Eltrombopag Phase III Study In Chinese Chronic ITP Patients

Number of Participants Achieving a Platelet Count >=50×10^9/L at Least Once During the First 6 Weeks of Stage 1

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.

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, the Whole Stage 2 and the Whole Stage 3

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.

Time frame: From the start of study treatment (Day 1) up to the end of Stage 3

Number of Participants With Bleeding as Assessed Using the World Health Organization (WHO) Bleeding Scale

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 for Stage 1, Baseline, Weeks 4, 8, 16, 20, 24 for Stage 2; Baseline, Weeks 25, 29, 73, 97, 121, 145, 169, 193, 217, 241, 265, 284 for Stage 3. Bleeding incidences at these time points are presented.

Time frame: From the start of study treatment (Day 1) up to the end of Stage 3

Number of Participants With Clinically Significant Bleeding as Assessed Using the World Health Organization (WHO) Bleeding Scale

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 frame: From the start of study treatment (Day 1) up to the end of Stage 3

Time to Response

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.

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, Whole Stages 2 & 3

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.

Time frame: From the start of study treatment (Day 1) up to the end of Stage 3

Number of Participants With a Platelet Count >=50×10^9/L During at Least 75% of Their Platelet Count Assessments

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.

Time frame: From the start of study treatment (Day 1) up to the end of Stage 3

Total Duration of Time a Participant Had a Platelet Count >=50×10^9/L

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.

Time frame: From the start of study treatment (Day 1) up to the end of Stage 3

Maximum Period of Time a Participant Had a Platelet Count Continuously >= 50 ×10^9/L

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.

Time frame: From the start of study treatment (Day 1) up to the end of Stage 3

Number of Participants That Reduced or Discontinued Baseline Concomitant ITP Medications During Stage 2 and Stage 3

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.

Time frame: From the start of Stage 2 to the end of Stage 3

Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

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.

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

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

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

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.

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

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.

Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6

Change From Baseline in Diastolic Blood Pressure

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.

Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5 and Week 6

Change From Baseline in Pulse Rate

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.

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

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.

Time frame: Baseline

Number of Participants With a Change From Baseline in Visual Acuity

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.

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

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.

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)

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.

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)

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.

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)

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.

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)

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.

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

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.

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

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.

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

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.

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

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.

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)

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.

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)

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.

Time frame: From the start of study until 24 hours post-dose of Week 2 Visit of Stage 2