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Eltrombopag With Standard Immunosuppression for Severe Aplastic Anemia

Primary Purpose

Severe Aplastic Anemia

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Cohort 1: hATG, CsA, EPAG Day 14 to Month 6
Cohort 2: hATG, CsA, EPAG Day 14 to Month 3
Cohort 3: hATG, CsA (dose reduced), EPAG day 1 to month 6
Extension Cohort
Sponsored by
National Heart, Lung, and Blood Institute (NHLBI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Severe Aplastic Anemia focused on measuring Pancytopenia, Immunosuppression, Hematopoesis, Autoimmunity, Thrombocytopenia

Eligibility Criteria

2 Years - 95 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

-INCLUSION CRITERIA:

  1. Severe aplastic anemia characterized by Bone marrow cellularity less than 30 percent (excluding lymphocytes)

    AND

    At least two of the following:

    • Absolute neutrophil count less than 500/microL
    • Platelet count less than 20,000/microL

    Absolute reticulocyte count less than 60,000/microL

  2. Age greater than or equal to 2 years old
  3. Weight greater than 12 kg

EXCLUSION CRITERIA:

  1. Known diagnosis of Fanconi anemia
  2. Evidence of a clonal disorder on cytogenetics performed within 12 weeks of study entry. Patients with super severe neutropenia (ANC less than 200 /microL) will not be excluded initially if cytogenetics are not available or pending. If evidence of a clonal disorder consistent with myelodysplasia is later identified, the patient will go off study.
  3. Prior immunosuppressive therapy with any ATG, alemtuzumab, or high dose cyclophosphamide
  4. SGOT or SGPT >5 times the upper limit of normal
  5. Subjects with known liver cirrhosis in severity that would preclude tolerability of cyclosporine and eltrombopag as evidenced by albumin < 35g/L
  6. Hypersensitivity to eltrombopag or its components
  7. Infection not adequately responding to appropriate therapy
  8. 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
  9. Potential subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects will not be eligible
  10. Current pregnancy, or unwillingness to take oral contraceptives or use a barrier method of birth control or practice abstinence to refrain from pregnancy if of childbearing potential during the course of this study
  11. 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.

Sites / Locations

  • National Institutes of Health Clinical Center, 9000 Rockville PikeRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Cohort 1: hATG, CsA, EPAG Day 14 to Month 6

Cohort 2: hATG, CsA, EPAG Day 14 to Month 3

Cohort 3: hATG, CsA (dose reduced), EPAG day 1 to month 6

Extrension Cohort

Arm Description

Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 6

Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 3

Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18months, and receive eltrombopag day 1 to month 6

Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18 months, and receive eltrombopag day 1 to month 6

Outcomes

Primary Outcome Measures

Rate of Complete Hematologic Response
Rate of complete hematologic response at six months for cohorts 1, 2 and 3.

Secondary Outcome Measures

Rate of Response at 3 and 12 Months Then Yearly; Rate of Relapse; Rate of Clonal Evolution to PNH, MDS and AML; Rate of Survival; Rate of Response for Relapse Subjects That Re-start Treatment and Effects of CsA Dose Starting at Month 6 to Month 24.
Secondary endpoints will also be evaluated for the study to include: (a) hematological response at 3 and 12 months and yearly thereafter; (b) relapse (c) clonal evolution to PNH, clonal chromosomal population in bone marrow, myelodysplasia by morphology, or acute leukemia; (d) survival; (e) health-related quality of life; (f) hematological response of relapse subjects that re-start treatment; and (g) affects of a 2.0mg/kg/day CsA dose starting month 6 for 18 months until month 24 on the rate of relapse of subjects deemed responders at month 6.

