Severe Aplastic Anemia
Conditions
Keywords
Aplastic Anaemia, Eltrombopag, HATG, ATGAM
Brief summary
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
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.
Sponsors
Novartis
Pfizer
European Society for Blood and Marrow Transplantation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 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 2. Male or female age \> 14 years; 3. Written informed consent 4. Willing and able to comply with all of the requirements and visits in the protocol 5. Understands that they can be randomised to either treatment arm 6. Negative pregnancy test for women of child bearing age 7. Written acceptance to use contraception (hormonal or barrier method of birth control; abstinence) for the entire duration of study participation.
Exclusion criteria
1. Prior immunosuppressive therapy with ATG (horse of rabbit) or any other lymphocyte depleting agent (i.e., alemtuzumab) 2. Eligibility to a sibling allogeneic stem cell transplantation 3. 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. 4. History or clinical suspect of constitutional aplastic anemia (i.e. Fanconi Anemia with positive DEB/MMC test or Dyskeratosis Congenita) 5. History of malignant tumors with active disease within 5 years from enrollment, and/or previous chemo-radiotherapy 6. Previous history of stem cell transplantation 7. Treatment with cyclosporin A unless * \<4 weeks of cyclosporin A treatment before enrolement and * wash out period of 2 weeks before enrollment 8. CMV viremia, as defined by positive PCR or pp65 test 9. WHO performance status ≥3 10. Pregnant or breast feeding patients 11. Patients with hepatic, renal or cardiac failure, or any other life- threatening concurrent disease 12. Patients with HIV infection 13. Patients without social health care assistance 14. Participation in another clinical trial within 1 month before the start of this trial 15. 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 16. subjects with known hypersensitivity to any of the component medications The presence of a Paroxysmal Nocturnal Hemoglobinuria clone is not an exclusion criterion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CR rate | 3 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Rate of CsA-independent hematological response at 24 months | 2 year | — |
| Cumulative incidence of PNH population occurrence and clinical hemolytic PNH occurrence | 2 year | — |
| Cumulative incidence of discontinuation of immunosuppressive therapy | 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 | 2 year | To look for the safety and tolerability of the investigational treatment |
| Cumulative incidences of clonal evolution | 2 year | — |
Countries
France, Italy, Netherlands, Spain, Switzerland, United Kingdom
Outcome results
None listed