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    Clinical Trial Results:
    A Phase 3, Randomised, Placebo-Controlled Trial of Arimoclomol in Amyotrophic Lateral Sclerosis

    Summary
    EudraCT number
    		 2018-000137-13
    Trial protocol
    		 FR   SE   GB   BE   NL   PL   ES   IT  
    Global end of trial date
    18 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Oct 2024
    First version publication date
    12 Oct 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ORARIALS-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03491462
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Zevra Denmark A/S
    Sponsor organisation address
    Nordre Fasanvej 215, Frederiksberg, Denmark, 2000
    Public contact
    Medical Affairs, Zevra Denmark A/S, +1 8882895607, medicalaffairs@zevra.com
    Scientific contact
    Medical Affairs, Zevra Denmark A/S, +1 8882895607, medicalaffairs@zevra.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
    05 Jan 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of chronic treatment with arimoclomol 1200 mg/day (400 mg TID) compared to placebo over 76 weeks in subjects with ALS as assessed with Combined Assessment of Function and Survival (CAFS)
    Protection of trial subjects
    The IRB or IEC reviewed all appropriate trial documentation including the protocols, patient information and ICFs including amendments to these. This trial was conducted in accordance with their protocol and with the following: • Consensus ethical principles derived from international guidelines including the current version of the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines. • Current version of applicable ICH GCP guidelines. • Applicable laws and regulations.
    Background therapy
    		 Patients were allowed to have been treated with a background stable dose of riluzole. Riluzole use was a stratification factor meaning that there was a chance that patients without background riluzole therapy received placebo.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jul 2018
    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: 19
    Country: Number of subjects enrolled
    Poland: 30
    Country: Number of subjects enrolled
    Spain: 37
    Country: Number of subjects enrolled
    Sweden: 12
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    France: 33
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United States: 57
    Country: Number of subjects enrolled
    Canada: 8
    Worldwide total number of subjects
    245
    EEA total number of subjects
    175
    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)
    176
    From 65 to 84 years
    69
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening was up to 4 weeks prior to Baseline if a washout period for an investigational treatment was required and to allow for laboratory re-tests (if required).

    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
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    ORARIALS-01 was a double-blinded trial in which arimoclomol, and placebo were visually identical and matched for taste. Neither the patient nor any of the investigator site staff or Sponsor staff (including CRO delegated staff) who were involved in the treatment or clinical evaluation and monitoring of the patients were aware of the treatment received. The packaging and labelling of the IMPs contained no evidence of their identity.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Drug: Arimoclomol
    Arm description
    		 248 mg arimoclomol base (equivalent to 400 mg arimoclomol citrate) 3 times daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Arimoclomol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Oral dosage 3 times daily for up to 76 weeks

    Arm title
    		 Drug: Placebo
    Arm description
    		 Matching placebo 3 times daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching capsules taken orally three-times daily

    Number of subjects in period 1 [1]
    		Drug: Arimoclomol Drug: Placebo
    Started
    160
    79
    Completed
    122
    63
    Not completed
    38
    16
         Physician decision
    3
    -
         Consent withdrawn by subject
    22
    15
         Adverse event, non-fatal
    11
    1
         Lost to follow-up
    2
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Subjects reported at baseline include the modified Intention to Treat (mITT) population, not on concomitant Edavarone treatment (N=6) and therefore not included in analysis

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Drug: Arimoclomol
    Reporting group description
    		 248 mg arimoclomol base (equivalent to 400 mg arimoclomol citrate) 3 times daily

    Reporting group title
    Drug: Placebo
    Reporting group description
    		 Matching placebo 3 times daily

