Brief Summary
The purpose of this study is to evaluate efficacy and safety of ianalumab compared to placebo in patients with warm autoimmune hemolytic anemia, who failed at least one line of treatment.
Brief Title
A Study of Efficacy and Safety of Ianalumab in Previously Treated Patients With Warm Autoimmune Hemolytic Anemia
Detailed Description
The primary objective is to demonstrate that either dose of ianalumab induces a durable hemoglobin response compared to placebo in patients with wAIHA.
The key secondary objective is to demonstrate that either dose of ianalumab maintains a durable hemoglobin response that is sustained beyond end of the treatment period, compared to placebo.
Participants are randomized to two different doses of ianalumab or placebo. Participants who were assigned to placebo arm and not responding to treatment may be treated with open label ianalumab using the higher dose.
The investigational treatment will be supplied in a double-blinded manner. For the open label period, ianalumab will be provided in an open label manner.
In addition to the randomized treatment (ianalumab or placebo), specific supportive care medication as defined in the protocol is allowed. If clinically indicated (e.g., to ensure patient safety), the treating physician may also administer rescue medication.
The study consists of the treatment period, efficacy and safety follow-up periods. The visit frequency will be every other week during the treatment and primary endpoint follow up period; for safety monitoring monthly during the first 20 weeks after last dose and afterwards quarterly up to 2 years from the last dose. For participants in durable response, additional visits for efficacy will occur monthly during the first 2 years after the last dose, and afterwards quarterly until loss of response or end of study, latest until up to 39 months post randomization of the last participant.
The key secondary objective is to demonstrate that either dose of ianalumab maintains a durable hemoglobin response that is sustained beyond end of the treatment period, compared to placebo.
Participants are randomized to two different doses of ianalumab or placebo. Participants who were assigned to placebo arm and not responding to treatment may be treated with open label ianalumab using the higher dose.
The investigational treatment will be supplied in a double-blinded manner. For the open label period, ianalumab will be provided in an open label manner.
In addition to the randomized treatment (ianalumab or placebo), specific supportive care medication as defined in the protocol is allowed. If clinically indicated (e.g., to ensure patient safety), the treating physician may also administer rescue medication.
The study consists of the treatment period, efficacy and safety follow-up periods. The visit frequency will be every other week during the treatment and primary endpoint follow up period; for safety monitoring monthly during the first 20 weeks after last dose and afterwards quarterly up to 2 years from the last dose. For participants in durable response, additional visits for efficacy will occur monthly during the first 2 years after the last dose, and afterwards quarterly until loss of response or end of study, latest until up to 39 months post randomization of the last participant.
Central Contacts
Central Contact Role
Contact
Central Contact Phone
1-888-669-6682
Central Contact Email
novartis.email@novartis.com
Central Contact Role
Contact
Central Contact Phone
+41613241111
Completion Date
Completion Date Type
Estimated
Conditions
Warm Autoimmune Hemolytic Anemia (wAIHA)
Eligibility Criteria
Key Inclusion Criteria:
* 18 years and older at time of signing consent
* Patients with primary or secondary wAIHA documented by positive direct antiglobulin test specific for anti-IgG or anti-IgA, who had an insufficient response to, or relapsed after at least one line of treatment, including patients with steroid resistance, dependence or intolerance
* Hemoglobin concentration at screening and at Week 1 \>=5 g/dL and \<10 g/dL, associated with presence of symptoms related to anemia
* The dose of supportive care must be stable for at least 4 weeks prior to randomization into the study
Key Exclusion Criteria:
* wAIHA secondary to hematologic disease involving bone marrow (e.g., CLL) or another immunologic disease requiring prohibited medication as per protocol. Patients with autoimmune diseases after wash-out from the treatments are allowed.
* Presence of other forms of AIHA (cold or intermediate forms), Evans Syndrome or other cytopenias
* Prior use of B-cell depleting therapy (e.g., rituximab) within 12 weeks prior to randomization, or without hematological response to the last course of B-cell depleting therapy
* Neutrophils: \<1000/mm3
* Serum creatinine \>1.5 × upper limit of normal (ULN)
* Immunoglobulin G (IgG) \<5g/L
* Active viral, bacterial or other infections (including tuberculosis and SARS-CoV-2) requiring systemic treatment at time of screening, or history of recurrent clinically significant infection
* Positivity for hepatitis C virus, hepatitis B surface antigen (HBsAg), or hepatitis B core antibody (HBcAb). HBcAb positive patients can be enrolled if HBsAg negative, HBV DNA negative, no pre-existing liver fibrosis is present and antiviral prophylaxis is given.
