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    Clinical Trial Results:
    A Double-blind, Placebo-controlled Study on the Effects of MIN-102 on Biochemical, Imaging, Neurophysiological, and Clinical Markers in Patients with Friedreich’s Ataxia

    Summary
    EudraCT number
    2018-004405-64
    Trial protocol
    BE   FR   DE   ES  
    Global end of trial date
    14 Sep 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    03 May 2021
    First version publication date
    03 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MT-2-03
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Minoryx Therapeutics BE SA
    Sponsor organisation address
    Rue Auguste Piccard 48, 6041 Gosselies, Belgium,
    Public contact
    Sílvia Pascual, Minoryx Therapeutics BE SA, 0034 935441466, spascual@minoryx.com
    Scientific contact
    Sílvia Pascual, Minoryx Therapeutics BE SA, 0034 935441466, spascual@minoryx.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
    09 Oct 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective was to evaluate the effect of 48 weeks’ treatment with MIN-102 compared to placebo on cervical spinal cord area as assessed by morphometric MRI measurements. Secondary objectives and exploratory objectives were also evaluated. The secondary objectives included evaluating the effect of 48 weeks of treatment with MIN-102 compared to placebo on: change from baseline in the SARA (Scale for the Assessment and Rating of Ataxia) total score; diffusion tensor imaging (DTI) of the cervical spinal cord; cervical spinal cord total N-acetylaspartate concentration/myo-inositol (tNAA/Mins) ratio (using magnetic resonance spectroscopy [MRS]); MRI quantitative susceptibility mapping (QSM) for iron concentration; dentate nuclei volume; fixel-based analyses (FBA) of the brain; cerebellar composite functional scale (CCFS); fatigue severity scale (FSS); quality of life assessments; clinical and patient global impression of improvement; safety and tolerability of MIN-102.
    Protection of trial subjects
    All study patients (caregivers as applicable) were required to read and sign an Informed Consent Form; if the patient was a minor, investigators were required to obtain written informed consent from a parent/legal guardian and written assent from the patient. Consent/assent was obtained prior to any study-specific screening procedures. As part of this procedure, the investigator or an associate would explain orally and in writing the nature, duration, and purpose of the study and the action of the drug in such a manner that the patient/parent was aware of the potential risks, inconveniences, or adverse effects. The parent/legal guardian was informed that the patient could withdraw from the study at any time. In the event of a protocol modification, the Informed Consent Form was to be updated as applicable, with subsequent institutional review board (IRB)/independent ethics committee (IEC) approval and re-consenting of patients. For optional evaluations of motor evoked potentials and cerebrospinal fluid sampling, additional informed consent and assent was required, which was documented using a check box in the main consent form. In addition, optional consent was required for the collection of results from SARA assessments conducted prior to screening, in patients for whom these data were available. The decision of a patient to participate in these optional assessments or not had no impact on their inclusion in the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Apr 2019
    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
    Belgium: 9
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Spain: 14
    Worldwide total number of subjects
    39
    EEA total number of subjects
    39
    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)
    14
    Adults (18-64 years)
    25
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 39 patient were enrolled between 02-Apr-2019 (first patient visit) and 14-Sep-2020 (last patient visit) and received treatment with MIN-102 or placebo.

    Pre-assignment
    Screening details
    Eleven patients were screened but not enrolled, with 7 patients failing to meet the eligibility criteria, 2 patients withdrawing consent, and 2 patients ineligible due to another reason.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject
    Blinding implementation details
    Patients were randomly assigned to MIN-102 or placebo in a 2:1 ratio using interactive response technology. Controls to maintain the double-blind status included: the oral suspensions containing active drug or placebo were indistinguishable in appearance and taste; the packaging and labeling of the bottles for both treatments was identical; dose adjustment (to achieve the target exposure) was managed by a central unblinded PK expert; random dose adjustments were made for placebo patients.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    MIN-102 group
    Arm description
    Patients in the MIN-102 group received oral MIN-102 once daily for 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    MIN-102
    Investigational medicinal product code
    Other name
    Leriglitazone hydrochloride
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received oral MIN-102 once daily for 48 weeks using a 10-mL syringe. Initial doses were 150 mg (adult males), 130 mg (adult females), and 2.2 mg/kg (patients ≥12 to 17 years). At Visit 1 (after 4 weeks of treatment) blood samples were collected for PK analysis; dosages for individuals were then modified by the PK specialist to achieve the desired plasma exposure of 170 µg.hr/mL in each patient. Patients received this dose throughout the study, unless reduction was necessary due to safety or tolerability. Administration could be temporarily interrupted if a patient experienced safety and/or tolerability issues or other conditions that prevented them taking study drug. Treatment was to be stopped if patients showed clinical signs of heart failure, left ventricular ejection fraction changes (drop to below 50% or an absolute drop of >10% from baseline), or if indicated after evaluating ECGs following elevations of NT-pro BNP (N-terminal pro B-type natriuretic peptide) >300 pg/mL.

