Severe Aplastic Anemia
Conditions
Keywords
severe acquired aplastic anemia, SAA, first line, eltrombopag, cyclosporine, h-ATG, severe aplastic anemia, aplastic anemia
Brief summary
The purpose of this study was to evaluate the efficacy and safety of eltrombopag in combination with cyclosporine alone as first-line therapy on overall hematologic response
Detailed description
This was an interventional phase II, single-arm, multicenter, open-label, study to investigate the efficacy and safety of the combination of eltrombopag and cyclosporine in treatment-naive, adult subjects with severe aplastic anemia (SAA) as first line therapy. Eligible subjects received eltrombopag and cyclosporine for up to 6 months. Participants who achieved hematologic response any time on or before 6 months were considered as responders; else they were considered as non-responders. Responders at Month 6 discontinued eltrombopag and started to taper cyclosporine until relapse or Month 24, whichever was early. Responders who relapsed prior to 6 months and non-responders discontinued the treatment at 6 months and were followed-up for 30 days. Responders who started to taper cyclosporine and relapsed prior to 24 months discontinued cyclosporine and were followed-up for 30 days.
Interventions
DRUGeltrombopag
Film-coated tablets (12.5 mg, 25 mg, 50 mg and 75 mg) administered orally, once daily for up to 6 months. East and Southeast Asian participants were treated with 100 mg once daily, to adjust for the lower apparent clearance of eltrombopag. All other participants were treated with 150 mg once daily.
DRUGCyclosporine
Supplied as oral soft gel capsules. The starting dose was based on body weight at 10.0 mg/kg/day (acceptable rounding range was from 9.5 to 10.5 mg/kg/day) in divided doses every 12 hours. After Day 1, dosing was titrated individually according to therapeutic trough level between 200 and 400 μg/L for 6 months. After 6 months (only for responders at Month 6), tapering of cyclosporine was done as follows: * 6-9 months: at the 6 months visit, the dose was reduced by 25% for 3 months * 9-12 months: at the 9 months visit, the dose was further reduced by 25% for another 3 months * 12-24 months: dose was maintained
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient had signed the Informed Consent (ICF) prior to any screening procedures 2. Patient was male/female ≥18 years old at the time of informed consent and able to swallow a tablet. 3. Patient had SAA characterized by: 1. Bone marrow cellularity \<30% (excluding lymphocytes) and 2. At least two of the following (peripheral blood): * Absolute neutrophil count \<500/µL * Platelet count \<20,000/µL * Absolute reticulocyte count \<60,000/µL 4. Normal ECG defined as the following as determined via the mean of a triplicate ECG * Resting heart rate: 50-90 bpm * QTcF at screening \<450 msec (for male patients), ≤460 msec (for female patients)
Exclusion criteria
1. Diagnosis of Fanconi anemia. 2. Evidence of a clonal hematologic bone marrow disorder on cytogenetics by central review 3. Prior immunosuppressive therapy with cyclosporine, alemtuzumab, rabbit or horse ATG and thrombopoietin receptor (TPO-R) agonists. 4. Hypersensitivity to eltrombopag or cyclosporine or their components. 5. AST or ALT \>3 x ULN. 6. Serum creatinine, total bilirubin, or alkaline phosphatase \>1.5 x ULN. 7. Patient with liver cirrhosis. 8. Patients who were human immune deficiency virus (HIV), hepatitis C virus or hepatitis B surface antigen (HBsAg) positive. HCV-RNA negative patients were allowed to be enrolled. 9. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient's ability to consent, be compliant with study procedures, tolerate protocol therapy, or that death within 30 days is likely. 10. Patients with cancer who were not considered cure, were on active chemotherapeutic treatment or who took drugs with hematological effects. 11. Administration of an investigational drug within 30 days or 5 half-lives, whichever was longer, preceding the first dose of study treatment. 12. Pregnancy statements and contraception requirements: Pregnancy or nursing (lactating) women Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant (or female partners of male patients), unless they were using highly effective methods of contraception during dosing and for 3 months after stopping medication. 13. Not able to understand the investigation nature of the study or to give informed consent. 14. Clinically significant ECG abnormality including cardiac arrhythmias (e. g. ventricular tachycardia) complete left bundle branch block, high grade atrioventricular block, or inability to determine the QTcF interval on the ECG. 15. Presence of cardiac disease, or family history of idiopathic sudden death or congenital long QT syndrome. 16. Risk factors for Torsades de Pointe including uncorrected hypokalemia or hypomagnesemia, or use of concomitant medication(s) with a known risk to prolong the QT interval that could not be discontinued or replaced by safe alternative medication per www.qtdrugs.org. 17. ECOG performance status of ≥2. 18. Patients under the age of 40 must be referred for consideration of allogeneic bone marrow transplantation (HSCT) if (human leukocyte antigen) HLA matching had been done and a suitable matched sibling donor was available and the patient was willing to undergo transplantation (i.e. patients who did not have a HLA match or were not medically fit, not willing or unable to undergo transplantation were considered for enrollment).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Hematologic Response Rate by 6 Months | Up to 6 months | Overall hematologic response rate by 6 months was defined as the percentage of participants with complete response (CR) or partial response (PR) any time on or before 6 months. PR was defined as any two of the following parameters at two consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement: * Absolute neutrophil count (ANC) \>500/μL * Platelet count \>20 000/μL * Reticulocyte count \>60 000/μL CR was defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements: * ANC \> 1 000/μL * Platelet count \>100 000/μL * Hemoglobin \>10 g/L |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Hematologic Response Rate at 12 and 24 Months | 12 and 24 months | Overall hematologic response rate at 12 and 24 months was defined as the percentage of participants with CR or PR at 12 and 24 months respectively. PR was defined as any two of the following parameters at two consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement: * ANC\>500/μL * Platelet count \>20 000/μL * Reticulocyte count \>60 000/μL CR was defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements: * ANC \> 1 000/μL * Platelet count \>100 000/μL * Hemoglobin \>10 g/L |
