Severe Aplastic Anemia (SAA)
Conditions
Keywords
Treatment naïve severe aplastic anemia, SAA, eltrombopag, ETB115, immunosuppressive therapy, rabbit anti-thymocyte globulin, r-ATG, cyclosporine A, CsA, East-Asian patients
Brief summary
This study was designed to evaluate the efficacy and safety of eltrombopag when added to r-ATG and CsA in treatment naive East-Asian adult and pediatric patients with severe aplastic anemia (SAA).
Detailed description
This was a non-randomized, open label, single arm, multi-center, Phase II study to evaluate the efficacy and safety of eltrombopag in combination with immunosuppressive therapy (IST) regimen of r-ATG + CsA in East-Asian patients with severe aplatsic anemia who had not received prior IST. Eligible participants were enrolled into the study and received eltrombopag (from Day 1 to Week 26) concomitantly with r-ATG (on Days 1-5) and CsA (from Day 1 to Week 26) in the core treatment part. Participants who were assessed as responders (meeting complete (CR) or partial (PR) response criteria) at Week 26 were eligible for the extension part of the study and continued treatment with eltrombopag and CsA after Week 26 up to Week 52. During the extension part, eltrombopag treatment was provided up to Week 52. CsA was maintained or tapered at the investigator's discretion according to local practice, with a total duration of at least 2 years (18 months after Week 26). There was a 30 days after end of treatment safety follow-up at the end of the extension part. All participants were offered to enter the long term follow-up after the discontinuation of eltrombopag, with yearly efficacy and clonal evolution assessments up to Year 3 (Week 156).
Interventions
DRUGeltrombopag
Tablet 25mg and 12.5mg
DRUGrabbit anti-thymocyte globulin (r-ATG)
r-ATG 25 mg sterile lyophilized powder in 10 mL vials for IV use
CsA 25mg Capsule or CsA 5.0g/50mL solution for oral use
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Written study informed consent and (where applicable) assent from the subject, parent, or guardian must be obtained prior to participation in the study. * Subjects of East Asian ethnicity aged ≥ 6 years old at the time of written informed consent and assent form (if applicable). * SAA characterized by: * Bone marrow cellularity \< 25%, or 25-50% with \< 30% residual hematopoietic cells and pancytopenia, with at least two of the following parameters in peripheral blood: * Absolute neutrophil count \< 0.5×109/L * Platelet count \< 20×109/L * Absolute reticulocyte count \< 20×109/L * HSCT not suitable or available as a treatment option (determined as per local practices or national guidelines), or has been refused by subject.
Exclusion criteria
* Prior IST with any ATG/ALG , alemtuzumab, high dose cyclophosphamide (≥ 45 mg/kg/day), CsA within 6 months, or prior thrombopoietin receptor agonists. * Eastern Cooperative Oncology Group (ECOG) performance status (age ≥ 16 years) \>2, or Lansky performance status (age \< 16 years) \<50. * Prior and/or active medical history of: * Known underlying congenital/inherited bone marrow failure or aplastic anemia (e.g.,such as but not limited to Fanconi anemia, congenital dyskeratosis, congenital amegakaryocytic thrombocytopenia, or Shwachman-Diamond Syndrome) * Symptomatic paroxysmal nocturnal hemoglobinuria (PNH) and/or PNH clones \>50% of polymorphonuclear neutrophil (PMN) or RBC at time of enrollment * Myelodysplastic syndrome (MDS) * Any cytogenetic abnormalities on karyotyping or FISH within 30 days of study enrollment (an evaluable karyotyping with at least 10 metaphases is mandatory for eligibility) * Other known or suspected underlying primary immunodeficiency * Any concomitant malignancies that have not fully recovered from treatment or have not been disease-free for 5 years * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>3 times the upper limit of normal (ULN). * Creatinine ≥ 2.5×local ULN * Past medical history of thromboembolism within 6 months, and/or prior or current antiphospholipid antibody syndrome (APS). * Presence of clinically active uncontrolled significant (of such severity that it would preclude the subject's ability to consent, be compliant with study procedures, tolerate protocol therapy) infection, including bacterial, fungal, mycobacterial, parasitic or viral infection, or any concurrent condition that, in the Investigator's opinion, would jeopardize the safety of the subject or compliance with the protocol * Any severe and/or uncontrolled medical conditions which could cause unacceptable safety risks or compromise compliance with the protocol, such as: * Known hepatocellular disease (e.g. active hepatitis or cirrhosis) * Impairment of gastrointestinal (GI) function or gastrointestinal disease that may significantly alter the absorption of study treatment (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome) * Active skin, mucosa, ocular or GI disorders of Grade \> 1 * Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening. A positive serology for Hepatitis B (HB) is considered as a positive test for HBsAg. In addition, if serology is negative for HBsAg but hepatitis B core antibody (HBcAb) is positive (regardless of hepatitis B surface antibody (HBsAb) status), a hepatitis B virus (HBV) DNA test will be performed and if positive the patient will be excluded. * Cardiac disorder (subjects with congestive heart disease of New York Heart Association (NYHA) functional classification Grade II/III/IV (for pediatric subjects, refer to the Grade II/III/IV of Modified ross heart failure classification for Children) should not be enrolled; subjects with NYHA Grade II due to cardiac disorder should not be enrolled but those with NYHA Grade II due to aplastic anemia (AA) may be enrolled.), arrhythmia with a risk of thrombosis (e.g. atrial fibrillation), pulmonary hypertension, or uncontrolled hypertension (\>180/100 mmHg).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response (CR) Rate at Week 26 | Week 26 (6 months after starting study treatment) | Complete response rate was defined as percentage of patients achieving complete response (CR). Complete response was defined as subjects meeting all the three criteria on two consecutive serial blood count measurements at least one week apart but not more than four weeks apart: * Absolute neutrophil count \> 1.0 ×10\^9/L * Platelet count \> 100 ×10\^9/L * Hemoglobin \> 100 g/L The participants who discontinued from the trial before Week 26 and those that received blood products prior to response assessment (7 days prior for platelet transfusions, 14 days for RBC transfusion and 21 days for growth factors) were treated as non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response (ORR) Rate | Week 13 (3 months), 26 weeks (6 months), 52 weeks and yearly after up to 3 years | Overall response rate was defined as percentage of patients achieving complete response (CR) or partial response (PR). Partial response (PR) was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in SAA, equivalent to at least 2 of the 3 criteria below, but not sufficient for a CR: * Absolute neutrophil count ≥ 0.5 × 10\^9/L * Platelet count ≥ 20 × 10\^9/L * Reticulocyte count ≥ 20 × 10\^9/L Complete response (CR) was defined as subjects meeting all the three criteria on two consecutive serial blood count measurements at least one week apart but not more than four weeks apart: * Absolute neutrophil count \> 1.0 ×10\^9/L * Platelet count \> 100 ×10\^9/L * Hemoglobin \> 100 g/L |
| Duration of Complete Response | Up to aproximately 3 years | Duration of response was derived as the time from first documented and confirmed complete response (CR) until the time of relapse or death, whichever occurred first. Duration of response was estimated using Kaplan-Meier method. Clinical relapse was considered as the occurrence of any of the following events in a participant who had achieved a hematological response (CR) but had subsequently lost response (not explained by any other independent concomitant medical conditions) in one blood count measurements: * Meeting again the criteria for SAA * Requirement for transfusion again for subjects who had been transfusion independent * Decrease in any of the peripheral blood counts to absolute neutrophil count \< 0.5 x10\^9/L or platelets \< 20 x10\^9/L. |
| Duration of Overall Response | Up to aproximately 3 years | Duration of response was derived as the time from first documented and confirmed response (either CR or PR) until the time of relapse or death, whichever occurred first. Duration of response was estimated using Kaplan-Meier method. Clinical relapse was considered as the occurrence of any of the following events in a participant who had achieved a hematological response (CR or PR) but had subsequently lost response (not explained by any other independent concomitant medical conditions) in one blood count measurements: * Meeting again the criteria for SAA * Requirement for transfusion again for subjects who had been transfusion independent * Decrease in any of the peripheral blood counts to absolute neutrophil count \< 0.5 x10\^9/L or platelets \< 20 x10\^9/L. |
| Overall Survival (OS) | Up to approximately 3 years | OS was defined as the time from the date of the first dose of study treatment to the date of death due to any cause. If a subject was not known to have died, survival was censored at the date of last contact. The distribution function of OS was estimated using the Kaplan- Meier method. |
| Overall Survival (OS) Rate | Week 26, Week 52 and yearly after up to 3 years | OS was defined as the time from the date of the first dose of study treatment to the date of death due to any cause. The OS rate is the estimated probability that a patient will remain event-free up to the specified time point and was obtained from the Kaplan-Meier survival estimates. If a subject was not known to have died, survival was censored at the date of last contact. |
