Cytopaenia
Conditions
Keywords
Eltrombopag, Aplastic Anemia (AA), Thrombocytopenia, Thrombopoietin, Bone Marrow, Bone Marrow Biopsy, Hematopoietic Stem Cells, Mature Blood Cells, Pancytopenia, Leukopenia, Platelets
Brief summary
This was a non-randomized, open-label, phase II study to assess the efficacy and safety of eltrombopag in Japanese moderate or more severe aplastic anemia (AA) subjects with a platelet count \<30,000/microliter who were refractory to anti-thymocyte globulin (ATG)-based immunosuppressive therapy (IST), who have relapsed after ATG-based IST, or who are ineligible for ATG-based IST. Eltrombopag was expected to improve trilineage blood cells and decrease transfusion frequency based on the result from the previous study in patients with severe AA. This study used the hematologic response rate, defined as the proportion of subjects showing improvement in at least one of the three blood cell lineages or a decrease in blood transfusion volume, as the primary endpoint. A total of 36 subjects were screened and 21 were enrolled in the study. Treatment with eltrombopag started at 25 milligram (mg)/day and increased by 25 mg/day every 2 weeks according to the platelet count up to 100 mg/day. Response assessment was performed at 3 months after starting the study treatment (Week 13). Subjects in whom the treatment was assessed as effective continued with the study treatment. Subjects in whom the treatment was assessed as effective (when meeting any of the response criteria) at 6 months after starting the study treatment (Week 26) might enter the extension phase and continue the treatment with eltrombopag. The primary endpoint was the hematologic response rate at Week26.
Interventions
DRUGEltrombopag 12.5 mg
White, round, film-coated tablets containing 12.5 mg of eltrombopag free acid (SB-497115-GR, eltrombopag) in each tablet
White, round, film-coated tablets containing 25 mg of eltrombopag free acid (SB-497115-GR, eltrombopag) in each tablet
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Subject has given written informed consent. If a subject is under 20 years, both the subject and the subject's legally acceptable representative have to give informed consent. * Japanese subjects aged \>=18 and \<80 years at the time of informed consent. * Diagnosis of moderate (stage II) or more Aplastic Anemia (AA) with platelet count \<30,000/microliter (based on the diagnosis criteria of AA established by the Study Group on Idiopathic Hematopoietic Disorder as a part of Research on Measures for Intractable Diseases supported by Health and Labor Science Research Grants). * Subjects who became refractory to Anti-thymocyte globulin (ATG)-based Immunosuppressive therapy (IST), who have relapsed after ATG-based IST, or who are ineligible for ATG-based IST. Note: Refractory or relapsed subjects to whom re-treatment with ATG is indicated should not be enrolled in the study. Subjects who have a sibling donor with matched human leukocyte antigen (HLA) should not be enrolled in the study. However, such subjects may be enrolled if the disease relapsed after hematopoietic stem cell transplantation (HSCT), if HSCT is not indicated, or the subject does not want to undergo HSCT. * Adequate organ function at screening and Day 1 as defined as follows: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<=3 × central laboratory upper limit of normal (ULN); Creatinine, total bilirubin, and alkaline phosphatase (ALP) \<1.5 × central laboratory ULN (total bilirubin \<2.5 × central laboratory ULN with Gilbert's Syndrome) * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): 0 or 1 * Subjects with QT interval corrected for heart rate by Fridericia's formula (QTcF) \<450 milliseconds (msec) or QTcF\<480 msec with branch block. Corrected QT interval duration (QTc) is QT interval corrected by Fridericia formula (QTcF), machine or manual over read. QTcF is based on single or averaged QTc value of triplicate electrocardiogram (ECG). * Subjects who meet one of the following conditions: Male subjects who have a female partner of childbearing potential must either have a prior vasectomy or agree to use an acceptable contraception from time of enrollment in the study until 16 weeks after the last dose of eltrombopag (based upon the lifecycle of sperm); Female subjects of non-childbearing potential (who are physiologically unable to become pregnant) defined as: Premenopausal women with documented bilateral oophorectomy, bilateral tubal ligation, or hysterectomy; or postmenopausal women after at least 12 months of natural amenorrhea \[if uncertain, postmenopausal state should be confirmed by hematology result of follicle stimulating hormone (FSH) \>40 milli international unit /milliliter (mIU/mL) or estradiol \<40 picogram (pg)/mL (\<140 picomole /Liter (pmole/L)\].; Female subjects of childbearing potential: Defined as those not meeting the definition of non-childbearing potential. Female subjects of childbearing potential must have a negative serum human chorionic gonadotropin (hCG) or urine pregnancy test within 7 days prior to the first dose of study treatment. It is recommended that the pregnancy test should be performed as close as possible to the first dose of study treatment. Female subjects with a positive pregnancy test must be excluded from the study. Subjects with a negative pregnancy test must use acceptable contraception including abstinence after the pregnancy test. Subjects must agree to use the acceptable contraception including abstinence from 14 days prior to the first dose of study treatment until 28 days after the last dose of eltrombopag. Key
Exclusion criteria
