A Phase 3 interventional study of eltrombopag and placebo in Purpura, Thrombocytopenic, Idiopathic and Hepatitis C, sponsored by Novartis Pharmaceuticals. Completed at 18 sites in China. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-12-03.
Sponsored by Novartis Pharmaceuticals · Phase 3, Interventional, and Treatment
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
2,321 studies on the registry are indexed under Hepatitis C; 102 are open to participants now.
This study's enrollment of 155 is above the median of 79 across 1,633 interventional studies indexed under Hepatitis C.
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A complete blood count (CBC), within the reference range, with the following exceptions:
Exclusion Criteria:
Thrombopoietin- receptor (TPO-R) agonist
Drug: eltrombopag
Placebo
Drug: placebo
TPO-R agonist
Also known as: ETB115
placebo
Number of Participants (Responders) Achieving a Platelet Count >=50×10^9/L After the First 6 Weeks of Stage 1
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.
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 >=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
This study includes three stages: 8-week double-blind stage (Stage 1), 24-week open-label stage (Stage 2) and prolonged open-label stage (Stage 3) with voluntary participation until eltrombopag became commercially available in China. Final Results for this study are presented in this report.
| Milestone | Placebo | Eltrombopag |
|---|---|---|
| Started | 51 | 104 |
| Completed | 12 | 39 |
| Not completed | 39 | 65 |
| Withdrew: Adverse event | 15 | 17 |
| Withdrew: Lack of efficacy | 9 | 25 |
| Withdrew: Protocol violation | 1 | 1 |
| Withdrew: Study closed/terminated | 0 | 2 |
| Withdrew: Lost to follow-up | 3 | 6 |
| Withdrew: Physician decision | 4 | 6 |
| Withdrew: Withdrawal by subject | 7 | 8 |
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.
| Participants | Placebo | Eltrombopag |
|---|---|---|
| Number of Participants (Responders) Achieving a Platelet Count >=50×10^9/L After the First 6 Weeks of Stage 1 | 3 | 60 |
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.
| Participants | Placebo | Eltrombopag |
|---|---|---|
| Number of Participants Achieving a Platelet Count >=50×10^9/L at Least Once During the First 6 Weeks of Stage 1 | 9 | 80 |
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.
| Participants | Placebo | Eltrombopag |
|---|---|---|
| Stage 1 (during the first 6 weeks) | 18 | 84 |
| Stage 2 (during 24 weeks) | 45 | 81 |
| Stage 3 | 36 | 72 |
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.
| Participants | Placebo | Eltrombopag |
|---|---|---|
| Stage 1: Baseline | 36 | 68 |
| Stage 1: Week 1 | 30 | 43 |
| Stage 1: Week 2 | 27 | 32 |
| Stage 1: Week 3 | 26 | 29 |
| Stage 1: Week 4 | 24 | 23 |
| Stage 1: Week 5 | 19 | 24 |
| Stage 1: Week 6 | 17 | 17 |
| Stage 2: Baseline | 22 | 64 |
| Stage 2: Week 4 | 8 | 7 |
| Stage 2: Week 8 | 6 | 12 |
| Stage 2: Week 16 | 5 | 8 |
| Stage 2: Week 20 | 3 | 1 |
| Stage 2: Week 24 | 3 | 6 |
| Stage 3: Baseline | 16 | 49 |
| Stage 3: Week 25 | 14 | 19 |
| Stage 3: Week 29 | 1 | 1 |
| Stage 3: Week 73 | 1 | 3 |
| Stage 3: Week 97 | 1 | 1 |
| Stage 3: Week 121 | 1 | 0 |
| Stage 3: Week 145 | 0 | 1 |
| Stage 3: Week 169 | 1 | 0 |
| Stage 3: Week 193 | 0 | 0 |
| Stage 3: Week 217 | 2 | 2 |
| Stage 3: Week 241 | — | 0 |
| Stage 3: Week 265 | — | 0 |
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.