| Duration of First Hematologic Response | Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6) | Duration of first hematologic response is the time from the date of the start of first response to the date of first relapse. Relapse is defined as no longer meeting definition of PR or CR. Kaplan-Meier method was used for the analysis. If no relapse occurred, the participant was censored at the date of last contact. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24. PR was defined as any 2 of the following parameters at 2 consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement: * ANC \>500/μL * Platelet count \>20 000/μL * Reticulocyte count \>60 000/μL. CR was defined as all 3 parameters meet the following criteria at 2 consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements: * ANC \>1 000/μL * Platelet count \>100 000/μL * Hemoglobin \>10 g/L |
| Relapse Rate by 6 and 24 Months | Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6) | Relapse was defined as no longer meeting the definition of PR (and not CR). Relapse rate by 6 months and 24 was defined as the percentage of responders by 6 months who relapsed prior to 6 months or prior to 24 months respectively. Responders by 6 months were participants who achieved CR or PR any time on or before 6 months. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24. PR: any 2 of the following parameters at 2 consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement: * ANC\>500/μL * Platelet count\>20 000/μL * Reticulocyte count\>60 000/μL. CR: all 3 parameters meet the following criteria at 2 consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements: * ANC\>1 000/μL * Platelet count\>100 000/μL * Hemoglobin\>10 g/L |
| Percentage of Participants With Evolution to Myelodysplasia, Paroxysmal Nocturnal Hemoglobinuria (PNH) and Leukemia | Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6) | The percentage of participants with evolution to myelodysplasia, PNH and acute leukemia occurring at any time during the study. Clonal evolution to myelodysplasia was defined as a new marrow cytogenic abnormality with or without characteristic dysplastic marrow findings. Clonal evolution to leukemia was defined as greater than 20% peripheral blood and/or marrow blasts. Clonal evolution to paroxysmal nocturnal hemoglobinuria (PNH) was defined as a clone at baseline \< 10% that rose to greater than 50% on study. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24 |
| Percentage of Participants Who Were Red Blood Cells (RBC) Transfusion Independent | Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6) | Percentage of participants who were RBC transfusion independent at least once by 6 months and by 24 months (responders only). Independence was defined as no RBC transfusion for at least 56 days. Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24. |
| Percentage of Participants Who Were Platelet Transfusion Independent | Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6) | Percentage of participants who were platelet transfusion independent at least once by 6 months and by 24 months (responders only). Independence was defined as no platelet transfusion for at least 28 days. Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24. |
| Longest Duration of Transfusion Independence (Platelet or RBC) | Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6) | Longest duration of transfusion independence (platelet or RBC) by 6 months and by 24 months (responders only). Transfusion independence was defined as no transfusions required in at least a 28-day period for platelet transfusion and at least 56-day period for RBC transfusion. The duration of the longest interval with transfusion independence was summarized using Kaplan-Meier analysis. Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24 |
| Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Baseline, every 2 weeks from Week 2 to Week 24 or End of Treatment Period 1 (for all participants); and at Week 38, Week 53, Month 24 or End of Treatment Period 2 (for responders at Month 6 only) | The FACT-G consists of 27-items divided into 4 domains (physical well-being, social well-being, emotional and functional well-being). All items of the FACT-G use a 5 point scale ranging from 0 to 4 with a 0 rating being not at all and a 4 rating being very much. Total FACT-G score is the sum of physical well-being score, social well-being score, emotional well-being score and functional well-being score. Score ranges from 0 to 108, with higher scores indicating better quality of life (QoL). A positive change from baseline indicates improvement in the QoL. Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24. |
| Overall Hematologic Response Rate by 3 Months | Up to 3 months | Overall hematologic response rate by 3 months was defined as the percentage of participants with CR or PR any time on or before 3 months. PR was defined as any two of the following parameters at two consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement: * ANC \>500/μL * Platelet count \>20 000/μL * Reticulocyte count \>60 000/μL CR was defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements: * ANC \> 1 000/μL * Platelet count \>100 000/μL * Hemoglobin \>10 g/L |
| Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Baseline, every 2 weeks from Week 2 to Week 24 or End of Treatment Period 1 (for all participants); and at Week 38, Week 53, Month 24 or End of Treatment Period 2 (for responders at Month 6 only) | The FACIT- Fatigue is a 13-item fatigue subscale that asks the patient to rate their degree of tiredness, weakness and fatigue. All items of the FACIT-Fatigue use a 5-point scale ranging from 0 to 4 with a 0 rating being not at all and a 4 rating being very much. Total score ranges from 0 to 52. Negatively worded items were reverse scored before summing so that higher total scores indicate less fatigue. A positive change from baseline indicates improvement. Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24. |
| Pharmacokinetic Parameter- Cmax of Eltrombopag When Combined With Cyclosporine | Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose. | Cmax is the observed maximum plasma concentration following administration. The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 microgram/milliliter (ug/mL). Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day. |
| Pharmacokinetic Parameter-AUClast of Eltrombopag When Combined With Cyclosporine | Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose | AUClast is the area under the curve calculated to the last quantifiable concentration point (Tlast). The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day. |
| Pharmacokinetic Parameter- AUCtau of Eltrombopag When Combined With Cyclosporine | Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose | AUCtau is the area under the curve calculated to the end of the dosing interval (tau). The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day. |
| Pharmacokinetic Parameter- Ctrough of Eltrombopag When Combined With Cyclosporine | Week 2 at pre-dose | Ctrough is the pre-dose plasma concentration. The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day. |
| Pharmacokinetic Parameter- Tmax of Eltrombopag When Combined With Cyclosporine | Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose | Tmax is the time to reach peak or maximum concentration. The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day. |
| Pharmacokinetic Parameter- CLss/F of Eltrombopag When Combined With Cyclosporine | Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose | CLss/F is the apparent systemic (or total body) clearance at steady state from plasma. The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day. |
| Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Baseline, every 2 weeks from Week 2 to Week 24 or End of Treatment Period 1 (for all participants); and at Week 38, Week 53, Month 24 or End of Treatment Period 2 (for responders at Month 6 only) | The FACT-TH18 is comprised of FACT-G and a thrombocytopenia specific questionnaire. FACT-G consists of 27-items divided into 4 domains (physical, social, emotional and functional well-being). FACT-TH18 has 18 additional items which asks the patient to rate degree of thrombocytopenia. All items of the FACT-TH18 use a 5 point scale ranging from 0 to 4, with 0 = not at all and 4 = very much. Total FACT-TH18 score is the sum of physical, social, emotional and functional well-being scores, and thrombocytopenia subscale. Score ranges from 0 to 180, with higher scores indicating better QoL. A positive change from baseline indicates improvement in the QoL. Results are presented for responders and non-responders. If any participant achieved hematologic response (CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24. |
Countries
Brazil, Hong Kong, India, Italy, Mexico, South Korea, Spain, Thailand, Turkey (Türkiye)
Participant flow
Recruitment details
The study was conducted across 20 centers in 9 countries.
Pre-assignment details
Participants received a combination of eltrombopag and cyclosporine for 6 months (Treatment period 1). Participants who were responders at 6 months were followed-up for cyclosporine tapering until relapse or Month 24 whichever was earlier (Treatment period 2)
Participants by arm
| Arm | Count |
|---|---|
| Eltrombopag + Cyclosporine Participants received eltrombopag (orally, 100 mg once daily for East/Southeast Asian participants / 150 mg once daily for all other participants) in combination with cyclosporine (orally, 10.0 mg/kg/day in divided doses every 12 hours) for up to 6 months. Thereafter, responders at Month 6 were treated with cyclosporine until Month 24 | 54 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Treatment Period 1 | Adverse Event | 6 |
| Treatment Period 1 | Death | 5 |
| Treatment Period 1 | Lack of Efficacy | 2 |
| Treatment Period 1 | Progressive disease | 1 |
| Treatment Period 1 | Subject/guardian decision | 1 |
| Treatment Period 1 | Technical Problems | 4 |
| Treatment Period 2 | Adverse Event | 2 |
| Treatment Period 2 | Lack of Efficacy | 5 |
| Treatment Period 2 | Physician Decision | 1 |
| Treatment Period 2 | Progressive disease | 2 |
Baseline characteristics
| Characteristic | Eltrombopag + Cyclosporine |
|---|---|
| Age, Continuous | 52.0 Years STANDARD_DEVIATION 17.88 |
| Race/Ethnicity, Customized East Asian | 7 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 22 Participants |
| Race/Ethnicity, Customized Mixed ethnicity | 1 Participants |
| Race/Ethnicity, Customized Not reported | 1 Participants |
| Race/Ethnicity, Customized Other | 4 Participants |
| Race/Ethnicity, Customized South Asian | 3 Participants |
| Race/Ethnicity, Customized Southeast Asian | 11 Participants |
| Race/Ethnicity, Customized West Asian | 5 Participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 8 / 54 |
| other Total, other adverse events | 47 / 54 |
| serious Total, serious adverse events | 27 / 54 |
Outcome results
Primary
Overall Hematologic Response Rate by 6 Months
