RAISE: Randomized Placebo-Controlled Idiopathic Thrombocytopenic Purpura (ITP) Study With Eltrombopag

Study Overview
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Brief Summary
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The rationale for this Phase III study is to evaluate the 6 month safety and efficacy of eltrombopag in the treatment of previously treated subjects with chronic ITP. The starting dose of eltrombopag, 50 mg, once daily was selected based upon the observed efficacy, safety and pharmacokinetics in a dose-finding Study (TRA100773). This Phase III study is a randomized, double-blind, placebo-controlled, Phase III study, to evaluate efficacy, safety and tolerability of eltrombopag, initially administered as 50 mg oral tablets once daily for six months in adult subjects with previously treated chronic ITP. Subjects will be randomized 2:1, eltrombopag to placebo, and will be stratified based upon splenectomy status, use of ITP medication at baseline and baseline platelet count less than or equal to 15,000/µL. Subjects will receive study medication for 6 months, during which the dose of study medication may be adjusted based upon individual platelet counts. In addition, subjects may taper off concomitant ITP medications and may receive any rescue treatments as dictated by local standard of care. After discontinuation of study medication, subjects will complete follow-up visits at weeks 1, 2, 4 and months 3 and 6.

Detailed Description
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A randomized, double-blind, placebo-controlled phase III study, to evaluate the efficacy, safety and tolerability of eltrombopag olamine (SB-497115-GR), a thrombopoietin receptor agonist, administered for 6 months as oral tablets once daily in adult subjects with previously treated chronic idiopathic thrombocytopenic purpura (ITP).

Official Title
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A Randomized, Double-blind, Placebo-controlled Phase III Study, to Evaluate the Efficacy, Safety and Tolerability of Eltrombopag Olamine (SB-497115-GR), a Thrombopoietin Receptor Agonist, Administered for 6 Months as Oral Tablets Once Daily in Adult Subjects With Previously Treated Chronic ITP.

Conditions
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Purpura, Thrombocytopaenic, Idiopathic

