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    Clinical Trial Results:
    A 36-month, multi-centre, randomized double-blind placebo-controlled study to evaluate the safety and efficacy of low dose Ladostigil in patients with Mild Cognitive Impairment (MCI)

    Summary
    EudraCT number
    		 2011-004187-30
    Trial protocol
    		 AT   DE  
    Global end of trial date
    26 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Dec 2017
    First version publication date
    20 Dec 2017
    Other versions
    Summary report(s)
    		 Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    CO17730
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Avraham Pharmaceuticals Ltd.
    Sponsor organisation address
    42 Hayarkon Street, Yavneh, Israel, 81227
    Public contact
    Moti Hacham, Chief Financial & Operation Officer., Avraham Pharmaceuticals Ltd. 42 Hayarkon st, Yavneh, 81227, +972 8-932-4000, motih@cls.co.il
    Scientific contact
    Moti Hacham, Chief Financial & Operation Officer., Avraham Pharmaceuticals Ltd. 42 Hayarkon st, Yavneh, 81227, +972 8-932-4000, motih@cls.co.il
    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
    16 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to assess whether 10 mg ladostigil q.d. can slow or stop the conversion from Mild Cognitive Impairment (MCI) to Alzheimer’s disease (AD) during a three year treatment period compared to placebo. The primary endpoint was the percentage of subjects that progressed from MCI to probable or possible AD according to NINCDS-ADRDA criteria. Conversion to AD was determined using Clinical Dementia Rating (CDR).
    Protection of trial subjects
    NA
    Background therapy
    		 NA
    Evidence for comparator
    		 A placebo group was required in order to differentiate any investigational drug effect from any improvement that could occur solely due to the close care and medical oversight given to patients under trial conditions. Patients assigned to the placebo group did not abandon standard medical treatment, since there are no currently approved drugs for treatment of MCI
    Actual start date of recruitment
    01 Jan 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
    Israel: 97
    Country: Number of subjects enrolled
    Austria: 47
    Country: Number of subjects enrolled
    Germany: 66
    Worldwide total number of subjects
    210
    EEA total number of subjects
    113
    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)
    31
    From 65 to 84 years
    175
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from January 2012 until July 2013. It was planned to recruit 50 patients in Austria, 50 patients in Germany and 100 patients in Israel.

    Pre-assignment
    Screening details
    		 Patients had to be diagnosed with MCI and had to fulfill the following main criteria: No AD with NINCDS-ADRDA diagnosis “none” WMS-VerPA <18 CDR 0.5 MMSE >24 Modified Hachinski Ischaemic Scale ≤4 Age 55-85 GDS ≤5 Caretaker with frequent contact to patient Scheltens score >1 Adequate visual and auditory acuity good health, not pregnant

    Pre-assignment period milestones
    Number of subjects started
    		 413 [1]
    Number of subjects completed
    		 210

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screening Failures: 203
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Only subjects that succesfully completed the Screening period were assigned to a treatment, and randomized (enrolled). However, all subjects that underwent screening assessments signed an informed consent
    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer
    Blinding implementation details
    There were no differences between ladostigil capsules and placebo capsules in shape, size, colour or weight. The manufacturing organization was strictly independent from the sponsor’s activities. No accidental unblinding by laboratory measurements was possible.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 100 patients were planned to receive placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule of Placebo once daily in the morning

    Arm title
    		 Ladostigil
    Arm description
    		 100 patients were planned to receive the active ingredient
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ladostigil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    10mg Ladostigil once daily in the morning

    Number of subjects in period 1
    		Placebo Ladostigil
    Started
    107
    103
    Completed
    55
    57
    Not completed
    52
    46
         Consent withdrawn by subject
    13
    19
         Caretaker withdrew consent
    1
    1
         Physician decision
    3
    2
         Other
    1
    1
         Death
    -
    1
         AE/SAE
    14
    7
         Sponsor decision
    1
    -
         early termination due to AD conversion
    17
    12
         Protocol deviation
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 100 patients were planned to receive placebo

    Reporting group title
    Ladostigil
    Reporting group description
    		 100 patients were planned to receive the active ingredient

    Reporting group values
    		 Placebo Ladostigil Total
    Number of subjects
    		 107 103 210
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 16 15 31
        From 65-84 years
    		 89 86 175
        85 years and over
    		 2 2 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71.4 ( 6.8 ) 71.3 ( 6.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 41 36 77
        Male
    		 66 67 133
    Subject analysis sets

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all randomized patients.

