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    Clinical Trial Results:
    Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 18-Month Safety and Efficacy Study of Leuco-methylthioninium bis(hydromethanesulfonate) in Subjects with Mild Alzheimer’s Disease

    Summary
    EudraCT number
    		 2012-002847-28
    Trial protocol
    		 DE   BE   GB   NL   ES   FI   IT   HR  
    Global end of trial date
    27 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Apr 2020
    First version publication date
    10 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TRx-237-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    TauRx Therapeutics Ltd
    Sponsor organisation address
    395 King Street, Aberdeen, United Kingdom,
    Public contact
    Information Desk, TauRx Therapeutics Ltd, +44 1224 440905, info@taurx.com
    Scientific contact
    Information Desk, TauRx Therapeutics Ltd, +44 1224 440905, info@taurx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Feb 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate clinical efficacy of leuco-methylthioninium bis(hydromethanesulfonate) (LMTM; hereafter referred to by the international nonproprietary name hydromethylthionine mesylate) in mild Alzheimer's disease based on change from Baseline on Alzheimer's Disease Assessment Scale – Cognitive Subscale (ADAS-cog₁₁) and Alzheimer's Disease Cooperative Study – Activities of Daily Living (ADCS-ADL₂₃), and to assess the safety and tolerability of LMTM 200 mg/day given for up to 78 weeks.
    Protection of trial subjects
    The following measures were repeatedly assessed throughout the course of the study to monitor subject safety: adverse events, clinical laboratory tests (blood and urine), pulse co-oximetry, vital signs, electrocardiograms, physical and neurological examinations, brain Magnetic Resonance Imaging (MRI), assessment of suicidal ideation/self harm, and evaluation potential signs/symptoms of serotonin toxicity.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Oct 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    United Kingdom: 88
    Country: Number of subjects enrolled
    Croatia: 25
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Finland: 28
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    United States: 524
    Worldwide total number of subjects
    795
    EEA total number of subjects
    253
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    195
    From 65 to 84 years
    565
    85 years and over
    35

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 1475 subjects provided informed consent, of whom 675 were considered to be screen failures. The most common reason for screen failure was not meeting CDR or MMSE total score requirements (11%). A total of 800 subjects were randomized; however, data for 5 subjects were excluded, thus 795 subjects were included in the ITT population.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Carer, Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LMTM 200 mg/day
    Arm description
    		 Subjects were to be administered LMTM 100 mg tablets twice daily for 78 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hydromethylthionine mesylate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LMTM 100 mg tablets were administered orally, in a twice daily regimen.

    Arm title
    		 LMTM 8 mg/day
    Arm description
    		 Subjects were to be administered LMTM 4 mg tablets twice daily for 78 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Hydromethylthionine mesylate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LMTM 4 mg tablets were administered orally, in a twice daily regimen to maintain the study blind.

    Number of subjects in period 1
    		LMTM 200 mg/day LMTM 8 mg/day
    Started
    399
    396
    Completed
    221
    305
    Not completed
    178
    91
         Adverse event, serious fatal
    1
    2
         Noncompliance with Study Drug
    8
    3
         Consent withdrawn by subject
    57
    25
         Physician decision
    2
    2
         Adverse event, non-fatal
    62
    23
         Other
    7
    7
         Consent withdrawn by caregiver
    20
    10
         Lost to follow-up
    7
    4
         Consent withdrawn by LAR
    -
    1
         Lack of efficacy
    8
    8
         Protocol deviation
    6
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LMTM 200 mg/day
    Reporting group description
    		 Subjects were to be administered LMTM 100 mg tablets twice daily for 78 weeks.

    Reporting group title
    LMTM 8 mg/day
    Reporting group description
    		 Subjects were to be administered LMTM 4 mg tablets twice daily for 78 weeks.

    Reporting group values
    		 LMTM 200 mg/day LMTM 8 mg/day Total
    Number of subjects
    		 399 396 795
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 70.6 ( 8.9 ) 70.5 ( 9.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 213 209 422
        Male
    		 186 187 373

    End points

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    End points reporting groups
    Reporting group title
    LMTM 200 mg/day
    Reporting group description
    		 Subjects were to be administered LMTM 100 mg tablets twice daily for 78 weeks.

