hATG+CsA vs hATG+CsA+Eltrombopag for SAA

Study Overview
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Brief Summary
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The null hypothesis of no difference in CR% at 3 months between the arms will be tested against the alternative of a difference in CR% at an alpha level of .05 by assessing the odds ratio for arm yielded by this model.

Detailed Description
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This is a superiority trial aiming to increase the 3 month complete response rate. The sample size is calculated on the hypothesis that the experimental treatment will increase the 3 months response rate up to 21% (by 3 folds, based on the 7% reported in Scheinberg et al [17]). Under these assumptions, the sample size to reject the null hypothesis is n=96 patients for each treatment arm, increased by 4% for possibly not evaluable patients (total number of 200 patients, 100 each treatment arm). Statistical design for sample size calculation: increase from 7% (control arm) to 21% (investigational arm) in 3 month complete response rate (two-sided binomial test); alpha-error 0.05; power 0.8.

Official Title
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A Prospective Randomized Multicenter Study Comparing Horse Antithymocyte Globuline (hATG) + Cyclosporine A (CsA) With or Without Eltrombopag as Front-line Therapy for Severe Aplastic Anemia Patients.

Conditions
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Severe Aplastic Anemia

Intervention / Treatment
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* Drug: hATG
* Drug: CsA
* Drug: Eltrombopag


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of severe or very severe aplastic anemia, defined by [29]: At least two of the following: Absolute neutrophil counts <0.5 x 109/L (severe) or <0.2 x 109/L (very severe) Platelet counts <20 x 109/L Reticulocyte counts <60 x 109/L Hypocellular bone marrow (<30% cellularity), without evidences of fibrosis or malignant cells Male or female age > 14 years; Written informed consent Willing and able to comply with all of the requirements and visits in the protocol Understands that they can be randomised to either treatment arm Negative pregnancy test for women of child bearing age Written acceptance to use contraception (hormonal or barrier method of birth control; abstinence) for the entire duration of study participation. Exclusion Criteria: Prior immunosuppressive therapy with ATG (horse of rabbit) or any other lymphocyte depleting agent (i.e., alemtuzumab) Eligibility to a sibling allogeneic stem cell transplantation Evidence of a myelodysplastic syndrome, defined by the presence of myelodysplastic features, excess of blasts or karyotypic abnormalities typical of MDS (according to revised WHO 2008 criteria) [30],, as well as other primitive marrow disease. Patients with diagnosis of AA with cytogenetic abnormalities which are recurrent in MDS (according to revised WHO 2008 criteria) [30] should be included in this category, and are not eligible for the study; patients with del(20q), +8 and -Y are not included in this category, and thus are eligible for this study. The list of karyotypic abnormalities which qualifies for the diagnosis of MDS are listed in the Appendix. History or clinical suspect of constitutional aplastic anemia (i.e. Fanconi Anemia with positive DEB/MMC test or Dyskeratosis Congenita) History of malignant tumors with active disease within 5 years from enrollment, and/or previous chemo-radiotherapy Previous history of stem cell transplantation Treatment with cyclosporin A unless <4 weeks of cyclosporin A treatment before enrolement and wash out period of 2 weeks before enrollment CMV viremia, as defined by positive PCR or pp65 test WHO performance status ≥3 Pregnant or breast feeding patients Patients with hepatic, renal or cardiac failure, or any other life- threatening concurrent disease Patients with HIV infection Patients without social health care assistance Participation in another clinical trial within 1 month before the start of this trial Patients and/or female partners of male patients not using highly effective method of birth control i.e. intrauterine device (IUD), hormonal (oral pill, injection, implants), tubal ligation or partner's vasectomy subjects with known hypersensitivity to any of the component medications The presence of a Paroxysmal Nocturnal Hemoglobinuria clone is not an exclusion criterion.

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: hATG + CsA<br>Control Arm | Drug: hATG<br> <br> * Other names: ATGAM;Drug: CsA<br> <br> |
| Experimental: hATG + CsA + Eltrombopag<br>Experimental | Drug: hATG<br> <br> * Other names: ATGAM;Drug: CsA<br> <br> Drug: Eltrombopag<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CR rate | The primary objective of this trial is to investigate whether Eltrombopag added to standard immunosuppressive treatment increases the rate of early (at three months) complete response in untreated AA patient. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to best heamatological response |  | 2 year | 
| Heamatological Response at 6, 12, 18 and 24 months |  | 2 year | 
| Cumulative incidence of response |  | 2 year | 
| Overall survival |  | 2 year | 
| Event-free survival |  | 2 year | 
| Cumulative incidence of relapse rate |  | 2 year | 
| Cumulative incidences of clonal evolution |  | 2 year | 
| Cumulative incidence of PNH population occurrence and clinical hemolytic PNH occurrence |  | 2 year | 
| Cumulative incidence of discontinuation of immunosuppressive therapy |  | 2 year | 
| Rate of CsA-independent hematological response at 24 months |  | 2 year | 
| Need for transfusions and number of transfusions required from treatment |  | 2 year | 
| Need for any supportive care |  | 2 year | 
| Comparison of number of SAEs between the two arms | To look for the safety and tolerability of the investigational treatment | 2 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aplastic Anaemia, Eltrombopag, HATG, ATGAM