Aplastic Anemia
Conditions
Keywords
Eltrombopag, rabbit anti-thymocyte globulin, additive effect, cyclosporine A, bone marrow, hematopoietic stem cells, pancytopenia, leukopenia, platelets, throbocytopenia, mature blood cells, bone marrow biopsy
Brief summary
This was an open label, non-randomized, phase II study of eltrombopag in combination with rabbit ATG/CsA in subjects with moderate or more severe AA who did not received prior ATG/ALG-based immunosuppressive therapy. The objective was to assess additive effects of eltorombopag on overall response rate (ORR) at 6 months (Week 26) of treatment with ATG/CsA. Subjects were assessed at least weekly for safety during the period from the start of ATG/CsA to 4 weeks after the start of administration of eltrombopag. After that, subjects had visits every 2 weeks until Week 26. Subjects in whom the treatment was assessed as effective at Week 26 could continued treatment with eltrombopag after 6 months when clinically indicated at the discretion of the investigator. There were five follow-up visits: at discontinuation of the treatment of eltrombopag, and Weeks 1, 2, 3, 4 and 26 after treatment discontinuation. As this study was the first Japanese phase II study in which this product was administered in combination with ATG/CsA to subjects with naive moderate or more severe AA, the subject number of this study was determined to be 10 based on the feasibility survey.
Interventions
DRUGEltrombopag
Eltrombopag was provided as white round film-coated tablets containing 12.5 mg or 25 mg of eltrombopag free acid (SB-497115-GR, eltrombopag).
DRUGRabbit ATG
Rabbit ATG, as an intravenous drip infusion, diluted by 500 mL of saline or 5% glucose injection was administered at a dose of 2.5 to 3.75 mg per kg per day as a slow intravenous infusion over 6 hours.
DRUGCsA
CsA as capsules, oral solution, or fine granule, was administered at a dose of 3 mg per kg twice a day.
Sponsors
Novartis Pharmaceuticals
Study design
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Japanese subjects aged \>=18 and \<71 years at the time of informed consent. Note: subjects aged \>=71 and \<75 may be eligible when clinically indicated at the discretion of the investigator by mutual agreement with Novartis medical advisor. * Diagnosed with moderate or more severe AA according to the diagnostic criteria of AA. The severity classification is: Stage I - Mild - Other than the stages below; Stage II - Moderate - At least two of the following conditions are met: Reticulocyte \<60,000/microliter, Neutrophil \<1,000/microliter, Platelet \<50,000/microliter; Stage III - Moderately severe - At least two of the following conditions are met and regular red blood cell transfusion (a need for transfusion of \>=2 units per month) is required: Reticulocyte \<60,000/microliter, Neutrophil \<1,000/microliter, Platelet \<50,000/microliter; Stage IV - Severe - At least two of the following conditions are met: Reticulocyte \<20,000/microliter, Neutrophil \<500/microliter, Platelet \<20,000/microliter; Stage V - Very severe - At least one of the following conditions is met in addition to neutrophil \<200/microliter: Reticulocyte \<20,000/microliter, Platelet \<20,000/microliter. * Subjects who are considered an indication for the treatment with rabbit ATG and CsA. * Adequate baseline organ function defined by the following criteria: Alanine aminotransferase (ALT), aspartate aminotransferase (AST)\<=3 × local upper limit of normal (ULN) Creatinine, total bilirubin, and alkaline phosphatase (ALP) \<1.5 × local ULN (total bilirubin \<2.5 × local ULN with Gilbert's Syndrome) * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): 0 or 1 * Subjects with QTcF\<450 millisecond (msec) or QTcF\<480 msec with branch block: QTc is QT interval corrected by Fridericia formula (QTcF), machine ,or manual overread. QTcF is based on single or averaged QTc value of triplicate ECG. * Subjects are able to understand and comply with protocol requirements and instructions. * Subjects have signed and dated informed consent. * 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 method of 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 \[if uncertain, postmenopausal state should be confirmed by hematology result of follicle stimulating hormone (FSH) \>40 milli-international units (mIU)/milliliter (mL) or estradiol \<40 picogram (pg)/mL (\<140 picomoles (pmol)/L)\]. 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 ATG/CsA. It is recommended that the pregnancy test should be performed as close as possible to the first dose of ATG/CsA. 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 ATG/CsA until 28 days after the last dose of eltrombopag.
