Eltrombopag Combined With Cyclosporine as First Line Therapy in Patients With Severe Acquired Aplastic Anemia
Condition: Severe Aplastic Anemia
MeSH terms: Anemia; Anemia, Aplastic
Intervention: eltrombopag; Cyclosporine
Intervention description: 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.; 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
Intervention MeSH terms: Cyclosporine; Cyclosporins
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 54.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: severe acquired aplastic anemia; SAA; first line; eltrombopag; cyclosporine; h-ATG; severe aplastic anemia; aplastic anemia

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
    

Eligibility criteria:

        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).