hATG+CsA vs hATG+CsA+Eltrombopag for SAA (RACE)
Primary Purpose
Severe Aplastic Anemia
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
hATG
CsA
Eltrombopag
Sponsored by
About this trial
This is an interventional treatment trial for Severe Aplastic Anemia focused on measuring Aplastic Anaemia, Eltrombopag, HATG, ATGAM
Eligibility Criteria
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.
Sites / Locations
- Hopital Jean Minjoz
- Hôpital Haut-Lévèque
- Hôpital Huriez
- Centre Hospitalier Lyon-Sud
- St. Louis Hospital
- Pontchaillou Hospital
- Hôpital Purpan
- Azienda Ospedaliera Papa Giovanni XXIII
- Istituto G. Gaslini children's Hospital
- San Martino Hospital
- Fondazione IRCCS ca Granda Ospedale
- 'Federico II' Medical School
- La Sapienza University Hospital
- AOU Città della Salute e della Scienza di Torino
- AMC
- UMCG
- Leiden University Medical Center
- UMCU
- Hospital Universitari Germans Trias I Pujol
- Institut Català d'Oncologia - Hospital Duran i Reynals
- Donostia Hospital
- Hospital La Fe
- University Hospital Basel
- University Hospital Bern
- University Hospital Zürich
- St. James Hospital
- King's College Hospital
- St. Bartholomew's Hospital
- City Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Experimental
Arm Label
hATG + CsA
hATG + CsA + Eltrombopag
Arm Description
Control Arm
Experimental
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Time to best heamatological response
Heamatological Response at 6, 12, 18 and 24 months
Cumulative incidence of response
Overall survival
Event-free survival
Cumulative incidence of relapse rate
Cumulative incidences of clonal evolution
Cumulative incidence of PNH population occurrence and clinical hemolytic PNH occurrence
Cumulative incidence of discontinuation of immunosuppressive therapy
Rate of CsA-independent hematological response at 24 months
Need for transfusions and number of transfusions required from treatment
Need for any supportive care
Comparison of number of SAEs between the two arms
To look for the safety and tolerability of the investigational treatment
Full Information
NCT ID
NCT02099747
First Posted
March 6, 2014
Last Updated
December 21, 2020
Sponsor
European Society for Blood and Marrow Transplantation
Collaborators
Novartis, Pfizer
1. Study Identification
Unique Protocol Identification Number
NCT02099747
Brief Title
hATG+CsA vs hATG+CsA+Eltrombopag for SAA
Acronym
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.
Study Type
Interventional
2. Study Status
Record Verification Date
December 2020
Overall Recruitment Status
Completed
Study Start Date
July 2015 (Actual)
Primary Completion Date
December 2020 (Actual)
Study Completion Date
December 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
European Society for Blood and Marrow Transplantation
Collaborators
Novartis, Pfizer
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Severe Aplastic Anemia
Keywords
Aplastic Anaemia, Eltrombopag, HATG, ATGAM
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
202 (Actual)
8. Arms, Groups, and Interventions
Arm Title
hATG + CsA
Arm Type
Active Comparator
Arm Description
Control Arm
Arm Title
hATG + CsA + Eltrombopag
Arm Type
Experimental
Arm Description
Experimental
Intervention Type
Drug
Intervention Name(s)
hATG
Other Intervention Name(s)
ATGAM
Intervention Type
Drug
Intervention Name(s)
CsA
Intervention Type
Drug
Intervention Name(s)
Eltrombopag
Primary Outcome Measure Information:
Title
CR rate
Description
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.
Time Frame
3 months
Secondary Outcome Measure Information:
Title
Time to best heamatological response
Time Frame
2 year
Title
Heamatological Response at 6, 12, 18 and 24 months
Time Frame
2 year
Title
Cumulative incidence of response
Time Frame
2 year
Title
Overall survival
Time Frame
2 year
Title
Event-free survival
Time Frame
2 year
Title
Cumulative incidence of relapse rate
Time Frame
2 year
Title
Cumulative incidences of clonal evolution
Time Frame
2 year
Title
Cumulative incidence of PNH population occurrence and clinical hemolytic PNH occurrence
Time Frame
2 year
Title
Cumulative incidence of discontinuation of immunosuppressive therapy
Time Frame
2 year
Title
Rate of CsA-independent hematological response at 24 months
Time Frame
2 year
Title
Need for transfusions and number of transfusions required from treatment
Time Frame
2 year
Title
Need for any supportive care
Time Frame
2 year
Title
Comparison of number of SAEs between the two arms
Description
To look for the safety and tolerability of the investigational treatment
Time Frame
2 year
10. Eligibility
Sex
All
Minimum Age & Unit of Time
15 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Antonio Risitano, MD, PhD
Organizational Affiliation
Federico II Medical School, Haematology Division, Napels
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Regis Peffault de Latour, MD, PhD
Organizational Affiliation
St. Louis Hospital, Haematology Division, Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hopital Jean Minjoz
City
Besancon
Country
France
Facility Name
Hôpital Haut-Lévèque
City
Bordeaux
Country
France
Facility Name
Hôpital Huriez
City
Lille
Country
France
Facility Name
Centre Hospitalier Lyon-Sud
City
Lyon
Country
France
Facility Name
St. Louis Hospital
City
Paris
Country
France
Facility Name
Pontchaillou Hospital
City
Rennes
Country
France
Facility Name
Hôpital Purpan
City
Toulouse
Country
France
Facility Name
Azienda Ospedaliera Papa Giovanni XXIII
City
Bergamo
Country
Italy
Facility Name
Istituto G. Gaslini children's Hospital
City
Genova
Country
Italy
Facility Name
San Martino Hospital
City
Genova
Country
Italy
Facility Name
Fondazione IRCCS ca Granda Ospedale
City
Milan
Country
Italy
Facility Name
'Federico II' Medical School
City
Naples
Country
Italy
Facility Name
La Sapienza University Hospital
City
Rome
Country
Italy
Facility Name
AOU Città della Salute e della Scienza di Torino
City
Turin
Country
Italy
Facility Name
AMC
City
Amsterdam
Country
Netherlands
Facility Name
UMCG
City
Groningen
Country
Netherlands
Facility Name
Leiden University Medical Center
City
Leiden
Country
Netherlands
Facility Name
UMCU
City
Utrecht
Country
Netherlands
Facility Name
Hospital Universitari Germans Trias I Pujol
City
Badalona
Country
Spain
Facility Name
Institut Català d'Oncologia - Hospital Duran i Reynals
City
Barcelona
Country
Spain
Facility Name
Donostia Hospital
City
San Sebastian
Country
Spain
Facility Name
Hospital La Fe
City
Valencia
Country
Spain
Facility Name
University Hospital Basel
City
Basel
Country
Switzerland
Facility Name
University Hospital Bern
City
Bern
Country
Switzerland
Facility Name
University Hospital Zürich
City
Zürich
Country
Switzerland
Facility Name
St. James Hospital
City
Leeds
Country
United Kingdom
Facility Name
King's College Hospital
City
London
Country
United Kingdom
Facility Name
St. Bartholomew's Hospital
City
London
Country
United Kingdom
Facility Name
City Hospital
City
Nottingham
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
34986284
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.
Results Reference
derived
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hATG+CsA vs hATG+CsA+Eltrombopag for SAA
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