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All analyses predominantly used the modified Intent-To-Treat (ITT) patient population, which included all patients who received at least one dose of medication and completed at least one post-Baseline assessment.

    Subject analysis sets values
    		 Safety mITT
    Number of subjects
    210
    202
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    31
    30
        From 65-84 years
    175
    168
        85 years and over
    4
    4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    71.3 ( 6.5 )
    70.8 ( 7.1 )
    Gender categorical
    Units: Subjects
        Female
    77
    76
        Male
    133
    126

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 100 patients were planned to receive placebo

    Reporting group title
    Ladostigil
    Reporting group description
    		 100 patients were planned to receive the active ingredient

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all randomized patients.

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All analyses predominantly used the modified Intent-To-Treat (ITT) patient population, which included all patients who received at least one dose of medication and completed at least one post-Baseline assessment.

    Primary: Time to Conversion from MCI to AD

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    End point title
    		 Time to Conversion from MCI to AD
    End point description
    The CDR was developed for the evaluation of staging severity of dementia. It was developed primarily for the use in persons with dementia of the Alzheimer type and it can also be used to stage dementia in patients with other illnesses. CDR scores are as follows: 0 = Normal 0.5 = Very Mild Dementia 1 = Mild Dementia 2 = Moderate Dementia 3 = Severe Dementia Thus, scores of ≥ 1 are indicative of conversion to AD. After treatment with ladostigil, 14 AD converters were reported and after treatment with placebo, 21 AD converters were reported, resulting in a conversion rate of 0.14 for ladostigil patients and a conversion rate of 0.20 for placebo patients over the whole study period of 36 months. The conversion rate from MCI to Alzheimer’s Disease was not significantly different between the ladostigil treatment group and the placebo treatment group.
    End point type
    Primary
    End point timeframe
    The CDR assessment was performed at baseline and at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months and 36 months regularly over the whole study period.
    End point values
    		 Placebo Ladostigil mITT
    Number of subjects analysed
    103
    99
    202
    Units: Numbers of Patients that converted to AD
    21
    14
    35
    Statistical analysis title
    		 Kaplan-Meier's survival method
    Statistical analysis description
    The Kaplan Meier's survival curves for the two treatments were compared using the Logrank test.
    Comparison groups
    Ladostigil v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval

    Secondary: The Effect of 10 mg ladostigil on GDS

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    End point title
    		 The Effect of 10 mg ladostigil on GDS
    End point description
    The GDS is a screening test for depressive symptoms in the elderly. This test is ideal for evaluating the clinical severity of depression. No significant difference between the ladostigil treatment group and the placebo treatment group could be observed in the whole mITT population after three years.
    End point type
    Secondary
    End point timeframe
    The GDS was assessed at Baseline and at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months and 36 months Visit, regularly over the whole study period (36 months).
    End point values
    		 Placebo Ladostigil Safety
    Number of subjects analysed
    107
    103
    210
    Units: GDS Score
    number (not applicable)
        GDS <=5
    107
    103
    210
        GDS >5
    7
    4
    11
    No statistical analyses for this end point

    Secondary: The effect of 10 mg ladostigil on DAD

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    End point title
    		 The effect of 10 mg ladostigil on DAD
    End point description
    The DAD was developed to fulfil the need for a disability measure designed specifically for the assessment of disability in community residing individuals with cognitive defects. The DAD scale was used to measure functional abilities in activities of daily living quantitatively and to monitor these abilities throughout the study. No significant difference between the ladostigil treatment group and the placebo treatment group could be observed in the whole mITT population after three years.
    End point type
    Secondary
    End point timeframe
    The DAD was assessed at Baseline and at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months and 36 months Visit, regularly over the whole study period (36 months).
    End point values
    		 Placebo Ladostigil
    Number of subjects analysed
    100
    98
    Units: DAD Score
        arithmetic mean (standard deviation)
    98.5 ( 4.1 )
    97.2 ( 7.4 )
    No statistical analyses for this end point

    Secondary: The Effect of 10 mg ladostigil on NTB

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    End point title
    		 The Effect of 10 mg ladostigil on NTB
    End point description
    The NTB is a well evaluated test instrument to measure drug efficiency in patients with cognitive impairment. It is a sensitive and reliable measure of cognitive change in patients with mild to moderate cognitive impairment. No significant difference between the ladostigil treatment group and the placebo treatment group could be observed in the whole mITT population after three years.
    End point type
    Secondary
    End point timeframe
    The NTB was assessed at Baseline and at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months and 36 months Visit, regularly over the whole study period (36 months).
    End point values
    		 Placebo Ladostigil
    Number of subjects analysed
    103
    99
    Units: z-scores for total NTB
        arithmetic mean (standard deviation)
    0.458 ( 0.757 )
    0.350 ( 0.835 )
    No statistical analyses for this end point

