A Phase 2 interventional study of Eltrombopag and Rabbit ATG in Aplastic Anemia, sponsored by Novartis Pharmaceuticals. Completed at 11 sites in Japan. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2019-07-26.
Sponsored by Novartis Pharmaceuticals · Phase 2, Interventional, and Treatment
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.
1,733 studies on the registry are indexed under Anemia; 246 are open to participants now.
This study's enrollment of 10 is below the median of 94 across 1,291 interventional studies indexed under Anemia.
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Exclusion Criteria:
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 wasadministered 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.
Drug: Eltrombopag · Drug: Rabbit ATG · Drug: CsA
Eltrombopag was provided as white round film-coated tablets containing 12.5 mg or 25 mg of eltrombopag free acid (SB-497115-GR, eltrombopag).
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.
CsA as capsules, oral solution, or fine granule, was administered at a dose of 3 mg per kg twice a day.
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
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
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
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
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
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
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
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
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
Duration of Hospitalization
Duration of hospitalization is the time period from the administration of ATG up to discharge.
Time frame: Week 26
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
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
Degree of Exposure to Eltrombopag : Average Daily Dose
Time frame: Week 104
Degree of Exposure to Eltrombopag : Cumulative Dose
The cumulative dose of drug administered to the subject will be calculated.
Time frame: Week 104
Degree of Exposure to Eltrombopag : Days on Study
Time frame: Week 104
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
Vital Signs (Blood Pressure) as a Measure of Safety and Tolerability
Vital sign measurements : blood pressure
Time frame: baseline and Week 26
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
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
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
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
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
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
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
Vital Signs (Temperature) as a Measure of Safety and Tolerability
Vital sign measurements : temperature
Time frame: baseline and Week 26
Vital Signs (Pulse Rate) as a Measure of Safety and Tolerability
Vital sign measurements : pulse rate.
Time frame: baseline and Week 26
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.
| Milestone | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Started | 10 |
| Completed | 6 |
| Not completed | 4 |
| Withdrew: Adverse event | 1 |
| Withdrew: Lack of efficacy | 3 |
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.
| Participants | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| CR+PR | 7 |
| CR | 0 |
| PR | 7 |
ORR will be calculated after 3 months of eltrombopag administration by measuring platelet, reticulocyte, neutrophil and transfusion independence.
| Participants | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| ORR at 3 Months | 2 |
CR and PR will be calculated after 3 months of eltrombopag administration by measuring platelet, reticulocyte, neutrophil and transfusion independence.
| Participants | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| CR | 0 |
| PR | 2 |
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.
| Participants | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| CR Rate Based on the Criteria Used in NIH 12-H-0150 Study at 6 Months | 1 |
The change in hematology values ( haemoglobin) were evaluated.
| g/L | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Haemoglobin changes from baseline, week 26 (g/L) | 24.6 ± 19.20 |
| Haemoglobin changes from baseline, week 104 (g/L) | 39.0 ± 3.61 |
The change in hematology values from baseline for platelets, neutrophils and reticulocytes were evaluated.
| Gi/L | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| neutrophils changes from baseline, week 26 (Gi/L) | 1.2196 ± 0.59501 |
| neutrophils changes from baseline, week 104 (Gi/L) | 1.2978 ± 0.65819 |
| platelets changes from baseline, week 26 (Gi/L) | 66.94 ± 57.187 |
| platelets changes from baseline, week 104 (Gi/L) | 107.33 ± 4.041 |
| reticulocytes changes from baseline week 26 (Gi/L) | 30.0175 ± 21.81519 |
| reticulocytes changes from baseline week104 (Gi/L) | 48.0900 ± 29.96719 |
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.
| mean of transfusions number | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Baseline RBC transfusions | 4.0 ± 3.10 |
| Week 26 RBC transfusions | 1.0 ± 2.24 |
| Baseline Platelet transfusion | 3.4 ± 2.77 |
| Week 26 Platelet transfusion | 1.0 ± 1.91 |
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.
