A Study of Efficacy and Safety of Ianalumab in Previously Treated Patients With Warm Autoimmune Hemolytic Anemia

Phase 3Active Not RecruitingNCT05648968

Novartis Pharmaceuticals90 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Warm Autoimmune Hemolytic Anemia (wAIHA)

Interventions

IanalumabBIOLOGICAL

i.v. infusion, prepared from concentrate solution

PlaceboDRUG

i.v. infusion, prepared from matching placebo

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

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.

Locations (54)

Outcomes

Primary Outcomes

Binary variable indicating whether a patient achieves a durable response

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

Time frame: Randomization to Week 25

Secondary Outcomes

Duration of response (Key Secondary)

• 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 frame: Randomization to end of study (up to 39 months after randomization of last patient)

Time from randomization to start of durable response in each treatment group

Durable response is defined as in primary endpoint.

Time frame: Randomization to end of study (up to 39 months after randomization of last patient)

Time from randomization to start of first response in each treatment group

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.

Time frame: Randomization to end of study (up to 39 months after randomization of last patient)

Time from randomization to start of complete response in each treatment group

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.

Data from ClinicalTrials.gov

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Michigan Center of Medical Research

Farmington Hills, Michigan, United States

University of Minnesota Med Center

Minneapolis, Minnesota, United States

Fred Hutchinson Cancer Center

Seattle, Washington, United States

Novartis Investigative Site

CABA, Buenos Aires, Argentina

Novartis Investigative Site

Caba, Argentina

Novartis Investigative Site

Caba, Argentina

Novartis Investigative Site

Garran, Australian Capital Territory, Australia

Novartis Investigative Site

Melbourne, Victoria, Australia

Novartis Investigative Site

Guangzhou, Guangdong, China

Novartis Investigative Site

Hangzhou, Zhejiang, China

...and 44 more locations

Time frame: Randomization to end of study (up to 39 months after randomization of last patient)

Response rate

Assessment of quality of response in each treatment group.

Time frame: Randomization to end of study (up to 39 months after randomization of last patient)

Complete response rate

Assessment of complete response rate in each treatment group.

Time frame: Randomization to end of study (up to 39 months after randomization of last patient)

Hemoglobine Levels

Assessment of hemoglobin levels in each treatment group.

Time frame: Randomization to end of study (up to 39 months after randomization of last patient)

Number of participants who received rescue treatment (overall & by type of rescue treatment)

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.

Time frame: Randomization to end of study (up to 39 months after randomization of last patient)

Percentage of participants who received rescue treatment (overall & by type of rescue treatment)

This is to assess the need for rescue treatment in all treatment groups.

Time frame: Randomization to end of study (up to 39 months after randomization of last patient)

Change from baseline in the the frequency and absolute number of CD19+ B cell counts

Change from baseline in the the frequency and absolute number of CD19+ B cell counts in whole blood

Time frame: Randomization to end of study (up to 39 months after randomization of last patient)

Time to first occurrence of B cell recovery, defined as ≥80% of baseline or ≥50 cells/μL

Time to first occurrence of B cell recovery, defined as ≥80% of baseline or ≥50 cells/μL in whole blood

Time frame: Randomization to end of study (up to 39 months after randomization of last patient)

Change from baseline in immunoglobulin levels

Change from baseline in immunoglobulin levels (change in titers of IgG, IgM, IgA)

Time frame: Randomization until month 30

Change from baseline in the 8 domain scores and in the summary scores (PCS, MCS) of SF-36 questionnaire

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.

Time frame: Randomization to end of study (up to 39 months after randomization of last patient)

Change from baseline in the T-score of PROMIS Fatigue-13a questionnaire

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.

Time frame: Randomization to end of study (up to 39 months after randomization of last patient)

Ianalumab PK parameter - AUClast

AUClast: area under the curve from time zero to last measurable concentration sampling time (tlast).

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).

Ianalumab PK parameter - AUCtau

AUCtau: the AUV calculated to the end of a dosing interval (tau).

Ianalumab PK parameter - Accumulation ratio Racc

Accumulation ratio calculated using AUC values obtained between last and first dose

Time frame: After last dose (pre-dose, 2 hours, 336 hours, 672 hours, 1344 hours, 2016 hours and 3360 hours post dose).

Ianalumab PK parameter - Cmax

Maximum (peak) observed plasma, blood, serum or other body fluid drug concentration

Ianalumab PK parameter - Tmax

Time to reach maximum (peak) plasma, blood, serum or other body fluid drug concentration

Immunogenicity of ianalumab

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.

Time frame: Randomization to end of study (up to 39 months after randomization of last patient)