    Other pre-specified: The Effect of 10 mg ladostigil on NeuroTrax Mindstreams

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    End point title
    		 The Effect of 10 mg ladostigil on NeuroTrax Mindstreams
    End point description
    The NeuroTrax Mindstreams Test requires patient interaction with the computer and provides normatively based and raw score results for each patient. The test is very patient-friendly and requires little orientation. Although the test is performed on a computer, it does not require the patient to know how to use one. NeuroTrax Mindstreams assesses the patient´s cognitive function by precisely measuring the patient´s performance on a series of interactive tests – revealing both the accuracy of the responses and the patient´s cognitive function by measuring the reaction times in milliseconds. No significant difference between the ladostigil treatment group and the placebo treatment group could be observed in the whole mITT population after three years.
    End point type
    Other pre-specified
    End point timeframe
    The NeuroTrax was assessed at Baseline and at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months and 36 months Visit, regularly over the whole study period (36 months).
    End point values
    		 Placebo Ladostigil
    Number of subjects analysed
    103
    99
    Units: Global Cognitive Score
        arithmetic mean (standard deviation)
    100 ( 12 )
    100 ( 14 )
    No statistical analyses for this end point

    Other pre-specified: The Effect of 10 mg ladostigil on Composite Cognitive Scores

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    End point title
    		 The Effect of 10 mg ladostigil on Composite Cognitive Scores
    End point description
    The Composite Cognitive Score is a combination of NTB and NeuroTrax scores. No significant difference between the ladostigil treatment group and the placebo treatment group could be observed in the whole mITT population after three years.
    End point type
    Other pre-specified
    End point timeframe
    The Composite Cognitive Scores were evaluated at Baseline and at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months and 36 months Visit, regularly over the whole study period (36 months).
    End point values
    		 Placebo Ladostigil
    Number of subjects analysed
    103
    99
    Units: Composite Cognitive Score
        arithmetic mean (standard deviation)
    0.151 ( 0.787 )
    0.476 ( 0.835 )
    No statistical analyses for this end point

    Other pre-specified: The Effect of 10 mg ladostigil on hippocampal, entorhinal cortex and whole brain volume

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    End point title
    		 The Effect of 10 mg ladostigil on hippocampal, entorhinal cortex and whole brain volume
    End point description
    A significant effect of ladostigil could be observed on whole brain volume. After a treatment period of three years, the atrophy of the whole brain was significantly smaller in patients that received ladostigil compared to patients that received placebo.
    End point type
    Other pre-specified
    End point timeframe
    The MRI Scans for determination of brain volume were performed at Baseline and at the 12 months, 24 months and 36 months Visit.
    End point values
    		 Placebo Ladostigil
    Number of subjects analysed
    103
    99
    Units: mm³
        arithmetic mean (standard deviation)
    1293721 ( 92130 )
    1313140 ( 85858 )
    No statistical analyses for this end point

    Other pre-specified: The Effect of 10 mg ladostigil on Immunological Parameters

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    End point title
    		 The Effect of 10 mg ladostigil on Immunological Parameters
    End point description
    Serum and peripheral blood mononuclear cells (PBMCs) were used for determination of immunological parameters. PBMCs were analysed by FACS for leukocyte subpopulations (CD4: T-effector and T-regulatory, CD8, monocytes, B cells, NK) and were stimulated with anti-CD3 to activate T cells. Anti-CD3 stimulation was performed also in the presence of increasing concentrations of methylprednisolone (MP). Supernates were collected at 24-72 hours and cytokines (primarily T-cell derived)/chemokines were measured by ELISA array. Furthermore, PBMCs were stimulated by LPS (0.1, 1, 10 and 100 ng/ml) or A-beta/heat shock protein (HSP) for 24 hours. Cytokines/chemokines were measured by ELISA arrays IL-1b, TNF-a, IL-6, IFN-g, IL-10 TGF-b IL-12 and nitric oxide. A statistically significant difference between placebo and ladostigil treatment was shown for T-helper cells only and the repective data are presented.
    End point type
    Other pre-specified
    End point timeframe
    Measurements of Immunological parameters were performed at Baseline V1 and at V4, V6 and V8. Due to organizational procedures, blood sampling for immunological assessments was done only at study sites in Israel.
    End point values
    		 Placebo Ladostigil
    Number of subjects analysed
    50
    47
    Units: cell count
        arithmetic mean (standard deviation)
    39.9 ( 9.8 )
    44.5 ( 12.7 )
    No statistical analyses for this end point

