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    Clinical Trial Results:
    A multicentre, multinational, randomised, open-labelled, parallel-group, active-controlled trial to compare the safety of once-weekly dosing of somapacitan (NNC0195-0092) with daily Norditropin® FlexPro® for 26 weeks in previously human growth hormone treated adults with growth hormone deficiency

    Summary
    EudraCT number
    2014-000290-39
    Trial protocol
    SE   DK   GB  
    Global end of trial date
    04 Jan 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Jan 2017
    First version publication date
    19 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    nn8640-4043
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02382939
    WHO universal trial number (UTN)
    U1111-1152-3664
    Other trial identifiers
    Japanese trial registration number: JapicCTI-152850
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Global Clinical Registry (GCR 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Global Clinical Registry (GCR 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.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 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the clinical safety of once-weekly dosing of somapacitan during 26 weeks of treatment in Adults with growth hormone deficiency subjects previously treated with daily human growth hormone.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (Oct 2013) and ICH Good Clinical Practice (GCP) (May 1996), ISO 14155 and FDA 21 CFR 312.120.
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    12 Feb 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
    Sweden: 8
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Denmark: 22
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Japan: 17
    Worldwide total number of subjects
    92
    EEA total number of subjects
    75
    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)
    73
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted at 26 sites in 6 countries. All 26 sites screened and randomised/ assigned patients to treatment. Denmark: 3 sites; France: 5 sites; Germany: 3 sites; Sweden: 3 sites; United Kingdom: 5 sites; Japan: 7 sites.

    Pre-assignment
    Screening details
    Subjects, who were diagnosed with adults with growth hormone deficiency ≥ 6 months (defined as 180 days) prior to screening and receiving treatment with human growth hormone at least 6 months (defined as 180 days) at screening, were enrolled.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Norditropin
    Arm description
    Subjects received subcutaneous (s.c.) injections of Norditropin daily for 26 weeks (8 weeks dose titration followed by 18 weeks fixed dose treatment) followed by 1 week washout. The starting dose of Norditropin was 0.2 mg/day (except females on oral oestrogen: 0.3 mg/day; subjects older than 60 years: 0.1 mg/day). An individualised dose titration regimen was used. Adjustment of dose was performed at weeks 2, 4, 6 and 8 based on insulin-like growth factor-I standard deviation score (IGF-I SDS) values: IGF-I SDS > 3: dose reduction by 0.1 mg/day; 2 < IGF-I SDS ≤ 3: dose reduction by 0.05 mg/day; 0 < IGF-I SDS ≤ 2: No need of dose adjustment; -2 < IGF-I SDS ≤ 0: Dose increment by 0.1 mg/day; IGF-I SDS ≤ -2: Dose increment by 0.2 mg/day. After the last dose adjustment (if any) at week 8, the individual dose level was fixed. The minimum and maximum daily dose was set to 0.05 mg and 1.1 mg (Japan: maximum daily dose was 1.0 mg).
    Arm type
    Active comparator

    Investigational medicinal product name
    Somatropin
    Investigational medicinal product code
    Other name
    Norditropin FlexPro 10 mg
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All subjects were trained in the use of the pen-injector and to inject themselves with trial drug under the supervision of the site staff. Norditropin® FlexPro® subjects injected themselves daily s.c. in the evening (standard treatment practice), except during observed trial administrations (where injections were done in the morning (up to 12 PM noon) and at least 12 hours after injection the evening.

    Arm title
    Somapacitan
    Arm description
    Subjects received s.c. injections of somapacitan once-weekly for 26 weeks (8 weeks dose titration followed by 18 weeks fixed dose treatment) followed by 1 week washout. The starting dose of somapacitan was 1.5 mg/week (except females on oral oestrogen 2.0 mg/week; subjects older than 60 years 1.0 mg/week). An individualised dose titration regimen was used. Adjustment of dose was performed at weeks 2, 4, 6 and 8 based on IGF-I SDS values: IGF-I SDS > 3: dose reduction by 1 mg; 2 < IGF-I SDS ≤ 3: dose reduction by 0.5 mg; 0 < IGF-I SDS ≤ 2: No need for dose adjustment; -2 < IGF-I SDS ≤ 0: Dose Increment by 0.7 mg; IGF-I SDS ≤ -2: Dose Increment by 1.5 mg. After the last dose adjustment (if any) at week 8, the individual dose level was fixed. The minimum and maximum weekly dose was set to 0.1 mg and 8 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    Somapacitan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All subjects were trained in the use of the pen-injector and to inject themselves with trial drug under the supervision of the site staff. Somapacitan subjects injected themselves once-weekly s.c. in the morning (no later than 10 am to ensure consistency of PK/PD with previous trials). On site visit days this could be extended until 12 PM (noon).

    Number of subjects in period 1
    Norditropin Somapacitan
    Started
    31
    61
    Exposed
    31
    61
    Completed
    28
    58
    Not completed
    3
    3
         Adverse event, non-fatal
    1
    1
         Consent withdrawn by subject
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Norditropin
    Reporting group description
    Subjects received subcutaneous (s.c.) injections of Norditropin daily for 26 weeks (8 weeks dose titration followed by 18 weeks fixed dose treatment) followed by 1 week washout. The starting dose of Norditropin was 0.2 mg/day (except females on oral oestrogen: 0.3 mg/day; subjects older than 60 years: 0.1 mg/day). An individualised dose titration regimen was used. Adjustment of dose was performed at weeks 2, 4, 6 and 8 based on insulin-like growth factor-I standard deviation score (IGF-I SDS) values: IGF-I SDS > 3: dose reduction by 0.1 mg/day; 2 < IGF-I SDS ≤ 3: dose reduction by 0.05 mg/day; 0 < IGF-I SDS ≤ 2: No need of dose adjustment; -2 < IGF-I SDS ≤ 0: Dose increment by 0.1 mg/day; IGF-I SDS ≤ -2: Dose increment by 0.2 mg/day. After the last dose adjustment (if any) at week 8, the individual dose level was fixed. The minimum and maximum daily dose was set to 0.05 mg and 1.1 mg (Japan: maximum daily dose was 1.0 mg).

    Reporting group title
    Somapacitan
    Reporting group description
    Subjects received s.c. injections of somapacitan once-weekly for 26 weeks (8 weeks dose titration followed by 18 weeks fixed dose treatment) followed by 1 week washout. The starting dose of somapacitan was 1.5 mg/week (except females on oral oestrogen 2.0 mg/week; subjects older than 60 years 1.0 mg/week). An individualised dose titration regimen was used. Adjustment of dose was performed at weeks 2, 4, 6 and 8 based on IGF-I SDS values: IGF-I SDS > 3: dose reduction by 1 mg; 2 < IGF-I SDS ≤ 3: dose reduction by 0.5 mg; 0 < IGF-I SDS ≤ 2: No need for dose adjustment; -2 < IGF-I SDS ≤ 0: Dose Increment by 0.7 mg; IGF-I SDS ≤ -2: Dose Increment by 1.5 mg. After the last dose adjustment (if any) at week 8, the individual dose level was fixed. The minimum and maximum weekly dose was set to 0.1 mg and 8 mg.

    Reporting group values
    Norditropin Somapacitan Total
    Number of subjects
    31 61 92
    Age Categorical
    Units: Subjects
        18-64 years
    23 50 73
        ≥ 65 years
    8 11 19
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    51.7 ± 17.1 48.1 ± 16.2 -
    Gender Categorical
    Units: Subjects
        Female
    14 28 42
        Male
    17 33 50

    End points

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    End points reporting groups
    Reporting group title
    Norditropin
    Reporting group description
    Subjects received subcutaneous (s.c.) injections of Norditropin daily for 26 weeks (8 weeks dose titration followed by 18 weeks fixed dose treatment) followed by 1 week washout. The starting dose of Norditropin was 0.2 mg/day (except females on oral oestrogen: 0.3 mg/day; subjects older than 60 years: 0.1 mg/day). An individualised dose titration regimen was used. Adjustment of dose was performed at weeks 2, 4, 6 and 8 based on insulin-like growth factor-I standard deviation score (IGF-I SDS) values: IGF-I SDS > 3: dose reduction by 0.1 mg/day; 2 < IGF-I SDS ≤ 3: dose reduction by 0.05 mg/day; 0 < IGF-I SDS ≤ 2: No need of dose adjustment; -2 < IGF-I SDS ≤ 0: Dose increment by 0.1 mg/day; IGF-I SDS ≤ -2: Dose increment by 0.2 mg/day. After the last dose adjustment (if any) at week 8, the individual dose level was fixed. The minimum and maximum daily dose was set to 0.05 mg and 1.1 mg (Japan: maximum daily dose was 1.0 mg).

