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Open-Label Study of Leuco-methylthioninium Bis(Hydromethanesulfonate) (LMTM) in Subjects With Alzheimer's Disease or Behavioral Variant Frontotemporal Dementia (bvFTD)

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ClinicalTrials.gov Identifier: NCT02245568
Recruitment Status : Terminated
First Posted : September 19, 2014
Results First Posted : June 2, 2020
Last Update Posted : June 2, 2020
Sponsor:
Information provided by (Responsible Party):
TauRx Therapeutics Ltd

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Alzheimer's Disease
Behavioral Variant Frontotemporal Dementia
Intervention Drug: LMTM
Enrollment 913
Recruitment Details  
Pre-assignment Details Subjects who completed a Phase 2 or 3 study of LMTM were eligible to enroll, pending their ability to meet the inclusion/exclusion criteria. A total of 913 subjects enrolled; however, data for 16 subjects in Spain were later excluded (GCP issues) and 1 UK subject was never dosed. Thus, 896 subjects are included in all analyses except disposition.
Arm/Group Title LMTM 100-300 mg/Day
Hide Arm/Group Description The initial LMTM dose was 200 mg/day (one 100-mg tablet twice daily), except in subjects with bvFTD who were taking a reduced dose (i.e., 100 mg/day) upon entering this extension study. The dose could be increased (after at least 13 weeks of treatment) or decreased (at any time at or after 2 weeks of treatment) by the Investigator in 100-mg increments or decrements. The maximum allowable dose was 300 mg/day (or in those countries where limited by a Competent Authority or Ethics Committee, 200 mg/day).
Period Title: Overall Study
Started 913
Completed 60
Not Completed 853
Reason Not Completed
Study terminated by Sponsor             346
Adverse Event             144
Lack of Efficacy             98
Withdrawal by Caregiver             85
Withdrawal by Subject             77
Withdrawal by Legal Representative             31
Missing (Site closure)             16
Physician Decision             14
Non-compliance with study drug             11
Death             9
Blue staining             6
Worsening dementia/caregiver withdrawal             6
Intolerance/dosing issues/interruption             5
Lost to Follow-up             5
Arm/Group Title LMTM 100-300 mg/Day
Hide Arm/Group Description The initial LMTM dose was 200 mg/day (one 100-mg tablet twice daily), except in subjects with bvFTD who were taking a reduced dose (i.e., 100 mg/day) upon entering this extension study. The dose could be increased (after at least 13 weeks of treatment) or decreased (at any time at or after 2 weeks of treatment) by the Investigator in 100-mg increments or decrements. The maximum allowable dose was 300 mg/day (or in those countries where limited by a Competent Authority or Ethics Committee, 200 mg/day).
Overall Number of Baseline Participants 896
Hide Baseline Analysis Population Description
A total of 913 subjects were enrolled, however, data for 16 subjects in Spain were excluded for analysis purposes and 1 UK subject was enrolled but never dosed; thus, 896 subjects are included in these analyses.
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 896 participants
69.2
(39 to 89)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 896 participants
Female
478
  53.3%
Male
418
  46.7%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 896 participants
Hispanic or Latino
24
   2.7%
Not Hispanic or Latino
864
  96.4%
Unknown or Not Reported
8
   0.9%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 896 participants
American Indian or Alaska Native
6
   0.7%
Asian
72
   8.0%
Native Hawaiian or Other Pacific Islander
1
   0.1%
Black or African American
18
   2.0%
White
783
  87.4%
More than one race
2
   0.2%
Unknown or Not Reported
14
   1.6%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 896 participants
Singapore 22
United States 459
United Kingdom 161
Malaysia 8
Russia 35
Spain 23
Canada 51
South Korea 13
Netherlands 2
Belgium 12
Finland 18
Taiwan 16
Australia 41
France 11
Germany 12
Croatia 11
Romania 1
1.Primary Outcome
Title Number of Participants With Serious or Non-serious Adverse Events
Hide Description Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Time Frame Up to 34 months
Hide Outcome Measure Data
Hide Analysis Population Description
The safety population was composed of participants dosed with 100-300 mg LMTM who were used for analysis. Safety was assessed over time by means of adverse event and concomitant medication recording; clinical laboratory tests; vital sign measurements and weight; 12-lead electrocardiograms; and targeted physical and neurological examinations.
