Clinical Evaluation of SB-497115-GR in Chronic Idiopathic Thrombocytopenic Purpura (ITP)

Study Overview
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Brief Summary
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This is a Phase II/III multicenter study comprising of the double-blind, followed by open-label phases to evaluate and compare the efficacy and tolerability of eltrombopag (SB-497115-GR) in chronic ITP patients

Official Title
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Clinical Evaluation of SB-497115-GR in Chronic Idiopathic Thrombocytopenic Purpura (ITP) -A Multicenter Study in Subjects With Chronic ITP Receiving a Double-Blind, Placebo-Controlled, Short-Term Treatment Followed by an Open-Label, Uncontrolled, Long-Term Treatment- <Phase II/III Study>

Conditions
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Chronic Idiopathic Thrombocytopenic Purpura, Purpura, Thrombocytopenic, Idiopathic

Intervention / Treatment
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* Drug: SB-497115-GR 12.5mg
* Drug: SB-497115-GR 25mg
* Drug: SB-497115-GR 12.5mg matching placebo
* Drug: SB-497115-GR 50 mg


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Subjects eligible for enrollment in the study must meet all of the following criteria. At Screening (Week -4 or -3) Diagnosed with ITP for at least 6 months prior to screening. Have a platelet count of <30,000/µL. Previously treated refractory or relapsed patients who have failed to achieve a platelet count of >=30,000/µL despite one or more prior therapies (either H. pylori eradication, corticosteroids, splenectomy, danazol or immunosuppressive drugs). (Note: Previous H. pylori eradication must have been completed at least 3 months prior to screening and clearly be ineffective). Previous treatment for ITP with splenectomy, rituximab, and cyclophosphamide must have been completed at Week -4 and clearly be ineffective. 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 screening. A complete blood count (CBC) within the reference range, with the following exceptions Hemoglobin: females >=9g/dL and males >=10g/dL are eligible for inclusion if hemorrhage is present. Neutrophil count >=1,500/µL (1.5x109/L) is required for inclusion. The following clinical chemistries MUST NOT exceed 1.2 times the normal reference range:creatinine, ALT, AST, total bilirubin and alkaline phosphatase. Albumin must be within 80 to 120% of normal range. Subject is >=20 years old. Female subjects must either be: of non-childbearing potential (bilateral tubal ligation or post-menopausal), or of childbearing potential and have a negative pregnancy test and agree to use contraceptive methods specified in the GSK List of Highly Effective Methods for Avoidance of Pregnancy Hospitalization status: No restriction. Gender: No restriction. Subject has signed and dated written informed consent. At Randomization (Week 0) Have a platelet count of <30,000/µL. Previous therapy for ITP with immunoglobulins (IVIG and anti-D) and vincristine must have been completed at least 2 weeks prior to randomization and the platelet count must show a clear downward trend after the last treatment with immunoglobulins. Subjects treated with corticosteroids or azathioprine must be receiving a dose that has been stable for at least 4 weeks prior to randomization. Prolongation of prothrombin time and activated partial thromboplastin time (aPTT) must not exceed 1.2 times the upper limit of the normal range with no history of hypercoagulable state. (Note: These parameters will be measured at screening or at randomization.) CBC and clinical chemistries fulfill the same criteria as those at screening. Reticulocyte count within the reference range or elevated in case of bleeding. (Note: This parameter will be measured at screening or at randomization.) Exclusion criteria: Subjects meeting any of the following criteria must not be enrolled in the study. At Screening (Week -4 or -3) Any severe medical condition (cardiac, hepatic or renal disorder) other than chronic ITP. (Note: Severe is defined as >=Grade 3 as a rule according to the Classification of the Severity of Adverse Experiences (PAB/SD Notification No.80, dated 29 June 1992) (Appendix X).) History of suspected or confirmed arterial or venous thrombosis (e.g., myocardial infarction, deep vein thrombosis) within the last 1 year. History of drug/alcohol abuse or dependence within 1 year prior to screening. Previous treatment with SB-497115-GR. Suspected blood disorder other than ITP. Suspected platelet aggregation abnormality. Suspected cyclic thrombocytopenia Current or history of HIV infection or hepatitis B virus or hepatitis C virus infections. Current or history of malignancy (Exception: Subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible). Female subjects who are nursing or pregnant, who may be pregnant, or who contemplate pregnancy during the study period. Subjects who are deemed unsuitable for the study by the investigator (or sub investigator). Subjects who are participating in any other clinical trials at present or ones who previously participated in clinical trials and were treated with investigational products within last one month. At Randomization (Week 0) Subject wishes to withdraw consent. Subject is lost to follow-up. Subject has consumed anti-platelet agents (e.g., ticlopidine and aspirin), anticoagulants, or non-steroidal anti-inflammatory drugs (NSAIDs) for 7days prior to the first dose of study medication and will require these medications during the study period. Subjects who are deemed unsuitable for the study by the investigator (or sub investigator).