    Reporting group title
    Somapacitan
    Reporting group description
    Subjects received s.c. injections of somapacitan once-weekly for 26 weeks (8 weeks dose titration followed by 18 weeks fixed dose treatment) followed by 1 week washout. The starting dose of somapacitan was 1.5 mg/week (except females on oral oestrogen 2.0 mg/week; subjects older than 60 years 1.0 mg/week). An individualised dose titration regimen was used. Adjustment of dose was performed at weeks 2, 4, 6 and 8 based on IGF-I SDS values: IGF-I SDS > 3: dose reduction by 1 mg; 2 < IGF-I SDS ≤ 3: dose reduction by 0.5 mg; 0 < IGF-I SDS ≤ 2: No need for dose adjustment; -2 < IGF-I SDS ≤ 0: Dose Increment by 0.7 mg; IGF-I SDS ≤ -2: Dose Increment by 1.5 mg. After the last dose adjustment (if any) at week 8, the individual dose level was fixed. The minimum and maximum weekly dose was set to 0.1 mg and 8 mg.

    Primary: Incidence of adverse events

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    End point title
    Incidence of adverse events [1]
    End point description
    An adverse event can be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. Total number of adverse events are reported. Analysis was performed on safety analysis set (all randomised subjects that received at least one dose of randomised treatment).
    End point type
    Primary
    End point timeframe
    From baseline to the end of the treatment period (26 weeks)
    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: As this is a safety endpoint, no statistical analysis was performed.
    End point values
    Norditropin Somapacitan
    Number of subjects analysed
    31
    61
    Units: adverse events
    81
    159
    No statistical analyses for this end point

    Primary: Incidence of injection site reactions

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    End point title
    Incidence of injection site reactions [2]
    End point description
    Number of total injection site reactions. Analysis was performed on safety analysis set.
    End point type
    Primary
    End point timeframe
    From baseline to the end of the treatment period (26 weeks)
    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: As this is a safety endpoint, no statistical analysis was performed.
    End point values
    Norditropin Somapacitan
    Number of subjects analysed
    31
    61
    Units: injection site reactions
    0
    2
    No statistical analyses for this end point

    Secondary: Occurrence of anti-NNC0195-0092 antibodies

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    End point title
    Occurrence of anti-NNC0195-0092 antibodies [3]
    End point description
    Number of subjects with anti-somapacitan (NNC0195-0092) antibodies. Analysis was performed on safety analysis set (subjects who received somapacitan only).
    End point type
    Secondary
    End point timeframe
    From baseline (randomisation) to end of treatment period (26 weeks)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was assessed in subjects who received only somapacitan. Hence, no results for Norditropin arm are reported.
    End point values
    Somapacitan
    Number of subjects analysed
    61
    Units: subjects
    0
    No statistical analyses for this end point

    Secondary: Change in Treatment Satisfaction Questionnaire for Medication (TSQM) scores (effectiveness, convenience, and global satisfaction scores)

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    End point title
    Change in Treatment Satisfaction Questionnaire for Medication (TSQM) scores (effectiveness, convenience, and global satisfaction scores)
    End point description
    The Treatment Satisfaction Questionnaire for Medication (TSQM-9) is a psychometric measure of a patient's satisfaction with medication. It consists of 3 subscales: effectiveness, convenience and global satisfaction. Items are rated on a 5- or 7- point scale according to subjects’ experience with the medication. Each domain score can vary from 0 to 100 with higher scores indicating higher effectiveness of treatment, more convenient use of medication and overall greater satisfaction with the treatment. Analysis was performed on full analysis set (all randomised subjects that received at least one dose of randomised treatment). Here, 'n' specifies the number of subjects with data available for specified category.
    End point type
    Secondary
    End point timeframe
    From baseline (randomisation) to end of treatment period (26 weeks)
    End point values
    Norditropin Somapacitan
    Number of subjects analysed
    31
    61
    Units: score on a scale
    arithmetic mean (standard deviation)
        Effectiveness (n=28, 53)
    3.8 ± 27.4
    9.7 ± 18.1
        Convenience (n=28, 55)
    3 ± 16.5
    15.3 ± 20.9
        Global satisfaction (n=28, 54)
    -1.2 ± 15.2
    5.4 ± 21
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to week 26
    Adverse event reporting additional description
    Subjects in the safety analysis set contributed to the evaluation of adverse events.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Norditropin
    Reporting group description
    Subjects received s.c. injections of Norditropin daily for 26 weeks (8 weeks dose titration followed by 18 weeks fixed dose treatment) followed by 1 week washout. The starting dose of Norditropin was 0.2 mg/day (except females on oral oestrogen: 0.3 mg/day; subjects older than 60 years: 0.1 mg/day). An individualised dose titration regimen was used. Adjustment of dose was performed at weeks 2, 4, 6 and 8 based on IGF-I SDS values: IGF-I SDS > 3: dose reduction by 0.1 mg/day; 2 < IGF-I SDS ≤ 3: dose reduction by 0.05 mg/day; 0 < IGF-I SDS ≤ 2: No need of dose adjustment; -2 < IGF-I SDS ≤ 0: Dose increment by 0.1 mg/day; IGF-I SDS ≤ -2: Dose increment by 0.2 mg/day. After the last dose adjustment (if any) at Week 8, the individual dose level was fixed. The minimum and maximum daily dose was set to 0.05 mg and 1.1 mg (Japan: maximum daily dose was 1.0 mg).

