Eltrombopag Phase III Study In Chinese Chronic ITP Patients

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01762761
First received: December 19, 2012
Last updated: March 26, 2015
Last verified: March 2015
  Purpose

This randomized, double-blind and open-label phase III study is aimed to determine the efficacy, tolerance and safety of eltrombopag in Chinese chronic primary immune thrombocytopenia (ITP) adult subjects. This study will be conducted in Chinese adult chronic ITP subjects who have not responded to or have relapsed after previous treatment for ITP, including first line therapy and /or splenectomy.

The primary objective of this study is to determine the efficacy of oral eltrombopag as a thrombopoietic agent treating previously treated chronic Chinese ITP patients comparing with placebo. The secondary objective is to assess the safety and tolerability of eltrombopag when administered for 6 weeks to previously treated adult chronic ITP patients comparing with the placebo. In addition, the long-term efficacy and safety of eltrombopag treatment will be also evaluated in the 24-week extension open-label phase after the double-blind phase as one of other study objectives. If the subject benefits from the eltrombopag treatment based on investigator's discretion, the subject can continue eltrombopag treatment until the commercial launch of eltrombopag in China. Furthermore, to understand the pharmacokinetics (PK) profile of eltrombopag and to explore the relationship between the PK and pharmacodynamics (PD) (platelet response), a PK/PD analysis will be embedded in this phase III study and conducted in the same patient population participated this phase III study.


Condition Intervention Phase
Purpura, Thrombocytopenic, Idiopathic and Hepatitis C
Drug: eltrombopag
Drug: placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Double-Blind and Open-label Phase III Study To Compare The Efficacy And Safety Of Eltrombopag With Placebo In Chinese Chronic ITP Patients

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of Participants (Responders) Achieving a Platelet Count >=50×10^9/L After the First 6 Weeks of Stage 1 [ Time Frame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1 ] [ Designated as safety issue: No ]
    The number of participants (responders) with platelet count >=50x10^9/L after 6 weeks of Stage 1 were compared between treatments using a logistic regression model adjusted for use of primary immune thrombocytopenia (ITP) medication at Baseline (yes/no), splenectomy (yes/no), Baseline platelet count <=15×10^9/L (yes/no) and treatment. Complete blood count including platelet count was done at Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6. Primary Analysis Data Set: a participant who withdrawals from Stage 1 or is emergently unblinded was classified as a negative response from the time of withdrawal or unblinding date and for all subsequent visits. In the event of a participant dying, information for all subsequent assessments would be considered missing. All intermittent missing data (apart from withdrawals) will be treated as missing.


Secondary Outcome Measures:
  • Number of Participants Achieving a Platelet Count >=50×10^9/L at Least Once During the First 6 Weeks of Stage 1 [ Time Frame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1 ] [ Designated as safety issue: No ]
    The number of participants (responders) with platelet count >=50×10^9/L at least once during the first 6 weeks of Stage 1 were compared between treatments using a logistic regression model adjusted for use of ITP medication at Baseline (yes/no), splenectomy (yes/no), Baseline platelet count <=15×10^9/L (yes/no) and treatment. Complete blood count including platelet count was done at Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6.

  • Number of Participants Achieving a Platelet Count >=30×10^9/L and at Least 2 Times the Baseline Platelet Count at Least Once During the 6 Weeks of Stage 1 [ Time Frame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1 ] [ Designated as safety issue: No ]
    The number of participants achieving a platelet count >=30×10^9/L and at least 2 times the Baseline platelet count at least once during the first 6 weeks of Stage 1 were analyzed. The Baseline platelet count is defined as the platelet count taken on Day 1 of the study or within 48 hours prior to the first dose of investigational product. Logistic regression analysis was adjusted for use of ITP medication at Baseline (yes/no), splenectomy (yes/no), Baseline platelet count <=15×10^9/L (yes/no) and treatment. Complete blood count including platelet count was done at Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6.