Ages Eligible for Study
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Minimum Age: 20 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: SB-497115-GR group<br>Subject will initiate treatment with SB-497115-GR 12.5mg once a day. Based on the subjects platelet count at each visit, the dose of SB-497115-GR may be adjusted at 12.5mg, 25mg or 50mg. | Drug: SB-497115-GR 12.5mg<br>* SB-497115-GR 12.5mg tablet once a day<br>Drug: SB-497115-GR 25mg<br>* SB-497115-GR 25mg tablet once a day<br>Drug: SB-497115-GR 50 mg<br>* SB-497115-GR 25mg tablet x2 once a day<br>* Other names: SB-497115-GR 50mg;|
| Placebo Comparator: placebo group<br>Subject will initiate treatment with SB-497115-GR 12.5mg matching placebo once a day. Based on the subjects platelet count at each visit, the dose of SB-497115-GR 12.5mg matching placebo may be increased to 2 tablet of SB-497115-GR 12.5mg matching placebo. | Drug: SB-497115-GR 12.5mg matching placebo<br>* SB-497115-GR 12.5mg matching placebo x1 or 2 tablet once a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Responders at Week 6 | A responder was defined as a participant with a platelet count within the target range (>=50 x 10^9/Liter and <=400 x 10^9/Liter). | Week 6 | 
| Percentage of Participants for Whom at Least 75% of Their Assessments During the Course of 26 Weeks of SB-497115-GR Treatment Met the Definition of Responders | A responder was defined as a participant with a platelet count within the target range (>=50 x 10^9/Liter and <=400 x 10^9/Liter). Participants receiving placebo in the double-blind phase received SB-497115-GR in the open-label phase for up to 26 weeks. Participants receiving SB-497115-GR in the double-blind phase for 7 weeks continued to receive SB-497115-GR in the open-label phase for 19 weeks. The data from these two groups were pooled as a 26 week treatment of SB-497115-GR group and analyzed for the efficacy and safety. | Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Assessed as Responders in at Least 4 Assessments Between Weeks 2 and 6 | A responder was defined as a participant with a platelet count within the target range (>=50 x 10^9/Liter and <=400 x 10^9/Liter) at at least 4 out of 5 scheduled visits. | Weeks 2 through 6 | 
| Percentage of Responders at Each Visit | A responder was defined as a participant with a platelet count within the target range (>=50 x 10^9/Liter and <=400 x 10^9/Liter). | Days 8, 15, 22, 29, 36, and 43 | 
| Mean Platelet Count at Each Visit | Blood taken from peripheral blood vessels was used for the measurement of platelet counts. | Baseline and Days 8, 15, 22, 29, 36, and 43 | 
| Mean Change From Baseline in Platelet Counts at Each Visit | Change from baseline was calculated as values at Days 8, 15, 22, 29, 36, and 43 minus baseline value | Baseline and Days 8, 15, 22, 29, 36, and 43 | 
| Percentage of Participants With Bleeding Episodes Since the Last Visit | When abnormal bleeding(s) was found since the last visit, it was recorded as a bleeding episode(s). | Days 1, 8, 15, 22, 29, 36, and 43 | 
| Number of Participants at Baseline and Days 8, 15, 22, 29, 36, and 43 of Treatment by Platelet Count Category | Blood taken from peripheral blood vessels was used for the measurement of platelet counts. | Baseline and Days 8, 15, 22, 29, 36, and 43 | 