    Reporting group title
    Somapacitan
    Reporting group description
    Subjects received s.c. injections of somapacitan once-weekly for 26 weeks (8 weeks dose titration followed by 18 weeks fixed dose treatment) followed by 1 week washout. The starting dose of somapacitan was 1.5 mg/week (except females on oral oestrogen 2.0 mg/week; subjects older than 60 years 1.0 mg/week). An individualised dose titration regimen was used. Adjustment of dose was performed at weeks 2, 4, 6 and 8 based on IGF-I SDS values: IGF-I SDS > 3: dose reduction by 1 mg; 2 < IGF-I SDS ≤ 3: dose reduction by 0.5 mg; 0 < IGF-I SDS ≤ 2: No need for dose adjustment; -2 < IGF-I SDS ≤ 0: Dose Increment by 0.7 mg; IGF-I SDS ≤ -2: Dose Increment by 1.5 mg. After the last dose adjustment (if any) at Week 8, the individual dose level was fixed. The minimum and maximum weekly dose was set to 0.1 mg and 8 mg.

    Serious adverse events
    Norditropin Somapacitan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 31 (6.45%)
    4 / 61 (6.56%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Patella fracture
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Mammoplasty
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal ischaemia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Short-bowel syndrome
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 61 (1.64%)
         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
    Norditropin Somapacitan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 31 (58.06%)
    30 / 61 (49.18%)
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 61 (1.64%)
         occurrences all number
    3
    1
    Headache
         subjects affected / exposed
    6 / 31 (19.35%)
    7 / 61 (11.48%)
         occurrences all number
    10
    11
    Sciatica
         subjects affected / exposed
    0 / 31 (0.00%)
    4 / 61 (6.56%)
         occurrences all number
    0
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 31 (3.23%)
    4 / 61 (6.56%)
         occurrences all number
    1
    5
    Fatigue
         subjects affected / exposed
    5 / 31 (16.13%)
    6 / 61 (9.84%)
         occurrences all number
    5
    7
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 31 (0.00%)
    4 / 61 (6.56%)
         occurrences all number
    0
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 31 (6.45%)
    5 / 61 (8.20%)
         occurrences all number
    2
    5
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 61 (1.64%)
         occurrences all number
    2
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 31 (25.81%)
    12 / 61 (19.67%)
         occurrences all number
    11
    13

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2015
    Two typing errors in the visit flow chart were corrected. No impact on subject safety or trial procedures: 1) The timing of visit 1 changed to ‘minimum 1 day prior to visit 2’. 2) Attend visit fasting: should read ‘No’ for visit 3 and ‘yes’ for visit 4. The master PI/informed consent was updated accordingly.
    27 Jan 2015
    Changes requested by the Voluntary Harmonisation Procedure were addressed: The guideline for the United Kingdom investigators concerning contraception requirements for study subjects to be identical to the one applicable for the Denmark investigators.
    11 May 2015
    Updates of procedures as well as clarifications of relevant sections in the protocol: 1) Local tolerability assessments: external review by a dermatologist was added to ensure that the clinical validity of photos supported the AE description. 2) Antibody analysis: process for follow up after last patient last visit of subjects with 2 consecutive positive antidrug antibody results. 3) French health authority: any immediate adverse effects on kidney function (eGFR creatinine ≤60 mL/min/1.73m2) to be reported as a critical laboratory alert. 4)Homeostasis model assessment calculation. 5) Process for tryptase sampling in case of severe hypersensitivity.

    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
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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