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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Aplastic Anemia

Intervention / Treatment
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* Drug: rabbit antithymocyte globulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Have acquired aplastic anaemia Time from diagnosis to study registration maximum 6 months No prior treatment except for haemopoietic growth factors given for no more than four weeks, and androgens Age minimum 16 years with no upper age limit Exclusion Criteria: Eligibility for an human leukocyte antigens (HLA)-matched sibling donor transplant for SAA patients Prior therapy with ATG or CSA Haematopoeitic growth factors more than 4 weeks before study enrolment Diagnosis of Fanconi anaemia, dyskeratosis congenita or congenital bone marrow failure syndrome Evidence of myelodysplastic disease Paroxysmal nocturnal haemoglobinuria with evidence of significant haemolysis, history of Paroxysmal Nocturnal Hemoglobinuria (PNH) associated thrombosis or a PNH clone >50% by flow cytometry Diagnosis or previous history of carcinoma (except local cervical, basal cell, squamous cells, or melanoma) Subject is pregnant (e.g. positive Human Chorionic Gonadotropin (HCG) test) or is breast feeding Severe uncontrolled infection or unexplained fever >38 degrees Celsius Subjects who have hepatic, renal cardiac, metabolic or other concurrent diseases of such severity that life expectancy is less than 3 months

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>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 | Drug: rabbit antithymocyte globulin<br>* 1.5 vials/10kg daily for 5 days<br>* Other names: Thymoglobuline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Response to Rabbit Antithymocyte Globulin (Thymoglobuline) | Complete Response (CR) defined as: Haemoglobin normal for age and gender, neutrophils > 1.5 x 10E9/l, platelets > 150 x 10E9/l. Partial Response (PR) defined as: transfusion independence (if previously dependent) or doubling or normalisation of at least one cell line or increase of baseline haemoglobin of > 3 g/dl (if initially <6) + neutrophils of > 0.5 x 10E9/l + platelets of > 20 x 10E9/l (if initially < 20) No Response (MR) is defined as: worse or not meeting criteria above | at 6months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Failure Free and Overall Survival of Participants to Rabbit Antithymocyte Globulin (Thymoglobuline) | Failure free survival is defined as a failure of the protocol: no achievement of response, relapse, disease progression requiring a second course of immune suppressive therapy (IST) or a stem cell transplant, death, or later clonal disorders such as Paroxysmal Nocturnal Hemoglobinuria (PNH), Myelodysplastic Syndrome (MDS) and Acute Myeloblastic Leukemia (AML). | at 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thymoglobuline, Rabbit ATG, Ciclosporin, Aplastic Anemia