* Known history of primary or secondary immunodeficiency, or a positive human immune deficiency virus (HIV) test result
* Live or live-attenuated vaccination within 4 weeks before randomization
* History of splenectomy
Other protocol-defined Inclusion/Exclusion may apply.
* 18 years and older at time of signing consent
* Patients with primary or secondary wAIHA documented by positive direct antiglobulin test specific for anti-IgG or anti-IgA, who had an insufficient response to, or relapsed after at least one line of treatment, including patients with steroid resistance, dependence or intolerance
* Hemoglobin concentration at screening and at Week 1 \>=5 g/dL and \<10 g/dL, associated with presence of symptoms related to anemia
* The dose of supportive care must be stable for at least 4 weeks prior to randomization into the study
Key Exclusion Criteria:
* wAIHA secondary to hematologic disease involving bone marrow (e.g., CLL) or another immunologic disease requiring prohibited medication as per protocol. Patients with autoimmune diseases after wash-out from the treatments are allowed.
* Presence of other forms of AIHA (cold or intermediate forms), Evans Syndrome or other cytopenias
* Prior use of B-cell depleting therapy (e.g., rituximab) within 12 weeks prior to randomization, or without hematological response to the last course of B-cell depleting therapy
* Neutrophils: \<1000/mm3
* Serum creatinine \>1.5 × upper limit of normal (ULN)
* Immunoglobulin G (IgG) \<5g/L
* Active viral, bacterial or other infections (including tuberculosis and SARS-CoV-2) requiring systemic treatment at time of screening, or history of recurrent clinically significant infection
* Positivity for hepatitis C virus, hepatitis B surface antigen (HBsAg), or hepatitis B core antibody (HBcAb). HBcAb positive patients can be enrolled if HBsAg negative, HBV DNA negative, no pre-existing liver fibrosis is present and antiviral prophylaxis is given.
* Known history of primary or secondary immunodeficiency, or a positive human immune deficiency virus (HIV) test result
* Live or live-attenuated vaccination within 4 weeks before randomization
* History of splenectomy
Other protocol-defined Inclusion/Exclusion may apply.
Inclusion Criteria
Inclusion Criteria:
* 18 years and older at time of signing consent
* Patients with primary or secondary wAIHA documented by positive direct antiglobulin test specific for anti-IgG or anti-IgA, who had an insufficient response to, or relapsed after at least one line of treatment, including patients with steroid resistance, dependence or intolerance
* Hemoglobin concentration at screening and at Week 1 \>=5 g/dL and \<10 g/dL, associated with presence of symptoms related to anemia
* The dose of supportive care must be stable for at least 4 weeks prior to randomization into the study
* 18 years and older at time of signing consent
* Patients with primary or secondary wAIHA documented by positive direct antiglobulin test specific for anti-IgG or anti-IgA, who had an insufficient response to, or relapsed after at least one line of treatment, including patients with steroid resistance, dependence or intolerance
* Hemoglobin concentration at screening and at Week 1 \>=5 g/dL and \<10 g/dL, associated with presence of symptoms related to anemia
* The dose of supportive care must be stable for at least 4 weeks prior to randomization into the study
Gender
All
Gender Based
false
Keywords
warm autoimmune hemolytic anemia
wAIHA
ianalumab
VAY736
B-cell depletion
B-cell Activating Factor Receptor (BAFF-R) blockade
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
100 Years
Minimum Age
18 Years
NCT Id
NCT05648968
Org Class
Industry
Org Full Name
Novartis
Org Study Id
CVAY736O12301
Overall Status
Recruiting
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Estimated
Official Title
A Phase 3, Randomized, Double-blind, Study to Assess Efficacy and Safety of Ianalumab (VAY736) Versus Placebo in Warm Autoimmune Hemolytic Anemia (wAIHA) Patients Who Failed at Least One Line of Treatment
Primary Outcomes
Outcome Description
Durable response: hemoglobin level ≥10 g/dL and ≥2 g/dL increase from baseline, for a period of at least eight consecutive weeks between W9 and W25, in the absence of rescue medication or prohibited treatment
Outcome Measure
Binary variable indicating whether a patient achieves a durable response
Outcome Time Frame
Randomization to Week 25
Secondary Ids
Secondary Id
2022-001773-31
Secondary Id
2024-510635-21-00
Secondary Outcomes
Outcome Description
• For patients who previously reached durable response:
Time from first hemoglobin assessment showing durable response to confirmed loss of durable response, defined as the first of the following events:
* hemoglobin level \<10 g/dL in at least two consecutive weekly assessments,
* start of any rescue medication or prohibited treatment,
* death; • For patients who did not achieve the durable response according to primary endpoint definition: duration will be 0 days
Time from first hemoglobin assessment showing durable response to confirmed loss of durable response, defined as the first of the following events:
* hemoglobin level \<10 g/dL in at least two consecutive weekly assessments,
* start of any rescue medication or prohibited treatment,
* death; • For patients who did not achieve the durable response according to primary endpoint definition: duration will be 0 days
Outcome Time Frame
Randomization to end of study (up to 39 months after randomization of last patient)
Outcome Measure
Duration of response (Key Secondary)
Outcome Description
Durable response is defined as in primary endpoint.
Outcome Time Frame
Randomization to end of study (up to 39 months after randomization of last patient)
Outcome Measure
Time from randomization to start of durable response in each treatment group
Outcome Description
Response is defined as hemoglobin level of at least 10 g/dL and an increase of at least 2 g/dl from baseline, or normalization of hemoglobin (at least 11 g/dL for women and 12 g/dL for men), without biochemical resolution of hemolysis.
Outcome Time Frame
Randomization to end of study (up to 39 months after randomization of last patient)
Outcome Measure
Time from randomization to start of first response in each treatment group
Outcome Description
Complete response is defined as normalization of hemoglobin levels and no evidence of hemolysis (normal levels of indirect bilirubin, LDH, haptoglobin and reticulocytes), in the absence of red blood cell transfusions.
Outcome Time Frame
Randomization to end of study (up to 39 months after randomization of last patient)
Outcome Measure
Time from randomization to start of complete response in each treatment group
Outcome Description
Assessment of quality of response in each treatment group.
Outcome Time Frame
Randomization to end of study (up to 39 months after randomization of last patient)
Outcome Measure
Response rate
Outcome Description
Assessment of complete response rate in each treatment group.
Outcome Time Frame
Randomization to end of study (up to 39 months after randomization of last patient)
Outcome Measure
Complete response rate
Outcome Description
Assessment of hemoglobin levels in each treatment group.
Outcome Time Frame
Randomization to end of study (up to 39 months after randomization of last patient)
Outcome Measure
Hemoglobine Levels
Outcome Description
This is to assess the need for rescue treatment in all treatment groups, measured as time-standardized numbers of each type of rescue treatment and as change from baseline in time-standardized number of transfusions.
Outcome Time Frame
Randomization to end of study (up to 39 months after randomization of last patient)
Outcome Measure
Number of participants who received rescue treatment (overall & by type of rescue treatment)
Outcome Description
This is to assess the need for rescue treatment in all treatment groups.
Outcome Time Frame
Randomization to end of study (up to 39 months after randomization of last patient)
Outcome Measure
Percentage of participants who received rescue treatment (overall & by type of rescue treatment)
Outcome Description
Change from baseline in the the frequency and absolute number of CD19+ B cell counts in whole blood
Outcome Time Frame
Randomization to end of study (up to 39 months after randomization of last patient)
Outcome Measure
Change from baseline in the the frequency and absolute number of CD19+ B cell counts
Outcome Description
Time to first occurrence of B cell recovery, defined as ≥80% of baseline or ≥50 cells/μL in whole blood
Outcome Time Frame
Randomization to end of study (up to 39 months after randomization of last patient)
Outcome Measure
Time to first occurrence of B cell recovery, defined as ≥80% of baseline or ≥50 cells/μL
Outcome Description
Change from baseline in immunoglobulin levels (change in titers of IgG, IgM, IgA)
Outcome Time Frame
Randomization until month 30
Outcome Measure
Change from baseline in immunoglobulin levels
Outcome Description
SF-36 v2.0 (acute) includes 36 items that assess general health related quality of life covering 8 domains: physical functioning, role functioning, bodily pain, general health, vitality, social functioning, role-emotional health and mental health.
