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    Clinical Trial Results:
    AN OPEN-LABEL MULTI-CENTER STUDY OF ECULIZUMAB IN CHILDREN AND ADOLESCENTS WITH A DIAGNOSIS OF PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA

    Summary
    EudraCT number
    2009-010402-11
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    12 May 2011

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Aug 2016
    First version publication date
    06 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M07-005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00867932
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals Incorporated
    Sponsor organisation address
    100 College Street, New Haven, United States, CT 06410
    Public contact
    European Clinical Trial Information, Alexion Europe SAS, + 33 1 47 10 06 06, clinicaltrials.eu@alxn.com
    Scientific contact
    European Clinical Trial Information, Alexion Europe SAS, + 33 1 47 10 06 06, clinicaltrials.eu@alxn.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000876-PIP01-10
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Nov 2011
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 May 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    12 May 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of Study M07-005 was to evaluate the PK and PD parameter estimates of eculizumab to confirm the dose regimens for paediatric patients with PNH
    Protection of trial subjects
    Patients must have been vaccinated against Neisseria meningitidis, Pneumococcus species, and Hemophilus influenzae type b at least 14 days prior to the start of study drug, or be vaccinated and receive treatment with appropriate antibiotics until 14 days after vaccination. Patients were excluded for prior treatment with eculizumab, presence or suspicion of bacterial infection or recurrent bacterial infections, or history of meningococcal, pneumococcal, or gonococcal disease. Patients were also excluded if pregnant, breastfeeding, or intending to conceive during the study period.
    Background therapy
    No background therapy was used in this trial.
    Evidence for comparator
    No comparator was used in this trial.
    Actual start date of recruitment
    02 Oct 2009
    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
    United States: 7
    Worldwide total number of subjects
    7
    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)
    1
    Adolescents (12-17 years)
    6
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment period lasted from October 2009 to January 2011. Three sites in the USA enrolled a total of 7 patients.

    Pre-assignment
    Screening details
    Screening phase was approx. 2 weeks. ICF and paediatric/adolescent assent forms were signed at or before Visit 1. Inclusion/exclusion criteria were obtained and evaluated. If all screening criteria are met, the patient was eligible to enter the treatment phase of the study after receiving a N. meningitidis, pneumococcus and hemophilus vaccination

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

    Arms
    Arm title
    eculizumab
    Arm description
    All 7 patients enrolled in the trial received eculizumab. There is no other arm in the trial.
    Arm type
    Experimental

    Investigational medicinal product name
    eculizumab
    Investigational medicinal product code
    eculizumab
    Other name
    Soliris
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    - If weight ≥30 kg: Induction loading: 600mg weekly x 4 Maintenance: 900mg Wk5; 900mg Q2wks - If weight 20 - <30kg: Induction/loading: 600mg weekly x 2 Maintenance: 600mg Wk3; 600mg Q2wks - If weight 10 - <20kg: Induction/loading: 600mg weekly x 1 Maintenance: 300mg Wk2; 300mg Q2wks - If weight 5 – <10 kg: Induction/loading: 300 mg Weekly for 1 Week Maintenance: 300mg Wk2; 300mg Q3wks Eculizumab was administered via a 35 minutes (+/-10 minutes) intravenous infusion.

    Number of subjects in period 1
    eculizumab
    Started
    7
    Induction Phase
    7
    Maintenance Phase
    7
    Completed
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    Seven patients aged 11–17 years were enrolled between October 2009 and January 2011; younger patients did not present for eligibility screening at the participating centers during the study period. All patients entered the body weight cohort of greater or equal to 30 kg. Each patient received all nine doses of eculizumab via peripheral vein and completed the study period of 12 weeks.

    Reporting group values
    Treatment Total
    Number of subjects
    7 7
    Age categorical
    Units: Subjects
        Children (2-11 years)
    1 1
        Adolescents (12-17 years)
    6 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    15.01 ± 2.2779 -
    Gender categorical
    Units: Subjects
        Female
    4 4
        Male
    3 3
    LDH
    LDH was collected during screening period and then at all visits during induction period, at visits 8 and 10 during maintenance period, at early termination visit and all visits during follow-up for early termination, as applicable.
    Units: Subjects
        Enrolled patients
    7 7
    Hematology
    Hb was collected for all patients at several time points durign the study
    Units: Subjects
        Enrolled patients
    7 7

    End points

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    End points reporting groups
    Reporting group title
    eculizumab
    Reporting group description
    All 7 patients enrolled in the trial received eculizumab. There is no other arm in the trial.