| mL | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Baseline RBC transfusion | 1600.0 ± 1239.35 |
| Week 26 RBC transfusion | 400.0 ± 894.43 |
| Baseline Platelet transfusion | 687.5 ± 559.18 |
| Week 26 Platelet transfusion | 200.0 ± 382.97 |
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.
| Participants | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Baseline RBC transfusion dependence | 6 |
| RBC Transfusion decrease or free | 4 |
| Baseline Platelet transfusion dependence | 8 |
| Platelet Transfusion decrease or free | 5 |
Duration of hospitalization is the time period from the administration of ATG up to discharge.
| days | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Duration of Hospitalization | 49.0 (13 to 123) |
The time to onset of CR and PR will be determined by measuring platelet, reticulocyte, neutrophil and transfusion independence.
| months | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Time to Onset of CR and PR | 3.75 (2.5 to 4.8) |
Duration for CR or PR will be determined by measuring platelet, reticulocyte, neutrophil and transfusion independence.
| months | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Duration of CR or PR | 17.28 (6.0 to 20.3) |
| mg/day | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Degree of Exposure to Eltrombopag : Average Daily Dose | 43.8 ± 23.19 |
The cumulative dose of drug administered to the subject will be calculated.
| mg | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Degree of Exposure to Eltrombopag : Cumulative Dose | 17687.5 ± 7179.77 |
| days | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Degree of Exposure to Eltrombopag : Days on Study | 493.7 ± 233.69 |
Adverse events will be collected from the start of study treatment until the approval.
| Participants | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| number of participants with an AE | 10 |
| with an AE related to any study treatment | 8 |
| with an AE related to Eltrombopag | 5 |
| with an AE related to CsA | 8 |
| number of participants with a SAE | 2 |
Vital sign measurements : blood pressure
| mmHg | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| baseline systolic blood pressure (mmHg) | 115.7 ± 15.06 |
| week 26 systolic blood pressure (mmHg) | 126.4 ± 17.12 |
| baseline diastolic blood pressure (mmHg) | 64.3 ± 11.78 |
| week 26 diastolic blood pressure (mmHg) | 76.9 ± 13.11 |
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.
| Participants | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| screening (baseline) — normal | 8 |
| screening (baseline) — abnormal not clinically significant | 2 |
| screening (baseline) — abnormal clinically significant | 0 |
| week 26 — normal | 6 |
| week 26 — abnormal not clinically significant | 3 |
| week 26 — abnormal clinically significant | 0 |
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.
| ng/mL | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Eltrombopag 25 mg day 15, 0h (predose) | 6070 ± NA |
| Eltrombopag 50 mg day 15, 0h (predose) | 20800 ± 7920 |
| Eltrombopag 75 mg day 15, 0h (predose) | 21800 ± 7370 |
Blood sample will be collected at 4 hours after repeat (14 days) dose of eltrombopag 75 mg
| ng/mL | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| day 15, 0 hour (predose) | 21800 ± 7370 |
| day 15, 4 hours (post dose) | 28400 ± 8960 |
The laboratory test values (haemoglobin and albumin) were calculated at each time point of evaluation.
| g/L | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| hemoglobin baseline (g/L) | 77.2 ± 4.52 |
| hemoglobin week 26 (g/L) | 102.4 ± 17.64 |
| Albumin baseline (g/L) | 38.7 ± 4.83 |
| Albumin Week 26 (g/L) | 44.9 ± 2.52 |
The laboratory test values (lymphocytes and neutrophils) were calculated at each time point of evaluation.
