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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

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.

Arms of the Study

Arm 1

Arm 2

Arm Type

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

NCT ID

NCT03347422

First Posted

November 16, 2017

Last Updated

December 1, 2022

Sponsor

Bioverativ, a Sanofi company

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

Data Monitoring Committee

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

Arm Title

Placebo/BIVV009

Arm Type

Experimental

Arm Description

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

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

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

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

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

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

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

Time Frame

Week 26

Title

Part B: Change From Baseline in Hemoglobin (Hgb) Level at Each Specified Time Points

Description

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

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