Scores for the 8 domains are generated, as well as a physical component summary (PCS) score and a mental component summary (MCS) score.
Responses to items are based on a 5-point Likert scale. Scores below 50 indicate less than average health, while scores above 50 indicate better than average health.
Scores for the 8 domains are generated, as well as a physical component summary (PCS) score and a mental component summary (MCS) score.
Responses to items are based on a 5-point Likert scale. Scores below 50 indicate less than average health, while scores above 50 indicate better than average health.
Outcome Time Frame
Randomization to end of study (up to 39 months after randomization of last patient)
Outcome Measure
Change from baseline in the 8 domain scores and in the summary scores (PCS, MCS) of SF-36 questionnaire
Outcome Description
Assessment of quality of life in each treatment group. The PROMIS Short Form v1.0 Fatigue-13a includes 13 items that assess fatigue. All items in the PROMIS-Fatigue-13a utilize a 5-point response scale (e.g., not at all, a little bit, somewhat, quite a bit, very much).
Higher scores on the PROMIS-Fatigue-13a represent greater fatigue.
Higher scores on the PROMIS-Fatigue-13a represent greater fatigue.
Outcome Time Frame
Randomization to end of study (up to 39 months after randomization of last patient)
Outcome Measure
Change from baseline in the T-score of PROMIS Fatigue-13a questionnaire
Outcome Description
AUClast: area under the curve from time zero to last measurable concentration sampling time (tlast).
Outcome Time Frame
After first dose of study treatment (pre-dose, 2 hours, 336 hours, 672 hours post dose) and after last dose (pre-dose, 2 hours, 336 hours, 672 hours, 1344 hours, 2016 hours and 3360 hours post dose).
Outcome Measure
Ianalumab PK parameter - AUClast
Outcome Description
AUCtau: the AUV calculated to the end of a dosing interval (tau).
Outcome Time Frame
After first dose of study treatment (pre-dose, 2 hours, 336 hours, 672 hours post dose) and after last dose (pre-dose, 2 hours, 336 hours, 672 hours, 1344 hours, 2016 hours and 3360 hours post dose).
Outcome Measure
Ianalumab PK parameter - AUCtau
Outcome Description
Accumulation ratio calculated using AUC values obtained between last and first dose
Outcome Time Frame
After last dose (pre-dose, 2 hours, 336 hours, 672 hours, 1344 hours, 2016 hours and 3360 hours post dose).
Outcome Measure
Ianalumab PK parameter - Accumulation ratio Racc
Outcome Description
Maximum (peak) observed plasma, blood, serum or other body fluid drug concentration
Outcome Time Frame
After first dose of study treatment (pre-dose, 2 hours, 336 hours, 672 hours post dose) and after last dose (pre-dose, 2 hours, 336 hours, 672 hours, 1344 hours, 2016 hours and 3360 hours post dose).
Outcome Measure
Ianalumab PK parameter - Cmax
Outcome Description
Time to reach maximum (peak) plasma, blood, serum or other body fluid drug concentration
Outcome Time Frame
After first dose of study treatment (pre-dose, 2 hours, 336 hours, 672 hours post dose) and after last dose (pre-dose, 2 hours, 336 hours, 672 hours, 1344 hours, 2016 hours and 3360 hours post dose).
Outcome Measure
Ianalumab PK parameter - Tmax
Outcome Description
Incidence and titer of anti-ianalumab antibodies in serum (ADA assay) over time. Confirmed anti-drug-antibody positive samples will be further characterized for neutralizing capacity.
Outcome Time Frame
Randomization to end of study (up to 39 months after randomization of last patient)
Outcome Measure
Immunogenicity of ianalumab
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)
100
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