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

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Brief Title

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

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

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 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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Response

Secondary Outcome

 Failure free and overall survival

Condition

Aplastic Anemia

Intervention

rabbit antithymocyte globulin

Study Arms / Comparison Groups

 Treatment Arm
Description:  Antithymocyte globuline with cyclosporin in first line treatment of patients with acquired severe aplastic anaemia and patients with non-severe aplastic anaemia who are transfusion dependent

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

35

Start Date

August 2008

Completion Date

December 2012

Primary Completion Date

September 2010

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 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
      

Gender

All

Ages

16 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Judith Marsh, Prof. MD., , 

Location Countries

France

Location Countries

France

Administrative Informations


NCT ID

NCT00471848

Organization ID

EudraCT: 2007-000902-55

Secondary IDs

RATGAA07

Responsible Party

Sponsor

Study Sponsor

European Group for Blood and Marrow Transplantation

Collaborators

 Genzyme, a Sanofi Company

Study Sponsor

Judith Marsh, Prof. MD., Principal Investigator, King's College Hospital, London


Verification Date

August 2012