    Reporting group title
    LMTM 8 mg/day
    Reporting group description
    		 Subjects were to be administered LMTM 4 mg tablets twice daily for 78 weeks.

    Primary: Change from Baseline to Week 78 in the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog₁₁)

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    End point title
    		 Change from Baseline to Week 78 in the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog₁₁)
    End point description
    End point type
    Primary
    End point timeframe
    78 weeks
    End point values
    		 LMTM 200 mg/day LMTM 8 mg/day
    Number of subjects analysed
    216
    299
    Units: none
        least squares mean (confidence interval 95%)
    6.41 (5.31 to 7.50)
    6.27 (5.31 to 7.24)
    Statistical analysis title
    		 ADAS-cog₁₁ Primary Analysis (ITT Population)
    Comparison groups
    LMTM 200 mg/day v LMTM 8 mg/day
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8584
    Method
    		 Mixed models analysis
    Confidence interval

    Primary: Change from Baseline to Week 78 in the Alzheimer's Disease Cooperative Study - Activities of Daily living (ADCS-ADL₂₃)

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    End point title
    		 Change from Baseline to Week 78 in the Alzheimer's Disease Cooperative Study - Activities of Daily living (ADCS-ADL₂₃)
    End point description
    End point type
    Primary
    End point timeframe
    78 weeks
    End point values
    		 LMTM 200 mg/day LMTM 8 mg/day
    Number of subjects analysed
    216
    298
    Units: none
        least squares mean (confidence interval 95%)
    -8.92 (-10.35 to -7.49)
    -8.18 (-9.43 to -6.92)
    Statistical analysis title
    		 ADCS-ADL₂₃ Primary Analysis (ITT Population)
    Comparison groups
    LMTM 200 mg/day v LMTM 8 mg/day
    Number of subjects included in analysis
    514
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4433
    Method
    		 Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were to be recorded from the time of screening and continued throughout the study, including the follow-up safety visit (week 78).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    LMTM 200 mg/day
    Reporting group description
    		 Subjects were to be administered LMTM 100 mg tablets twice daily for 78 weeks.

    Reporting group title
    LMTM 8 mg/day
    Reporting group description
    		 Subjects were to be administered LMTM 4 mg tablets twice daily for 78 weeks.