* Treatment with ATG in the past 12 months. Note: Subjects who are receiving cyclosporine or anabolic steroids (excluding danazol) at a stable dose may be enrolled if laboratory values are stable at screening. * Congenital aplastic anemia (e.g., Fanconi anemia, congenital dyskeratosis) * Paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size determined by flow cytometry \>=50% * Presence of chromosomal aberration (-7/7q- detected by fluorescence in situ hybridization (FISH), or other aberrations detected by Giemsa (G)-band staining) Note: Subjects with the result by G-band staining (bone marrow aspiration) not adopted into the abnormal clone definition of An International System for Human Cytogenetic Nomenclature (ISCN) can be enrolled as no chromosomal aberration. * Past history of thromboembolism or current use of anticoagulants. Note: Subjects with antiphospholipid antibody syndrome (APS) should not be enrolled. * Past or current history of malignant tumor. Note: Subjects who have a history of completely resected malignant tumor and have been disease-free for 5 years are eligible. * Subjects who test positive for hepatitis B surface (HBs) antigen, hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) antibody at screening. Note: Subjects with inactive hepatitis B may be enrolled. Judgment of inactive hepatitis B will be done by the medical advisor. * Subjects with concurrent uncontrollable severe infection (e.g., sepsis) * Hepatic cirrhosis * Cardiac disorder (congestive heart disease of New York Heart Association (NYHA) functional classification Grade II/III/IV), or arrhythmia with a risk of thrombosis (e.g., atrial fibrillation). Note: Subjects with NYHA Grade II due to cardiac disorder should not be enrolled but those with NYHA Grade II due to Aplastic Anemia (AA) may be enrolled. * Alcohol or drug abuse * Pregnant women (a positive serum or urine pregnancy test within 7 days prior to the first dose of study treatment) or lactating women. Note: Female subjects who are lactating are eligible to participate if they discontinue nursing prior to the first dose of study treatment and refrain from nursing until 5 days after the treatment completion. * Past history of immediate or delayed hypersensitivity to compounds chemically similar to eltrombopag or their activators * Treatment with another investigational product within 30 days or the period 5-fold longer than the half-life of the investigational product, whichever longer, prior to the first dose of eltrombopag * Prior treatment with eltrombopag, romiplostim, or any other Thrombopoietin (TPO) receptor agonist * Use of prohibited concomitant medications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hematological Response at Week 26 | D183 (Week 26) | Hematologic response rate at 6 months (at WeeK 26) after the start of study treatment was defined as the percentage of subjects who met any of the response criteria (Platelet count, Hemoglobin level, Neutrophil count). 1 ) Platelet count: an increase from baseline by 20,000/μL or more (In the absence of platelet transfusion), or no platelet transfusion requirements for 8 weeks; 2) Hemoglobin: When the baseline hemoglobin level is \<9 g/dL: Without RBC transfusion at baseline, an increase from baseline by 1.5 g/dL or more; With RBC transfusion at baseline, a decrease of at least 4 units in RBC transfusions in the post-treatment 8-week period compared to the pre-treatment 8-week period (1 unit = RBC derived from 200 mL blood); 3) Neutrophil count: an increase from baseline by 500/μL or more (in the absence of granulocyte colony-stimulating factor (G-CSF)), or (if \< 500/μL at baseline) an increase by 100 % or more. Only descriptive analysis done. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hemoglobin From Baseline in the Absence of Red Blood Cell (RBC) Transfusion Over Time | Up to 2.5 years | The changes in observed values for Hemoglobin were summarized. The measurements were followed up to Week 26 and thereafter in the extension part (Up to the launch of the product after approval, which will be approximately up to two and a half years). Only descriptive analysis done. |
| Change in Neutrophil Count From Baseline in the Absence of Granulocyte-colony Stimulating Factor (G-CSF) Over Time | Up to 2.5 years | The changes in observed values for Neutrophil Count were summarized. The measurements were followed up to Week 26 and thereafter in the extension part (Up to the launch of the product after approval, which will be approximately up to two and a half years). Only descriptive analysis done. |
| Hematological Response at Week 13 in Terms of the Platelet Count, Hemoglobin Level and Neutrophil Count | Week 13 | The frequency and percentage were calculated with 95% confidence interval (CI) of responses (which meet each response criteria) of platelet count, hemoglobin and neutrophil count at Week 13. |
| Duration of Hematological Response in Participants Who Responded at the Week 13 | Up to 2.5 years | The duration of haematological response was defined, for subjects who responded at the Week 13 visit, as the number of months from the first date of a response until the first date of a relapse or the date the subject was last assessed. Only subjects with at least 2 response assessments were included in the duration of response assessment. The measurements were followed up to Week 26 and thereafter in the extension part (Up to the launch of the product after approval, which will be approximately up to two and a half years). Only descriptive analysis done. |
| Volume of (Platelet and RBC) Transfusion in Each Period | Day 1, Day 92 (Week 13), Day 183 (Week 26), Extension W39 and Extension W52 | The amount of blood transfusion (platelets, RBC) were summarized. The measurements were followed up to Week 26 and thereafter in the extension part (Up to the launch of the product after approval, which will be approximately up to two and a half years). Only descriptive analysis done. |
| Frequency of (Platelet and RBC) Transfusion in Each Period | Day 1, Day 92 (Week 13), Day 183 (Week 26), Extension W39 and Extension W52 | The frequency of blood transfusion (platelets, RBC) were summarized. The measurements were followed up to Week 26 and thereafter in the extension part (Up to the launch of the product after approval, which will be approximately up to two and a half years). Only descriptive analysis done. |