| Red Blood Cells (RBC) and Platelet Transfusion-free Interval Before Week 13 and 26 | Week 13, 26 | Transfusion-free interval was defined as the time from most recent RBC/platelet transfusion preceding response assessment to the date of response assessment. |
| Percentage of Participants Who Become RBC Transfusion Independent | From date of first dose to approximately 3 years | Transfusion independent participants were defined as those participants who were transfusion dependent at baseline but became transfusion free for a period of ≥ 8 weeks post-baseline for RBCs. |
| Complete Response (CR) Rate | Week 13 (3 months), Week 52 (12 months) and yearly after up to 3 years | Complete response rate was defined as percentage of patients achieving complete response (CR). Complete response was defined as subjects meeting all the three criteria on two consecutive serial blood count measurements at least one week apart but not more than four weeks apart: * Absolute neutrophil count \> 1.0 ×10\^9/L * Platelet count \> 100 ×10\^9/L * Hemoglobin \> 100 g/L The participants who discontinued from the trial before Week 26 and those that received blood products prior to response assessment (7 days prior for platelet transfusions, 14 days for RBC transfusion and 21 days for growth factors) were treated as non-responders. |
| Time From the Date of First Dose of Investigational Treatment to the Date of First Occurrence of Any Clonal Evolution Events | From date of first dose to approximately 3 years | Clonal evolution events were assessed by karyotyping (G-banding) and FISH (Fluorescence in situ hybridization) targeting abnormalities including, but not restricted to chromosome 3q del,5q del, monosomy 7, trisomy 8 and those associated with SAA (Severe aplastic anemia), MDS (Myelodysplastic syndrome), AML (Acute myeloid leukemia). Time to clonal evolution was to be estimated using the Kaplan-Meier method. |
| Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: AUClast | Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose | AUClast is the area under the curve from time zero to the last measurable concentration sampling time. Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach. |
| Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: AUCtau | Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose | AUCtau is area under the curve calculated to the end of a dosing interval (tau) at steady-state Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach. |
| Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: Ctrough | Pre-dose on day 15 after initation of eltrombopag and and pre-dose on the 15th day after each new dose up to week 26 | Cthrough is the pre-dose concentration at the end of dose interval. Blood samples were collected to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach. Eltrombopag was administered orally once daily with initial doses of 75mg/day for ≥ 12 years old and 37.5 mg/day for participants between ≥ 6 and \< 12 years. Doses could be adjusted based on platelet count every 2 weeks by decreasing it by 25 mg/day (12.5 mg/day, for participants below 12 years old) if the platelet count was above 200×10\^9/L. or interrupted if platelet count rose above 400×10\^9/L. In partial response participants dose could be restarted or increased to that before the decrease if platelet counts \< 30 x10\^9/L, Hb\< 90 g/L, ANC\< 0.5 x 10\^9/L or participant needed transfusion. In complete response participants dose could be restarted or increased to that before decrease if blood counts dropped to not meet CR criteria. |
| Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: Cmax | Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose | Cmax is the The maximum (peak) observed plasma drug concentration after dose administration. Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach. |
| Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: Tmax | Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose | Tmax is the time to reach maximum (peak) plasma drug concentration after dose administration. Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach. |
| Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: CLss/F | Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose | CLss/F is Apparent systemic (or total body) clearance at steady state from plasma. Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach. |
| Percentage of Participants Who Become Platelet Transfusion Independent | From date of first dose to approximately 3 years | Transfusion independent participants were defined as those participants who were transfusion dependent at baseline but became transfusion free for a period of ≥ 4 weeks post-baseline for platelets. |
Countries
China, Japan, South Korea, Taiwan
Participant flow
Recruitment details
Participants were enrolled at 12 sites in 4 different countries
Pre-assignment details
there was an up to 30 days screening period (day -30 to -1) before first treatment (day 1).
