Study Assessed the Safety and Efficacy of Eltrombopag in Chinese Refractory or Relapsed Severe Aplastic Anemia (SAA) Subjects.

Novartis Pharmaceuticals20 enrolled

Overview

This was a non-randomized, open-label, phase II study to assess the efficacy and safety of eltrombopag in Chinese subjects with refractory or relapsed severe aplastic anemia (SAA). Treatment with eltrombopag was started at 25 mg/day and increased by 25 mg/day every 2 weeks according to the platelet count up to 150 mg/day. The hematological response rate was assessed at 3, 6 months and 1 year after starting the study treatment (Week 13, 26 and 52).

This was a bridging study to support China registration. An estimation strategy rather than a formal hypothesis testing was pursued. Twenty subjects were enrolled into the study. Treatment with eltrombopag started at 25 mg/day and increased by 25 mg/day every 2 weeks according to the platelet count, up to 150 mg/day. Hematological response rate was assessed at 3, 6 months and 1 year (Week 13, 26 and 52) after starting the study treatment. Subjects in whom the treatment was found to be effective at 6 months continued to receive the treatment. Eltrombopag was discontinued if the treatment was ineffective at 6 months. Subjects discontinued eltrombopag before 6 months if any of the treatment discontinuation criteria was met. Analysis set for the primary endpoint was Full Analysis Set (FAS) and subjects who discontinue from the study before Week 26 were treated as non-responders in the response analysis. Eltrombopag treatment was provided to subjects who were considered to require continued treatment at Week 26. After Week 26, if all of the hematologic response criteria (i.e., platelet count \> 50×109/L, hemoglobin level \> 100 g/L without transfusion, and neutrophil count \> 1.0×109/L) remained fulfilled for more than 8 weeks, the dose of eltrombopag was decreased by half. If the response continued for further 8 weeks even at the decreased dose, the treatment was discontinued. If a decrease in any of the hematologic values (i.e., platelet count \< 30×109/L, hemoglobin \< 90 g/L, or neutrophil count \< 0.5×109/L) was found after dose reduction, the dose was increased to the previous level. Furthermore, after treatment interruption, the treatment was restarted if any of the hematologic values decreased to the above-mentioned levels. The response assessment and safety evaluation were performed at Week 52. The Extension part of this study started 1 year (Week 52) after the initiation of study treatment. This part was included in the study with an ethical consideration for subjects who required continued treatment. The continued treatment was provided up to the launch of eltrombopag after approval. Follow-up visit was performed 30 days after the discontinuation of eltrombopag treatment. To better understand the pharmacokinetics (PK) characteristics of eltrombopag in Chinese severe aplastic anemia (SAA) patient population, intensive PK blood samples were collected only in the initial 12 Chinese subjects receiving 25 mg/day dose after reaching steady-state, to provide evaluable full PK profiles. Steady-state trough concentrations were collected at other dose levels and in other subjects.

Conditions

Aplastic Anemia

Interventions

EltrombopagDRUG

Eltrombopag are film-coated tablets containing 25 mg of eltrombopag free acid in each tablet.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Chinese patients aged greater than or equal to 18 years old. * Patient with a previous diagnosis of severe aplastic anemia and had insufficient response following at least one treatment course in the period time of \> 6 months of immunosuppression with a regimen containing anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG), and/or cyclophosphamide, or alemtuzumab. * Platelet count ≤ 30 × 10\^9/L at screening. * Patient must not currently have the option of stem cell transplantation. * Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0-2. * Patient with QTcF (Fridericia's QT correction formula) at screening \<450 msec, or \<480 msec with bundle branch block, as determined via the mean of a triplicate ECG and assessed at site. Exclusion Criteria: * Treatment with ATG/ALG, cyclophosphamide or alemtuzumab in the past 6 months. * Congenital aplastic anemia * AST or ALT ≥3 times the upper limit of normal. * Creatinine, total bilirubin, and alkaline phosphatase (ALP) ≥ 1.5× local ULN (total bilirubin ≥ 2.5 × local ULN with Gilbert's Syndrome). * Paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size determined by flow cytometry ≥ 50%. * Presence of chromosomal aberration (-7/7q- detected by fluorescence in situ hybridization (FISH), or other aberrations detected by G-band staining). * Evidence of a clonal hematologic bone marrow disorder on cytogenetics. * Past medical history of thromboembolism within 6 months or current use of anticoagulants. * Have any concomitant malignancies and must be fully recovered from treatment for any other malignancy and have been disease-free for 5 years. * Patient with clinically significant (of such severity that it would preclude the patient's ability to consent, be compliant with study procedures, tolerate protocol therapy) bacterial, fungal, mycobacterial, parasitic or viral infection (Patient with acute bacterial infections requiring antibiotic use should delay Screening/enrollment until the course of antibiotic therapy has been completed). * Patient with known hepatocellular disease * Presences of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening. * Cardiac disorder (NYHA) functional classification Grade II/III/IV * Past medical history of immediate or delayed hypersensitivity to compounds chemically similar to eltrombopag or their excipients. * Treatment with another investigational product within 30 days. * Prior treatment with eltrombopag, romiplostim, or any other TPO (thrombopoietin) receptor agonist. * Positive result for HIV (Human Immunodeficiency Virus) antibody test. * Pregnant or nursing (lactating) woman. * Woman of child-bearing potential.

