Clinical trial NCT02099747: hATG+CsA vs hATG+CsA+Eltrombopag for SAA
Official title: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Severe Aplastic Anemia
Keywords: Aplastic Anaemia
Eltrombopag
HATG
ATGAM
Lead sponsor: European Society for Blood and Marrow Transplantation
Sponsor class: NETWORK
Collaborators: name: Novartis
name: Pfizer
First posted: 2014-03-31
Enrollment: 202
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: CR rate
timeFrame: 3 months
Secondary outcomes:
measure: Time to best heamatological response
timeFrame: 2 year
measure: Heamatological Response at 6, 12, 18 and 24 months
timeFrame: 2 year
measure: Cumulative incidence of response
timeFrame: 2 year
measure: Overall survival
timeFrame: 2 year
measure: Event-free survival
timeFrame: 2 year
measure: Cumulative incidence of relapse rate
timeFrame: 2 year
measure: Cumulative incidences of clonal evolution
timeFrame: 2 year
measure: Cumulative incidence of PNH population occurrence and clinical hemolytic PNH occurrence
timeFrame: 2 year
measure: Cumulative incidence of discontinuation of immunosuppressive therapy
timeFrame: 2 year
measure: Rate of CsA-independent hematological response at 24 months
timeFrame: 2 year
measure: Need for transfusions and number of transfusions required from treatment
timeFrame: 2 year
measure: Need for any supportive care
timeFrame: 2 year
measure: Comparison of number of SAEs between the two arms
timeFrame: 2 year
Other outcomes:
Locations:
city: Besancon
country: France
facility: Hopital Jean Minjoz
city: Bordeaux
country: France
facility: Hôpital Haut-Lévèque
city: Lille
country: France
facility: Hôpital Huriez
city: Lyon
country: France
facility: Centre Hospitalier Lyon-Sud
city: Paris
country: France
facility: St. Louis Hospital
city: Rennes
country: France
facility: Pontchaillou Hospital
city: Toulouse
country: France
facility: Hôpital Purpan
city: Bergamo
country: Italy
facility: Azienda Ospedaliera Papa Giovanni XXIII
city: Genova
country: Italy
facility: Istituto G. Gaslini children's Hospital
city: Genova
country: Italy
facility: San Martino Hospital
city: Milan
country: Italy
facility: Fondazione IRCCS ca Granda Ospedale
city: Naples
country: Italy
facility: 'Federico II' Medical School
city: Rome
country: Italy
facility: La Sapienza University Hospital
city: Turin
country: Italy
facility: AOU Città della Salute e della Scienza di Torino
city: Amsterdam
country: Netherlands
facility: AMC
city: Groningen
country: Netherlands
facility: UMCG
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Utrecht
country: Netherlands
facility: UMCU
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias I Pujol
city: Barcelona
country: Spain
facility: Institut Català d'Oncologia - Hospital Duran i Reynals
city: San Sebastian
country: Spain
facility: Donostia Hospital
city: Valencia
country: Spain
facility: Hospital La Fe
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Bern
country: Switzerland
facility: University Hospital Bern
city: Zürich
country: Switzerland
facility: University Hospital Zürich
city: Leeds
country: United Kingdom
facility: St. James Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: St. Bartholomew's Hospital
city: Nottingham
country: United Kingdom
facility: City Hospital
Study officials:
affiliation: Federico II Medical School, Haematology Division, Napels
name: Antonio Risitano, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Louis Hospital, Haematology Division, Paris
name: Regis Peffault de Latour, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Peffault de Latour R, Kulasekararaj A, Iacobelli S, Terwel SR, Cook R, Griffin M, Halkes CJM, Recher C, Barraco F, Forcade E, Vallejo JC, Drexler B, Mear JB, Smith AE, Angelucci E, Raymakers RAP, de Groot MR, Daguindau E, Nur E, Barcellini W, Russell NH, Terriou L, Iori AP, La Rocca U, Sureda A, Sanchez-Ortega I, Xicoy B, Jarque I, Cavenagh J, Sicre de Fontbrune F, Marotta S, Munir T, Tjon JML, Tavitian S, Praire A, Clement L, Rabian F, Marano L, Hill A, Palmisani E, Muus P, Cacace F, Frieri C, van Lint MT, Passweg JR, Marsh JCW, Socie G, Mufti GJ, Dufour C, Risitano AM; Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation. Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. N Engl J Med. 2022 Jan 6;386(1):11-23. doi: 10.1056/NEJMoa2109965.