Exclusion criteria
* Diagnosis of congenital AA (e.g. Fanconi anemia or Dyskeratosis congenital). * Subjects who have a sibling donor with matched human leukocyte antigen (HLA) or who underwent hematopoietic stem cell transplantation (HSCT) previously. However, such subjects may be enrolled if HSCT is not indicated, or the subject does not want to undergo HSCT. * Subjects with abnormal chromosome (monosomy 7 detected by fluorescence in situ hybridization (FISH), or other aberrations detected by G-band staining). Note: Subjects with abnormal chromosome which is not adopted into the clone definition of An International System for Human Cytogenetic Nomenclature (ISCN) may be enrolled after consulting with medical monitor. * Previous ATG/ALG-based immunosuppressive therapy or steroid pulse therapy for AA. * Treatment with CsA within 6 months before administration of ATG. * Subjects with a paroxysmal nocturnal hemoglobinuria (PNH) clone size in granulocytes of \>50% by flow cytometric analysis. * Pre-existing cardiac disease (congestive heart failure New York Heart Association (NYHA) Grade II/III/IV), or arrhythmias known to involve the risk of thromboembolic events (e.g. atrial fibrillation) * Past history of thromboembolic event (including anti-phospholipid antibody syndrome) and current use of anticoagulants. * Subjects with past or current malignancy. 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. * Infection not adequately responding to appropriate therapy. * Subject with liver cirrhosis * Subjects with any clinically significant severe cardiac, renal, or hepatic medical condition. * Pregnant women (a positive serum or urine pregnancy test within 7 days prior to the first dose of ATG/CsA or lactating women) Note: Female subjects who are lactating are eligible to participate if they discontinue nursing prior to the first dose of ATG/CsA and refrain from nursing until 5 days after the completion of treatment with eltrombopag. * Known hypersensitivity, intolerance or allergy to rabbit ATG, cyclosporine A, eltrombopag or any of their excipients. * Current alcohol or drug abuse. * Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) proceeding the first dose of ATG/CsA. * Subjects who is not candidates for ATG. * Subjects who is not candidates for CsA. * History of treatment with eltrombopag, romiplostim or other thrombopoietin-receptor (TPO-R) agonists.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ORR at 6 Months: Overall Response Rate (ORR) Defined as the Number of Participants Who Met the Criteria of Either Complete Response (CR) or Partial Response (PR) at Week 26 | Week 26 | ORR will be calculated after 6 months of eltrombopag administration by measuring platelet, reticulocyte, neutrophil and transfusion independence. ORR includes Complete Response (CR) and Partial Response (PR) Rate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response (CR), and Partial Response (PR) Rate at 3 Months | Week 14 | CR and PR will be calculated after 3 months of eltrombopag administration by measuring platelet, reticulocyte, neutrophil and transfusion independence. |
| CR Rate Based on the Criteria Used in NIH 12-H-0150 Study at 6 Months | Week 26 | CR criteria used in NIH 12-H-150 study is as follows: Hemoglobin \>10 gram (g)/ deciliter (dL), and Absolute neutrophil count (ANC) \>1,000/microliter, and Platelets \>100,000/microliter. |
| Changes in Hematology Parameters (Haemoglobin) in the Absence of Platelet Transfusion | Week 26 and week 104 | The change in hematology values ( haemoglobin) were evaluated. |
| Changes in Hematology Parameters in the Absence of Platelet Transfusion | Week 26 and week 104 | The change in hematology values from baseline for platelets, neutrophils and reticulocytes were evaluated. |
| Frequency of Platelet and Red Blood Cells (RBC) Transfusions | Baseline, Week 26 | RBC transfusion dependency defined as at least one RBC transfusion within 8 weeks prior to D1. Platelet or RBC transfusions will be based on physician's subjective judgement. Platelet transfusion will be done if the platelet count is less than 10×10\^9/liter (L) with significant bleeding tendency or the platelet count is less than 20×10\^9/L with pyrexia. RBC transfusion will be done to keep the hemoglobin concentration at over 7 g/dL or in the presence of clinical symptoms such as dyspnea. |
| Volume of Platelet and RBC Transfusions | Baseline, Week 26 | Platelet or RBC transfusions will be based on physician's subjective judgement. Platelet transfusion will be done if the platelet count is less than 10×10\^9/L with significant bleeding tendency or the platelet count is less than 20×10\^9/L with pyrexia. RBC transfusion will be done to keep the hemoglobin concentration at over 7 g/dL or in the presence of clinical symptoms such as dyspnea. |
| The Proportion of Subjects Whose Transfusion Unit (or Volume) Are Decreased or Who Became Transfusion (Platelet, RBC) Independent | Week 26 | The proportions of the subjects for whom the amount of blood transfusion (platelets and RBC) decreased or the proportions of the subjects for whom blood transfusion (platelets and RBC) became unnecessary. Platelet transfusion will be done if the platelet count is less than 10×10\^9/L with significant bleeding tendency or the platelet count is less than 20×10\^9/L with pyrexia. RBC transfusion will be done to keep the hemoglobin concentration at over 7 g/dL or in the presence of clinical symptoms such as dyspnea. |
