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    Clinical Trial Results:
    XanADu: A Phase II, Double-Blind, 12-Week, Randomised, Placebo-Controlled Study to Assess the Safety, Tolerability and Efficacy of Xanamem™ in Subjects with Mild Dementia due to Alzheimer’s Disease (AD)

    Summary
    EudraCT number
    		 2016-001049-24
    Trial protocol
    		 GB  
    Global end of trial date
    15 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 May 2022
    First version publication date
    07 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ACW0002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02727699
    WHO universal trial number (UTN)
    		 U1111-1177-5932
    Sponsors
    Sponsor organisation name
    ICON Clinical Research Pty Ltd
    Sponsor organisation address
    South County Business Park, Leopardstown, Dublin, Ireland, 18
    Public contact
    Project Management, ICON Clinical Research Pty Ltd, +61 298593907, tom.olson@iconplc.com
    Scientific contact
    Project Management, ICON Clinical Research Pty Ltd, +61 298593907, tom.olson@iconplc.com
    Sponsor organisation name
    Actinogen Medical Limited
    Sponsor organisation address
    SUITE 901, LEVEL 9, 109 PITT STREET, SYDNEY, Australia, 2000
    Public contact
    Miriam Roesner, Actinogen Medical, +61 289647401, miriam.roesner@actinogen.com.au
    Scientific contact
    Tamara Miller, Actinogen Medical, +61 289647401, tamara.miller@actinogen.com.au
    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
    06 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the extent to which Xanamem™ improves performance from Baseline to end of treatment (EOT) compared to placebo, as measured by changes in AD COMposite Scores (ADCOMs, composite data derived from Alzheimer's Disease Assessment Scales - Cognitive subscale version 14 [ADAS-Cog v14], Clinical Dementia Rating Scale - Sum of Boxes [CDR-SOB], and Mini-Mental Status Examination [MMSE]) and ADAS-Cog v14 as primary endpoints in subjects with mild dementia due to probable AD.
    Protection of trial subjects
    Data Safety Monitoring Board A DSMB consisting of two sponsor-independent clinical experts and one sponsor independent statistical expert will be established. The DSMB will periodically meet for the review of accumulating study data, including safety (AE and laboratory data), PD data and NFM data, and will also be involved in the interim efficacy analysis. The DSMB will have access to unblinded data. The DSMB will submit its recommendations in writing to Actinogen Medical who are responsible for responding to the recommendations of the DSMB and taking appropriate action. The investigators will only be informed by Actinogen Medical/ICON if the study is stopped or if additional PD subjects need to be enrolled. The DSMB may choose to make additional evaluations at any time if they feel this is warranted from a safety point of view. Data Safety Monitoring Board Nerve Function Monitoring Sub-committee The DSMB Nerve Function Monitoring sub-committee consists of two experts in neurophysiology, one of which will be the DSMB Chairperson. The unblinded NFM data will be primarily reviewed by the DSMB Nerve Function Monitoring sub committee. When there is a confirmed nerve safety signal, this is escalated to the DSMB for consideration and recommendations for the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Mar 2017
    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
    United Kingdom: 29
    Country: Number of subjects enrolled
    Australia: 48
    Country: Number of subjects enrolled
    United States: 108
    Worldwide total number of subjects
    185
    EEA total number of subjects
    0
    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)
    43
    From 65 to 84 years
    142
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 At study start, it was planned that 20 study sites would be initiated in three countries (Australia, the United Kingdom [UK] and the United States of America [USA]). Following amendments to the study and the protocol, a total of 27 study sites were initiated (6 in Australia, 6 in the UK, and 15 in the USA). Recruitment period: 23Mar2017-08Oct2018.

