Cyclosporine + Eltrombopag for Aplastic Anemia

Overseen By Bhavisha A Patel, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Must be taking: Cyclosporine, Eltrombopag

Must not be taking: Antiretrovirals, Chemotherapy

Disqualifiers: Fanconi anemia, Clonal disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

80 Participants Needed

Trial Summary

What is the purpose of this trial?

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....

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss your specific situation with the trial coordinators.

What data supports the effectiveness of the drug combination Cyclosporine and Eltrombopag for treating aplastic anemia?

Research shows that adding eltrombopag to standard immunosuppressive therapy, which includes cyclosporine and horse antithymocyte globulin, improves treatment effectiveness in patients with severe aplastic anemia. Eltrombopag has been effective in increasing blood cell counts and maintaining stable levels even after stopping the drug. ^{1 2 3 4 5}

Is the combination of Cyclosporine and Eltrombopag safe for treating aplastic anemia?

The combination of Cyclosporine and Eltrombopag has been generally well tolerated in patients with aplastic anemia, with some mild adverse reactions that were manageable. Eltrombopag can cause increased liver enzymes, and some patients may develop clonal cytogenetic abnormalities or dysplasia, but these side effects are relatively uncommon. ^{2 3 4 5 6}

How is the drug combination of Cyclosporine and Eltrombopag unique for treating aplastic anemia?

The combination of Cyclosporine and Eltrombopag is unique because it combines an immunosuppressant (Cyclosporine) with a thrombopoietin receptor agonist (Eltrombopag), which may enhance the effectiveness of standard immunosuppressive therapy in patients with severe aplastic anemia, especially those who are treatment-naive or have not responded to previous treatments. ^{1 2 4 7 8}

Research Team

Bhavisha A Patel, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria

This trial is for people aged 3 and older with severe aplastic anemia, a condition where the bone marrow doesn't make enough blood cells. Participants must have specific low blood cell counts, weigh over 12Kg, and not have HIV, certain infections or cancers, heart issues, liver cirrhosis or be on conflicting medications. Pregnant women or those who can't use contraception are excluded.

Inclusion Criteria

I am at least 3 years old.

I have severe aplastic anemia with very low blood cell counts.

Weight >12Kg

Exclusion Criteria

I cannot swallow.

I am not pregnant or nursing.

I do not have serious heart conditions or recent heart issues.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Remote screening via telephone conference

Initial Treatment

Participants take a lower oral dose of CsA and EPAG for 6 months, with weekly telephone calls until they visit the Clinical Center

8 weeks

Weekly telephone calls

Standard Treatment

Participants may receive h-ATG at the Clinical Center for 4 days, with a central line placed

4 days

In-person at Clinical Center

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up visits at 3 months, 6 months, and annually for 5 years

5 years

In-person visits at 3 months, 6 months, and annually

Treatment Details

Interventions

• Cyclosporine
• Eltrombopag
• Horse-Anti-thymocyte-Globulin

Trial Overview The study tests if starting oral Cyclosporine (CsA) and Eltrombopag (EPAG) early before horse anti-thymocyte globulin (h-ATG) helps treat severe aplastic anemia. Patients take CsA twice daily and EPAG for six months; some may receive h-ATG at NIH Clinical Center.

Participant Groups

Group I: SAA Experimental Treatment 3 Interventions

Subjects with SAA treated with early initiation of oral treatment

Cyclosporine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Neoral for:

• Prevention of organ rejection in kidney, liver, heart, lung, pancreas, and bone marrow transplants
• Treatment of severe psoriasis
• Treatment of nephrotic syndrome

Approved in United States as Neoral for:

• Prevention of organ rejection in kidney, liver, and heart transplants
• Treatment of severe rheumatoid arthritis
• Treatment of severe psoriasis

Approved in Canada as Neoral for:

• Prevention of organ rejection in kidney, liver, heart, lung, pancreas, and bone marrow transplants
• Treatment of severe psoriasis
• Treatment of nephrotic syndrome

Approved in Japan as Neoral for:

• Prevention of organ rejection in kidney, liver, and heart transplants
• Treatment of severe rheumatoid arthritis
• Treatment of severe psoriasis

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Findings from Research

In a phase 3 trial involving 197 previously untreated patients with severe aplastic anemia, the addition of eltrombopag to standard immunosuppressive therapy significantly improved the complete response rate at 3 months from 10% to 22%.

Eltrombopag also accelerated the time to response, with patients receiving it showing a median time to first response of 3.0 months compared to 8.8 months for those not receiving it, all without increasing the incidence of severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. Peffault de Latour, R., Kulasekararaj, A., Iacobelli, S., et al.[2023]

Eltrombopag, when used in combination with immunosuppressive therapy, shows a high overall hematologic response rate of 88% in patients with aplastic anemia, indicating its efficacy in this treatment context.

