Clinical Trials List
Protocol NumberTRx-237-015
2013-01-01 - 2015-12-31
Phase III
Terminated5
Study ended1
ICD-10G30.0
Alzheimer's disease with early onset
ICD-10G30.1
Alzheimer's disease with late onset
ICD-10G30.8
Other Alzheimer's disease
ICD-10G30.9
Alzheimer's disease, unspecified
ICD-9331.0
Alzheimer's disease
Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 12-Month Trial of Leuco-methylthioninium bis(hydromethanesulfonate) in Subjects with Mild to Moderate Alzheimer's Disease
-
Trial Applicant
WORLDWIDE CLINICAL TRIALS (TAIWAN) CO., LTD.
-
Sponsor
TauRx Therapeutics Ltd
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Terminated
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- KuoLun Huang Division of Neurology
- Hong-Chou Kuo Division of Neurology
- 莊雯莉 Division of Neurology
- Wen-Chuin Hsu Division of Neurology
- 衛優遊 Division of Radiology
The Actual Total Number of Participants Enrolled
0 Terminated
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Chin-Wei Huang Division of Neurology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Chon-Haw Tsai Division of Neurology
- Kang-Hsu Lin Division of Neurology
- Hui-Chun Huang Division of Neurology
- Ming-Kuei Lu Division of Neurology
- Yi-Ting Hsu Division of Neurology
- Wei-Shih Huang Division of Neurology
The Actual Total Number of Participants Enrolled
3 Study ended
Condition/Disease
Alzeheimer's Disease
Objectives
Primary:
1. To demonstrate the clinical efficacy of at least one dose level of leuco-methylthioninium
bis(hydromethanesulfonate) (also known as LMTM, TRx0237) in mild to moderate Alzheimer’s disease as
assessed by change from baseline on:
Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-cog11)
Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change (ADCS-CGIC) -
independently rated
2. To determine the safety and tolerability of LMTM 150 and 250 mg/day
Secondary:
3. To evaluate the effect of LMTM on functional activities of daily living using the Alzheimer’s Disease
Cooperative Study – Activities of Daily Living (ADCS-ADL23)
4. To evaluate the effects of LMTM on other aspects of Alzheimer’s disease including cognition (Mini-Mental
Status Examination, MMSE)
Test Drug
LMTM
Active Ingredient
Leuco-methylthioninium bis(hydromethanesulfonate)
Dosage Form
tablet
Dosage
100
125
4
75
125
4
75
Endpoints
Efficacy:
Assessments will be made at Baseline (Visit 2, pre-dose), after 13, 26, 39, and 52 weeks of treatment, and at the
4-week off-treatment follow-up visit by assessors/raters who are not involved in the assessment of safety using the
following instruments:
ADAS-cog11
ADCS-CGIC (a separate rater who remains blinded throughout study to results of other efficacy assessments)
ADCS-ADL23
The MMSE will be rated at Screening, after 26 and 52 weeks of treatment, and at the 4-week off-treatment follow-up
visit.
FDG-PET/CT will be performed at those centers with appropriate capability for imaging; imaging will occur during
Screening/Baseline and after 26 and 52 weeks of treatment; brain MRI (obtained approximately every 3 months for
evaluation of ARIA, see below) will also be evaluated for whole brain volume at Week 52. Imaging data will be
evaluated centrally by independent readers who are not involved in the clinical conduct of the study. FDG-PET/CT
data will be evaluated by a nuclear physician who is experienced in neuro PET and trained on the study endpoints and
MRI data will be reviewed by an experienced neuroradiologist.
CDR will only be assessed at Screening to determine a CDR total score for severity/inclusion determination.
Assessments will be made at Baseline (Visit 2, pre-dose), after 13, 26, 39, and 52 weeks of treatment, and at the
4-week off-treatment follow-up visit by assessors/raters who are not involved in the assessment of safety using the
following instruments:
ADAS-cog11
ADCS-CGIC (a separate rater who remains blinded throughout study to results of other efficacy assessments)
ADCS-ADL23
The MMSE will be rated at Screening, after 26 and 52 weeks of treatment, and at the 4-week off-treatment follow-up
visit.
FDG-PET/CT will be performed at those centers with appropriate capability for imaging; imaging will occur during
Screening/Baseline and after 26 and 52 weeks of treatment; brain MRI (obtained approximately every 3 months for
evaluation of ARIA, see below) will also be evaluated for whole brain volume at Week 52. Imaging data will be
evaluated centrally by independent readers who are not involved in the clinical conduct of the study. FDG-PET/CT
data will be evaluated by a nuclear physician who is experienced in neuro PET and trained on the study endpoints and
MRI data will be reviewed by an experienced neuroradiologist.