Arm/Group Title LMTM 100-300 mg/Day
Hide Arm/Group Description:
The initial LMTM dose was 200 mg/day (one 100-mg tablet twice daily), except in subjects with bvFTD who were taking a reduced dose (i.e., 100 mg/day) upon entering this extension study. The dose could be increased (after at least 13 weeks of treatment) or decreased (at any time at or after 2 weeks of treatment) by the Investigator in 100-mg increments or decrements. The maximum allowable dose was 300 mg/day (or in those countries where limited by a Competent Authority or Ethics Committee, 200 mg/day).
Overall Number of Participants Analyzed 896
Measure Type: Count of Participants
Unit of Measure: Participants
734
  81.9%
Time Frame Up to 34 months
Adverse Event Reporting Description Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
 
Arm/Group Title LMTM 100-300 mg/Day
Hide Arm/Group Description The initial LMTM dose was 200 mg/day (one 100-mg tablet twice daily), except in subjects with bvFTD who were taking a reduced dose (i.e., 100 mg/day) upon entering this extension study. The dose could be increased (after at least 13 weeks of treatment) or decreased (at any time at or after 2 weeks of treatment) by the Investigator in 100-mg increments or decrements. The maximum allowable dose was 300 mg/day (or in those countries where limited by a Competent Authority or Ethics Committee, 200 mg/day).
All-Cause Mortality
LMTM 100-300 mg/Day
Affected / at Risk (%)
Total   15/896 (1.67%)    
Hide Serious Adverse Events
LMTM 100-300 mg/Day
Affected / at Risk (%) # Events
Total   146/896 (16.29%)    
Blood and lymphatic system disorders   
Anaemia  1  1/896 (0.11%)  1
Haemolytic anaemia  1  2/896 (0.22%)  2
Neutropenia  1  1/896 (0.11%)  1
Thrombocytopenia  1  1/896 (0.11%)  1
Cardiac disorders   
Acute coronary syndrome  1  1/896 (0.11%)  1
Acute myocardial infarction  1  1/896 (0.11%)  1
Atrial fibrillation  1  1/896 (0.11%)  1
Atrial flutter  1  2/896 (0.22%)  2
Atrioventricular block  1  1/896 (0.11%)  1
Bradycardia  1  2/896 (0.22%)  3
Cardiac arrest  1  1/896 (0.11%)  1
Cardiac failure congestive  1  2/896 (0.22%)  2
Cardio-respiratory arrest  1  1/896 (0.11%)  1
Myocardial infarction  1  1/896 (0.11%)  1
Pericardial effusion  1  1/896 (0.11%)  1
Sick sinus syndrome  1  1/896 (0.11%)  1
Congenital, familial and genetic disorders   
Hydrocele  1  1/896 (0.11%)  1
Gastrointestinal disorders   
Abdominal pain  1  1/896 (0.11%)  1
Colitis microscopic  1  2/896 (0.22%)  2
Diarrhoea  1  1/896 (0.11%)  1
Duodenal ulcer perforation  1  1/896 (0.11%)  1
Faecaloma  1  1/896 (0.11%)  1
Gastritis  1  1/896 (0.11%)  1
Intestinal obstruction  1  1/896 (0.11%)  1
Large intestinal obstruction  1  1/896 (0.11%)  1
Nausea  1  1/896 (0.11%)  1
Pancreatitis  1  1/896 (0.11%)  1
Vomiting  1  1/896 (0.11%)  1
General disorders   
Chest pain  1  4/896 (0.45%)  4
Hepatobiliary disorders   
Cholecystitis  1  1/896 (0.11%)  1
Cholelithiasis  1  2/896 (0.22%)  2
Immune system disorders   
Hypersensitivity  1  1/896 (0.11%)  1
Infections and infestations   
Appendicitis  1  3/896 (0.33%)  3
Bacterial pyelonephritis  1  1/896 (0.11%)  1
Bronchitis  1  1/896 (0.11%)  1
Cellulitis  1  1/896 (0.11%)  1
Cholecystitis infective  1  1/896 (0.11%)  1
Clostridium difficile infection  1  1/896 (0.11%)  1
Lower respiratory tract infection  1  1/896 (0.11%)  1
