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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 (Cadenza)

Primary Purpose

Cold Agglutinin Disease

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
sutimlimab (BIVV009)
placebo
Sponsored by
Bioverativ, a Sanofi company
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cold Agglutinin Disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Arizona Oncology Associates PC
  • USC/Keck School of Medicine
  • Georgetown University Medical Center
  • Cleveland Clinic Florida
  • Massachusetts General Hospital
  • Brigham and Women's Hospital
  • Washington University School of Medicine
  • Montefiore Medical Center
  • New York Medical College at Westchester Medical Center
  • East Carolina University
  • Cleveland Clinic
  • Hospital of the University of Pennsylvania
  • University of Pittsburgh Medical Center
  • UW Hospitals and Clinics
  • USC Health Clinics
  • Ballarat Oncology & Haematology
  • Monash Medical Centre
  • Perth Blood Institute
  • Medical University of Vienna
  • ZNA Stuivenberg
  • University Hospitals Leuven
  • St. Michael's Hospital
  • McGill University Health Center
  • CHU d'Angers
  • Hôpital de Caen
  • Centre Hospitalier Henri Mondor
  • Centre Hospitalier Lyon Sud
  • Gemeinschaftspraxis Hämatologie-Onkologie
  • Universitätsklinikum Essen
  • Univ Ulm, Inst Klin. Transfusions. Immungen
  • Hadassah Medical Center
  • Laniado Hospital
  • A. O. Spedali Civili di Brescia
  • Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico
  • U.O.C. Ematologia- Policlinico "A. Gemelli"
  • U.O.C. Ematologia Ospedale San Bortolo
  • Japanese Red Cross Society Himeji Hospital
  • Ishikawa Prefectural Central Hospital
  • Tokai University Hospital
  • Osaka University Hospital
  • Saitama Medical University Hospital
  • Aichi Medical University Hospital
  • Academisch Medisch Centrum
  • Leids Universitair Medisch Centrum
  • Haukeland University Hospital
  • St Olavs Hospital, Avdeling for blodsykdommer
  • Hospital Universitario Puerta de Hierro
  • Hospital Clinci i Provincial de Barcelona
  • Hospital Universitario Virgen del Rocio
  • Hospital Universitario Dr. Peset
  • St James Hospital, Leeds
  • Imperial College Healthcare NHS Trust, Hammersmith Hospital
  • University College London

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

BIVV009/BIVV009

Placebo/BIVV009

Arm Description

Participants with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an intravenous (IV) infusion of BIVV009 6.5 g (for participants less than [<]75 kilograms [kg]) or 7.5 g dose (for participants 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), received placebo on Week 26 and continued to receive BIVV009 6.5 or 7.5 g in Part B, every 2 weeks starting at Week 27 for up to an additional 149 weeks (for 6.5 g) or 121 weeks (for 7.5 g). All participants who completed Part A elected to continue in Part B.

Participants with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of placebo matched to BIVV009 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) received BIVV009 6.5 (if <75 kg) or 7.5 g (if >=75 kg) in Part B, on Week 26 and Week 27 and every 2 weeks thereafter for up to an additional 123 weeks (for 6.5 g) or 137 weeks (for 7.5 g). All participants who completed Part A elected to continue in Part B.

Outcomes

Primary Outcome Measures

Part A: Percentage of Participants With Response to Treatment
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).
Part B: Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious AEs (SAEs)
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).

Secondary Outcome Measures

Part A: Mean Change From Baseline in Hemoglobin (Hgb) Level at the Treatment Assessment Timepoint
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.
Part A: Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at the 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 (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.
Part A: Mean Change From Baseline in Total Bilirubin Levels at the Treatment Assessment Timepoint
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.
Part A: Mean Change From Baseline in Lactate Dehydrogenase (LDH) at the Treatment Assessment Timepoint
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.
Part A: Percentage of Participants With Solicited Symptomatic Anemia at Week 26
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.
Part B: Change From Baseline in Hemoglobin (Hgb) Level at Each Specified Time Points
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.
Part B: Change From Baseline in Total Bilirubin Levels at Each Specified Time Points
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.
Part B: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score (Quality of Life) at Each Specified Time Points
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).
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 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).
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
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).
Part B: Number of Participants With Response to Participant's Global Impression of (Fatigue) Severity (PGIS) Questionnaire at Each Specified Time Points
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).
Part B: Number of Participants With Response to Participant's Global Impression of Change (PGIC) Questionnaire at Each Specified Time Points
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).
Part B: Mean Change From Baseline in Lactate Dehydrogenase (LDH) Level at Each Specified Time Points
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).
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.
Part B: Mean Change From Baseline in Haptoglobin Values at Each Specified Time Points
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.
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, visit to a generalist doctor or visit to a specialist doctor), hospitalization visit and visit to hospital emergency is reported.

