Clinical trial NCT03347396: A Study to Assess the Efficacy and Safety of BIVV009 (Sutimlimab) in Participants With Primary Cold Agglutinin Disease Who Have a Recent History of Blood Transfusion (Cardinal Study)
Official title: A Phase 3, Pivotal, Open-label, Multicenter Study to Assess the Efficacy and Safety of Sutimlimab in Patients With Primary Cold Agglutinin Disease Who Have a Recent History of Blood Transfusion
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Agglutinin Disease, Cold
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2017-11-20
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of Part A was to determine whether sutimlimab administration resulted in a greater than or equal to (\>=) 2 grams per deciliter (g/dL) increase in hemoglobin (Hgb) levels or increased Hgb to \>= 12 g/dL and obviated the need for blood transfusion during treatment in participants with primary cold agglutinin disease (CAD) who had a recent history of blood transfusion. The purpose of Part B was to evaluate the long-term safety and tolerability of sutimlimab in participants with CAD.


Eligibility criteria: Inclusion Criteria:

* Body weight of \>= 39 kg at screening.
* Confirmed diagnosis of primary 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; e) Immunoglobulin G (IgG) DAT less than or equal to (\<=) 1+, and f) No overt malignant disease.
* History of at least one documented blood transfusion within 6 months of enrollment.
* Hemoglobin level \<= 10.0 g/dL.
* Bilirubin level above the normal reference range, including participants with Gilbert's Syndrome.

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 (e.g., active hepatitis C, pneumonia).
* Clinical diagnosis of systemic lupus erythematosus; or other autoimmune disorders with anti-nuclear antibodies at Screening. Anti-nuclear antibodies of long-standing duration without associated clinical symptoms 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 (e.g., with bendamustine, fludarabine, ibrutinib, or cytotoxic drugs) within 6 months prior to enrollment.