Intervention / Treatment
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* Drug: eltrombopag
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: A subject will be eligible for inclusion in this study only if all of the following criteria apply: Subject has signed and dated a written informed consent. Adults (≥18 years) diagnosed with chronic ITP according to the American Society for Hematology/British Committee for Standards in Hematology (ASH/BCSH) guidelines [George, 1996; BCSH, 2003], and platelet count < 30,000/μL on Day 1 (or within 24 hours prior to dosing on Day 1). In addition, a peripheral blood smear should support the diagnosis of ITP with no evidence of other causes of thrombocytopenia (e.g. pseudothrombocytopenia, myelofibrosis). The physical examination should not suggest any disease which may cause thrombocytopenia other than ITP. Subjects who have previously received one or more prior ITP therapies. Previous treatments for ITP include but are not limited to corticosteroids, immunoglobulins, azathioprine, danazol, cyclophosphamide and/or rituximab. Subjects must have either initially responded (platelet count > 100,000/μL) to a previous ITP therapy or have had a bone marrow examination consistent with ITP within 3 years to rule out myelodysplastic syndromes or other causes of thrombocytopenia. Previous therapy for ITP with immunoglobulins (IVIg and anti-D) must have been completed at least 1 week prior to randomization and the platelet count must show a clear downward trend after the last treatment with immunoglobulins. Previous treatment for ITP with splenectomy, rituximab and cyclophosphamide must have been completed at least 4 weeks prior to randomization, or clearly be ineffective. Subjects treated with concomitant ITP medication (e.g. corticosteroids or azathioprine) must be receiving a dose that has been stable for at least 4 weeks prior to randomization. Subjects treated with cyclosporine A, mycophenolate mofetil or danazol must be receiving a dose that has been stable for at least 3 months prior to randomization. The medication should be continued with a stable dose for the initial 6 weeks of study Concomitant ITP Therapy) Prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) must be within 80 to 120% of the normal range with no history of hypercoagulable state. A complete blood count (CBC), within the reference range (including WBC differential not indicative of a disorder other than ITP), with the following exceptions: < 30,000 platelets/μL on Day 1 (or within 24 hours of Day 1) is required for inclusion, Hemoglobin: Subjects with hemoglobin levels between 10 g/dL (100 g/L) and the lower limit of normal are eligible for inclusion, if anemia is clearly attributable to ITP (excessive blood loss). ANC ≥ 1500/μL (1.5 x 10^9/L) is required for inclusion (elevated WBC/ANC due to steroid treatment is acceptable). The following clinical chemistries MUST NOT exceed the upper limit of normal (ULN) reference range by more than 20%: creatinine, ALT, AST, total bilirubin, and alkaline phosphatase. In addition, total albumin must not be below the lower limit of normal (LLN) by more than 10%. Subject is practicing an acceptable method of contraception (documented in chart). Female subjects (or female partners of male subjects) must either be of non-childbearing potential (hysterectomy, bilateral oophorectomy, bilateral tubal ligation or post-menopausal > 1 year), or of childbearing potential and use one of the following highly effective methods of contraception (i.e., Pearl Index <1.0%) from two weeks prior to administration of study medication, throughout the study, and 28 days after completion or premature discontinuation from the study: Complete abstinence from intercourse; Intrauterine device (IUD); Two forms of barrier contraception (diaphragm plus spermicide, and for males condom plus spermicide); Male partner is sterile prior to entry into the study and is the only partner of the female; Systemic contraceptives (combined or progesterone only). Subject is able to understand and comply with protocol requirements and instructions and intends to complete the study as planned. Exclusion criteria: A subject will NOT be eligible for inclusion in this study if any of the following criteria apply: Any clinically relevant abnormality, other than ITP, identified on the screening examination or any other medical condition or circumstance, which in the opinion of the investigator makes the subject unsuitable for participation in the study or suggests another primary diagnosis (e.g., thrombocytopenia is secondary to another disease). Concurrent malignant disease and/or history of cancer treatment with cytotoxic chemotherapy and/or radiotherapy. Any prior history of arterial or venous thrombosis (stroke, transient ischemic attack, myocardial infarction, deep vein thrombosis or pulmonary embolism), AND ≥ two of the following risk factors: hormone replacement therapy, systemic contraception (containing estrogen), smoking, diabetes, hypercholesterolemia, medication for hypertension, cancer, hereditary thrombophilic disorders (e.g., Factor V Leiden, ATIII deficiency, etc), or any other family history of arterial or venous thrombosis. Pre-existing cardiovascular disease (congestive heart failure, New York Heart Association [NYHA] Grade III/IV), or arrhythmia known to increase the risk of thromboembolic events (e.g. atrial fibrillation), or subjects with a QTc >450 msec. Female subjects who are nursing or pregnant (positive serum or urine b-human chorionic gonadotrophin pregnancy test) at screening or pre-dose on Day 1. History of alcohol/drug abuse. Treatment with an investigational drug within 30 days or five half-lives (whichever is longer) preceding the first dose of study medication. Subject treated with drugs that affect platelet function (including but not limited to aspirin, clopidogrel and/or NSAIDs) or anti-coagulants for > 3 consecutive days within 2 weeks of the study start and until the end of the study. History of platelet agglutination abnormality that prevents reliable measurement of platelet counts. All subjects with secondary immune thrombocytopenia, including those with laboratory or clinical evidence of HIV infection, anti-phospholipid antibody syndrome, chronic hepatitis B infection, hepatitis C virus infection, or any evidence for active hepatitis at the time of subject screening. If a potential subject has no clinical history that would support HIV infection or hepatitis infection, no further laboratory screening is necessary; however, standard medical practice would suggest further evaluation of patients who have risk factors for these infections. Previous participation in a clinical study with eltrombopag. Patients planning to have cataract surgery. In France, a subject is neither affiliated with nor a beneficiary of a social security category.

