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    Clinical Trial Results:
    Active-controlled phase IIIb study to investigate the ability of the HAP score to predict responders to Octagam 5% in patients with early relapsing multiple sclerosis (PREDICT trial)

    Summary
    EudraCT number
    2012-005086-12
    Trial protocol
    AT   HU   DE   BG   PL  
    Global end of trial date
    15 Feb 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Mar 2017
    First version publication date
    03 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GAM-27
    Additional study identifiers
    ISRCTN number
    ISRCTN82177408
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Octapharma AG
    Sponsor organisation address
    Seidenstraße 2, Lachen, Switzerland, CH-8853
    Public contact
    Clinical Research Department, Octapharma Pharmazeutika Produktionsgesellschaft m.b. H., +43 161032 1202, barbara.pyringer@octapharma.com
    Scientific contact
    Clinical Research Department, Octapharma Pharmazeutika Produktionsgesellschaft m.b. H., +43 161032 1202, barbara.pyringer@octapharma.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
    08 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Feb 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to investigate the ability of the HAP score to accurately predict responders to Octagam 5%.
    Protection of trial subjects
    This trial was conducted in accordance to the principles of GCP, ensuring that the rights, safety and well-being of patients are protected and in consistency with the Declaration of Helsinki. Inclusion and exclusion criteria were carefully defined in order to protect subjects from contraindications, interactions with other medication and safety factors associated with the investigational medicinal product. Throughout the study safety was assessed, such as occurrence of AEs, lab values, vital signs and physical examinations.
    Background therapy
    n.a.
    Evidence for comparator
    The active comparator was interferon-beta subcutaneous (IFN-β sc) Betaferon (250µg/mL) or glatiramer acetate (GA) Copaxone (20 mg/mL) The active comparator injections took place at home and were recorded on a patient diary which patients took with them to the study site visits so that the data could be transferred into the eCRF. The visit scheme stayed the same as for IMP-treated patients.
    Actual start date of recruitment
    17 Dec 2013
    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
    Russian Federation: 87
    Country: Number of subjects enrolled
    Ukraine: 46
    Country: Number of subjects enrolled
    Serbia: 1
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Bulgaria: 33
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 1
    Worldwide total number of subjects
    174
    EEA total number of subjects
    40
    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)
    174
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Within 3 weeks, after completion of screening assessments, a blood sample for HAP scoring was analysed and the patient was classified to be a predicted responder or non-responder to Octagam 5% .

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    There was no blinding of the study medication in this study. In this rater-blinded study, blinding procedures were applicable only to raters.

    Arms
    Arm title
    Overall trial
    Arm description
    Octagam 5% was to be given every 4 (±1) weeks at the study site during the 24-month treatment period (i.e., 26 infusions), while active comparator (IFN-β sc/GA) was to be given according to the manufacturer’s prescribing information, either at study site or at home every other day (IFN-β 1b sc) or daily (GA).
    Arm type
    Experimental

    Investigational medicinal product name
    Copaxone
    Investigational medicinal product code
    Other name
    GA (Glatiramer acetate)
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    GA was to be given according to the manufacturer’s prescribing information as a sc daily injection.

    Investigational medicinal product name
    Betaferon
    Investigational medicinal product code
    Other name
    IFN-ß 1b
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    IFN-ß 1b was to be given according to the manufacturer’s prescribing information as a sc injection every other day.

    Investigational medicinal product name
    Octagam 5%
    Investigational medicinal product code
    Other name
    Human normal Immunoglobulin 5%
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Octagam 5%, 0.6 g/kg, intravenously (iv) at 4-weekly (±1 week) intervals.

    Number of subjects in period 1
    Overall trial
    Started
    174
    Completed
    0
    Not completed
    174
         premature termination of study
    174

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    -

    Reporting group values
    Overall trial Total
    Number of subjects
    174 174
    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)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    174 174
        From 65-84 years
    0 0
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    108 108
        Male
    66 66

    End points

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    End points reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    Octagam 5% was to be given every 4 (±1) weeks at the study site during the 24-month treatment period (i.e., 26 infusions), while active comparator (IFN-β sc/GA) was to be given according to the manufacturer’s prescribing information, either at study site or at home every other day (IFN-β 1b sc) or daily (GA).