| Duration of Hospitalization | Week 26 | Duration of hospitalization is the time period from the administration of ATG up to discharge. |
| Time to Onset of CR and PR | Week 26 | The time to onset of CR and PR will be determined by measuring platelet, reticulocyte, neutrophil and transfusion independence. |
| Duration of CR or PR | Week 104 | Duration for CR or PR will be determined by measuring platelet, reticulocyte, neutrophil and transfusion independence. |
| Degree of Exposure to Eltrombopag : Average Daily Dose | Week 104 | — |
| Degree of Exposure to Eltrombopag : Cumulative Dose | Week 104 | The cumulative dose of drug administered to the subject will be calculated. |
| ORR at 3 Months | Week 14 | ORR will be calculated after 3 months of eltrombopag administration by measuring platelet, reticulocyte, neutrophil and transfusion independence. |
| Number of Participants With Adverse Events | though study completion , approximately 2 years | Adverse events will be collected from the start of study treatment until the approval. |
| Vital Signs (Blood Pressure) as a Measure of Safety and Tolerability | baseline and Week 26 | Vital sign measurements : blood pressure |
| 12-lead Electrocardiogram (ECG) as Measure of Safety and Tolerability | Baseline, Week 26 | Triplicate 12-lead ECGs will be obtained at designated time points during the study using an ECG machine that calculates the heart rate and measures PR, QRS, QT, and QT interval corrected by Fridericia formula (QTcF) intervals. |
| The Trough Concentrations of Eltrombopag Following Repeat Doses of at 75 mg, 50 mg and 25 mg | day 15 | Blood samples will be collected after repeat (14 days) doses of eltrombopag 75, 50, 25 mg to determine the plasma eltrombopag concentration prior to the next dose. |
| The Concentration After 4 Hours of Dose of Eltrombopag 75 mg | day 15 | Blood sample will be collected at 4 hours after repeat (14 days) dose of eltrombopag 75 mg |
| Composite of Laboratory Parameters Assessment as a Safety Measure (Haemoglobin and Albumin). | Baseline, Week 26 | The laboratory test values (haemoglobin and albumin) were calculated at each time point of evaluation. |
| Composite of Laboratory Parameters Assessment as a Safety Measure (Lymphocytes and Neutrophils). | Baseline, Week 26 | The laboratory test values (lymphocytes and neutrophils) were calculated at each time point of evaluation. |
| Composite of Laboratory Parameters Assessment as a Safety Measure (Alcaline Phosphatase and Aspartate Amino Transferase) . | Baseline, Week 26 | The laboratory test values (Alcaline Phosphatase and Aspartate Amino Transferase) were calculated at each time point of evaluation. |
| Composite of Laboratory Parameters Assessment as a Safety Measure. | Baseline, Week 26 | The laboratory test values (hematological /biochemical examinations) were calculated at each time point of evaluation. |
| Vital Signs (Temperature) as a Measure of Safety and Tolerability | baseline and Week 26 | Vital sign measurements : temperature |
| Vital Signs (Pulse Rate) as a Measure of Safety and Tolerability | baseline and Week 26 | Vital sign measurements : pulse rate. |
| Degree of Exposure to Eltrombopag : Days on Study | Week 104 | — |
Countries
Japan
Participant flow
Recruitment details
10 subject started eltrombopag, and 1 subject was withdrawn from the study before starting eltrombopag, as he did not meet the eligibility criteria prior to receiving eltrombopag.
Participants by arm
| Arm | Count |
|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm Subjects received rabbit ATG diluted by 500 mL of saline or 5% glucose injection at a dose of 2.5 to 3.75 mg per kilogram (kg) per day for 5 days as a slow intravenous infusion over 6 hours. CsA was administered at a dose of 3 mg per kg twice a day from day 0. The dose level was adjusted based on the monitoring of blood level or renal function. Eltrombopag was initiated on day 14 and it could be delayed up to 2 weeks if the subject had infection, serum sickness, or other adverse events. Eltrombopag was administered orally once a day at fasting at an initial dose of 75 mg, and the dose adjusted every 2 weeks according to the platelet count. Eltrombopag and CsA were continued until Week 26. After Week 26, eligible subjects received eltrombopag; and CsA was tapered or maintained as per the investigator's discretion. | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Lack of Efficacy | 3 |
Baseline characteristics
| Characteristic | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Age, Continuous | 55.5 years |
| Race/Ethnicity, Customized Asian Japanese | 10 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 2 / 10 |
Outcome results
Primary
ORR at 6 Months: Overall Response Rate (ORR) Defined as the Number of Participants Who Met the Criteria of Either Complete Response (CR) or Partial Response (PR) at Week 26
ORR will be calculated after 6 months of eltrombopag administration by measuring platelet, reticulocyte, neutrophil and transfusion independence. ORR includes Complete Response (CR) and Partial Response (PR) Rate.
