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    Summary
    EudraCT Number:2017-003538-10
    Sponsor's Protocol Code Number:BIVV009-03
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-12-18
    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
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2017-003538-10
    A.3Full title of the trial
    A PIVOTAL, OPEN-LABEL, MULTICENTER STUDY TO ASSESS THE
    EFFICACY AND SAFETY OF BIVV009 IN PATIENTS WITH PRIMARY COLD AGGLUTININ DISEASE WHO HAVE A RECENT HISTORY OF BLOOD TRANSFUSION
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Open-Label with BIVV009 in patients with Cold Agglutinin Disease
    A.3.2Name or abbreviated title of the trial where available
    Cardinal Study
    A.4.1Sponsor's protocol code numberBIVV009-03
    A.5.4Other Identifiers
    Name:IND #Number:128,190
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBioverativ USA, Inc.
    B.1.3.4CountryUnited States
    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 supportBioverativ USA Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPharm-Olam, LLC
    B.5.2Functional name of contact pointClinical Trial Dept
    B.5.3 Address:
    B.5.3.1Street Address450 N. Sam Houston Parkway, E. Suite 250
    B.5.3.2Town/ cityHouston TX
    B.5.3.3Post code77060
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1713-559-79001133
    B.5.6E-mailtracy.klenk@pharm-olam.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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEMA/OD/177/15
    D.3 Description of the IMP
    D.3.1Product nameBIVV009
    D.3.2Product code BIVV009
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBIVV009
    D.3.9.2Current sponsor codeBIVV009
    D.3.9.3Other descriptive nameCOMPLEMENT C1 ESTERASE INHIBITOR
    D.3.9.4EV Substance CodeSUB22696
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number18
    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 No
    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
    Primary Cold Agglutinin Disease
    E.1.1.1Medical condition in easily understood language
    Autoimmune Disease against red blood cells (Haemolytic Anaemia)
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10073785
    E.1.2Term Autoimmune haemolytic anaemia
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part A:
    The primary objective of Part A is to determine whether BIVV009 administration results in a ≥ 2 g/dL increase in hemoglobin (Hgb) levels or increases Hgb to ≥ 12 g/dL and obviates the need for blood transfusion during treatment in patients with primary CAgD who have a recent history of transfusion

    Part B:
    The primary objective of Part B is to evaluate the long-term safety and tolerability of BIVV009 in patients with primary CAgD.
    E.2.2Secondary objectives of the trial
    Part A:
    Efficacy:
    •To assess the effect of BIVV009 on clinical events and laboratory parameters related to hemolysis and anemia in patients with primary CAgD
    •To assess the effect of BIVV009 on quality of life (QOL) in patients with primary CAgD
    Safety:
    •To evaluate the overall safety and tolerability of BIVV009 in patients with primary CAgD
    Exploratory:
    •To assess the effect of BIVV009 on specific complications of CAgD
    •To evaluate the effect of BIVV009 on certain disease-related biomarkers in patients with primary CAgD
    •To evaluate the pharmacokinetics of BIVV009

    Part B:
    •The secondary objective of Part B is to investigate the durability of response during long-term treatment with BIVV009 in patients with primary CAgD.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Adult males and females ≥ 18 years of age at Screening
    2.Body weight of ≥ 39 kg at screening
    3.Confirmed diagnosis of primary CAgD based on the following criteria:
    a.Chronic hemolysis,
    b.Polyspecific direct antiglobulin test (DAT) positive,
    c.Monospecific DAT strongly positive for C3d,
    d.Cold agglutinin titer ≥ 64 at 4 degrees Celsius,
    e.IgG DAT ≤ 1+, and
    f.No overt malignant disease
    4.History of at least one documented blood transfusion within 6 months of enrollment
    5.Hemoglobin level ≤ 10.0 g/dL
    6.Bilirubin level above the normal reference range
    7.Ferritin level within the normal reference ranges unless outside normal range and deemed not clinically significant by the Investigator (or designee)
    8.Presence of one or more of the following CAgD-related signs or symptoms within 3 months of Screening:
    a.Symptomatic anemia defined as:
    i.Fatigue,
    ii.Weakness,
    iii.Shortness of breath,
    iv.Palpitations, fast heart beat
    v.Light headedness and/or
    vi.Chest pain
    b.Acrocyanosis
    c.Raynaud’s syndrome
    d.Hemoglobinuria
    e.Disabling circulatory symptoms, and/or
    f.Major adverse vascular event (including thrombosis)
    9.Bone marrow biopsy within 6 months of Screening with no overt evidence of lymphoproliferative disease or other hematological malignancy. An additional bone marrow biopsy will be required if the prior bone marrow is deemed unsuitable for analysis by the Sponsor.