  • Number of Participants With Bleeding as Assessed Using the World Health Organization (WHO) Bleeding Scale [ Time Frame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1 ] [ Designated as safety issue: No ]
    The WHO Bleeding Scale is a measure of bleeding severity with the following grades: grade 0 = no bleeding, grade 1= petechiae, grade 2= mild blood loss, grade 3 = gross blood loss, and grade 4 = debilitating blood loss. The WHO Bleeding Scale were dichotomized to indicate no bleeding vs bleeding, i.e. 0=grade 0 and 1=grades 1, 2, 3 or 4. Generalized linear mixed model was applied with a Logit canonical link function for repeated binary data, allowing for Baseline dichotomized WHO bleeding grade, use of ITP medication at Baseline (yes/no), splenectomy (yes/no), Baseline platelet count <=15×10^9/L (yes/no) and treatment as fixed effects, and the participant was treated as a random effect. Bleeding incidences were recorded at Screening, Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6. All Bleeding incidences at each visit are presented.

  • Number of Participants With Clinically Significant Bleeding as Assessed Using the World Health Organization (WHO) Bleeding Scale [ Time Frame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1 ] [ Designated as safety issue: No ]
    The WHO Bleeding Scale is a measure of bleeding severity with the following grades: grade 0 = no bleeding, grade 1= petechiae, grade 2= mild blood loss, grade 3 = gross blood loss, and grade 4 = debilitating blood loss. The WHO Bleeding Scale grades were dichotomized into the following categories: no clinically significant bleeding = Grade 0 to 1; clinically significant bleeding = Grade 2 to 4. Generalized linear mixed model with a Logit canonical link function for repeated binary data, allowing for Baseline dichotomized WHO bleeding grade, use of ITP medication at Baseline (yes/no), splenectomy (yes/no), Baseline platelet count <=15×10^9/L (yes/no) and treatment as fixed effects, and the participant was treated as a random effect.

  • Time to Response [ Time Frame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1 ] [ Designated as safety issue: No ]
    Time to response is defined as time from the startin of treatment to the first time of achieving a platelet count >=50x10^9/L during the first 6 weeks of Stage 1. Time to response is summarized using Kaplan-Meier estimates and compared between treatment groups using a stratified log-rank test, stratifying for the use of ITP medication at Baseline (yes/no), splenectomy (yes/no), Baseline platelet count <=15x10^9/L (yes/no). The pike estimator of the treatment hazard ratio is based on the stratified log-rank test. Complete blood count including platelet count was done at Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6.

  • Number of Participants Who Required Protocol-defined Rescue Treatment During the First 6 Weeks of Stage 1 [ Time Frame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1 ] [ Designated as safety issue: No ]
    Rescue treatment is defined as either a new ITP medication, an increase in dose of concomitant ITP medication from Baseline, a platelet transfusion, or a splenectomy. Logistic regression analysis was adjusted for use of ITP medication at Baseline (yes/no), splenectomy (yes/no), Baseline platelet count <=15x10^9/L (yes/no) and treatment.

  • Number of Participants With a Platelet Count >=50×10^9/L During at Least 75% of Their Platelet Count Assessments [ Time Frame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1 ] [ Designated as safety issue: No ]
    The number of participants with a platelet count >=50×10^9/L during at least 75% of their platelet count assessments was analyzed up to the end of Week 6 of Stage 1. Logistic regression analysis was adjusted for use of ITP medication at Baseline (yes/no), splenectomy (yes/no), Baseline platelet count <=15x10^9/L (yes/no) and treatment. Complete blood count including platelet count was done at Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6.

  • Total Duration of Time a Participant Had a Platelet Count >=50×10^9/L [ Time Frame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1 ] [ Designated as safety issue: No ]
    Total duration of time a participant had platelet count >=50 x 10^9/L was analyzed using the van Elteren stratified rank test with stratification factors including the use of ITP medication at Baseline (yes/no), splenectomy (yes/no) and Baseline platelet count <=15x10^9/L (yes/no). Complete blood count including platelet count was done at Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6.

  • Maximum Period of Time a Participant Had a Platelet Count Continuously >= 50 ×10^9/L [ Time Frame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1 ] [ Designated as safety issue: No ]
    Maximum period of time a participant had a platelet count continously >=50 x 10^9/L was analyzed using the van Elteren stratified rank test with stratification factors including the use of ITP medication at Baseline (yes/no), splenectomy (yes/no) and Baseline platelet count <=15x10^9/L (yes/no). Complete blood count including platelet count was done at Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6.