    Pre-assignment
    Screening details
    		 It was planned that approximately 174 subjects would be enrolled to ensure 156 subjects would complete the 12 week double-blind study period (78 subjects in each treatment group). At study-end, in total, 457 subjects were screened, of whom 185 subjects were randomised (91:94 Xanamem to placebo) to the study with 171 subjects completed.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer
    Blinding implementation details
    To ensure blinding, the study drug (Xanamem™ capsules) and the matching placebo have the same shape and size. Labels on the study drug containers will not identify treatment a subject is randomised to. Traceability of the treatment is ensured by the study drug number.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Xanamem™
    Arm description
    		 Oral Xanamem™ capsules 10mg, to be administered once daily Xanamem™: Xanamem™ is formulated in green and cream coloured size 3, Coni-Snap shaped gelatin capsules as an excipient blend at a dose of 10mg. It contains active pharmaceutical ingredient of UE2343 (Laboratory code for Xanamem)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Xanamem (UE2343)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule of Xanamem was administered orally with approximately 200 mL of preferably warm water QD, preferably with food in the morning, to eligible subjects from Baseline (Week 0) to EOT (Week 12) for a total of 12 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo which is identical in appearance to the test product except that it contains no active ingredient, to be administered once daily Placebo (for Xanamem™): Excipient blend capsules manufactured to mimic Xanamem™ capsules
    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
    One capsule of the matching placebo was administered orally with approximately 200 mL of preferably warm water QD, preferably with food in the morning, to eligible subjects from Baseline (Week 0) to EOT (Week 12) for a total of 12 weeks.

    Number of subjects in period 1
    		Xanamem™ Placebo
    Started
    91
    94
    Completed
    82
    89
    Not completed
    9
    5
         Consent withdrawn by subject
    5
    3
         Physician decision
    -
    1
         Adverse event, non-fatal
    2
    -
         Sponsor decision
    1
    -
         Lack of efficacy
    1
    -
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Xanamem™
    Reporting group description
    		 Oral Xanamem™ capsules 10mg, to be administered once daily Xanamem™: Xanamem™ is formulated in green and cream coloured size 3, Coni-Snap shaped gelatin capsules as an excipient blend at a dose of 10mg. It contains active pharmaceutical ingredient of UE2343 (Laboratory code for Xanamem)

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo which is identical in appearance to the test product except that it contains no active ingredient, to be administered once daily Placebo (for Xanamem™): Excipient blend capsules manufactured to mimic Xanamem™ capsules

    Reporting group values
    		 Xanamem™ Placebo Total
    Number of subjects
    		 91 94 185
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 19 24 43
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        <= 18 years
    		 0 0 0
        Between 18 and 64 years
    		 0 0 0
        >= 65 years
    		 72 70 142
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71.3 ± 8.71 70.8 ± 8.20 -
    Gender categorical
    Units: Subjects
        Female
    		 52 54 106
        Male
    		 39 40 79
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 4 3 7
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 18 19 37
        White
    		 69 70 139
        Unknown or Not Reported
    		 0 2 2
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 165.49 ± 9.665 166.36 ± 8.964 -
    Body mass index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 27.31 ± 5.024 27.08 ± 6.570 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 74.90 ± 15.964 74.88 ± 18.774 -

    End points

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    End points reporting groups
    Reporting group title
    Xanamem™
    Reporting group description
    		 Oral Xanamem™ capsules 10mg, to be administered once daily Xanamem™: Xanamem™ is formulated in green and cream coloured size 3, Coni-Snap shaped gelatin capsules as an excipient blend at a dose of 10mg. It contains active pharmaceutical ingredient of UE2343 (Laboratory code for Xanamem)

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo which is identical in appearance to the test product except that it contains no active ingredient, to be administered once daily Placebo (for Xanamem™): Excipient blend capsules manufactured to mimic Xanamem™ capsules