Overall hematologic response rate by 6 months was defined as the percentage of participants with complete response (CR) or partial response (PR) any time on or before 6 months. PR was defined as any two of the following parameters at two consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement: * Absolute neutrophil count (ANC) \>500/μL * Platelet count \>20 000/μL * Reticulocyte count \>60 000/μL CR was defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements: * ANC \> 1 000/μL * Platelet count \>100 000/μL * Hemoglobin \>10 g/L
Time frame: Up to 6 months
Population: Full Analysis Set (FAS) including all subjects who received at least one dose of study treatment (eltrombopag or cyclosporine).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eltrombopag + Cyclosporine | Overall Hematologic Response Rate by 6 Months | 46.3 Percentage of participants |
Secondary
Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome
The FACT-TH18 is comprised of FACT-G and a thrombocytopenia specific questionnaire. FACT-G consists of 27-items divided into 4 domains (physical, social, emotional and functional well-being). FACT-TH18 has 18 additional items which asks the patient to rate degree of thrombocytopenia. All items of the FACT-TH18 use a 5 point scale ranging from 0 to 4, with 0 = not at all and 4 = very much. Total FACT-TH18 score is the sum of physical, social, emotional and functional well-being scores, and thrombocytopenia subscale. Score ranges from 0 to 180, with higher scores indicating better QoL. A positive change from baseline indicates improvement in the QoL. Results are presented for responders and non-responders. If any participant achieved hematologic response (CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24.
Time frame: Baseline, every 2 weeks from Week 2 to Week 24 or End of Treatment Period 1 (for all participants); and at Week 38, Week 53, Month 24 or End of Treatment Period 2 (for responders at Month 6 only)
Population: FAS including all subjects who received at least one dose of study treatment (eltrombopag or cyclosporine). Only participants with an evaluable baseline visit and at least one evaluable post-baseline visit were included in the analysis. Number analyzed are the number of participants with data available for analysis at the given category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 8 (Treatment period 1) - Responders | 9.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 10 (Treatment period 1) - Responders | 3.4 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 12 (Treatment period 1) - Responders | 9.3 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 14 (Treatment period 1) - Responders | 6.4 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 16 (Treatment period 1) - Responders | 7.8 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 18 (Treatment period 1) - Responders | 13.9 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 20 (Treatment period 1) - Responders | 11.8 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 22 (Treatment period 1) - Responders | 13.5 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 24 (Treatment period 1) - Responders | 14.5 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 26 (Treatment period 1) - Responders | 18.2 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | End of treatment period 1 - Responders | 13.9 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 53 (Treatment period 2)- Responders | 22.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | End of treatment period 2 - Responders | 6.9 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 2 (Treatment period 1) - Non-Responders | 0.6 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 4 (Treatment period 1) - Non-Responders | 2.1 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 14 (Treatment period 1) - Non-Responders | 2.8 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 18 (Treatment period 1) - Non-Responders | 0.5 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | End of treatment period 1 - Non-Responders | -1.4 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 2 (Treatment period 1) - Responders | 2.3 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 4 (Treatment period 1) - Responders | -1.5 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 6 (Treatment period 1) - Responders | 8.4 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 38 (Treatment period 2)- Responders | 21.7 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Month 24 (Treatment period 2)- Responders | 35.7 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 6 (Treatment period 1) - Non-Responders | -1.5 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 8 (Treatment period 1) - Non-Responders | 2.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 10 (Treatment period 1) - Non-Responders | 5.2 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 12 (Treatment period 1) - Non-Responders | 1.8 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 16 (Treatment period 1) - Non-Responders | 2.1 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 20 (Treatment period 1) - Non-Responders | 2.4 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 22 (Treatment period 1) - Non-Responders | -1.3 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 24 (Treatment period 1) - Non-Responders | 0.7 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of FACT - Thrombocytopenia 18 (FACT-TH18) Patient Reported Outcome | Week 26 (Treatment period 1) - Non-Responders | -1.4 Score on a scale |
Secondary
Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome
The FACT-G consists of 27-items divided into 4 domains (physical well-being, social well-being, emotional and functional well-being). All items of the FACT-G use a 5 point scale ranging from 0 to 4 with a 0 rating being not at all and a 4 rating being very much. Total FACT-G score is the sum of physical well-being score, social well-being score, emotional well-being score and functional well-being score. Score ranges from 0 to 108, with higher scores indicating better quality of life (QoL). A positive change from baseline indicates improvement in the QoL. Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24.
