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Rabbit Antithymocyte Globulin (Thymoglobuline) With Ciclosporin for Patients With Acquired Aplastic Anaemia

Information source: European Group for Blood and Marrow Transplantation
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Aplastic Anemia

Intervention: rabbit antithymocyte globulin (Drug)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: European Group for Blood and Marrow Transplantation

Official(s) and/or principal investigator(s):
Judith Marsh, Prof. MD., Principal Investigator, Affiliation: King's College Hospital, London

Summary

To assess the tolerability and effectiveness of rabbit antithymocyte globulin (ATG, Thymoglobuline) with ciclosporin in the first line treatment of patients with acquired severe aplastic anaemia, and patients with non-severe aplastic anaemia and who are transfusion dependent.

Clinical Details

Official title: Prospective Phase II Study of Rabbit Antithymocyte Globulin (ATG, Thymoglobuline«, Genzyme) With Ciclosporin for Patients With Acquired Aplastic Anaemia and Comparison With Matched Historical Patients Treated With Horse ATG and Ciclosporin

Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Response

Secondary outcome: Failure free and overall survival

Detailed description: Traditionally horse antithymocyte globulin (ATG) has been the preferred animal source of ATG as first line treatment for acquired aplastic anaemia (AA) patients who are ineligible for bone marrow transplantation (BMT). For severe AA (SAA) the combination of ATG and Ciclosporin (CSA) results in response in 60-75% of patients and the response is superior to using either agent alone. The addition of granulocyte colony stimulating factor (G-CSF) to the combination of ATG and CSA has so far shown no significant benefit in terms of response and survival, but an EBMT prospective study is currently evaluating this further in a larger number of patients. For patients with NSAA who are transfusion dependent, the combination of ATG and CSA was shown to be superior to CSA alone in an EBMT prospective randomised study, with a higher response rate, superior blood counts and improved disease free survival using the combination of ATG with CSA. There have been no phase II studies of rabbit ATG (Thymoglobuline®) in the treatment of AA as first line therapy. Preliminary results from a small single centre study compared horse ATG (ATGAM) with rabbit ATG (Fresenius) in children and showed response rates of 93% and 47%, respectively, but it is likely that different preparations of rabbit ATG will vary in their efficacy. Rabbit ATG is more commonly used for a second course following relapse or lack of response to a first course of horse ATG. Rabbit ATG in combination with CSA and G-CSF was used in patients with SAA who had failed to respond to a course of horse ATG with CSA and G-CSF. Overall response (transfusion independence) was seen in 23/30 (77%) of patients after a median of 95 days and complete response (neutrophils > 2. 0, haemoglobin > 11, and platelets > 100) in 9/30 (30%). Rabbit ATG was well tolerated; no anaphylaxis or severe side effects were reported. Another study of 43 patients treated with rabbit ATG and CSA following non-response or relapse after horse ATG and CSA, showed 30% response rate among non-responding patients and 65% response rate for relapsing patients. Studies comparing the antibody specificities between Thymoglobuline® and Lymphoglobuline® are in broad agreement, but (a) Lymphoglobuline® has fewer studies and those reported are older, because the product is older and has been less extensively developed (b) antibodies against certain epitopes are inconsistently present (c) not all antibody specificities have been examined in some studies and (d) different methods of testing have been used. There is a view that it is the immunogen and not the animal species which is most important in creating differences between different ATGs.

Eligibility

Minimum age: 16 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Must fulfil definition of aplastic anaemia: There must be at least two of the following:

- haemoglobin < 10g/dl

- platelet count < 50 x 109/l

- neutrophil count < 1. 5 x 109/l, and a hypocellular bone marrow on bone marrow

biopsy SAA as defined by a hypocellular bone marrow of <25% cellularity and two of the following:

- neutrophil count < 0. 5 x 109/l

- platelets < 20 x 109/l

- reticulocytes < 20 x 109/l

NSAA as defined by a hypocellular bone marrow and cytopenia in at least two cell lines and neutrophil count > 0. 5 x 109/l, and red cell and/or platelet transfusion dependence 2. Have acquired aplastic anaemia 3. Time from diagnosis to study registration maximum 6 months 4. No prior treatment except for haemopoietic growth factors given for no more than four weeks, and androgens 5. Age minimum 16 years with no upper age limit Exclusion Criteria: 1. Eligibility for an HLA-matched sibling donor transplant for SAA patients 2. Prior therapy with ATG or CSA 3. Haematopoeitic growth factors more than 4 weeks before study enrolment 4. Diagnosis of Fanconi anaemia, dyskeratosis congenita or congenital bone marrow failure syndrome 5. Evidence of myelodysplastic disease 6. Paroxysmal nocturnal haemoglobinuria with evidence of significant haemolysis, history of PNH associated thrombosis or a PNH clone >50% by flow cytometry 7. Diagnosis or previous history of carcinoma (except local cervical, basal cell, squamous cells, or melanoma) 8. Subject is pregnant (e. g. positive HCG test) or is breast feeding 9. Severe uncontrolled infection or unexplained fever >38oC 10. Subjects who have hepatic, renal cardiac, metabolic or other concurrent diseases of such severity that life expectancy is less than 3 months

Locations and Contacts

Henri Mondor Hospital, Creteil, France

Hopital St. Louis, Paris 75475, France

University Hospital Essen, Essen, Germany

University Hospital Eppendorf, Hamburg, Germany

Medical University Hannover, Hannover, Germany

Universit├Ątsklinikum - Institut f├╝r klinische Transfusionsmedizin, Ulm 89081, Germany

Ospedale San Martino, Genova 16132, Italy

King Faisal Specialist Hospital & Research Cnetre, Riyadh, Saudi Arabia

University Hospital, Basel 4031, Switzerland

Royal Bournemouth, Bournemouth, United Kingdom

Addenbrooke's Hospital, Cambridge, United Kingdom

King's College Hospital, London, United Kingdom

St George's Hospital/ St George's University of London, London Sw17 0RE, United Kingdom

Nottingham Universitry Hospital Trust, Nottingham, United Kingdom

Additional Information

Starting date: August 2008
Last updated: August 23, 2012

Page last updated: August 23, 2015

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