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 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).

Time frame: From Week 5 through Week 26

Population: Analysis was performed on Part A-full analysis set (FAS) which included all participants who received at least 1 dose (including partial dose) of study drug. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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).

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)

Population: Analysis was performed on Part B safety analysis set (SAS) which included all participants who received at least 1 dose (including partial dose) of study drug in Part B. Data for this outcome measures was planned to be collected and analyzed for dose-wise reporting groups (BIVV009 6.5g and BIVV009 7.5 g).

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.

Time frame: Baseline, treatment assessment timepoint (i.e., average of Week 23, 25 and 26)

Population: Analysis was performed on Part A-FAS. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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.

Time frame: Baseline, treatment assessment timepoint (i.e., average of Week 23, 25 and 26)

Population: Analysis was performed on Part A-FAS. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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.

Time frame: Baseline, treatment assessment timepoint (i.e., average of Week 23, 25 and 26)

Population: Analysis was performed on Part A-FAS. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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.

Time frame: Baseline, treatment assessment timepoint (i.e., average of Week 23, 25 and 26)

Population: Analysis was performed on Part A-FAS. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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.

Time frame: From Week 5 up to Week 26

Population: Analysis was performed on Part A-FAS. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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.

Time frame: From Week 5 up to Week 26

Population: Analysis was performed on Part A-FAS. Here, 'overall number of participants analyzed' = number of participants with at least 1 transfusion. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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.

Time frame: Baseline, Weeks 39, 51, 63, 75, 87, 99, 111, 123, 135 and ET Visit/SFU visit (i.e., up to Week 185)

Population: Analysis was performed on Part B-FAS. Here, 'number analyzed' = participants with available data for each specified category. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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).

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)

Population: Analysis was performed on Part B-FAS. Here, 'number analyzed' = participants with available data for each specified category. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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).

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)

Population: Analysis was performed on Part B-FAS. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure and 'number analyzed' = participants with available data for each specified category. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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).

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)

Population: Analysis was performed on Part B-FAS. Here, 'number analyzed' = participants with available data for each specified category. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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.

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)

Population: Analysis was performed on Part B-FAS. Here, 'number analyzed' = participants with available data for each specified category. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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).

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)

Population: Analysis was performed on Part B-FAS which included all participants who enrolled in Part B study and received at least 1 dose (including partial dose) of study drug. Here, 'number analyzed' = participants with available data for each specified category. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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).

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)

Population: Analysis was performed on Part B-FAS. Here, 'number analyzed' = participants with available data for each specified category. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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.

Time frame: From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)

Population: Analysis was performed on Part-B FAS. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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.

Time frame: From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)

Population: Analysis was performed on Part B-FAS. Here, 'overall number of participants analyzed' = number of participants with at least 1 transfusion. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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.

Time frame: From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)

Population: Analysis was performed on Part B-FAS. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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).

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)

Population: Analysis was performed on Part B-FAS. Here, 'number analyzed' = participants with available data for each specified category. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).

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).

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)

Population: Analysis was performed on Part B-FAS population. Here, 'number analyzed' = participants with available data for each specified category. Data for this outcome measure was planned to be collected and analyzed for combined population (i.e., all participants who received BIVV009 \[either at 6.5 g or 7.5 g\]).