Full Information

First Posted
November 16, 2017
Last Updated
December 1, 2022
Sponsor
Bioverativ, a Sanofi company
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1. Study Identification

Unique Protocol Identification Number
NCT03347422
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
Acronym
Cadenza
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Completed
Study Start Date
March 17, 2018 (Actual)
Primary Completion Date
December 3, 2021 (Actual)
Study Completion Date
December 3, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bioverativ, a Sanofi company

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.
Detailed Description
The planned total study duration per participant was approximately 1.5 to 2.5 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cold Agglutinin Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
42 (Actual)

8. Arms, Groups, and Interventions

Arm Title
BIVV009/BIVV009
Arm Type
Experimental
Arm Description
Participants with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an intravenous (IV) infusion of BIVV009 6.5 g (for participants less than [<]75 kilograms [kg]) or 7.5 g dose (for participants 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), received placebo on Week 26 and continued to receive BIVV009 6.5 or 7.5 g in Part B, every 2 weeks starting at Week 27 for up to an additional 149 weeks (for 6.5 g) or 121 weeks (for 7.5 g). All participants who completed Part A elected to continue in Part B.
Arm Title
Placebo/BIVV009
Arm Type
Experimental
Arm Description
Participants with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of placebo matched to BIVV009 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) received BIVV009 6.5 (if <75 kg) or 7.5 g (if >=75 kg) in Part B, on Week 26 and Week 27 and every 2 weeks thereafter for up to an additional 123 weeks (for 6.5 g) or 137 weeks (for 7.5 g). All participants who completed Part A elected to continue in Part B.
Intervention Type
Drug
Intervention Name(s)
sutimlimab (BIVV009)
Intervention Description
Pharmaceutical form: solution for injection Route of administration: intravenous (i.v.)
Intervention Type
Drug
Intervention Name(s)
placebo
Intervention Description
Pharmaceutical form: solution for injection Route of administration: intravenous (i.v.)
Primary Outcome Measure Information:
Title
Part A: Percentage of Participants With Response to Treatment
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).
Time Frame
From Week 5 through Week 26
Title
Part B: Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious AEs (SAEs)
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).
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 Outcome Measure Information:
Title
Part A: Mean Change From Baseline in Hemoglobin (Hgb) Level at the Treatment Assessment Timepoint
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.
Time Frame
Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
Title
Part A: Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score at the Treatment Assessment Timepoint
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.
Time Frame
Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
Title
Part A: Mean Change From Baseline in Total Bilirubin Levels at the Treatment Assessment Timepoint
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.
Time Frame
Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
Title
Part A: Mean Change From Baseline in Lactate Dehydrogenase (LDH) at the Treatment Assessment Timepoint
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.
Time Frame
Baseline (Week 0), treatment assessment timepoint (i.e., average of Week 23, 25 and 26)
Title
Part A: Percentage of Participants With Solicited Symptomatic Anemia at Week 26
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.
Time Frame
Week 26
Title
Part B: Change From Baseline in Hemoglobin (Hgb) Level at Each Specified Time Points
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.
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)
Title
Part B: Change From Baseline in Total Bilirubin Levels at Each Specified Time Points
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.
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)
Title
Part B: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Score (Quality of Life) at Each Specified Time Points
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).
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)
Title
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
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).
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)
Title
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
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).
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)
Title
Part B: Number of Participants With Response to Participant's Global Impression of (Fatigue) Severity (PGIS) Questionnaire at Each Specified Time Points
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).
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)
Title
Part B: Number of Participants With Response to Participant's Global Impression of Change (PGIC) Questionnaire at Each Specified Time Points
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).
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)
Title
Part B: Mean Change From Baseline in Lactate Dehydrogenase (LDH) Level at Each Specified Time Points
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).
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)
Title
Part B: Number of Blood Transfusions Per Participant
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.
Time Frame
From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)
Title
Part B: Mean Change From Baseline in Haptoglobin Values at Each Specified Time Points
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.
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)
Title
Part B: Number of Healthcare Visits by Type
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.
Time Frame
