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    Clinical Trial Results:
    A multicenter, double-blind, randomized, placebo-controlled, parallel-group study to determine the efficacy and safety of lucerastat oral monotherapy in adult subjects with Fabry disease.

    Summary
    EudraCT number
    2017-003369-85
    Trial protocol
    GB   AT   NL   BE   IE   ES   NO   IT  
    Global end of trial date
    02 Sep 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Aug 2022
    First version publication date
    25 Aug 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ID-069A301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03425539
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Idorsia Pharmaceuticals Ltd
    Sponsor organisation address
    Hegenheimermattweg 91, Allschwil, Switzerland, 4123
    Public contact
    Clinical Trial Disclosure Desk, Idorsia Pharmaceuticals Ltd, clinical-trials-disclosure@idorsia.com
    Scientific contact
    Clinical Trial Disclosure Desk, Idorsia Pharmaceuticals Ltd, clinical-trials-disclosure@idorsia.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
    27 Sep 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To determine the effect of lucerastat on neuropathic pain in subjects with Fabry disease (FD).
    Protection of trial subjects
    The protocol and any material provided to the subject (such as a subject information sheet or description of the study used to obtain informed consent) were reviewed and approved by the appropriate Independent Ethics Committee (IEC) or Institutional Review Board (IRB) before the study was started. Sponsor personnel and the investigators ensured that the study was conducted in full compliance with ICH-GCP guidelines, the principles of the “Declaration of Helsinki”, and with the laws and regulations of the countries in which the study was conducted. Both the sponsor and the investigator had the right to terminate the study at any time, and in such a case, were responsible for protecting the subjects’ interests. The investigator was responsible for maintaining the subjects’ identities in strictest confidence. Prior to any study procedure and after adequate explanation of the aims, methods, objectives, and potential hazards of the study, written informed consent was obtained from each participating subject. It was made clear to each subject that he or she was completely free to refuse to enter the study, or to withdraw from it at any time for any reason.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 May 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    United States: 32
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 4
    Worldwide total number of subjects
    118
    EEA total number of subjects
    50
    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)
    111
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 49 sites in 14 countries, including North America (USA, CAN), Europe (Austria, Belgium, Germany, Ireland, Italy, Netherlands, Norway, Poland, Spain, Switzerland, UK), and Australia.

    Pre-assignment
    Screening details
    Screening period: From signing informed consent to the day before subject randomization (6 to 7 weeks duration).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Lucerastat
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Lucerastat
    Investigational medicinal product code
    ACT-434964
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lucerastat (ACT-434964) was provided as hard-gelatin capsules containing 250 mg of lucerastat. Capsules were administered orally b.i.d. to provide a lucerastat dose of 250, 500, 750, or 1000 mg b.i.d. based on the subject’s eGFR.

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo capsules were administered orally b.i.d., with the number of capsules administered based on the subject’s eGFR.

    Number of subjects in period 1
    Lucerastat Placebo
    Started
    80
    38
    Completed
    75
    34
    Not completed
    5
    4
         Consent withdrawn by subject
    3
    -
         Adverse event, non-fatal
    2
    2
         Randomized but not treated
    -
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lucerastat
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    Lucerastat Placebo Total
    Number of subjects
    80 38 118
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    74 37 111
        From 65-84 years
    6 1 7
    Age continuous
    Units: years
        median (full range (min-max))
    38 (18 to 74) 39 (18 to 65) -
    Gender categorical
    Units: Subjects
        Female
    43 20 63
        Male
    37 18 55

    End points

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    End points reporting groups
    Reporting group title
    Lucerastat
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Primary: Neuropathic pain monthly score (modified BPI-SF3): Change from baseline to Month 6