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 plus standard of care<br>Subjects will initiate treatment with 50 mg eltrombopag or matching placebo once daily. Based upon the subjects platelet count at each visit, the dose of eltrombopag may be adjusted either up or down. | Drug: eltrombopag<br>* Subjects will initiate treatment with either 50 mg eltrombopag or matching placebo once daily. Based upon the subjects platelet count at each visit, the dose of eltrombopag may be adjusted either up or down.<br>|
| Placebo Comparator: placebo plus standard of care<br>Subjects will initiate treatment with 50 mg eltrombopag or matching placebo once daily. Based upon the subjects platelet count at each visit, the dose of eltrombopag may be adjusted either up or down. | Drug: Placebo<br>* Subjects will initiate treatment with either 50 mg eltrombopag or matching placebo once daily. Based upon the subjects platelet count at each visit, the dose of eltrombopag may be adjusted either up or down<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Responders | The percentage of evaluable participants who achieved a platelet response (defined as a platelet count between 50,000 and 400,000 microliter) at each nominal on-therapy day and 4 weeks post-treatment | Baseline; each on-therapy treatment day; Weeks 10, 14, 18, 22, and 26; and Weeks 1, 2, and 4 post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of Median Platelet Counts | Platelet counts were measured by blood draw. | Baseline; Day 8 through Week 26 on-treatment; and 1, 2, 4 week follow-up visits | 
| Percentage of Participants Initiating Rescue Treatment On-therapy | Percentage of participants initiating new ITP medication, an increased dose of concomitant ITP medication from baseline, platelet transfusion, or splenectomy. | Anytime from Day 1 to Week 26 | 
| Maximum and Total Weeks of Platelet Response | Response is defined as a platelet count between 50,000 and 400,000 platelets per microliter. | Day 1 through Week 26 on-treatment | 
| Percentage of Participants With a Reduction in Use of Baseline ITP Medication | Percentage of participants who experienced a reduction in their baseline concomitant ITP medication use | From Day 1 through Week 26 on-treatment | 
| WHO Bleeding Scale | Summary of World Health Organization (WHO) bleeding scores at each nominal visit. WHO Grades 1-4 = any bleeding; WHO Grades 2-4 = clinically significant bleeding | Baseline, all nominal visits on-therapy defined as Day 8, Day 15, Day 22, Day 29, Day 36, Day 43, Week 10, Week 14, Week 18, Week 22, Week 26, and 1, 2 and 4 week follow-up visits | 
| HR-QoL Instrument and Domain Scores From the SF-36v2 Questionnaire at Baseline, Week 6, Week 14, and Week 26 or Early Discontinuation From Study Treatment | Health-related quality of life (HR-QoL) patient reported outcomes from the short form-36v2 (SF-36v2) questionnaire. Scores could range from 0 (worst possible) to 100 (best possible). | Baseline, Week 6, Week 14, and Week 26/Early Withdrawal | 
| HR-QoL Instrument and Domain Scores From the FACIT-F Questionnaire at Baseline, Week 6, Week 14, and Week 26 or Early Discontinuation From Study Treatment | Health-related quality of life (HR-QoL) patient reported outcomes from the functional assessment of chronic illness therapy fatigue (FACIT-F) questionnaire. Scores could range from 0 (worst possible) to 52 (best possible). | Baseline, Week 6, Week 14, and Week 26/Early Withdrawal | 
| HR-QoL Instrument and Domain Scores for the FACT-Th Questionnaire at Baseline, Week 6, Week 14, and Week 26 or Early Discontinuation From Study Treatment | Health-related quality of life (HR-QoL) patient reported outcomes from the functional assessment of cancer therapy thrombocytopenia (FACT-Th) questionnaire (six selected items). Scores could range from 0 (worst possible) to 24 (best possible). | Baseline, Week 6, Week 14, and Week 26/Early Withdrawal | 
| HR-QoL Instrument and Domain Scores From the MEI-SF Questionnaire at Baseline, Week 6, Week 14, and Week 26 or Early Discontinuation From Study Treatment | Health-related quality of life (HR-QoL) patient reported outcomes from the motivation and energy inventory-short form (MEI-SF) questionnaire. Scores could range from 0 (worst possible) to 72 (best possible). | Baseline, Week 6, Week 14, and Week 26/Early Withdrawal | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ITP, idiopathic, platelets, purpura, thrombocytopenia, Idiopathic Thrombocytopenic Purpura, thrombocytopenic