  • Number of Participants That Reduced or Discontinued Baseline Concomitant ITP Medications During Stage 2 and Stage 3 [ Time Frame: From the start of Week 1 of Stage 2 to the end of last week of Stage 3 ] [ Designated as safety issue: No ]
    The number of participants taking concomitant ITP medications on Day 1 of Stage 1 who had a decrease in the dose or frequency of ITP medication or stopped ITP medication at any point during Stage 2 or Stage 3 will be presented. The Baseline concomitant ITP medication for Stage 2 and Stage 3 is defined as ITP medications taken prior to the first dose of investigational product of Stage 1. This study is still ongoing and this endpoint can only be analyzed when the stage 2 and stage 3 complete.

  • Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) [ Time Frame: From the start of study treatment (Day 1) up to the end of Week 8 of Stage 1 ] [ Designated as safety issue: No ]
    An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product whether or not considered related to the medicinal product.A SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, is a congenital anomaly/birth defect or is associated with protocol specified liver injury and impaired liver function or is any protocol specific AEs.

  • Number of Participants With the Maximum Toxicity Grade for the Indicated Clinical Chemistry Parameters [ Time Frame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1 ] [ Designated as safety issue: No ]
    Clinical chemistry parameters aspartate amino transferase (AST), alanine amino transferase (ALT), gamma glutamyl transferase (GGT), total bilirubin, albumin, alkaline phosphatase, calcium, potassium, creatinine, glucose and sodium were evaluated at Baseline, at all on therapy visits, and at Week 1, Week 2, Week 3, and Week 4 visits during the follow-up period and were summarized according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4 (NCI CTCAE V4.0): Grade 0, none; Grade 1, mild; Grade 2, moderate; Grade 3, severe or medically significant; Grade 4, life-threatening consequences; Grade 5, death related to AE. Day 1 assessment was considered as Baseline; if Day 1 was not available then Screening assessment is taken as Baseline. For creatinine, Baseline is defined as the average of Screening and Day 1 values if available and prior to first dose. Maximum post-Baseline toxicity grade included any scheduled or unscheduled post-Baseline assessment

  • Number of Participants With the Maximum Toxicity Grade for the Indicated Hematology Parameters [ Time Frame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1 ] [ Designated as safety issue: No ]
    Clinical hematology parameters hemoglobin, lymphocytes, platelet count, total neutrophils, white blood cell count evaluations were performed at Baseline, at all on-therapy visits, and at Week 1, Week 2, Week 3, and Week 4 visits during the follow-up period and were summarized according to the NCI CTCAE V4.0: Grade 0, none; Grade 1, mild; Grade 2, moderate; Grade 3, severe or medically significant; Grade 4, life-threatening consequences; Grade 5, death related to AE. Day 1 assessment was considered as Baseline; if Day 1 was not available then Screening assessment is taken as Baseline. Maximum post-Baseline toxicity grade included any scheduled or unscheduled post-Baseline assessment.

  • Change From Baseline in Systolic Blood Pressure [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6 ] [ Designated as safety issue: No ]
    Systolic blood pressure was measured in the sitting position at Baseline, Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6. Day 1 assessment was considered as Baseline; if Day 1 was not available then the Screening assessment was considered as Baseline. Change from Baseline was calculated as the value at post-Baseline time point minus the value at Baseline.

  • Change From Baseline in Diastolic Blood Pressure [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6 ] [ Designated as safety issue: No ]
    Diastolic blood pressure was measured in sitting position at Baseline, Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6. Day 1 assessment was considered as Baseline; if Day 1 was not available then the Screening assessment was considered as Baseline. Change from Baseline was calculated as the value at post-Baseline time point minus the value at Baseline.

  • Change From Baseline in Pulse Rate [ Time Frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6 ] [ Designated as safety issue: No ]
    Pulse rate was measured at Baseline, Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6. Day 1 assessment was considered as Baseline; if Day 1 was not available then the Screening assessment was considered as Baseline. Change from Baseline was calculated as the value at post-Baseline time point minus the value at Baseline.

  • Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Finding at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Resting 12-lead ECG was obtained at Baseline. Day 1 assessment was considered as Baseline; if Day 1 was not available then the Screening assessment was considered as Baseline. ECG was also obtained when there was clinical symptom that potentially related to cardiac dysfunction based on investigator's judgement.