Time frame: Baseline, every 2 weeks from Week 2 to Week 24 or End of Treatment Period 1 (for all participants); and at Week 38, Week 53, Month 24 or End of Treatment Period 2 (for responders at Month 6 only)
Population: FAS including all subjects who received at least one dose of study treatment (eltrombopag or cyclosporine). Only participants with an evaluable baseline visit and at least one evaluable post-baseline visit were included in the analysis. Number analyzed are the number of participants with data available for analysis at the given category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 2 (Treatment period 1) - Responders | -2.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 6 (Treatment period 1) - Responders | -0.3 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 8 (Treatment period 1) - Responders | 0.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 10 (Treatment period 1) - Responders | -1.3 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 14 (Treatment period 1) - Responders | 1.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 16 (Treatment period 1) - Responders | -2.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 18 (Treatment period 1) - Responders | 3.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 20 (Treatment period 1) - Responders | -1.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 22 (Treatment period 1) - Responders | 1.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 24 (Treatment period 1) - Responders | 1.8 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 26 (Treatment period 1) - Responders | 1.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | End of treatment period 1 - Responders | -1.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 38 (Treatment period 2)- Responders | 5.7 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 53 (Treatment period 2)- Responders | 4.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 2 (Treatment period 1) - Non-Responders | -0.3 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 6 (Treatment period 1) - Non-Responders | -3.6 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 8 (Treatment period 1) - Non-Responders | 1.5 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 10 (Treatment period 1) - Non-Responders | -0.9 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 12 (Treatment period 1) - Non-Responders | -0.3 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 16 (Treatment period 1) - Non-Responders | 0.3 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 18 (Treatment period 1) - Non-Responders | -2.6 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 20 (Treatment period 1) - Non-Responders | -1.5 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 24 (Treatment period 1) - Non-Responders | 2.7 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 26 (Treatment period 1) - Non-Responders | -2.7 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | End of treatment period 1 - Non-Responders | -2.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 4 (Treatment period 1) - Non-Responders | -1.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 14 (Treatment period 1) - Non-Responders | -0.3 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 22 (Treatment period 1) - Non-Responders | -1.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 4 (Treatment period 1) - Responders | -3.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Week 12 (Treatment period 1) - Responders | 0.8 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | Month 24 (Treatment period 2)- Responders | 22.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Cancer Therapy - General (FACT-G) Patient Reported Outcome | End of treatment period 2 - Responders | 13.5 Score on a scale |
Secondary
Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome
The FACIT- Fatigue is a 13-item fatigue subscale that asks the patient to rate their degree of tiredness, weakness and fatigue. All items of the FACIT-Fatigue use a 5-point scale ranging from 0 to 4 with a 0 rating being not at all and a 4 rating being very much. Total score ranges from 0 to 52. Negatively worded items were reverse scored before summing so that higher total scores indicate less fatigue. A positive change from baseline indicates improvement. Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24.
Time frame: Baseline, every 2 weeks from Week 2 to Week 24 or End of Treatment Period 1 (for all participants); and at Week 38, Week 53, Month 24 or End of Treatment Period 2 (for responders at Month 6 only)
Population: FAS including all subjects who received at least one dose of study treatment (eltrombopag or cyclosporine). Only participants with an evaluable baseline visit and at least one evaluable post-baseline visit were included in the analysis. Number analyzed are the number of participants with data available for analysis at the given category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 6 (Treatment period 1) - Non-Responders | 0.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 2 (Treatment period 1) - Responders | 3.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 4 (Treatment period 1) - Responders | 2.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 6 (Treatment period 1) - Responders | 4.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 8 (Treatment period 1) - Responders | 6.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 10 (Treatment period 1) - Responders | 4.5 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 12 (Treatment period 1) - Responders | 5.5 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 14 (Treatment period 1) - Responders | 6.5 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 16 (Treatment period 1) - Responders | 6.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 18 (Treatment period 1) - Responders | 7.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 20 (Treatment period 1) - Responders | 6.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 22 (Treatment period 1) - Responders | 6.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 24 (Treatment period 1) - Responders | 6.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 26 (Treatment period 1) - Responders | 7.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | End of treatment period 1 - Responders | 6.