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    Summary
    EudraCT Number:2014-005115-16
    Sponsor's Protocol Code Number:FORMA-04
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-04-22
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2014-005115-16
    A.3Full title of the trial
    Prospective, open-label, uncontrolled, Phase III study to assess the efficacy, safety, and pharmacokinetics of Octafibrin for on-demand
    treatment of acute bleeding and to prevent bleeding during and after surgery in paediatric subjects with congenital fibrinogen de-ficiency
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Prospective, open-label, uncontrolled, Phase III study to assess the efficacy, safety, and pharmacokinetics of Octafibrin for on-demand
    treatment of acute bleeding and to prevent bleeding during and after surgery in paediatric subjects with congenital fibrinogen de-ficiency
    A.4.1Sponsor's protocol code numberFORMA-04
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/258/2017
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorOctapharma AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportOctapharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOctapharma AG
    B.5.2Functional name of contact pointSVP Clinical R&D Haematology
    B.5.3 Address:
    B.5.3.1Street AddressSeidenstrasse 2
    B.5.3.2Town/ cityLachen
    B.5.3.3Post codeCH-8853
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number0041554512141
    B.5.6E-mailsigurd.knaub@octapharma.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Fibryga
    D.2.1.1.2Name of the Marketing Authorisation holderOctapharma Pharmazeutika ProduktionsgesmbH
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameOctafibrin
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product Yes
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Congenital fibrinogendeficiency
    E.1.1.1Medical condition in easily understood language
    Disease in which the blood is unable to clot and you have a bleeding episode or need to undergo surgery.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate the efficacy of Octafibrin for on-demand treatment of acute bleeding episodes (spontaneous or after trauma)
    E.2.2Secondary objectives of the trial
    •To determine the single-dose pharmacokinetics of Octafibrin in paediatric subjects with congenital fibrinogen deficiency
    •To investigate an association between the overall clinical assessment of haemostatic efficacy and surrogate endpoint ‘clot strength’ or ‘clot firmness’ (referred to as ‘maximum clot firmness’ [MCF] in this protocol) via thromboelastometry (ROTEM). Therefore, MCF as surrogate efficacy parameter will be determined before & after the first infusion of IMP for treatment of a bleeding episode
    •To achieve a peak target plasma fibrinogen level of 100 mg/dL in minor bleeds and 150 mg/dL for major bleeds 1 hr post-infusion
    •To determine response to Octafibrin based on incremental in vivo recovery.
    •To demonstrate efficacy of Octafibrin in preventing bleeding during and after surgery and the safety of Octafibrin in subjects with congenital fibrinogen deficiency, incl. immunogenicity, thromboembolic complications, and early signs of allergic or hypersensitivity reactions
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Aged <12 years (at the start of treatment)
    2. Documented diagnosis of congenital fibrinogen deficiency, expected to require on-demand treatment for bleeding or surgical prophylaxis:
    – Fibrinogen deficiency manifested as afibrinogenaemia or severe hypofibrin-ogenaemia
    – Historical plasma fibrinogen activity of <50 mg/dL or levels below the limit of detection of the local assay method.
    3. Expected to have an acute bleeding episode (spontaneous or after trauma) or planning to undergo elective surgery
    4. Informed consent signed by the subject’s legal guardian
    E.4Principal exclusion criteria
    1. Life expectancy <6 months
    2. Bleeding disorder other than congenital fibrinogen deficiency, including
    dysfibrinogenaemia
    3. Prophylactic treatment with a fibrinogen concentrate
    4. Treatment with:
    – Any fibrinogen concentrate or other fibrinogen-containing blood product within 2 weeks prior to start of treatment for the PK phase, a bleeding episode, or surgery
    – Any coagulation-active drug (i.e., non-steroidal anti-inflammatory drugs, warfarin, coumarin derivatives, platelet aggregation inhibitors) within 1 week prior to start of the PK phase or treatment for the bleeding episode or surgery, or as a planned or expected medication during the time period from Day 1 until 24 hours (i.e., 1 day) after the last Octafibrin infusion
    5. Presence or history of:
    – Hypersensitivity to study medication
    – Deep vein thrombosis or pulmonary embolism within 1 year prior to start of treatment for the bleeding episode or surgery
    – Arterial thrombosis within 1 year prior to start of treatment for the bleeding
    episode or surgery
    – Hypersensitivity to human plasma proteins
    – Oesophageal varicose bleeding
    – End-stage liver disease (i.e., Child-Pugh score B or C)
    6. Known positive HIV infection with a viral load >200 particles/μL or >400,000 copies/mL
    7. Polytrauma 1 year prior to start of treatment for the bleeding episode or surgery
    8. Diagnosis or suspicion of a neutralizing anti-fibrinogen inhibitor currently or at any time in the past
    9. Acute or chronic medical condition which may, in the opinion of investigator,
    affect the conduct of the study, including subjects receiving immune-modulating drugs (other than anti-retroviral chemotherapy), such as alpha-interferon, prednisone (equivalent to >10 mg/day), or similar drugs, at study start
    10. Treatment with IMP in another interventional clinical study currently or during the past 4 weeks
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the overall clinical assessment of the haemostatic efficacy of Octafibrin in treating the first documented bleeding episode of each patient. The first bleeding episode covers the time period from the first Octafibrin infusion for the treat-ment of a bleeding episode until 24 hours (i.e., 1 day) after the last infusion or the end of the treatment observation period, whichever comes last.