| Percentage of Participants With Reduced Volume of Transfusion (Platelet and RBC) | Up to 2.5 years | The proportion of the participants for whom the amount of blood transfusion (platelets and RBC) is decreased was measured and reported as a percentage. The measurements were followed up to Week 26 and thereafter in the extension part (Up to the launch of the product after approval, which will be approximately up to two and a half years). Only descriptive analysis done. This analysis was performed for the subjects who were baseline transfusion dependent. |
| Change in Platelet Count From Baseline in the Absence of Platelet Transfusion Over Time | Up to 2.5 years | The changes in observed values for Platelet Count were summarized. The measurements were followed up to Week 26 and thereafter in the extension part (Up to the launch of the product after approval, which will be approximately up to two and a half years). Only descriptive analysis done. |
| Long-term Safety and Tolerability of Eltrombopag | Up to 30 days after last dose of study treatment | The frequency and percentage of subjects who experienced adverse events (AEs), serious adverse events (SAEs) and deaths by primary system organ class (SOC) and MedDRA preferred term were summarized. |
| Number of Participants With Bleeding Events and Severity of Bleeding | Up to 30 days after last dose of study treatment | The measurements were followed up to Week 26 and thereafter in the extension part. |
| Maximum Observed Plasma Concentration (Cmax) for Eltrombopag | Day 14 at 25 mg QD (-0.05, 0.15, 0.30, 0.45, 1.00, 1.30 and 24.00), at 50,75 and 100 mg QD (pre-dose) | At some study sites, full blood sampling for pharmacokinetic (PK) evaluation of Eltrombopag was performed on Day 14 to calculate Cmax, tmax, AUC(0-t), and AUC(0-tau). PK parameters were calculated from plasma concentration-time data using non-compartmental methods. |
| Time to Reach the Maximum Plasma Concentration (Tmax) for Eltrombopag | Day 14 at 25 mg QD (-0.05, 0.15, 0.30, 0.45, 1.00, 1.30 and 24.00), at 50,75 and 100 mg QD (pre-dose) | At some study sites, full blood sampling for pharmacokinetic (PK) evaluation of Eltrombopag was performed on Day 14 to calculate Cmax, tmax, AUC(0-t), and AUC(0-tau). PK parameters were calculated from plasma concentration-time data using non-compartmental methods. |
| Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration Within a Subject Across All Treatments (AUC 0-t) and Over the Dosing Interval (AUC 0-tau) for Eltrombopag | Day 14 at 25 mg QD (-0.05, 0.15, 0.30, 0.45, 1.00, 1.30 and 24.00), at 50,75 and 100 mg QD (pre-dose) | At some study sites, full blood sampling for pharmacokinetic (PK) evaluation of Eltrombopag was performed on Day 14 to calculate Cmax, tmax, AUC(0-t), and AUC(0-tau). PK parameters were calculated from plasma concentration-time data using non-compartmental methods. |
| Mean Change in Eltrombopag Concentration in Pharmacokinetic Serum Samples Over Time at Days 14 and 15 | Day 14 (pre-dose, 1, 2, 4, 6, 8 and 24 post-dose), Day 15 (pre-dose) | At every study center, blood samples was be collected on Day 15 of multiple doses of eltrombopag 25 mg to determine the plasma eltrombopag concentration prior to the next dose (trough concentration). In addition, one-point pre-dose blood sampling was performed at every study center on Day 15 of multiple doses of eltrombopag 50 mg, 75 mg and 100 mg to determine trough concentrations. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. |
| Percentage of Participants Who Become Transfusion (Platelet and RBC) Independent | Up to 2.5 years | The proportion of participants for whom blood transfusion (platelets and RBC) became unnecessary was measured and reported as a percentage. The measurements were followed up to Week 26 and thereafter in the extension part (Up to the launch of the product after approval, which will be approximately up to two and a half years). Only descriptive analysis done. This analysis was performed for the subjects who were baseline transfusion dependent. |
Countries
Japan
Participant flow
Recruitment details
The study took place in 12 clinical sites in Japan
Pre-assignment details
The target number of subjects enrolled was 20. A total 36 subjects were screened and 21 were enrolled in the study. All 21 subjects enrolled received at least 1 dose of study treatment and were included in the planned analysis sets (full analysis set, safety population and pharmacokinetic population).
Participants by arm
| Arm | Count |
|---|---|
| Eltrombopag Subjects were assigned the investigational product (eltrombopag 25 mg/day) orally once a day under fasting condition. The dose adjustment was done every 2 weeks according to the platelet count (increased by eltrombopag 25 mg/day every 2 weeks according to the platelet count up to 100 mg/day). | 21 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Investigator discretion | 1 |
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Protocol-defined stopping criteria | 2 |
| Overall Study | Protocol deviation | 1 |
Baseline characteristics
| Characteristic | Eltrombopag |
|---|---|
| Age, Continuous | 53.0 Years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 21 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 21 |
| other Total, other adverse events | 20 / 21 |
| serious Total, serious adverse events | 6 / 21 |
Outcome results
Primary
Hematological Response at Week 26
Hematologic response rate at 6 months (at WeeK 26) after the start of study treatment was defined as the percentage of subjects who met any of the response criteria (Platelet count, Hemoglobin level, Neutrophil count). 1 ) Platelet count: an increase from baseline by 20,000/μL or more (In the absence of platelet transfusion), or no platelet transfusion requirements for 8 weeks; 2) Hemoglobin: When the baseline hemoglobin level is \<9 g/dL: Without RBC transfusion at baseline, an increase from baseline by 1.5 g/dL or more; With RBC transfusion at baseline, a decrease of at least 4 units in RBC transfusions in the post-treatment 8-week period compared to the pre-treatment 8-week period (1 unit = RBC derived from 200 mL blood); 3) Neutrophil count: an increase from baseline by 500/μL or more (in the absence of granulocyte colony-stimulating factor (G-CSF)), or (if \< 500/μL at baseline) an increase by 100 % or more. Only descriptive analysis done.