Full Information

First Posted
June 14, 2012
Last Updated
March 22, 2023
Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
Collaborators
Novartis
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1. Study Identification

Unique Protocol Identification Number
NCT01623167
Brief Title
Eltrombopag With Standard Immunosuppression for Severe Aplastic Anemia
Official Title
Eltrombopag Added to Standard Immunosuppression in Treatment-Naive Severe Aplastic Anemia
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 2, 2012 (Actual)
Primary Completion Date
January 30, 2018 (Actual)
Study Completion Date
January 30, 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
Collaborators
Novartis

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Background: Severe aplastic anemia is a rare and serious blood disorder. It happens when the immune system starts to attack the bone marrow cells. This causes the bone marrow to stop making red blood cells, platelets, and white blood cells. Standard treatment for this disease is horse-ATG and cyclosporine, which suppress the immune system and stop it from attacking the bone marrow. However, this treatment does not work in all people. Some people still have poor blood cell counts even after treatment. Eltrombopag is a drug designed to mimic a protein in the body called thrombopoietin. It helps the body to make more platelets. It may also cause the body to make more red and white blood cells. Studies have shown that eltrombopag may be useful when added to standard treatment for severe aplastic anemia. It may help improve poor blood cell counts. Objectives: - To test the safety and effectiveness of adding eltrombopag to standard immunosuppressive therapy for severe aplastic anemia. Eligibility: - Individuals at least 2 years of age who have severe aplastic anemia that has not yet been treated. Design: Participants will be screened with a physical exam, medical history, and blood tests. Blood and urine samples will be collected. Participants will start treatment with horse-ATG and cyclosporine. Treatment will be given according to the standard of care for the disease. Cohort 1: After 14 days, participants will start taking eltrombopag. They will take eltrombopag for up to 6 months. Cohort 2: After 14 days, participants will start taking eltrombopag. They will take eltrombopag for up to 3 months. Cohort 3 and Extension Cohort: Participants will start taking eltrombopag on Day 1. They will take eltrombopag for up to 6 months. Participants may receive other medications to prevent infections during treatment. Treatment will be monitored with frequent blood tests. Participants will also fill out questionnaires about their symptoms and their quality of life.
Detailed Description
Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized by pancytopenia and a hypocellular bone marrow. Allogeneic bone marrow transplantation offers the opportunity for cure in younger patients, but most are not suitable candidates for transplantation due to advanced age or lack of a histocompatible donor. Comparable long-term survival in SAA is attainable with immunosuppressive treatment with horse anti-thymocyte globulin (h-ATG) and cyclosporine (CsA). However, of those patients treated with h-ATG/CsA, one quarter to one third will not respond, and 30-40% of responders relapse. The majority of the hematologic responses observed following initial h-ATG/CsA are partial, with only a few patients achieving normal blood counts. Furthermore, analysis of our own extensive clinical data suggests that poor blood count responses to a single course of ATG (non-robust responders), even when transfusion-independence is achieved, predicts a worse prognosis than when robust hematologic improvement is achieved (protocol 90-H-0146). The explanation for partial recovery and relapse are not fully understood, but incomplete elimination of auto-reactive T cells and insufficient stem cell reserve are both possible. Furthermore, 10-15% of SAA patients treated with standard immunosuppression will develop an abnormal karyotype in follow-up, with monosomy 7 being most common, which portends progression to myelodysplasia and leukemia. In contrast, malignant clonal evolution is rare in complete responders to