    Subject analysis set title
    Safety population (SAF) - Copaxone
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    subjects treated with Copaxone

    Subject analysis set title
    Safety population (SAF) - Betaferon
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    subject treated with Betaferon

    Subject analysis set title
    Safety population (SAF)- Octagam 5%
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    subject treated with Octagam 5%

    Subject analysis set title
    IFN-b sc/GA
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Comparator group receiving either Betaferon or Copaxone

    Primary: Heidelberg Assay Panel (HAP) Response Predition

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    End point title
    Heidelberg Assay Panel (HAP) Response Predition [1]
    End point description
    The primary objective of the study was to investigate the ability of the HAP score to accurately predict responders to Octagam 5%. Predicted Responder (HAP score ranging from 0 to 4 points) or predicted non-responder (HAP score ranging from 5 to 9 points). Primary endpoint was superiority with regard to decreased annualised relapse rate (ARR) of Octagam 5% treatment in patients pre-classified as predicted responders compared to predicted non-responders to Octagam 5% treatment.
    End point type
    Primary
    End point timeframe
    throughout the study
    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: Data didn´t support initial assumptions with respect to ARR and therefore all previous considerations of statistical power and sample size are obsolete. Relapses observed are basically distributed uniformly across range of HAP scores with no discernible tendency that patients with a lower HAP score had an increased treatment benefit. This contradicts the initial study assumptions, and is also reflected in an ARR ratio between predicted response and non-response groups close to 1.
    End point values
    Safety population (SAF)- Octagam 5% IFN-b sc/GA
    Number of subjects analysed
    88
    86
    Units: Number of patients
        Predicted Responders
    59
    60
        Predicted Non-Responders
    29
    26
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The condition of the subject was monitored throughout the study. 24 hours SAE reporting requirement.
    Adverse event reporting additional description
    All SAEs, suspected to be related to study treatment or not, were reported by telephone, fax or e-mail immediately to the sponsor.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Safety analysis population (Octagam)
    Reporting group description
    -

    Reporting group title
    Safety analysis population (Copaxone)
    Reporting group description
    -

    Reporting group title
    Safety analysis population (Betaferon)
    Reporting group description
    -