    Arm title
    Placebo group
    Arm description
    Patients in the placebo group received oral matching placebo once daily for 48 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received placebo once daily for 48 weeks using a 10-mL syringe. Random dose adjustments were made for patients receiving placebo in order to maintain the blind.

    Number of subjects in period 1
    MIN-102 group Placebo group
    Started
    26
    13
    Completed
    20
    12
    Not completed
    6
    1
         Study drug withdrawal by patient/parent/guardian
    1
    1
         Participation withdrawal by patient/parent/guardia
    1
    -
         Adverse event, non-fatal
    4
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MIN-102 group
    Reporting group description
    Patients in the MIN-102 group received oral MIN-102 once daily for 48 weeks.

    Reporting group title
    Placebo group
    Reporting group description
    Patients in the placebo group received oral matching placebo once daily for 48 weeks.

    Reporting group values
    MIN-102 group Placebo group Total
    Number of subjects
    26 13 39
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    10 4 14
        Adults (18-64 years)
    16 9 25
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    23.1 ± 9.79 25.8 ± 12.67 -
    Gender categorical
    Units: Subjects
        Female
    11 6 17
        Male
    15 7 22
    Race
    Units: Subjects
        White
    20 10 30
        Not recorded
    6 3 9
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    5 0 5
        Not Hispanic or Latino
    15 10 25
        Not recorded
    6 3 9
    Height
    Units: cm
        arithmetic mean (standard deviation)
    162.8 ± 11.78 169.7 ± 11.60 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    58.5 ± 17.73 62.1 ± 16.57 -
    Time since genetic diagnosis
    The time (years) since genetic diagnosis of FRDA at date of informed consent. If diagnosis date was partial, then time is difference of years.
    Units: Years
        arithmetic mean (standard deviation)
    5.16 ± 4.458 6.18 ± 4.977 -
    Time since onset of symptoms
    The time (years) since the onset of FRDA symptoms at date of informed consent. If symptoms date was partial, then time is difference of years.
    Units: Years
        arithmetic mean (standard deviation)
    9.63 ± 5.146 12.27 ± 8.081 -
    Age at onset of symptoms
    The age of the patient at the onset of symptoms. If the symptoms date was partial, then time is difference of years.
    Units: Years
        arithmetic mean (standard deviation)
    14.2 ± 7.50 14.3 ± 7.81 -

    End points

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    End points reporting groups
    Reporting group title
    MIN-102 group
    Reporting group description
    Patients in the MIN-102 group received oral MIN-102 once daily for 48 weeks.

    Reporting group title
    Placebo group
    Reporting group description
    Patients in the placebo group received oral matching placebo once daily for 48 weeks.

