- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03413306
Eltrombopag+hATG+CsA vs. hATG+CsA in Children With Severe AA
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
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
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Anticipated)
Phase
- Phase 3
Contacts and Locations
Study Contact
- Name: Olga Goronkova, MD
- Phone Number: 5527 +7-495-287-65-70
- Email: goronkova@yandex.ru
Study Locations
-
-
-
Moscow, Russian Federation, 117198
- Recruiting
- Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology
-
Contact:
- Zhanna Shekhovtsova
- Phone Number: 4956647078
- Email: zhanna.shekhovtsova@fccho-moscow.ru
-
Contact:
- Eugene Pashanov, Prof. PhD
- Phone Number: +79262205578
- Email: e.pashanov@gmail.com
-
Sub-Investigator:
- Olga Goronkova
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Eltrombopag + IST (ATG + CsA)
|
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.
Other Names:
Other Names:
|
Active Comparator: IST (ATG + CsA)
|
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
ORR (CR + PR)
Time Frame: 4 months
|
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.
|
4 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Overall survival
Time Frame: 2 years
|
2 years
|
|
Platelet count
Time Frame: 4 and 6 months
|
4 and 6 months
|
|
Hemoglobin
Time Frame: 4 and 6 months
|
4 and 6 months
|
|
Neutrophil count
Time Frame: 4 and 6 months
|
4 and 6 months
|
|
Cumulative incidence of response
Time Frame: 4 and 6 months
|
4 and 6 months
|
|
Duration of hematologic response
Time Frame: 2 years
|
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
|
2 years
|
Event-free survival
Time Frame: 2 years
|
2 years
|
|
Cumulative incidence of relapse
Time Frame: 2 years
|
2 years
|
|
Cumulative incidences of clonal evolution
Time Frame: 2 years
|
2 years
|
|
Cumulative incidence of PNH population occurrence and clinical hemolytic PNH occurrence
Time Frame: 2 years
|
2 years
|
|
Cumulative incidence of adverce effects
Time Frame: 4 months
|
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.
|
4 months
|
Cumulative incidence of adverce effects
Time Frame: 4 months
|
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.
|
4 months
|
Comparison of cumulative incidence of adverce effects in two arms
Time Frame: 2 years
|
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.
|
2 years
|
Collaborators and Investigators
Investigators
- Principal Investigator: Galina Novichkova, Dmitry Rogachev National Medical Research Center Of Pediatric Hematology, Oncology and Immunology
- Principal Investigator: Alexei Maschan, Dmitry Rogachev National Medical Research Center Of Pediatric Hematology, Oncology and Immunology
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- NCPHOI-2016-01
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Acquired Aplastic Anemia
-
Nagoya UniversityUnknownAcquired Aplastic Anemia.Japan
-
Asan Medical CenterUnknownAcquired Aplastic AnemiaKorea, Republic of
-
King Faisal Specialist Hospital & Research CenterCompleted
-
National University Hospital, SingaporeUnknownHaematological Malignancies | Acquired Aplastic AnaemiaSingapore
-
Assistance Publique - Hôpitaux de ParisNot yet recruitingSevere Aplastic Anemia | Idiopathic Aplastic Anemia | Moderate Aplastic Anemia Requiring Transfusions
-
University of UtahNovartisCompletedSevere Aplastic Anemia | Moderate Aplastic Anemia | Very Severe Aplastic AnemiaUnited States
-
Assistance Publique - Hôpitaux de ParisCompletedHereditary Diseases | Relapse | Acquired Aplastic Anemia | Absence of an HLA Identical DonorFrance
-
City of Hope Medical CenterNational Cancer Institute (NCI)RecruitingRecurrent Severe Aplastic Anemia | Refractory Severe Aplastic AnemiaUnited States
-
Peking University People's HospitalRecruiting
-
Boston Children's HospitalNational Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health... and other collaboratorsRecruitingSevere Aplastic AnemiaUnited States
Clinical Trials on Eltrombopag
-
Novartis PharmaceuticalsCompletedPurpura, Thrombocytopenic, IdiopathicRussian Federation
-
Fondazione Progetto EmatologiaCompletedChronic Lymphocytic Leukemia | Purpura, Thrombocytopenic, Idiopathic | Non Hodgkin's Lymphoma | Autoimmune Thrombocytopenia | Autoimmune Thrombocytopenic PurpuraItaly
-
Weill Medical College of Cornell UniversityNovartisTerminatedImmune ThrombocytopeniaUnited States
-
Institute of Hematology & Blood Diseases Hospital...Xijing Hospital; Xi'an Central Hospital; The Second Hospital of Hebei Medical... and other collaboratorsActive, not recruitingPreviously Treated Primary Immune ThrombocytopeniaChina
-
Tel-Aviv Sourasky Medical CenterNovartisRecruitingB Cell Lymphoma | CART TreatmentIsrael
-
Gruppo Italiano Malattie EMatologiche dell'AdultoCompletedPrimacy Immune ThrombocytopeniaItaly
-
Novartis PharmaceuticalsCompletedPurpura, Thrombocytopaenic, Idiopathic
-
Nanfang Hospital of Southern Medical UniversityGuangzhou First People's Hospital; Second Affiliated Hospital, Sun Yat-Sen... and other collaboratorsUnknownAcute Myeloid Leukemia | Thrombocytopenia | EltrombopagChina
-
IRCCS Policlinico S. MatteoCompleted