| Percentage of Responders at Each Visit | A responder was defined as a participant with a platelet count within the target range (>=50 x 10^9/Liter and <=400 x 10^9/Liter). Participants receiving placebo in the double-blind phase received SB-497115-GR in the open-label phase for up to 26 weeks. Participants receiving SB-497115-GR in the double-blind phase for 7 weeks continued to receive SB-497115-GR in the open-label phase for 19 weeks. The data from these two groups were pooled as a 26 week treatment of SB-497115-GR group and analyzed for the efficacy and safety. | Days 8, 15, 22, 29, 36, and 43; Weeks 10, 14, 18, 22, and 26 | 
| Mean Platelet Counts of Participants at Each Visit | Blood taken from peripheral blood vessels was used for the measurement of platelet counts. Participants receiving placebo in the double-blind phase received SB-497115-GR in the open-label phase for up to 26 weeks. Participants receiving SB-497115-GR in the double-blind phase for 7 weeks continued to receive SB-497115-GR in the open-label phase for 19 weeks. The data from these two groups were pooled as a 26 week treatment of SB-497115-GR group and analyzed for the efficacy and safety. | Baseline; Days 8, 15, 22, 29, 36, and 43; Weeks 10, 14, 18, 22, and 26 | 
| Mean Change From Baseline in Platelet Counts at Each Visit | Change from baseline was calculated as values at Days 8, 15, 22, 29, 36, and 43 and Weeks 10, 14, 18, 22, and 26 minus baseline value. Participants receiving placebo in the double-blind phase received SB-497115-GR in the open-label phase for up to 26 weeks. Participants receiving SB-497115-GR in the double-blind phase for 7 weeks continued to receive SB-497115-GR in the open-label phase for 19 weeks. The data from these two groups were pooled as a 26 week treatment of SB-497115-GR group and analyzed for the efficacy and safety. | Baseline; Days 8, 15, 22, 29, 36, and 43; Weeks 10, 14, 18, 22, and 26 | 
| Mean Maximum Duration for Which Participants Maintained Platelet Counts >=50 x 10^9/Liter and <=400 x 10^9/Liter | Maximum duration is measured as the longest period (days) for which a participant continuously maintained platelet counts within the target range (>=50 x 10^9/Liter and <=400 x 10^9/Liter). Participants receiving placebo in the double-blind phase received SB-497115-GR in the open-label phase for up to 26 weeks. Participants receiving SB-497115-GR in the double-blind phase for 7 weeks continued to receive SB-497115-GR in the open-label phase for 19 weeks. The data from these two groups were pooled as a 26 week treatment of SB-497115-GR group and analyzed for the efficacy and safety. | Weeks 1 through 26 | 
| Mean Total Time for Which Participants Maintained Platelet Counts >=50 x 10^9/Liter and <=400 x 10^9/Liter | Total time is measured as the cumulative number of days over which platelet counts were maintained within the target range (>=50 x 10^9/Liter and <=400 x 10^9/Liter). Participants receiving placebo in the double-blind phase received SB-497115-GR in the open-label phase for up to 26 weeks. Participants receiving SB-497115-GR in the double-blind phase for 7 weeks continued to receive SB-497115-GR in the open-label phase for 19 weeks. The data from these two groups were pooled as a 26 week treatment of SB-497115-GR group and analyzed for the efficacy and safety. | Weeks 1 through 26 | 
| Percentage of Participants With Bleeding Episode Since the Last Visit | When abnormal bleeding(s) was found since the last visit, it was recorded as a bleeding episode(s). Participants receiving placebo in the double-blind phase received SB-497115-GR in the open-label phase for up to 26 weeks. Participants receiving SB-497115-GR in the double-blind phase for 7 weeks continued to receive SB-497115-GR in the open-label phase for 19 weeks. The data from these two groups were pooled as a 26 week treatment of SB-497115-GR group and analyzed for the efficacy and safety. | Days 1, 8, 15, 22, 29, 36, and 43; Weeks 10, 14, 18, 22, and 26 | 