    Serious adverse events
    		 LMTM 200 mg/day LMTM 8 mg/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    71 / 398 (17.84%)
    76 / 396 (19.19%)
         number of deaths (all causes)
    5
    4
         number of deaths resulting from adverse events
    5
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal papillary mucinous neoplasm
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    2 / 398 (0.50%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 398 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant hypertension
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subgaleal haematoma
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    3 / 398 (0.75%)
    4 / 396 (1.01%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perforated ulcer
         subjects affected / exposed
    2 / 398 (0.50%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 398 (0.50%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Homicide
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    2 / 398 (0.50%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abnormal behaviour
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    2 / 398 (0.50%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    2 / 398 (0.50%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    2 / 398 (0.50%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delusion
         subjects affected / exposed
    1 / 398 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    11 / 398 (2.76%)
    12 / 396 (3.03%)
         occurrences causally related to treatment / all
    0 / 16
    2 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 398 (0.00%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    3 / 398 (0.75%)
    6 / 396 (1.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 398 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 398 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 398 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 398 (0.50%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 398 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 398 (0.25%)
    3 / 396 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 398 (0.50%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 398 (0.75%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    2 / 398 (0.50%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    2 / 398 (0.50%)
    3 / 396 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Amyloid related imaging abnormalities
         subjects affected / exposed
    1 / 398 (0.25%)
    4 / 396 (1.01%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain stem haemorrhage
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serotonin syndrome
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    4 / 398 (1.01%)
    5 / 396 (1.26%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colonic stenosis
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    2 / 398 (0.50%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis relapsing
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 398 (0.00%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 398 (0.00%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 398 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Babesiosis
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 398 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cryptosporidiosis infection
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 398 (0.50%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    2 / 398 (0.50%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 398 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 398 (0.00%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 398 (0.25%)
    5 / 396 (1.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 398 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food intolerance
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 398 (0.25%)
    2 / 396 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LMTM 200 mg/day LMTM 8 mg/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    342 / 398 (85.93%)
    333 / 396 (84.09%)
    Investigations
    Blood folate decreased
         subjects affected / exposed
    30 / 398 (7.54%)
    18 / 396 (4.55%)
         occurrences all number
    32
    20
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    34 / 398 (8.54%)
    44 / 396 (11.11%)
         occurrences all number
    46
    58
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    30 / 398 (7.54%)
    27 / 396 (6.82%)
         occurrences all number
    35
    33
    Headache
         subjects affected / exposed
    27 / 398 (6.78%)
    24 / 396 (6.06%)
         occurrences all number
    30
    24
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    20 / 398 (5.03%)
    12 / 396 (3.03%)
         occurrences all number
    22
    12
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    41 / 398 (10.30%)
    22 / 396 (5.56%)
         occurrences all number
    43
    27
    Diarrhoea
         subjects affected / exposed
    124 / 398 (31.16%)
    66 / 396 (16.67%)
         occurrences all number
    187
    85
    Vomiting
         subjects affected / exposed
    28 / 398 (7.04%)
    12 / 396 (3.03%)
         occurrences all number
    33
    13
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    20 / 398 (5.03%)
    7 / 396 (1.77%)
         occurrences all number
    24
    11
    Anxiety
         subjects affected / exposed
    25 / 398 (6.28%)
    28 / 396 (7.07%)
         occurrences all number
    28
    31
    Depression
         subjects affected / exposed
    17 / 398 (4.27%)
    28 / 396 (7.07%)
         occurrences all number
    20
    31
    Agitation
         subjects affected / exposed
    24 / 398 (6.03%)
    16 / 396 (4.04%)
         occurrences all number
    26
    19
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    24 / 398 (6.03%)
    12 / 396 (3.03%)
         occurrences all number
    30
    15
    Dysuria
         subjects affected / exposed
    35 / 398 (8.79%)
    3 / 396 (0.76%)
         occurrences all number
    40
    3
    Pollakiuria
         subjects affected / exposed
    28 / 398 (7.04%)
    10 / 396 (2.53%)
         occurrences all number
    29
    11
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    22 / 398 (5.53%)
    18 / 396 (4.55%)
         occurrences all number
    22
    19
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    20 / 398 (5.03%)
    21 / 396 (5.30%)
         occurrences all number
    25
    21
    Urinary tract infection
         subjects affected / exposed
    47 / 398 (11.81%)
    32 / 396 (8.08%)
         occurrences all number
    62
    44
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    23 / 398 (5.78%)
    5 / 396 (1.26%)
         occurrences all number
    24
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Feb 2013
    In Protocol Version 2.1, revisions (relative to Protocol Version 1.0) included the following: study personnel information was corrected and/or updated; background information was updated to include new reproductive toxicity findings (the discussion of contraceptive measures was also updated accordingly); inclusion and exclusion criteria were modified; and clarifications and/or modifications to efficacy, safety, and other assessments and procedural activities were incorporated. Additional administrative and/or editorial revisions were incorporated to eliminate discrepancies or provide clarification.
    30 Oct 2013
    In Protocol Version 3.0, revisions included modifications and/or clarifications to the overall protocol/background information; inclusion/exclusion criteria; study drug administration/packaging; efficacy, safety, and other assessments/procedures; statistical analysis; and administrative procedures. Target recruitment was modified to 700 subjects (350 per arm).
    11 Dec 2013
    In Protocol Version 4.0, revisions included clarifications and/or modifications to the inclusion and exclusion criteria, safety and other assessments or procedures, as well as other administrative revisions.
    25 Sep 2015
    In Protocol Version 7.0, revisions (relative to Protocol Version 4.0) included updates to administrative and background information, clarifications to exclusion criteria, modifications to study objectives and efficacy/statistical analyses, safety and exploratory assessments and/or procedures, as well as other minor revisions to provide further clarification. Modifications to the procedures for quality assurance, clinical monitoring, and dose reduction were incorporated.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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