Time frame: D183 (Week 26)
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eltrombopag | Hematological Response at Week 26 | 47.6 Percentage of participants |
Secondary
Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration Within a Subject Across All Treatments (AUC 0-t) and Over the Dosing Interval (AUC 0-tau) for Eltrombopag
At some study sites, full blood sampling for pharmacokinetic (PK) evaluation of Eltrombopag was performed on Day 14 to calculate Cmax, tmax, AUC(0-t), and AUC(0-tau). PK parameters were calculated from plasma concentration-time data using non-compartmental methods.
Time frame: Day 14 at 25 mg QD (-0.05, 0.15, 0.30, 0.45, 1.00, 1.30 and 24.00), at 50,75 and 100 mg QD (pre-dose)
Population: Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least one valid PK concentration value, was considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag | Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration Within a Subject Across All Treatments (AUC 0-t) and Over the Dosing Interval (AUC 0-tau) for Eltrombopag | AUC(0-t) | 123000 Hours*nanograms/milliliter (hr*ng/mL) | Standard Deviation 92900 |
| Eltrombopag | Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration Within a Subject Across All Treatments (AUC 0-t) and Over the Dosing Interval (AUC 0-tau) for Eltrombopag | AUC(0-tau) | 99200 Hours*nanograms/milliliter (hr*ng/mL) | Standard Deviation 119000 |
Secondary
Change in Hemoglobin From Baseline in the Absence of Red Blood Cell (RBC) Transfusion Over Time
The changes in observed values for Hemoglobin were summarized. The measurements were followed up to Week 26 and thereafter in the extension part (Up to the launch of the product after approval, which will be approximately up to two and a half years). Only descriptive analysis done.
Time frame: Up to 2.5 years
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag | Change in Hemoglobin From Baseline in the Absence of Red Blood Cell (RBC) Transfusion Over Time | Baseline | 70.4 Gram/Liter (g/L) | Standard Deviation 13.95 |
| Eltrombopag | Change in Hemoglobin From Baseline in the Absence of Red Blood Cell (RBC) Transfusion Over Time | D92 Week13 | 4.9 Gram/Liter (g/L) | Standard Deviation 11.91 |
| Eltrombopag | Change in Hemoglobin From Baseline in the Absence of Red Blood Cell (RBC) Transfusion Over Time | D183 Week26 | 8.8 Gram/Liter (g/L) | Standard Deviation 17.08 |
| Eltrombopag | Change in Hemoglobin From Baseline in the Absence of Red Blood Cell (RBC) Transfusion Over Time | Extension W39 | 19.3 Gram/Liter (g/L) | Standard Deviation 22.29 |
| Eltrombopag | Change in Hemoglobin From Baseline in the Absence of Red Blood Cell (RBC) Transfusion Over Time | Extension W52 | 24.0 Gram/Liter (g/L) | Standard Deviation 21.11 |
| Eltrombopag | Change in Hemoglobin From Baseline in the Absence of Red Blood Cell (RBC) Transfusion Over Time | Extension W78 | 32.8 Gram/Liter (g/L) | Standard Deviation 19.58 |
| Eltrombopag | Change in Hemoglobin From Baseline in the Absence of Red Blood Cell (RBC) Transfusion Over Time | Extension W104 | 34.4 Gram/Liter (g/L) | Standard Deviation 20.44 |
| Eltrombopag | Change in Hemoglobin From Baseline in the Absence of Red Blood Cell (RBC) Transfusion Over Time | Extension W130 | 31.6 Gram/Liter (g/L) | Standard Deviation 16.99 |
| Eltrombopag | Change in Hemoglobin From Baseline in the Absence of Red Blood Cell (RBC) Transfusion Over Time | Extension W156 | 16.0 Gram/Liter (g/L) | — |
| Eltrombopag | Change in Hemoglobin From Baseline in the Absence of Red Blood Cell (RBC) Transfusion Over Time | Withdrawal | -3.0 Gram/Liter (g/L) | Standard Deviation 13.85 |
| Eltrombopag | Change in Hemoglobin From Baseline in the Absence of Red Blood Cell (RBC) Transfusion Over Time | Last Assessment On-Therapy | 10.0 Gram/Liter (g/L) | Standard Deviation 20.14 |
Secondary
Change in Neutrophil Count From Baseline in the Absence of Granulocyte-colony Stimulating Factor (G-CSF) Over Time
The changes in observed values for Neutrophil Count were summarized. The measurements were followed up to Week 26 and thereafter in the extension part (Up to the launch of the product after approval, which will be approximately up to two and a half years). Only descriptive analysis done.