Participants by arm
| Arm | Count |
|---|---|
| Eltrombopag Participants received eltrombopag in combination with r-ATG and CsA. | 36 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 3 |
| Overall Study | Guardian Decision | 1 |
| Overall Study | Participant decision | 4 |
Baseline characteristics
| Characteristic | Eltrombopag |
|---|---|
| Age, Categorical <=18 years | 8 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants |
| Age, Continuous | 34.7 years STANDARD_DEVIATION 18.97 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 36 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 36 | 2 / 34 |
| other Total, other adverse events | 36 / 36 | 0 / 0 |
| serious Total, serious adverse events | 14 / 36 | 0 / 0 |
Outcome results
Primary
Complete Response (CR) Rate at Week 26
Complete response rate was defined as percentage of patients achieving complete response (CR). Complete response was defined as subjects meeting all the three criteria on two consecutive serial blood count measurements at least one week apart but not more than four weeks apart: * Absolute neutrophil count \> 1.0 ×10\^9/L * Platelet count \> 100 ×10\^9/L * Hemoglobin \> 100 g/L The participants who discontinued from the trial before Week 26 and those that received blood products prior to response assessment (7 days prior for platelet transfusions, 14 days for RBC transfusion and 21 days for growth factors) were treated as non-responders.
Time frame: Week 26 (6 months after starting study treatment)
Population: The Full Analysis Set (FAS) comprised of all participants to whom study treatment has been assigned and who received at least one dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Complete Response (CR) Rate at Week 26 | All participants | 16.7 percentage of participants |
| Eltrombopag | Complete Response (CR) Rate at Week 26 | < 18 years | 25 percentage of participants |
| Eltrombopag | Complete Response (CR) Rate at Week 26 | 18-64 years | 15.4 percentage of participants |
| Eltrombopag | Complete Response (CR) Rate at Week 26 | ≥ 65 years | 0 percentage of participants |
Secondary
Complete Response (CR) Rate
Complete response rate was defined as percentage of patients achieving complete response (CR). Complete response was defined as subjects meeting all the three criteria on two consecutive serial blood count measurements at least one week apart but not more than four weeks apart: * Absolute neutrophil count \> 1.0 ×10\^9/L * Platelet count \> 100 ×10\^9/L * Hemoglobin \> 100 g/L The participants who discontinued from the trial before Week 26 and those that received blood products prior to response assessment (7 days prior for platelet transfusions, 14 days for RBC transfusion and 21 days for growth factors) were treated as non-responders.