  • Number of Participants With a Change From Baseline in Visual Acuity [ Time Frame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1 ] [ Designated as safety issue: No ]
    Visual acuity is a measure of the spatial resolution of the visual processing system. Acuity is a measure of visual performance and is unrelated to the eyeglass prescription required to correct vision. Normal visual acuity is commonly referred to as 20/20 vision. Evaluation was done for oculus sinister (OS) for the left eye, oculus dexter (OD) for the right eye. Change from Baseline was calculated as the value at post-Baseline time point minus the value at Baseline.

  • Number of Participants With the Indicated Grading of Myelofibrosis Using Bone Marrow Biopsy at Screening [ Time Frame: Screening ] [ Designated as safety issue: No ]
    Bone marrow biopsy was performed at Screening and then obtained when clinically indicated. Whenever a peripheral blood smear confirmed the presence of immature or dysplastic cells, a bone marrow examination was performed. Myelofibrosis (MF) was graded from Grade MF-0 to MF-3 where MF-0=scattered linear reticulin with no intersections (cross-overs) corresponding to normal bone marrow; MF-1=loose network of reticulin with many intersections; especially in perivascular areas; MF-2=diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis; MF-3=diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis.

  • Pharmacokinetic (PK) Assessments for Eltrombopag for Apparent Volume of Distribution of Central Compartment (Vc/F), Apparent Volume of Distribution of Peripheral Compartment (Vp/F) [ Time Frame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2 ] [ Designated as safety issue: No ]
    Vc/F is apparent volume of distribution of plasma (VDP) in central compartment and Vp/F is apparent VDP in peripheral compartment. PK assessments were made with one group of serial sampling [Samples collected at pre-dose and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 24 hr post-dose] and one group of sparse assessment [Samples collected at pre-dose, between 2 to 4 hr and 5 to 8 hr post-dose]. Pre-dose samples were collected within 2 hr prior to dosing, all other samples were collected within 10 minutes(min) for samples collected between 1 and 6 hrs and within 30 mins for samples collected at 8 and 24 hr. PK analysis was conducted using a population approach with non-linear mixed effects modeling methods. Point estimates of population PK parameters are presented.

  • Pharmacokinetic Assessments for Eltrombopag for Apparent Clearance (CL/F), Apparent Inter-compartmental Clearance (Q/F) [ Time Frame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2 ] [ Designated as safety issue: No ]
    CL/F is defined as the apparent oral clearance from plasma and Q/F is defined as apparent intercompartmental clearance. PK assessments were made with one group of serial sampling [Samples collected at pre-dose and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 24 hr post-dose] and one group of sparse assessment [Samples collected at pre-dose, between 2 to 4 hr and 5 to 8 hr post-dose]. Pre-dose samples were collected within 2 hr prior to dosing, all other samples were collected within 10 min for samples collected between 1 and 6 hr and within 30 min for samples collected at 8 and 24 hr. PK analysis was conducted using a population approach with non-linear mixed effects modeling methods. Point estimates of population PK parameters are presented.

  • Pharmacokinetic Assessments for Eltrombopag for Absorption Rate Constant (Ka) [ Time Frame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2 ] [ Designated as safety issue: No ]
    Ka is defined as the absorption rate constant. PK assessments were made with one group of serial sampling [Samples collected at pre-dose and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 24 hr post-dose] and one group of sparse assessment [Samples collected at pre-dose, between 2 to 4 hr and 5 to 8 hr post-dose]. Pre-dose samples were collected within 2 hrs prior to dosing, all other samples were collected within 10 min for samples collected between 1 and 6 hrs and within 30 mins for samples collected at 8 and 24 hr. PK analysis was conducted using a population approach with non-linear mixed effects modeling methods. Point estimates of population PK parameter is presented.

  • Pharmacokinetic Assessments for Eltrombopag for Absorption Lag Time (ALAG) [ Time Frame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2 ] [ Designated as safety issue: No ]
    Absorption lag time (ALAG) is defined as the time taken for a drug to appear in the systemic circulation following administration. PK assessments were made with one group of serial sampling [Samples collected at pre-dose and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 24 hr post-dose] and one group of sparse assessment [Samples collected at pre-dose, between 2 to 4 hrs and 5 to 8 hrs post-dose]. Pre-dose samples were collected within 2 hrs prior to dosing, all other samples were collected within 10 min for samples collected between 1 and 6 hr and within 30 min for samples collected at 8 and 24 hr. PK analysis was conducted using a population approach with non-linear mixed effects modeling methods. Point estimates of population PK parameter is presented.