    Primary: Change from Baseline in spinal cord area cervical segment C2-C3

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    End point title
    Change from Baseline in spinal cord area cervical segment C2-C3
    End point description
    Values provided here are the least squares (LS) mean (standard error [SE]) change from Baseline to Week 48 area in measurements of spinal cord cervical segment C2-C3 area, estimated from the MRI T1-weighted brain image for the modified intent-to-treat (mITT) population. The mITT consisted of all patients who took at least 1 dose (partial or complete) of study drug and had at least 1 post-baseline spinal cord area cervical segment C2-C3 measurement and SARA assessment at the same visit. There was no conclusive outcome from the primary objective to evaluate the change from Baseline in cervical spinal cord area after 48 weeks of treatment. In both treatment groups, there was no clinically meaningful change in area from Baseline to Week 48; numerical differences between the groups (a small decrease in the area in the MIN-102 group [least squares (LS) mean change -0.394 mm²] and a small increase in the placebo group [0.076 mm²]) were not considered to be clinically relevant.
    End point type
    Primary
    End point timeframe
    Baseline to Week 48
    End point values
    MIN-102 group Placebo group
    Number of subjects analysed
    20 [1]
    12 [2]
    Units: mm²
        least squares mean (standard error)
    -0.39420 ± 0.55483
    0.07648 ± 0.71655
    Notes
    [1] - Two patients in the mITT population did not undergo MRI at both baseline and Week 48.
    [2] - All patients in the mITT population underwent MRI at both baseline and Week 48.
    Statistical analysis title
    Primary endpoint analysis
    Comparison groups
    Placebo group v MIN-102 group
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    [3]
    P-value
    = 0.608 [4]
    Method
    ANCOVA
    Confidence interval
    Notes
    [3] - In this study, formal statistical significance on the individual endpoints was not sought. The study looked for clinically meaningful effects based on the effect sizes and associated 95% confidence intervals with p-values being used only as a guide to activity.
    [4] - P value for the difference between treatment arms in the mITT population.

    Secondary: Change from Baseline in MRI QSM for iron concentration

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    End point title
    Change from Baseline in MRI QSM for iron concentration
    End point description
    This secondary efficacy endpoint evaluated the effect of 48 weeks of treatment with MIN-102 compared to placebo on magnetic resonance imaging (MRI) quantitative susceptibility mapping (QSM) for iron concentration. Values reported here are for the mITT population. At Baseline, the mean iron concentration was comparable in the MIT-102 and placebo groups (64.89 ppb and 73.86 ppb, respectively). The LS mean change from Baseline to 48 weeks saw little change in the MIN-102 group (increase of 0.098 ppb), with an increase of 4.858 ppb in the placebo group.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    MIN-102 group Placebo group
    Number of subjects analysed
    17 [5]
    9 [6]
    Units: parts per billion
        least squares mean (standard error)
    0.09757 ± 1.32894
    4.85848 ± 1.84216
    Notes
    [5] - Five patients in the mITT population did not undergo QSM assessment at both baseline and Week 48.
    [6] - Three patients in the mITT population did not undergo QSM assessment at both baseline and Week 48.
    Statistical analysis title
    Secondary efficacy endpoint analysis
    Comparison groups
    Placebo group v MIN-102 group
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.05 [7]
    Method
    ANCOVA
    Confidence interval
    Notes
    [7] - P value for the difference between treatment arms in the mITT population.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs) were recorded from Baseline until the Follow-up Visit, which occurred 28 +/-5 days after the last dose of study drug.
    Adverse event reporting additional description
    TEAEs were defined as AEs occurring on or after the first dose of study treatment. Adverse events that were recorded more than twice in any group are reported here.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    MIN-102 group
    Reporting group description
    Patients in the MIN-102 group received oral MIN-102 once daily for 48 weeks.

    Reporting group title
    Placebo group
    Reporting group description
    Patients in the placebo group received oral matching placebo once daily for 48 weeks.

