hATG+CsA vs hATG+CsA+Eltrombopag for SAA

Severe Aplastic Anemia Clinical Trial

— RACE  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02099747
• Other study ID #: EBMT-RACE
• Secondary ID: 2014-000363-40
• Status: Completed
• Phase: Phase 3
• Start date: July 2015
• Est. completion date: December 2020

Study information

• Verified date: December 2020
• Source: European Group for Blood and Marrow Transplantation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 202
• Est. completion date: December 2020
• Est. primary completion date: December 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Anemia
• Anemia, Aplastic
• Severe Aplastic Anemia

Intervention

Drug:
• hATG

• CsA

• Eltrombopag

Locations

Country	Name	City	State
France	Hopital Jean Minjoz	Besancon
France	Hôpital Haut-Lévèque	Bordeaux
France	Hôpital Huriez	Lille
France	Centre Hospitalier Lyon-Sud	Lyon
France	St. Louis Hospital	Paris
France	Pontchaillou Hospital	Rennes
France	Hôpital Purpan	Toulouse
Italy	Azienda Ospedaliera Papa Giovanni XXIII	Bergamo
Italy	Istituto G. Gaslini children's Hospital	Genova
Italy	San Martino Hospital	Genova
Italy	Fondazione IRCCS ca Granda Ospedale	Milan
Italy	'Federico II' Medical School	Naples
Italy	La Sapienza University Hospital	Rome
Italy	AOU Città della Salute e della Scienza di Torino	Turin
Netherlands	AMC	Amsterdam
Netherlands	UMCG	Groningen
Netherlands	Leiden University Medical Center	Leiden
Netherlands	UMCU	Utrecht
Spain	Hospital Universitari Germans Trias I Pujol	Badalona
Spain	Institut Català d'Oncologia - Hospital Duran i Reynals	Barcelona
Spain	Donostia Hospital	San Sebastian
Spain	Hospital La Fe	Valencia
Switzerland	University Hospital Basel	Basel
Switzerland	University Hospital Bern	Bern
Switzerland	University Hospital Zürich	Zürich
United Kingdom	St. James Hospital	Leeds
United Kingdom	King's College Hospital	London
United Kingdom	St. Bartholomew's Hospital	London
United Kingdom	City Hospital	Nottingham

Sponsors (3)

Lead Sponsor	Collaborator
European Group for Blood and Marrow Transplantation	Novartis, Pfizer

Countries where clinical trial is conducted

France,  Italy,  Netherlands,  Spain,  Switzerland,  United Kingdom, 

Outcome

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

External Links

•   RACE