A PHASE 3, 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 - Cardinal Study

• Register: EUCTR
• Last refreshed on: 21 December 2021
• Main ID: EUCTR2017-003538-10-AT
• Date of registration: 10/10/2017
• Prospective Registration: Yes
• Primary sponsor: Bioverativ USA Inc.
• Public title: A PHASE 3, 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 - Cardinal Study
• Scientific title: A PHASE 3, 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 - Cardinal Study
• Date of first enrolment: 15/11/2017
• Target sample size: 20
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-003538-10
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no; Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belgium, Canada, France, Germany, Israel, Italy, Japan, Netherlands, New Zealand, Norway, Spain, United Kingdom, United States

Contacts

• Name: Clinical Trial Dept
• Affiliation: Bioverativ USA Inc.

• Name: Clinical Trial Dept
• Affiliation: Bioverativ USA Inc.

Key inclusion & exclusion criteria

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, including patients with Gilbert’s Syndrome
7.Ferritin levels above the lower limit of normal. Concurrent treatment with iron supplementation is permitted if the patient has been on a stable dose during the previous 4 weeks.
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.Documented Vaccinations against encapsulated bacterial pathogens (Neisseria meningitis, including serogroup B meningococcus where available, Haemophilus influenzae, and Streptococcus pneumoniae) within 5 years of enrollment or as specified in Section 6.1.1.1.
11. Adequate IV access
12. If female, must be post-menopausal, surgically sterile, or be established on (= 3 months prior to Screening) and agree to continue to use the same highly effective methods of birth control throughout the study and for 9 weeks following administration of the last dose of study drug
13. Males must be surgically sterile for at least 90 days or when sexually active with female partners of child-bearing potential will agree to use highly effective contraception from Day 0 until 9 weeks days following administration of the last dose of study drug.
14. Able to comprehend and give informed consent
15. Able to comply with the requirements of the study and to complete the full sequence of protocol-related procedures
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 15
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 5

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. Anti-nuclear 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 (Section 6.1.1.3).
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.
13. History of hypersensitivity to BIVV009 or any of its components.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Primary Cold Agglutinin Disease
MedDRA version: 20.0 Level: PT Classification code 10073785 Term: Autoimmune haemolytic anaemia System Organ Class: 10005329 - Blood and lymphatic system disorders

Intervention(s)

Product Name: BIVV009
Product Code: BIVV009
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: BIVV009
Current Sponsor code: BIVV009
Other descriptive name: TNT009
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 18-

Product Name: BIVV009
Product Code: BIVV009
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: BIVV009
Current Sponsor code: BIVV009
Other descriptive name: TNT009
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-

Primary Outcome(s)

Main Objective: 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.

Primary 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

Secondary Objective: 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.

Timepoint(s) of evaluation of this end point: Week 26 (EOT)

Secondary Outcome(s)

Secondary 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

Timepoint(s) of evaluation of this end point: Week 26 (EOT)

Secondary ID(s)

128,190

BIVV009-03

Source(s) of Monetary Support

Bioverativ USA Inc.

Ethics review

Status: Approved
Approval date: 07/11/2017
Contact: