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    Clinical Trial Results:
    An Open-Label, Single Dose Pharmacokinetic Study of Xyntha (Moroctocog Alfa [AF-CC], Recombinant Factor VIII) in Male Chinese Subjects with Hemophilia A

    Summary
    EudraCT number
    2015-003685-88
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    28 Aug 2015

    Results information
    Results version number
    v1
    This version publication date
    11 Jun 2016
    First version publication date
    11 Jun 2016
    Other versions
    v2

    Trial information

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    Trial identification
    Sponsor protocol code
    B1831082
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 800-718-1021, ClinicalTrials.gov_Inquiries@Pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 800-718-1021, ClinicalTrials.gov_Inquiries@Pfizer.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
    28 Aug 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Aug 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to characterize single dose pharmacokinetic (PK) profile of Factor VIII (FVIII) activity after administration of Xyntha in male Chinese subjects with hemophilia A.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 13
    Worldwide total number of subjects
    13
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    3
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    5
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    This study enrolled Chinese male subjects who were age 6 years or older with severe hemophilia A (FVIII activity <1%) previously treated with >150 exposure days to any FVIII-containing product.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Xyntha 50 IU/kg
    Arm description
    Subjects were administered a single dose of recombinant antihemophilic factor (Xyntha) at approximately 50 international units per kilogram (IU/kg) infused intravenously (IV) over 10 minutes (actual dose received ranged from 42.55 IU/kg to 60.00 IU/kg).
    Arm type
    Experimental

    Investigational medicinal product name
    moroctocog alfa, recombinant FVIII
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    single dose 50 IU/kg by IV infusion

    Number of subjects in period 1
    Xyntha 50 IU/kg
    Started
    13
    Completed
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Xyntha 50 IU/kg
    Reporting group description
    Subjects were administered a single dose of recombinant antihemophilic factor (Xyntha) at approximately 50 international units per kilogram (IU/kg) infused intravenously (IV) over 10 minutes (actual dose received ranged from 42.55 IU/kg to 60.00 IU/kg).

    Reporting group values
    Xyntha 50 IU/kg Total
    Number of subjects
    13 13
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    3 3
        Adolescents (12-17 years)
    5 5
        Adults (18-64 years)
    5 5
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    24.4 ± 19.6 -
    Gender, Male/Female
    Units: participants
        Female
    0 0
        Male
    13 13

    End points

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    End points reporting groups
    Reporting group title
    Xyntha 50 IU/kg
    Reporting group description
    Subjects were administered a single dose of recombinant antihemophilic factor (Xyntha) at approximately 50 international units per kilogram (IU/kg) infused intravenously (IV) over 10 minutes (actual dose received ranged from 42.55 IU/kg to 60.00 IU/kg).

    Primary: Maximum Plasma FVIII Activity (Cmax)

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    End point title
    Maximum Plasma FVIII Activity (Cmax) [1]
    End point description
    The PK parameter analysis population is defined as all subjects enrolled and treated who have at least 1 of the PK parameters of primary interest reported.
    End point type
    Primary
    End point timeframe
    Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this primary endpoint. No formal statistical inference or statistical modeling was to be performed. All PK parameters were summarized descriptively.
    End point values
    Xyntha 50 IU/kg
    Number of subjects analysed
    13
    Units: IU/milliliter (mL)
        geometric mean (geometric coefficient of variation)
    1.147 ± 44
    No statistical analyses for this end point

    Primary: Area Under the Plasma FVIII Activity-Time Profile from Time 0 to Time of the Last Quantifiable Concentration (AUClast)

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    End point title
    Area Under the Plasma FVIII Activity-Time Profile from Time 0 to Time of the Last Quantifiable Concentration (AUClast) [2]
    End point description
    The PK parameter analysis population is defined as all subjects enrolled and treated who have at least 1 of the PK parameters of primary interest reported.
    End point type
    Primary
    End point timeframe
    Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this primary endpoint. No formal statistical inference or statistical modeling was to be performed. All PK parameters were summarized descriptively.
    End point values
    Xyntha 50 IU/kg
    Number of subjects analysed
    13
    Units: IU*hour/mL
        geometric mean (geometric coefficient of variation)
    14.49 ± 57
    No statistical analyses for this end point

    Primary: Area Under the Plasma FVIII Activity-Time Profile from Time 0 Extrapolated to Infinite Time (AUCinf)

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    End point title
    Area Under the Plasma FVIII Activity-Time Profile from Time 0 Extrapolated to Infinite Time (AUCinf) [3]
    End point description
    The PK parameter analysis population is defined as all subjects enrolled and treated who have at least 1 of the PK parameters of primary interest reported.
    End point type
    Primary
    End point timeframe
    Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this primary endpoint. No formal statistical inference or statistical modeling was to be performed. All PK parameters were summarized descriptively.
    End point values
    Xyntha 50 IU/kg
    Number of subjects analysed
    13
    Units: IU*hour/mL
        geometric mean (geometric coefficient of variation)
    15.21 ± 58
    No statistical analyses for this end point