Time frame: Week 26
Population: Full analysis set; population obtained by excluding subjects: Eltrombopag was never administered to the subject during the study, subject had no baseline data: platelet count, hemoglobin, neutrophil count, and transfusion,subject had no data after the start of rabbit ATG therapy: platelet count, hemoglobin, neutrophil count, and transfusion.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | ORR at 6 Months: Overall Response Rate (ORR) Defined as the Number of Participants Who Met the Criteria of Either Complete Response (CR) or Partial Response (PR) at Week 26 | CR+PR | 7 Participants |
| Eltrombopag+Rabbit ATG/CsA Arm | ORR at 6 Months: Overall Response Rate (ORR) Defined as the Number of Participants Who Met the Criteria of Either Complete Response (CR) or Partial Response (PR) at Week 26 | CR | 0 Participants |
| Eltrombopag+Rabbit ATG/CsA Arm | ORR at 6 Months: Overall Response Rate (ORR) Defined as the Number of Participants Who Met the Criteria of Either Complete Response (CR) or Partial Response (PR) at Week 26 | PR | 7 Participants |
Secondary
12-lead Electrocardiogram (ECG) as Measure of Safety and Tolerability
Triplicate 12-lead ECGs will be obtained at designated time points during the study using an ECG machine that calculates the heart rate and measures PR, QRS, QT, and QT interval corrected by Fridericia formula (QTcF) intervals.
Time frame: Baseline, Week 26
Population: safety population: The safety population consisted of all subjects who received at least one dose of eltrombopag.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | 12-lead Electrocardiogram (ECG) as Measure of Safety and Tolerability | screening (baseline) | normal | 8 Participants |
| Eltrombopag+Rabbit ATG/CsA Arm | 12-lead Electrocardiogram (ECG) as Measure of Safety and Tolerability | screening (baseline) | abnormal not clinically significant | 2 Participants |
| Eltrombopag+Rabbit ATG/CsA Arm | 12-lead Electrocardiogram (ECG) as Measure of Safety and Tolerability | screening (baseline) | abnormal clinically significant | 0 Participants |
| Eltrombopag+Rabbit ATG/CsA Arm | 12-lead Electrocardiogram (ECG) as Measure of Safety and Tolerability | week 26 | normal | 6 Participants |
| Eltrombopag+Rabbit ATG/CsA Arm | 12-lead Electrocardiogram (ECG) as Measure of Safety and Tolerability | week 26 | abnormal not clinically significant | 3 Participants |
| Eltrombopag+Rabbit ATG/CsA Arm | 12-lead Electrocardiogram (ECG) as Measure of Safety and Tolerability | week 26 | abnormal clinically significant | 0 Participants |
Secondary
Changes in Hematology Parameters (Haemoglobin) in the Absence of Platelet Transfusion
The change in hematology values ( haemoglobin) were evaluated.
Time frame: Week 26 and week 104
Population: Full analysis set; population obtained by excluding subjects: Eltrombopag was never administered to the subject during the study, subject had no baseline data: platelet count, hemoglobin, neutrophil count, and transfusion,subject had no data after the start of rabbit ATG therapy: platelet count, hemoglobin, neutrophil count, and transfusion.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Changes in Hematology Parameters (Haemoglobin) in the Absence of Platelet Transfusion | Haemoglobin changes from baseline, week 26 (g/L) | 24.6 g/L | Standard Deviation 19.2 |
| Eltrombopag+Rabbit ATG/CsA Arm | Changes in Hematology Parameters (Haemoglobin) in the Absence of Platelet Transfusion | Haemoglobin changes from baseline, week 104 (g/L) | 39.0 g/L | Standard Deviation 3.61 |
Secondary
Changes in Hematology Parameters in the Absence of Platelet Transfusion
The change in hematology values from baseline for platelets, neutrophils and reticulocytes were evaluated.
Time frame: Week 26 and week 104
Population: Full analysis set; population obtained by excluding subjects: Eltrombopag was never administered to the subject during the study, subject had no baseline data: platelet count, hemoglobin, neutrophil count, and transfusion,subject had no data after the start of rabbit ATG therapy: platelet count, hemoglobin, neutrophil count, and transfusion.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Changes in Hematology Parameters in the Absence of Platelet Transfusion | platelets changes from baseline, week 104 (Gi/L) | 107.33 Gi/L | Standard Deviation 4.041 |
| Eltrombopag+Rabbit ATG/CsA Arm | Changes in Hematology Parameters in the Absence of Platelet Transfusion | reticulocytes changes from baseline week 26 (Gi/L) | 30.0175 Gi/L | Standard Deviation 21.81519 |
| Eltrombopag+Rabbit ATG/CsA Arm | Changes in Hematology Parameters in the Absence of Platelet Transfusion | reticulocytes changes from baseline week104 (Gi/L) | 48.0900 Gi/L | Standard Deviation 29.96719 |
| Eltrombopag+Rabbit ATG/CsA Arm | Changes in Hematology Parameters in the Absence of Platelet Transfusion | neutrophils changes from baseline, week 26 (Gi/L) | 1.2196 Gi/L | Standard Deviation 0.59501 |
| Eltrombopag+Rabbit ATG/CsA Arm | Changes in Hematology Parameters in the Absence of Platelet Transfusion | neutrophils changes from baseline, week 104 (Gi/L) | 1.2978 Gi/L | Standard Deviation 0.65819 |
| Eltrombopag+Rabbit ATG/CsA Arm | Changes in Hematology Parameters in the Absence of Platelet Transfusion | platelets changes from baseline, week 26 (Gi/L) | 66.94 Gi/L | Standard Deviation 57.187 |
Secondary
Complete Response (CR), and Partial Response (PR) Rate at 3 Months
CR and PR will be calculated after 3 months of eltrombopag administration by measuring platelet, reticulocyte, neutrophil and transfusion independence.