    Serious adverse events
    Safety analysis population (Octagam) Safety analysis population (Copaxone) Safety analysis population (Betaferon)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 88 (3.41%)
    3 / 54 (5.56%)
    1 / 32 (3.13%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer metastatic
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 54 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Ectopic pregnancy
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 54 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 54 (1.85%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 54 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Chronic tonsillitis
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 54 (1.85%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 54 (1.85%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Safety analysis population (Octagam) Safety analysis population (Copaxone) Safety analysis population (Betaferon)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 88 (44.32%)
    25 / 54 (46.30%)
    20 / 32 (62.50%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    5 / 88 (5.68%)
    0 / 54 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    5
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 54 (1.85%)
    2 / 32 (6.25%)
         occurrences all number
    0
    1
    3
    Blood pressure increased
         subjects affected / exposed
    6 / 88 (6.82%)
    1 / 54 (1.85%)
    0 / 32 (0.00%)
         occurrences all number
    8
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    5 / 88 (5.68%)
    1 / 54 (1.85%)
    0 / 32 (0.00%)
         occurrences all number
    15
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 88 (4.55%)
    4 / 54 (7.41%)
    7 / 32 (21.88%)
         occurrences all number
    7
    19
    10
    Paraesthesia
         subjects affected / exposed
    3 / 88 (3.41%)
    0 / 54 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    3
    0
    2
    Somnolence
         subjects affected / exposed
    5 / 88 (5.68%)
    1 / 54 (1.85%)
    0 / 32 (0.00%)
         occurrences all number
    12
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 88 (1.14%)
    3 / 54 (5.56%)
    3 / 32 (9.38%)
         occurrences all number
    1
    3
    4
    Influenza like illness
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 54 (0.00%)
    10 / 32 (31.25%)
         occurrences all number
    1
    0
    21
    Injection site erythema
         subjects affected / exposed
    0 / 88 (0.00%)
    10 / 54 (18.52%)
    5 / 32 (15.63%)
         occurrences all number
    0
    11
    7
    Injection site haematoma
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 54 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    2
    Injection site induration
         subjects affected / exposed
    0 / 88 (0.00%)
    3 / 54 (5.56%)
    1 / 32 (3.13%)
         occurrences all number
    0
    5
    1
    Injection site mass
         subjects affected / exposed
    0 / 88 (0.00%)
    3 / 54 (5.56%)
    0 / 32 (0.00%)
         occurrences all number
    0
    3
    0
    Injection site pain
         subjects affected / exposed
    0 / 88 (0.00%)
    16 / 54 (29.63%)
    3 / 32 (9.38%)
         occurrences all number
    0
    24
    4
    Injection site pruritus
         subjects affected / exposed
    0 / 88 (0.00%)
    3 / 54 (5.56%)
    0 / 32 (0.00%)
         occurrences all number
    0
    3
    0
    Pyrexia
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 54 (1.85%)
    3 / 32 (9.38%)
         occurrences all number
    3
    2
    7
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 88 (2.27%)
    1 / 54 (1.85%)
    3 / 32 (9.38%)
         occurrences all number
    2
    1
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 88 (2.27%)
    2 / 54 (3.70%)
    2 / 32 (6.25%)
         occurrences all number
    4
    3
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2013
    Amendment 1: Amendment #1, dated 22-Oct-2013, described changes made to the original protocol Version 2.0 and was used to create a separate protocol for use in Bulgaria only (Version 3.0). The following changes were made in Amendment #1, to comply with recommendations made by the Bulgarian Drug Agency: • The in- and exclusion criteria were amended to exclude patients who were at risk of developing side effects of the study medicinal products (active comparators), or of gadolinium, or in whom the active control products were contraindicated. • Continuous mental monitoring with the help of the PHQ-9 questionnaire, a standard and validated tool for assessing and monitoring depression severity, was to be conducted for Bulgarian patients who were to receive active comparator. • The investigator was to discuss further treatment options with the patient already after a first confirmed relapse or a worsening of EDSS by at least 1.0 point confirmed at two assessments separated by at least 12 weeks during the treatment period. After a second confirmed relapse, the patient was to be withdrawn and was to be treated with available medication best suitable for the patient at the Investigator’s discretion.
    27 Nov 2013
    Amendment 2: Amendment #2, dated 27-Nov-2013, described changes made to the original protocol Version 2.0 and was used to create a separate protocol for use in Russia only (Version 4.0), to comply with recommendations made by the Russian Drug Agency: • As the study investigated a theory of validity of use of a HAP score and the drug efficacy within the treatment of MS, it was recommended to change the phase of the study to Phase 2. • The primary endpoint was amended to clearly reflect that the decision on predicted response or predicted non-response was made on the basis of the HAP score.
    22 May 2014
    Amendment 3: Amendment #3, dated 22-May-2014, described changes made to protocol Version 2.0 and was used to create Version 5.0 of the protocol used in all countries except Bulgaria and Russia. This version was used as the basis for this clinical study report. The same changes were incorporated into Version 3.0 of the protocol to produce Version 6.0 for Bulgaria, and into Version 4.0 of the protocol to produce Version 7.0 for Russia. The amendment was issued primarily to incorporate advice from the Steering Committee on the exclusion criteria and support enrolment of patients without biasing the study results with the slightly enlarged study population and to maintain the safety of the participants: • The exclusion criterion #2 on excluding patients who had ever had any previous treatment with immunosuppressive agents was amended to a wording that excluded immunosuppressive medication such as azathioprine, mitoxantrone, cyclophosphamide, as well as teriflunomide or fingolimod, in the previous 6 months prior to inclusion in the study. A new exclusion criterion was added to exclude treatment with biological immunosuppressants such as rituximab or similar immune cell depleting therapies in the previous 18 months. • A new exclusion criterion was added: patients with a history of deep vein thrombosis or thrombotic complications after IVIG therapy were excluded to cover for potential predisposition to IVIG side effects. • Clinical response definition had been slightly inconsistent with regard to MRI activity, and was therefore unambiguously stated in a new separate section of the protocol (Section 3.2.4, Clinical Response Definition). • Shipment of blood samples to Heidelberg, Germany for HAP assay was specified to be done on the same day as the blood draw, with arrival at 10 am the following day the latest. • It was clarified that, for the first 50 patients, IMP treatment was to be started only when the Central Laboratory had confirmed arrival of the post-screenin
    06 Oct 2015
    Amendment 4: Amendment #4, dated 06-Oct-2015, described changes made to protocol Version 5.0 and was used to create Version 8.0 of the protocol, used in all countries except Bulgaria and Russia. The same changes were incorporated into Version 6.0 of the protocol to produce Version 9.0 for Bulgaria, and into Version 7.0 of the protocol to produce Version 10.0 for Russia. As the study was prematurely discontinued, no patients were enrolled under this amendment.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    09 Dec 2015
    Early termination of the study due to lack of confirmation of the study assumptions
    -

    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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