Brief Summary
The purpose of Part A was to determine whether sutimlimab administration resulted in a greater than or equal to (\>=)1.5 grams 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 was to evaluate the long-term safety and tolerability of sutimlimab in participants with primary CAD.
Brief Title
A Study to Assess the Efficacy and Safety of BIVV009 (Sutimlimab) in Participants With Primary Cold Agglutinin Disease Without A Recent History of Blood Transfusion
Detailed Description
The planned total study duration per participant was approximately 1.5 to 2.5 years.
Completion Date
Completion Date Type
Actual
Conditions
Cold Agglutinin Disease
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, and e) Immunoglobulin G DAT less than or equal to (\<=) 1+, and, f) No overt malignant disease.
* 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.
* History of blood transfusion within 6 months of screening, or history of more than one blood transfusion within 12 months of screening.
* Clinically relevant infection of any kind within the month preceding enrollment (example, 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 would be adjudicated on a case-by-case basis during the confirmatory review of participant eligibility.
* Positive hepatitis panel (including hepatitis B surface antigen and/or hepatitis C virus antibody) prior to or at screening.
* Positive human immunodeficiency virus 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.
The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
* 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, and e) Immunoglobulin G DAT less than or equal to (\<=) 1+, and, f) No overt malignant disease.
* 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.
* History of blood transfusion within 6 months of screening, or history of more than one blood transfusion within 12 months of screening.
* Clinically relevant infection of any kind within the month preceding enrollment (example, 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 would be adjudicated on a case-by-case basis during the confirmatory review of participant eligibility.
* Positive hepatitis panel (including hepatitis B surface antigen and/or hepatitis C virus antibody) prior to or at screening.
* Positive human immunodeficiency virus 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.
The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Inclusion 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, and e) Immunoglobulin G DAT less than or equal to (\<=) 1+, and, f) No overt malignant disease.
* Hemoglobin level \<= 10.0 g/dL.
* Bilirubin level above the normal reference range, including participants with Gilbert's Syndrome.
* 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, and e) Immunoglobulin G DAT less than or equal to (\<=) 1+, and, f) No overt malignant disease.
* Hemoglobin level \<= 10.0 g/dL.
* Bilirubin level above the normal reference range, including participants with Gilbert's Syndrome.
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT03347422
Org Class
Industry
Org Full Name
Sanofi
Org Study Id
EFC16216
Overall Status
Completed
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of Sutimlimab in Patients With Primary Cold Agglutinin Disease Without a Recent History of Blood Transfusion
Primary Outcomes
Outcome Description
A participant was considered a responder: if he or she did not receive blood transfusion from Week 5 through Week 26 (end of treatment) and did not receive treatment for CAD beyond what was permitted per protocol. Additionally, participant's hemoglobin (Hgb) level must have increased to \>=1.5 grams per deciliter (g/dL) from baseline (defined as last Hgb value before administration of first dose of study drug) at treatment assessment timepoint (defined as average of values from the Week 23, 25, and 26 visits). Percentage of responders was calculated together with 95% exact Clopper-Pearson confidence interval (CI).
Outcome Measure
Part A: Percentage of Participants With Response to Treatment
Outcome Time Frame
From Week 5 through Week 26
Outcome Description
Adverse Event (AE): any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. Treatment emergent serious adverse events (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 congenital anomaly/birth defect, was medically important event. Treatment emergent adverse events (TEAEs): AEs that developed, worsened or became serious during the treatment-emergent (TE) period (from first investigational medicinal product \[IMP\] administration in Part B to last IMP administration + 9 weeks follow-up period).
Outcome Measure
Part B: Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious AEs (SAEs)
Outcome Time Frame
Part B, 6.5 g cohort: From first dose (Week 26) up to 149 weeks of treatment + 9 weeks of follow-up (i.e., up to Week 184); Part B, 7.5 g cohort: From first dose (Week 26) up to 137 weeks of treatment + 9 weeks of follow-up (i.e., up to Week 172)
Secondary Ids
Secondary Id
2017-003539-12
Secondary Id
BIVV009-04
Secondary Outcomes
Outcome Description
Mean change from baseline (Week 0) in Hemoglobin (Hgb) 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. 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.
Outcome Time Frame
Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
Outcome Measure
Part A: Mean Change From Baseline in Hemoglobin (Hgb) Level at the Treatment Assessment Timepoint
Outcome Description
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 (Week 0) 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.
Outcome Time Frame
Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
Outcome Measure
Part A: Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at the Treatment Assessment Timepoint
Outcome Description
Mean change from baseline (Week 0) in total bilirubin 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. Baseline was defined as the last non-missing value prior to the first administration of study drug.
Outcome Time Frame
Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
Outcome Measure
Part A: Mean Change From Baseline in Total Bilirubin Levels at the Treatment Assessment Timepoint
Outcome Description
Mean change from baseline (Week 0) 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. Baseline was defined as the last non-missing value prior to the first administration of study drug.
Outcome Time Frame
Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
Outcome Measure
Part A: Mean Change From Baseline in Lactate Dehydrogenase (LDH) at the Treatment Assessment Timepoint
Outcome Description
Symptomatic anemia was defined as having following symptoms: i. Fatigue; ii. Weakness; iii. Shortness of breath; iv. Palpitations, fast heartbeat; v. Light headedness and/or vi. Chest pain. Percentage of participants with solicited symptomatic anemia symptoms was reported in this outcome measure.
Outcome Time Frame
Week 26
Outcome Measure
Part A: Percentage of Participants With Solicited Symptomatic Anemia at Week 26
Outcome Description
Change from baseline (Week 0) in Hgb levels at each specified time points (i.e., Week 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, 81, 83,85,87, 89,91, 93, 95, 97, 99,101,103, 105, 107,109, 111,113,115,117,119, 121,123, 125, 127,129,131,133,135,137,139,141,143,145,147,149,151,153, 155,157,159,161,163,165,167,169,171,173,175 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. Early Termination (ET) visit/safety follow up (SFU) visit was 9 weeks after administration of last dose (i.e., up to Week 184). Here, "0" in the number analyzed field signifies that none of participants were available for assessment at the specified timepoints.
Outcome Time Frame
Baseline (Week 0), every 2 weeks starting from Week 27 till Week 175 and at ET/SFU visit (i.e., up to Week 184)
Outcome Measure
Part B: Change From Baseline in Hemoglobin (Hgb) Level at Each Specified Time Points
Outcome Description
Change from baseline (Week 0) in total bilirubin levels at each specified time points (i.e., Week 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, 81,83, 85, 87, 89, 91, 93, 95, 97, 99,101,103, 105, 107,109, 111,113,115,117,119, 121, 123, 125, 127,129,131,133,135,137,139,141,143, 145,147,149,151,153,155,157,159, 161,163,165,167,169,171,173,175 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 184). Here, "0" in the number analyzed field signifies that none of participants were available for assessment at the specified timepoints.
Outcome Time Frame
Baseline (Week 0), every 2 weeks starting from Week 27 till Week 175 and at ET/SFU visit (i.e., up to Week 184)
Outcome Measure
Part B: Change From Baseline in Total Bilirubin Levels at Each Specified Time Points
Outcome Description
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 184).
Outcome Time Frame
Baseline (Week 0), Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171 and ET Visit/SFU visit (i.e., up to Week 184)
Outcome Measure
Part B: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score (Quality of Life) at Each Specified Time Points
Outcome Description
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 that ranged from 0 (poor health) to 100 (better health). Higher scores = better HRQOL. Baseline (Week 0): last non-missing value prior to first administration of study drug in Part A. ET visit/SFU visit: 9 weeks after administration of last dose (i.e., up to Week 184).
Outcome Time Frame
Baseline (Week 0), Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171 and ET Visit/SFU visit (i.e., up to Week 184)
Outcome 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
Outcome Description
EQ-5D-5L included 2 components: 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 problem, slight problem, moderate problem, severe problem and extreme problems measured with Likert scale. EQ-5D-5L responses converted into single index utility score between 0 to 1. Higher score=better health. EQ-5D-5L VAS rated participant's current health state on scale from 0 (worst imaginable health) to 100 (best imaginable health). Baseline (Week 0): last non-missing value prior to first administration of study drug in Part A. ET visit/SFU visit: 9 weeks after administration of last dose (i.e., up to Week 184).
Outcome Time Frame
Baseline (Week 0), Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171 and ET Visit/SFU visit (i.e., up to Week 184)
Outcome 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 Each Specified Time Points
Outcome Description
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 184).
Outcome Time Frame
Baseline (Week 0), Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171 and ET Visit/SFU visit (i.e., up to Week 184)
Outcome Measure
Part B: Number of Participants With Response to Participant's Global Impression of (Fatigue) Severity (PGIS) Questionnaire at Each Specified Time Points
Outcome Description
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 184).
Outcome Time Frame
Baseline (Week 0), Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135, 147, 159, 171 and ET Visit/SFU visit (i.e., up to Week 184)
Outcome Measure
Part B: Number of Participants With Response to Participant's Global Impression of Change (PGIC) Questionnaire at Each Specified Time Points
Outcome Description
Change from baseline (Week 0) in LDH levels at each specified time points (i.e., Week 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, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107,109, 111, 113, 115, 117, 119, 121,123, 125, 127,129,131,133,135,137,139,141,143,145,147, 149, 151,153,155,157,159,161,163,165,167,169, 171, 173, 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/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184).
Outcome Time Frame
Baseline (Week 0), every 2 weeks starting from Week 27 till Week 175 and at ET/SFU visit (i.e., up to Week 184)
Outcome Measure
Part B: Mean Change From Baseline in Lactate Dehydrogenase (LDH) Level at Each Specified Time Points
Outcome Description
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.
Outcome Time Frame
From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)
Outcome Measure
Part B: Number of Blood Transfusions Per Participant
Outcome Description
Change from baseline (Week 0) in haptoglobin values at each specified time points (i.e., Week 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, 81, 83, 85, 87, 89, 91, 93, 95, 97,99,101,103, 105, 107,109, 111,113,115,117,119, 121,123, 125, 127, 129,131,133,135,137,139,141,143, 145,147,149,151,153,155,157,159, 161,163,165,167,169,171,173,175 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/SFU visit was 9 weeks after administration of last dose (i.e., up to Week 184). Haptoglobin values \<0.2 were imputed as 0.2.
Outcome Time Frame
Baseline (Week 0), every 2 weeks starting from Week 27 till Week 175 and at ET/SFU visit (i.e., up to Week 184)
Outcome Measure
Part B: Mean Change From Baseline in Haptoglobin Values at Each Specified Time Points
Outcome Description
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, visit to a generalist doctor or visit to a specialist doctor), hospitalization visit and visit to hospital emergency is reported.
Outcome Time Frame
From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)
Outcome Measure
Part B: Number of Healthcare Visits by Type
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Irina Murakhovskaya
Investigator Email
imurakho@montefiore.org
Investigator Phone
IMURAKHO
Categories Mesh Debug
Blood Disorders --- ANEMIA, HEMOLYTIC
Blood Disorders --- ANEMIA
Blood & Bone Marrow Cancers --- ANEMIA
Blood Disorders --- HEMATOLOGIC DISEASES
Blood & Bone Marrow Cancers --- HEMATOLOGIC DISEASES
Infectious Disease --- IMMUNE SYSTEM DISEASES
Lung --- IMMUNE SYSTEM DISEASES
MeSH Terms
ANEMIA, HEMOLYTIC, AUTOIMMUNE
ANEMIA, HEMOLYTIC
ANEMIA
HEMATOLOGIC DISEASES
HEMIC AND LYMPHATIC DISEASES
AUTOIMMUNE DISEASES
IMMUNE SYSTEM DISEASES
SUTIMLIMAB
COUNTERFEIT DRUGS
SUBSTANDARD DRUGS
PHARMACEUTICAL PREPARATIONS