| Percentage of Participants With a Reduction in Dose and/or Number of Drugs of Concomitant ITP Medications From Baseline | ITP medications are drugs, such as steroids or immunoglobulin, to be used for ITP. Participants receiving placebo in the double-blind phase received SB-497115-GR in the open-label phase for up to 26 weeks. Participants receiving SB-497115-GR in the double-blind phase for 7 weeks continued to receive SB-497115-GR in the open-label phase for 19 weeks. The data from these two groups were pooled as a 26 week treatment of SB-497115-GR group and analyzed for the efficacy and safety. | Baseline through Week 26 | 
| Percentage of Participants Who Received Rescue Treatment for ITP | Rescue treatment for ITP is treatment applied to participants at high bleeding risk, such as those undergoing platelet transfusion or dose increase of steroids. Participants receiving placebo in the double-blind phase received SB-497115-GR in the open-label phase for up to 26 weeks. Participants receiving SB-497115-GR in the double-blind phase for 7 weeks continued to receive SB-497115-GR in the open-label phase for 19 weeks. The data from these two groups were pooled as a 26 week treatment of SB-497115-GR group and analyzed for the efficacy and safety. | Weeks 1 through 26 | 
| Mean Number of Days of Concomitant ITP Medication Use Per Month | Cumulative number of days for which a participant received ITP medication during the treatment/total treatment period (months). Participants receiving placebo in the double-blind phase received SB-497115-GR in the open-label phase for up to 26 weeks. Participants receiving SB-497115-GR in the double-blind phase for 7 weeks continued to receive SB-497115-GR in the open-label phase for 19 weeks. The data from these two groups were pooled as a 26 week treatment of SB-497115-GR group and analyzed for the efficacy and safety. | Weeks 1 through 26 | 
| Pharmacokinetics of SB-497115-GR, Cmax | Cmax: Peak plasma concentration of SB-497115 | Week 9 or 10 | 
| Pharmacokinetics of SB-497115-GR, Tmax | tmax: Time when Cmax was achieved | Week 9 or 10 | 
| Pharmacokinetics of SB-497115, t1/2 | t1/2 is half life based on the terminal phase | Week 9 or 10 | 
| Pharmacokinetics of SB-497115-GR, Lambda z | Lambda z is first order rate constant associated with the terminal portion of the plasma concentration curve. | Week 9 or 10 | 
| Pharmacokinetics of SB-497115-GR, AUClast and AUC0-24 | AUC is area under a concentration vs. time curve. AUC0-24 (Area under the plasma concentration-time curve between 0 to 24 hrs) is calculated using the following equation: AUC0-24= AUClast + Clast × (1 - e-λz × [24-tlast])/λz. AUClast is AUC (area under a curve) computed to the last observation. Clast is concentration of last observation. | Week 9 or 10 | 
| Pharmacokinetics of SB-497115-GR, CL/F | CL/F: CL is an estimate of the total body clearance, and F is the fraction of dose absorbed. | Week 9 or 10 | 
| Pharmacokinetics of SB-497115-GR, Vz/F | VZ/F: VZ is the volume of distribution based on the terminal phase, and F is the fraction of dose absorbed. | Week 9 or 10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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thrombopoietin,, immunosuppressive therapy,, eltrombopag,, idiopathic thrombocytopenic purpura,, blood platelet,, splenectomy