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 38 (Treatment period 2)- Responders | 6.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 53 (Treatment period 2)- Responders | 8.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Month 24 (Treatment period 2)- Responders | 9.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | End of treatment period 2 - Responders | 11.5 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 2 (Treatment period 1) - Non-Responders | -0.5 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 4 (Treatment period 1) - Non-Responders | -2.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 8 (Treatment period 1) - Non-Responders | -1.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 10 (Treatment period 1) - Non-Responders | 0.5 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 12 (Treatment period 1) - Non-Responders | -1.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 14 (Treatment period 1) - Non-Responders | -1.5 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 16 (Treatment period 1) - Non-Responders | -0.5 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 18 (Treatment period 1) - Non-Responders | -6.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 20 (Treatment period 1) - Non-Responders | -6.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 22 (Treatment period 1) - Non-Responders | -4.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 24 (Treatment period 1) - Non-Responders | -7.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | Week 26 (Treatment period 1) - Non-Responders | -8.0 Score on a scale |
| Eltrombopag + Cyclosporine | Change From Baseline in Scores of Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT- Fatigue) Patient Reported Outcome | End of treatment period 1 - Non-Responders | -4.0 Score on a scale |
Secondary
Duration of First Hematologic Response
Duration of first hematologic response is the time from the date of the start of first response to the date of first relapse. Relapse is defined as no longer meeting definition of PR or CR. Kaplan-Meier method was used for the analysis. If no relapse occurred, the participant was censored at the date of last contact. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24. PR was defined as any 2 of the following parameters at 2 consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement: * ANC \>500/μL * Platelet count \>20 000/μL * Reticulocyte count \>60 000/μL. CR was defined as all 3 parameters meet the following criteria at 2 consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements: * ANC \>1 000/μL * Platelet count \>100 000/μL * Hemoglobin \>10 g/L
Time frame: Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)
Population: All participants in the FAS who achieved hematologic response (either CR or PR) any time on or before the 6 months visit
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eltrombopag + Cyclosporine | Duration of First Hematologic Response | 351.0 Days |
Secondary
Longest Duration of Transfusion Independence (Platelet or RBC)
Longest duration of transfusion independence (platelet or RBC) by 6 months and by 24 months (responders only). Transfusion independence was defined as no transfusions required in at least a 28-day period for platelet transfusion and at least 56-day period for RBC transfusion. The duration of the longest interval with transfusion independence was summarized using Kaplan-Meier analysis. Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24
Time frame: Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)
Population: FAS including all subjects who received at least one dose of study treatment (eltrombopag or cyclosporine)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Eltrombopag + Cyclosporine | Longest Duration of Transfusion Independence (Platelet or RBC) | Day 1 to 6 months- Responders | NA Days |
| Eltrombopag + Cyclosporine | Longest Duration of Transfusion Independence (Platelet or RBC) | Day 1 to 24 months- Responders | NA Days |
| Eltrombopag + Cyclosporine | Longest Duration of Transfusion Independence (Platelet or RBC) | Day 1 to 6 months- Non-Responders | 87.0 Days |
Secondary
Overall Hematologic Response Rate at 12 and 24 Months
Overall hematologic response rate at 12 and 24 months was defined as the percentage of participants with CR or PR at 12 and 24 months respectively. PR was defined as any two of the following parameters at two consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement: * ANC\>500/μL * Platelet count \>20 000/μL * Reticulocyte count \>60 000/μL CR was defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements: * ANC \> 1 000/μL * Platelet count \>100 000/μL * Hemoglobin \>10 g/L
Time frame: 12 and 24 months
Population: FAS including all subjects who received at least one dose of study treatment (eltrombopag or cyclosporine).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag + Cyclosporine | Overall Hematologic Response Rate at 12 and 24 Months | At 24 months | 18.5 Percentage of participants |
| Eltrombopag + Cyclosporine | Overall Hematologic Response Rate at 12 and 24 Months | At 12 months | 18.5 Percentage of participants |
Secondary
Overall Hematologic Response Rate by 3 Months
Overall hematologic response rate by 3 months was defined as the percentage of participants with CR or PR any time on or before 3 months. PR was defined as any two of the following parameters at two consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement: * ANC \>500/μL * Platelet count \>20 000/μL * Reticulocyte count \>60 000/μL CR was defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements: * ANC \> 1 000/μL * Platelet count \>100 000/μL * Hemoglobin \>10 g/L
Time frame: Up to 3 months
Population: FAS including all subjects who received at least one dose of study treatment (eltrombopag or cyclosporine).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eltrombopag + Cyclosporine | Overall Hematologic Response Rate by 3 Months | 40.7 Percentage of participants |
Secondary
Percentage of Participants Who Were Platelet Transfusion Independent
Percentage of participants who were platelet transfusion independent at least once by 6 months and by 24 months (responders only). Independence was defined as no platelet transfusion for at least 28 days. Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24.