CDR will only be assessed at Screening to determine a CDR total score for severity/inclusion determination.
Inclution Criteria
1. Diagnosis according to the National Institute on Aging (NIA) and Alzheimer’s Association (AA) criteria of:
All cause dementia
and
Probable Alzheimer’s disease
2. Clinical Dementia Rating (CDR) total score of 1 (mild) to 2 (moderate) and Mini-Mental State Examination
(MMSE) score of 14-26 (inclusive) at Screening
3. Age ≤90 years at Screening
4. Modified Hachinski ischemic score of ≤4 at Screening
5. Females must meet one of the following:
Surgically sterile (hysterectomy, bilateral oophorectomy) for at least 6 months minimum
Have undergone bilateral tubal ligation at least 6 months prior
Post-menopausal for at least 1 year
Using adequate contraception (such as condoms, foams, jellies, diaphragm, intrauterine device [IUD], oral or
long-acting injected contraceptives for at least 3 months prior to Baseline); vasectomized partner; or true
abstinence (when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence [e.g.,
calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of
contraception); subjects must agree to continue to maintain adequate contraception throughout participation
in the study
6. 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
7. Has an identified caregiver who meets 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
8. If currently taking an acetylcholinesterase inhibitor (AChEI), i.e., donepezil, galantamine, or rivastigmine, and/or
memantine:
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 before Baseline (Visit 2)
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 Baseline) 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
9. Able to comply with the study procedures in the view of the investigator
All cause dementia
and
Probable Alzheimer’s disease
2. Clinical Dementia Rating (CDR) total score of 1 (mild) to 2 (moderate) and Mini-Mental State Examination
(MMSE) score of 14-26 (inclusive) at Screening
3. Age ≤90 years at Screening
4. Modified Hachinski ischemic score of ≤4 at Screening
5. Females must meet one of the following:
Surgically sterile (hysterectomy, bilateral oophorectomy) for at least 6 months minimum
Have undergone bilateral tubal ligation at least 6 months prior
Post-menopausal for at least 1 year
Using adequate contraception (such as condoms, foams, jellies, diaphragm, intrauterine device [IUD], oral or
long-acting injected contraceptives for at least 3 months prior to Baseline); vasectomized partner; or true
abstinence (when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence [e.g.,
calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of
contraception); subjects must agree to continue to maintain adequate contraception throughout participation
in the study
6. 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
7. Has an identified caregiver who meets 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
8. If currently taking an acetylcholinesterase inhibitor (AChEI), i.e., donepezil, galantamine, or rivastigmine, and/or
memantine:
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 before Baseline (Visit 2)
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 Baseline) 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
9. Able to comply with the study procedures in the view of the investigator
Exclusion Criteria
1. Significant CNS disorder other than Alzheimer’s disease, e.g., Parkinson’s disease, multiple sclerosis, progressive
supranuclear palsy, hydrocephalus, Huntington’s disease
2. Significant intracranial focal or vascular pathology seen on brain MRI scan within a maximum of 28 days before
Baseline that would, based on the independent reviewer imaging evaluation, lead to a diagnosis other than
probable Alzheimer’s disease or that puts the subject at risk of Amyloid Related Imaging Abnormalities (ARIA),
including:
other focal brain lesions judged clinically relevant
a single area of superficial siderosis
> 4 cerebral microhemorrhages (regardless of their anatomical location or diagnostic characterization as
“possible” or “definite”)
evidence of a prior macrohemorrhage
3. Clinical evidence or history of any of the following within specified period before Baseline:
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)
4. Epilepsy (a single prior seizure is considered acceptable)
5. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition – Text Revision (DSM IV-TR) criteria met
(and not subsequently revised) for any of the following within specified period:
Major depressive disorder (current)
Schizophrenia (lifetime)
Other psychotic disorders, bipolar disorder, substance (including alcohol) related disorders (within the past
5 years)
6. Metal implants in the head (except dental), pacemaker, cochlear implants, or any other non-removable items that
are contraindications to MR imaging; MR compatible prosthetics, clips, stents, or any other device proven to be
compatible will be allowed.
7. Resides in hospital or moderate to high dependency continuous care facility (residence in low grade assisted
living facility where there is sufficient autonomy to permit valid evaluation of activities of daily living is
permitted).