Time frame: Week 14
Population: Full analysis set; population obtained by excluding subjects: Eltrombopag was never administered to the subject during the study, subject had no baseline data: platelet count, hemoglobin, neutrophil count, and transfusion,subject had no data after the start of rabbit ATG therapy: platelet count, hemoglobin, neutrophil count, and transfusion.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Complete Response (CR), and Partial Response (PR) Rate at 3 Months | CR | 0 Participants |
| Eltrombopag+Rabbit ATG/CsA Arm | Complete Response (CR), and Partial Response (PR) Rate at 3 Months | PR | 2 Participants |
Secondary
Composite of Laboratory Parameters Assessment as a Safety Measure.
The laboratory test values (hematological /biochemical examinations) were calculated at each time point of evaluation.
Time frame: Baseline, Week 26
Population: safety set:The safety population consisted of all subjects who received at least one dose of eltrombopag.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure. | Direct Bilirubin baseline (umol/L) | 2.565 umol/L | Standard Deviation 0.9012 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure. | Direct Bilirubin week 26 (umol/L) | 2.850 umol/L | Standard Deviation 1.2092 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure. | Indirect Bilirubin baseline (umol/L) | 5.301 umol/L | Standard Deviation 2.2002 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure. | Indirect Bilirubin week 26 (umol/L) | 6.080 umol/L | Standard Deviation 1.7336 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure. | Total Bilirubin baseline (umol/L) | 7.866 umol/L | Standard Deviation 2.9287 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure. | Total Bilirubin week 26 (umol/L) | 8.930 umol/L | Standard Deviation 2.5331 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure. | Creatinine baseline (umol/L) | 59.6700 umol/L | Standard Deviation 11.86193 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure. | Creatinine week 26 (umol/L) | 79.9529 umol/L | Standard Deviation 23.55122 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure. | Potassium baseline (umol/L) | 3.88 umol/L | Standard Deviation 0.371 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure. | Potassium week 26 (umol/L) | 4.27 umol/L | Standard Deviation 0.335 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure. | Sodium baseline (umol/L) | 140.7 umol/L | Standard Deviation 1.42 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure. | Sodium week 26 (umol/L) | 140.4 umol/L | Standard Deviation 1.74 |
Secondary
Composite of Laboratory Parameters Assessment as a Safety Measure (Alcaline Phosphatase and Aspartate Amino Transferase) .
The laboratory test values (Alcaline Phosphatase and Aspartate Amino Transferase) were calculated at each time point of evaluation.
Time frame: Baseline, Week 26
Population: safety set:The safety population consisted of all subjects who received at least one dose of eltrombopag.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure (Alcaline Phosphatase and Aspartate Amino Transferase) . | Alcaline phosphatase baseline (IU/L) | 186.7 IU/L | Standard Deviation 57.03 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure (Alcaline Phosphatase and Aspartate Amino Transferase) . | Alcaline phosphatase Week 26 (IU/L) | 319.6 IU/L | Standard Deviation 114.58 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure (Alcaline Phosphatase and Aspartate Amino Transferase) . | Alanine Amino Transferase baseline (IU/L) | 14.3 IU/L | Standard Deviation 3.71 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure (Alcaline Phosphatase and Aspartate Amino Transferase) . | Alanine Amino Transferase Week 26(IU/L) | 16.8 IU/L | Standard Deviation 7.48 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure (Alcaline Phosphatase and Aspartate Amino Transferase) . | Aspartate Amino Transferase baseline (IU/L) | 14.9 IU/L | Standard Deviation 2.47 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure (Alcaline Phosphatase and Aspartate Amino Transferase) . | Aspartate Amino Transferase Week 26(IU/L) | 18.8 IU/L | Standard Deviation 4.66 |
Secondary
Composite of Laboratory Parameters Assessment as a Safety Measure (Haemoglobin and Albumin).
The laboratory test values (haemoglobin and albumin) were calculated at each time point of evaluation.
Time frame: Baseline, Week 26
Population: safety set:The safety population consisted of all subjects who received at least one dose of eltrombopag.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure (Haemoglobin and Albumin). | hemoglobin baseline (g/L) | 77.2 g/L | Standard Deviation 4.52 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure (Haemoglobin and Albumin). | hemoglobin week 26 (g/L) | 102.4 g/L | Standard Deviation 17.64 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure (Haemoglobin and Albumin). | Albumin baseline (g/L) | 38.7 g/L | Standard Deviation 4.83 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure (Haemoglobin and Albumin). | Albumin Week 26 (g/L) | 44.9 g/L | Standard Deviation 2.52 |
Secondary
Composite of Laboratory Parameters Assessment as a Safety Measure (Lymphocytes and Neutrophils).