    Serious adverse events
    MIN-102 group Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Dilatation atrial
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.35%
    Non-serious adverse events
    MIN-102 group Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 26 (100.00%)
    13 / 13 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    4
    0
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    8 / 26 (30.77%)
    0 / 13 (0.00%)
         occurrences all number
    13
    0
    Fatigue
         subjects affected / exposed
    10 / 26 (38.46%)
    3 / 13 (23.08%)
         occurrences all number
    14
    3
    Generalised oedema
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    5
    0
    Oedema peripheral
         subjects affected / exposed
    19 / 26 (73.08%)
    0 / 13 (0.00%)
         occurrences all number
    44
    0
    Peripheral swelling
         subjects affected / exposed
    4 / 26 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    8
    0
    Pyrexia
         subjects affected / exposed
    4 / 26 (15.38%)
    1 / 13 (7.69%)
         occurrences all number
    6
    1
    Swelling face
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 13 (0.00%)
         occurrences all number
    4
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 26 (15.38%)
    4 / 13 (30.77%)
         occurrences all number
    9
    7
    Investigations
    Blood cholesterol increased
         subjects affected / exposed
    5 / 26 (19.23%)
    1 / 13 (7.69%)
         occurrences all number
    5
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    4 / 26 (15.38%)
    1 / 13 (7.69%)
         occurrences all number
    4
    1
    Haemoglobin decreased
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    Haemoglobin increased
         subjects affected / exposed
    2 / 26 (7.69%)
    3 / 13 (23.08%)
         occurrences all number
    2
    3
    Lymphocyte count increased
         subjects affected / exposed
    2 / 26 (7.69%)
    3 / 13 (23.08%)
         occurrences all number
    3
    3
    Mean cell haemoglobin concentration decreased
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 13 (15.38%)
         occurrences all number
    1
    3
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    8 / 26 (30.77%)
    0 / 13 (0.00%)
         occurrences all number
    9
    0
    Neutrophil count decreased
         subjects affected / exposed
    3 / 26 (11.54%)
    3 / 13 (23.08%)
         occurrences all number
    7
    6
    Red blood cell count decreased
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    4
    0
    Urine cytology abnormal
         subjects affected / exposed
    3 / 26 (11.54%)
    1 / 13 (7.69%)
         occurrences all number
    5
    1
    Urine output increased
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    Weight increased
         subjects affected / exposed
    12 / 26 (46.15%)
    2 / 13 (15.38%)
         occurrences all number
    15
    2
    White blood cell count decreased
         subjects affected / exposed
    4 / 26 (15.38%)
    2 / 13 (15.38%)
         occurrences all number
    10
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 26 (19.23%)
    4 / 13 (30.77%)
         occurrences all number
    6
    5
    Dyspnoea
         subjects affected / exposed
    0 / 26 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    4
    Oropharyngeal pain
         subjects affected / exposed
    5 / 26 (19.23%)
    3 / 13 (23.08%)
         occurrences all number
    7
    3
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 26 (11.54%)
    3 / 13 (23.08%)
         occurrences all number
    3
    5
    Headache
         subjects affected / exposed
    16 / 26 (61.54%)
    5 / 13 (38.46%)
         occurrences all number
    34
    12
    Paraesthesia
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 13 (7.69%)
         occurrences all number
    4
    1
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    4 / 26 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    7
    0
    Lacrimation increased
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 13 (0.00%)
         occurrences all number
    4
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 26 (11.54%)
    1 / 13 (7.69%)
         occurrences all number
    3
    1
    Nausea
         subjects affected / exposed
    5 / 26 (19.23%)
    2 / 13 (15.38%)
         occurrences all number
    5
    2
    Vomiting
         subjects affected / exposed
    5 / 26 (19.23%)
    1 / 13 (7.69%)
         occurrences all number
    5
    2
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences all number
    5
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 26 (19.23%)
    2 / 13 (15.38%)
         occurrences all number
    7
    3
    Back pain
         subjects affected / exposed
    3 / 26 (11.54%)
    3 / 13 (23.08%)
         occurrences all number
    3
    5
    Neck pain
         subjects affected / exposed
    4 / 26 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    5
    0
    Pain in extremity
         subjects affected / exposed
    2 / 26 (7.69%)
    3 / 13 (23.08%)
         occurrences all number
    3
    4
    Metabolism and nutrition disorders
    Vitamin B12 deficiency
         subjects affected / exposed
    4 / 26 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    4
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    2
    4
    Influenza
         subjects affected / exposed
    5 / 26 (19.23%)
    2 / 13 (15.38%)
         occurrences all number
    7
    3
    Nasopharyngitis
         subjects affected / exposed
    8 / 26 (30.77%)
    6 / 13 (46.15%)
         occurrences all number
    10
    9
    Rhinitis
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 13 (15.38%)
         occurrences all number
    4
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jul 2019
    Protocol amendment: v2.0 • Update of prohibited concomitant medications.
    31 Oct 2019
    Protocol amendment: v3.0 • Clarification of discontinuation criteria in case of NT-pro BNP elevations for participant safety. • Clarification of requirements of the End of Treatment visit.
    25 Feb 2020
    Protocol amendment: v4.0 • Addition of exploratory objectives with recorded MRI data, including analysis of further brain regions. • Addition of main metabolite M3 to PK analysis. • Change of statistical analysis of the primary endpoint from a 2-sample t-test to an analysis of covariance (ANCOVA) model.

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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