Time frame: Week 13 (3 months), Week 52 (12 months) and yearly after up to 3 years
Population: The Full Analysis Set (FAS) comprised of all participants to whom study treatment has been assigned and who received at least one dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Complete Response (CR) Rate | Week 13 | 5.6 percentage of participants |
| Eltrombopag | Complete Response (CR) Rate | Week 52 | 30.6 percentage of participants |
| Eltrombopag | Complete Response (CR) Rate | Year 2 | 30.6 percentage of participants |
| Eltrombopag | Complete Response (CR) Rate | Year 3 | 30.6 percentage of participants |
Secondary
Duration of Complete Response
Duration of response was derived as the time from first documented and confirmed complete response (CR) until the time of relapse or death, whichever occurred first. Duration of response was estimated using Kaplan-Meier method. Clinical relapse was considered as the occurrence of any of the following events in a participant who had achieved a hematological response (CR) but had subsequently lost response (not explained by any other independent concomitant medical conditions) in one blood count measurements: * Meeting again the criteria for SAA * Requirement for transfusion again for subjects who had been transfusion independent * Decrease in any of the peripheral blood counts to absolute neutrophil count \< 0.5 x10\^9/L or platelets \< 20 x10\^9/L.
Time frame: Up to aproximately 3 years
Population: Participants in the Full Analysis Set (FAS) who achieved complete response. FAS comprised of all participants to whom study treatment has been assigned and who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eltrombopag | Duration of Complete Response | NA months |
Secondary
Duration of Overall Response
Duration of response was derived as the time from first documented and confirmed response (either CR or PR) until the time of relapse or death, whichever occurred first. Duration of response was estimated using Kaplan-Meier method. Clinical relapse was considered as the occurrence of any of the following events in a participant who had achieved a hematological response (CR or PR) but had subsequently lost response (not explained by any other independent concomitant medical conditions) in one blood count measurements: * Meeting again the criteria for SAA * Requirement for transfusion again for subjects who had been transfusion independent * Decrease in any of the peripheral blood counts to absolute neutrophil count \< 0.5 x10\^9/L or platelets \< 20 x10\^9/L.
Time frame: Up to aproximately 3 years
Population: Participants in the Full Analysis Set (FAS) who achieved a response. FAS comprised of all participants to whom study treatment has been assigned and who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eltrombopag | Duration of Overall Response | NA months |
Secondary
Overall Response (ORR) Rate
Overall response rate was defined as percentage of patients achieving complete response (CR) or partial response (PR). Partial response (PR) was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in SAA, equivalent to at least 2 of the 3 criteria below, but not sufficient for a CR: * Absolute neutrophil count ≥ 0.5 × 10\^9/L * Platelet count ≥ 20 × 10\^9/L * Reticulocyte count ≥ 20 × 10\^9/L Complete response (CR) was defined as subjects meeting all the three criteria on two consecutive serial blood count measurements at least one week apart but not more than four weeks apart: * Absolute neutrophil count \> 1.0 ×10\^9/L * Platelet count \> 100 ×10\^9/L * Hemoglobin \> 100 g/L
Time frame: Week 13 (3 months), 26 weeks (6 months), 52 weeks and yearly after up to 3 years
Population: The Full Analysis Set (FAS) comprised of all participants to whom study treatment has been assigned and who received at least one dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Overall Response (ORR) Rate | Week 13 | 66.7 percentage of participants |
| Eltrombopag | Overall Response (ORR) Rate | Week 26 | 77.8 percentage of participants |
| Eltrombopag | Overall Response (ORR) Rate | Week 52 | 66.7 percentage of participants |
| Eltrombopag | Overall Response (ORR) Rate | Year 2 | 50.0 percentage of participants |
| Eltrombopag | Overall Response (ORR) Rate | Year 3 | 41.7 percentage of participants |
Secondary
Overall Survival (OS)
OS was defined as the time from the date of the first dose of study treatment to the date of death due to any cause. If a subject was not known to have died, survival was censored at the date of last contact. The distribution function of OS was estimated using the Kaplan- Meier method.