The laboratory test values (lymphocytes and neutrophils) were calculated at each time point of evaluation.
Time frame: Baseline, Week 26
Population: safety set:The safety population consisted of all subjects who received at least one dose of eltrombopag.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure (Lymphocytes and Neutrophils). | White blood cell count baseline (Gi/L) | 1.896 Gi/L | Standard Deviation 0.92 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure (Lymphocytes and Neutrophils). | White blood cell count week 26(Gi/L) | 2.682 Gi/L | Standard Deviation 0.8347 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure (Lymphocytes and Neutrophils). | lymphocytes baseline (Gi/L) | 1.3943 Gi/L | Standard Deviation 0.60771 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure (Lymphocytes and Neutrophils). | lymphocytes week 26 (Gi/L) | 0.7108 Gi/L | Standard Deviation 0.34079 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure (Lymphocytes and Neutrophils). | Total Neutrophils Baseline (Gi/L) | 0.4033 Gi/L | Standard Deviation 0.3823 |
| Eltrombopag+Rabbit ATG/CsA Arm | Composite of Laboratory Parameters Assessment as a Safety Measure (Lymphocytes and Neutrophils). | Total Neutrophils Week 26 (Gi/L) | 1.6120 Gi/L | Standard Deviation 0.468 |
Secondary
CR Rate Based on the Criteria Used in NIH 12-H-0150 Study at 6 Months
CR criteria used in NIH 12-H-150 study is as follows: Hemoglobin \>10 gram (g)/ deciliter (dL), and Absolute neutrophil count (ANC) \>1,000/microliter, and Platelets \>100,000/microliter.
Time frame: Week 26
Population: Full analysis set; population obtained by excluding subjects: Eltrombopag was never administered to the subject during the study, subject had no baseline data: platelet count, hemoglobin, neutrophil count, and transfusion,subject had no data after the start of rabbit ATG therapy: platelet count, hemoglobin, neutrophil count, and transfusion.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | CR Rate Based on the Criteria Used in NIH 12-H-0150 Study at 6 Months | 1 Participants |
Secondary
Degree of Exposure to Eltrombopag : Average Daily Dose
Time frame: Week 104
Population: safety population:The safety population consisted of all subjects who received at least one dose of eltrombopag.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Degree of Exposure to Eltrombopag : Average Daily Dose | 43.8 mg/day | Standard Deviation 23.19 |
Secondary
Degree of Exposure to Eltrombopag : Cumulative Dose
The cumulative dose of drug administered to the subject will be calculated.
Time frame: Week 104
Population: safety population:The safety population consisted of all subjects who received at least one dose of eltrombopag.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Degree of Exposure to Eltrombopag : Cumulative Dose | 17687.5 mg | Standard Deviation 7179.77 |
Secondary
Degree of Exposure to Eltrombopag : Days on Study
Time frame: Week 104
Population: safety population:The safety population consisted of all subjects who received at least one dose of eltrombopag.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Degree of Exposure to Eltrombopag : Days on Study | 493.7 days | Standard Deviation 233.69 |
Secondary
Duration of CR or PR
Duration for CR or PR will be determined by measuring platelet, reticulocyte, neutrophil and transfusion independence.
Time frame: Week 104
Population: Number of participants who responded to treatment (7 out of the 10 participants)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Duration of CR or PR | 17.28 months |
Secondary
Duration of Hospitalization
Duration of hospitalization is the time period from the administration of ATG up to discharge.
Time frame: Week 26
Population: Full analysis set; population obtained by excluding subjects: Eltrombopag was never administered to the subject during the study, subject had no baseline data: platelet count, hemoglobin, neutrophil count, and transfusion,subject had no data after the start of rabbit ATG therapy: platelet count, hemoglobin, neutrophil count, and transfusion.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Duration of Hospitalization | 49.0 days |
Secondary
Frequency of Platelet and Red Blood Cells (RBC) Transfusions
RBC transfusion dependency defined as at least one RBC transfusion within 8 weeks prior to D1. Platelet or RBC transfusions will be based on physician's subjective judgement. Platelet transfusion will be done if the platelet count is less than 10×10\^9/liter (L) with significant bleeding tendency or the platelet count is less than 20×10\^9/L with pyrexia. RBC transfusion will be done to keep the hemoglobin concentration at over 7 g/dL or in the presence of clinical symptoms such as dyspnea.
Time frame: Baseline, Week 26
Population: full analysis set, participants who were transfusion dependant
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Frequency of Platelet and Red Blood Cells (RBC) Transfusions | Baseline RBC transfusions | 4.0 mean of transfusions number | Standard Deviation 3.1 |
| Eltrombopag+Rabbit ATG/CsA Arm | Frequency of Platelet and Red Blood Cells (RBC) Transfusions | Week 26 RBC transfusions | 1.0 mean of transfusions number | Standard Deviation 2.24 |
| Eltrombopag+Rabbit ATG/CsA Arm | Frequency of Platelet and Red Blood Cells (RBC) Transfusions | Baseline Platelet transfusion | 3.4 mean of transfusions number | Standard Deviation 2.77 |
| Eltrombopag+Rabbit ATG/CsA Arm | Frequency of Platelet and Red Blood Cells (RBC) Transfusions | Week 26 Platelet transfusion | 1.0 mean of transfusions number | Standard Deviation 1.91 |
Secondary
Number of Participants With Adverse Events
Adverse events will be collected from the start of study treatment until the approval.