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    End point title
    Neuropathic pain monthly score (modified BPI-SF3): Change from baseline to Month 6
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to Month 6
    End point values
    Lucerastat Placebo
    Number of subjects analysed
    80
    37
    Units: Score
        least squares mean (confidence interval 95%)
    -1.64 (-2.11 to -1.16)
    -2.05 (-2.73 to -1.37)
    Statistical analysis title
    Neuropathic pain monthly score: ANCOVA
    Statistical analysis description
    Neuropathic pain monthly score (modified BPI-SF3): main analysis of change from baseline to Month 6 (ANCOVA)
    Comparison groups
    Lucerastat v Placebo
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.3189
    Method
    ANCOVA
    Parameter type
    LS Mean difference vs. placebo
    Point estimate
    0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    1.23
    Notes
    [1] - An ANCOVA was applied to the change from baseline to Month 6 including the terms baseline value, the two stratification factors (sex and ERT treatment status), and the treatment group.

    Secondary: Plasma Gb3 (ng/ml): Change from baseline to Month 6

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    End point title
    Plasma Gb3 (ng/ml): Change from baseline to Month 6
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to Month 6
    End point values
    Lucerastat Placebo
    Number of subjects analysed
    80
    37
    Units: ng/ml
        least squares mean (confidence interval 95%)
    -672.68 (-798.91 to -546.46)
    200.84 (14.29 to 387.40)
    No statistical analyses for this end point

    Secondary: Abdominal pain monthly score: Change from baseline to Month 6

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    End point title
    Abdominal pain monthly score: Change from baseline to Month 6
    End point description
    From baseline to Month 6
    End point type
    Secondary
    End point timeframe
    From baseline to Month 6
    End point values
    Lucerastat Placebo
    Number of subjects analysed
    61
    29
    Units: Score
        least squares mean (confidence interval 95%)
    -1.37 (-1.86 to -0.87)
    -1.68 (-2.38 to -0.98)
    No statistical analyses for this end point

    Secondary: Number of days with diarrhea: Change from baseline to Month 6

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    End point title
    Number of days with diarrhea: Change from baseline to Month 6
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to Month 6
    End point values
    Lucerastat Placebo
    Number of subjects analysed
    48
    25
    Units: Number of days
        arithmetic mean (standard deviation)
    -3.45 ( 4.96 )
    -3.95 ( 9.29 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events from the treatment period are reported.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Lucerastat
    Reporting group description
    Lucerastat