    Primary: ADAS-Cog v14

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    End point title
    		 ADAS-Cog v14
    End point description
    Change in Alzheimer's Disease Assessment Scales - Cognitive Subscale Score, version 14 (ADAS-Cog v14). Total scores of ADAS Cog 14 range from 0 to 90, with higher scores indicating greater disease severity.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Xanamem™ Placebo
    Number of subjects analysed
    86
    92
    Units: Change in score
        arithmetic mean (standard deviation)
    -1.5 ± 6.47
    -0.7 ± 6.65
    Statistical analysis title
    		 ADAS-Cog Score
    Statistical analysis description
    ADAS-Cog v14 score is sum of all 14 items of ADAS-Cog v14. An analysis of covariance model was used to assess the change in ADAS-Cog v14 score from Baseline (Week 0) to EOT (Week 12). The ANCOVA model included treatment group as fixed effects and the Baseline value as a covariate. The primary efficacy hypothesis was: H0: μP ≤ μX; H1: μP > μX, where μP and μX denoted the change from Baseline to EOT in ADAS-Cog v14 for placebo and Xanamem, respectively.
    Comparison groups
    Xanamem™ v Placebo
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.343
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - The test was performed at a type I error rate of 0.05 one-sided, with a priori hierarchical handling of multiplicity, based on the least squares (LS) means for EOT (Week 12). ANCOVA was used to derive 90% and 95% confidence intervals with Baseline ADCOMs score and treatment as covariates. The primary efficacy analysis did not replace missing EOT (Week 12).

    Primary: AD COMposite Scores

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    End point title
    		 AD COMposite Scores
    End point description
    Change in AD COMposite Scores (ADCOMs- ADCOMs, composite score is derived from a weighted linear combination of items from commonly used outcome scales Cognitive Subscale Version 14 [ADAS-Cog v14], Clinical Dementia Rating Scale - Sum of Boxes [CDR-SOB], and Mini-Mental Status Examination [MMSE]. Th ADCOMs range: 0 - 1.97, whereas a lover score is interpreted as a better result. Included scales: ADAS-Cog v14 (range: 0-90): A lower score is indicative of better cognition, a higher score indicates higher cognitive impairment. CDR-SUB (range: 0-18): A lower score is indicative of better cognition, a higher score indicates higher cognitive impairment. MMSE (range: 0-30): A higher score is indicative of better cognition, a lower score indicates higher cognitive impairment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Xanamem™ Placebo
    Number of subjects analysed
    86
    92
    Units: Change in score
        arithmetic mean (standard deviation)
    0.02472 ± 0.144135
    0.01908 ± 0.151502
    Statistical analysis title
    		 ADCOMs
    Statistical analysis description
    An analysis of covariance model was used to assess the change in ADCOMs score from Baseline (Week 0) to EOT (Week 12). The ANCOVA model included treatment group as fixed effects and the Baseline value as a covariate. The primary efficacy hypothesis was: H0: μP ≤ μX; H1: μP > μX, where μP and μX denoted the change from Baseline to EOT in ADCOMs for placebo and Xanamem, respectively.
    Comparison groups
    Xanamem™ v Placebo
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.795
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [2] - The test was performed at a type I error rate of 0.05 one-sided, with a priori hierarchical handling of multiplicity, based on the least squares (LS) means for EOT (Week 12). ANCOVA was used to derive 90% and 95% confidence intervals with Baseline ADCOMs score and treatment as covariates. The primary efficacy analysis did not replace missing EOT (Week 12).

    Secondary: RAVLT - Recall list A

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    End point title
    		 RAVLT - Recall list A
    End point description
    Change in Rey Auditory Verbal Learning Test (RAVLT) RAVLT will be administered using five trials, with individual scores from 0-15. The total score is the combined score of all five trials, ranging from 0 to 75, whereas a lower score is considered a worse outcome and a higher score a better outcome. Recall List A - Total number of correct words
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Xanamem™ Placebo
    Number of subjects analysed
    86
    90
    Units: Change in score
        arithmetic mean (standard deviation)
    0.3 ± 6.54
    0.4 ± 6.31
    No statistical analyses for this end point

    Secondary: RAVLT - Recall list B

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    End point title
    		 RAVLT - Recall list B
    End point description
    Change in Rey Auditory Verbal Learning Test (RAVLT) RAVLT will be administered using five trials, with individual scores from 0-15. The total score is the combined score of all five trials, ranging from 0 to 75, whereas a lower score is considered a worse outcome and a higher score a better outcome. Recall List B - Number of correct words
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Xanamem™ Placebo
    Number of subjects analysed
    86
    90
    Units: Change in words
        arithmetic mean (standard deviation)
    0.3 ± 1.63
    0.1 ± 1.30
    No statistical analyses for this end point