Time frame: though study completion , approximately 2 years
Population: safety population:The safety population consisted of all subjects who received at least one dose of eltrombopag.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Number of Participants With Adverse Events | number of participants with an AE | 10 Participants |
| Eltrombopag+Rabbit ATG/CsA Arm | Number of Participants With Adverse Events | with an AE related to any study treatment | 8 Participants |
| Eltrombopag+Rabbit ATG/CsA Arm | Number of Participants With Adverse Events | with an AE related to Eltrombopag | 5 Participants |
| Eltrombopag+Rabbit ATG/CsA Arm | Number of Participants With Adverse Events | with an AE related to CsA | 8 Participants |
| Eltrombopag+Rabbit ATG/CsA Arm | Number of Participants With Adverse Events | number of participants with a SAE | 2 Participants |
Secondary
ORR at 3 Months
ORR will be calculated after 3 months of eltrombopag administration by measuring platelet, reticulocyte, neutrophil and transfusion independence.
Time frame: Week 14
Population: Full analysis set; population obtained by excluding subjects: Eltrombopag was never administered to the subject during the study, subject had no baseline data: platelet count, hemoglobin, neutrophil count, and transfusion,subject had no data after the start of rabbit ATG therapy: platelet count, hemoglobin, neutrophil count, and transfusion.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | ORR at 3 Months | 2 Participants |
Secondary
The Concentration After 4 Hours of Dose of Eltrombopag 75 mg
Blood sample will be collected at 4 hours after repeat (14 days) dose of eltrombopag 75 mg
Time frame: day 15
Population: pharmacokinetic population: The PK population was defined as all subjects whose PK samples were collected and measured.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | The Concentration After 4 Hours of Dose of Eltrombopag 75 mg | day 15, 0 hour (predose) | 21800 ng/mL | Standard Deviation 7370 |
| Eltrombopag+Rabbit ATG/CsA Arm | The Concentration After 4 Hours of Dose of Eltrombopag 75 mg | day 15, 4 hours (post dose) | 28400 ng/mL | Standard Deviation 8960 |
Secondary
The Proportion of Subjects Whose Transfusion Unit (or Volume) Are Decreased or Who Became Transfusion (Platelet, RBC) Independent
The proportions of the subjects for whom the amount of blood transfusion (platelets and RBC) decreased or the proportions of the subjects for whom blood transfusion (platelets and RBC) became unnecessary. Platelet transfusion will be done if the platelet count is less than 10×10\^9/L with significant bleeding tendency or the platelet count is less than 20×10\^9/L with pyrexia. RBC transfusion will be done to keep the hemoglobin concentration at over 7 g/dL or in the presence of clinical symptoms such as dyspnea.
Time frame: Week 26
Population: Full analysis set; population obtained by excluding subjects: Eltrombopag was never administered to the subject during the study, subject had no baseline data: platelet count, hemoglobin, neutrophil count, and transfusion,subject had no data after the start of rabbit ATG therapy: platelet count, hemoglobin, neutrophil count, and transfusion.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | The Proportion of Subjects Whose Transfusion Unit (or Volume) Are Decreased or Who Became Transfusion (Platelet, RBC) Independent | Baseline Platelet transfusion dependence | 8 Participants |
| Eltrombopag+Rabbit ATG/CsA Arm | The Proportion of Subjects Whose Transfusion Unit (or Volume) Are Decreased or Who Became Transfusion (Platelet, RBC) Independent | Baseline RBC transfusion dependence | 6 Participants |
| Eltrombopag+Rabbit ATG/CsA Arm | The Proportion of Subjects Whose Transfusion Unit (or Volume) Are Decreased or Who Became Transfusion (Platelet, RBC) Independent | RBC Transfusion decrease or free | 4 Participants |
| Eltrombopag+Rabbit ATG/CsA Arm | The Proportion of Subjects Whose Transfusion Unit (or Volume) Are Decreased or Who Became Transfusion (Platelet, RBC) Independent | Platelet Transfusion decrease or free | 5 Participants |
Secondary
The Trough Concentrations of Eltrombopag Following Repeat Doses of at 75 mg, 50 mg and 25 mg
Blood samples will be collected after repeat (14 days) doses of eltrombopag 75, 50, 25 mg to determine the plasma eltrombopag concentration prior to the next dose.