Time frame: Up to approximately 3 years
Population: The Full Analysis Set (FAS) comprised of all participants to whom study treatment has been assigned and who received at least one dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eltrombopag | Overall Survival (OS) | NA Months |
Secondary
Overall Survival (OS) Rate
OS was defined as the time from the date of the first dose of study treatment to the date of death due to any cause. The OS rate is the estimated probability that a patient will remain event-free up to the specified time point and was obtained from the Kaplan-Meier survival estimates. If a subject was not known to have died, survival was censored at the date of last contact.
Time frame: Week 26, Week 52 and yearly after up to 3 years
Population: The Full Analysis Set (FAS) comprised of all participants to whom study treatment has been assigned and who received at least one dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eltrombopag | Overall Survival (OS) Rate | Week 26 | 97.2 percent probability |
| Eltrombopag | Overall Survival (OS) Rate | Week 52 | 97.2 percent probability |
| Eltrombopag | Overall Survival (OS) Rate | Year 2 | 94.1 percent probability |
| Eltrombopag | Overall Survival (OS) Rate | Year 3 | 90.9 percent probability |
Secondary
Percentage of Participants Who Become Platelet Transfusion Independent
Transfusion independent participants were defined as those participants who were transfusion dependent at baseline but became transfusion free for a period of ≥ 4 weeks post-baseline for platelets.
Time frame: From date of first dose to approximately 3 years
Population: The Full Analysis Set (FAS) subjects who were transfusion dependent at baseline. FAS comprised of all participants to whom study treatment has been assigned and who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eltrombopag | Percentage of Participants Who Become Platelet Transfusion Independent | 88.2 percentage of participants |
Secondary
Percentage of Participants Who Become RBC Transfusion Independent
Transfusion independent participants were defined as those participants who were transfusion dependent at baseline but became transfusion free for a period of ≥ 8 weeks post-baseline for RBCs.
Time frame: From date of first dose to approximately 3 years
Population: Full Analysis Set (FAS) subjects who were transfusion dependent at baseline. FAS comprised of all participants to whom study treatment has been assigned and who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eltrombopag | Percentage of Participants Who Become RBC Transfusion Independent | 86.2 percentage of participants |
Secondary
Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: AUClast
AUClast is the area under the curve from time zero to the last measurable concentration sampling time. Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach.
Time frame: Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose
Population: Participants in the PAS with a an available value for the outcome measure. The Pharmacokinetic analysis set (PAS) includes all participants who received at least one dose of eltrombopag and provide at least one evaluable PK sample.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eltrombopag | Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: AUClast | 602000 ng*h/mL | Standard Deviation 239000 |
Secondary
Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: AUCtau
AUCtau is area under the curve calculated to the end of a dosing interval (tau) at steady-state Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach.
Time frame: Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose
Population: Participants in the PAS with a an available value for the outcome measure. The Pharmacokinetic analysis set (PAS) includes all participants who received at least one dose of eltrombopag and provide at least one evaluable PK sample.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eltrombopag | Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: AUCtau | 585000 ng*h/mL | Standard Deviation 231000 |
Secondary
Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: CLss/F
CLss/F is Apparent systemic (or total body) clearance at steady state from plasma. Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach.
Time frame: Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose
Population: Participants in the PAS with a an available value for the outcome measure. The Pharmacokinetic analysis set (PAS) includes all participants who received at least one dose of eltrombopag and provide at least one evaluable PK sample.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eltrombopag | Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: CLss/F | 0.148 Liter/hour | Standard Deviation 0.0618 |
Secondary
Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: Cmax
Cmax is the The maximum (peak) observed plasma drug concentration after dose administration. Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach.
