RATGAA07: Rabbit Antithymocyte Globulin (Thymoglobuline) With Ciclosporin for Patients With Acquired Aplastic Anaemia

• Sponsor: European Society for Blood and Marrow Transplantation (Other)
• Overall Status: Completed
• CT.gov ID: NCT00471848
• Collaborator: Genzyme, a Sanofi Company (Industry)
• Enrollment: 35
• Locations: 14
• Arm: 1
• Duration (Months): 54
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Aplastic Anemia	Drug: rabbit antithymocyte globulin	Phase 2

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

1. 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 Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Aug 1, 2008
• Actual Primary Completion Date: Oct 1, 2011
• Actual Study Completion Date: Feb 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Arm 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	Drug: rabbit antithymocyte globulin; 1.5 vials/10kg daily for 5 days; Other Names: Thymoglobuline

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Response to Rabbit Antithymocyte Globuline (Thymoglobuline) [at 6months]

   Complet 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

Secondary Outcome Measures

1. Failure Free and Overall Survival of Participants to Rabbit Antithymocyte Globuline (Thymoglobuline) [at 2 years]

   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 PNH, MDS and AML.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. Have acquired aplastic anaemia

2. Time from diagnosis to study registration maximum 6 months

3. No prior treatment except for haemopoietic growth factors given for no more than four weeks, and androgens

4. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Henri Mondor Hospital	Creteil		France
2	Hopital St. Louis	Paris		France	75475
3	University Hospital Essen	Essen		Germany
4	University Hospital Eppendorf	Hamburg		Germany
5	Medical University Hannover	Hannover		Germany
6	Universitätsklinikum - Institut für klinische Transfusionsmedizin	Ulm		Germany	89081
7	Ospedale San Martino	Genova		Italy	16132
8	King Faisal Specialist Hospital & Research Cnetre	Riyadh		Saudi Arabia
9	University Hospital	Basel		Switzerland	4031
10	Royal Bournemouth	Bournemouth		United Kingdom
11	Addenbrooke's Hospital	Cambridge		United Kingdom
12	St George's Hospital/ St George's University of London	London		United Kingdom	Sw17 0RE
13	King's College Hospital	London		United Kingdom
14	Nottingham Universitry Hospital Trust	Nottingham		United Kingdom

Sponsors and Collaborators

• European Society for Blood and Marrow Transplantation
• Genzyme, a Sanofi Company

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Sponsor's website
• Publication

Publications

None provided.

• Responsible Party: European Society for Blood and Marrow Transplantation
• ClinicalTrials.gov Identifier: NCT00471848
• Other Study ID Numbers: EudraCT: 2007-000902-55; RATGAA07
• First Posted: May 10, 2007
• Last Update Posted: Oct 18, 2021
• Last Verified: Sep 1, 2021

• Keywords provided by European Society for Blood and Marrow Transplantation: Thymoglobuline; Rabbit ATG; Ciclosporin; Aplastic Anemia
• Additional relevant MeSH terms: Anemia; Anemia, Aplastic; Thymoglobulin; Antilymphocyte Serum

Study Results

Participant Flow

Recruitment Details	14 sites in 6 countries were open to include patients; in the end 10 sites entered all 35 patients. First Patient In (FPI) 04-Aug-2008, Last Patient In (LPI) 30-Sep-2010
Pre-assignment Detail	Naive aplastic anaemia patients

Arm/Group Title	Treatment Arm
Arm/Group 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; the results were compared with historical controls from the European Group for Blood and Marrow Transplantation (EBMT) database. Patients were matched for age and disease status (NSAA, SAA, VSAA)
Period Title: Overall Study
STARTED	35
COMPLETED	35
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment Arm
Arm/Group 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; the results were compared with historical controls from the EBMT database. Patients were matched for age and disease status (NSAA, SAA, VSAA)
Overall Participants	35
Age (Count of Participants)
<=18 years	2 5.7%
Between 18 and 65 years	30 85.7%
>=65 years	3 8.6%
Sex: Female, Male (Count of Participants)
Female	13 37.1%
Male	22 62.9%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Response to Rabbit Antithymocyte Globuline (Thymoglobuline)
Description	Complet 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
Time Frame	at 6months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Arm
Arm/Group 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 rabbit antithymocyte globulin: 1.5 vials/10kg daily for 5 days
Measure Participants	35
CR	1 2.9%
PR	11 31.4%
NR	18 51.4%
Transplanted	3 8.6%
Dead	2 5.7%

2. Secondary Outcome

Title	Failure Free and Overall Survival of Participants to Rabbit Antithymocyte Globuline (Thymoglobuline)
Description	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 PNH, MDS and AML.
Time Frame	at 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Experimental: Treament Arm
Arm/Group 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
All Cause Mortality
	Experimental: Treament Arm
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Experimental: Treament Arm
	Affected / at Risk (%)	# Events
Total	27/35 (77.1%)
Cardiac disorders
Cardiac Arrest	1/35 (2.9%)	1
Vasovagal Episode	1/35 (2.9%)	1
Endocrine disorders
Pancreatic endocrine, glucose intolerance	1/35 (2.9%)	1
Eye disorders
Retinopathy	1/35 (2.9%)	1
Gastrointestinal disorders
Pyrexia	1/35 (2.9%)	1
Abdominal Pain	1/35 (2.9%)	1
Duodenal Ulcer	1/35 (2.9%)	1
Gastritis	1/35 (2.9%)	1
General disorders
Death	6/35 (17.1%)	6
Disease progression	2/35 (5.7%)	2
Pyrexia with rigours	1/35 (2.9%)	1
Unrelated Donor Stem Cell Transplant	1/35 (2.9%)	1
Immune system disorders
Allergic Reaction / Hypersensitivy	1/35 (2.9%)	1
Serum Sickness	2/35 (5.7%)	2
Infections and infestations
Bacterial Infections	1/35 (2.9%)	1
Blood-reactivation	1/35 (2.9%)	1
Coccy geal fistula abscessed	1/35 (2.9%)	1
Colonisation in Staphylococcus aures methicillin resistant	1/35 (2.9%)	1
Facial Infection	1/35 (2.9%)	1
Febrile Neutropenia	5/35 (14.3%)	6
Klebsiella Septicaemia	1/35 (2.9%)	1
Hickmann Line Infection	1/35 (2.9%)	1
Infection	2/35 (5.7%)	2
Neutropenic sepsis	5/35 (14.3%)	5
Neutropenic Fever	1/35 (2.9%)	1
Norovirus infection	1/35 (2.9%)	1
Sepsis	3/35 (8.6%)	4
Investigations
Elevated ALT levels	1/35 (2.9%)	1
Hyper Bilirubinimia	1/35 (2.9%)	1
Metabolism and nutrition disorders
Renal Impairment	1/35 (2.9%)	1
Cholestasis	1/35 (2.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary Clonal Malignancy	1/35 (2.9%)	1
Nervous system disorders
Headache	1/35 (2.9%)	1
Seizures	1/35 (2.9%)	1
Respiratory, thoracic and mediastinal disorders
Bilateral Basal Pneumonia	1/35 (2.9%)	1
Dyspnea	1/35 (2.9%)	1
Other (Not Including Serious) Adverse Events
	Experimental: Treament Arm
	Affected / at Risk (%)	# Events
Total	0/35 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Participating PIs can not publish on the patients they have included in this prospective trial before the results of the trial have been published in a peer-reviewed journal.