Locations (5)

Novartis Investigative Site

Nanjing, Jiangsu, China

Novartis Investigative Site

Nanchang, Jiangxi, China

Novartis Investigative Site

Chengdu, Sichuan, China

Novartis Investigative Site

Tianjin, China

Outcomes

Primary Outcomes

Hematologic Response Rate at 6 Months (Week 26) by Investigator

Hematologic response rate: percentage of subjects who met any of the International Working Group criteria: Platelet count: If platelet transfusion independent at baseline (BL): Transfusion independent and increase from BL by 20×10\^9/L or more; If platelet transfusion dependent at BL: No platelet transfusion requirement for 8 weeks; Hemoglobin: If red blood cells (RBC) transfusion independent at BL: transfusion independent and increase from BL by 15 g/L or more; If RBC transfusion dependent at BL: A decrease of at least 4 units in RBC transfusions in the post-treatment 8-week period (1 unit = RBC derived from 200 mL blood) or no RBC transfusion requirement for 8 weeks; Neutrophil count: In the absence of granulocyte colony stimulating factor (G-CSF) taken within 21 days preceding the blood sample collection: Increase from BL by 0.5×10\^9/L or more, or (if \< 0.5×10\^9/L at BL) increase by 100% or more. Patients who discontinued from the trial before week 26 were treated as non-responders.

Time frame: 6 months (Week 26)

Secondary Outcomes

Hematologic Response Rate by Investigator

Hematologic response rate: percentage of subjects who met any of the International Working Group criteria: Platelet count: If platelet transfusion independent at baseline (BL): Transfusion independent and increase from BL by 20×10\^9/L or more; If platelet transfusion dependent at BL: No platelet transfusion requirement for 8 wks; Hemoglobin: If red blood cells (RBC) transfusion independent at BL: transfusion independent and increase from BL by 15 g/L or more; If RBC transfusion dependent at BL: A decrease of at least 4 units in RBC transfusions in the post-treatment 8-week period (1 unit =RBC derived from 200 mL blood) or no RBC transfusion requirement for 8 wks; Neutrophil count: In the absence of granulocyte colony stimulating factor (G-CSF) taken within 21 days preceding the blood sample collection: Increase from BL by 0.5×10\^9/L or more, or (if \< 0.5×10\^9/L at BL) increase by 100% or more. Patients who discontinued from the trial before wks 13 \& 26 were treated as non-responders.

Time frame: Week (Wk) 13, Week 52

Change From Baseline in Platelet Count

Data from ClinicalTrials.gov

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Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Novartis Investigative Site

Change (increase from baseline) in platelet count (in the absence of platelet transfusion) were calculated according to the lab test results entered into the case report form (CRF) that were summarized at each visit using descriptive statistics. Platelet Count (×109/L) was assessed in hematology test.

Time frame: Baseline, Week 13, Week 26, Week 52

Change From Baseline in Hemoglobin Levels

Change (increase from baseline) in hemoglobin (in the absence of red blood cell (RBC) transfusion) were calculated according to the lab test results entered into the CRF that were summarized at each visit using descriptive statistics. Hemoglobin level (g/L) was assessed in hematology test.

Time frame: Baseline, Week 13, Week 26 and Week 52

Change From Baseline in Neutrophil Count

Change (increase from baseline) in neutrophil count (in the absence of granulocyte colony stimulating factor (G-CSF) and calculated according to the lab test results entered into the CRF that were summarized at each visit using descriptive statistics). Neutrophil count (×109/L) was assessed in hematology test.

Time frame: Baseline, Week 13, Week 26 and Week 52

Time to Hematologic Response by Investigator

Time to hematological response was defined as the time from the date of first study drug administration to the first hematological response. If a participant did not meet hematological response before or at the cutoff date, censoring was performed using the date of last assessment.