    Reporting group values
    		 Drug: Arimoclomol Drug: Placebo Total
    Number of subjects
    		 160 79 239
    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)
    		 113 60 173
        From 65-84 years
    		 47 19 66
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.0 ( 11.26 ) 56.6 ( 9.97 ) -
    Gender categorical
    Units: Subjects
        Female
    		 54 34 88
        Male
    		 106 45 151
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 13 7 20
        Not Hispanic or Latino
    		 132 64 196
        Unknown or Not Reported
    		 15 8 23
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 1 2
        White
    		 136 66 202
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 23 11 34
    Revised ALS Functional Rating Scale
    The ALSFRS-R score is based on a rating scale where 12 functions are rated on 5-point ordinal rating scales (from 0 to 4) with a maximum score of 48 (sum of all 12 items). The higher the score the better functioning.
    Units: Units on a scale
        arithmetic mean (standard deviation)
    		 40.6 ( 3.93 ) 40.2 ( 3.65 ) -
    Percent (%) Predicted Slow Vital Capacity (SVC)
    Slow Vital Capacity (SVC) is a measure of breathing function. SVC measures the volume that can be exhaled from a full inhalation after exhaling to a maximum as slowly as possible. The percent (%) of predicted SVC is reported.
    Units: Percent (%) predicted SVC
        arithmetic mean (standard deviation)
    		 95.8 ( 15.98 ) 98.1 ( 14.78 ) -
    Subject analysis sets

    Subject analysis set title
    Subject Analysis Set 1
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All participants in the modified intention-to-treat (mITT) population

    Subject analysis sets values
    		 Subject Analysis Set 1
    Number of subjects
    239
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male
    Ethnicity
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported
    Race
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Native Hawaiian or Other Pacific Islander
        Black or African American
        White
        More than one race
        Unknown or Not Reported
    Revised ALS Functional Rating Scale
    The ALSFRS-R score is based on a rating scale where 12 functions are rated on 5-point ordinal rating scales (from 0 to 4) with a maximum score of 48 (sum of all 12 items). The higher the score the better functioning.
    Units: Units on a scale
        arithmetic mean (standard deviation)
    40.5 ( 3.83 )
    Percent (%) Predicted Slow Vital Capacity (SVC)
    Slow Vital Capacity (SVC) is a measure of breathing function. SVC measures the volume that can be exhaled from a full inhalation after exhaling to a maximum as slowly as possible. The percent (%) of predicted SVC is reported.
    Units: Percent (%) predicted SVC
        arithmetic mean (standard deviation)
    96.5 ( 15.60 )

    End points

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    End points reporting groups
    Reporting group title
    Drug: Arimoclomol
    Reporting group description
    		 248 mg arimoclomol base (equivalent to 400 mg arimoclomol citrate) 3 times daily

    Reporting group title
    Drug: Placebo
    Reporting group description
    		 Matching placebo 3 times daily

    Subject analysis set title
    Subject Analysis Set 1
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All participants in the modified intention-to-treat (mITT) population

    Primary: Combined Assessment of Function and Survival (CAFS)

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    End point title
    		 Combined Assessment of Function and Survival (CAFS)
    End point description
    Combined Assessment of Function and Survival (CAFS) is a composite endpoint that includes 1) the change from baseline in revised ALS functional rating scale (ALSFRS-R) and 2) the survival endpoint (time to permanent assisted ventilation [PAV], tracheostomy or death). On the ALSFRS-R, 12 functions are rated on 5-point ordinal rating scales (from 0 to 4) with a total score range (minimum and maximum score) of 0-48 (sum of all 12 items). The higher the score the better functioning. For the survival endpoint, the longer time to PAV, tracheostomy, or death the better outcome. A patient's CAFS score represents a patient's rank in the study based on comparing the patient's outcome for both the change in ALSFRS-R and the time to event (PAV, tracheostomy, or death) to the outcome for all other patients in the study in a pairwise fashion. A higher rank score (range 0-1) is considered a better outcome. The reported values are the mean rank scores in each group for the composite endpoint.
    End point type
    Primary
    End point timeframe
    Over 76 Weeks
    End point values
    		 Drug: Arimoclomol Drug: Placebo
    Number of subjects analysed
    160
    79
    Units: score on a scale
        arithmetic mean (standard deviation)
    0.51 ( 0.291 )
    0.49 ( 0.283 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Drug: Arimoclomol v Drug: Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6208
    Method
    		 Gehan's extended Wilcoxon's test
    Confidence interval

