Efficacy and Safety of Eltrombopag + Tacrolimus in Chinese Refractory or Relapsed Aplastic Anemia Patients

This is a randomized, open-label, phase II study to compare the efficacy of eltrombopag combined with tacrolimus to eltrombopag alone in Chinese subjects with refractory or relapsed aplastic anemia. The safety would also be evaluated. Patients would be randomized to receive eltrombopag alone or eltrombopag combined with tacrolimus. 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, or the best response was achieved. Tacrolimus will be given at 1mg bid with the target trough concentration of 4-10 ng/mL throughout the study. The hematological response rate and safety will be recorded and compared at 3, 6 months and 1 year after starting the study treatment (Week 13, 26 and 52).

Study Overview

• Status: Completed
• Conditions: Drug Effect; Aplastic Anemia
• Intervention / Treatment: Drug: Placebo (for Tacrolimus); Drug: Tacrolimus

• Study Type: Interventional
• Enrollment (Actual): 114
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Peking Union Medical College Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 85 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patient with a previous diagnosis of aplastic anemia and had no response or relapsed following at least one treatment course in a period time of ≥ 6 months of immunosuppression containing CsA or CsA+anti-thymocyte globulin (ATG);
2. Current diagnosis of aplastic anemia by bone marrow biopsy;
3. did not receive HSCT nor were HSCT candidates;
4. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0-2;
5. 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.
6. Subjects are able to understand and comply with protocol requirements and instructions and have signed and dated informed consent.

Exclusion Criteria:

1. Congenital aplastic anemia;
2. Presence of chromosomal aberration;
3. Evidence of a clonal hematologic bone marrow disorder on cytogenetics;
4. Have any concomitant malignancies and must be fully recovered from treatment for any other malignancy and have been disease-free for 5 years;
5. AST or ALT ≥3 times the upper limit of normal;
6. Serum creatinine, total bilirubin, or alkaline phosphatase >1.5 x ULN;
7. Cardiac disorder (NYHA) functional classification Grade II/III/IV;
8. Past history of thromboembolic event (including anti-phospholipid antibody syndrome) and current use of anticoagulants;
9. Infection not adequately responding to appropriate therapy;
10. Other known or suspected underlying primary immunodeficiency;
11. Prior treatment with eltrombopag, romiplostim, or any other TPO (thrombopoietin) receptor agonist;
12. Pregnant or nursing (lactating) woman;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Eltrombopag; Eltrombopag and the placebo would be applied. 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, or the best response was achieved.	Drug: Placebo (for Tacrolimus); placebo will be given at 1mg bid.; Other Names: control
Experimental: Eltrombopag + Tacrolimus; Eltrombopag and tacrolimus would be applied. 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, or the best response was achieved. Tacrolimus will be given at 1mg bid with the target trough concentration of 4-10 ng/mL throughout the study.	Drug: Tacrolimus; Tacrolimus will be given at 1mg bid with the target trough concentration to be 4-10 ng/mL.; Other Names: experimental

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR at 6 Months	Overall Response Rate (ORR) Defined as the Number of Participants Who Met the Criteria of Either Complete Response (CR) or Partial Response (PR) at Week 26	Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR at 3 Months	ORR will be calculated after 3 months of treatment by measuring platelet, reticulocyte, neutrophil and transfusion independence.	Week 14
Changes in Haemoglobin in the Absence of Red Blood Cells Transfusion	The change in hematology values ( haemoglobin) were evaluated	Week 26
Changes in Platelet in the Absence of Platelet Transfusion	The change in hematology values (platelet) were evaluated	Week 26
Duration of hematologic response	Time from the date of the start of the first response to the date of first relapse defined as again meeting criteria for aplastic anemia	by 6 months (all patients), at 24 months (responders only)
Percentage of patients with clonal evolution to myelodysplasia, PNH, acute leukemia	Clonal evolution to myelodysplasia is defined as a new marrow cytogenic abnormality with or without characteristic dysplastic marrow findings. Evolution to leukemia is defined as greater than 20% peripheral blood and/or marrow blasts. Evolution to paroxysmal nocturnal hemoglobinuria (PNH) is defined as a clone at baseline < 10% that rose to greater than 50% on study.	12 months

Collaborators and Investigators

• Sponsor: Peking Union Medical College Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2020
• Primary Completion (Actual): July 30, 2022
• Study Completion (Actual): July 31, 2022

Study Registration Dates

• First Submitted: May 21, 2020
• First Submitted That Met QC Criteria: May 21, 2020
• First Posted (Actual): May 27, 2020

Study Record Updates

• Last Update Posted (Estimate): January 19, 2023
• Last Update Submitted That Met QC Criteria: January 17, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Bone Marrow Failure Disorders; Anemia; Anemia, Aplastic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: ELT-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: individual participant data would be accepted upon request
• IPD Sharing Time Frame: 10 years
• IPD Sharing Access Criteria: email request
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

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