Eltrombopag Combined With Cyclosporine as First Line Therapy in Patients With Severe Acquired Aplastic Anemia

NCT ID: NCT02998645

Last Updated: 2023-12-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 54 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-05-11
• Study Completion Date: 2022-05-30

Brief 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

Detailed Description

This was an interventional phase II, single-arm, multicenter, open-label, study to investigate the efficacy and safety of the combination of eltrombopag and cyclosporine in treatment-naive, adult subjects with severe aplastic anemia (SAA) as first line therapy.

Eligible subjects received eltrombopag and cyclosporine for up to 6 months. Participants who achieved hematologic response any time on or before 6 months were considered as responders; else they were considered as non-responders.

Responders at Month 6 discontinued eltrombopag and started to taper cyclosporine until relapse or Month 24, whichever was early. Responders who relapsed prior to 6 months and non-responders discontinued the treatment at 6 months and were followed-up for 30 days.

Responders who started to taper cyclosporine and relapsed prior to 24 months discontinued cyclosporine and were followed-up for 30 days.

Conditions

Severe Aplastic Anemia

Keywords

severe acquired aplastic anemia; SAA; first line; eltrombopag; cyclosporine; h-ATG; severe aplastic anemia; aplastic anemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Eltrombopag + cyclosporine

Participants received eltrombopag (orally, 150 mg once daily for non-Asian participants / 100 mg once daily for participants of Asian ancestry) in combination with cyclosporine (orally, 10.0 mg/kg/day in divided doses every 12 hours) for up to 6 months. Thereafter, responders at Month 6 were treated with cyclosporine until Month 24

Group Type: EXPERIMENTAL

eltrombopag

Intervention Type: DRUG

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.

Cyclosporine

Intervention Type: DRUG

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

Interventions

eltrombopag

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.

Intervention Type: DRUG

Cyclosporine

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 Type: DRUG

Other Intervention Names

ETB115

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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Ribeirão Preto, São Paulo, Brazil

Novartis Investigative Site

São Paulo, São Paulo, Brazil

Novartis Investigative Site

Hong Kong, , Hong Kong

Novartis Investigative Site

Hyderabad, Telangana, India

Novartis Investigative Site

Vellore, , India

Novartis Investigative Site

Bologna, BO, Italy

Novartis Investigative Site

Brescia, BR, Italy

Novartis Investigative Site

Milan, MI, Italy

Novartis Investigative Site

Mexico D F, Mexico City, Mexico

Novartis Investigative Site

Monterrey, Nuevo León, Mexico

Novartis Investigative Site

Puebla City, , Mexico

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

Seoul, , South Korea

Novartis Investigative Site

Donostia / San Sebastian, Basque Country, Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Bangkok, , Thailand

Novartis Investigative Site

Bangkok, , Thailand

Novartis Investigative Site

Chiang Mai, , Thailand

Novartis Investigative Site

Istanbul, , Turkey (Türkiye)

Novartis Investigative Site

Samsun, , Turkey (Türkiye)

Countries

Hungary; Netherlands; Brazil; Hong Kong; India; Italy; Mexico; South Korea; Spain; Thailand; Turkey (Türkiye)

References

Scheinberg P, Finelli C, Montano-Figueroa EH, Vallejo C, Norasetthada L, Calado RT, Turgut M, Peffault de Latour R, Kriemler-Krahn U, Haenig J, Clark J, Jang J. Activity and safety of eltrombopag in combination with cyclosporin A as first-line treatment of adults with severe aplastic anaemia (SOAR): a phase 2, single-arm study. Lancet Haematol. 2024 Mar;11(3):e206-e215. doi: 10.1016/S2352-3026(23)00395-2. Epub 2024 Feb 6.

Reference Type: DERIVED

PMID: 38335978 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-002814-29

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CETB115E2403

Identifier Type: -

Identifier Source: org_study_id