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    Clinical Trial Results:
    Safety in Haemolytic PNH Patients Treated with Eculizumab: A Multi-center Open-label Research Design Study (SHEPHERD)

    Summary
    EudraCT number
    2004-002795-42
    Trial protocol
    SE   IE   DE   GB   IT   ES  
    Global end of trial date
    18 Oct 2006

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

    Trial information

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    Trial identification
    Sponsor protocol code
    C04-002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00122304
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Alexion Pharmaceuticals Incorporated
    Sponsor organisation address
    100 College Street, New Haven, CT, United States, 06510
    Public contact
    European Clinical Trial Information, Alexion Europe SAS, +33 1 47 10 06 06, clinicaltrials.eu@alexion.com
    Scientific contact
    European Clinical Trial Information, Alexion Europe SAS, +33 1 47 10 06 06, clinicaltrials.eu@alexion.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
    06 Jan 2007
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Mar 2006
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Oct 2006
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the safety of eculizumab in patients with transfusion-dependent haemolytic paroxysmal nocturnal haemoglobinuria (PNH)
    Protection of trial subjects
    Patients must have been vaccinated for Neisseria meningitidis 14 days prior to randomisation.
    Background therapy
    -
    Evidence for comparator
    No comparator was used in this trial.
    Actual start date of recruitment
    16 Dec 2004
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 25
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United Kingdom: 14
    Worldwide total number of subjects
    97
    EEA total number of subjects
    64
    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)
    90
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 33 clinical sites in Australia, Belgium, Canada, Germany, Ireland, Italy, Netherlands, Spain, Sweden, Switzerland, United States and the United Kingdom participated and enrolled patients in this study.

    Pre-assignment
    Screening details
    Subjects who had at least one transfusion in the 2 years prior to screening, and were meeting all of the inclusion/exclusion criteria were eligible to enter this study. 107 subjects were screened, 97 were enrolled and received eculizumab.

    Pre-assignment period milestones
    Number of subjects started
    97
    Number of subjects completed
    97

    Period 1
    Period 1 title
    Treatment Phase (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable (open-label study)

    Arms
    Arm title
    eculizumab
    Arm description
    During the Induction Period, patients received 600 mg of eculizumab IV once a week for 4 doses, followed by 900 mg eculizumab IV 1 week later for 1 dose. During the Maintenance Period, patients received 900 mg eculizumab IV every 2 weeks for approximately 24 doses. Each dose was administered by IV infusion over a 25- to 45-minute period.
    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
    600 mg of eculizumab once a week for 4 weeks, followed by 900 mg of eculizumab 1 week later for 1 dose, then 900 mg of eculizumab every 2 weeks up through 52 weeks.

    Number of subjects in period 1
    eculizumab
    Started
    97
    Completed
    96
    Not completed
    1
         Adverse event, serious fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    eculizumab
    Reporting group description
    During the Induction Period, patients received 600 mg of eculizumab IV once a week for 4 doses, followed by 900 mg eculizumab IV 1 week later for 1 dose. During the Maintenance Period, patients received 900 mg eculizumab IV every 2 weeks for approximately 24 doses. Each dose was administered by IV infusion over a 25- to 45-minute period.

    Reporting group values
    eculizumab Total
    Number of subjects
    97 97
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    90 90
        65 to 75 years
    5 5
        Superior or equal to 75 year old
    2 2
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    41 (29 to 51) -
    Gender categorical
    Units: Subjects
        Female
    49 49
        Male
    48 48
    Race
    Units: Subjects
        Caucasian
    88 88
        Asian
    3 3
        Black
    3 3
        Other
    3 3
    Blood Type
    Units: Subjects
        A-
    10 10
        A+
    31 31
        B-
    3 3
        B+
    5 5
        AB-
    1 1
        AB+
    5 5
        O-
    6 6
        O+
    36 36
    Weight
    Units: kilogram(s)
        median (inter-quartile range (Q1-Q3))
    73.5 (62.8 to 81.1) -
    Height
    Units: centimeters
        median (inter-quartile range (Q1-Q3))
    173 (163 to 180) -
    Haemoglobin prior to transfusion
    Units: gram(s)/deciliter
        median (inter-quartile range (Q1-Q3))
    7.5 (6.9 to 8.3) -
    Haemoglobin after transfusion
    Units: gram(s)/deciliter
        median (inter-quartile range (Q1-Q3))
    9.4 (8.2 to 10.1) -
    Number of packed red blood cell (RBC) units transfused
    Units: Number of units
        median (inter-quartile range (Q1-Q3))
    8 (4 to 24) -

    End points

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    End points reporting groups
    Reporting group title
    eculizumab
    Reporting group description
    During the Induction Period, patients received 600 mg of eculizumab IV once a week for 4 doses, followed by 900 mg eculizumab IV 1 week later for 1 dose. During the Maintenance Period, patients received 900 mg eculizumab IV every 2 weeks for approximately 24 doses. Each dose was administered by IV infusion over a 25- to 45-minute period.

