or cervical/vault cap] with spermicidal foam, gel, film, cream, or suppository; intrauterine device [IUD] or system, or oral or long-acting injected or implanted hormonal contraceptives for at least 3 months prior to Baseline; or vasectomized partner [with the appropriate post-vasectomy 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
7. 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
8. Has one or more identified adult caregivers who meet the following criteria:
• 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
9. If currently taking an AChEI (i.e., donepezil, galantamine, or rivastigmine) and/or memantine, at the time of Screening:
• 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
• 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 Screening) 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
10. Able to comply with the study procedures in the view of the Investigator
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 90
F.1.3 Elderly (>=
Exclusion criteria:
1.Significant CNS disorder other than bvFTD
2.Other significant intracranial pathology seen on brain MRI scan that would lead to a diagnosis other than probable bvFTD or that puts the subject at risk of Amyloid Related Imaging Abnormalities including: 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.Biomarker evidence of underlying AD pathology as etiology of dementia
4.Expressive language deficits such that the subject is too severely impaired to allow testing at Baseline
5.Meets research criteria for Amyotrophic Lateral Sclerosis or motor;evidence of mild motor neuron disease on examination is allowed if not expected to interfere with subject's completion of study but prominent bulbar symptoms would be exclusionary
6.Meets diagnostic criteria for probable bvFTD but has a proven mutation producing non-tau,non-TDP-43 pathology
7.Clinical evidence or history of:
·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)
8.Epilepsy (a single prior seizure is considered acceptable)
9.Rapid eye movement sleep behavior disorder
10.DSM IV-TR criteria met for the following within specified period:
·Major depressive disorder (current)
·Schizophrenia (lifetime)
·Other psychotic disorders, bipolar disorder (within the past 5 years),or substance related disorders (within the past 2 years)
11.Metal implants in the head (except dental),pacemaker, any other non-removable items that are contraindications to MR imaging; any device proven to be MR compatible will be allowed
12.Resides in hospital or moderate to high dependency continuous care facility
13.History of swallowing difficulties
14.Pregnant or breastfeeding
15.G6PD deficiency
16.History of significant hematological abnormality or current acute or chronic clinically significant abnormality, including:
·Hereditary or acquired methemoglobinemia or Baseline measurement of MetHb >2.0%
·Hemoglobinopathy, myelodysplastic syndrome, hemolytic anemia,or splenectomy
·Screening value below normal range for hemoglobin and vitamin B12 or folate
17.Abnormal serum chemistry laboratory value at Screening clinically relevant.In addition, subjects with the following abnormalities must be excluded:
·Creatinine clearance <50 mL/min at Screening
·Thyroid stimulating hormone above laboratory normal range
18.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 uncontrolled atrial fibrillation on Screening ECG or history of atrial fibrillation that is not currently controlled or where the QT interval cannot be assessed by triplicate ECGs
·QTcF at Screening >460 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
·Hypotension
·Heart rate <48 bpm or >96 bpm by measurement of vital signs or by ECG at Screening
19.Preexisting or current signs or symptoms of respiratory failure. Subjects with previously diagnosed moderate

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

behavioral variant Frontotemporal Dementia (bvFTD)
MedDRA version: 18.0 Level: PT Classification code 10068968 Term: Frontotemporal dementia System Organ Class: 10029205 - Nervous system disorders

Intervention(s)

Product Name: Leuco-methylthioninium bis(hydromethanesulfonate)
Product Code: LMTM/TRx0237
Pharmaceutical Form: Tablet
INN or Proposed INN: N/A
CAS Number: 1236208-20-0
Current Sponsor code: TRx0237
Other descriptive name: N,N,N’,N’-tetramethyl-10H-phenothiazine-3,7-diaminium bis(methanesulfonate)
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: - To evaluate the effect of LMTM as measured by the following additional global, disease severity, and motor impairment scales:
• Modified Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change (Modified ADCS- CGIC) -– independently rated
• Frontotemporal Dementia Rating Scale (FRS)
• Functional Activities Questionnaire (FAQ)
• Unified Parkinson’s Disease Rating Scale (UPDRS Parts II and III)

- To evaluate the safety and tolerability of LMTM

Timepoint(s) of evaluation of this end point: Efficacy will be evaluated at baseline and after 4 months (16 weeks), 8 months (32 weeks), and 12 months (52 weeks)

Main Objective: To demonstrate the efficacy of LMTM as assessed by the change from Baseline on:
• Addenbrooke’s Cognitive Examination Scale Revised (ACE-R)
• Symptomatic effect as reflected by the Functional Activities Questionnaire (FAQ)
• Disease-modifying effect based on reduction in decline in whole brain volume (WBV), using change from Baseline as measured by the Brain Boundary Shift Integral (BBSI) by MRI imaging

Primary end point(s): Primary Efficacy endpoint:
• Change from Baseline to Week 52 in the ACE-R
• Either of two co-primary endpoints:
o Change from Baseline to Week 52 in FAQ
o Reduction in decline in whole brain volume at Week 52, using change from Baseline as measured by the Brain Boundary Shift Integral (BBSI) by MRI imaging

Secondary Outcome(s)

Secondary end point(s): Secondary clinical endpoints include the following:
• Modified CGIC
• FRS
• UPDRS Parts II and III

Timepoint(s) of evaluation of this end point: Safety assessment will performed during screening, then at Baseline (pre dose and during the 4-hour post-dose observation), and 4,8,16,24,32,42 and 52 weeks after Baseline, and approximately 4 weeks after the last dose of study drug( if applicable)
Blood will be collected at Baseline and as possible at each subsequent on-treatment visit through Week 52 for purposes of population pharmacokinetic (PK) analysis of MT concentrations

A single blood sample for genotyping may be collected any time after eligibility for randomization and participation in the study has been confirmed at Baseline (Visit 2).

Secondary ID(s)

TRx-237-007

2011-005529-34-DE

Source(s) of Monetary Support

TauRx Therapeutics Ltd

Ethics review

Status: Approved
Approval date: 17/01/2013
Contact:

Results

• Results available: Yes
• Date Posted: 02/02/2020
• Date Completed: 22/02/2016
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-005529-34/results