Study of Ianalumab Versus Placebo in Addition to First-line Corticosteroids in Primary Immune Thrombocytopenia (ITP)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect of two different doses of ianalumab versus placebo in addition to first-line corticosteroids in maintaining platelet count ≥30 G/L in adult participants with primary ITP.

Detailed Description
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This is a multi-center, randomized, double-blind Phase 3 study to assess the efficacy and safety of two different doses of ianalumab compared to placebo in adults with primary ITP (platelets count <30 G/L) who require first-line standard-of-care corticosteroids. After completion of the screening period, the participants will enter the randomized treatment period (ianalumab/placebo with standard of care corticosteroids). After the treatment period, all participants will enter the follow-up period to be monitored for efficacy and safety or safety only depending on how they respond to the study treatment.

Official Title
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A Phase III, Randomized, Double-blind Study of Ianalumab (VAY736) Versus Placebo in Addition to First-line Corticosteroids in Primary Immune Thrombocytopenia (VAYHIT1)

Conditions
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Primary Immune Thrombocytopenia (ITP)

Intervention / Treatment
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* Biological: Ianalumab
* Drug: Placebo
* Drug: Corticosteroids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent prior to participation in the study. Male or female participants aged 18 years and older on the day of signing informed consent Primary ITP diagnosed within 3 months before initiating first-line ITP therapy (corticosteroids, IVIG) Platelet count below 30 G/L before starting any first-line ITP therapy (corticosteroids, IVIG) Response (platelet count >=50 G/L) to corticosteroids (+/- IVIG) at any time prior to randomization. Note: Platelet count measured within 7 days of platelet transfusion will not be considered as response. Key Exclusion Criteria: Evans syndrome or any other cytopenia Current life-threatening bleeding Previous ITP treatment, including splenectomy, except for corticosteroids and/or IVIG initiated as first-line therapy for up to 28 days before randomization and rescue corticosteroids and/or IVIG given prior to confirmed diagnosis of primary ITP . Prior use of B-cell depleting therapy (e.g., rituximab). Absolute neutrophil count below 1.0 G/L at randomization Participants with concurrent coagulation disorders and/or receiving anti-platelet or anticoagulant medication with an exemption of low dose of acetylsalicylic acid Other protocol-defined Inclusion/Exclusion may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ianalumab Lower dose<br>Lower dose of ianalumab administered intravenously with corticosteroids oral or parental (if clinically justified) | Biological: Ianalumab<br>* Intravenously infusion, prepared from concentrate solution<br>* Other names: VAY736;Drug: Corticosteroids<br>* Oral or parental (if clinically justified)<br>|
| Experimental: Ianalumab Higher dose<br>Higher dose of ianalumab administered intravenously with corticosteroids oral or parental (if clinically justified) | Biological: Ianalumab<br>* Intravenously infusion, prepared from concentrate solution<br>* Other names: VAY736;Drug: Corticosteroids<br>* Oral or parental (if clinically justified)<br>|
| Placebo Comparator: Placebo<br>Placebo administered intravenously with corticosteroids oral or parental (if clinically justified) | Drug: Placebo<br>* Intravenously infusion, prepared from matching placebo<br>Drug: Corticosteroids<br>* Oral or parental (if clinically justified)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time from randomization to treatment failure (TTF) | Time from randomization until platelet count below 30 G/L, need for a rescue treatment or start of a second-line therapy or death. | Randomization to end of study (up to 39 months after randomization of last patient) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) rate in each treatment group | Complete Response (CR) rate at each timepoint defined as the proportion of participants with any platelet count of at least 100 G/L in the absence of rescue treatment or new ITP treatment. | Randomization to end of study (up to 39 months after randomization of last patient) | 
| Response (R) rate in each treatment group | Response (R) rate at each timepoint defined as the proportion of participants with any platelet count of at least 50 G/L in the absence of rescue treatment or new ITP treatment. | Randomization to end of study (up to 39 months after randomization of last patient) | 
| Time to complete response in each treatment group | Time from randomization to date of first complete response. | Randomization to end of study (up to 39 months after randomization of last patient) | 
| Duration of response in each treatment group | Time from achievement of complete response to loss of complete response | Randomization to end of study (up to 39 months after randomization of last patient) | 