8. History of swallowing difficulties (note: study drug should be swallowed whole and MUST NOT be broken,
crushed, or chewed)
9. Pregnant or breastfeeding
10. History of significant hematological abnormality or current acute or chronic clinically significant abnormality,
including:
History of hereditary or acquired methemoglobinemia or baseline measurement of methemoglobin (MetHb)
> 2.0% (confirmed on repeat)
History of hemoglobinopathy, myelodysplastic syndrome, hemolytic anemia, or splenectomy
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Baseline value below age/sex appropriate lower limit of the central laboratory normal range for any of the
following:
o Hemoglobin (subject may be treated and re-screened after 3 months)
o Vitamin B12 or folate (subject may be treated and re-screened after 3 months)
11. Abnormal serum chemistry laboratory value at Screening deemed to be clinically relevant by the investigator,
e.g., considered to have the potential to increase the risk associated with study participation or administration of
investigational product and, in the judgment of the investigator, would make the subject inappropriate for entry
into this study. In addition, subjects with either of the following abnormalities must be excluded:
Creatinine clearance < 30 mL/min at Screening, estimated by the central laboratory according to the
Cockcroft and Gault equation
Thyroid stimulating hormone (TSH) above laboratory normal range (subject may be treated and re-screened after 3 months)
12. Clinically significant (in the opinion of the investigator) cardiovascular disease or abnormal assessments such as:
Hospitalization for acute coronary syndrome (acute myocardial infarction or unstable angina) 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 atrial fibrillation on ECG or history of atrial fibrillation that is not currently controlled
QTcB (QT corrected for heart rate using Bazett’s formula) at Screening or Baseline > 450 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, systolic blood pressure > 160 mmHg, or diastolic blood
pressure > 100 mmHg, after 5 minutes in a seated position at Screening or at Baseline
Hypotension: systolic blood pressure < 100 mmHg after 5 minutes in a seated position at Screening or at
Baseline
Heart rate < 48 bpm or > 96 bpm by measurement of vital signs (after 5 minutes in a seated position) or by
ECG at Screening or at Baseline
13. Preexisting or current signs or symptoms of respiratory failure, e.g., caused by chronic obstructive pulmonary
disease, bronchial asthma, lung fibrosis, or other disease; in addition, subjects should be excluded if they have:
Previously diagnosed moderate to severe sleep apnea not adequately controlled
14. Concurrent acute or chronic clinically significant (in the opinion of the investigator) immunologic, hepatic (such
as presence of encephalopathy or ascites), or endocrine disease (not adequately treated) and/or other unstable or
major disease other than Alzheimer’s disease
Subjects with primary biliary cirrhosis should be excluded
15. 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
16. Prior intolerance or hypersensitivity to MT-containing drug, similar organic dyes, or any of the excipients
17. Treatment currently or within 3 months before Baseline with any of the following medications (unless otherwise
noted):
Moderate to strong inhibitors of CYP1A2 (e.g., ciprofloxacin, fluvoxamine)
Tacrine
Anxiolytics and/or sedatives/hypnotics before cognitive testing (exceptions: sedation for MRI or short-acting
benzodiazepines, chloral hydrate, or zolpidem taken regularly at bedtime)
Antipsychotics
o Clozapine, olanzepine (and there is no intent to initiate therapy during the course of the study)
o Other antipsychotics are allowable, preferably at a stable dose and regimen
Carbamazepine, primidone
Drugs associated with methemoglobinemia, e.g., dapsone, local anesthetics such as benzocaine used
chronically, primaquine and related antimalarials, sulfonamides
18. Prior participation in a clinical trial as follows:
Phase 3 clinical trial of a product for cognition within the 3 months prior to Screening (unless confirmed to
have been randomized to placebo)
A clinical trial of a drug, biologic, or therapeutic device in which the last dose/administration was received
within 28 days prior to Baseline
supranuclear palsy, hydrocephalus, Huntington’s disease
2. Significant intracranial focal or vascular pathology seen on brain MRI scan within a maximum of 28 days before
Baseline that would, based on the independent reviewer imaging evaluation, lead to a diagnosis other than
probable Alzheimer’s disease or that puts the subject at risk of Amyloid Related Imaging Abnormalities (ARIA),
including:
other focal brain lesions judged clinically relevant
a single area of superficial siderosis
> 4 cerebral microhemorrhages (regardless of their anatomical location or diagnostic characterization as
“possible” or “definite”)
evidence of a prior macrohemorrhage
3. Clinical evidence or history of any of the following within specified period before Baseline:
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)
4. Epilepsy (a single prior seizure is considered acceptable)
5. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition – Text Revision (DSM IV-TR) criteria met
(and not subsequently revised) for any of the following within specified period:
Major depressive disorder (current)
Schizophrenia (lifetime)
Other psychotic disorders, bipolar disorder, substance (including alcohol) related disorders (within the past
5 years)
6. Metal implants in the head (except dental), pacemaker, cochlear implants, or any other non-removable items that
are contraindications to MR imaging; MR compatible prosthetics, clips, stents, or any other device proven to be
compatible will be allowed.