    Primary: Time to Reach Maximum Observed Plasma Concentration (Tmax)

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    End point title
    Time to Reach Maximum Observed Plasma Concentration (Tmax) [4]
    End point description
    The PK parameter analysis population is defined as all subjects enrolled and treated who have at least 1 of the PK parameters of primary interest reported.
    End point type
    Primary
    End point timeframe
    Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this primary endpoint. No formal statistical inference or statistical modeling was to be performed. All PK parameters were summarized descriptively.
    End point values
    Xyntha 50 IU/kg
    Number of subjects analysed
    13
    Units: hour
        median (full range (min-max))
    0.5 (0.25 to 3)
    No statistical analyses for this end point

    Primary: Clearance (CL)

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    End point title
    Clearance (CL) [5]
    End point description
    Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. The PK parameter analysis population is defined as all subjects enrolled and treated who have at least 1 of the PK parameters of primary interest reported.
    End point type
    Primary
    End point timeframe
    Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this primary endpoint. No formal statistical inference or statistical modeling was to be performed. All PK parameters were summarized descriptively.
    End point values
    Xyntha 50 IU/kg
    Number of subjects analysed
    13
    Units: mL/hour/kg
        geometric mean (geometric coefficient of variation)
    3.295 ± 56
    No statistical analyses for this end point

    Primary: Volume of Distribution at Steady-State (Vss)

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    End point title
    Volume of Distribution at Steady-State (Vss) [6]
    End point description
    Volume of distribution is the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the volume of distribution at steady-state. The PK parameter analysis population is defined as all subjects enrolled and treated who have at least 1 of the PK parameters of primary interest reported.
    End point type
    Primary
    End point timeframe
    Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this primary endpoint. No formal statistical inference or statistical modeling was to be performed. All PK parameters were summarized descriptively.
    End point values
    Xyntha 50 IU/kg
    Number of subjects analysed
    13
    Units: mL/kg
        geometric mean (geometric coefficient of variation)
    53.96 ± 29
    No statistical analyses for this end point

    Primary: Terminal Phase Rate Constant (Kel)

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    End point title
    Terminal Phase Rate Constant (Kel) [7]
    End point description
    Terminal phase rate constant is the absolute value of the slope of a linear regression during the terminal phase of the natural­-logarithm transformed concentration-­time profile. The PK parameter analysis population is defined as all subjects enrolled and treated who have at least 1 of the PK parameters of primary interest reported.
    End point type
    Primary
    End point timeframe
    Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this primary endpoint. No formal statistical inference or statistical modeling was to be performed. All PK parameters were summarized descriptively.
    End point values
    Xyntha 50 IU/kg
    Number of subjects analysed
    13
    Units: 1/hour
        geometric mean (geometric coefficient of variation)
    0.06039 ± 39
    No statistical analyses for this end point

    Primary: Terminal Elimination Half-Life (t1/2)

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    End point title
    Terminal Elimination Half-Life (t1/2) [8]
    End point description
    Terminal half-life is the time measured for the plasma concentration to decrease by one half. The PK parameter analysis population is defined as all subjects enrolled and treated who have at least 1 of the PK parameters of primary interest reported.
    End point type
    Primary
    End point timeframe
    Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this primary endpoint. No formal statistical inference or statistical modeling was to be performed. All PK parameters were summarized descriptively.
    End point values
    Xyntha 50 IU/kg
    Number of subjects analysed
    13
    Units: hour
        arithmetic mean (standard deviation)
    12.24 ± 4.4172
    No statistical analyses for this end point

    Primary: Mean Residence Time (MRT)

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    End point title
    Mean Residence Time (MRT) [9]
    End point description
    MRT = AUMCinf / AUCinf, where AUMCinf is the area under the first moment curve from zero time to infinity calculated as AUMCinf = AUMCt + ((t x Ct) / kel) + (Ct / kel^2). AUMCt is the area under the first moment curve from zero time to time t calculated using the trapezoidal method. The PK parameter analysis population is defined as all subjects enrolled and treated who have at least 1 of the PK parameters of primary interest reported.
    End point type
    Primary
    End point timeframe
    Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this primary endpoint. No formal statistical inference or statistical modeling was to be performed. All PK parameters were summarized descriptively.
    End point values
    Xyntha 50 IU/kg
    Number of subjects analysed
    13
    Units: hour
        geometric mean (geometric coefficient of variation)
    16.37 ± 38
    No statistical analyses for this end point

