Eltrombopag+hATG+CsA vs. hATG+CsA in Children With Severe AA
Primary Purpose
Acquired Aplastic Anemia
Status
Unknown status
Phase
Phase 3
Locations
Russian Federation
Study Type
Interventional
Intervention
Eltrombopag
IST (ATG + CsA)
Sponsored by
About this trial
This is an interventional treatment trial for Acquired Aplastic Anemia focused on measuring aplastic anemia, immunosupressive therapy, ATG, eltrombopag
Eligibility Criteria
Inclusion Criteria:
- Clinical diagnosis of severe and very severe Aplastic anemia
- 2 - 18 years old
- Written informed consent signed by a parent or legal guardian prior to initiation of any study specific procedure.
- Absence of HLA-identical family member
Exclusion Criteria:
1. myelodysplastic syndrome 4. Prior immunosuppressive therapy 5. Patients with hepatic, renal or cardiac failure, or any other life- threatening concurrent disease 6. hypersensitivity to any of the component medications 7. Creatinine >2.5 mg/dL× the upper limit of normal, 8. Total bilirubin >1.5 × the upper limit of normal mg/dL , 9. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3-5 × the upper limit of normal
Sites / Locations
- Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and ImmunologyRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Eltrombopag + IST (ATG + CsA)
IST (ATG + CsA)
Arm Description
Outcomes
Primary Outcome Measures
ORR (CR + PR)
The primary objective of this trial is to investigate whether Eltrombopag added to standard immunosupressive treatment hATG and CsA increases the overal (partial + complete) response rate at four months in untreated children with severe aquired aplastic anemia.
Secondary Outcome Measures
Platelet count
Hemoglobin
Neutrophil count
Cumulative incidence of response
Duration of hematologic response
Time from the date of the start of response to the date of relapse defined as again meeting criteria for severe or moderate aplastic anemia
Overall survival
Event-free survival
Cumulative incidence of relapse
Cumulative incidences of clonal evolution
Cumulative incidence of PNH population occurrence and clinical hemolytic PNH occurrence
Cumulative incidence of adverce effects
Number of participants with severe adverse events (3-5 stage CTCAE v.4.0) associated with assessment of eltrombopag usage in patients with severe aplastic anemia in 4 months after first day of treatment. Death before evidence of adverce event is competing event.
Cumulative incidence of adverce effects
Number of participants with severe adverse events (3-5 stage CTCAE v.4.0) associated with assessment of eltrombopag dose in patients with severe aplastic anemia in 4 months after first day of treatment. Death before evidence of adverce event is competing event.
Comparison of cumulative incidence of adverce effects in two arms
comparison between two arms of number of participants with severe adverse events (3-5 stage CTCAE v.4.0) associated with treatment in patients with severe aplastic anemia in 2 years after first day of treatment with death before evidence of adverce event as a competing event.
Full Information
NCT ID
NCT03413306
First Posted
December 22, 2017
Last Updated
March 12, 2021
Sponsor
Federal Research Institute of Pediatric Hematology, Oncology and Immunology
1. Study Identification
Unique Protocol Identification Number
NCT03413306
Brief Title
Eltrombopag+hATG+CsA vs. hATG+CsA in Children With Severe AA
Official Title
A Phase II Multicenter Randomized Study of Eltrombopag Combined With Cyclosporine and hATG Versus hATG and CsA as First Line Treatment in Pediatric Patients With Severe Acquired Aplastic Anemia
Study Type
Interventional
2. Study Status
Record Verification Date
March 2021
Overall Recruitment Status
Unknown status
Study Start Date
December 10, 2016 (Actual)
Primary Completion Date
October 20, 2022 (Anticipated)
Study Completion Date
October 20, 2022 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Federal Research Institute of Pediatric Hematology, Oncology and Immunology
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
The analysis of our own clinical data suggests that majority of the hematologic responses observed after the course of h-ATG/CsA is partial, and about 10% tend to have cyclosporine dependence.