Time frame: Up to 2.5 years
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag | Change in Neutrophil Count From Baseline in the Absence of Granulocyte-colony Stimulating Factor (G-CSF) Over Time | Baseline | 0.8247 Giga/Liter (Gi/L) | Standard Deviation 0.47985 |
| Eltrombopag | Change in Neutrophil Count From Baseline in the Absence of Granulocyte-colony Stimulating Factor (G-CSF) Over Time | D92 Week13 | 0.3321 Giga/Liter (Gi/L) | Standard Deviation 0.51398 |
| Eltrombopag | Change in Neutrophil Count From Baseline in the Absence of Granulocyte-colony Stimulating Factor (G-CSF) Over Time | D183 Week26 | 0.2046 Giga/Liter (Gi/L) | Standard Deviation 0.4364 |
| Eltrombopag | Change in Neutrophil Count From Baseline in the Absence of Granulocyte-colony Stimulating Factor (G-CSF) Over Time | Extension W39 | 0.4537 Giga/Liter (Gi/L) | Standard Deviation 0.87231 |
| Eltrombopag | Change in Neutrophil Count From Baseline in the Absence of Granulocyte-colony Stimulating Factor (G-CSF) Over Time | Extension W52 | 0.5236 Giga/Liter (Gi/L) | Standard Deviation 0.58529 |
| Eltrombopag | Change in Neutrophil Count From Baseline in the Absence of Granulocyte-colony Stimulating Factor (G-CSF) Over Time | Extension W78 | 0.8579 Giga/Liter (Gi/L) | Standard Deviation 0.6232 |
| Eltrombopag | Change in Neutrophil Count From Baseline in the Absence of Granulocyte-colony Stimulating Factor (G-CSF) Over Time | Extension W104 | 0.6312 Giga/Liter (Gi/L) | Standard Deviation 1.05205 |
| Eltrombopag | Change in Neutrophil Count From Baseline in the Absence of Granulocyte-colony Stimulating Factor (G-CSF) Over Time | Extension W130 | 1.1835 Giga/Liter (Gi/L) | Standard Deviation 1.97999 |
| Eltrombopag | Change in Neutrophil Count From Baseline in the Absence of Granulocyte-colony Stimulating Factor (G-CSF) Over Time | Extension W156 | -0.1712 Giga/Liter (Gi/L) | — |
| Eltrombopag | Change in Neutrophil Count From Baseline in the Absence of Granulocyte-colony Stimulating Factor (G-CSF) Over Time | Withdrawal | 0.3246 Giga/Liter (Gi/L) | Standard Deviation 0.72222 |
| Eltrombopag | Change in Neutrophil Count From Baseline in the Absence of Granulocyte-colony Stimulating Factor (G-CSF) Over Time | Last Assessment On-Therapy | 0.4307 Giga/Liter (Gi/L) | Standard Deviation 1.22084 |
Secondary
Change in Platelet Count From Baseline in the Absence of Platelet Transfusion Over Time
The changes in observed values for Platelet Count were summarized. The measurements were followed up to Week 26 and thereafter in the extension part (Up to the launch of the product after approval, which will be approximately up to two and a half years). Only descriptive analysis done.
Time frame: Up to 2.5 years
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag | Change in Platelet Count From Baseline in the Absence of Platelet Transfusion Over Time | Baseline | 12.19 Giga/Liter (Gi/L) | Standard Deviation 7.155 |
| Eltrombopag | Change in Platelet Count From Baseline in the Absence of Platelet Transfusion Over Time | D92 Week13 | 6.32 Giga/Liter (Gi/L) | Standard Deviation 7.698 |
| Eltrombopag | Change in Platelet Count From Baseline in the Absence of Platelet Transfusion Over Time | D183 Week26 | 13.09 Giga/Liter (Gi/L) | Standard Deviation 14.015 |
| Eltrombopag | Change in Platelet Count From Baseline in the Absence of Platelet Transfusion Over Time | Extension W39 | 23.50 Giga/Liter (Gi/L) | Standard Deviation 22.037 |
| Eltrombopag | Change in Platelet Count From Baseline in the Absence of Platelet Transfusion Over Time | Extension W52 | 21.50 Giga/Liter (Gi/L) | Standard Deviation 15.72 |
| Eltrombopag | Change in Platelet Count From Baseline in the Absence of Platelet Transfusion Over Time | Extension W78 | 36.69 Giga/Liter (Gi/L) | Standard Deviation 23.798 |
| Eltrombopag | Change in Platelet Count From Baseline in the Absence of Platelet Transfusion Over Time | Extension W104 | 35.79 Giga/Liter (Gi/L) | Standard Deviation 21.389 |
| Eltrombopag | Change in Platelet Count From Baseline in the Absence of Platelet Transfusion Over Time | Extension W130 | 42.79 Giga/Liter (Gi/L) | Standard Deviation 28.795 |
| Eltrombopag | Change in Platelet Count From Baseline in the Absence of Platelet Transfusion Over Time | Extension W156 | 25.50 Giga/Liter (Gi/L) | — |
| Eltrombopag | Change in Platelet Count From Baseline in the Absence of Platelet Transfusion Over Time | Withdrawal | 8.81 Giga/Liter (Gi/L) | Standard Deviation 19.387 |
| Eltrombopag | Change in Platelet Count From Baseline in the Absence of Platelet Transfusion Over Time | Last Assessment On-Therapy | 18.38 Giga/Liter (Gi/L) | Standard Deviation 24.017 |
Secondary
Duration of Hematological Response in Participants Who Responded at the Week 13
The duration of haematological response was defined, for subjects who responded at the Week 13 visit, as the number of months from the first date of a response until the first date of a relapse or the date the subject was last assessed. Only subjects with at least 2 response assessments were included in the duration of response assessment. The measurements were followed up to Week 26 and thereafter in the extension part (Up to the launch of the product after approval, which will be approximately up to two and a half years). Only descriptive analysis done.
