Overview

This trial is active, not recruiting.

Condition purpura, thrombocytopenic, idiopathic and hepatitis c
Treatments eltrombopag, placebo
Phase phase 3
Sponsor GlaxoSmithKline
Start date February 2013
End date June 2014
Trial size 155 participants
Trial identifier NCT01762761, 113765

Summary

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking double blind (subject, caregiver, investigator, outcomes assessor)
Primary purpose treatment
Arm
(Experimental)
Thrombopoietin- receptor (TPO-R) agonist
eltrombopag revolade
TPO-R agonist
(Placebo Comparator)
Placebo
placebo no other name
placebo

Primary Outcomes

Measure
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

Secondary Outcomes

Measure
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
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
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
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
Time to Response
time frame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1
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
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
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
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
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
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
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
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
Change From Baseline in Systolic Blood Pressure
time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6
Change From Baseline in Diastolic Blood Pressure
time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6
Change From Baseline in Pulse Rate
time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6
Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Finding at Baseline
time frame: Baseline
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
Number of Participants With the Indicated Grading of Myelofibrosis Using Bone Marrow Biopsy at Screening
time frame: Screening
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
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
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
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
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
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
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
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
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
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

Eligibility Criteria

Male or female participants at least 18 years old.

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.

Additional Information

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
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.
Trial information was received from ClinicalTrials.gov and was last updated in March 2015.
Information provided to ClinicalTrials.gov by GlaxoSmithKline.