    Secondary: RAVLT - Final recall of List A

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    End point title
    		 RAVLT - Final recall of List A
    End point description
    Change in Rey Auditory Verbal Learning Test (RAVLT) RAVLT will be administered using five trials, with individual scores from 0-15. The total score is the combined score of all five trials, ranging from 0 to 75, whereas a lower score is considered a worse outcome and a higher score a better outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Xanamem™ Placebo
    Number of subjects analysed
    85
    90
    Units: Change in words
        arithmetic mean (standard deviation)
    0.2 ± 3.14
    0.4 ± 2.40
    No statistical analyses for this end point

    Secondary: CDR-SOB

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    End point title
    		 CDR-SOB
    End point description
    Change in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB) The CDR is obtained through semi-structured interviews of patients and informants, and cognitive functioning is rated in six domains of functioning: memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a five-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment. The CDR-SOB is based on summing each of the domain box scores, with scores ranging from 0-18, whereas lower scores represent better outcomes and higher scores worse outcomes.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Xanamem™ Placebo
    Number of subjects analysed
    85
    91
    Units: Score
        arithmetic mean (standard deviation)
    0.25 ± 1.276
    0.16 ± 1.325
    No statistical analyses for this end point

    Secondary: MMSE

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    End point title
    		 MMSE
    End point description
    Change in Mini-Mental Status Examination (MMSE) MMSE total score (0 - 30) is a sum of all 30 point questionnaire of MMSE. A score of 20 to 24 suggests mild dementia, 13 to 20 suggests moderate dementia, and less than 12 indicates severe dementia.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Xanamem™ Placebo
    Number of subjects analysed
    86
    91
    Units: Score
        arithmetic mean (standard deviation)
    0.2 ± 3.09
    -0.2 ± 2.85
    No statistical analyses for this end point

    Secondary: NPI (Neuropsychiatric Inventory)

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    End point title
    		 NPI (Neuropsychiatric Inventory)
    End point description
    Change in Neuropsychiatric Inventory (NPI) The NPI includes questions to ten behavioural and two neurodegenerative domains. Raters recorded neuropsychiatric symptoms using a 1-4 scale for frequency and a 1-3 scale for severity for each item in the instrument, with the score for each domain being: domain score = frequency x severity. The total score is calculated by adding the scores of the first 10 domain scores. The two neurodegenerative items are not included in the NPI total score as they form part of the depression syndrome in some patients and were specifically excluded from the dysphoria subscale of the NPI in order to allow that subscale to focus on mood symptoms. The total NPI-score minimum is 0 and the maximum 144. A lower score is considered a better outcome, a higher score a worse outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Xanamem™ Placebo
    Number of subjects analysed
    85
    92
    Units: Score
    arithmetic mean (standard deviation)
        NPI Total Score
    0.9 ± 8.67
    0.8 ± 9.09
        Delusions
    0.0 ± 0.38
    0.1 ± 0.87
        Hallucinations
    0.1 ± 0.60
    0.0 ± 0.36
        Agitation/Aggression
    0.2 ± 2.02
    0.2 ± 1.91
        Depression/Dysphoria
    0.0 ± 1.34
    0.0 ± 1.91
        Anxiety
    0.1 ± 1.70
    -0.4 ± 2.08
        Elation/Euphoria
    0.1 ± 0.92
    0.0 ± 0.67
        Apathy/Indifference
    0.0 ± 2.18
    0.3 ± 2.11
        Disinhibition
    0.1 ± 1.15
    0.1 ± 1.03
        Irritability/Lability
    0.1 ± 1.94
    0.5 ± 2.17
        Aberrant Motor Behaviour
    -0.1 ± 2.98
    0.2 ± 2.37
        Sleep
    0.2 ± 2.47
    0.0 ± 1.83
        Appetite and Eating Disorders
    0.1 ± 3.18
    -0.1 ± 2.02
    No statistical analyses for this end point