Time frame: Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)
Population: FAS including all subjects who received at least one dose of study treatment (eltrombopag or cyclosporine).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eltrombopag + Cyclosporine | Percentage of Participants Who Were Platelet Transfusion Independent | Day 1 to 6 months- Responders | 25 Participants |
| Eltrombopag + Cyclosporine | Percentage of Participants Who Were Platelet Transfusion Independent | Day 1 to 24 months- Responders | 25 Participants |
| Eltrombopag + Cyclosporine | Percentage of Participants Who Were Platelet Transfusion Independent | Day 1 to 6 months- Non-responders | 13 Participants |
Secondary
Percentage of Participants Who Were Red Blood Cells (RBC) Transfusion Independent
Percentage of participants who were RBC transfusion independent at least once by 6 months and by 24 months (responders only). Independence was defined as no RBC transfusion for at least 56 days. Results are presented for responders and non-responders. If any participant achieved hematologic response (either CR or PR) any time on or before 6 months, they were considered as responders, else they were considered as non-responders. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24.
Time frame: Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)
Population: FAS including all subjects who received at least one dose of study treatment (eltrombopag or cyclosporine).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eltrombopag + Cyclosporine | Percentage of Participants Who Were Red Blood Cells (RBC) Transfusion Independent | Day 1 to 6 months- Responders | 17 Participants |
| Eltrombopag + Cyclosporine | Percentage of Participants Who Were Red Blood Cells (RBC) Transfusion Independent | Day 1 to 24 months- Responders | 20 Participants |
| Eltrombopag + Cyclosporine | Percentage of Participants Who Were Red Blood Cells (RBC) Transfusion Independent | Day 1 to 6 months- Non-Responders | 5 Participants |
Secondary
Percentage of Participants With Evolution to Myelodysplasia, Paroxysmal Nocturnal Hemoglobinuria (PNH) and Leukemia
The percentage of participants with evolution to myelodysplasia, PNH and acute leukemia occurring at any time during the study. Clonal evolution to myelodysplasia was defined as a new marrow cytogenic abnormality with or without characteristic dysplastic marrow findings. Clonal evolution to leukemia was defined as greater than 20% peripheral blood and/or marrow blasts. Clonal evolution to paroxysmal nocturnal hemoglobinuria (PNH) was defined as a clone at baseline \< 10% that rose to greater than 50% on study. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24
Time frame: Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)
Population: FAS including all subjects who received at least one dose of study treatment (eltrombopag or cyclosporine).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eltrombopag + Cyclosporine | Percentage of Participants With Evolution to Myelodysplasia, Paroxysmal Nocturnal Hemoglobinuria (PNH) and Leukemia | 0 Percentage of participants |
Secondary
Pharmacokinetic Parameter-AUClast of Eltrombopag When Combined With Cyclosporine
AUClast is the area under the curve calculated to the last quantifiable concentration point (Tlast). The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
Time frame: Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose
Population: Participants in the Pharmacokinetic Analysis Set (PAS) including participants who provided at least one evaluable PK concentration. Only participants with an evaluable PK parameter (Cmax) were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag + Cyclosporine | Pharmacokinetic Parameter-AUClast of Eltrombopag When Combined With Cyclosporine | East/Southeast Asian ethnicity | 583 hour*microgram/milliliter (h*ug/mL) | Geometric Coefficient of Variation 38.3 |
| Eltrombopag + Cyclosporine | Pharmacokinetic Parameter-AUClast of Eltrombopag When Combined With Cyclosporine | Non-East/Southeast Asian ethnicity | 702 hour*microgram/milliliter (h*ug/mL) | Geometric Coefficient of Variation 59.9 |
Secondary
Pharmacokinetic Parameter- AUCtau of Eltrombopag When Combined With Cyclosporine
AUCtau is the area under the curve calculated to the end of the dosing interval (tau). The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
Time frame: Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose
Population: Participants in the Pharmacokinetic Analysis Set (PAS) including participants who provided at least one evaluable PK concentration. Only participants with an evaluable PK parameter (AUCtau) were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag + Cyclosporine | Pharmacokinetic Parameter- AUCtau of Eltrombopag When Combined With Cyclosporine | East/Southeast Asian ethnicity | 686 hour*microgram/milliliter (h*ug/mL) | Geometric Coefficient of Variation 32.4 |
| Eltrombopag + Cyclosporine | Pharmacokinetic Parameter- AUCtau of Eltrombopag When Combined With Cyclosporine | Non-East/Southeast Asian ethnicity | 727 hour*microgram/milliliter (h*ug/mL) | Geometric Coefficient of Variation 33 |
Secondary
Pharmacokinetic Parameter- CLss/F of Eltrombopag When Combined With Cyclosporine
CLss/F is the apparent systemic (or total body) clearance at steady state from plasma. The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
Time frame: Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose
Population: Participants in the Pharmacokinetic Analysis Set (PAS) including participants who provided at least one evaluable PK concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag + Cyclosporine | Pharmacokinetic Parameter- CLss/F of Eltrombopag When Combined With Cyclosporine | East/Southeast Asian ethnicity | 146 milliliter/hour (mL/h) | Geometric Coefficient of Variation 32.4 |
| Eltrombopag + Cyclosporine | Pharmacokinetic Parameter- CLss/F of Eltrombopag When Combined With Cyclosporine | Non-East/Southeast Asian ethnicity | 206 milliliter/hour (mL/h) | Geometric Coefficient of Variation 33 |
Secondary
Pharmacokinetic Parameter- Cmax of Eltrombopag When Combined With Cyclosporine
Cmax is the observed maximum plasma concentration following administration. The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 microgram/milliliter (ug/mL). Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
Time frame: Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose.