    10.Vaccinations against encapsulated bacterial pathogens (Neisseria meningitis, Meningitis B, Haemophilus influenzae, and Streptococcus pneumoniae) within 5 years of enrollment or as specified in Appendix B.
    E.4Principal exclusion criteria
    1.Cold agglutinin syndrome secondary to infection, rheumatologic disease, or active hematologic malignancy
    2.Clinically relevant infection of any kind within the month preceding enrollment (eg, active hepatitis C, pneumonia)
    3.Clinical diagnosis of systemic lupus erythematosus (SLE); or other autoimmune disorders with anti-nuclear antibodies at Screening
    4.Positive hepatitis panel (including hepatitis B surface antigen and/or hepatitis C virus antibody) prior to or at Screening
    5.Positive human immunodeficiency virus (HIV) antibody at Screening
    6.Treatment with rituximab monotherapy within 3 months or rituximab combination therapies (eg, with bendamustine, fludarabine, ibrutinib, or cytotoxic drugs) within 6 months prior to enrollment
    7.Concurrent treatment with corticosteroids other than a stable daily dose equivalent to ≤ 10 mg/day prednisone for previous 3 months
    8.Erythropoietin deficiency. Concurrent treatment with erythropoietin is permitted if the patient has been on a stable dose for the previous 3 months.
    9.Concurrent usage of iron supplementation unless the patient has been on a stable dose for at least 4 weeks.
    10.Clinically significant medical history or ongoing chronic illness that would jeopardize the safety of the patient or compromise the quality of the data derived from his/her participation in this study (as determined by the Investigator [or designee]) at Screening
    11.Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days or 5 half lives, whichever is greater, prior to treatment start
    12.Females who are pregnant, lactating, or, if having reproductive potential, are considered potentially unreliable with respect to contraceptive practice
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the responder rate. A patient will be considered a responder if he or she did not receive a blood transfusion from Week 5 through Week 26 (EOT) and did not receive treatment for CAgD beyond what is permitted per protocol. Additionally, the patient’s Hgb level must meet either of the following criteria:
    • Hgb level is ≥ 12 g/dL at the treatment assessment endpoint (defined as mean value from Weeks 23, 25, and 26), or
    • Hgb increased ≥ 2 g/dL from baseline (defined as the last Hgb value before administration of the first dose of study drug) at treatment assessment endpoint
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 26 (EOT)
    E.5.2Secondary end point(s)
    •Mean change from baseline in bilirubin (excluding patients with Gilbert’s Syndrome) at the treatment assessment endpoint (mean of values at Week 23, 25, and 26)
    •Mean change from baseline in QOL, as assessed by the change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale scores at the treatment assessment endpoint
    •Mean change from baseline in lactate dehydrogenase (LDH) at the treatment assessment endpoint
    •Number of transfusions and number of units after the first 5 weeks of study drug administration
    •Mean change from baseline in Hgb at the treatment assessment endpoint
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 26 (EOT)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    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.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA37
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    Israel
    Japan
    United States
    Austria
    Belgium
    Denmark
    France
    Germany
    Hungary
    Italy
    Netherlands
    Norway
    Poland
    Spain
    Switzerland
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    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 subject Last Visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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 No
    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) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 Yes
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 14
    F.4.2.2In the whole clinical trial 20
    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 of care
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-12-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-09-15
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