The aim of the current study is to improve the rate and the quality of hematologic response as well as to prevent delayed complications such as relapse and clonal progression by means of adding eltrombopag to standard immunosuppressive therapy
Detailed Description
This trial will evaluate safety and efficacy of combination eltrombopag with standard hATG/CSA as first line therapy in patients with SAA. The primary endpoint is going to be estimating the rate of complete hematologic response at the point in four months after the end of the treatment. Secondary endpoints are probability of relapse, hematologic blood count recovery in 6 and 12 months after the treatment, survival, clonal evolution into myelodysplasia and leukemia
Aplastic anemia can be treated effectively with allogeneic bone marrow transplantation and immunosuppressive therapy with horse anti-thymocyte globulin (h-ATG) and cyclosporine (CsA), allowing to achieve a comparable long-term survival about 80%. However, one third of the patients treated with h-ATG/CsA, does not respond, and 25-30% of the responders relapse. The analysis of our clinical data suggests that majority of the hematologic responses observed following initial h-ATG/CsA are partial, with only a few patients achieving normal blood counts, and about 10% tend to have cyclosporine dependence. Although horse ATG/CsA provides represented a major advance in the treatment of SAA, such condition as refractory course of the disease, incomplete response, relapse, and clonal evolution limit the success of this treatment. Thus, new regimens are needed to overcome these limitations and provide a better alternative to stem cell transplantation.
One option of improving the quality of hematologic responses is influencing underlying stem cell function. Previous attempts to improve response by hematopoietic cytokines, including erythropoietin and G-CSF, have failed. Thrombopoietin is the principal endogenous regulator of platelet production. In addition, TPO also has stimulatory effects onto primitive multilineage progenitors and stem cells in vitro and animal models. Eltrombopag (Revolade), an oral 2nd generation small molecule TPO-agonist, is approved for treatment of chronic immune thrombocytopenic purpura and SAA who had insufficient response to immunosuppressive therapy. Eltrombopag increases platelets in healthy subjects and in thrombocytopenic patients, and recently has showed clinically significant hematologic responses in refractory SAA patients. The aim of this tudy to improve hematologic response rate and its quality, as well as to prevent late complications such as relapse and clonal progression, by adding eltrombopag into standard immunosuppressive therapy This trial evaluates safety and efficacy of combining eltrombopag with standard hATG/CSA as the first line of therapy in patients with SAA. The primary endpoint is going to be estimation of the rate of complete hematologic response in 4 months. Secondary endpoints are probability of relapse, robust hematologic blood count recovery in 6 and 12 months after the treatment, survival, clonal evolution to myelodysplasia and leukemia.
This is a trial aiming to increase 4 months overall response rate. The sample size is calculated on the hypothesis that the experimental treatment will increase the 4 months response rate in 20% in comparison with standard IST treatment arm. Under these assumptions, the sample size to reject the null hypothesis is n=100 patients, 50 patients in each treatment arm; alpha-error 0.05; power 0.75.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acquired Aplastic Anemia
Keywords
aplastic anemia, immunosupressive therapy, ATG, eltrombopag
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
100 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Eltrombopag + IST (ATG + CsA)
Arm Type
Experimental
Arm Title
IST (ATG + CsA)
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Eltrombopag
Other Intervention Name(s)
Revolade
Intervention Description
Eltrombopag is an oral mimetic thrombopoietin selectively binding transmembrane and juxtamembrane domains of the thrombopoietin receptor different from the binding site of thrombopoietin. Therefore it does not compete for binding with the native molecule. It is promoting thrombopoiesis and release platelets from mature megakaryocytes. Also it promotes more primitive multilineage progenitors and hematopoietic stem cells to proliferate and differentiate into thrombocytes, erythrocytes and leukocytes.
Intervention Type
Drug
Intervention Name(s)
IST (ATG + CsA)
Other Intervention Name(s)
controle
Primary Outcome Measure Information:
Title
ORR (CR + PR)
Description
The primary objective of this trial is to investigate whether Eltrombopag added to standard immunosupressive treatment hATG and CsA increases the overal (partial + complete) response rate at four months in untreated children with severe aquired aplastic anemia.