    Secondary: NTB - Executive Domain

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    End point title
    		 NTB - Executive Domain
    End point description
    Change in Neuropsychological Test Batteries (NTB) - Executive Domains: Controlled Oral Word Association - Test (COWAT) and Total Correct Response (CFT) Total NTB score is the sum of COWAT and CFT. During the COWAT test, the subject is asked to mention as many words as possible beginning with different letters (F, A, S) within 1 minute each. The number of words for each letter is recorded, the score is the sum of all words. There is no minimum or maximum score, whereas more words indicate a better outcome. During the CFT test, the subject is given 1 minute to produce as many unique words as possible within a semantic category. The subject's score is the number of unique correct words. There is no minimum or maximum score whereas a score of under 14 is interpreted as concerning regarding cognition.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Xanamem™ Placebo
    Number of subjects analysed
    86
    91
    Units: Score
    arithmetic mean (standard deviation)
        COWAT Total Correct Words
    0.5 ± 8.08
    0.5 ± 8.12
        CTF Total Correct Responses
    0.3 ± 8.53
    -0.7 ± 6.28
        NTB Total Score
    0.8 ± 11.50
    -0.2 ± 9.84
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Median treatment duration (weeks) was 12 weeks (range: 0.14, 13.0 weeks) for subjects in the Xanamem group and 12 weeks (range: 0.14, 13.1 weeks) for subjects in the placebo group.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Xanamem™
    Reporting group description
    		 Oral Xanamem™ capsules 10mg, to be administered once daily Xanamem™: Xanamem™ is formulated in green and cream coloured size 3, Coni-Snap shaped gelatin capsules as an excipient blend at a dose of 10mg. It contains active pharmaceutical ingredient of UE2343

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo which is identical in appearance to the test product except that it contains no active ingredient, to be administered once daily Placebo (for Xanamem™): Excipient blend capsules manufactured to mimic Xanamem™ capsules

    Serious adverse events
    		 Xanamem™ Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 91 (4.40%)
    4 / 94 (4.26%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Vibration test abnormal
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 94 (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
    Fall
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary cavitation
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 94 (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
    Pneumonia
         subjects affected / exposed
    2 / 91 (2.20%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 94 (1.06%)
         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
    		 Xanamem™ Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 91 (36.26%)
    32 / 94 (34.04%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    3 / 91 (3.30%)
    6 / 94 (6.38%)
         occurrences all number
    4
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 91 (9.89%)
    10 / 94 (10.64%)
         occurrences all number
    11
    11
    Dizziness
         subjects affected / exposed
    8 / 91 (8.79%)
    4 / 94 (4.26%)
         occurrences all number
    8
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 91 (6.59%)
    5 / 94 (5.32%)
         occurrences all number
    7
    5
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 91 (1.10%)
    5 / 94 (5.32%)
         occurrences all number
    1
    5
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    6 / 91 (6.59%)
    2 / 94 (2.13%)
         occurrences all number
    9
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Aug 2016
    Protocol Amendment 1 was implemented on 8 August 2016 to include comprehensive nerve function monitoring in all randomised subjects and not just a sub-set of subjects, amendment of the dosing schedule to a once daily dose up-titration regimen in order to reduce plasma exposure; clarification around the cerebrospinal fluid sampling; amendment of pharmacokinetic sampling with sparse pharmacokinetic sampling being conducted in all randomised subjects; addition of procedures used to measure orthostatic changes in blood pressure and heart rate.
    16 Oct 2017
    Protocol Amendment 4 was implemented on 16 October 2017. The primary reason for this protocol amendment was to implement an interim and efficacy analysis of 50 completed, evaluable participants to coincide with the scheduled Data Safety Monitoring Board review of the same subjects’ safety data. Blood chemistry parameters have been slightly broadened to increase participant eligibility for the study. The proposed new blood chemistry parameters are still within safe limits. Explicit exclusion criteria were also introduced to ensure that potential participants with a functional deficit at foot level were not enrolled into the study. Additional exclusion criteria were also added to exclude participants with disorders affecting hypothalamic-pituitary-adrenal axis function or with uncontrolled conditions relating to glucose and lipid metabolism.

    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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