    Secondary: Change from Baseline to Week 76 (or End-of-Trial) in Revised ALS Functional Rating Scale (ALSFRS-R)

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    End point title
    		 Change from Baseline to Week 76 (or End-of-Trial) in Revised ALS Functional Rating Scale (ALSFRS-R)
    End point description
    The ALSFRS-R score is based on a rating scale where 12 functions are rated on 5-point ordinal rating scales (from 0 to 4) with a maximum score of 48 (sum of all 12 items). The higher the score the better functioning.
    End point type
    Secondary
    End point timeframe
    Week 76 (or end of trial)
    End point values
    		 Drug: Arimoclomol Drug: Placebo
    Number of subjects analysed
    160
    79
    Units: units on a scale
        arithmetic mean (standard deviation)
    -15.4 ( 8.71 )
    -15.0 ( 9.10 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 76 (or End-of-Trial) in Percent (%) Predicted Slow Vital Capacity (SVC)

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    End point title
    		 Change from Baseline to Week 76 (or End-of-Trial) in Percent (%) Predicted Slow Vital Capacity (SVC)
    End point description
    Slow Vital Capacity (SVC) is a measure of breathing function. SVC measures the volume that can be exhaled from a full inhalation after exhaling to a maximum as slowly as possible. The percent (%) of predicted SVC is reported.
    End point type
    Secondary
    End point timeframe
    Week 76 (or end of trial)
    End point values
    		 Drug: Arimoclomol Drug: Placebo
    Number of subjects analysed
    160
    79
    Units: percent (%) predicted SVC
        arithmetic mean (standard deviation)
    -30.65 ( 26.346 )
    -30.38 ( 23.839 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study medication up to 76 weeks. Assessed every week.
    Adverse event reporting additional description
    Safety population included all participants not on edaravone at baseline who received any amount of study medication. Analysis included all events occurring during on-treatment observation period, starting at date of first administration of study medication, until 14 days following the latest administration of study drug or last dose/end-of-trial.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Arimoclomol (up to 76 Weeks)
    Reporting group description
    		 -

    Reporting group title
    Placebo (up to 76 Weeks)
    Reporting group description
    		 -