| Participants | Placebo | Eltrombopag |
|---|---|---|
| Stage 1: Baseline | 5 | 14 |
| Stage 1:Week 1 | 5 | 12 |
| Stage 1: Week 2 | 4 | 13 |
| Stage 1: Week 3 | 6 | 11 |
| Stage 1: Week 4 | 5 | 7 |
| Stage 1: Week 5 | 2 | 8 |
| Stage 1: Week 6 | 4 | 6 |
| Stage 2: Baseline | 3 | 13 |
| Stage 2: Week 4 | 1 | 0 |
| Stage 2: Week 8 | 0 | 1 |
| Stage 2: Week 16 | 1 | 1 |
| Stage 2: Week 20 | 1 | 0 |
| Stage 2: Week 24 | 0 | 0 |
| Stage 3: Baseline | 1 | 9 |
| Stage 3: Week 25 | 1 | 0 |
| Stage 3: Week 29 | 1 | 0 |
| Stage 3: Week 73 | 0 | 0 |
| Stage 3: Week 97 | 0 | 0 |
| Stage 3: Week 121 | 0 | 0 |
| Stage 3: Week 145 | — | 0 |
| Stage 3: Week 169 | 0 | 0 |
| Stage 3: Week 193 | 0 | 0 |
| Stage 3: Week 217 | 0 | 0 |
| Stage 3: Week 241 | — | 0 |
| Stage 3: Week 265 | — | 0 |
| Stage 3: Week 286 | 0 | — |
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.
| Weeks | Placebo | Eltrombopag |
|---|---|---|
| Time to Response | NA (NA to NA) | 3.14 (3.00 to 4.14) |
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.
| Participants | Placebo | Eltrombopag |
|---|---|---|
| Stage 1 (first 6 weeks) | 17 | 9 |
| Stage 2 | 16 | 14 |
| Stage 3 | 13 | 21 |
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.
| Participants | Placebo | Eltrombopag |
|---|---|---|
| Stage 1 (first 6 weeks) | 1 | 23 |
| Stage 2 | 10 | 38 |
| Stage 3 | 13 | 30 |
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.
| Weeks | Placebo | Eltrombopag |
|---|---|---|
| Stage 1 (first 6 weeks) | 0.00 (0.00 to 5.1) | 1.79 (0.14 to 5.1) |
| Stage 2 | 4.07 (0.0 to 23.3) | 7.29 (0.0 to 24.6) |
| Stage 3 | 27.00 (0.0 to 227.4) | 43.71 (0.0 to 224.0) |
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.
| Weeks | Placebo | Eltrombopag |
|---|---|---|
| Stage 1 (first 6 weeks) | 0.00 (0.00 to 0.00) | 1.57 (0.14 to 3.07) |
| Stage 2 | 2.71 (0.0 to 23.3) | 5.00 (0.0 to 24.6) |
| Stage 3 | 16.43 (0.0 to 227.1) | 28.14 (0.0 to 227.1) |
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.
| Participants | Placebo | Eltrombopag |
|---|---|---|
| Stage 2 | 19 | 20 |
| Stage 3 | 5 | 16 |
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.