| Gi/L | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| White blood cell count baseline (Gi/L) | 1.896 ± 0.9200 |
| White blood cell count week 26(Gi/L) | 2.682 ± 0.8347 |
| lymphocytes baseline (Gi/L) | 1.3943 ± 0.60771 |
| lymphocytes week 26 (Gi/L) | 0.7108 ± 0.34079 |
| Total Neutrophils Baseline (Gi/L) | 0.4033 ± 0.38230 |
| Total Neutrophils Week 26 (Gi/L) | 1.6120 ± 0.468 |
The laboratory test values (Alcaline Phosphatase and Aspartate Amino Transferase) were calculated at each time point of evaluation.
| IU/L | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Alcaline phosphatase baseline (IU/L) | 186.7 ± 57.03 |
| Alcaline phosphatase Week 26 (IU/L) | 319.6 ± 114.58 |
| Alanine Amino Transferase baseline (IU/L) | 14.3 ± 3.71 |
| Alanine Amino Transferase Week 26(IU/L) | 16.8 ± 7.48 |
| Aspartate Amino Transferase baseline (IU/L) | 14.9 ± 2.47 |
| Aspartate Amino Transferase Week 26(IU/L) | 18.8 ± 4.66 |
The laboratory test values (hematological /biochemical examinations) were calculated at each time point of evaluation.
| umol/L | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Direct Bilirubin baseline (umol/L) | 2.565 ± 0.9012 |
| Direct Bilirubin week 26 (umol/L) | 2.850 ± 1.2092 |
| Indirect Bilirubin baseline (umol/L) | 5.301 ± 2.2002 |
| Indirect Bilirubin week 26 (umol/L) | 6.080 ± 1.7336 |
| Total Bilirubin baseline (umol/L) | 7.866 ± 2.9287 |
| Total Bilirubin week 26 (umol/L) | 8.930 ± 2.5331 |
| Creatinine baseline (umol/L) | 59.6700 ± 11.86193 |
| Creatinine week 26 (umol/L) | 79.9529 ± 23.55122 |
| Potassium baseline (umol/L) | 3.88 ± 0.371 |
| Potassium week 26 (umol/L) | 4.27 ± 0.335 |
| Sodium baseline (umol/L) | 140.7 ± 1.42 |
| Sodium week 26 (umol/L) | 140.4 ± 1.74 |
Vital sign measurements : temperature
| °C | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| baseline temperature (°C) | 36.55 ± 0.448 |
| week 26 temperature (°C) | 36.71 ± 0.379 |
Vital sign measurements : pulse rate.
| beats/min | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| baseline heart rate (beats /min) | 76.2 ± 10.38 |
| week 26 heart rate (beats/min) | 80.4 ± 10.82 |
Collected over Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit up to approximately 2 years.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Eltrombopag+ATG/CsA | 0/10 (0%) | 2/10 (20%) | 10/10 (100%) |
| Event | Eltrombopag+ATG/CsA |
|---|---|
| Febrile neutropeniaBlood and lymphatic system disorders | 1/10 |
| NephrolithiasisRenal and urinary disorders | 1/10 |
| Event | Eltrombopag+ATG/CsA |
|---|---|
| NauseaGastrointestinal disorders | 6/10 |
| HeadacheNervous system disorders | 5/10 |
| ConstipationGastrointestinal disorders | 4/10 |
| VomitingGastrointestinal disorders | 4/10 |
| OedemaGeneral disorders | 4/10 |
| PyrexiaGeneral disorders | 4/10 |
| Renal impairmentRenal and urinary disorders | 4/10 |
| HypertensionVascular disorders | 4/10 |
| StomatitisGastrointestinal disorders | 3/10 |
| NasopharyngitisInfections and infestations | 3/10 |
| Age, Continuous(years) | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Median | 55.5 (39 to 67) |
| Sex: Female, Male(Participants) | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Female | 7 |
| Male | 3 |
| Race/Ethnicity, Customized(Participants) | Eltrombopag+Rabbit ATG/CsA Arm |
|---|---|
| Asian Japanese | 10 |
This study is completed, as verified in May 2019. You cannot join it, but the record below documents what was studied.
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