    Serious adverse events
    		 Arimoclomol (up to 76 Weeks) Placebo (up to 76 Weeks)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 160 (22.50%)
    20 / 79 (25.32%)
         number of deaths (all causes)
    29
    18
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Rectal cancer
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    3 / 160 (1.88%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 79 (1.27%)
         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
    Medical device site inflammation
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    7 / 160 (4.38%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 160 (1.25%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    2 / 160 (1.25%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 2
    Hypoxia
         subjects affected / exposed
    2 / 160 (1.25%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stridor
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Assisted suicide
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 160 (1.25%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    2 / 160 (1.25%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical observation
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (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
    Femur fracture
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    2 / 160 (1.25%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (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
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pupils unequal
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal perforation
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 79 (1.27%)
         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
    Fistula
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 160 (2.50%)
    5 / 79 (6.33%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Respiratory tract infection
         subjects affected / exposed
    2 / 160 (1.25%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 79 (1.27%)
         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 / 160 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 79 (1.27%)
         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
    		 Arimoclomol (up to 76 Weeks) Placebo (up to 76 Weeks)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    149 / 160 (93.13%)
    71 / 79 (89.87%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 160 (5.63%)
    2 / 79 (2.53%)
         occurrences all number
    9
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    33 / 160 (20.63%)
    17 / 79 (21.52%)
         occurrences all number
    55
    37
    Post lumbar puncture syndrome
         subjects affected / exposed
    10 / 160 (6.25%)
    6 / 79 (7.59%)
         occurrences all number
    10
    6
    Contusion
         subjects affected / exposed
    9 / 160 (5.63%)
    4 / 79 (5.06%)
         occurrences all number
    9
    6
    Procedural pain
         subjects affected / exposed
    5 / 160 (3.13%)
    4 / 79 (5.06%)
         occurrences all number
    5
    5
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 160 (2.50%)
    4 / 79 (5.06%)
         occurrences all number
    4
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    34 / 160 (21.25%)
    21 / 79 (26.58%)
         occurrences all number
    57
    31
    Dizziness
         subjects affected / exposed
    16 / 160 (10.00%)
    4 / 79 (5.06%)
         occurrences all number
    18
    4
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    15 / 160 (9.38%)
    5 / 79 (6.33%)
         occurrences all number
    16
    7
    Fatigue
         subjects affected / exposed
    9 / 160 (5.63%)
    2 / 79 (2.53%)
         occurrences all number
    10
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    33 / 160 (20.63%)
    11 / 79 (13.92%)
         occurrences all number
    38
    13
    Nausea
         subjects affected / exposed
    27 / 160 (16.88%)
    3 / 79 (3.80%)
         occurrences all number
    35
    3
    Diarrhoea
         subjects affected / exposed
    16 / 160 (10.00%)
    8 / 79 (10.13%)
         occurrences all number
    22
    11
    Dyspepsia
         subjects affected / exposed
    6 / 160 (3.75%)
    5 / 79 (6.33%)
         occurrences all number
    7
    5
    Abdominal pain
         subjects affected / exposed
    5 / 160 (3.13%)
    4 / 79 (5.06%)
         occurrences all number
    6
    5
    Flatulence
         subjects affected / exposed
    4 / 160 (2.50%)
    4 / 79 (5.06%)
         occurrences all number
    4
    5
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 160 (0.63%)
    5 / 79 (6.33%)
         occurrences all number
    1
    5
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    7 / 160 (4.38%)
    4 / 79 (5.06%)
         occurrences all number
    8
    4
    Rash
         subjects affected / exposed
    9 / 160 (5.63%)
    2 / 79 (2.53%)
         occurrences all number
    10
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    23 / 160 (14.38%)
    7 / 79 (8.86%)
         occurrences all number
    27
    7
    Depression
         subjects affected / exposed
    8 / 160 (5.00%)
    7 / 79 (8.86%)
         occurrences all number
    8
    7
    Sleep disorder
         subjects affected / exposed
    3 / 160 (1.88%)
    4 / 79 (5.06%)
         occurrences all number
    3
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    14 / 160 (8.75%)
    7 / 79 (8.86%)
         occurrences all number
    15
    9
    Arthralgia
         subjects affected / exposed
    10 / 160 (6.25%)
    5 / 79 (6.33%)
         occurrences all number
    13
    5
    Musculoskeletal pain
         subjects affected / exposed
    10 / 160 (6.25%)
    5 / 79 (6.33%)
         occurrences all number
    12
    5
    Pain in extremity
         subjects affected / exposed
    11 / 160 (6.88%)
    2 / 79 (2.53%)
         occurrences all number
    12
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    14 / 160 (8.75%)
    15 / 79 (18.99%)
         occurrences all number
    18
    23
    Pneumonia
         subjects affected / exposed
    10 / 160 (6.25%)
    3 / 79 (3.80%)
         occurrences all number
    17
    8
    Urinary tract infection
         subjects affected / exposed
    12 / 160 (7.50%)
    7 / 79 (8.86%)
         occurrences all number
    14
    11
    Influenza
         subjects affected / exposed
    10 / 160 (6.25%)
    4 / 79 (5.06%)
         occurrences all number
    11
    5
    Bronchitis
         subjects affected / exposed
    6 / 160 (3.75%)
    5 / 79 (6.33%)
         occurrences all number
    6
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jul 2019
    protocol version 5.0 added in-clinic visits in response to an urgent safety measure that was initiated by the DMC in response to cases of increased transaminases. To monitor increased transaminases, the remote visits 4, 6, and 8 (Week 8, 16, and 32) was changed to inperson visits and a blood sample was to be taken. This was done to enable routine monitoring of patients monthly for the first 6 months of the trial, as recommended by the DMC. Furthermore, discontinuation criteria were updated according to FDA Guidance for Industry on Drug-Induced Liver Injury (DILI) in relation to the urgent safety measure.

    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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