    Primary: Intravascular haemolysis measured by LDH AUC

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    End point title
    Intravascular haemolysis measured by LDH AUC [1]
    End point description
    A quantitative assessment of haemolysis was obtained by calculating the AUC for LDH from Baseline to Week 52, and the data were analysed using a Wilcoxon signed rank test.
    End point type
    Primary
    End point timeframe
    Through week 52
    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
    97
    Units: U/L × day
        median (full range (min-max))
    -632264 (-1788824 to -74498)
    No statistical analyses for this end point

    Secondary: Levels of fatigue

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    End point title
    Levels of fatigue
    End point description
    The Quality-of-Life (QoL) instrument FACIT-Fatigue scale version 4 was utilised to collect QoL data. The scoring guideline for the FACIT-Fatigue scale version 4 instrument was used to calculate the QoL score; per the corresponding scoring guideline, scores can range from 0 to 52, with higher scores indicating improvement in fatigue. Data reported indicate change of FACIT-Fatigue Scores Between Baseline at several time points.
    End point type
    Secondary
    End point timeframe
    The FACIT-Fatigue SCALE was administered through 52 weeks.
    End point values
    eculizumab
    Number of subjects analysed
    97
    Units: QoL score
    arithmetic mean (standard error)
        Baseline
    30.8 ± 1.2
        Change from baseline at Wk 1
    5.6 ± 1
        Change from baseline at Wk 2
    7.1 ± 0.98
        Change from baseline at Wk 3
    9.1 ± 1.1
        Change from baseline at Wk 4
    8.9 ± 1.12
        Change from baseline at Wk 12
    9.9 ± 1.2
        Change from baseline at Wk 26
    11.8 ± 1.2
        Change from baseline at Wk 52
    12.2 ± 1.09
    No statistical analyses for this end point

    Secondary: Intravascular haemolysis measured as change in LDH from baseline

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    End point title
    Intravascular haemolysis measured as change in LDH from baseline
    End point description
    Data reported describe change of lactate dehydrogenase (LDH) values from Baseline to selected time points through 52 Weeks.
    End point type
    Secondary
    End point timeframe
    Through 52 weeks.
    End point values
    eculizumab
    Number of subjects analysed
    97
    Units: U/L
    arithmetic mean (standard error)
        Baseline
    2200.7 ± 104.9
        Week 1
    -1519.5 ± 87.05
        Week 2
    -1794.4 ± 100.71
        Week 3
    -1895.4 ± 102.86
        Week 4
    -1901.2 ± 103.87
        Week 12
    -1811.2 ± 111.19
        Week 26
    -1869.4 ± 109.33
        Week 52
    -1908.7 ± 105.11
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Information regarding AEs was collected from the time the patient signed the informed consent form up to 30 days after the last dose of eculizumab was administered.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    7
    Reporting groups
    Reporting group title
    eculizumab
    Reporting group description
    -

    Serious adverse events
    eculizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 97 (19.59%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Thromboembolism
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Brain herniation
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Rib fracture
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 97 (3.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Haemolysis
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anaemia macrocytic
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Paroxysmal nocturnal haemoglobinuria
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhagic cerebral infarction
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    2 / 97 (2.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal insufficiency
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pyelonephritis
         subjects affected / exposed
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    eculizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    95 / 97 (97.94%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    6 / 97 (6.19%)
         occurrences all number
    8
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    8 / 97 (8.25%)
         occurrences all number
    16
    Pharyngolaryngeal pain
         subjects affected / exposed
    8 / 97 (8.25%)
         occurrences all number
    12
    Cough
         subjects affected / exposed
    6 / 97 (6.19%)
         occurrences all number
    6
    Bronchitis
         subjects affected / exposed
    5 / 97 (5.15%)
         occurrences all number
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    51 / 97 (52.58%)
         occurrences all number
    94
    Dizziness
         subjects affected / exposed
    14 / 97 (14.43%)
         occurrences all number
    18
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    19 / 97 (19.59%)
         occurrences all number
    27
    Influenza-like illness
         subjects affected / exposed
    8 / 97 (8.25%)
         occurrences all number
    11
    Oedema peripheral
         subjects affected / exposed
    6 / 97 (6.19%)
         occurrences all number
    6
    Fatigue
         subjects affected / exposed
    5 / 97 (5.15%)
         occurrences all number
    7
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    9 / 97 (9.28%)
         occurrences all number
    10
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    20 / 97 (20.62%)
         occurrences all number
    39
    Diarrhoea
         subjects affected / exposed
    12 / 97 (12.37%)
         occurrences all number
    15
    Abdominal pain
         subjects affected / exposed
    11 / 97 (11.34%)
         occurrences all number
    14
    Vomiting
         subjects affected / exposed
    10 / 97 (10.31%)
         occurrences all number
    35
    Constipation
         subjects affected / exposed
    9 / 97 (9.28%)
         occurrences all number
    11
    Abdominal pain upper
         subjects affected / exposed
    6 / 97 (6.19%)
         occurrences all number
    6
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    7 / 97 (7.22%)
         occurrences all number
    9
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    15 / 97 (15.46%)
         occurrences all number
    19
    Arthralgia
         subjects affected / exposed
    12 / 97 (12.37%)
         occurrences all number
    15
    Myalgia
         subjects affected / exposed
    10 / 97 (10.31%)
         occurrences all number
    15
    Pain in extremity
         subjects affected / exposed
    8 / 97 (8.25%)
         occurrences all number
    10
    Muscle cramp
         subjects affected / exposed
    6 / 97 (6.19%)
         occurrences all number
    8
    Neck pain
         subjects affected / exposed
    5 / 97 (5.15%)
         occurrences all number
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    31 / 97 (31.96%)
         occurrences all number
    44
    Upper respiratory tract infection
         subjects affected / exposed
    29 / 97 (29.90%)
         occurrences all number
    35
    Urinary tract infection
         subjects affected / exposed
    13 / 97 (13.40%)
         occurrences all number
    15
    Herpes simplex
         subjects affected / exposed
    9 / 97 (9.28%)
         occurrences all number
    11
    Viral infection
         subjects affected / exposed
    7 / 97 (7.22%)
         occurrences all number
    7
    Gastroenteritis
         subjects affected / exposed
    6 / 97 (6.19%)
         occurrences all number
    7
    Sinusitis
         subjects affected / exposed
    5 / 97 (5.15%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2005
    The purpose of this global amendment was to broaden the study population and to identify a primary surrogate endpoint for efficacy, namely lactate dehydrogenase as area under the curve.

    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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