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    Lucerastat Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 80 (6.25%)
    1 / 37 (2.70%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Ventricular tachycardia
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Implantable defibrillator insertion
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 37 (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
    Drug withdrawal syndrome
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 37 (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
    Hepatitis viral
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic encephalopathy
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 37 (2.70%)
         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
    Lucerastat Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 80 (57.50%)
    21 / 37 (56.76%)
    Investigations
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 80 (0.00%)
    4 / 37 (10.81%)
         occurrences all number
    0
    4
    Injury, poisoning and procedural complications
    Vaccination complication
         subjects affected / exposed
    5 / 80 (6.25%)
    1 / 37 (2.70%)
         occurrences all number
    10
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 80 (11.25%)
    4 / 37 (10.81%)
         occurrences all number
    11
    4
    Neuralgia
         subjects affected / exposed
    6 / 80 (7.50%)
    3 / 37 (8.11%)
         occurrences all number
    6
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 80 (3.75%)
    6 / 37 (16.22%)
         occurrences all number
    3
    7
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 37 (5.41%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 37 (5.41%)
         occurrences all number
    1
    2
    Abdominal distension
         subjects affected / exposed
    4 / 80 (5.00%)
    4 / 37 (10.81%)
         occurrences all number
    4
    4
    Abdominal pain
         subjects affected / exposed
    4 / 80 (5.00%)
    1 / 37 (2.70%)
         occurrences all number
    5
    2
    Diarrhoea
         subjects affected / exposed
    9 / 80 (11.25%)
    1 / 37 (2.70%)
         occurrences all number
    10
    1
    Dry mouth
         subjects affected / exposed
    4 / 80 (5.00%)
    1 / 37 (2.70%)
         occurrences all number
    4
    1
    Flatulence
         subjects affected / exposed
    7 / 80 (8.75%)
    1 / 37 (2.70%)
         occurrences all number
    7
    1
    Nausea
         subjects affected / exposed
    11 / 80 (13.75%)
    1 / 37 (2.70%)
         occurrences all number
    13
    1
    Vomiting
         subjects affected / exposed
    6 / 80 (7.50%)
    0 / 37 (0.00%)
         occurrences all number
    7
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    6 / 80 (7.50%)
    0 / 37 (0.00%)
         occurrences all number
    6
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 80 (6.25%)
    0 / 37 (0.00%)
         occurrences all number
    5
    0
    Back pain
         subjects affected / exposed
    5 / 80 (6.25%)
    2 / 37 (5.41%)
         occurrences all number
    5
    2
    Muscle spasms
         subjects affected / exposed
    2 / 80 (2.50%)
    2 / 37 (5.41%)
         occurrences all number
    4
    3
    Infections and infestations
    COVID-19
         subjects affected / exposed
    2 / 80 (2.50%)
    2 / 37 (5.41%)
         occurrences all number
    2
    2
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    8 / 80 (10.00%)
    5 / 37 (13.51%)
         occurrences all number
    10
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Apr 2018
    1. The definition of neuropathic pain was split to improve readability and subject comprehension. The descriptor “numbness” was removed from the description as it was considered to be a distinct concept that does not necessarily describe neuropathic pain severity. The concept of intermittence was also added to the definition of neuropathic pain. 2. A new Patient Global Impression of Severity scale was added to assess the overall severity of neuropathic pain. 3. It was clarified that current guidelines for the diagnosis and treatment of FD were to be followed. 4. A more explicit definition of the global end of the study was included. 5. The process of eDiary data availability, transfer, encoding, and the measures taken to maintain privacy of the subject were clarified. 6. Exclusion criteria were adjusted to emphasize that any subject at high risk of developing clinical signs of organ involvement within the time period of the study, as per investigator judgment would be excluded from the study.
    25 Oct 2018
    The results of a clinical drug-drug interaction (DDI) study (ID-069-105) with the organic cation transporter 2 (OCT2) inhibitor cimetidine led to the conclusion that lucerastat can be administered concomitantly with OCT2 inhibitors without need for dose adaptation. Therefore, respective protocol restrictions at study entry (exclusion criterion #15) and during the study (forbidden concomitant therapy) related to the use of OCT2 inhibitors have been removed.
    01 Oct 2020
    The main reason for the amendment was to change the methodology used to analyze the primary endpoint from a dichotomous responder analysis, based on a reduction of at least 30% from baseline to Month 6 in modified BPI-SF3 score, to an analysis of the change from baseline to Month 6 in modified BPI-SF3 score. Analyzing the primary endpoint as a continuous variable avoided a loss in information caused by the dichotomization of the endpoint variable. It required fewer subjects to maintain the statistical power to detect a difference between lucerastat and placebo. With the proposed continuous analysis, 99 subjects are required to achieve a power of 87.2%, which is comparable to the power in the range of 81.984.1% for the current responder analysis based on 108 subjects. The dichotomous responder analysis was documented to support and establish clinical relevance. This change was agreed with the FDA in order to help overcome challenges in recruitment of subjects with a rare disease in the context of the COVID 19 pandemic and complete the study. The change was restricted to the primary statistical analysis and did not alter the study population or the study's primary objective.
    24 Aug 2021
    The main purpose of the amendment was to change the statistical method used to analyze the secondary endpoint "Change from baseline to Month 6 in the number of days with at least 1 stool of a BSS consistency Type 6 or 7", from a parametric analysis (assuming normality) to a non-parametric analysis. This change in analysis was warranted because the blinded baseline data review suggested that the endpoint was not normally distributed. The necessity to make a change to this analysis method was discussed with the FDA; the change is restricted to the statistical analysis of the last secondary endpoint in the testing strategy and does not alter the study population and the primary and secondary objectives of the study.

    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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