Pneumonia  1  6/896 (0.67%)  6
Sepsis  1  4/896 (0.45%)  5
Urinary tract infection  1  11/896 (1.23%)  11
Urosepsis  1  1/896 (0.11%)  1
Viral upper respiratory tract infection  1  1/896 (0.11%)  1
Injury, poisoning and procedural complications   
Concussion  1  1/896 (0.11%)  1
Facial bones fracture  1  1/896 (0.11%)  1
Fall  1  9/896 (1.00%)  9
Femoral neck fracture  1  1/896 (0.11%)  1
Femur fracture  1  2/896 (0.22%)  2
Hip fracture  1  2/896 (0.22%)  2
Humerus fracture  1  1/896 (0.11%)  1
Overdose  1  1/896 (0.11%)  1
Pelvic fracture  1  1/896 (0.11%)  1
Pulmonary contusion  1  1/896 (0.11%)  1
Rib fracture  1  1/896 (0.11%)  1
Road traffic accident  1  1/896 (0.11%)  1
Spinal compression fracture  1  1/896 (0.11%)  1
Subdural haematoma  1  1/896 (0.11%)  1
Upper limb fracture  1  1/896 (0.11%)  1
Investigations   
Blood glucose increased  1  1/896 (0.11%)  1
Liver function test abnormal  1  1/896 (0.11%)  1
Weight decreased  1  1/896 (0.11%)  1
Metabolism and nutrition disorders   
Dehydration  1  4/896 (0.45%)  4
Diabetic ketoacidosis  1  1/896 (0.11%)  1
Hypercalcaemia  1  1/896 (0.11%)  1
Hypokalaemia  1  1/896 (0.11%)  1
Hypovolaemia  1  1/896 (0.11%)  1
Musculoskeletal and connective tissue disorders   
Back pain  1  1/896 (0.11%)  1
Costochondritis  1  1/896 (0.11%)  1
Musculoskeletal pain  1  1/896 (0.11%)  1
Rotator cuff syndrome  1  2/896 (0.22%)  2
Spondylolisthesis  1  1/896 (0.11%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
B-cell lymphoma  1  1/896 (0.11%)  1
Bladder cancer  1  1/896 (0.11%)  1
Breast cancer  1  1/896 (0.11%)  1
Breast cancer recurrent  1  1/896 (0.11%)  1
Chronic lymphocytic leukaemia  1  1/896 (0.11%)  1
Malignant melanoma  1  1/896 (0.11%)  1
Metastatic neoplasm  1  1/896 (0.11%)  1
Non-Hodgkin's lymphoma  1  1/896 (0.11%)  1
Oesophageal carcinoma  1  1/896 (0.11%)  1
Ovarian cancer  1  1/896 (0.11%)  1
Pancreatic carcinoma  1  1/896 (0.11%)  1
Prostate cancer  1  1/896 (0.11%)  1
Renal cell carcinoma  1  1/896 (0.11%)  1
Squamous cell carcinoma of lung  1  1/896 (0.11%)  1
Tonsil cancer  1  1/896 (0.11%)  1
Nervous system disorders   
Altered state of consciousness  1  1/896 (0.11%)  1
Cerebral haemorrhage  1  1/896 (0.11%)  1
Cerebrovascular accident  1  2/896 (0.22%)  2
Coordination abnormal  1  1/896 (0.11%)  1
Dementia  1  1/896 (0.11%)  1
Dementia Alzheimer's type  1  3/896 (0.33%)  3
Grand mal convlusion  1  1/896 (0.11%)  1
Headache  1  1/896 (0.11%)  1
Ischaemic stroke  1  1/896 (0.11%)  1
Lacunar infarction  1  1/896 (0.11%)  1
Loss of consciousness  1  2/896 (0.22%)  2
Migraine  1  1/896 (0.11%)  1
Presyncope  1  1/896 (0.11%)  1
Seizure like phenomena  1  1/896 (0.11%)  1
Serotonin syndrome  1  1/896 (0.11%)  1
Syncope  1  6/896 (0.67%)  7
Transient ischaemic attack  1  4/896 (0.45%)  4
Tremor  1  1/896 (0.11%)  1
VIIth nerve paralysis  1  1/896 (0.11%)  1
Psychiatric disorders   
Abnormal behavior  1  1/896 (0.11%)  1
Aggression  1  3/896 (0.33%)  3
Agitation  1  4/896 (0.45%)  4
Confusional state  1  1/896 (0.11%)  1
Delirium  1  3/896 (0.33%)  3
Hallucination, visual  1  1/896 (0.11%)  1
Hypersexuality  1  1/896 (0.11%)  1
Mental status changes  1  3/896 (0.33%)  4
Staring  1  1/896 (0.11%)  1
Suicidal ideation  1  3/896 (0.33%)  3
Suicidal attempt  1  1/896 (0.11%)  1
Renal and urinary disorders   
Bladder mass  1  1/896 (0.11%)  1
Bladder prolapse  1  1/896 (0.11%)  1
Cystitis noninfective  1  1/896 (0.11%)  1
Haematuria  1  1/896 (0.11%)  1
Nephrolithiasis  1  2/896 (0.22%)  2
Nephropathy  1  1/896 (0.11%)  1
Renal failure, acute  1  2/896 (0.22%)  2
Renal impairment  1  1/896 (0.11%)  1
Urinary tract obstruction  1  1/896 (0.11%)  1
Reproductive system and breast disorders   
Uterine prolapse  1  2/896 (0.22%)  2
Respiratory, thoracic and mediastinal disorders   
Acute pulmonary oedema  1  1/896 (0.11%)  1
Acute respiratory failure  1  4/896 (0.45%)  4
Dyspnoea  1  1/896 (0.11%)  1
Hypoxia  1  1/896 (0.11%)  1
Pleural effusion  1  1/896 (0.11%)  2
Pulmonary embolism  1  3/896 (0.33%)  3
Respiratory failure  1  1/896 (0.11%)  1
Skin and subcutaneous tissue disorders   
Hyperhidrosis  1  1/896 (0.11%)  1
Vascular disorders   
Circulatory collapse  1  2/896 (0.22%)  3
Deep vein thrombosis  1  1/896 (0.11%)  1
Hypertensive crisis  1  1/896 (0.11%)  1
Hypotension  1  1/896 (0.11%)  1
Orthostatic hypotension  1  2/896 (0.22%)  2
Thrombosis  1  1/896 (0.11%)  1
1
Term from vocabulary, MedDRA Version 16.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
LMTM 100-300 mg/Day
Affected / at Risk (%) # Events
Total   717/896 (80.02%)    
Blood and lymphatic system disorders   
Anaemia  1  43/896 (4.80%)  45
Gastrointestinal disorders   
Diarrhoea  1  123/896 (13.73%)  174
Nausea  1  44/896 (4.91%)  56
Constipation  1  18/896 (2.01%)  19
Vomiting  1  36/896 (4.02%)  40
General disorders   
Fatigue  1  20/896 (2.23%)  23
Infections and infestations   
Urinary tract infection  1  49/896 (5.47%)  72
Lower respiratory tract infection  1  18/896 (2.01%)  21
Nasopharyngitis  1  27/896 (3.01%)  31
Upper respiratory tract infection  1  27/896 (3.01%)  34
Injury, poisoning and procedural complications   
Fall  1  62/896 (6.92%)  79
Investigations   
Blood creatine phosphokinase increased  1  21/896 (2.34%)  21
Creatinine renal clearance decreased  1  33/896 (3.68%)  37
Haemoglobin decreased  1  40/896 (4.46%)  44
Weight decreased  1  30/896 (3.35%)  31
Musculoskeletal and connective tissue disorders   
Arthralgia  1  27/896 (3.01%)  34
Back pain  1  18/896 (2.01%)  21
Nervous system disorders   
Dizziness  1  23/896 (2.57%)  31
Headache  1  29/896 (3.24%)  33
Psychiatric disorders   
Agitation  1  46/896 (5.13%)  59
Anxiety  1  32/896 (3.57%)  35
Confusional state  1  34/896 (3.79%)  39
Depression  1  21/896 (2.34%)  21
Insomnia  1  19/896 (2.12%)  21
Renal and urinary disorders   
Pollakiuria  1  55/896 (6.14%)  58
Urinary incontinence  1  60/896 (6.70%)  67
Dysuria  1  39/896 (4.35%)  45
Micturition urgency  1  29/896 (3.24%)  30
Respiratory, thoracic and mediastinal disorders   
Cough  1  24/896 (2.68%)  24
Vascular disorders   
Hypertension  1  20/896 (2.23%)  20
1
Term from vocabulary, MedDRA Version 16.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Diane Downie
Organization: TauRx Therapeutics Ltd
Phone: +44 1224440905
EMail: info@taurx.com
Layout table for additonal information
Responsible Party: TauRx Therapeutics Ltd
ClinicalTrials.gov Identifier: NCT02245568    
Other Study ID Numbers: TRx-237-020
First Submitted: August 27, 2014
First Posted: September 19, 2014
Results First Submitted: May 15, 2020
Results First Posted: June 2, 2020
Last Update Posted: June 2, 2020