    Primary: Incremental Recovery (INCREC)

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    End point title
    Incremental Recovery (INCREC) [10]
    End point description
    Incremental recovery is the increase in circulating FVIII activity for every IU of Xyntha administered per kilogram of body weight. The PK parameter analysis population is defined as all subjects enrolled and treated who have at least 1 of the PK parameters of primary interest reported.
    End point type
    Primary
    End point timeframe
    Pre-dose and 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32, 48, and 72 hours post-dose
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this primary endpoint. No formal statistical inference or statistical modeling was to be performed. All PK parameters were summarized descriptively.
    End point values
    Xyntha 50 IU/kg
    Number of subjects analysed
    13
    Units: IU/deciliter (dL) per IU/kg
        geometric mean (geometric coefficient of variation)
    2.284 ± 44
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects with Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects with Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. AEs included both SAEs and non-SAEs. The safety analysis population included all subjects who received at least 1 dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Day 28
    End point values
    Xyntha 50 IU/kg
    Number of subjects analysed
    13
    Units: subjects
        Number of Subjects with AEs
    4
        Number of Subjects with SAEs
    2
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects with Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern

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    End point title
    Number of Subjects with Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern
    End point description
    The following laboratory parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell count and morphology, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen, creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid, albumin, and total protein); urinalysis (pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, urobilinogen, urine bilirubin, microscopy [if urine dipstick was positive for blood, protein, nitrites or leukocyte esterase]); others (urine drug screening, FVIII inhibitor assay, FVIII activity, prothrombin time [PT], activated partial thromboplastin time [APTT], anti-human immunodeficiency virus [HIV] 1, hepatitis C virus antibody [HCVAb], HAVAb, HBsAg, HBsAb, HBcAb). Only parameters which met abnormality criteria are reported.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Day 4
    End point values
    Xyntha 50 IU/kg
    Number of subjects analysed
    13
    Units: subjects
        APTT >1.1X upper limit of normal (ULN)
    13
        Potassium <0.9X lower limit of normal (LLN)
    1
        Urine urobilinogen >=1
    6
        Urine leukocyte esterase >=1
    1
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects with Potentially Clinically Significant Vital Signs Findings

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    End point title
    Number of Subjects with Potentially Clinically Significant Vital Signs Findings
    End point description
    Vital signs assessment included pulse rate and blood pressure. Criteria for vital sign values meeting potential clinical concern included: supine pulse rate <50 beats per minute (bpm), >=30 bpm increase from baseline, or >25 bpm decrease from baseline; systolic blood pressure (SBP) <90 milliliters of mercury (mmHg), >=30 mmHg increase from baseline, or >=30 mmHg decrease from baseline; diastolic blood pressure (DBP) <50 mmHg, >=20 mmHg increase from baseline, or >=20 mmHg decrease from baseline. The safety analysis population included all subjects who received at least 1 dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Day 4
    End point values
    Xyntha 50 IU/kg
    Number of subjects analysed
    13
    Units: subjects
        Supine SBP <90 mmHg
    0
        Supine DBP <50 mmHg
    0
        Supine Pulse Rate <50 bpm
    0
        Supine SBP >=30 mmHg Increase from Baseline
    0
        Supine DBP >=20 mmHg Increase from Baseline
    0
        Supine Pulse Rate >=30 bpm Increase from Baseline
    1
        Supine SBP >=30 mmHg Decrease from Baseline
    0
        Supine DBP >=20 mmHg Decrease from Baseline
    0
        Supine Pulse Rate >=25 bpm Decrease from Baseline
    0
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects with Positive FVIII Inhibitor Activity at Day 4

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    End point title
    Number of Subjects with Positive FVIII Inhibitor Activity at Day 4
    End point description
    As with all FVIII products, subjects using Xyntha were monitored for the development of FVIII inhibitors. Values >= 0.6 Bethesda Unit (BU) per mL were considered positive results. The safety analysis population included all subjects who received at least 1 dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    Day 4
    End point values
    Xyntha 50 IU/kg
    Number of subjects analysed
    13
    Units: subjects
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Day 28
    Adverse event reporting additional description
    The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 subject and as nonserious in another, or 1 subject may have experienced both an AE and SAE during the study. All treated subjects were included in the analysis.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Xyntha 50 IU/kg
    Reporting group description
    Subjects were administered a single dose of recombinant antihemophilic factor (Xyntha) at approximately 50 IU/kg infused IV over 10 minutes (actual dose received by subjects ranged from 42.55 IU/kg to 60.00 IU/kg).

    Serious adverse events
    Xyntha 50 IU/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 13 (15.38%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Blood and lymphatic system disorders
    Factor VIII inhibition
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Xyntha 50 IU/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 13 (15.38%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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