| Participants | Placebo | Eltrombopag |
|---|---|---|
| Stage 1: Any AE | 34 | 66 |
| Stage 1: Any SAE | 5 | 5 |
| Stage 2: Any AE | 43 | 64 |
| Stage 2: Any SAE | 6 | 11 |
| Stage 3: any AE | 38 | 70 |
| Stage 3: Any SAE | 11 | 21 |
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
| Participants | Placebo | Eltrombopag |
|---|---|---|
| AST, Grade 1 | 8 | 10 |
| AST, Grade 2 | 0 | 2 |
| AST, Grade 3 | 0 | 0 |
| AST, Grade 4 | 0 | 0 |
| AST, Grade 5 | 0 | 0 |
| ALT, Grade 1 | 11 | 14 |
| ALT, Grade 2 | 2 | 1 |
| ALT, Grade 3 | 1 | 1 |
| ALT, Grade 4 | 0 | 0 |
| ALT, Grade 5 | 0 | 0 |
| GGT,Grade 1 | 10 | 10 |
| GGT,Grade 2 | 2 | 2 |
| GGT,Grade 3 | 0 | 0 |
| GGT,Grade 4 | 0 | 0 |
| GGT,Grade 5 | 0 | 0 |
| Total Bilirubin, Grade 1 | 2 | 17 |
| Total Bilirubin, Grade 2 | 0 | 1 |
| Total Bilirubin, Grade 3 | 0 | 0 |
| Total Bilirubin, Grade 4 | 0 | 0 |
| Total Bilirubin, Grade 5 | 0 | 0 |
| Albumin, Grade 1 | 2 | 10 |
| Albumin, Grade 2 | 1 | 2 |
| Albumin, Grade 3 | 0 | 0 |
| Albumin, Grade 4 | 0 | 0 |
| Albumin, Grade 5 | 0 | 0 |
| Alkaline Phosphatase, Grade 1 | 1 | 8 |
| Alkaline Phosphatase, Grade 2 | 0 | 0 |
| Alkaline Phosphatase, Grade 3 | 0 | 0 |
| Alkaline Phosphatase, Grade 4 | 0 | 0 |
| Alkaline Phosphatase, Grade 5 | 0 | 0 |
| Calcium, Grade 1 | 4 | 16 |
| Calcium, Grade 2 | 5 | 13 |
| Calcium, Grade 3 | 0 | 0 |
| Calcium, Grade 4 | 0 | 0 |
| Calcium, Grade 5 | 0 | 0 |
| Potassium, Grade 1 | 25 | 25 |
| Potassium, Grade 2 | 0 | 1 |
| Potassium, Grade 3 | 1 | 7 |
| Potassium, Grade 4 | 0 | 0 |
| Potassium, Grade 5 | 0 | 0 |
| Creatinine, Grade 1 | 0 | 2 |
| Creatinine, Grade 2 | 0 | 0 |
| Creatinine, Grade 3 | 0 | 0 |
| Creatinine, Grade 4 | 0 | 1 |
| Creatinine, Grade 5 | 0 | 0 |
| Glucose, Grade 1 | 14 | 34 |
| Glucose, Grade 2 | 4 | 13 |
| Glucose, Grade 3 | 2 | 2 |
| Glucose, Grade 4 | 0 | 0 |
| Glucose, Grade 5 | 0 | 0 |
| Sodium, Grade 1 | 10 | 19 |
| Sodium, Grade 2 | 0 | 0 |
| Sodium, Grade 3 | 0 | 1 |
| Sodium, Grade 4 | 0 | 0 |
| Sodium, Grade 5 | 0 | 0 |
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.
| Participants | Placebo | Eltrombopag |
|---|---|---|
| Hemoglobin, Grade 1 | 21 | 35 |
| Hemoglobin, Grade 2 | 1 | 11 |
| Hemoglobin, Grade 3 | 3 | 4 |
| Hemoglobin, Grade 4 | 0 | 0 |
| Hemoglobin, Grade 5 | 0 | 0 |
| Lymphocytes, Grade 1 | 0 | 2 |
| Lymphocytes, Grade 2 | 12 | 16 |
| Lymphocytes, Grade 3 | 0 | 1 |
| Lymphocytes, Grade 4 | 0 | 0 |
| Lymphocytes, Grade 5 | 0 | 0 |
| Platelet count, Grade 1 | 1 | 1 |
| Platelet count, Grade 2 | 0 | 11 |
| Platelet count, Grade 3 | 5 | 26 |
| Platelet count, Grade 4 | 44 | 66 |
| Platelet count, Grade 5 | 0 | 0 |
| Total Neutrophils, Grade 1 | 5 | 7 |
| Total Neutrophils, Grade 2 | 3 | 3 |
| Total Neutrophils, Grade 3 | 0 | 0 |
| Total Neutrophils, Grade 4 | 0 | 0 |
| Total Neutrophils, Grade 5 | 0 | 0 |
| White Blood Cell Count, Grade 1 | 4 | 9 |
| White Blood Cell Count, Grade 2 | 1 | 2 |
| White Blood Cell Count, Grade 3 | 0 | 0 |
| White Blood Cell Count, Grade 4 | 0 | 0 |
| White Blood Cell Count, Grade 5 | 0 | 0 |
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.