Population: Participants in the Pharmacokinetic Analysis Set (PAS) including participants who provided at least one evaluable PK concentration. Only participants with an evaluable PK sample collected at each timepoint were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag + Cyclosporine | Pharmacokinetic Parameter- Cmax of Eltrombopag When Combined With Cyclosporine | East/Southeast Asian ethnicity | 29.1 microgram/milliliter (ug/mL) | Geometric Coefficient of Variation 43.5 |
| Eltrombopag + Cyclosporine | Pharmacokinetic Parameter- Cmax of Eltrombopag When Combined With Cyclosporine | Non-East/Southeast Asian ethnicity | 38.7 microgram/milliliter (ug/mL) | Geometric Coefficient of Variation 38 |
Secondary
Pharmacokinetic Parameter- Ctrough of Eltrombopag When Combined With Cyclosporine
Ctrough is the pre-dose plasma concentration. The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
Time frame: Week 2 at pre-dose
Population: Participants in the Pharmacokinetic Analysis Set (PAS) including participants who provided at least one evaluable PK concentration. Only participants with an evaluable PK parameter (Ctrough) were included in the analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag + Cyclosporine | Pharmacokinetic Parameter- Ctrough of Eltrombopag When Combined With Cyclosporine | East/Southeast Asian ethnicity | 19.3 microgram/milliliter (ug/mL) | Geometric Coefficient of Variation 45.3 |
| Eltrombopag + Cyclosporine | Pharmacokinetic Parameter- Ctrough of Eltrombopag When Combined With Cyclosporine | Non-East/Southeast Asian ethnicity | 27.2 microgram/milliliter (ug/mL) | Geometric Coefficient of Variation 44.1 |
Secondary
Pharmacokinetic Parameter- Tmax of Eltrombopag When Combined With Cyclosporine
Tmax is the time to reach peak or maximum concentration. The plasma samples from all participants were assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) was 0.1 ug/mL. Concentration values below the LLOQ were reported as zero, and missing samples were labeled accordingly. Results are reported by ethnicity: East/Southeast Asian participants received eltrombopag planned dose of 100mg/day and all other participants received eltrombopag planned dose of 150mg/day.
Time frame: Week 2 at pre-dose and 2, 4, 6 and 8 hours post-dose
Population: Participants in the Pharmacokinetic Analysis Set (PAS) including participants who provided at least one evaluable PK concentration. Only participants with an evaluable PK parameter (Tmax) were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Eltrombopag + Cyclosporine | Pharmacokinetic Parameter- Tmax of Eltrombopag When Combined With Cyclosporine | East/Southeast Asian ethnicity | 5.79 Hours |
| Eltrombopag + Cyclosporine | Pharmacokinetic Parameter- Tmax of Eltrombopag When Combined With Cyclosporine | Non-East/Southeast Asian ethnicity | 3.75 Hours |
Secondary
Relapse Rate by 6 and 24 Months
Relapse was defined as no longer meeting the definition of PR (and not CR). Relapse rate by 6 months and 24 was defined as the percentage of responders by 6 months who relapsed prior to 6 months or prior to 24 months respectively. Responders by 6 months were participants who achieved CR or PR any time on or before 6 months. Only participants who achieved hematologic response of CR or PR at Month 6 were followed up until Month 24. PR: any 2 of the following parameters at 2 consecutive measurements at least 7 days apart and no platelet transfusion within 7 days of platelet measurement: * ANC\>500/μL * Platelet count\>20 000/μL * Reticulocyte count\>60 000/μL. CR: all 3 parameters meet the following criteria at 2 consecutive measurements at least 7 days apart and no platelet transfusions within 7 days of platelet measurement and no red blood cell transfusion with 14 days of the hemoglobin measurements: * ANC\>1 000/μL * Platelet count\>100 000/μL * Hemoglobin\>10 g/L
Time frame: Up to 6 months (non-responders at Month 6) and up to 24 months (responders at Month 6)
Population: All participants in the FAS who achieved hematologic response (either CR or PR) any time on or before the 6 months visit
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag + Cyclosporine | Relapse Rate by 6 and 24 Months | By 24 months | 44.0 Percentage of participants |
| Eltrombopag + Cyclosporine | Relapse Rate by 6 and 24 Months | By 6 months | 32.0 Percentage of participants |