Early Initiation of Oral Therapy With Cyclosporine and Eltrombopag for Treatment Naive Severe Aplastic Anemia (SAA)

Background:

Severe aplastic anemia (SAA) is a rare and serious blood disorder. It causes the immune system to turn against bone marrow cells. Standard treatment for SSA is a combination of 3 drugs (Cyclosporine [CsA], Eltrombopag [EPAG], and horse anti-thymocyte globulin [h-ATG]). Researchers want to see if starting people at a lower dose of CsA with EPAG before giving them h-ATG is helpful.

Objective:

To learn if early initiation of oral therapy with CsA and EPAG is safe and effective in people who have SAA and have not been treated with a course of immunosuppressive therapy and EPAG.

Eligibility:

People ages 3 and older with SAA

Design:

Participants will be screened with:

• medical history
• physical exam
• electrocardiogram
• blood tests
• family history
• bone marrow biopsy
• current medicines.

Participants may be screened remotely via telephone conference.

Participants will take a lower oral dose of CsA and EPAG. They will take CsA twice a day for 6 months. They will take EPAG for 6 months. Those who cannot visit the NIH Clinical Center within 72 hours will start taking the drugs at home. They will have weekly telephone calls with NIH staff until they visit the Clinical Center.

Participants may get h-ATG at the Clinical Center for 4 days. For this, they will have a central line placed. It is a plastic tube inserted into a neck, chest, or arm vein.

Participants will repeat most screening tests throughout the study.

Participants will have follow-up visits at the Clinical Center at 3 months, 6 months, and annually for 5 years after the start of the study....

Study Overview

• Status: Recruiting
• Conditions: Severe Aplastic Anemia
• Intervention / Treatment: Drug: Eltrombopag; Drug: Cyclosporine; Drug: Horse-Anti-thymocyte-Globulin

Detailed Description

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure characterized by pancytopenia and a hypocellular marrow. Allogeneic bone marrow transplantation is curative in younger patients, but older age and/or lack of a suitable donor have limited application of this procedure. As an alternative to transplant, immunosuppressive treatment (IST) has provided durable remissions and similar long term survival [1]. Approximately 2/3 of patients who receive IST with horse anti-thymocyte globulin (h-ATG) and cyclosporine (CsA) have blood count recovery, but 25-30% do not respond and 30-40% will relapse. A likely explanation for partial recovery and relapse is incomplete elimination of auto-reactive T cells and insufficient stem cell reserve.

Thrombopoietin (TPO) is a key regulator of hematopoietic stem cell renewal and survival. To improve the hematologic response rate, our group assessed the addition of eltrombopag (EPAG), a synthetic mimetic of TPO, to IST in treatment na(SqrRoot) ve SAA. This combination achieved a higher complete response rate to about 50% and an overall response rate to 80%, both superior to historic controls [2]. This regimen received FDA approval in November 2018. Combined therapy is now being tested in a European randomized study. Furthermore, protocols have been developed internationally to determine whether EPAG and CsA, without ATG, are sufficient to improve blood counts, in countries where ATG is not available.

The long-term complications, relapse and clonal evolution, were no worse with the addition of EPAG than in our historical cohort, but still remain a problem. Clonal evolution occurs in 10-15% of patients and is defined as development of myelodysplastic syndrome or acute myeloid leukemia with characteristic cytogenetic abnormalities of aneuploidy, especially monosomy 7 or deletion 7q. There are no predictive tools to identify patients at higher risk for either of these two long term events.

Because SAA is a rare disease, treatment has been recommended to take place at a specialized center. However, delays in reaching such centers and initiating therapy are common. From current understanding of the disease, immune destruction of cells is ongoing during this period, likely impacting on both short and long term outcomes. We propose early initiation of lower dose CsA (2mg/kg/day) and EPAG to decrease ongoing immune destruction and stimulate HSPC while awaiting full work up and transfer to the Clinical Center (CC).