| Millimeters of mercury (mm Hg) | Placebo | Eltrombopag |
|---|---|---|
| Week 1 | -0.3 ± 8.86 | -0.7 ± 12.65 |
| Week 2 | -2.0 ± 9.83 | -0.2 ± 14.08 |
| Week 3 | 0.3 ± 12.61 | -1.5 ± 14.05 |
| Week 4 | -0.2 ± 13.24 | -2.7 ± 14.37 |
| Week 5 | -3.0 ± 12.02 | -2.8 ± 12.57 |
| Week 6 | -1.5 ± 13.25 | -2.3 ± 13.62 |
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.
| mm Hg | Placebo | Eltrombopag |
|---|---|---|
| Week 1 | -0.3 ± 6.66 | -0.5 ± 8.90 |
| Week 2 | -1.1 ± 8.01 | -0.1 ± 10.91 |
| Week 3 | -1.0 ± 7.16 | -1.5 ± 10.40 |
| Week 4 | -0.9 ± 8.51 | -1.4 ± 9.57 |
| Week 5 | -3.0 ± 8.39 | -1.8 ± 9.78 |
| Week 6 | -2.2 ± 9.44 | -1.0 ± 9.71 |
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.
| Beats per minute | Placebo | Eltrombopag |
|---|---|---|
| Week 1 | -0.5 ± 6.88 | 0.2 ± 8.54 |
| Week 2 | -2.2 ± 9.23 | 0.2 ± 9.54 |
| Week 3 | 1.6 ± 10.31 | 0.2 ± 8.79 |
| Week 4 | -0.1 ± 7.32 | 0.8 ± 8.52 |
| Week 5 | 0.0 ± 9.06 | 0.0 ± 7.32 |
| Week 6 | -2.1 ± 8.55 | 0.1 ± 8.06 |
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.
| Particpants | Placebo | Eltrombopag |
|---|---|---|
| Normal | 36 | 57 |
| Abnormal, not clinically significant | 14 | 43 |
| Abnormal, clinically significant | 0 | 4 |
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.
| Participants | Placebo | Eltrombopag |
|---|---|---|
| OD | 24 | 33 |
| OS | 22 | 35 |
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.
| Participants | Placebo | Eltrombopag |
|---|---|---|
| MF Score 0 | 38 | 83 |
| MF Score 1 | 13 | 19 |
| MF Score 2 | 0 | 0 |
| MF Score 3 | 0 | 0 |
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.
| Liters | Eltrombopag |
|---|---|
| Vc/F | 8.80 (7.84 to 9.76) |
| Vp/F | 33.6 (17.0 to 50.2) |
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.
| Liters per hour(L/hr) | Eltrombopag |
|---|---|
| CL/F | 0.370 (0.336 to 0.404) |
| Q/F | 0.561 (0.444 to 0.678) |
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.
| Per hour (1/hr) | Eltrombopag |
|---|---|
| Pharmacokinetic Assessments for Eltrombopag for Absorption Rate Constant (Ka) | 1.58 (1.05 to 2.11) |
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.
| Hour | Eltrombopag |
|---|---|
| Pharmacokinetic Assessments for Eltrombopag for Absorption Lag Time (ALAG) | 0.855 (0.816 to 0.894) |
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.
| Microgram* hour per milliliter(μg.hr/mL) | Eltrombopag |
|---|---|
| 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 | 88.8 (78.0 to 101) |
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.