immunosuppression. Although horse ATG/CsA represented a major advance in the treatment of SAA, refractoriness, incomplete responses, relapse, and clonal evolution limit the success of this modality. Thus, newer regimens are needed to address these limitations, and provide a better alternative to stem cell transplantation. One approach to augment the quality of hematologic responses is to improve underlying stem cell function. Previous attempts to improve responses in SAA with hematopoietic cytokines including erythropoietin, G-CSF, and stem cell factor, have failed. Thrombopoietin (TPO) is the principal endogenous regulator of platelet production. In addition, TPO also has stimulatory effects on more primitive multilineage progenitors and stem cells in vitro and in animal models. Eltrombopag (Promacta ), an oral 2nd generation small molecule TPO-agonist, is currently approved for treatment of chronic immune thrombocytopenic purpura (ITP), chronic hepatitis C-associated thrombocytopenia, and severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. Eltrombopag increases platelets in healthy subjects and in thrombocytopenic patients with chronic ITP and hepatitis C virus (HCV) infection. Our Branch recently completed a pilot study of eltrombopag in refractory SAA. We saw encouraging clinical results in a cohort of patients who have failed on average two prior immunosuppressive regimens (Olnes et al. ASH Annual Meeting Abstracts, San Diego, CA, 2011, oral presentation and N Engl J Med 2012;367:11-9.1). Of the twenty-five SAA patients treated with eltrombopag by mouth for three months, eleven (44%) patients met protocol criteria of clinically meaningful hematologic responses, without significant toxicity. Nine patients demonstrated an improvement in thrombocytopenia (>20k/ L increase or transfusion independence), hemoglobin improved in two patients (>1.5g/dL or achieved transfusion independence, and four patients had a significant response in their neutrophil count. When responders continued the drug beyond three months, the hematologic response to eltrombopag increased; a trilineage response was observed in four patients, and a bilineage response occurred in another four, with median follow-up of 13 months. These results suggest that stem cell depletion, a major component of the pathophysiology of SAA, might be directly addressed by eltrombopag administration. The aim of the current study would be to improve the hematologic response rate and its quality, as well as prevent late complications such as relapse and clonal progression, by addition of eltrombopag to standard immunosuppressive therapy. This trial will evaluate the safety and efficacy of combining eltrombopag with standard hATG/CSA as first line therapy in patients with SAA. The primary endpoint will be the rate of complete hematologic response at six months. Secondary endpoints are relapse, robust hematologic blood count recovery at 3, 6, and 12 months, survival, clonal evolution to myelodysplasia and leukemia, marrow stem cell content and hematological response of relapse patients that re-start treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Severe Aplastic Anemia
Keywords
Pancytopenia, Immunosuppression, Hematopoesis, Autoimmunity, Thrombocytopenia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
207 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1: hATG, CsA, EPAG Day 14 to Month 6
Arm Type
Experimental
Arm Description
Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 6
Arm Title
Cohort 2: hATG, CsA, EPAG Day 14 to Month 3
Arm Type
Experimental
Arm Description
Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 3
Arm Title
Cohort 3: hATG, CsA (dose reduced), EPAG day 1 to month 6
Arm Type
Experimental
Arm Description
Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18months, and receive eltrombopag day 1 to month 6
Arm Title
Extrension Cohort
Arm Type
Experimental
Arm Description
Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18 months, and receive eltrombopag day 1 to month 6
Intervention Type
Drug
Intervention Name(s)
Cohort 1: hATG, CsA, EPAG Day 14 to Month 6
Other Intervention Name(s)
Horse Antithymocyte Globulin, Cyclosporine, Promacta, Eltrombopag
Intervention Description
hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months, eltrombopag (experimental) administered Day 14 to month 6
Intervention Type
Drug
Intervention Name(s)
Cohort 2: hATG, CsA, EPAG Day 14 to Month 3
Other Intervention Name(s)
Horse Antithymocyte Globulin, Cyclosporine, Promacta, Eltrombopag
Intervention Description
hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months, eltrombopag (experimental) administered Day 14 to month 3
Intervention Type
Drug
Intervention Name(s)
Cohort 3: hATG, CsA (dose reduced), EPAG day 1 to month 6
Other Intervention Name(s)
Horse Antithymocyte Globulin, Cyclosporine, Promacta, Eltrombopag
Intervention Description
hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months at higher dose, then reduced dose for 18 months, eltrombopag (experimental) administered Day 1 to month 6
Intervention Type
Drug
Intervention Name(s)
Extension Cohort
Other Intervention Name(s)
Horse Antithymocyte Globulin (hATG), Cyclosporine (CsA), Promacta, Eltrombopag (EPAG)
Intervention Description
Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18 months, and receive eltrombopag day 1 to month 6
Primary Outcome Measure Information:
Title
Rate of Complete Hematologic Response
Description
Rate of complete hematologic response at six months for cohorts 1, 2 and 3.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Rate of Response at 3 and 12 Months Then Yearly; Rate of Relapse; Rate of Clonal Evolution to PNH, MDS and AML; Rate of Survival; Rate of Response for Relapse Subjects That Re-start Treatment and Effects of CsA Dose Starting at Month 6 to Month 24.
Description
Secondary endpoints will also be evaluated for the study to include: (a) hematological response at 3 and 12 months and yearly thereafter; (b) relapse (c) clonal evolution to PNH, clonal chromosomal population in bone marrow, myelodysplasia by morphology, or acute leukemia; (d) survival; (e) health-related quality of life; (f) hematological response of relapse subjects that re-start treatment; and (g) affects of a 2.0mg/kg/day CsA dose starting month 6 for 18 months until month 24 on the rate of relapse of subjects deemed responders at month 6.
Time Frame
3 months to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
95 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
-INCLUSION CRITERIA: Severe aplastic anemia characterized by Bone marrow cellularity less than 30 percent (excluding lymphocytes) AND At least two of the following: Absolute neutrophil count less than 500/microL Platelet count less than 20,000/microL Absolute reticulocyte count less than 60,000/microL Age greater than or equal to 2 years old Weight greater than 12 kg EXCLUSION CRITERIA: Known diagnosis of Fanconi anemia Evidence of a clonal disorder on cytogenetics performed within 12 weeks of study entry. Patients with super severe neutropenia (ANC less than 200 /microL) will not be excluded initially if cytogenetics are not available or pending. If evidence of a clonal disorder consistent with myelodysplasia is later identified, the patient will go off study. Prior immunosuppressive therapy with any ATG, alemtuzumab, or high dose cyclophosphamide SGOT or SGPT >5 times the upper limit of normal Subjects with known liver cirrhosis in severity that would preclude tolerability of cyclosporine and eltrombopag as evidenced by albumin < 35g/L Hypersensitivity to eltrombopag or its components Infection not adequately responding to appropriate therapy 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 Potential subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects will not be eligible Current pregnancy, or unwillingness to take oral contraceptives or use a barrier method of birth control or practice abstinence to refrain from pregnancy if of childbearing potential during the course of this study 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Olga J Rios, R.N.
Phone
(301) 496-4462
Email
olga.rios@nih.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Bhavisha Patel, M.D.
Phone
301.402.3477
Email
bhavisha.patel@nih.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Neal S Young, M.D.
Organizational Affiliation
National Heart, Lung, and Blood Institute (NHLBI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
Phone
800-411-1222
Ext
TTY8664111010
Email
prpl@cc.nih.gov

