Clinical trial NCT01762761: Eltrombopag Phase III Study In Chinese Chronic ITP Patients
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Purpura, Thrombocytopenic, Idiopathic and Hepatitis C
Keywords: eltrombopag
TPO-R agonist
Chronic ITP
ETB115
Chinese chronic ITP patients
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-01-08
Enrollment: 155
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Primary outcomes:
measure: Number of Participants (Responders) Achieving a Platelet Count >=50×10^9/L After the First 6 Weeks of Stage 1
timeFrame: 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
timeFrame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1
measure: 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, the Whole Stage 2 and the Whole Stage 3
timeFrame: From the start of study treatment (Day 1) up to the end of Stage 3
measure: Number of Participants With Bleeding as Assessed Using the World Health Organization (WHO) Bleeding Scale
timeFrame: From the start of study treatment (Day 1) up to the end of Stage 3
measure: Number of Participants With Clinically Significant Bleeding as Assessed Using the World Health Organization (WHO) Bleeding Scale
timeFrame: From the start of study treatment (Day 1) up to the end of Stage 3
measure: Time to Response
timeFrame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1
measure: Number of Participants Who Required Protocol-defined Rescue Treatment During the First 6 Weeks of Stage 1, Whole Stages 2 & 3
timeFrame: From the start of study treatment (Day 1) up to the end of Stage 3
measure: Number of Participants With a Platelet Count >=50×10^9/L During at Least 75% of Their Platelet Count Assessments
timeFrame: From the start of study treatment (Day 1) up to the end of Stage 3
measure: Total Duration of Time a Participant Had a Platelet Count >=50×10^9/L
timeFrame: From the start of study treatment (Day 1) up to the end of Stage 3
measure: Maximum Period of Time a Participant Had a Platelet Count Continuously >= 50 ×10^9/L
timeFrame: From the start of study treatment (Day 1) up to the end of Stage 3
measure: Number of Participants That Reduced or Discontinued Baseline Concomitant ITP Medications During Stage 2 and Stage 3
timeFrame: From the start of Stage 2 to the end of Stage 3
measure: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
timeFrame: From the start of study treatment (Day 1) up to the end of Week 8 of Stage 1
measure: Number of Participants With the Maximum Toxicity Grade for the Indicated Clinical Chemistry Parameters
timeFrame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1
measure: Number of Participants With the Maximum Toxicity Grade for the Indicated Hematology Parameters
timeFrame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1
measure: Change From Baseline in Systolic Blood Pressure
timeFrame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6
measure: Change From Baseline in Diastolic Blood Pressure
timeFrame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6
measure: Change From Baseline in Pulse Rate
timeFrame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6
measure: Number of Participants With the Indicated 12-lead Electrocardiogram (ECG) Finding at Baseline
timeFrame: Baseline
measure: Number of Participants With a Change From Baseline in Visual Acuity
timeFrame: From the start of study treatment (Day 1) up to the end of Week 6 of Stage 1
measure: Number of Participants With the Indicated Grading of Myelofibrosis Using Bone Marrow Biopsy at Screening
timeFrame: Screening
measure: Pharmacokinetic (PK) Assessments for Eltrombopag for Apparent Volume of Distribution of Central Compartment (Vc/F), Apparent Volume of Distribution of Peripheral Compartment (Vp/F)
timeFrame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2
measure: Pharmacokinetic Assessments for Eltrombopag for Apparent Clearance (CL/F), Apparent Inter-compartmental Clearance (Q/F)
timeFrame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2
measure: Pharmacokinetic Assessments for Eltrombopag for Absorption Rate Constant (Ka)
timeFrame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2
measure: Pharmacokinetic Assessments for Eltrombopag for Absorption Lag Time (ALAG)
timeFrame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2
measure: 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
timeFrame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2
measure: Post-hoc Estimates of Maximum Observed Concentration (Cmax) for Eltrombopag After 50 mg Once Daily Dose of Eltrombopag
timeFrame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2
measure: Percentage of Participants Estimated as Responders to Eltrombopag by the Pharmacokinetic/ Pharmacodynamic Model
timeFrame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2
measure: 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
timeFrame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2
measure: Pharmacodynamic Parameter- Production Rate of Platelet Precursors (KIN)
timeFrame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2
measure: Pharmacodynamic Parameter-Maturation Rate of Platelet Precursors (KOUT)
timeFrame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2
Other outcomes:
Locations:
city: Fuzhou
country: China
facility: Novartis Investigative Site
state: Fujian
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Zhongshan
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Changsha
country: China
facility: Novartis Investigative Site
state: Hunan
city: Nanjing
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Suzhou
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Nanchang
country: China
facility: Novartis Investigative Site
state: Jiangxi
city: Jianan
country: China
facility: Novartis Investigative Site
state: Shandong
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Chengdu
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Tianjin
country: China
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Liu X, Hou M, Li J, Jin J, Huang M, Yu Z, Xu X, Zhang X, Yang R. Efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia: stage 2 results from a multicenter phase III study. Platelets. 2022 Jan 2;33(1):82-88. doi: 10.1080/09537104.2020.1847267. Epub 2020 Nov 29.