Time frame: Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose
Population: Participants in the PAS with a an available value for the outcome measure. The Pharmacokinetic analysis set (PAS) includes all participants who received at least one dose of eltrombopag and provide at least one evaluable PK sample.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Eltrombopag | Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: Cmax | 32500 ng/mL | Standard Deviation 12300 |
Secondary
Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: Ctrough
Cthrough is the pre-dose concentration at the end of dose interval. Blood samples were collected to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach. Eltrombopag was administered orally once daily with initial doses of 75mg/day for ≥ 12 years old and 37.5 mg/day for participants between ≥ 6 and \< 12 years. Doses could be adjusted based on platelet count every 2 weeks by decreasing it by 25 mg/day (12.5 mg/day, for participants below 12 years old) if the platelet count was above 200×10\^9/L. or interrupted if platelet count rose above 400×10\^9/L. In partial response participants dose could be restarted or increased to that before the decrease if platelet counts \< 30 x10\^9/L, Hb\< 90 g/L, ANC\< 0.5 x 10\^9/L or participant needed transfusion. In complete response participants dose could be restarted or increased to that before decrease if blood counts dropped to not meet CR criteria.
Time frame: Pre-dose on day 15 after initation of eltrombopag and and pre-dose on the 15th day after each new dose up to week 26
Population: Participants in the PAS with a an available value for the outcome measure. The Pharmacokinetic analysis set (PAS) includes all participants who received at least one dose of eltrombopag and provide at least one evaluable PK sample.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eltrombopag | Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: Ctrough | 20200 ng/mL | Standard Deviation 9410 |
Secondary
Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: Tmax
Tmax is the time to reach maximum (peak) plasma drug concentration after dose administration. Blood samples were collected from patients to assess the plasma concentrations of eltrombopag using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS) approach.
Time frame: Pre-dose, and 2, 4, 6, 8 and 24 hours post-dose on Day 14 after initial dose
Population: Participants in the PAS with a an available value for the outcome measure. The Pharmacokinetic analysis set (PAS) includes all participants who received at least one dose of eltrombopag and provide at least one evaluable PK sample.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Eltrombopag | Plasma Pharmacokinetics (PK) Parameters of Eltrombopag: Tmax | 5.59 hours | Standard Deviation 5.64 |
Secondary
Red Blood Cells (RBC) and Platelet Transfusion-free Interval Before Week 13 and 26
Transfusion-free interval was defined as the time from most recent RBC/platelet transfusion preceding response assessment to the date of response assessment.
Time frame: Week 13, 26
Population: The Full Analysis Set (FAS) subjects with response assessment at week 13 and 26. FAS comprised of all participants to whom study treatment has been assigned and who received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eltrombopag | Red Blood Cells (RBC) and Platelet Transfusion-free Interval Before Week 13 and 26 | RBC transfusion-free interval - Week 13 | 36.3 days | Standard Deviation 25.62 |
| Eltrombopag | Red Blood Cells (RBC) and Platelet Transfusion-free Interval Before Week 13 and 26 | RBC transfusion-free interval - Week 26 | 98.9 days | Standard Deviation 57.97 |
| Eltrombopag | Red Blood Cells (RBC) and Platelet Transfusion-free Interval Before Week 13 and 26 | Platelet transfusion-free interval - Week 13 | 34.0 days | Standard Deviation 25.64 |
| Eltrombopag | Red Blood Cells (RBC) and Platelet Transfusion-free Interval Before Week 13 and 26 | Platelet transfusion-free interval - Week 26 | 97.3 days | Standard Deviation 58.93 |
Secondary
Time From the Date of First Dose of Investigational Treatment to the Date of First Occurrence of Any Clonal Evolution Events
Clonal evolution events were assessed by karyotyping (G-banding) and FISH (Fluorescence in situ hybridization) targeting abnormalities including, but not restricted to chromosome 3q del,5q del, monosomy 7, trisomy 8 and those associated with SAA (Severe aplastic anemia), MDS (Myelodysplastic syndrome), AML (Acute myeloid leukemia). Time to clonal evolution was to be estimated using the Kaplan-Meier method.
Time frame: From date of first dose to approximately 3 years
Population: Participants who received at least one dose of study treatment and presented a clonal evolution event.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eltrombopag | Time From the Date of First Dose of Investigational Treatment to the Date of First Occurrence of Any Clonal Evolution Events | NA weeks |