Agglutinin Disease, ColdPhase 3NCT03347396
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)
A Phase 3 study testing BIVV009 in people with Agglutinin Disease, Cold, run by Bioverativ, a Sanofi company at 49 sites in 14 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Agglutinin Disease, Cold
- What is being tested?
- BIVV009
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 49 sitesin 14 countries
- Study dates
- 5 Mar 2018to 5 Oct 2021
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
49 sites in 14 countries.
49 sites in 14 countries
United States13 sites
Massachusetts General Hospital
Boston, Massachusetts, 02114
Brigham and Women's Hospital
Boston, Massachusetts, 02115
Cleveland Clinic
Cleveland, Ohio, 44195
Georgetown University Medical Center
Georgetown, District of Columbia, 20007
East Carolina University
Greenville, North Carolina, 27834
USC/Keck School of Medicine
Los Angeles, California, 90033
UW Hospitals and Clinics
Madison, Wisconsin, 53792
Montefiore Medical Center
New York, New York, 10461
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, 19104
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, 15232
Arizona Oncology Associates PC
Tucson, Arizona, 85711
New York Medical College at Westchester Medical Center
Valhalla, New York, 10595
The Oncology Institute of Hope and Innovation
Whittier, California, 90603
Italy4 sites
A. O. Spedali Civili di Brescia
Brescia, 25123
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Milan, 20122
U.O.C. Ematologia- Policlinico "A. Gemelli"
Rome, 00168
U.O.C. Ematologia Ospedale San Bortolo
Vicenza, 36100
Spain4 sites
Hospital Clinci i Provincial de Barcelona
Barcelona, 08036
Hospital Universitario Puerta de Hierro
Majadahonda, Madrid, 28222
Hospital Universitario Virgen del Rocio
Seville, 41013
Hospital Universitario Dr. Peset
Valencia, 46017
Australia3 sites
Ballarat Oncology & Haematology
Ballarat, Victoria, 3350
USC Health Clinics
Buderim, Queensland, 4556
Monash Medical Centre
Clayton, Victoria, 3168
Belgium3 sites
ZNA Stuivenberg
Antwerp, 2060
Centre Hospitalier Jolimont
La Louvière, 7100
University Hospitals Leuven
Leuven, 3000
Canada3 sites
University of Alberta
Edmonton, T6G1Z1
McGill University Health Center
Montreal, Quebec, H4A3J1
St. Michael's Hospital
Toronto, Ontario, M5B1W8
France3 sites
CHU de Caen
Caen, 14033
Centre Hospitalier Henri Mondor
Créteil, 94000
Centre Hospitalier Lyon Sud
Lyon, 69495
Germany3 sites
Gemeinschaftspraxis Hämatologie-Onkologie
Dresden, 1307
Universitätsklinikum Essen
Essen, 45147
Univ Ulm, Inst Klin. Transfusions. Immungen
Ulm, 89081
Israel3 sites
Hadassah Medical Center
Jerusalem, 91120
Laniado Hospital
Netanya, 4244916
Tel Aviv Sourasky Medical Center
Tel Aviv, 64239
Japan3 sites
Saitama Medical University Hospital
Iruma-gun, Saitama, 350-0495
Tokai University Hospital
Isehara, Kanagawa, 259-1193
Juntendo University Nerima Hospital
Tokyo, Tokyo-To, 177-8521
Norway3 sites
Haukeland University Hospital
Bergen, 5053
Oslo University Hospital
Oslo, 0372
St Olavs Hospital, Avdeling for blodsykdommer
Trondheim, 7030
United Kingdom2 sites
St James Hospital, Leeds
Leeds, LS9 7TF
University College London
London, WC1E 6AG
About this 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
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.
- Conditions
- Agglutinin Disease, Cold
- Being tested
- BIVV009
- Medical subject headings
- Anemia, Hemolytic, Autoimmune
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BIVV009Drug
Also called Sutimlimab
Sutimlimab was administered as intravenous (IV) infusion.
| Study group | Role | What they receive |
|---|---|---|
| BIVV009 | Experimental | Participants with primary CAD who had a recent history of transfusion (defined as at least 1 transfusion during the last 6 months prior to screening) received an intravenous (IV) infusion of BIVV009 6.5 grams (g) (if body weight was less than [<] 75 kilograms [kg]) or BIVV009 7.5 g (if body weight was greater than or equal to [>=] 75 kg) on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25. Participants who completed Part A per protocol through the end of treatment visit (Week 26) could continue to receive BIVV009 in Part B, every 2 weeks starting at Week 27 for up to an additional 149 weeks. All participants who completed Part A elected to continue in Part B. Receives: Drug: BIVV009 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Part A: Percentage of Participants With Response to Treatment
A participant was considered a responder: if he or she did not receive a blood transfusion from Week 5 through Week 26 (end of treatment in Part A) and did not receive treatment for CAD beyond what was permitted per protocol. Additionally, the participant's hemoglobin (Hgb) level must meet either of the following criteria: Hgb level >= 12 grams per deciliter (g/dL) at the treatment assessment endpoint (defined as the average of the values from the Week 23, 25, and 26 visits), 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. Percentage of responders was calculated together with a 95% exact Clopper-Pearson confidence interval (CI).
Measured: From Week 5 through Week 26
Part B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
An Adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. TESAEs was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the treatment-emergent (TE) period (from the first investigational medicinal product [IMP] administration in Part B to the last IMP administration + 9 weeks follow up period).
Measured: 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 (18)
Part A: Mean Change From Baseline in Bilirubin Levels at the Treatment Assessment Timepoint
Mean change from baseline in bilirubin levels at the treatment assessment timepoint was reported in this outcome measure. Treatment assessment timepoint was defined as the average of the values from the Week 23, 25, and 26 visits. Least squares (LS) mean and 95% confidence interval (CI) was assessed by Mixed Model for Repeated Measures (MMRM) approach using heterogeneous Toeplitz (TOEPH) covariance matrix with change from baseline as the dependent variable and baseline value and visits as independent variables. Baseline was defined as the last non-missing value prior to the first administration of study drug.
Measured: Baseline, treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
Part A: Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score (Quality of Life) at Treatment Assessment Timepoint
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 were added to obtain a total score. Total score ranged from 0 to 52, with higher score indicating more fatigue. Treatment assessment timepoint was defined as the average of the values from the Week 23, 25, and 26 visits. LS mean and 95% CI was assessed by MMRM approach using TOEPH covariance matrix with change from baseline as the dependent variable and baseline value and visits as independent variables. Baseline was defined as the last non-missing value prior to the first administration of study drug.
Measured: Baseline, treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
Part A: Mean Change From Baseline in Lactate Dehydrogenase (LDH) at the Treatment Assessment Timepoint
Mean change from baseline in LDH at the treatment assessment timepoint is reported in this outcome measure. Treatment assessment timepoint was defined as the average of the values from the Week 23, 25, and 26 visits. LS mean and 95% CI was assessed by MMRM approach using TOEPH covariance matrix with change from baseline as the dependent variable and baseline value and visits as independent variables. Baseline was defined as the last non-missing value prior to the first administration of study drug.
Measured: Baseline, treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
Part A: Number of Blood Transfusions Per Participant
A participant was to receive a transfusion if his or her Hgb level met either of the following criteria: Hgb was <9 g/dL and the participant had symptoms of anemia or Hgb was <7 g/dL and the participant was asymptomatic. Number of transfusions after the first 5 weeks of study drug administration and up to Week 26 are reported in this outcome measure.
Measured: From Week 5 up to Week 26
Part A: Number of Blood Units Transfused Per Participant
A participant was to receive a transfusion if his or her Hgb level met either of the following criteria: -Hgb was <9 g/dL and the participant had symptoms of anemia or Hgb was <7 g/dL and the participant was asymptomatic. Number of blood units transfused after the first 5 weeks of study drug administration and up to Week 26 are reported in this outcome measure.
Measured: From Week 5 up to Week 26
Part A: Mean Change From Baseline in Hemoglobin (Hgb) Level at the Treatment Assessment Timepoint
Mean change from baseline (Week 0) in Hgb at treatment assessment timepoint is reported in this outcome measure. Treatment assessment timepoint was defined as the average of the values from the Week 23, 25, and 26 visits. LS mean and 95% CI was assessed by MMRM approach using TOEPH covariance matrix with change from baseline as the dependent variable and baseline value and visits as independent variables. Baseline was defined as the last non-missing value prior to the first administration of study drug.
Measured: Baseline, treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
Part B: Change From Baseline in Hemoglobin (Hgb) Level at Each Specified Time Points
Change From Hgb level from baseline (Week 0) at each specified time points (i.e., 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 and early termination/safety follow up [ET/SFU] Visit) is reported in this outcome measure. Baseline was defined as the last non-missing value prior to the first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 185).
Measured: 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)
Part B: Change From Baseline in Bilirubin Levels at Each Specified Time Points
Change from baseline (Week 0) in bilirubin levels at each specified time point (i.e., 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 and ET/SFU Visit) is reported in this outcome measure. Baseline was defined as the last non-missing value prior to the first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 185).
Measured: 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)
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
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 were added to obtain a total score. The Total score ranged from 0 to 52, with higher score indicating more fatigue. Baseline (Week 0) was defined as the last non-missing value prior to the first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 185).
Measured: 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)
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
SF-12: 12 item-questionnaire assessed health-related quality of life (HRQOL) contained 12 items, categorized into 8 domains (subscales) of functioning and well-being: physical functioning, role-physical, role emotional, mental health, bodily pain, general health, vitality and social functioning, with each domain score ranged from 0 (poor health) to 100 (better health). Higher scores = good health condition. These 8 domains were further summarized into 2 summary scores, PCS and MCS for which, score ranged 0 (poor health) to 100 (better health). Higher scores = better HRQOL. Baseline (Week 0) was defined as the last non-missing value prior to first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 185). Change from baseline in SF-12 PCS and MCS scores is reported in this outcome measure.
Measured: Baseline, Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135 and ET Visit/SFU visit (i.e., up to Week 185)
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
EQ-5D-5L:standardized, participant-rated questionnaire to assess health-related quality of life. EQ-5D-5L includes 2 components: EQ-5D-5L health state utility index (descriptive system) and Visual Analog Scale (VAS). EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response option: no problems, slight problems, moderate problems, severe problems, and extreme problems measured with Likert scale. EQ-5D-5L responses relating to 5 dimensions are converted into a single index utility score between 0 to 1, where higher score=better health state. The EQ-5D-5L VAS rated participant's current health state on a scale from 0=worst imaginable health state to 100 =best imaginable health state. Baseline (Week 0): last non-missing value prior to first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 185).
Measured: 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)
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
The PGIS is a self-reported scale. The PGIS is a 1-item questionnaire designed to assess participant's impression of disease severity using a 5-point scale ranging from 1 to 5, where 1=none, 2= mild, 3=moderate, 4=severe, 5=very severe. Higher scores indicated greater severity. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 185).
Measured: 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)
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
PGIC is a self-administered questionnaire to evaluate the improvement or worsening compared to the start of the study. PGIC was assessed on a 7-point Likert scale ranged from 1 (greatly improved) to 7 (greatly worsened). Categories were defined based on the PGIC scores as follows: 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse and 7=very much worsen. Higher scores indicated greater severity. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 185).
Measured: 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)
Part B: Mean Change From Baseline in Lactate Dehydrogenase (LDH) Level at Each Specified Time Points
Mean change from baseline in LDH levels at each specified time points (i.e., 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 and ET/SFU Visit) is reported in this outcome measure. Baseline (Week 0) was defined as the last non-missing value prior to the first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 185).
Measured: 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)
Part B: Number of Blood Transfusions Per Participant
A participant was to receive a transfusion if his or her Hgb level met either of the following criteria: Hgb was <9 g/dL and the participant had symptoms of anemia or Hgb was <7 g/dL and the participant was asymptomatic.
Measured: From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)
Part B: Number of Blood Units Transfused Per Participant
A participant was to receive a transfusion if his or her Hgb level met either of the following criteria: Hgb was <9 g/dL and the participant had symptoms of anemia or Hgb was <7 g/dL and the participant was asymptomatic.
Measured: From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)
Part B: Change From Baseline in Haptoglobin Values at Each Specified Time Points
Change in Haptoglobin values from baseline at each specified time points (i.e., 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 and ET/SFU Visit) is reported in this outcome measure. Baseline was defined as the last non-missing value prior to the first administration of study drug in Part A. ET visit/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 185). Haptoglobin values <0.2 were imputed as 0.2.
Measured: 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)
Part B: Number of Healthcare Visits by Type
In this outcome measure, number of healthcare visits which included non-study healthcare resource utilization visit (consisted mainly of extra visits to the office of the study doctor, or visit to a generalist doctor, or visit to a specialist doctor) and hospitalization visit and visit to hospital emergency is reported.
Measured: From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Nov 2017
- Study start5 Mar 2018
- Primary completion5 Oct 2021
- Study completion5 Oct 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Agglutinin Disease, ColdStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- Bioverativ, a Sanofi company
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Clinical Sciences & Operations, Study director, Sanofi
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03347396
- Sponsor's protocol ID
- EFC16215
- Other IDs
- BIVV009-03, 2017-003538-10, 2017
- Status last verified
- Oct 2022
- First submitted
- 16 Nov 2017
- Last updated
- 31 Oct 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org
Publications
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
Roth A, Broome CM, Barcellini W, Tvedt THA, Miyakawa Y, D'Sa S, Cella D, Bozzi S, Jayawardene D, Yoo R, Shafer F, Wardecki M, Weitz IC. Long-term sutimlimab improves quality of life for patients with cold agglutinin disease: CARDINAL 2-year follow-up. Blood Adv. 2023 Oct 10;7(19):5890-5897. doi: 10.1182/bloodadvances.2022009318.
PubMed 37459203Roth A, Barcellini W, D'Sa S, Miyakawa Y, Broome CM, Michel M, Kuter DJ, Jilma B, Tvedt THA, Weitz IC, Yoo R, Jayawardene D, Vagge DS, Kralova K, Shafer F, Wardecki M, Lee M, Berentsen S. Sustained inhibition of complement C1s with sutimlimab over 2 years in patients with cold agglutinin disease. Am J Hematol. 2023 Aug;98(8):1246-1253. doi: 10.1002/ajh.26965. Epub 2023 May 29.
PubMed 37246953Roth 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.
PubMed 35999387Tvedt 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.
PubMed 34778998Roth 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.
PubMed 33826820
Study at a glance
From the registry record, last updated by the sponsor on 31 Oct 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03347396
- Acronym / sponsor ID
- EFC16215
- Conditions
- Agglutinin Disease, Cold
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- Bioverativ, a Sanofi companyIndustry (pharma, biotech, devices)
- Study start
- 5 Mar 2018 (actual)
- Primary completion
- 5 Oct 2021 (actual)
- Study completion
- 5 Oct 2021 (actual)
- First posted
- 20 Nov 2017 (actual)
- Results
- Posted 31 Oct 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| BIVV009 | Experimental | Drug: BIVV009Participants with primary CAD who had a recent history of transfusion (defined as at least 1 transfusion during the last 6 months prior to screening) received an intravenous (IV) infusion of BIVV009 6.5 grams (g) (if body weight was less than [<] 75 kilograms [kg]) or BIVV009 7.5 g (if body weight was greater than or equal to [>=] 75 kg) on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25. Participants who completed Part A per protocol through the end of treatment visit (Week 26) could continue to receive BIVV009 in Part B, every 2 weeks starting at Week 27 for up to an additional 149 weeks. All participants who completed Part A elected to continue in Part B. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (6 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BIVV009Also: SutimlimabSutimlimab was administered as intravenous (IV) infusion. | Drug | BIVV009 |
Primary outcome
Part A: Percentage of Participants With Response to Treatment
Time frame: From Week 5 through Week 26
A participant was considered a responder: if he or she did not receive a blood transfusion from Week 5 through Week 26 (end of treatment in Part A) and did not receive treatment for CAD beyond what was permitted per protocol. Additionally, the participant's hemoglobin (Hgb) level must meet either of the following criteria: Hgb level >= 12 grams per deciliter (g/dL) at the treatment assessment endpoint (defined as the average of the values from the Week 23, 25, and 26 visits), 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. Percentage of responders was calculated together with a 95% exact Clopper-Pearson confidence interval (CI).
Part B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
Time frame: 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)
An Adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. TESAEs was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the treatment-emergent (TE) period (from the first investigational medicinal product [IMP] administration in Part B to the last IMP administration + 9 weeks follow up period).
18 secondary outcomes
Part A: Mean Change From Baseline in Bilirubin Levels at the Treatment Assessment Timepoint
Time frame: Baseline, treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
Part A: Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score (Quality of Life) at Treatment Assessment Timepoint
Time frame: Baseline, treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
Part A: Mean Change From Baseline in Lactate Dehydrogenase (LDH) at the Treatment Assessment Timepoint
Time frame: Baseline, treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
Part A: Number of Blood Transfusions Per Participant
Time frame: From Week 5 up to Week 26
Part A: Number of Blood Units Transfused Per Participant
Time frame: From Week 5 up to Week 26
Part A: Mean Change From Baseline in Hemoglobin (Hgb) Level at the Treatment Assessment Timepoint
Time frame: Baseline, treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
Part B: Change From Baseline in Hemoglobin (Hgb) Level at Each Specified Time Points
Time frame: 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)
Part B: Change From Baseline in Bilirubin Levels at Each Specified Time Points
Time frame: 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)
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
Time frame: 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)
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
Time frame: Baseline, Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135 and ET Visit/SFU visit (i.e., up to Week 185)
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
Time frame: 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)
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
Time frame: 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)
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
Time frame: 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)
Part B: Mean Change From Baseline in Lactate Dehydrogenase (LDH) Level at Each Specified Time Points
Time frame: 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)
Part B: Number of Blood Transfusions Per Participant
Time frame: From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)
Part B: Number of Blood Units Transfused Per Participant
Time frame: From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)
Part B: Change From Baseline in Haptoglobin Values at Each Specified Time Points
Time frame: 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)
Part B: Number of Healthcare Visits by Type
Time frame: From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Oct 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publicationAlexander 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
- Derived from this study: PubMed 37459203Roth A, Broome CM, Barcellini W, Tvedt THA, Miyakawa Y, D'Sa S, Cella D, Bozzi S, Jayawardene D, Yoo R, Shafer F, Wardecki M, Weitz IC. Long-term sutimlimab improves quality of life for patients with cold agglutinin disease: CARDINAL 2-year follow-up. Blood Adv. 2023 Oct 10;7(19):5890-5897. doi: 10.1182/bloodadvances.2022009318.
- Derived from this study: PubMed 37246953Roth A, Barcellini W, D'Sa S, Miyakawa Y, Broome CM, Michel M, Kuter DJ, Jilma B, Tvedt THA, Weitz IC, Yoo R, Jayawardene D, Vagge DS, Kralova K, Shafer F, Wardecki M, Lee M, Berentsen S. Sustained inhibition of complement C1s with sutimlimab over 2 years in patients with cold agglutinin disease. Am J Hematol. 2023 Aug;98(8):1246-1253. doi: 10.1002/ajh.26965. Epub 2023 May 29.
- Derived from this study: PubMed 35999387Roth 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.
- Derived from this study: PubMed 34778998Tvedt 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.
- Derived from this study: PubMed 33826820Roth 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.
- Individual participant dataSharing planned: Yes. Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Clinical Sciences & Operations study director
Sanofi
49 sites in 14 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing BIVV009 in people with Agglutinin Disease, Cold, run by Bioverativ, a Sanofi company at 49 sites in 14 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 49 sites in United States, Italy, Spain, Australia, Belgium and 9 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 31 Oct 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Part A: Percentage of Participants With Response to Treatment (time frame: From Week 5 through Week 26). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03347396, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Oct 2022.