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    Summary
    EudraCT Number:2017-003539-12
    Sponsor's Protocol Code Number:EFC16216
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-10-30
    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 ConcernedGermany - PEI
    A.2EudraCT number2017-003539-12
    A.3Full title of the trial
    A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF BIVV009 IN PATIENTS WITH PRIMARY COLD AGGLUTININ DISEASE WITHOUT A RECENT HISTORY OF BLOOD TRANSFUSION
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to determine the safety and effectiveness of study drug BIVV009 in patients with Primary Agglutinin Disease without recent history of blood transfusions
    A.3.2Name or abbreviated title of the trial where available
    Cadenza
    A.4.1Sponsor's protocol code numberEFC16216
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03347422
    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
    B.5.3.3Post codeTX 77060
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1713-559-7900 1133
    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 nameTNT009
    D.3.9.4EV Substance CodeSUB177476
    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.IMP: 2
    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 nameTNT009
    D.3.9.4EV Substance CodeSUB177476
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    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
    The purpose of Part A is to determine whether sutimlimab administration results in a greater than or equal to (>=)1.5 gram per deciliter (g/dL)
    increase in hemoglobin (Hgb) level and avoidance of transfusion in participants with primary cold agglutinin disease (CAD) without a recent history of blood transfusion.

    The purpose of Part B is to evaluate the long-term safety and tolerability of sutimlimab in participants with primary CAD.
    E.2.2Secondary objectives of the trial
    Part A:
    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 specific complications of CAgD (acrocyanosis, Raynaud's syndrome, hemoglobinuria, and thromboembolism)
    To assess the effect of BIVV009 on quality of life (QOL) in patients with primary CAgD.

    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
    • Body weight of greater than or equal to (>=) 39 kilogram (kg) at Screening
    • Confirmed diagnosis of primary cold agglutinin disease (CAD) 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 degree Celsius, and e)
    Immunoglobulin G (IgG) DAT less than or equal to (<=) 1+, and, f) No overt malignant disease
    • Hemoglobin level <= 10.0 gram per deciliter (g/dL)
    • Bilirubin level above the normal reference range, including patients with Gilbert's Syndrome
    E.4Principal exclusion criteria
    • Cold agglutinin syndrome secondary to infection, rheumatologic disease, or active hematologic malignancy
    • Clinically relevant infection of any kind within the month preceding enrollment (example, active hepatitis C, pneumonia)
    • Clinical diagnosis of systemic lupus erythematosus (SLE); or other autoimmune disorders with anti-nuclear antibodies at Screening. Antinuclear antibodies of long-standing duration without associated clinical
    symptoms will be adjudicated on a case-by-case basis during the Confirmatory Review of Patient Eligibility
    • Positive hepatitis panel (including hepatitis B surface antigen and/or hepatitis C virus antibody) prior to or at Screening
    • Positive human immunodeficiency virus (HIV) antibody at Screening
    • Treatment with rituximab monotherapy within 3 months or rituximab combination therapies (example, with bendamustine, fludarabine,
    ibrutinib, or cytotoxic drugs) within 6 months prior to enrollment
    E.5 End points
    E.5.1Primary end point(s)
    Part A: Percentage of Participants With Response (R). A participant 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 primary cold agglutinin disease (CAD) beyond what is
    permitted per protocol. Additionally, the participant's hemoglobin (Hgb)
    level must meet the following criterion: Hgb increase greater than or
    equal to (>=) 1.5 gram per deciliter (g/dL) from baseline (defined as the
    last Hgb value before administration of the first dose of study drug.
    Part B: Number of Participants With Treatment-emergent Adverse Events
    (AEs) and Serious AEs (SAEs). An adverse event (AE) was any untoward
    medical occurrence in a participant who received study drug without
    regard to possibility of causal relationship.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part A: Up to Week 26
    Part B: Approximately 1 year from end of Week 26 of Part A
    E.5.2Secondary end point(s)
    Part A:
    1. Mean Change From Baseline in Hemoglobin (Hgb) Level up to Week 26.
    2. Mean Change From Baseline in Bilirubin up to Week 26.
    3. Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score (Quality of Life). FACIT-Fatigue scale consists of 13 questions assessed using a 5 point scale (0=not at all; 1 = a little bit, 2 = somewhat, 3 = quite a bit and 4 = very much). Responses to each question are added to obtain a total score. The range of possible scores is 0-52, with higher score indicating more fatigue.
    4. Mean Change From Baseline in Lactate Dehydrogenase (LDH) up to Week 26.
    5. Percentage of Participants With Solicited Symptomatic Anemia at End of Treatment (EOT). Symptomatic anemia is defined as fatigue,
    weakness, shortness of breath, palpitations, fast heart beat, light headedness, and/or chest pain.
    Part B:
    6. Mean Change From Week 27 in Hemoglobin (Hgb) Level.
    7. Mean Change From Week 27 in Bilirubin (total).
    8. Mean Change From Week 27 in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score (Quality of Life). FACITFatigue
    scale consists of 13 questions assessed using a 5 point scale (0=not at all; 1 = a little bit, 2 = somewhat, 3 = quite a bit and 4 = very much). Responses to each question are added to obtain a total score. The range of possible scores is 0-52, with higher score indicating more fatigue.
    9. Mean Change From Week 27 in five level EuroQol five dimensions questionnaire (EQ-5D-5L). The EQ-5D descriptive system comprises 5
    dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has a 5-level response: no problems, slight problems, moderate problems, severe problems, and extreme problems. A scale with score 0-100 is used to collect response on current health status. Higher the score better the health.
    10. Mean Change From Week 27 in 12-item short form survey (SF-12). SF-12 health survey is a self-reported questionnaire to measure
    participant's profile of functional health and well-being. It includes 12 questions (Q).
    11. Patient's Global Impression of [Fatigue] Severity (PGIS) total score in different timepoints. PGIS is a 5-point response to the severity of the fatigue over the past weeks where 1 indicates No fatigue" to 5 as "very
    severe". The assessments will be performed every 3 months beginning after Week 27 up to Week 77.
    12. Patient's Global Impression of Change (PGIC) total score in different timepoints. PGIC is a 7-point response to the change of overall status of
    quality of life where 1 indicates "Very much improved" to 7 as "very much worse". The assessments will be performed every 3 months
    beginning after Week 27 up to Week 77.
    13. Mean Change From Week 27 in Lactate Dehydrogenase (LDH) level.
    14. Number of transfusions.
    15. Mean Change From Week 27 in Haptoglobin.
    16. Number of healthcare visits by type. Number of healthcare visits by type such as office visit, hospital ER visit, hospitalization, and ICU stay
    will be reported for the approximately 1 year duration of Part B.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1, 2, 3, 4. Baseline Up to Week 26
    5. At Part A EOT (Day 182)
    6, 7, 8, 9, 10, 11, 12, 13, 14, 15. From Week 27 (Part B baseline ) up to Week 77
    16. Approximately 1 year from end of Week 26 of Part A
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned3
    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
    New Zealand
    United States
    Austria
    Belgium
    Denmark
    France
    Germany
    Hungary
    Italy
    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
    LSLV
    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 months5
    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 months5
    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: 4
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 36
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 27
    F.4.2.2In the whole clinical trial 40
    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 Decision2018-02-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-01-09
    P. End of Trial
    P.End of Trial StatusCompleted
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