Time Frame
4 months
Secondary Outcome Measure Information:
Title
Platelet count
Time Frame
4 and 6 months
Title
Hemoglobin
Time Frame
4 and 6 months
Title
Neutrophil count
Time Frame
4 and 6 months
Title
Cumulative incidence of response
Time Frame
4 and 6 months
Title
Duration of hematologic response
Description
Time from the date of the start of response to the date of relapse defined as again meeting criteria for severe or moderate aplastic anemia
Time Frame
2 years
Title
Overall survival
Time Frame
2 years
Title
Event-free survival
Time Frame
2 years
Title
Cumulative incidence of relapse
Time Frame
2 years
Title
Cumulative incidences of clonal evolution
Time Frame
2 years
Title
Cumulative incidence of PNH population occurrence and clinical hemolytic PNH occurrence
Time Frame
2 years
Title
Cumulative incidence of adverce effects
Description
Number of participants with severe adverse events (3-5 stage CTCAE v.4.0) associated with assessment of eltrombopag usage in patients with severe aplastic anemia in 4 months after first day of treatment. Death before evidence of adverce event is competing event.
Time Frame
4 months
Title
Cumulative incidence of adverce effects
Description
Number of participants with severe adverse events (3-5 stage CTCAE v.4.0) associated with assessment of eltrombopag dose in patients with severe aplastic anemia in 4 months after first day of treatment. Death before evidence of adverce event is competing event.
Time Frame
4 months
Title
Comparison of cumulative incidence of adverce effects in two arms
Description
comparison between two arms of number of participants with severe adverse events (3-5 stage CTCAE v.4.0) associated with treatment in patients with severe aplastic anemia in 2 years after first day of treatment with death before evidence of adverce event as a competing event.
Time Frame
2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Clinical diagnosis of severe and very severe Aplastic anemia
2 - 18 years old
Written informed consent signed by a parent or legal guardian prior to initiation of any study specific procedure.
Absence of HLA-identical family member
Exclusion Criteria:
1. myelodysplastic syndrome 4. Prior immunosuppressive therapy 5. Patients with hepatic, renal or cardiac failure, or any other life- threatening concurrent disease 6. hypersensitivity to any of the component medications 7. Creatinine >2.5 mg/dL× the upper limit of normal, 8. Total bilirubin >1.5 × the upper limit of normal mg/dL , 9. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3-5 × the upper limit of normal
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Olga Goronkova, MD
Phone
+7-495-287-65-70
Ext
5527
Email
goronkova@yandex.ru
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Galina Novichkova
Organizational Affiliation
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Alexei Maschan
Organizational Affiliation
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology
City
Moscow
ZIP/Postal Code
117198
Country
Russian Federation
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Zhanna Shekhovtsova
Phone
4956647078
Email
zhanna.shekhovtsova@fccho-moscow.ru
First Name & Middle Initial & Last Name & Degree
Eugene Pashanov, Prof. PhD
Phone
+79262205578
Email
e.pashanov@gmail.com
First Name & Middle Initial & Last Name & Degree
Olga Goronkova
12. IPD Sharing Statement
Citations:
PubMed Identifier
35446936
Citation
Goronkova O, Novichkova G, Salimova T, Kalinina I, Baidildina D, Petrova U, Antonova K, Sadovskaya M, Suntsova E, Evseev D, Matveev V, Venyov D, Khachatryan L, Litvinov D, Pshonkin A, Ovsyannikova G, Kotskaya N, Gobadze D, Olshanskaya Y, Popov A, Raykina E, Mironenko O, Voronin K, Purbueva B, Boichenko E, Dinikina Y, Guseynova E, Sherstnev D, Kalinina E, Mezentsev S, Streneva O, Yudina N, Plaksina O, Erega E, Maschan M, Maschan A. Efficacy of combined immunosuppression with or without eltrombopag in children with newly diagnosed aplastic anemia. Blood Adv. 2023 Mar 28;7(6):953-962. doi: 10.1182/bloodadvances.2021006716.
Results Reference
derived
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Eltrombopag+hATG+CsA vs. hATG+CsA in Children With Severe AA
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