    Primary: PK and PD evaluation

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    End point title
    PK and PD evaluation [1]
    End point description
    PD response was measured by the capacity of patient serum to lyse chicken erythrocytes in a human serum-complement hemolytic assay; complete complement blockade was defined as <20% hemolysis in vitro. All baseline trough plasma levels of eculizumab were undetectable. Peak and trough eculizumab concentrations increased gradually and reached a plateau by week 4. At week 12, median trough eculizumab levels were 192.5 mcg/ml (range 124.2-321.1) and median peak levels were 425.4 mcg/ml (range 220.5-556.1). The max and min conc. of eculizumab, and AUC were significantly associated with the change from baseline in LDH at the follow-up visits (P=0.0273, P=0.0250 and P=0.0263 respectively). Prior start of eculizumab, in vitro hemolysis of <20%, that is, inducing complete complement blockade, after steady-state levels were reached at week 4.
    End point type
    Primary
    End point timeframe
    PK ad PD samples were collected before and after completing the administration of eculizumab at each visit.
    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: This study is a single arm trial and the system did not support statistical analyses for this single arm trial.
    End point values
    eculizumab
    Number of subjects analysed
    7
    Units: mcg/ml
    median (full range (min-max))
        Median trough at week 12
    192.5 (124.2 to 321.1)
        Median peak at week 12
    425.4 (220.5 to 556.1)
    No statistical analyses for this end point

    Secondary: Safety

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    End point title
    Safety
    End point description
    Examination of treatment-emergent adverse events
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    eculizumab
    Number of subjects analysed
    7
    Units: Number of AE
        Patients with at least one TEAE
    7
        Patients with no TEAE
    0
        Patients with any serious TEAE
    2
        Total number of TEAE
    69
        Mild severity
    4
        Moderate severity
    1
        Severe severity
    2
        unrelated (relationship)
    2
        possible (relationship)
    3
        probable (relationship)
    2
        Definite (relationship)
    0
    No statistical analyses for this end point

    Secondary: Efficacy - Mean change of LDH from baseline at week 12

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    End point title
    Efficacy - Mean change of LDH from baseline at week 12
    End point description
    The area under the curve (AUC) for the change of LDH from baseline (week 0 to week 12) was also calculated.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    eculizumab
    Number of subjects analysed
    7
    Units: U*Day/L
    number (not applicable)
        Mean LDH AUC of change from baseline
    -60634
    No statistical analyses for this end point

    Secondary: Efficacy - Mean Plasma-free Haemoglobin

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    End point title
    Efficacy - Mean Plasma-free Haemoglobin
    End point description
    Plasma-free haemoglobin levels were analyzed at 12 weeks.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    eculizumab
    Number of subjects analysed
    7
    Units: milligram(s)/dl
    number (not applicable)
        Mean plasma-free haemoglobin conc. (baseline)
    17.7
        Mean plasma-free haemoglobin conc. (week 12)
    7.44
    No statistical analyses for this end point

    Secondary: Efficacy - LDH values and change of LDH from baseline

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    End point title
    Efficacy - LDH values and change of LDH from baseline
    End point description
    Efficacy summary of LDH values and change of LDH from baseline.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    eculizumab
    Number of subjects analysed
    7
    Units: U/L
    number (not applicable)
        Mean change from baseline (week 1)
    -672
        Mean change from baseline (week 2)
    -763
        Mean change from baseline (week 3)
    -752
        Mean change from baseline (week 4)
    -761
        Mean change from baseline (week 8)
    -747
        Mean change from baseline (week 12)
    -771
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time patient signs the informed consent form up to 8 weeks after last dose of eculizumab
    Adverse event reporting additional description
    Treatment-emergent adverse events (TEAEs) that occurred in at least 2 subjects during the study are reported here. TEAEs are defined as an event not present prior to exposure to eculizumab or any event already present that worsens in either intensity or frequency following exposure to eculizumab.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    All participating patients in the trial
    Reporting group description
    -

    Serious adverse events
    All participating patients in the trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 7 (28.57%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Blood and lymphatic system disorders
    Anaemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Aplastic anaemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Headache
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vaginal haemorrhage
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Acute sinusitis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheter site cellulitis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis media acute
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    All participating patients in the trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    2
    Nervous system disorders
    Headache
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    5 / 7 (71.43%)
         occurrences all number
    5
    General disorders and administration site conditions
    Pyrexia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal pain upper
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    2
    Infections and infestations
    Upper respiratory tract infection
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Nov 2010
    Amendment 2 (protocol v3.0): Modify the protocol to restrict inclusion criteria as agreed in the Paediatric Investigation Plan for eculizumab. Further to the evaluation of the Paediatric Investigation Plan for eculizumab by the European Paediatric Committee, the protocol inclusion criteria was modified as follows: 1. To update dosing for patients 2 - 17 years old and weight ≥5kg. 2. To include vaccination requirements previously described in the methodology section of the protocol as an inclusion requirement. In addition, to add vaccination requirements for Pneumococci and Haemophilus. 3. To only include paediatric patients in whom haemolysis contributes to the anaemia. 4. To not include patients with history of meningococcal/pneumococcal/gonococcal disease. 5. To add an external data monitoring committee (DMC) to monitor safety. 6. To add an exploratory endpoint to assess correlation between LDH and PNH clone size.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/24777716
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