    Other pre-specified: The Effect of 10 mg ladostigil on Global CDR and CDR sum-of-boxes Score

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    End point title
    		 The Effect of 10 mg ladostigil on Global CDR and CDR sum-of-boxes Score
    End point description
    The Clinical Dementia Rating (CDR) was used to monitor the clinical staging of dementia. This was done via characterizing six domains of cognitive and functional performance via the 5-point scale of the CDR. No significant difference between the ladostigil treatment group and the placebo treatment group could be observed in the whole mITT population after three years.
    End point type
    Other pre-specified
    End point timeframe
    The CDR and CDR Sum of boxes was assessed at Baseline and at 3 months, 6 months, 12 months, 18 months, 24 months, 30 months and 36 months Visit, regularly over the whole study period (36 months).
    End point values
    		 Placebo Ladostigil
    Number of subjects analysed
    103
    99
    Units: Patient numbers as percentage
    number (not applicable)
        Score 0
    16
    7
        Score 0.5
    82
    92
        Score 1
    2
    2
        SCore 1.5
    0
    0
    No statistical analyses for this end point

    Other pre-specified: The Effect of 10 mg ladostigil on MMSE score

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    End point title
    		 The Effect of 10 mg ladostigil on MMSE score
    End point description
    The MMSE is a frequently used screening instrument for cognitive impairment. The instrument provides for evaluation of orientation, memory, attention, concentration, naming, repetition, comprehension, ability to create a sentence and to copy two intersecting polygons. It was used to exclude severe cognitive impairment indicated by a score lower than 24. The highest (best) score is 30. No significant difference between the ladostigil treatment group and the placebo treatment group could be observed in the whole mITT population after three years.
    End point type
    Other pre-specified
    End point timeframe
    The MMSE was assessed at Baseline and at the 36 months visit or early termination visit.
    End point values
    		 Placebo Ladostigil
    Number of subjects analysed
    103
    99
    Units: MMSE Score
        arithmetic mean (standard deviation)
    27.2 ( 3.2 )
    27.7 ( 2.6 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After Baseline, all new findings or worsening of a pre-existing finding (if considered clinically significant) had to be reported as Adverse event. Data pertaining to AEs were collected during each study visit.
    Adverse event reporting additional description
    At each study visit, the Investigator asked a general question, e.g."Have you experienced any other/new health problems since your last visit?" Furthermore, clinically significant findings of the physical examination, neurological examination, vital signs, ECG, laboratory assessments and Urinalysis were considered AEs:
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 All Patients randomized to receive placebo

    Reporting group title
    Ladostigil
    Reporting group description
    		 All patients randomized to receive Ladostigil

    Serious adverse events
    		 Placebo Ladostigil
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 107 (26.17%)
    26 / 103 (25.24%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Investigations
    Intraocular pressure increased
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    4 / 107 (3.74%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         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
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extrasystoles
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 107 (1.87%)
    3 / 103 (2.91%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (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
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         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
    Arthritis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractured coccyx
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic floor muscle weakness
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (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
    Appendicitis
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Electrolyte imbalance
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Ladostigil
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    85 / 107 (79.44%)
    85 / 103 (82.52%)
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 107 (2.80%)
    6 / 103 (5.83%)
         occurrences all number
    3
    6
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    6 / 107 (5.61%)
    4 / 103 (3.88%)
         occurrences all number
    10
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 107 (5.61%)
    7 / 103 (6.80%)
         occurrences all number
    6
    8
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 107 (6.54%)
    4 / 103 (3.88%)
         occurrences all number
    8
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 107 (6.54%)
    8 / 103 (7.77%)
         occurrences all number
    7
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 107 (3.74%)
    7 / 103 (6.80%)
         occurrences all number
    4
    10
    Back pain
         subjects affected / exposed
    10 / 107 (9.35%)
    6 / 103 (5.83%)
         occurrences all number
    10
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    13 / 107 (12.15%)
    11 / 103 (10.68%)
         occurrences all number
    15
    15

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    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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