7. Resides in hospital or moderate to high dependency continuous care facility (residence in low grade assisted
living facility where there is sufficient autonomy to permit valid evaluation of activities of daily living is
permitted).
8. History of swallowing difficulties (note: study drug should be swallowed whole and MUST NOT be broken,
crushed, or chewed)
9. Pregnant or breastfeeding
10. History of significant hematological abnormality or current acute or chronic clinically significant abnormality,
including:
History of hereditary or acquired methemoglobinemia or baseline measurement of methemoglobin (MetHb)
> 2.0% (confirmed on repeat)
History of hemoglobinopathy, myelodysplastic syndrome, hemolytic anemia, or splenectomy
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Baseline value below age/sex appropriate lower limit of the central laboratory normal range for any of the
following:
o Hemoglobin (subject may be treated and re-screened after 3 months)
o Vitamin B12 or folate (subject may be treated and re-screened after 3 months)
11. Abnormal serum chemistry laboratory value at Screening deemed to be clinically relevant by the investigator,
e.g., considered to have the potential to increase the risk associated with study participation or administration of
investigational product and, in the judgment of the investigator, would make the subject inappropriate for entry
into this study. In addition, subjects with either of the following abnormalities must be excluded:
Creatinine clearance < 30 mL/min at Screening, estimated by the central laboratory according to the
Cockcroft and Gault equation
Thyroid stimulating hormone (TSH) above laboratory normal range (subject may be treated and re-screened after 3 months)
12. Clinically significant (in the opinion of the investigator) cardiovascular disease or abnormal assessments such as:
Hospitalization for acute coronary syndrome (acute myocardial infarction or unstable angina) 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 atrial fibrillation on ECG or history of atrial fibrillation that is not currently controlled
QTcB (QT corrected for heart rate using Bazett’s formula) at Screening or Baseline > 450 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, systolic blood pressure > 160 mmHg, or diastolic blood
pressure > 100 mmHg, after 5 minutes in a seated position at Screening or at Baseline
Hypotension: systolic blood pressure < 100 mmHg after 5 minutes in a seated position at Screening or at
Baseline
Heart rate < 48 bpm or > 96 bpm by measurement of vital signs (after 5 minutes in a seated position) or by
ECG at Screening or at Baseline
13. Preexisting or current signs or symptoms of respiratory failure, e.g., caused by chronic obstructive pulmonary
disease, bronchial asthma, lung fibrosis, or other disease; in addition, subjects should be excluded if they have:
Previously diagnosed moderate to severe sleep apnea not adequately controlled
14. Concurrent acute or chronic clinically significant (in the opinion of the investigator) immunologic, hepatic (such
as presence of encephalopathy or ascites), or endocrine disease (not adequately treated) and/or other unstable or
major disease other than Alzheimer’s disease
Subjects with primary biliary cirrhosis should be excluded
15. 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
16. Prior intolerance or hypersensitivity to MT-containing drug, similar organic dyes, or any of the excipients
17. Treatment currently or within 3 months before Baseline with any of the following medications (unless otherwise
noted):
Moderate to strong inhibitors of CYP1A2 (e.g., ciprofloxacin, fluvoxamine)
Tacrine
Anxiolytics and/or sedatives/hypnotics before cognitive testing (exceptions: sedation for MRI or short-acting
benzodiazepines, chloral hydrate, or zolpidem taken regularly at bedtime)
Antipsychotics
o Clozapine, olanzepine (and there is no intent to initiate therapy during the course of the study)
o Other antipsychotics are allowable, preferably at a stable dose and regimen
Carbamazepine, primidone
Drugs associated with methemoglobinemia, e.g., dapsone, local anesthetics such as benzocaine used
chronically, primaquine and related antimalarials, sulfonamides
18. Prior participation in a clinical trial as follows:
Phase 3 clinical trial of a product for cognition within the 3 months prior to Screening (unless confirmed to
have been randomized to placebo)
A clinical trial of a drug, biologic, or therapeutic device in which the last dose/administration was received
within 28 days prior to Baseline
The Estimated Number of Participants
-
Taiwan
100 participants
-
Global
833 participants
