A Study to Assess Efficacy and Safety of Eltrombopag in Combination With a Short Course of Dexamethasone in Patients With Newly Diagnosed ITP

Study Overview
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Brief Summary
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The purpose of this study is to compare the ability of eltrombopag in combination with a short course of high-dose dexamethasone to induce sustained response off treatment in patients with newly-diagnosed ITP versus 1-3 cycles of dexamethasone monotherapy. The unmet clinical need and the potential for eltrombopag when added to steroids to improve the treatment outcome and the potential to induce sustained response off treatment serve as the basis for clinical investigation of eltrombopag in first-line ITP.

Detailed Description
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This is a Phase II, multicenter, 1:1 randomized, open-label study to compare the efficacy and safety of eltrombopag in combination with a short course of high-dose dexamethasone to 1-3 cycles of high-dose dexamethasone monotherapy, as first-line treatment in adult patients with newly diagnosed ITP. Adult patients with newly diagnosed ITP who have platelet counts < 30 × 109/L and require treatment will be screened, and if eligible, will be randomized to either Arm A (eltrombopag in combination with a short course of dexamethasone) or Arm B (1-3 cycles of dexamethasone monotherapy). The study will be conducted in the following periods: Screening Period: Patients will be screened for 14 days based on the inclusion and exclusion criteria Treatment Period: Arm A: Patients will be treated for 26 weeks during the treatment period. Patients who reach platelet counts ≥ 30 × 109/L and maintain counts ≥ 30 × 109/L during the tapering phase will be eligible for treatment discontinuation. Duration of tapering before treatment discontinuation at Week 26 will be 6 weeks. Arm B: Patients will be treated up to 12 weeks during the treatment period. Patients who reach platelet counts ≥ 30 × 109/L and maintain counts ≥ 30 × 109/L after 1-3 cycles of dexamethasone treatment will be eligible for treatment discontinuation. Patients with platelet counts < 30 × 109/L after 3 cycles of dexamethasone treatment will be offered a course of eltrombopag treatment within the study and will discontinue from study at week 52. Observation period: After completion of treatment period, all patients will be observed for sustained response off treatment until week 52. Only patients with sustained response at week 52 will be followed for another 26 weeks. Patients who relapse between Week 52 and Week 78 will discontinue the study.

Official Title
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A Phase II, Randomized (1:1) Open Label Study to Assess the Efficacy and Safety of Eltrombopag in Combination With Dexamethasone Compared to Dexamethasone, as First-line Treatment in Adult Patients With Newly Diagnosed Immune Thrombocytopenia

Conditions
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Immune Thrombocytopenia (ITP)