Primary outcomes:
measure: Part A: Percentage of Participants With Response to Treatment
timeFrame: From Week 5 through Week 26
measure: Part B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: Part B, 6.5 g cohort: From first dose (Week 27) up to 143 weeks of treatment + 9 weeks of follow-up (i.e., up to Week 179); Part B, 7.5 g cohort: From first dose (Week 27) up to 149 weeks of treatment + 9 weeks of follow-up (i.e., up to Week 185)
Secondary outcomes:
measure: Part A: Mean Change From Baseline in Bilirubin Levels at the Treatment Assessment Timepoint
timeFrame: Baseline, treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
measure: Part A: Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score (Quality of Life) at Treatment Assessment Timepoint
timeFrame: Baseline, treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
measure: Part A: Mean Change From Baseline in Lactate Dehydrogenase (LDH) at the Treatment Assessment Timepoint
timeFrame: Baseline, treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
measure: Part A: Number of Blood Transfusions Per Participant
timeFrame: From Week 5 up to Week 26
measure: Part A: Number of Blood Units Transfused Per Participant
timeFrame: From Week 5 up to Week 26
measure: Part A: Mean Change From Baseline in Hemoglobin (Hgb) Level at the Treatment Assessment Timepoint
timeFrame: Baseline, treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
measure: Part B: Change From Baseline in Hemoglobin (Hgb) Level at Each Specified Time Points
timeFrame: Baseline, Weeks 27,29,31,33,35,37,39,41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 83, 87, 91, 95, 99, 103, 107, 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, ET/SFU (up to Week 185)
measure: Part B: Change From Baseline in Bilirubin Levels at Each Specified Time Points
timeFrame: Baseline, Weeks 27,29,31,33,35,37,39,41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 83, 87, 91, 95, 99, 103, 107, 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, ET/SFU (up to Week 185)
measure: Part B: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score (Quality of Life) at Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147,159, 171 and Early Termination (ET) Visit/Safety Follow-up Visit
timeFrame: Baseline, Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147,159, 171 and ET Visit/SFU visit (i.e., up to Week 185)
measure: Part B: Change From Baseline in 12-Item Short-Form Survey (SF-12) Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores at Each Specified Time Points
timeFrame: Baseline, Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135 and ET Visit/SFU visit (i.e., up to Week 185)
measure: Part B: Change From Baseline in 5-level European Quality of Life 5-Dimensions 5-Level Questionnaire (EQ-5D-5L) Health State Utility Index and VAS Scores at Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147,159, 171 and ET Visit/SFU Visit
timeFrame: Baseline, Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147,159, 171 and ET Visit/SFU visit (i.e., up to Week 185)
measure: Part B: Number of Participants With Response to Participant's Global Impression of (Fatigue) Severity (PGIS) Questionnaire at Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147,159, 171 and at ET Visit/SFU Visit
timeFrame: At Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147,159, 171 and at ET Visit/SFU visit (i.e., up to Week 185)
measure: Part B: Number of Participants With Response to Participant's Global Impression of Change (PGIC) Questionnaire at Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147,159, 171 and at ET Visit/SFU Visit
timeFrame: At Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147,159, 171 and at ET Visit/SFU visit (i.e., up to Week 185)
measure: Part B: Mean Change From Baseline in Lactate Dehydrogenase (LDH) Level at Each Specified Time Points
timeFrame: Baseline, Weeks 27,29,31,33,35,37,39,41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 83, 87, 91, 95, 99, 103, 107, 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, ET/SFU (up to Week 185)
measure: Part B: Number of Blood Transfusions Per Participant
timeFrame: From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)
measure: Part B: Number of Blood Units Transfused Per Participant
timeFrame: From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)
measure: Part B: Change From Baseline in Haptoglobin Values at Each Specified Time Points
timeFrame: Baseline, Weeks 27,29,31,33,35,37,39,41,43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 83, 87, 91, 95, 99, 103, 107, 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, ET/SFU (up to Week 185)
measure: Part B: Number of Healthcare Visits by Type
timeFrame: From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Arizona Oncology Associates PC
state: Arizona
city: Los Angeles
country: United States
facility: USC/Keck School of Medicine
state: California
city: Whittier
country: United States
facility: The Oncology Institute of Hope and Innovation
state: California
city: Georgetown
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: New York
country: United States
facility: Montefiore Medical Center
state: New York
city: Valhalla
country: United States
facility: New York Medical College at Westchester Medical Center
state: New York
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Madison
country: United States
facility: UW Hospitals and Clinics
state: Wisconsin
city: Buderim
country: Australia
facility: USC Health Clinics
state: Queensland
city: Ballarat
country: Australia
facility: Ballarat Oncology & Haematology
state: Victoria
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Antwerpen
country: Belgium
facility: ZNA Stuivenberg
city: La Louvière
country: Belgium
facility: Centre Hospitalier Jolimont
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Montréal
country: Canada
facility: McGill University Health Center
state: Quebec
city: Edmonton
country: Canada
facility: University of Alberta
city: Caen
country: France
facility: CHU de Caen
city: Créteil
country: France
facility: Centre Hospitalier Henri Mondor
city: Lyon
country: France
facility: Centre Hospitalier Lyon Sud
city: Dresden
country: Germany
facility: Gemeinschaftspraxis Hämatologie-Onkologie
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Ulm
country: Germany
facility: Univ Ulm, Inst Klin. Transfusions. Immungen
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Netanya
country: Israel
facility: Laniado Hospital
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Brescia
country: Italy
facility: A. O. Spedali Civili di Brescia
city: Milan
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Rome
country: Italy
facility: U.O.C. Ematologia- Policlinico "A. Gemelli"
city: Vicenza
country: Italy
facility: U.O.C. Ematologia Ospedale San Bortolo
city: Isehara
country: Japan
facility: Tokai University Hospital
state: Kanagawa
city: Iruma-gun
country: Japan
facility: Saitama Medical University Hospital
state: Saitama-Ken
city: Tokyo
country: Japan
facility: Juntendo University Nerima Hospital
state: Tokyo-To
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Trondheim
country: Norway
facility: St Olavs Hospital, Avdeling for blodsykdommer
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro
state: Madrid
city: Barcelona
country: Spain
facility: Hospital Clinci i Provincial de Barcelona
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Universitario Dr. Peset
city: Leeds
country: United Kingdom
facility: St James Hospital, Leeds
city: London
country: United Kingdom
facility: University College London
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Alexander Röth, Wilma Barcellini, Shirley D'Sa, Yoshitaka Miyakawa, Catherine M Broome, Marc Michel, David J. Kuter, Bernd Jilma, Tor Henrik Anderson Tvedt, Stella Lin, Xiaoyu Jiang, Caroline Reuter, William Hobbs, Sigbjørn Berentsen; Inhibition of Complement C1s with Sutimlimab in Patients with Cold Agglutinin Disease (CAD): Results from the Phase 3 Cardinal Study. Blood 2019; 134 (Supplement_2): LBA-2. doi: https://doi.org/10.1182/blood-2019-132490
citation: Roth A, Barcellini W, Tvedt THA, Miyakawa Y, Kuter DJ, Su J, Jiang X, Hobbs W, Arias JM, Shafer F, Weitz IC. Sutimlimab improves quality of life in patients with cold agglutinin disease: results of patient-reported outcomes from the CARDINAL study. Ann Hematol. 2022 Oct;101(10):2169-2177. doi: 10.1007/s00277-022-04948-y. Epub 2022 Aug 23.
citation: Tvedt THA, Steien E, Ovrebo B, Haaverstad R, Hobbs W, Wardecki M, Tjonnfjord GE, Berentsen SA. Sutimlimab, an investigational C1s inhibitor, effectively prevents exacerbation of hemolytic anemia in a patient with cold agglutinin disease undergoing major surgery. Am J Hematol. 2022 Feb 1;97(2):E51-E54. doi: 10.1002/ajh.26409. Epub 2021 Dec 11. No abstract available.
citation: Roth A, Barcellini W, D'Sa S, Miyakawa Y, Broome CM, Michel M, Kuter DJ, Jilma B, Tvedt THA, Fruebis J, Jiang X, Lin S, Reuter C, Morales-Arias J, Hobbs W, Berentsen S. Sutimlimab in Cold Agglutinin Disease. N Engl J Med. 2021 Apr 8;384(14):1323-1334. doi: 10.1056/NEJMoa2027760.