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    Clinical Trial Results:
    A phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate efficacy and safety of octreotide capsules in patients who previously tolerated and demonstrated biochemical control on injectable somatostatin receptor ligands (SRL) treatment

    Summary
    EudraCT number
    		 2017-000737-31
    Trial protocol
    		 GB   DE   HU   NL   SE   DK   PL   IT   BG   LV   SI   RO  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Sep 2020
    First version publication date
    11 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OOC-ACM-303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03252353
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Chiasma, Inc.
    Sponsor organisation address
    140 Kendrick Street, Building C East, Needham, United States, MA 02494
    Public contact
    Asi Haviv, Chiasma, Inc., +972 8-939-3888, Asi@chiasmapharma.com
    Scientific contact
    Asi Haviv, Chiasma, Inc., +972 8-939-3888, Asi@chiasmapharma.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
    Interim
    Date of interim/final analysis
    11 Jul 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Jun 2019
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To assess maintenance of biochemical control with octreotide capsules compared to placebo in patients with acromegaly, who previously demonstrated biochemical control on somatostatin receptor ligands (SRLs)
    Protection of trial subjects
    Not applicable
    Background therapy
    		 Parenteral SRL monotherapy (octreotide or lanreotide but not pasireotide).
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    30 Aug 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Turkey: 3
    Country: Number of subjects enrolled
    United States: 21
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Slovenia: 2
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Latvia: 1
    Worldwide total number of subjects
    56
    EEA total number of subjects
    22
    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
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was performed from 30 Aug 2017 (first site intiated) to 13 Jun 2019 (last patient completed core study period).

    Pre-assignment
    Screening details
    		 The Screening period consisted of 2 screening visits to assess whether the average insulin-like growth factor-1 (IGF-1) level was ≤ 1 times the upper limit of normal (ULN) to determine eligibility. Screening visit 2 was scheduled within 2 weeks prior to randomisation.

    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, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Octreotide
    Arm description
    		 Octreotide 40, 60, or 80 mg/day (individual dose titration).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Octreotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Octreotide treatment was started at a total dose of 40 mg/day. Dose escalation (based on measurement of the patient’s circulating IGF-1 levels and acromegaly-related Symptoms) was performed in a stepwise manner to 60 mg/day or 80 mg/day. Study drug was taken twice daily, in the morning and in the evening.

    Arm title
    		 Placebo
    Arm description
    		 Octreotide matching placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Octreotide-matching placebo was started at a capsule number matching a total dose of 40 mg/day. Dose escalation (based on measurement of the patient’s circulating IGF-1 levels and acromegaly-related Symptoms) was performed in a stepwise manner to a capsule number matching 60 mg/day or 80 mg/day. Study drug was taken twice daily, in the morning and in the evening.

    Number of subjects in period 1
    		Octreotide Placebo
    Started
    28
    28
    Completed
    28
    28

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Octreotide
    Reporting group description
    		 Octreotide 40, 60, or 80 mg/day (individual dose titration).

    Reporting group title
    Placebo
    Reporting group description
    		 Octreotide matching placebo

    Reporting group values
    		 Octreotide Placebo Total
    Number of subjects
    		 28 28 56
    Age categorical
    Only adult subjects were enrolled.
    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)
    		 21 22 43
        From 65-84 years
    		 7 6 13
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.3 ( 11.97 ) 54.2 ( 10.96 ) -
    Gender categorical
    Units: Subjects
        Female
    		 12 14 26
        Male
    		 16 14 30
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This population includes all randomized patients. The FAS served as the primary efficacy analysis population for the DPC period of the study. The safety set and the per protocol set were identical to the FAS.

    Subject analysis sets values
    		 Full analysis set
    Number of subjects
    56
    Age categorical
    Only adult subjects were enrolled.
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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 65-84 years
    13
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54.7 ( 11.38 )
    Gender categorical
    Units: Subjects
        Female
    26
        Male
    30

    End points

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    End points reporting groups
    Reporting group title
    Octreotide
    Reporting group description
    		 Octreotide 40, 60, or 80 mg/day (individual dose titration).

    Reporting group title
    Placebo
    Reporting group description
    		 Octreotide matching placebo

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This population includes all randomized patients. The FAS served as the primary efficacy analysis population for the DPC period of the study. The safety set and the per protocol set were identical to the FAS.

    Primary: Proportion of Patients Who Maintain Their Biochemical Response at the End of the Double Blind Placebo Controlled Period

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    End point title
    		 Proportion of Patients Who Maintain Their Biochemical Response at the End of the Double Blind Placebo Controlled Period
    End point description
    Maintenance of response was defined by using the average IGF-1 level of the last 2 available assessments between weeks 34 and 36 in the DPC period. If the average IGF-1 is ≤ 1×ULN, a patient was classified as a responder (i.e., maintained their biochemical response). If the average IGF-1 is > 1×ULN, a patient was classified as a non-responder. Patients who discontinued study medication during the DPC period for any reason were classified as non-responders for the primary analysis, regardless of their IGF-1 values.
    End point type
    Primary
    End point timeframe
    Week 36
    End point values
    		 Octreotide Placebo
    Number of subjects analysed
    28
    28
    Units: Subjects
        Responder
    16
    5
        Non-responder
    12
    23
    Statistical analysis title
    		 Analysis of primary endpoint
    Statistical analysis description
    An exact logistic regression model, with covariates for treatment, baseline SRL dose (low vs mid or high) and baseline IGF-1 level (< median vs ≥ median) was used.
    Comparison groups
    Octreotide v Placebo
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0079
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.7674
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.444
         upper limit
    		 28.2115
    Notes
    [1] - If the two-sided p-value was < 0.05, octreotide capsules were declared superior to placebo.

    Secondary: Proportion of Patients Who Maintain GH Response at the End of the Double Blind Placebo Controlled Period

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    End point title
    		 Proportion of Patients Who Maintain GH Response at the End of the Double Blind Placebo Controlled Period
    End point description
    Maintenance of GH response was defined as having mean Growth Hormone (5 measurements 30 minutes apart) < 2.5 ng/mL at the end of the double blind placebo controlled period, out of those who were responders on SRL injections at Screening.
    End point type
    Secondary
    End point timeframe
    Week 36
    End point values
    		 Octreotide Placebo
    Number of subjects analysed
    28
    28
    Units: Subjects
        Responder
    21
    7
        Non-responder
    7
    21
    No statistical analyses for this end point

    Secondary: Proportion of Patients Who Begin Rescue Treatment

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    End point title
    		 Proportion of Patients Who Begin Rescue Treatment
    End point description
    Proportion of Patients who Began Rescue Treatment Prior to and Including Week 36.
    End point type
    Secondary
    End point timeframe
    Week 36
    End point values
    		 Octreotide Placebo
    Number of subjects analysed
    28
    28
    Units: Subjects
    7
    19
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    1 year, 10 months
    Adverse event reporting additional description
    Safety population: All participants enrolled in the study who received any amount of the study drug.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Octreotide
    Reporting group description
    		 Octreotide treatment was started at a total dose of 40 mg/day. Dose escalation was based on measurement of the patient’s circulating IGF-1 levels and acromegaly-related symptoms. Dose escalation was performed in a stepwise manner to 60 mg/day or 80 mg/day.

    Reporting group title
    Placebo
    Reporting group description
    		 Octreotide matching placebo

    Serious adverse events
    		 Octreotide Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 28 (3.57%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Joint dislocation
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Octreotide Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 28 (100.00%)
    27 / 28 (96.43%)
    Investigations
    Blood glucose increased
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 28 (3.57%)
         occurrences all number
    5
    2
    Gamma-glutamyltransferase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 28 (10.71%)
         occurrences all number
    1
    4
    Insulin-like growth factor increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Weight increased
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 28 (7.14%)
         occurrences all number
    2
    2
    Nervous system disorders
    Carpal tunnel syndrome
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 28 (14.29%)
    4 / 28 (14.29%)
         occurrences all number
    5
    5
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 28 (14.29%)
    9 / 28 (32.14%)
         occurrences all number
    7
    17
    Hypoaesthesia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Paraesthesia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    7 / 28 (25.00%)
         occurrences all number
    2
    8
    Influenza like illness
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Oedema peripheral
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    3 / 28 (10.71%)
         occurrences all number
    2
    3
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Peripheral swelling
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 28 (10.71%)
    4 / 28 (14.29%)
         occurrences all number
    4
    4
    Gastrointestinal disorders
    Abdominal discomfort
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 28 (14.29%)
    3 / 28 (10.71%)
         occurrences all number
    4
    4
    Abdominal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 28 (7.14%)
         occurrences all number
    3
    2
    Abdominal pain upper
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 28 (10.71%)
         occurrences all number
    1
    3
    Constipation
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 28 (10.71%)
    4 / 28 (14.29%)
         occurrences all number
    4
    5
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 28 (28.57%)
    6 / 28 (21.43%)
         occurrences all number
    9
    6
    Dyspepsia
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 28 (3.57%)
         occurrences all number
    3
    2
    Flatulence
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    Large intestine polyp
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 28 (21.43%)
    3 / 28 (10.71%)
         occurrences all number
    7
    3
    Tongue disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 28 (14.29%)
    0 / 28 (0.00%)
         occurrences all number
    4
    0
    Hepatobiliary disorders
    Cholelithiasis
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 28 (21.43%)
    7 / 28 (25.00%)
         occurrences all number
    10
    8
    Night sweats
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    Psychiatric disorders
    Anxiety
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 28 (7.14%)
         occurrences all number
    2
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Systematic
         subjects affected / exposed
    9 / 28 (32.14%)
    16 / 28 (57.14%)
         occurrences all number
    11
    28
    Arthritis
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 28 (7.14%)
         occurrences all number
    3
    4
    Back pain
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    4 / 28 (14.29%)
         occurrences all number
    2
    5
    Musculoskeletal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 28 (7.14%)
         occurrences all number
    1
    4
    Osteoarthritis
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 28 (0.00%)
         occurrences all number
    3
    0
    Pain in extremity
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    3
    Soft tissue swelling
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 28 (10.71%)
         occurrences all number
    1
    3
    Infections and infestations
    Nasopharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 28 (10.71%)
    4 / 28 (14.29%)
         occurrences all number
    33
    5
    Sinusitis
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 28 (0.00%)
         occurrences all number
    3
    0
    Upper respiratory tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    Urinary tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 28 (3.57%)
         occurrences all number
    6
    2
    Metabolism and nutrition disorders
    Hypercholesterolaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Aug 2017
    Changed the order of the secondary objectives and secondary efficacy endpoints; added an exploratory endpoint (ie, proportion of patients who require rescue medication [eg, re-initiate SRL treatment]); and modified the definition of the FAS.
    29 Nov 2017
    Updated the Sponsor’s street address; removed the following secondary objective: “to assess relative change in IGF-1 and GH on octreotide capsules compared to placebo”; added the following secondary endpoint: “proportion of patients who begin rescue treatment prior to and including week 36”; recategorized 2 of the endpoints from secondary endpoints to descriptive endpoints; removed the following exploratory endpoint: “proportion of patients who require rescue medication (eg, re-initiate SRL treatment)”; modified the statistical methods for the secondary efficacy analyses; and added statistical methods for the descriptive endpoint analyses.

    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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