  • Post-hoc Estimates of Plasma Eltrombopag Area Under the Concentration-time Curve Over a Dosing Interval (AUC[0-tau]) After 50 mg Once Daily Dose of Eltrombopag [ Time Frame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2 ] [ Designated as safety issue: No ]
    AUC[0-tau] is defined as area under the concentration-time curve over a dosing interval (24 hr) of Eltrombopag atsteady-state after 50 mg once daily dose of eltrombopag. PK analysis was conducted using a population approach with non-linear mixed effects modeling methods. Post-hoc estimates of steady-state eltrombopag was determined based on the final PK model. Individual PK parameters were derived from the final PK model by an empirical Bayes estimation. Summary of steady-state AUC(0-tau) of eltrombopag is presented here.

  • Post-hoc Estimates of Maximum Observed Concentration (Cmax) for Eltrombopag After 50 mg Once Daily Dose of Eltrombopag [ Time Frame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2 ] [ Designated as safety issue: No ]
    Cmax is defined as maximum observed concentration after 50 mg once daily dose of eltrombopag. PK analysis was conducted using a population approach with non-linear mixed effects modeling methods. Post-hoc estimates of steady-state eltrombopag Cmax was determined based on the final PK model. Individual PK parameters were derived from the final PK model by an empirical Bayes estimation. Summary of steady-state Cmax of eltrombopag .is presented here.

  • Percentage of Participants Estimated as Responders to Eltrombopag by the Pharmacokinetic/ Pharmacodynamic Model [ Time Frame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2 ] [ Designated as safety issue: No ]
    Responders are participants whose SLOP estimates are larger than zero. The Pharmacokinetic/ Pharmacodynamic relationship between eltrombopag concentrations and the platelet response was described by a four-compartment life span model, representing one precursor production compartment, two transit/maturation compartments and one blood platelet compartment.

  • Pharmacodynamic Parameter-Linear Proportionality Constant of Drug Effect (SLOP): the Proportional Increase of Platelet Production Rate With Each 1-μg/mL Increase in Eltrombopag Plasma Concentration [ Time Frame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2 ] [ Designated as safety issue: No ]
    The Pharmacokinetic/ Pharmacodynamic relationship between eltrombopag concentrations and the platelet response was described by a four-compartment life span model, representing one precursor production compartment, two transit/maturation compartments and one blood platelet compartment.

  • Pharmacodynamic Parameter- Production Rate of Platelet Precursors (KIN) [ Time Frame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2 ] [ Designated as safety issue: No ]
    The Pharmacokinetic/ Pharmacodynamic relationship between eltrombopag concentrations and the platelet response was described by a four-compartment life span model, representing one precursor production compartment, two transit/maturation compartments and one blood platelet compartment. The estimate of KIN was fixed to 1.43x10^9/L.hr.

  • Pharmacodynamic Parameter-Maturation Rate of Platelet Precursors (KOUT) [ Time Frame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2 ] [ Designated as safety issue: No ]
    The Pharmacokinetic/ Pharmacodynamic relationship between eltrombopag concentrations and the platelet response was described by a four-compartment life span model, representing one precursor production compartment, two transit/maturation compartments and one blood platelet compartment. The estimate of KOUT was fixed to 0.0253 /hr.


Enrollment: 155
Study Start Date: February 2013
Estimated Study Completion Date: July 2017
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Eltrombopag
Thrombopoietin- receptor (TPO-R) agonist
Drug: eltrombopag
TPO-R agonist
Other Name: revolade
Placebo Comparator: Placebo
Placebo
Drug: placebo
placebo
Other Name: no other name

Detailed Description:

This randomized, double-blind and open-label phase III study is aimed to determine the efficacy, tolerance and safety of eltrombopag in Chinese chronic primary immune thrombocytopenia (ITP) adult subjects. This study will be conducted in Chinese adult chronic ITP subjects who have not responded to or have relapsed after previous treatment for ITP, including first line therapy and /or splenectomy.

