Eltrombopag Phase III Study In Chinese Chronic ITP Patients

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

The primary objective of this study was to determine the efficacy of oral eltrombopag as a thrombopoietic agent treating previously treated chronic Chinese ITP patients compared to placebo. The secondary objective was to assess the safety and tolerability of eltrombopag when administered for 6 weeks to previously treated adult chronic ITP patients compared with placebo. In addition, the long-term efficacy and safety of eltrombopag treatment was also evaluated in the 24-week extension open-label phase after the double-blind phase as one of other study objectives. If the subject benefited from the eltrombopag treatment based on the investigator's discretion, the subject could continue on 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 was embedded in this phase III study and conducted in the same patient population who participated this phase III study.

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

The primary objective of this study was to determine the efficacy of oral eltrombopag as a thrombopoietic agent treating previously treated chronic Chinese ITP patients compared to placebo. The secondary objective was to assess the safety and tolerability of eltrombopag when administered for 6 weeks to previously treated adult chronic ITP patients compared to placebo. In addition, the long-term efficacy and safety of eltrombopag treatment was also evaluated in the 24-week extension open-label phase after the double-blind phase as one of other study objectives. If the subject benefited from the eltrombopag treatment based on the investigator's discretion, the subject could continue the 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 was embedded in this phase III study and conducted in the same patient population who participated this phase III study.

155 eligible subjects were 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 was 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 include 3 stages. The stage 1 was an 8-week double-blind, randomized, placebo-controlled treatment period. Following completion of Stage 1 and after completing the data cleanup of the initial 6 weeks, the investigator was 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 occurred at the Week 2 visit during stage 2 of the study, when all subjects were receiving eltrombopag. After the completion of stage 2, subjects could continue the the eltrombopag treatment in stage 3, if he/she benefited from the continuous eltrombopag treatment based on the investigator's judgement.

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

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

Following completion of Stage 2, if the subject benefited from the eltrombopag treatment based on the investigator's discretion, the subject could voluntarily enter stage 3, during which the subject continued eltrombopag treatment until the commercial launch of eltrombopag in C

Eligibility 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.