| Stable response at 6 months | Percentage of participants with at least 2 platelet count collected at month 6 (between study dates 107 and 183) and at least 66% of platelet counts qualified as a response | At 6 months | 
| Stable response at 1 year | Percentage of participants with at least 2 platelet counts collected at year 1 (between study days 296 and 379) and at least 66% of platelet counts qualified as a response | At 1 year | 
| Percentage of participants with bleeding events overall and by World Health Organization (WHO) bleeding scale severity | This is to assess the incidence and severity of bleeding in each treatment arm | Randomization to end of study (up to 39 months after randomization of last patient) | 
| Number of participants with bleeding events overall and by World Health Organization (WHO) bleeding scale severity | This is to assess the number and severity of bleeding in each treatment arm | Randomization to end of study (up to 39 months after randomization of last patient) | 
| Number of participants receiving rescue treatment (cummulative dose/duration of steroids exposure) | This is to assess the number of participants receiving rescue treatment. | Randomization to end of study (up to 39 months after randomization of last patient) | 
| Percentage of participants receiving rescue treatment (cummulative dose/duration of steroids exposure) | This is to assess the need of rescue treatment in each treatment group by percentage. | Randomization to end of study (up to 39 months after randomization of last patient) | 
| Cumulative dose/duration of steroids exposure | Duration of exposure to corticosteroids calculated from randomization (first dose) to end of study or last last contact date (if the participant is lost to follow-up). | From screening to end of study (up to 39 months after randomization of last patient) | 
| Change from baseline on total scores of the PROMIS SF v1.0 Fatigue 13a | The Patient-Reported Outcomes Measurement Information System (PROMIS) Short Form v1.0 Fatigue 13a includes 13 items that assess fatigue | From screening (baseline) till end of study (up to 39 months after randomization of last patient) | 
| Change from baseline in ITP-PAQ domain scores | The ITP-PAQ is a 44 item scale for measuring HRQoL in adults with ITP across ten scales: Symptoms, Bother-Physical Health, Fatigue/Sleep, Activity, Fear, Psychological Health, Work, Social Activity, Women's Reproductive Health, and Overall QoL. Each item is rated on a Likert type scale | From screening (baseline) till end of study (up to 39 months after randomization of last patient) | 
| Change from baseline in frequency of CD19+ B cell counts | Post baseline frequency (%within the CD45) of CD19+ B cell counts compare to baseline. | Randomization to end of study (up to 39 months after randomization of last patient) | 
| Change from baseline in absolute number of CD19+ B cell counts | Post baseline absolute number of CD19+ B cell counts compare with baseline | Randomization to end of study (up to 39 months after randomization of last patient) | 
| Time to first occurrence of B-cell recovery | B-cell recovery, defined as ≥80% of baseline or ≥50 cells/μL | Randomization to end of study (up to 39 months after randomized of last patient) | 
| Change from baseline in inmmunoglobulins | Change from baseline in immunoglobulin levels | Randomization to end of study (up to 39 months after last randomized patients) | 
| PK parameters: AUClast | AUClast: area under the curve from time zero till the last measurable concentration sampling time (tlast) | After first dose (pre-dose, 2, 168, 336 and 504 hours post dose) and after last dose (pre-dose, 2, 336, 672, 1344, 2016, 3360 hours post dose) | 
| PK parameter: AUCtau | Area under the curve calculated to the end of a dosing interval (tau) | After first dose (pre-dose, 2, 168, 336 and 504 hours post dose) and after last dose (pre-dose, 2, 336, 672, 1344, 2016, 3360 hours post dose) | 
| PK parameters: Cmax | Maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration | After first dose (pre-dose, 2, 168, 336 and 504 hours post dose) and after last dose (pre-dose, 2, 336, 672, 1344, 2016, 3360 hours post dose) | 
| PK parameters: Tmax | Time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration | After first dose (pre-dose, 2, 168, 336 and 504 hours post dose) and after last dose (pre-dose, 2, 336, 672, 1344, 2016, 3360 hours post dose) | 
| PK parameters: Accumulation ratio Racc | Accumulation ratio calculated using AUC values obtained between the last and first dose | After last dose (pre-dose, 2, 336, 672, 1344, 2016, 3360 hours post dose) | 
| Incidence of anti-ianalumab antibodies in serum (ADA assay) over time | Anti-drug antibodies (ADA) will be evaluated in samples collected from all participants assess the immunogenicity of ianalumab | Up to Week 33 | 
| Titer of anti-ianalumab antibodies in serum (ADA assay) over time | Anti-drug antibodies (ADA) will be evaluated in samples collected from all participants assess the immunogenicity of ianalumab | Up to Week 33 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary immune thrombocytopenia (ITP), ianalumab, VAY736, B-cell depletion, B-cell Activating Factor Receptor (BAFF-R) blockade