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

A Non-randomized, Open-label, Multi-center, Phase II Study to Assess the Safety and Efficacy of Eltrombopag in Chinese Subjects With Refractory or Relapsed Severe Aplastic Anemia

This is 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 will be 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 will be assessed at 3, 6 months and 1 year after starting the study treatment (Week 13, 26 and 52).

Study Overview

• Status: Completed
• Conditions: Aplastic Anemia
• Intervention / Treatment: Drug: Eltrombopag 25 mg

Detailed Description

This is 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 were to discontinue eltrombopag before 6 months if any of the treatment discontinuation criteria were met.

Analysis set for the primary endpoint is 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 PK characteristics of eltrombopag in Chinese SAA patient population, intensive PK blood samples was 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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Tianjin, China, 300052
    • Novartis Investigative Site
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • Novartis Investigative Site
  • Jiangxi
    • Nanchang, Jiangxi, China, 330006
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
  • Tianjin
    • Tianjin, Tianjin, China, 300020
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.
• 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.

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Eltrombopag; Subjects will start eltrombopag treatment at 25 mg/day since Day 1.	Drug: Eltrombopag 25 mg; film-coated tablets containing 25 mg of eltrombopag free acid in each tablet; Other Names: ETB115

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hematologic response rate	Hematologic response rate is defined as the percentage of all subjects who meet any of the IWG criteria (International Working Group).	6 months (Week 26)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hematologic response rate	Hematologic response rate is defined as the percentage of all subjects who meet any of the IWG criteria (International Working Group).	Week 13 and Week 52
Changes in platelet count	Changes in platelet count in the absence of platelet transfusion.	Baseline to Week 26 or up to 3.5 years
Changes in hemoglobin count	Changes in hemoglobin in the absence of RBC (Red Blood Cell) transfusion.	Baseline to Week 26 or up to 3.5 years
Changes in neutrophil count	Changes in neutrophil count in the absence of G-CSF (Granulocyte Colony Stimulating Factor).	Baseline to Week 26 or up to 3.5 years
Time to hematologic response	Time to hematologic response (any response according to the response criteria for the primary endpoint).	Baseline to Week 26 or up to 3.5 years
Duration of hematologic response	Duration of hematologic response (any response according to the response criteria for the primary endpoint).	Baseline to Week 26 or up to 3.5 years
Frequency of transfusion	Frequency of transfusion (platelet and RBC (Red Blood Cell))	Baseline to Week 26 or up to 3.5 years
Volume of transfusion	Volume of transfusion (platelet and RBC (Red Blood Cell))	Baseline to Week 26 or up to 3.5 years
Plasma concentration of eltrombopag including the trough concentrations	Plasma concentration of eltrombopag including the trough.	Baseline to Week 26
Rate of clonal evolution	Rate of clonal evolution including clonal evolution to PNH (Paroxysmal Nocturnal Hemoglobinuria), evolution to AML (Acute Myeloid Leukemia) or MDS (Myelodysplastic Syndromes).	Baseline to Week 26 or up to 3.5 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): December 9, 2019
• Primary Completion (Actual): July 16, 2021
• Study Completion (Actual): May 17, 2023

Study Registration Dates

• First Submitted: June 13, 2019
• First Submitted That Met QC Criteria: June 13, 2019
• First Posted (Actual): June 17, 2019

Study Record Updates

• Last Update Posted (Estimated): November 13, 2023
• Last Update Submitted That Met QC Criteria: November 9, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Eltrombopag; Severe Aplastic Anemia; ETB115; Chinese subject; Chinese refractory or relapsed SAA subjects; refractory severe aplastic anemia; relapsed severe aplastic anemia
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Bone Marrow Failure Disorders; Anemia; Anemia, Aplastic
• Other Study ID Numbers: CETB115E2202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No