    The investigator’s overall clinical assessment of haemostatic efficacy for bleeding will be based on a 4 point haemostatic efficacy scale (see table below). The final efficacy assessment of each patient will be adjudicated by the Independent Data Monitoring & Endpoint Adjudication Committee (IDMEAC). The number of subjects per outcome category will be assessed in the final analysis.
    4 point haemostatic efficacy scale
    - Excellent:Immediate and complete cessation of bleeding in the absence of other hae-mostatic intervention as clinically assessed by the treating physician; and/or <10% drop in haemoglobin compared to pre-infusion.
    - Good: ventual complete cessation of bleeding in the absence of other haemostatic intervention as clinically assessed by the treating physician; and/or <20% drop in haemoglobin compared to pre-infusion.
    - Moderate: Incomplete cessation of bleeding and additional haemostatic intervention required, as clinically assessed by the treating physician; and/or between 20 and 25% drop in haemoglobin compared to pre- infusion.
    -None: No cessation of bleeding and alternative haemostatic intervention required, as clinically assessed by the treating physician; and/or >25% drop in haemo-globin compared to pre-infusion.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Time period from the first Octafibrin infusion for the treatment of a bleeding episode until 24 hours (i.e., 1 day) after the last infusion or the end of the treatment observation period, whichever comes last.
    E.5.2Secondary end point(s)
    PK endpoints:
    • Area under the concentration-time curve (AUC)
    • Response: Incremental In Vivo Recovery (IVR)
    • Classical IVR
    • Terminal elimination half-life (t1/2)
    • Maximum plasma concentration (Cmax)
    • Time to reach maximum plasma concentration (Tmax)
    • Volume of distribution (Vss)
    • Clearance (Cl)

    Secondary efficacy endpoints:
    • MCF assessment
    • Fibrinogen plasma level
    • Response after the first infusion of each bleeding episode as indicated by incremen-tal IVR, calculated as the maximum increase in plasma fibrinogen (Clauss data) be-tween the pre-infusion and the 3-hour post-infusion measurement, divided by the ex-act dose of Octafibrin (expressed as mg/kg dosed).
    • Efficacy of Octafibrin in all bleeding episodes collected in the study using the inves-tigator’s overall clinical assessment of haemostatic efficacy for bleeding based on a 4 point haemostatic efficacy scale.
    • Efficacy of Octafibrin in surgical prophylaxis will be assessed at the end of surgery by the surgeon and post-operatively by the haematologist using the following scales as defined per protocol

    Safety endpoints:
    • Vital signs
    • Physical examination
    • Thromboembolic event (TEE) questionnaire
    • Routine clinical laboratory assessment, including coagulation parameters
    • Adverse events (AEs), including thromboembolic complications and early signs of allergic or hypersensitivity reactions
    • Thrombogenicity testing before and after each IMP infusion for the treatment of bleeding, except on the Day of Last Infusion
    • Immunogenicity testing before the first infusion of IMP and on Day 30 after the treatment of each bleeding episode
    E.5.2.1Timepoint(s) of evaluation of this end point
    PK endpoints: day 1, day 2, day 4, day 7, day 10, day 14
    •MCF : before 1st infusion and 1 hr after end of first infusion
    •Fibrinogen plasma level: before and 1 hour after the end of each infusion &s and 24 hours after last infusion or end of the observation period of each documented bleeding episode).
    •Response after 1st infusion of each bleeding episode as indicated by incremen-tal IVR
    •Vital signs: day 1 before 1st infusion, 1hr and 3 hrs post-infusion.
    •Physical examination: d 14
    •Thromboembolic event (TEE) questionnaire: throughozt the study
    •Adverse events (AEs) throughout the study
    •Thrombogenicity: before & after each IMP infusion except on the Day of Last Infusion
    •Immunogenicity before 1st infusion of IMP and on Day 30 after the treatment of each bleeding episode
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA Yes
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    India
    Iran, Islamic Republic of
    Lebanon
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last visit of last subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 12
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 3
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 6
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 3
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children aged 0 to 11 years of age
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 12
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard care treatment
    G. Investigator Networks to be involved in the Trial
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: India
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