In patients with refractory aplastic anemia treated with eltrombopag alone, the response rate drops to 47%, and there are concerns about karyotype abnormalities, with a 17% rate observed in this group, highlighting potential safety issues associated with the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Eltrombopag for Aplastic Anemia: A Systematic Review and Meta-analysis. Hong, Y., Li, X., Wan, B., et al.[2022]

In a study of 89 aplastic anemia patients, the combination of cyclosporine (CSA) and eltrombopag (EPAG) showed similar overall response rates to the combination of CSA, EPAG, and antithymocyte globulin (ATG), indicating that CSA + EPAG may be an effective alternative treatment.

The CSA + EPAG combination resulted in fewer side effects compared to the standard treatment with ATG, with a mortality rate of 7.8% in the ATG group and no deaths in the CSA + EPAG group, suggesting a potentially safer option for newly diagnosed patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclosporine plus eltrombopag in the treatment of aplastic anemia with or without antithymocyte immunoglobulin: A multicenter real-world retrospective study. Chen, M., Liu, Q., Gao, Y., et al.[2023]

In a study of 76 treatment-naive patients with transfusion-dependent non-severe aplastic anemia, eltrombopag combined with cyclosporine A significantly improved hematological response and complete response rates compared to cyclosporine A alone over a follow-up period of up to 12 months.

Eltrombopag treatment led to a shorter median time to platelet transfusion independence and a lower volume of platelet transfusions needed, indicating its efficacy in promoting platelet recovery, while adverse events were mild and well tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of Eltrombopag on Response to Immunosuppressive Therapy in Patients with Transfusion-Dependent Non-Severe Aplastic Anemia]. Lin, Y., Zhang, RD., Lin, ZH., et al.[2023]

Eltrombopag is an effective treatment for patients with severe aplastic anemia who do not respond to immunosuppressive therapy, showing a hematological response in at least 40% of patients after 12-16 weeks of treatment.

The drug works by stimulating hematopoietic stem cells and increasing platelet, red blood cell, and neutrophil counts, while being generally well tolerated, though it can cause increased liver transaminases and some cytogenetic abnormalities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eltrombopag: a review of its use in patients with severe aplastic anaemia. McCormack, PL.[2018]

In a study of 13 patients with transfusion-dependent non-severe aplastic anemia, the combination of eltrombopag and cyclosporine A resulted in a high overall hematological response rate of 92% after 3 months, with 2 patients achieving complete response and 9 achieving partial response.

The treatment was generally safe, with only mild and manageable adverse reactions reported in 5 patients, although one patient developed paroxysmal nocturnal hemoglobinuria after 6 months, indicating the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The efficacy of eltrombopag plus cyclosporine A in patients with transfusion-dependent non-severe aplastic anemia: a retrospective study from single center]. Chen, Y., Zha, Q., Huang, F., et al.[2022]

In a study involving 39 healthy adults, the combination of cyclosporine with eltrombopag reduced the drug's plasma exposure by up to 39%, but these changes were not deemed clinically significant due to the ability to adjust eltrombopag doses based on patient needs.

The study found that all treatment combinations were safe and well-tolerated, with no serious adverse events reported, indicating a favorable safety profile for using eltrombopag with cyclosporine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of cyclosporine coadministration on the pharmacokinetics of eltrombopag in healthy volunteers. Aslanis, V., Zhang, J., Lomeli, B., et al.[2019]

In a study of 25 pediatric patients with severe aplastic anemia, the addition of eltrombopag to standard immunosuppressive therapy showed a satisfactory hematological response, with 29% achieving complete response at 6 and 12 months.

The combination therapy was well tolerated, with no significant differences in infection rates between the groups, although one patient experienced transient liver enzyme elevation, indicating a need for monitoring but not major safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eltrombopag in children with severe aplastic anemia. Lesmana, H., Jacobs, T., Boals, M., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. [2023]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Eltrombopag for Aplastic Anemia: A Systematic Review and Meta-analysis. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Cyclosporine plus eltrombopag in the treatment of aplastic anemia with or without antithymocyte immunoglobulin: A multicenter real-world retrospective study. [2023]

4. China pubmed.ncbi.nlm.nih.gov

[Effect of Eltrombopag on Response to Immunosuppressive Therapy in Patients with Transfusion-Dependent Non-Severe Aplastic Anemia]. [2023]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Eltrombopag: a review of its use in patients with severe aplastic anaemia. [2018]

6. China pubmed.ncbi.nlm.nih.gov

[The efficacy of eltrombopag plus cyclosporine A in patients with transfusion-dependent non-severe aplastic anemia: a retrospective study from single center]. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Effect of cyclosporine coadministration on the pharmacokinetics of eltrombopag in healthy volunteers. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Eltrombopag in children with severe aplastic anemia. [2022]