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

Purpura, Thrombocytopenic, Idiopathic Clinical Trial

Official title:

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>

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00540423
• Other study ID #: 108109
• Status: Completed
• Phase: Phase 3
• First received: October 5, 2007
• Last updated: March 29, 2011
• Start date: September 2007
• Est. completion date: December 2008

Study information

• Verified date: March 2011
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: Japan: Ministry of Health, Labor and Welfare
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 23
• Est. completion date: December 2008
• Est. primary completion date: December 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 20 Years and older

Eligibility

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

1. Hemoglobin: females >=9g/dL and males >=10g/dL are eligible for inclusion if hemorrhage is present.

2. 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).

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Idiopathic Thrombocytopenic Purpura
• Purpura
• Purpura, Thrombocytopenic
• Purpura, Thrombocytopenic, Idiopathic

Intervention

Drug:
• SB-497115-GR 12.5mg
SB-497115-GR 12.5mg tablet once a day
• SB-497115-GR 25mg
SB-497115-GR 25mg tablet once a day
• SB-497115-GR 12.5mg matching placebo
SB-497115-GR 12.5mg matching placebo x1 or 2 tablet once a day
• SB-497115-GR 50 mg
SB-497115-GR 25mg tablet x2 once a day

Locations

Country	Name	City	State
Japan	GSK Investigational Site	Gifu
Japan	GSK Investigational Site	Hiroshima
Japan	GSK Investigational Site	Ibaraki
Japan	GSK Investigational Site	Osaka
Japan	GSK Investigational Site	Osaka
Japan	GSK Investigational Site	Tochigi
Japan	GSK Investigational Site	Tokyo

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Pharmacokinetics of SB-497115-GR, Cmax	Cmax: Peak plasma concentration of SB-497115	Week 9 or 10	No
Secondary	Pharmacokinetics of SB-497115-GR, Tmax	tmax: Time when Cmax was achieved	Week 9 or 10	No
Secondary	Pharmacokinetics of SB-497115, t1/2	t1/2 is half life based on the terminal phase	Week 9 or 10	No
Secondary	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	No
Secondary	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-?z × [24-tlast])/?z. AUClast is AUC (area under a curve) computed to the last observation. Clast is concentration of last observation.	Week 9 or 10	No
Secondary	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	No
Secondary	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	No