A Study of Efficacy and Safety of Ianalumab Versus Placebo in Addition to Eltrombopag in Primary Immune Thrombocytopenia Patients Who Failed Steroids

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 added to eltrombopag to prolong Time to Treatment Failure (TTF) in adults with primary ITP who failed previous first-line treatment with steroids.

Detailed Description
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This is a multicenter, randomized, double-blinded phase 3 study to assess efficacy and safety of two different doses of ianalumab versus placebo in addition to eltrombopag in adults with primary ITP (platelet count <30 G/L) who failed previous first-line treatment with corticosteroids. After completion of the screening period, the participants will enter the randomized treatment period (ianalumab/placebo with eltrombopag) followed by the eltrombopag tapering period. Afterwards, all participants will enter the follow-up period to be monitored for efficacy and safety or safety only depending on how the participants responded to the study treatment.

Official Title
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A Phase 3 Randomized, Double-blind Study of Ianalumab (VAY736) Versus Placebo in Addition to Eltrombopag in Patients With Primary Immune Thrombocytopenia (ITP) Who Had an Insufficient Response or Relapsed After First Line Steroid Treatment (VAYHIT2)

Conditions
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Primary Immune Thrombocytopenia

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


Participation Criteria
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Eligibility Criteria
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Key Inclusion criteria Male or female patients aged 18 years and older on the day of signing the informed consent. A signed informed consent must be obtained prior to participation in the study. A diagnosis of primary ITP, with insufficient response to, or relapse after a first-line corticosteroid therapy ± IVIG. Patient with platelet count <30G/L (whom eltrombopag is clinically indicated as per physician's discretion) and with no contraindication to receive eltrombopag Key Exclusion criteria ITP patients who received second-line ITP treatments (other than steroid therapy± IVIG) including splenectomy. However, patients exposed to thrombopoietin receptor agonists (TPO-RAs) for a limited time (max one week) before screening are eligible. Patients with key lab abnormalities and patients with Evans syndrome or any other cytopenia, (patients with low grade anemia related to bleeding or iron deficiency are eligible). Patients with history of clinically significant hematological disorders, or with marked altered hematologic parameters Patients with current or history of life-threatening bleeding Patient that are Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), Hepatitis B surface Antigen (HBsAg)/ Hepatitis B core antibody (HBcAb)-positive. HBcAb-positive patients can be enrolled if HBsAg negative, HBV DNA negative, no pre-existing liver fibrosis is present and antiviral prophylaxis is given Patients with known active or uncontrolled infection requiring systemic treatment during screening period Patients with hepatic impairment Patients with concurrent coagulation disorders and/or receiving antiplatelet or anticoagulant medication with an exemption of low dose of acetylsalicylic acid (≤150 mg daily) Female patients who are pregnant or nursing Other protocol-defined inclusion/exclusion criteria 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: Treatment arm 1<br>Participants will receive eltrombopag and ianalumab lower dose | Biological: Ianalumab<br>* Concentrate for solution for infusion for intravenous use<br>* Other names: VAY736;Drug: Eltrombopag<br>* Film-coated tablet for oral use<br>* Other names: ETB115;|
| Experimental: Treatment arm 2<br>Participants will receive eltrombopag and ianalumab higher dose | Biological: Ianalumab<br>* Concentrate for solution for infusion for intravenous use<br>* Other names: VAY736;Drug: Eltrombopag<br>* Film-coated tablet for oral use<br>* Other names: ETB115;|
| Placebo Comparator: Treatment arm 3<br>Participants will receive eltrombopag and placebo | Drug: Eltrombopag<br>* Film-coated tablet for oral use<br>* Other names: ETB115;Drug: Placebo<br>* Concentrate for solution for infusion for intravenous use.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time from randomization until treatment failure | Time from randomization until treatment failure is defined as the time from randomization date until the first of the following events indicative of treatment failure: platelet count below 30 G/L start of a new ITP treatment need for a rescue treatment ineligibility to taper or inability to discontinue eltrombopag death | Randomization to until end of study (up to 39 months after randomization of last participant) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response rate at each timepoint | Percentage of participants with any platelet count of at least 100 G/L in the absence of rescue treatment or new ITP treatment | Randomization to until end of study (up to 39 months after randomization of last participant) | 
| Response rate at each timepoint | Percentage of participants with any platelet count of at least 50 G/L in the absence of rescue treatment or new ITP treatment | Randomization to until end of study (up to 39 months after randomization of last participant) | 
| Best response rate across all timepoints | Percentage of participants with a best response rate of either response or complete response | Randomization to until end of study (up to 39 months after randomization of last participant) | 
| Time to first response/time to first complete response | Time from randomization to date of first response and time from randomization to date of first complete response | Time from randomization up to the longest observed treatment period duration | 
| Duration of response | Time from achievement of response to treatment failure Stable response at 6 months | Randomization to until end of study (up to 39 months after randomization of last participant) | 
| Stable response at 6 months | Percentage of participants with at least 3 platelet count collected at month 6 between (study days 121 and 183 and at least 75% of platelet counts qualified as a response | At 6 months | 
| Stable response at 1 year | Percentage of participants with at least 2 platelet count collected at year 1 between (study days 296 and 379 and at least 66% of platelet counts qualified as a response | At 1 year | 
| Duration of complete response | Time from achievement of complete response to loss of complete response stable response at 1 year period | Randomization to end of study (up to 39 months after randomization of last participant) | 
| Rate of participants who successfully taper and discontinue eltrombopag in each treatment arm | Probability to be treatment failure-free (as defined for the primary efficacy endpoint) | up to week 24 | 
| Percentage of participants with bleeding events according to World Health Organization (WHO) | Percentage of participants reporting bleeding events according to WHO bleeding scale | Randomization to until end of study (up to 39 months after randomization of last participant) | 
| Number of participants receiving rescue treatment | Number of participants who are in need of rescue treatment in each treatment arm | Randomization to until end of study (up to 39 months after randomization of last participant) | 
| Percentage of participants receiving rescue treatment | Percentage of participants who are in need of rescue treatment | Randomization to until end of study (up to 39 months after randomization of last participant) | 
| Change from baseline in the frequency of CD19+ B-cell counts | Post-baseline frequency of CD19+ B-cell counts (percentage within CD45) compared to baseline | Randomization to until end of study (up to 39 months after randomization of last participant) | 
| Change from baseline in the absolute number of CD19+ B-cell counts | Post-baseline absolute number of CD19+ B-cell counts compared to baseline | Randomization to until end of study (up to 39 months after randomization of last participant) | 
| Change from baseline on T-score 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 in adults. | From screening (baseline) until end of study (up 39 months after randomization of last participant) | 
| Change from baseline in ITP PAQ domain scores of symptoms, fatigue, bother (uncomfortable), activity | 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, overall QoL. Each item is rated on a Likert type scale. Each scale is scored from 0 to 100. Higher scores represent better HRQoL. | From screening (baseline) until end of study (up 39 months after randomization of last participant) | 
| Time to first occurence of B-cell recovery defined as ≥80% of baseline ≥50 cells/µL | Time to B-cell recovery defined as ≥80% of baseline or ≥50 cells/µL | Randomization to until end of study (up to 39 months after randomization of last participant) | 
| Change from baseline in immunoglobulins | Change from baseline in immunoglobulin levels | Randomization to until end of study (up to 39 months after randomization of last participant) | 
| PK parameters: AUClast | AUClast: Area under the curve from time zero to 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 parameters: AUCtau | 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 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) observed 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 after 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 assessing 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 assessing 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, eltrombopag