Time frame: day 15
Population: pharmacokinetic population:The PK population was defined as all subjects whose PK samples were collected and measured.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | The Trough Concentrations of Eltrombopag Following Repeat Doses of at 75 mg, 50 mg and 25 mg | Eltrombopag 25 mg day 15, 0h (predose) | 6070 ng/mL | — |
| Eltrombopag+Rabbit ATG/CsA Arm | The Trough Concentrations of Eltrombopag Following Repeat Doses of at 75 mg, 50 mg and 25 mg | Eltrombopag 50 mg day 15, 0h (predose) | 20800 ng/mL | Standard Deviation 7920 |
| Eltrombopag+Rabbit ATG/CsA Arm | The Trough Concentrations of Eltrombopag Following Repeat Doses of at 75 mg, 50 mg and 25 mg | Eltrombopag 75 mg day 15, 0h (predose) | 21800 ng/mL | Standard Deviation 7370 |
Secondary
Time to Onset of CR and PR
The time to onset of CR and PR will be determined by measuring platelet, reticulocyte, neutrophil and transfusion independence.
Time frame: Week 26
Population: Full analysis set; population obtained by excluding subjects: Eltrombopag was never administered to the subject during the study, subject had no baseline data: platelet count, hemoglobin, neutrophil count, and transfusion,subject had no data after the start of rabbit ATG therapy: platelet count, hemoglobin, neutrophil count, and transfusion.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Time to Onset of CR and PR | 3.75 months |
Secondary
Vital Signs (Blood Pressure) as a Measure of Safety and Tolerability
Vital sign measurements : blood pressure
Time frame: baseline and Week 26
Population: safety set:The safety population consisted of all subjects who received at least one dose of eltrombopag.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Vital Signs (Blood Pressure) as a Measure of Safety and Tolerability | baseline systolic blood pressure (mmHg) | 115.7 mmHg | Standard Deviation 15.06 |
| Eltrombopag+Rabbit ATG/CsA Arm | Vital Signs (Blood Pressure) as a Measure of Safety and Tolerability | week 26 systolic blood pressure (mmHg) | 126.4 mmHg | Standard Deviation 17.12 |
| Eltrombopag+Rabbit ATG/CsA Arm | Vital Signs (Blood Pressure) as a Measure of Safety and Tolerability | baseline diastolic blood pressure (mmHg) | 64.3 mmHg | Standard Deviation 11.78 |
| Eltrombopag+Rabbit ATG/CsA Arm | Vital Signs (Blood Pressure) as a Measure of Safety and Tolerability | week 26 diastolic blood pressure (mmHg) | 76.9 mmHg | Standard Deviation 13.11 |
Secondary
Vital Signs (Pulse Rate) as a Measure of Safety and Tolerability
Vital sign measurements : pulse rate.
Time frame: baseline and Week 26
Population: safety set:The safety population consisted of all subjects who received at least one dose of eltrombopag.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Vital Signs (Pulse Rate) as a Measure of Safety and Tolerability | baseline heart rate (beats /min) | 76.2 beats/min | Standard Deviation 10.38 |
| Eltrombopag+Rabbit ATG/CsA Arm | Vital Signs (Pulse Rate) as a Measure of Safety and Tolerability | week 26 heart rate (beats/min) | 80.4 beats/min | Standard Deviation 10.82 |
Secondary
Vital Signs (Temperature) as a Measure of Safety and Tolerability
Vital sign measurements : temperature
Time frame: baseline and Week 26
Population: safety set:The safety population consisted of all subjects who received at least one dose of eltrombopag.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Vital Signs (Temperature) as a Measure of Safety and Tolerability | baseline temperature (°C) | 36.55 °C | Standard Deviation 0.448 |
| Eltrombopag+Rabbit ATG/CsA Arm | Vital Signs (Temperature) as a Measure of Safety and Tolerability | week 26 temperature (°C) | 36.71 °C | Standard Deviation 0.379 |
Secondary
Volume of Platelet and RBC Transfusions
Platelet or RBC transfusions will be based on physician's subjective judgement. Platelet transfusion will be done if the platelet count is less than 10×10\^9/L with significant bleeding tendency or the platelet count is less than 20×10\^9/L with pyrexia. RBC transfusion will be done to keep the hemoglobin concentration at over 7 g/dL or in the presence of clinical symptoms such as dyspnea.
Time frame: Baseline, Week 26
Population: Full analysis set, patients who were transfusion dependent
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag+Rabbit ATG/CsA Arm | Volume of Platelet and RBC Transfusions | Week 26 RBC transfusion | 400.0 mL | Standard Deviation 894.43 |
| Eltrombopag+Rabbit ATG/CsA Arm | Volume of Platelet and RBC Transfusions | Baseline Platelet transfusion | 687.5 mL | Standard Deviation 559.18 |
| Eltrombopag+Rabbit ATG/CsA Arm | Volume of Platelet and RBC Transfusions | Baseline RBC transfusion | 1600.0 mL | Standard Deviation 1239.35 |
| Eltrombopag+Rabbit ATG/CsA Arm | Volume of Platelet and RBC Transfusions | Week 26 Platelet transfusion | 200.0 mL | Standard Deviation 382.97 |