The aim of this study is to test feasibility and safety of initiating oral therapy before arriving to the NIH, based on diagnostic tests performed by local physicians and interpretation from experts here. Treatment will be initiated remotely but under complete guidance and supervision of the research team at the Hematology Branch. All patients except the ones who achieve complete response will receive standard three drug regimen upon completion of work up here at the CC. Primary endpoint of the study will be to assess feasibility and safety as a composite measure of misdiagnosis, non-compliance with the regimen or failure to establish care at the Clinical Center within 8 weeks of initiating treatment, and TRSAE (treatment related serious adverse events). Initial treatment period of 8 weeks may be extended in special circumstances. Secondary endpoints are response rates at landmark time points, relapse, overall survival, and clonal evolution.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Olga J Rios, R.N.; Phone Number: (301) 496-4462; Email: olga.rios@nih.gov
• Study Contact Backup: Name: Bhavisha A Patel, M.D.; Phone Number: (301) 402-3477; Email: bhavisha.patel@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR); Phone Number: TTY8664111010 800-411-1222; Email: prpl@cc.nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

  1. Age >= 3 years old
  2. Weight >12Kg
  3. Severe aplastic anemia:

• Bone marrow cellularity <30% (excluding lymphocytes) AND At least two of the following:

  • Absolute neutrophil count <500/microliter
  • Platelet count <20,000/microliter
  • Absolute reticulocyte count <60,000/microliter

EXCLUSION CRITERIA:

1. Known diagnosis or high suspicion of Fanconi anemia or other constitutional marrow failure syndrome
2. Evidence of a clonal disorder on cytogenetics performed within 12 weeks of study entry involving chromosome 7 or complex karyotype. Patient will not be excluded if cytogenetics are not done or are pending
3. A course of prior immunosuppressive therapy (ATG, cyclosporine, alemtuzumab, and high dose cyclophosphamide), or eltrombopag
4. SGOT or SGPT >2.5 times the upper limit of normal or total bilirubin >1.5 x upper limit of normal
5. Subjects with liver cirrhosis (as determined by the investigator).
6. Subjects with human immunodeficiency virus (HIV) who are not receiving antiretroviral therapy, have detectable HIV RNA viral load and have CD4 cell count <200/microliter, or are on anti-retroviral therapy that interacts with the study drugs. subjects will not be excluded if HIV testing is pending or unavailable.
7. Glomerular filtration rate (GFR) <40 mL/min/1.73m^2
8. Hypersensitivity to EPAG or its components
9. Infection not adequately responding to appropriate therapy
10. 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 tolerate protocol therapy, or that death within 7-10 days is likely
11. Potential subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects will not be eligible
12. Inability to understand the investigational nature of the study or to give informed consent or does not have a legally authorized representative or surrogate that can provide informed consent.
13. Inability to swallow
14. Unable to participate in audio/video telecommunication
15. Inability to ship the study drug to participant
16. History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease, including any of the following: Recent myocardial infarction (within last 6 months), uncontrolled congestive heart failure, unstable angina (within last 6 months), clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker.), long QT syndrome, family history of idiopathic sudden death, congenital long QT syndrome or additional risk factors for cardiac repolarization abnormality, as determined by the investigator.
17. Impaired cardiac function, such as: Corrected QTc >450 msec using Fridericia correction (QTcF) on the screening ECG (using triplicate ECGs), other clinically significant cardiovascular disease (e.g., uncontrolled hypertension, history of labile hypertension), history of known structural abnormalities (e.g. cardiomyopathy).
18. Concurrent participation in an investigational study within 30 days prior to enrollment or within 5-half-lives of the investigational product, whichever is longer. Note: parallel enrollment in a disease registry is permitted.
19. Known thrombophilic risk factors. Exception: Subjects for whom the potential benefits of participating in the study outweigh the potential risks of thromboembolic events, as determined by the investigator.

20. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception during dosing of study treatment. Basic contraception methods include:

    • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
    • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
    • Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject
    • Barrier methods of contraception: Condom or Occlusive cap. For the UK: with spermicidal foam/gel/film/cream/ vaginal suppository

    • Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.