Time frame: Baseline to Week 26

Duration of Hematologic Response by Investigator

Duration of hematologic response (any response according to the response criteria for the primary endpoint). For subjects who responded, duration of response was defined as the number of weeks from the first date of hematological response until the first date of relapse or death. Only participants with at least two response assessments were included for the duration of hematologic response assessment.

Time frame: up to approx. 3.5 years

Frequency of Platelets Transfusion

For subjects receiving transfusion (platelets) at baseline, the frequency of platelet transfusion in each period (Baseline: 4 weeks before Day 1; Week 13, 26, 52: 4 weeks before each visit day) was summarized using descriptive statistics.

Time frame: Baseline, Week 13, Week 26 and Week 52

Amount of Platelets Transfusion

The amount of transfusion was defined as the sum of transfusion multiplied by the volume of transfusion.

Time frame: Baseline, Week 13, Week 26 and Week 52

Frequency of Red Blood Cells (RBC) Transfusion

For subjects receiving transfusion (RBC (Red Blood Cell)) at baseline, the frequency of RBC transfusion in each period (Baseline: 8 weeks before Day 1; Week 13, 26, 52: 8 weeks before each visit day) was summarized using descriptive statistics.

Time frame: Baseline, Week 13, Week 26 and Week 52

Amount of Red Blood Cells (RBC) Transfusion

The amount of RBC transfusion was defined as the sum of transfusion multiplied by the volume of transfusion.

Time frame: Baseline, Week 13, Week 26 and Week 52

Plasma PK Parameters of Eltrombopag: Cmax

Cmax is the maximum (peak) observed plasma drug concentration after single dose administration (mass\*volume-1). Blood samples were collected from patients to assess the plasma concentrations of eltrombopag. The plasma concentrations were used to determine the PK characteristics of eltrombopag. Serial intensive PK blood samples were collected for the initial 25 mg/day dose to provide at least 12 participants with evaluable PK profiles at steady state.

Time frame: pre-dose, and 1, 2, 4, 6, 8 and 24 hours post-dose on Day 14

Plasma PK Parameters of Eltrombopag: Tmax

Tmax is the time to reach maximum (peak) plasma drug concentration after single dose administration (time). Blood samples were collected from all patients to assess the plasma concentrations of eltrombopag. The plasma concentrations were used to determine the PK characteristics of eltrombopag. Serial intensive PK blood samples were collected for the initial 25 mg/day dose to provide at least 12 participants with evaluable PK profiles at steady state.

Time frame: pre-dose, and 1, 2, 4, 6, 8 and 24 hours post-dose on Day 14

Plasma PK Parameters of Eltrombopag: AUCtau & AUClast

AUCtau is the area under the curve calculated to the end of a dosing interval (tau) at steady-state (amount\*time\*volume-1). AUClast is the AUC calculated from time 0 to the time of the last quantifiable concentration. Blood samples were collected from patients to assess the plasma concentrations of eltrombopag. The plasma concentrations were used to determine the PK characteristics of eltrombopag. Serial intensive PK blood samples were collected for the initial 25 mg/day dose to provide at least 12 participants with evaluable PK profiles at steady state.

Time frame: pre-dose, and 1, 2, 4, 6, 8 and 24 hours post-dose on Day 14

Plasma PK Parameters of Eltrombopag: CLss/F

Steady State (CLss/F) is the apparent systemic (or total body) clearance at steady state from plasma (volume/time) following drug administration. Blood samples were collected from patients to assess the plasma concentrations of eltrombopag. The plasma concentrations were used to determine the PK characteristics of eltrombopag. Serial intensive PK blood samples were collected for the initial 25 mg/day dose to provide at least 12 participants with evaluable PK profiles at steady state.

Time frame: pre-dose, and 1, 2, 4, 6, 8 and 24 hours post-dose on Day 14

Plasma Trough Concentration of Eltrombopag

Ctrough is the pre-dose concentration at the end of dose interval (mass\*volume-1). Blood samples were collected from patients to assess the plasma concentrations of eltrombopag. The plasma concentrations were used to determine the PK characteristics of eltrombopag. Serial intensive PK blood samples were collected for the initial 25 mg/day dose to provide at least 12 participants with evaluable PK profiles at steady state. Sparse PK blood samples were collected for the other doses and in the rest of the patients for Ctrough assessment.

Time frame: Pre-dose sample on the 15th day after each new dose level was started

Number of Participants With Clonal Evolution

Number of participants with clonal evolution with a normal karyotype at baseline including clonal evolution to PNH (Paroxysmal Nocturnal Hemoglobinuria), evolution to AML (Acute Myeloid Leukemia) or MDS (Myelodysplastic Syndromes).

Time frame: From Baseline up to approx. 2.9 years