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

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Brief Title

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

Official Title

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

Brief Summary


      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.


      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


      People ages 3 and older with SAA


      Participants will be screened with:

      medical history

      physical exam


      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....

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). Secondary endpoints are
      response rates at landmark time points, relapse, overall survival, and clonal evolution.

Study Phase

Phase 2

Study Type


Primary Outcome

Composite measure of TRSAE, mis- and altered diagnosis, and non-compliance with the regimen or failure to establish care at the NIH CC

Secondary Outcome

 Hematological response


Severe Aplastic Anemia



Study Arms / Comparison Groups

Description:  Subjects with SAA treated with early initiation of oral treatment


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

May 7, 2020

Completion Date

May 31, 2027

Primary Completion Date

March 1, 2023

Eligibility 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

               -  Absolute neutrophil count <500/microliter

               -  Platelet count <20,000/microliter

               -  Absolute reticulocyte count <60,000/microliter


          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

             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

         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.




3 Years - N/A

Accepts Healthy Volunteers



Neal S Young, M.D., (301) 496-4462, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

Study Sponsor

Neal S Young, M.D., Principal Investigator, National Heart, Lung, and Blood Institute (NHLBI)

Verification Date

August 5, 2022