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

NCT ID: NCT00471848

Last Updated: 2023-09-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 35 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-08-31
• Study Completion Date: 2013-02-28

Brief 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.

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 European Group for Blood and Marrow Transplantation (EBMT) prospective study is currently evaluating this further in a larger number of patients. For patients with non-severe aplastic anaemia (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.

Conditions

Aplastic Anemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment Arm

Antithymocyte globulin with cyclosporin in first line treatment of patients with acquired severe aplastic anaemia and patients with non-severe aplastic anaemia who are transfusion dependent

Group Type: EXPERIMENTAL

rabbit antithymocyte globulin

Intervention Type: DRUG

1.5 vials/10kg daily for 5 days

Interventions

rabbit antithymocyte globulin

1.5 vials/10kg daily for 5 days

Intervention Type: DRUG

Other Intervention Names

Thymoglobuline

Eligibility 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 human leukocyte antigens (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 Paroxysmal Nocturnal Hemoglobinuria (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 Human Chorionic Gonadotropin (HCG) test) or is breast feeding

9. Severe uncontrolled infection or unexplained fever >38 degrees Celsius

10. Subjects who have hepatic, renal cardiac, metabolic or other concurrent diseases of such severity that life expectancy is less than 3 months

• Minimum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genzyme, a Sanofi Company

INDUSTRY

Sponsor Role: collaborator

European Society for Blood and Marrow Transplantation

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Judith Marsh, Prof. MD.

Role: PRINCIPAL_INVESTIGATOR

King's College Hospital NHS Trust

Locations

Henri Mondor Hospital

Créteil, , France

Hopital St. Louis

Paris, , France

University Hospital Essen

Essen, , Germany

University Hospital Eppendorf

Hamburg, , Germany

Medical University Hannover

Hanover, , Germany

Universitätsklinikum - Institut für klinische Transfusionsmedizin

Ulm, , Germany

Ospedale San Martino

Genova, , Italy

King Faisal Specialist Hospital & Research Cnetre

Riyadh, , Saudi Arabia

University Hospital

Basel, , Switzerland

Royal Bournemouth

Bournemouth, , United Kingdom

Addenbrooke's Hospital

Cambridge, , United Kingdom

St George's Hospital/ St George's University of London

London, , United Kingdom

King's College Hospital

London, , United Kingdom

Nottingham Universitry Hospital Trust

Nottingham, , United Kingdom

Countries

France; Germany; Italy; Saudi Arabia; Switzerland; United Kingdom

References

Marsh JC, Bacigalupo A, Schrezenmeier H, Tichelli A, Risitano AM, Passweg JR, Killick SB, Warren AJ, Foukaneli T, Aljurf M, Al-Zahrani HA, Hochsmann B, Schafhausen P, Roth A, Franzke A, Brummendorf TH, Dufour C, Oneto R, Sedgwick P, Barrois A, Kordasti S, Elebute MO, Mufti GJ, Socie G; European Blood and Marrow Transplant Group Severe Aplastic Anaemia Working Party. Prospective study of rabbit antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia Working Party. Blood. 2012 Jun 7;119(23):5391-6. doi: 10.1182/blood-2012-02-407684. Epub 2012 Apr 27.

Reference Type: RESULT

PMID: 22544699 (View on PubMed)

Related Links

http://www.ebmt.org

Sponsor's website

https://pubmed.ncbi.nlm.nih.gov/22544699/

Publication

Other Identifiers

RATGAA07

Identifier Type: -

Identifier Source: secondary_id

EudraCT: 2007-000902-55

Identifier Type: -

Identifier Source: org_study_id