The primary objective of this study is to determine the efficacy of oral eltrombopag as a thrombopoietic agent treating previously treated chronic Chinese ITP patients comparing with placebo. The secondary objective is to assess the safety and tolerability of eltrombopag when administered for 6 weeks to previously treated adult chronic ITP patients comparing with the placebo. In addition, the long-term efficacy and safety of eltrombopag treatment will be also evaluated in the 24-week extension open-label phase after the double-blind phase as one of other study objectives. If the subject benefits from the eltrombopag treatment based on investigator's discretion, the subject can continue eltrombopag treatment until the commercial launch of eltrombopag in China. Furthermore, to understand the pharmacokinetics (PK) profile of eltrombopag and to explore the relationship between the PK and pharmacodynamics (PD) (platelet response), a PK/PD analysis will be embedded in this phase III study and conducted in the same patient population participated this phase III study.

Approximately 150 eligible subjects will be randomized to either eltrombopag or matching placebo treatment in 2:1 ratio in stage 1(the 8-week double blind stage). Randomization for stage 1 will be stratified by splenectomy status (Yes/No), use of concomitant maintenance ITP therapy (Yes/No) and, baseline platelet count ( no more than 15×109/L, or >15×109/L). This study includes 3 stages. The stage 1 will be an 8-week double-blind, randomized, placebo-controlled treatment period. Following completion of Stage 1 and after completing the data clean for the initial 6 weeks, the investigator will be un-blinded to treatment assignment on an individual subject basis to enable appropriate starting dose selection for stage 2, a 24-week open-label treatment period. PK sampling and assessments will occur at the Week 2 visit during stage 2 of the study, when all subjects are receiving eltrombopag. After the completion of stage 2, subjects may continue the eltrombopag treatment in stage 3, if he/she can benefit from the continuous eltrombopag treatment based on investigator's judgement.

The initial dose of eltrombopag administration is 25 mg orally once daily. During the 8 weeks double-blind treatment, dose of investigational product will be adjusted according to the weekly subject platelet count.

The eligible subjects who have completed stage 1 (8 weeks of double-blind treatment period: the first 6 weeks data will be used for primary endpoint analysis and the last 2 weeks will be data clean period during which period the blinded treatment is continued as to the first 6 weeks) would enter a voluntary open-label stage 2 (24-week open-label extension phase) in which subjects from both eltrombopag group and placebo group will have the opportunity to receive eltrombopag treatment. Subjects unwilling or unqualified (such as the subjects who meet the stopping criteria) to participate in extension treatment will attend follow-up visits for 4 weeks after the completion of double-blind phase. During open-label stage 2 during which period all eligible subjects will receive open label eltrombopag treatment. The dose of eltrombopag will be continuously adjusted according to the subject's platelet count.

Following completion of Stage 2, if the subject benefits from the eltrombopag treatment based on investigator's discretion, the subject can voluntarily enter stage 3, during which the subject will continue eltrombopag treatment until the commercial launch of eltrombopag in China.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subject is ≥18 years old.
  2. Diagnosed with ITP for at least 12 months prior to screening, and have a platelet count of <30 X109/L on Day 1 (or within 48 hours prior to dosing on Day 1).
  3. Patients who have no response or relapsed after splenectomy. Or patients who have not been splenectomised and have either not responded to one or more prior therapies (except splenectomy), or who have relapsed prior therapy.
  4. Previous therapy for ITP including rescue must have been completed at least 2 weeks prior to randomization.
  5. Subjects treated with maintenance immunosuppressive therapy must be receiving a dose that has been stable for at least 1 month.
  6. No pre-existing cardiac disease within the last 3 months. No arrhythmia known to increase the risk of thrombolic events (e.g. atrial fibrillation), or patients with a Corrected QT interval (QTc) >450msec or QTc >480 for patients with a Bundle Branch Block.
  7. No history of clotting disorder, other than ITP.
  8. A complete blood count (CBC), within the reference range, with the following exceptions:

    • Platelets <30×109/L on Day 1 (or within 48hours of Day 1) is required for inclusion,
    • Hemoglobin: females and males 10.0 g/dl are eligible for inclusion,
    • Absolute neutrophil count (ANC) ≥1500/µL (1.5×109/L) is required for inclusion
  9. Blood chemistry test result no exceed normal by more than 20%. Total albumin must not be below the lower limit of normal (LLN) by more than 10%.
  10. Subject is non-childbearing potential of childbearing potential and use acceptable methods of contraception from two weeks prior to administration of study medication, throughout the study, and 28 days after completion or premature discontinuation from the study.