      • In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
21. Female subjects who are nursing or pregnant (positive serum or urine B-human chorionic gonadotrophin (B-hCG) pregnancy test) at screening or pre-dose on Day 1
22. Sexually active males unless they use a condom during intercourse while taking the drug during treatment, and for 7 days after stopping treatment (and for an additional 12 weeks [for genotoxic compounds]) and should not father a child in this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via semen.

INCLUSION OF PREGNANT WOMEN, FETUSES OR NEONATES:

The protocol does not intentionally enroll pregnant women due to unknown fetal risk with eltrombopag. However, if a patient gets pregnant during the trial participation period, she may remain on study for non-invasive safety and outcomes follow-up.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Participants with Severe Aplastic Anemia in Early Initiation of Cyclosporine and Eltrombopag; Treatment-naïve Severe Aplastic Anemia (SAA) participants start Cyclosporine (CsA) on Day 1 at 2 mg/kg/day. At initiation of Horse Anti-Thymocyte-Globulin (h-ATG), dosing increases to 3 mg/kg every 12 hours for those ≥12 years (6 mg/kg/day total) and 6 mg/kg every 12 hours for those <12 years (12 mg/kg/day total). Actual body weight is used unless >125% ideal body weight (IBW), where adjusted IBW applies. CsA is titrated to a trough of 200-400 mcg/L. At 6 months, responders reduce to 2 mg/kg/day through 24 months, with return to full dosing if relapse occurs. h-ATG is given at 40 mg/kg/day for 4 days IV, unless the patient already shows a complete response at the initial NIH visit after remote oral therapy. Eltrombopag (EPAG) starts on Day 1 at 150 mg/day for ages 12-17, 75 mg/day for ages 6-11, and 2.5 mg/kg/day for ages 3-5. For East and Southeast Asian patients, starting doses are reduced to 75 mg/day (ages 12-85), 37.5 mg/day (ages 6-11), and 1.25 mg/kg/day (ages 3-5).	Drug: Eltrombopag; Between 12 and 17yo (adult dose of 150mg) Between 6 and 11yo (75 mg) Between 3 and 5 yo (2.5 mg/kg); Other Names: EPAG; Drug: Cyclosporine; Day 1 to start of h-ATG: 2mg/kg/day by mouth (All subjects) Start of h-ATG to Month 6: 3 mg/kg/dose by mouth administered every 12 hours (12yo and above) 6 mg/kg/dose by mouth administered every 12 hours (less than 12yo) Month 6 to Month 24: Dosing to be adjusted based on response; Other Names: CsA; Drug: Horse-Anti-thymocyte-Globulin; h-ATG at a dose of 40 mg/kg/day for 4 days (intravenously for approximately 4 hours daily) Note: Omitted in patients who have achieved a complete response at the initial NIH visit after initiating oral treatment remotely; Other Names: H-ATG
Experimental: Extension Cohort; Treatment-naïve Severe Aplastic Anemia (SAA) participants start Cyclosporine (CsA) on Day 1 at 2 mg/kg/day. At initiation of Horse Anti-Thymocyte-Globulin (h-ATG), dosing increases to 3 mg/kg every 12 hours for those ≥12 years (6 mg/kg/day total) and 6 mg/kg every 12 hours for those <12 years (12 mg/kg/day total). Actual body weight is used unless >125% ideal body weight (IBW), where adjusted IBW applies. CsA is titrated to a trough of 200-400 mcg/L. At 6 months, responders reduce to 2 mg/kg/day through 24 months, with return to full dosing if relapse occurs. h-ATG is given at 40 mg/kg/day for 4 days IV, unless the patient already shows a complete response at the initial NIH visit after remote oral therapy. Eltrombopag (EPAG) starts on Day 1 at 150 mg/day for ages 12-17, 75 mg/day for ages 6-11, and 2.5 mg/kg/day for ages 3-5. For East and Southeast Asian patients, starting doses are reduced to 75 mg/day (ages 12-85), 37.5 mg/day (ages 6-11), and 1.25 mg/kg/day (ages 3-5).	Drug: Eltrombopag; Between 12 and 17yo (adult dose of 150mg) Between 6 and 11yo (75 mg) Between 3 and 5 yo (2.5 mg/kg); Other Names: EPAG; Drug: Cyclosporine; Day 1 to start of h-ATG: 2mg/kg/day by mouth (All subjects) Start of h-ATG to Month 6: 3 mg/kg/dose by mouth administered every 12 hours (12yo and above) 6 mg/kg/dose by mouth administered every 12 hours (less than 12yo) Month 6 to Month 24: Dosing to be adjusted based on response; Other Names: CsA; Drug: Horse-Anti-thymocyte-Globulin; h-ATG at a dose of 40 mg/kg/day for 4 days (intravenously for approximately 4 hours daily) Note: Omitted in patients who have achieved a complete response at the initial NIH visit after initiating oral treatment remotely; Other Names: H-ATG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Meeting Safety and Feasibility Criteria During Study Treatment Period With Oral Treatment (Low Dose Cyclosporine and Eltrombopag) Until the Start of Standard of Care Treatment (Horse Anti-thymocyte-globulin)	For the primary endpoint of this study, the treatment is defined to be "feasible" to a participant if he/she meets the safety and feasibility criteria. Safety and feasibility criteria is a composite measure defined as TRSAE, mis- and altered diagnosis, and non-compliance with the regimen or failure to establish care at the National Institutes of Health Clinical Center. Study treatment period is defined as the duration from the initiation of oral treatment (low dose Cyclosporine and Eltrombopag) to the start of standard of care treatment (Day 1 of horse anti-thymocyte-globulin).	Up to 12 Weeks from the initiation of oral treatment (Low Dose Cyclosporine and Eltrombopag)