From Week 27 up to 149 weeks of treatment (i.e., up to Week 176)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Sciences & Operations
Organizational Affiliation
Sanofi
Official's Role
Study Director
Facility Information:
Facility Name
Arizona Oncology Associates PC
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85711
Country
United States
Facility Name
USC/Keck School of Medicine
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
Georgetown University Medical Center
City
Georgetown
State/Province
District of Columbia
ZIP/Postal Code
20007
Country
United States
Facility Name
Cleveland Clinic Florida
City
Weston
State/Province
Florida
ZIP/Postal Code
33331
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Montefiore Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10461
Country
United States
Facility Name
New York Medical College at Westchester Medical Center
City
Valhalla
State/Province
New York
ZIP/Postal Code
10595
Country
United States
Facility Name
East Carolina University
City
Greenville
State/Province
North Carolina
ZIP/Postal Code
27834
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Hospital of the University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
University of Pittsburgh Medical Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15232
Country
United States
Facility Name
UW Hospitals and Clinics
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States
Facility Name
USC Health Clinics
City
Buderim
State/Province
Queensland
ZIP/Postal Code
4556
Country
Australia
Facility Name
Ballarat Oncology & Haematology
City
Ballarat
State/Province
Victoria
ZIP/Postal Code
3350
Country
Australia
Facility Name
Monash Medical Centre
City
Clayton
State/Province
Victoria
ZIP/Postal Code
3168
Country
Australia
Facility Name
Perth Blood Institute
City
West Perth
State/Province
Western Australia
ZIP/Postal Code
6005
Country
Australia
Facility Name
Medical University of Vienna
City
Vienna
ZIP/Postal Code
1090
Country
Austria
Facility Name
ZNA Stuivenberg
City
Antwerpen
ZIP/Postal Code
2060
Country
Belgium
Facility Name
University Hospitals Leuven
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
St. Michael's Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5B1W8
Country
Canada
Facility Name
McGill University Health Center
City
Montréal
State/Province
Quebec
ZIP/Postal Code
H4A3J1
Country
Canada
Facility Name
CHU d'Angers
City
Angers Cedex 9
ZIP/Postal Code
49933
Country
France
Facility Name
Hôpital de Caen
City
Caen
ZIP/Postal Code
14033
Country
France
Facility Name
Centre Hospitalier Henri Mondor
City
Créteil
ZIP/Postal Code
94000
Country
France
Facility Name
Centre Hospitalier Lyon Sud
City
Pierre-Bénite
ZIP/Postal Code
69495
Country
France
Facility Name
Gemeinschaftspraxis Hämatologie-Onkologie
City
Dresden
ZIP/Postal Code
1307
Country
Germany
Facility Name
Universitätsklinikum Essen
City
Essen
ZIP/Postal Code
45147
Country
Germany
Facility Name
Univ Ulm, Inst Klin. Transfusions. Immungen
City
Ulm
ZIP/Postal Code
89081
Country
Germany
Facility Name
Hadassah Medical Center
City
Jerusalem
ZIP/Postal Code
91120
Country
Israel
Facility Name
Laniado Hospital
City
Netanya
ZIP/Postal Code
4244916
Country
Israel
Facility Name
A. O. Spedali Civili di Brescia
City
Brescia
ZIP/Postal Code
25123
Country
Italy
Facility Name
Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico
City
Milan
ZIP/Postal Code
20122
Country
Italy
Facility Name
U.O.C. Ematologia- Policlinico "A. Gemelli"
City
Rome
ZIP/Postal Code
00168
Country
Italy
Facility Name
U.O.C. Ematologia Ospedale San Bortolo
City
Vicenza
ZIP/Postal Code
36100
Country
Italy
Facility Name
Japanese Red Cross Society Himeji Hospital
City
Himeji
State/Province
Hyogo
ZIP/Postal Code
670-8540
Country
Japan
Facility Name
Ishikawa Prefectural Central Hospital
City
Kanazawa
State/Province
Ishikawa-ken
ZIP/Postal Code
9208530
Country
Japan
Facility Name
Tokai University Hospital
City
Isehara
State/Province
Kanagawa
ZIP/Postal Code
259-1193
Country
Japan
Facility Name
Osaka University Hospital
City
Suita
State/Province
Osaka
ZIP/Postal Code
565-0871
Country
Japan
Facility Name
Saitama Medical University Hospital
City
Iruma-gun
State/Province
Saitama-Ken
ZIP/Postal Code
350-0495
Country
Japan
Facility Name
Aichi Medical University Hospital
City
Nagakute
ZIP/Postal Code
480-1195
Country
Japan
Facility Name
Academisch Medisch Centrum
City
Amsterdam
ZIP/Postal Code
1105
Country
Netherlands
Facility Name
Leids Universitair Medisch Centrum
City
Leiden
ZIP/Postal Code
2333
Country
Netherlands
Facility Name
Haukeland University Hospital
City
Bergen
ZIP/Postal Code
5053
Country
Norway
Facility Name
St Olavs Hospital, Avdeling for blodsykdommer
City
Trondheim
ZIP/Postal Code
7030
Country
Norway
Facility Name
Hospital Universitario Puerta de Hierro
City
Majadahonda
State/Province
Madrid
ZIP/Postal Code
28222
Country
Spain
Facility Name
Hospital Clinci i Provincial de Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Hospital Universitario Virgen del Rocio
City
Sevilla
ZIP/Postal Code
41013
Country
Spain
Facility Name
Hospital Universitario Dr. Peset
City
Valencia
ZIP/Postal Code
46017
Country
Spain
Facility Name
St James Hospital, Leeds
City
Leeds
ZIP/Postal Code
LS9 7TF
Country
United Kingdom
Facility Name
Imperial College Healthcare NHS Trust, Hammersmith Hospital
City
London
ZIP/Postal Code
W12 0HS
Country
United Kingdom
Facility Name
University College London
City
London
ZIP/Postal Code
WC1E 6AG
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
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
Citations:
PubMed Identifier
35687757
Citation
Roth A, Berentsen S, Barcellini W, D'Sa S, Jilma B, Michel M, Weitz IC, Yamaguchi M, Nishimura JI, Vos JMI, Storek M, Wong N, Patel P, Jiang X, Vagge DS, Wardecki M, Shafer F, Lee M, Broome CM. Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial. Blood. 2022 Sep 1;140(9):980-991. doi: 10.1182/blood.2021014955.
Results Reference
derived

Learn more about this trial

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

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