Exclusion Criteria:

  1. Patients with any prior history of arterial or venous thrombosis, 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, antiphospholipid syndrome, etc).
  2. Any clinically relevant abnormality, other than ITP,which in the opinion of the investigator makes the subject unsuitable for participation in the study.
  3. Female subjects who are nursing or pregnant at screening or pre-dose on Day 1.
  4. History of alcohol/drug abuse or dependence within 12 months of the study.
  5. Treatment with thrombopoietin or an investigational drug within 30 days or five half-lives (whichever is longer) preceding the first dose of study medication.
  6. Subjects who have previously received eltrombopag or any other thrombopoietin receptor agonist.
  7. Subject has consumed aspirin, aspirin-containing compounds, salicylates, anticoagulants, quinine or non-steroidal anti-inflammatories (NSAIDs) for >3 consecutive days within 2 weeks of the study start and until the end of the study.
  8. Consumption of any herbal or dietary supplements, excluding vitamin or mineral supplements, within 1 week of the study start.
  9. History of platelet aggregation that prevents reliable measurement of platelet counts.
  10. An abnormality in bone marrow examination result, other than ITP, identified on the screening examination, which in the opinion of the investigator makes the subject unsuitable for participation in the study (e.g. ≥MF-2 according to EU consensus scale [Thiele, 2005]) or suggests another primary diagnosis (e.g. Thrombocytopenia is secondary to another disease).
  11. Any laboratory or clinical evidence for HIV infection.
  12. Any clinical history for hepatitis C infection; chronic hepatitis B infection; or any evidence for active hepatitis at the time of subject screening. Laboratory test shows positive serology for Hepatitis C or Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded.
  13. Patients expected to require rescue on Day 1 of the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01762761

Locations
China, Fujian
GSK Investigational Site
Fuzhou, Fujian, China, 350001
China, Guangdong
GSK Investigational Site
Guangzhou, Guangdong, China, 510080
GSK Investigational Site
Guangzhou, Guangdong, China, 510515
GSK Investigational Site
Zhongshan, Guangdong, China, 528403
China, Hunan
GSK Investigational Site
Changsha, Hunan, China, 410013
China, Jiangsu
GSK Investigational Site
Nanjing, Jiangsu, China, 210029
China, Jiangxi
GSK Investigational Site
Nanchang, Jiangxi, China, 330006
China, Shandong
GSK Investigational Site
Jianan, Shandong, China, 250012
China, Zhejiang
GSK Investigational Site
Hangzhou, Zhejiang, China, 310003
China
GSK Investigational Site
Beijing, China, 100730
GSK Investigational Site
Beijing, China, 100034
GSK Investigational Site
Beijing, China, 100083
GSK Investigational Site
Beijing, China, 100044
GSK Investigational Site
Chengdu, China, 610041
GSK Investigational Site
Jiang Su Province, China, 215006
GSK Investigational Site
Shanghai, China, 200025
GSK Investigational Site
Shanghai, China
GSK Investigational Site
Tianjin, China, 300020
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01762761     History of Changes
Other Study ID Numbers: 113765
Study First Received: December 19, 2012
Results First Received: January 19, 2015
Last Updated: March 26, 2015
Health Authority: United States: Food and Drug Administration
China: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
eltrombopag
TPO-R agonist
Chronic ITP

Additional relevant MeSH terms:
Purpura, Thrombocytopenic
Purpura, Thrombocytopenic, Idiopathic
Autoimmune Diseases
Blood Coagulation Disorders
Blood Platelet Disorders
Hematologic Diseases
Hemorrhage
Hemorrhagic Disorders
Immune System Diseases
Pathologic Processes
Purpura
Signs and Symptoms
Skin Manifestations
Thrombocytopenia
Thrombotic Microangiopathies

ClinicalTrials.gov processed this record on July 30, 2015