| Nanogram/ Milliliter (ng/mL) | Eltrombopag |
|---|---|
| Post-hoc Estimates of Maximum Observed Concentration (Cmax) for Eltrombopag After 50 mg Once Daily Dose of Eltrombopag | 6916 (6205 to 7708) |
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.
| Percentage of participants | Eltrombopag |
|---|---|
| Percentage of Participants Estimated as Responders to Eltrombopag by the Pharmacokinetic/ Pharmacodynamic Model | 89 |
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.
| Milliliter/microgram | Eltrombopag |
|---|---|
| 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 | 0.860 (0.639 to 1.08) |
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.
| 1 x 10^9/L.hr | Eltrombopag |
|---|---|
| Pharmacodynamic Parameter- Production Rate of Platelet Precursors (KIN) | 1.43 |
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.
| 1/ hr | Eltrombopag |
|---|---|
| Pharmacodynamic Parameter-Maturation Rate of Platelet Precursors (KOUT) | 0.0253 |
Collected over Adverse Event (AE) timeframe: Adverse events were collected from study start (form first dose of study treatment) until end of study treatment plus 30 days post-treatment, up to a maximum duration of approx. 70 months.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo | 3/51 (5.9%) | 17/51 (33.3%) | 48/51 (94.1%) |
| Eltrombopag | 0/104 (0%) | 33/104 (31.7%) | 90/104 (86.5%) |
| Event | Placebo | Eltrombopag |
|---|---|---|
| PLATELET COUNT DECREASEDInvestigations | 4/51 | 1/104 |
| THROMBOCYTOPENIABlood and lymphatic system disorders | 2/51 | 3/104 |
| ACUTE MYOCARDIAL INFARCTIONCardiac disorders | 2/51 | 0/104 |
| DEATHGeneral disorders | 2/51 | 0/104 |
| CATARACTEye disorders | 1/51 | 4/104 |
| CEREBRAL INFARCTIONNervous system disorders | 1/51 | 4/104 |
| LENTICULAR OPACITIESEye disorders | 1/51 | 0/104 |
| INTESTINAL OBSTRUCTIONGastrointestinal disorders | 1/51 | 0/104 |
| INTUSSUSCEPTIONGastrointestinal disorders | 1/51 | 0/104 |
| GASTROENTERITISInfections and infestations | 1/51 | 0/104 |
| Event | Placebo | Eltrombopag |
|---|---|---|
| NASOPHARYNGITISInfections and infestations | 21/51 | 28/104 |
| UPPER RESPIRATORY TRACT INFECTIONInfections and infestations | 13/51 | 39/104 |
| ALANINE AMINOTRANSFERASE INCREASEDInvestigations | 19/51 | 26/104 |
| ASPARTATE AMINOTRANSFERASE INCREASEDInvestigations | 18/51 | 22/104 |
| HYPOKALAEMIAMetabolism and nutrition disorders | 14/51 | 20/104 |
| URINARY TRACT INFECTIONInfections and infestations | 13/51 | 19/104 |
| BLOOD BILIRUBIN UNCONJUGATED INCREASEDInvestigations | 10/51 | 10/104 |
| BLOOD BILIRUBIN INCREASEDInvestigations | 9/51 | 19/104 |
| ANAEMIABlood and lymphatic system disorders | 9/51 | 17/104 |
| DIARRHOEAGastrointestinal disorders | 8/51 | 11/104 |
| Age, Continuous(Years) | Placebo | Eltrombopag | Total |
|---|---|---|---|
| Mean | 41.3 ± 12.83 | 44.7 ± 15.91 | 43.6 ± 15.01 |
| Sex: Female, Male(Participants) | Placebo | Eltrombopag | Total |
|---|---|---|---|
| Female | 40 | 77 | 117 |
| Male | 11 | 27 | 38 |
| Race/Ethnicity, Customized(Participants) | Placebo | Eltrombopag | Total |
|---|---|---|---|
| Asian - East Asian Heritage | 51 | 104 | 155 |
Plan to share: Yes — Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
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