Secondary Outcome Measures

Outcome Measure	Time Frame
Relapse	At 1, 2, 3, 6 and 12 months and yearly thereafter
Hematological Response	At 1, 2, 3, 6 and 12 months and yearly thereafter
Clonal Evolution to PNH, Clonal Chromosomal Population in Bone Marrow, Myelodysplasia by Morphology, or Acute Leukemia	At 1, 2, 3, 6 and 12 months and yearly thereafter
Overall Survival	At 5 Years (60 Months)
Hematological Response of Relapse Subjects That Re-start Treatment With Cyclosporine and/or Eltrombopag	At 1, 2, 3, 6 and 12 months and yearly thereafter
Freedom From h-ATG	At 1, 2, 3, 6 and 12 months and yearly thereafter

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Bhavisha A Patel, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2020
• Primary Completion (Actual): December 18, 2024
• Study Completion (Estimated): December 18, 2033

Study Registration Dates

• First Submitted: March 10, 2020
• First Submitted That Met QC Criteria: March 10, 2020
• First Posted (Actual): March 11, 2020

Study Record Updates

• Last Update Posted (Actual): March 9, 2026
• Last Update Submitted That Met QC Criteria: February 17, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Immunosuppression; Autoimmunity; T-cells; Thrombocytopenia; Hematopoiesis
• Additional Relevant MeSH Terms: Bone Marrow Failure Disorders; Cytopenia; Immune System Diseases; Hematologic Diseases; Bone Marrow Diseases; Anemia; Blood Platelet Disorders; Hemic and Lymphatic Diseases; Thrombocytopenia; Autoimmune Diseases; Anemia, Aplastic; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Polycyclic Compounds; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Macrocyclic Compounds; Biological Products; Complex Mixtures; Peptides, Cyclic; Cyclosporins; Immune Sera; Cyclosporine; Antilymphocyte Serum; eltrombopag
• Other Study ID Numbers: 200033; 20-H-0033

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: Starting approximately 6 months after publication and available indefinitely.
• IPD Sharing Access Criteria: Data may be shared through an open or closed repository as appropriate.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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