Time frame: Up to 2.5 years
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Eltrombopag | Duration of Hematological Response in Participants Who Responded at the Week 13 | Hematological Response | 10.68 Months |
| Eltrombopag | Duration of Hematological Response in Participants Who Responded at the Week 13 | Platelet/Platelet Transfusion | 32.62 Months |
| Eltrombopag | Duration of Hematological Response in Participants Who Responded at the Week 13 | Hemoglobin/RBC Transfusion Response | 19.19 Months |
| Eltrombopag | Duration of Hematological Response in Participants Who Responded at the Week 13 | Neutrophils Response | 3.02 Months |
Secondary
Frequency of (Platelet and RBC) Transfusion in Each Period
The frequency of blood transfusion (platelets, RBC) were summarized. The measurements were followed up to Week 26 and thereafter in the extension part (Up to the launch of the product after approval, which will be approximately up to two and a half years). Only descriptive analysis done.
Time frame: Day 1, Day 92 (Week 13), Day 183 (Week 26), Extension W39 and Extension W52
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag | Frequency of (Platelet and RBC) Transfusion in Each Period | Day 1 (Platelets) | 3.0 Tansfusion | Standard Deviation 1.55 |
| Eltrombopag | Frequency of (Platelet and RBC) Transfusion in Each Period | Day 1 (RBC) | 4.1 Tansfusion | Standard Deviation 2.51 |
| Eltrombopag | Frequency of (Platelet and RBC) Transfusion in Each Period | Day 92 (Week 13) (Platelets) | 2.0 Tansfusion | Standard Deviation 2.19 |
| Eltrombopag | Frequency of (Platelet and RBC) Transfusion in Each Period | Day 92 (Week 13) (RBC) | 2.9 Tansfusion | Standard Deviation 2.41 |
| Eltrombopag | Frequency of (Platelet and RBC) Transfusion in Each Period | Day 183 (Week 26) (Platelets) | 1.4 Tansfusion | Standard Deviation 1.95 |
| Eltrombopag | Frequency of (Platelet and RBC) Transfusion in Each Period | Day 183 (Week 26) (RBC) | 1.9 Tansfusion | Standard Deviation 2.64 |
| Eltrombopag | Frequency of (Platelet and RBC) Transfusion in Each Period | Extension W39 (Platelets) | 0.0 Tansfusion | Standard Deviation 0 |
| Eltrombopag | Frequency of (Platelet and RBC) Transfusion in Each Period | Extension W39 (RBC) | 0.8 Tansfusion | Standard Deviation 2.12 |
| Eltrombopag | Frequency of (Platelet and RBC) Transfusion in Each Period | Extension W52 (Platelets) | 0.0 Tansfusion | Standard Deviation 0 |
| Eltrombopag | Frequency of (Platelet and RBC) Transfusion in Each Period | Extension W52 (RBC) | 0.9 Tansfusion | Standard Deviation 2.47 |
Secondary
Hematological Response at Week 13 in Terms of the Platelet Count, Hemoglobin Level and Neutrophil Count
The frequency and percentage were calculated with 95% confidence interval (CI) of responses (which meet each response criteria) of platelet count, hemoglobin and neutrophil count at Week 13.
Time frame: Week 13
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eltrombopag | Hematological Response at Week 13 in Terms of the Platelet Count, Hemoglobin Level and Neutrophil Count | 61.9 Percentage of participants |
Secondary
Long-term Safety and Tolerability of Eltrombopag
The frequency and percentage of subjects who experienced adverse events (AEs), serious adverse events (SAEs) and deaths by primary system organ class (SOC) and MedDRA preferred term were summarized.
Time frame: Up to 30 days after last dose of study treatment
Population: Safety Analysis Set, all subjects who took at least one dose of study treatment. A subject with multiple adverse events within a primary system organ class was counted only once in the total row. Only descriptive analysis done.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Long-term Safety and Tolerability of Eltrombopag | AEs by Primary SOC (SOC) | 100 Percentage of participants |
| Eltrombopag | Long-term Safety and Tolerability of Eltrombopag | Grade 1 AEs by Primary SOC (SOC) | 85.7 Percentage of participants |
| Eltrombopag | Long-term Safety and Tolerability of Eltrombopag | Grade 2 AEs by Primary SOC (SOC) | 81.0 Percentage of participants |
| Eltrombopag | Long-term Safety and Tolerability of Eltrombopag | Grade 3 AEs by Primary SOC (SOC) | 42.9 Percentage of participants |
| Eltrombopag | Long-term Safety and Tolerability of Eltrombopag | Grade 4 AEs by Primary SOC (SOC) | 4.8 Percentage of participants |
| Eltrombopag | Long-term Safety and Tolerability of Eltrombopag | SAEs by Primary System Organ Class (SOC) | 28.6 Percentage of participants |
Secondary
Maximum Observed Plasma Concentration (Cmax) for Eltrombopag
At some study sites, full blood sampling for pharmacokinetic (PK) evaluation of Eltrombopag was performed on Day 14 to calculate Cmax, tmax, AUC(0-t), and AUC(0-tau). PK parameters were calculated from plasma concentration-time data using non-compartmental methods.