Intervention / Treatment
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* Drug: Eltrombopag
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study. Men and women ≥ 18 years of age Newly diagnosed with primary ITP (time from diagnosis within 3 months) Platelet count < 30 × 109/L at screening and a need for treatment (per physician's discretion) Note: If pre-treatment is necessary, platelet count data performed directly before pre-treatment (can be used for study inclusion (screening value). Treatment-naïve patients will be included based on their platelet counts performed at screening Exclusion Criteria: Previous history of treatment for ITP, except any ITP-directed therapy for a maximum of 3 days within 7 days before randomization Patients with diagnosis of secondary thrombocytopenia Patients who have life threatening bleeding complications per physician´s discretion Patients with a history of thromboembolic events or known risk factors for thromboembolism Serum creatinine > 1.5 mg/dL Total bilirubin (TBIL) > 1.5 × upper limit of normal (ULN) Aspartate transaminase (AST) > 3.0 × ULN Alanine transaminase (ALT) > 3.0 × ULN Patients who are human immun deficiency virus (HIV),hepatitis C virus (HCV) or hepatitis B surface antigen (HBsAg) positive Patients with hepatic impairment (Child-Pugh score > 5) Patients with known active or uncontrolled infections not responding to appropriate therapy History of current diagnosis of cardiac disease or impaired cardiac function denoted Patients who have active malignancy Patients with evidence of current alcohol/drug abuse Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance with the study procedures 18. Female subjects who are nursing or pregnant (positive serum or urine B-human chorionic gonadotrophin (B-hCG) pregnancy test) at screening or pre-dose on Day 1 19. Women of child-bearing potential and males unwilling to use adequate contraception during the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eltrombopag + Dexamethasone<br>Patients will be treated with eltrombopag in combination with a standard high-dose dexamethasone (1 cycle: 40 mg QD from day 1-4) to induce sustained response off treatment. | Drug: Eltrombopag<br>* Eltrombopag is for oral use and comes in 25, 50 and 75 mg tablets. Prescribed dose is taken once daily.<br>* Other names: ETB115;Drug: Dexamethasone<br>* Dexamethasone is for oral use and comes in 8 mg tablets. Prescribed dose is taken once daily.<br>|
| Active Comparator: Dexamethasone<br>Patients will be treated with a standard high-dose dexamethasone (1-3 cycles: 40 mg QD day 1-4 every 14-28 days) to induce sustained response off treatment | Drug: Dexamethasone<br>* Dexamethasone is for oral use and comes in 8 mg tablets. Prescribed dose is taken once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with sustained response off treatment at 52 weeks | Sustained response off treatment at 52 weeks is defined as maintain platelet count ≥ 30 × 109/L after treatment discontinuation in the absence of bleeding events ≥ Grade II or use of any rescue medication at all visits until Week 52 | Study treatment discontinuation until week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with overall response at Week 52 | Overall response at week 52 is defined as platelet count ≥ 30 × 109/L and ≥ 2 fold increase of screeening platelets after treatment discontinuation in the absence of bleeding events ≥ Grade II and no rescue therapy at all visits until Week 52 | Study treatment discontinuation until week 52 | 
| Duration of sustained response off treatment | Duration of sustained response off treatment is defined as time of treatment discontinuation until platelet count < 30 × 109/L or bleeding events ≥ Grade II or use of any rescue therapy | Study treatment discontinuation until lost of response (up to 78 weeks) | 
| Percentage of patients with sustained response off treatment at Week 78 | Sustained response off treatment at week 78 is defined as maintain platelet count ≥ 30 × 109/L after treatment discontinuation in the absence of bleeding events ≥ Grade II or use of any rescue medication at all visits until Week 78 | Study treatment discontinuation until week 78 | 
| Overall response by Week 4 | Overall response by week 4 is defined as platelet count ≥ 30 × 109/L and ≥ 2 fold increase of screening platelet count and absence of bleeding and no rescue therapy at least once by Week 4 | Screening up to 4 weeks | 
| Complete response by Week 4 | Complete Response by week 4 is defined as platelet count ≥ 100 × 109/L and absence of bleeding and no rescue therapy at least once by Week 4 | Baseline up to 4 weeks | 
| Absolute changes in platelet count from screening to baseline and toto various time points | Absolute changes in platelet count from screening to baseline and to 1, 2, 4, 12, 26 and 52 weeks | Screening, baseline, 1, 2, 4, 12, 26, and 52 weeks | 
| Relative changes in platelet count from screening to baseline and to various time points | Relative changes in platelet count from screening to baseline and to 1, 2, 4, 12, 26, and 52 weeks | Screening, baseline, 1, 2, 4, 12, 26, and 52 weeks | 
| Time to overall response | Time to overall response is defined as time from starting study treatment to time of achievement of overall response. Overall response is defined as a platelet count ≥ 30 × 109/L and ≥ 2 fold increase of baseline platelet count and absence of bleeding and no rescue therapy | Time from starting study treatment to achievement of overall response (up to 78 weeks) | 
| Time to complete response | Time to complete response is defined as time from starting study treatment to time of achievement of complete response. Complete response is defined as a platelet count ≥ 100 × 109/L and absence of bleeding and no rescue therapy | Time from starting study treatment to achievement of complete response (up to 78 weeks) | 
| Duration of overall and complete response | Duration of overall or complete response is defined as time of achievement of overall or complete response (as defined above) until lost of overall or complete response | Achievement of overall or complete response until lost of response (up to 78 weeks) | 
| Change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionaire | The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) instrument is a 13-item validated tool used to measure an individual's level of fatigue during usual daily activities over the past 7 days. Items are scored on a 0-4 response scale (4=not at all to 0=very much) where the total possible score ranges from 0-52 (alle items are summed up to create the total score); higher scores represent better HRQoL | Baseline to 1, 2, 4, 12, 26, and 52 weeks | 
| Change from baseline in Short Form 36 Health Survey (SF-36v2) questionaire | SF-36v2 is a validated instrument with 36 questions to measure general physical and mental health status via assessment of 8 domains-Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health-over the past 4 weeks. The SF-36 is scored using norm-based scoring procedures and scores ranging from 0-100; higher scores represent better HRQoL | Baseline to 1, 2, 4, 12, 26, and 52 weeks | 
| Incidence and severity of bleeding events | Incidence and severity of bleeding assessed by the modified World Health Organization (WHO) Bleeding Scale; Bleeding is graded based on a 1-4 scale (1=minor bleeding to 4=severe bleeding) | Baseline up to 78 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ITP, Eltrombopag, Dexamethasone, Sustained response off treatment, TFR, Adult, ETB115, Platelets, Thrombocytopenic, Thrombopoietin receptor Agonist, Newly-diagnosed, Blood bleeding disorder