12. IPD Sharing Statement

Citations:
PubMed Identifier
16778145
Citation
Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006 Oct 15;108(8):2509-19. doi: 10.1182/blood-2006-03-010777. Epub 2006 Jun 15.
Results Reference
background
PubMed Identifier
2981406
Citation
Zoumbos NC, Gascon P, Djeu JY, Trost SR, Young NS. Circulating activated suppressor T lymphocytes in aplastic anemia. N Engl J Med. 1985 Jan 31;312(5):257-65. doi: 10.1056/NEJM198501313120501.
Results Reference
background
PubMed Identifier
3311225
Citation
Young NS, Leonard E, Platanias L. Lymphocytes and lymphokines in aplastic anemia: pathogenic role and implications for pathogenesis. Blood Cells. 1987;13(1-2):87-100.
Results Reference
background
PubMed Identifier
28423296
Citation
Townsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, Weinstein B, Valdez J, Lotter J, Feng X, Desierto M, Leuva H, Bevans M, Wu C, Larochelle A, Calvo KR, Dunbar CE, Young NS. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med. 2017 Apr 20;376(16):1540-1550. doi: 10.1056/NEJMoa1613878.
Results Reference
background
PubMed Identifier
34724566
Citation
Zaimoku Y, Patel BA, Adams SD, Shalhoub R, Groarke EM, Lee AAC, Kajigaya S, Feng X, Rios OJ, Eager H, Alemu L, Quinones Raffo D, Wu CO, Flegel WA, Young NS. HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia. Blood. 2021 Dec 30;138(26):2799-2809. doi: 10.1182/blood.2021012895.
Results Reference
derived
PubMed Identifier
34525188
Citation
Patel BA, Groarke EM, Lotter J, Shalhoub R, Gutierrez-Rodrigues F, Rios O, Quinones Raffo D, Wu CO, Young NS. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study. Blood. 2022 Jan 6;139(1):34-43. doi: 10.1182/blood.2021012130.
Results Reference
derived
PubMed Identifier
33910334
Citation
Zaimoku Y, Patel BA, Shalhoub R, Groarke EM, Feng X, Wu CO, Young NS. Predicting response of severe aplastic anemia to immunosuppression combined with eltrombopag. Haematologica. 2022 Jan 1;107(1):126-133. doi: 10.3324/haematol.2021.278413.
Results Reference
derived
PubMed Identifier
33410523
Citation
Groarke EM, Patel BA, Gutierrez-Rodrigues F, Rios O, Lotter J, Baldoni D, St Pierre A, Shalhoub R, Wu CO, Townsley DM, Young NS. Eltrombopag added to immunosuppression for children with treatment-naive severe aplastic anaemia. Br J Haematol. 2021 Feb;192(3):605-614. doi: 10.1111/bjh.17232. Epub 2021 Jan 7. Erratum In: Br J Haematol. 2022 Jun;197(5):640-641.
Results Reference
derived
PubMed Identifier
29958797
Citation
Giudice V, Wu Z, Kajigaya S, Fernandez Ibanez MDP, Rios O, Cheung F, Ito S, Young NS. Circulating S100A8 and S100A9 protein levels in plasma of patients with acquired aplastic anemia and myelodysplastic syndromes. Cytokine. 2019 Jan;113:462-465. doi: 10.1016/j.cyto.2018.06.025. Epub 2018 Jun 27.
Results Reference
derived
PubMed Identifier
29674506
Citation
Giudice V, Banaszak LG, Gutierrez-Rodrigues F, Kajigaya S, Panjwani R, Ibanez MDPF, Rios O, Bleck CK, Stempinski ES, Raffo DQ, Townsley DM, Young NS. Circulating exosomal microRNAs in acquired aplastic anemia and myelodysplastic syndromes. Haematologica. 2018 Jul;103(7):1150-1159. doi: 10.3324/haematol.2017.182824. Epub 2018 Apr 19.
Results Reference
derived
PubMed Identifier
29419434
Citation
Giudice V, Feng X, Lin Z, Hu W, Zhang F, Qiao W, Ibanez MDPF, Rios O, Young NS. Deep sequencing and flow cytometric characterization of expanded effector memory CD8+CD57+ T cells frequently reveals T-cell receptor Vbeta oligoclonality and CDR3 homology in acquired aplastic anemia. Haematologica. 2018 May;103(5):759-769. doi: 10.3324/haematol.2017.176701. Epub 2018 Feb 1.
Results Reference
derived
PubMed Identifier
26354756
Citation
Hosokawa K, Muranski P, Feng X, Keyvanfar K, Townsley DM, Dumitriu B, Chen J, Kajigaya S, Taylor JG, Hourigan CS, Barrett AJ, Young NS. Identification of novel microRNA signatures linked to acquired aplastic anemia. Haematologica. 2015 Dec;100(12):1534-45. doi: 10.3324/haematol.2015.126128. Epub 2015 Sep 9.
Results Reference
derived
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2012-H-0150.html
Description
NIH Clinical Center Detailed Web Page

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Eltrombopag With Standard Immunosuppression for Severe Aplastic Anemia

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