Time frame: Day 14 at 25 mg QD (-0.05, 0.15, 0.30, 0.45, 1.00, 1.30 and 24.00), at 50,75 and 100 mg QD (pre-dose)
Population: Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least one valid PK concentration value, was considered.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eltrombopag | Maximum Observed Plasma Concentration (Cmax) for Eltrombopag | 6410 nanogram per milliliter (ng/mL) | Standard Deviation 4200 |
Secondary
Mean Change in Eltrombopag Concentration in Pharmacokinetic Serum Samples Over Time at Days 14 and 15
At every study center, blood samples was be collected on Day 15 of multiple doses of eltrombopag 25 mg to determine the plasma eltrombopag concentration prior to the next dose (trough concentration). In addition, one-point pre-dose blood sampling was performed at every study center on Day 15 of multiple doses of eltrombopag 50 mg, 75 mg and 100 mg to determine trough concentrations. PK parameters were calculated from plasma concentration-time data using non-compartmental methods.
Time frame: Day 14 (pre-dose, 1, 2, 4, 6, 8 and 24 post-dose), Day 15 (pre-dose)
Population: Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least one valid PK concentration value, was considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag | Mean Change in Eltrombopag Concentration in Pharmacokinetic Serum Samples Over Time at Days 14 and 15 | Eltrombopag 25 mg (Day 14) - 0Hr | 4530 nanogram per milliliter (ng/mL) | Standard Deviation 3870 |
| Eltrombopag | Mean Change in Eltrombopag Concentration in Pharmacokinetic Serum Samples Over Time at Days 14 and 15 | Eltrombopag 25 mg (Day 14) - 1Hr | 5240 nanogram per milliliter (ng/mL) | Standard Deviation 3740 |
| Eltrombopag | Mean Change in Eltrombopag Concentration in Pharmacokinetic Serum Samples Over Time at Days 14 and 15 | Eltrombopag 25 mg (Day 14) - 2Hr | 5980 nanogram per milliliter (ng/mL) | Standard Deviation 3990 |
| Eltrombopag | Mean Change in Eltrombopag Concentration in Pharmacokinetic Serum Samples Over Time at Days 14 and 15 | Eltrombopag 25 mg (Day 14) - 4Hr | 5870 nanogram per milliliter (ng/mL) | Standard Deviation 3870 |
| Eltrombopag | Mean Change in Eltrombopag Concentration in Pharmacokinetic Serum Samples Over Time at Days 14 and 15 | Eltrombopag 25 mg (Day 14) - 6Hr | 5720 nanogram per milliliter (ng/mL) | Standard Deviation 4130 |
| Eltrombopag | Mean Change in Eltrombopag Concentration in Pharmacokinetic Serum Samples Over Time at Days 14 and 15 | Eltrombopag 25 mg (Day 14) - 8Hr | 5430 nanogram per milliliter (ng/mL) | Standard Deviation 4170 |
| Eltrombopag | Mean Change in Eltrombopag Concentration in Pharmacokinetic Serum Samples Over Time at Days 14 and 15 | Eltrombopag 25 mg (Day 14) - 24Hr | 4390 nanogram per milliliter (ng/mL) | Standard Deviation 3680 |
| Eltrombopag | Mean Change in Eltrombopag Concentration in Pharmacokinetic Serum Samples Over Time at Days 14 and 15 | Eltrombopag 25 mg (Day 15) - 0Hr | 3730 nanogram per milliliter (ng/mL) | Standard Deviation 2430 |
| Eltrombopag | Mean Change in Eltrombopag Concentration in Pharmacokinetic Serum Samples Over Time at Days 14 and 15 | Eltrombopag 50 mg (Day 15) - 0Hr | 8530 nanogram per milliliter (ng/mL) | Standard Deviation 6410 |
| Eltrombopag | Mean Change in Eltrombopag Concentration in Pharmacokinetic Serum Samples Over Time at Days 14 and 15 | Eltrombopag 75 mg (Day 15) - 0Hr | 15200 nanogram per milliliter (ng/mL) | Standard Deviation 12000 |
| Eltrombopag | Mean Change in Eltrombopag Concentration in Pharmacokinetic Serum Samples Over Time at Days 14 and 15 | Eltrombopag 100 mg (Day 15) - 0Hr | 19300 nanogram per milliliter (ng/mL) | Standard Deviation 15000 |
Secondary
Number of Participants With Bleeding Events and Severity of Bleeding
The measurements were followed up to Week 26 and thereafter in the extension part.
Time frame: Up to 30 days after last dose of study treatment
Population: Safety Analysis Set, all subjects who took at least one dose of study treatment. A subject with multiple adverse events within a primary system organ class was counted only once in the total row. Only descriptive analysis done.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Number of Participants With Bleeding Events and Severity of Bleeding | AE Bleeding - On Treatment | 11 N° of Participants with Bleeding events |
| Eltrombopag | Number of Participants With Bleeding Events and Severity of Bleeding | Grade 1 AE Bleeding - On Treatment | 9 N° of Participants with Bleeding events |
| Eltrombopag | Number of Participants With Bleeding Events and Severity of Bleeding | Grade 2 AE Bleeding - On Treatment | 2 N° of Participants with Bleeding events |
| Eltrombopag | Number of Participants With Bleeding Events and Severity of Bleeding | AE Bleeding - Followup Phase | 6 N° of Participants with Bleeding events |
| Eltrombopag | Number of Participants With Bleeding Events and Severity of Bleeding | Grade 1 AE Bleeding - Followup Phase | 5 N° of Participants with Bleeding events |
| Eltrombopag | Number of Participants With Bleeding Events and Severity of Bleeding | Grade 2 AE Bleeding - Followup Phase | 1 N° of Participants with Bleeding events |
| Eltrombopag | Number of Participants With Bleeding Events and Severity of Bleeding | SAE Bleeding - On Treatment | 0 N° of Participants with Bleeding events |
| Eltrombopag | Number of Participants With Bleeding Events and Severity of Bleeding | SAE Bleeding - Followup Phase | 3 N° of Participants with Bleeding events |
| Eltrombopag | Number of Participants With Bleeding Events and Severity of Bleeding | Grade 2 SAE Bleeding - Followup Phase | 1 N° of Participants with Bleeding events |
| Eltrombopag | Number of Participants With Bleeding Events and Severity of Bleeding | Grade 1 SAE Bleeding - Followup Phase | 2 N° of Participants with Bleeding events |
Secondary
Percentage of Participants Who Become Transfusion (Platelet and RBC) Independent
The proportion of participants for whom blood transfusion (platelets and RBC) became unnecessary was measured and reported as a percentage. The measurements were followed up to Week 26 and thereafter in the extension part (Up to the launch of the product after approval, which will be approximately up to two and a half years). Only descriptive analysis done. This analysis was performed for the subjects who were baseline transfusion dependent.
Time frame: Up to 2.5 years
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Percentage of Participants Who Become Transfusion (Platelet and RBC) Independent | Platelet Transfusion Independence | 66.7 Percentage of participants |
| Eltrombopag | Percentage of Participants Who Become Transfusion (Platelet and RBC) Independent | RBC Transfusion Independence | 47.4 Percentage of participants |
Secondary
Percentage of Participants With Reduced Volume of Transfusion (Platelet and RBC)
The proportion of the participants for whom the amount of blood transfusion (platelets and RBC) is decreased was measured and reported as a percentage. The measurements were followed up to Week 26 and thereafter in the extension part (Up to the launch of the product after approval, which will be approximately up to two and a half years). Only descriptive analysis done. This analysis was performed for the subjects who were baseline transfusion dependent.
Time frame: Up to 2.5 years
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Percentage of Participants With Reduced Volume of Transfusion (Platelet and RBC) | Platelet Transfusion Decrease | 83.3 Percentage of participants |
| Eltrombopag | Percentage of Participants With Reduced Volume of Transfusion (Platelet and RBC) | RBC Transfusion Decrease | 73.7 Percentage of participants |
Secondary
Time to Reach the Maximum Plasma Concentration (Tmax) for Eltrombopag
At some study sites, full blood sampling for pharmacokinetic (PK) evaluation of Eltrombopag was performed on Day 14 to calculate Cmax, tmax, AUC(0-t), and AUC(0-tau). PK parameters were calculated from plasma concentration-time data using non-compartmental methods.
Time frame: Day 14 at 25 mg QD (-0.05, 0.15, 0.30, 0.45, 1.00, 1.30 and 24.00), at 50,75 and 100 mg QD (pre-dose)
Population: Pharmacokinetic Analysis Set (PAS), which consisted of all participants with at least one valid PK concentration value, was considered.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eltrombopag | Time to Reach the Maximum Plasma Concentration (Tmax) for Eltrombopag | 2.00 Hour |
Secondary
Volume of (Platelet and RBC) Transfusion in Each Period
The amount of blood transfusion (platelets, RBC) were summarized. The measurements were followed up to Week 26 and thereafter in the extension part (Up to the launch of the product after approval, which will be approximately up to two and a half years). Only descriptive analysis done.
Time frame: Day 1, Day 92 (Week 13), Day 183 (Week 26), Extension W39 and Extension W52
Population: The Full Analysis Set (FAS), which consisted of all participants with an observed value, was considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag | Volume of (Platelet and RBC) Transfusion in Each Period | Day 1 (Platelets) | 600.0 milliliter (mL) | Standard Deviation 309.84 |
| Eltrombopag | Volume of (Platelet and RBC) Transfusion in Each Period | Day 1 (RBC) | 1663.2 milliliter (mL) | Standard Deviation 1083.31 |
| Eltrombopag | Volume of (Platelet and RBC) Transfusion in Each Period | Day 92 (Week 13) (Platelets) | 400.0 milliliter (mL) | Standard Deviation 438.18 |
| Eltrombopag | Volume of (Platelet and RBC) Transfusion in Each Period | Day 92 (Week 13) (RBC) | 1152.9 milliliter (mL) | Standard Deviation 978.59 |
| Eltrombopag | Volume of (Platelet and RBC) Transfusion in Each Period | Day 183 (Week 26) (Platelets) | 280.0 milliliter (mL) | Standard Deviation 389.87 |
| Eltrombopag | Volume of (Platelet and RBC) Transfusion in Each Period | Day 183 (Week 26) (RBC) | 800.0 milliliter (mL) | Standard Deviation 1131.37 |
| Eltrombopag | Volume of (Platelet and RBC) Transfusion in Each Period | Extension W39 (Platelets) | 0.0 milliliter (mL) | Standard Deviation 0 |
| Eltrombopag | Volume of (Platelet and RBC) Transfusion in Each Period | Extension W39 (RBC) | 300.0 milliliter (mL) | Standard Deviation 848.53 |
| Eltrombopag | Volume of (Platelet and RBC) Transfusion in Each Period | Extension W52 (Platelets) | 0.0 milliliter (mL) | Standard Deviation 0 |
| Eltrombopag | Volume of (Platelet and RBC) Transfusion in Each Period | Extension W52 (RBC) | 400.0 milliliter (mL) | Standard Deviation 1131.37 |