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Rabbit Antithymocyte Globulin Versus Campath-1H for Treating Severe Aplastic Anemia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Danielle Townsley, M.D., National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00065260
First received: July 18, 2003
Last updated: February 3, 2016
Last verified: February 2016
  Purpose

Severe aplastic anemia, characterized by pancytopenia and a hypocellular bone marrow, is effectively treated by immunosuppressive therapy, usually a combination of antithymocyte globulin (ATG) and cyclosporine (CsA). Survival rates following this regimen are equivalent to those achieved with allogeneic stem cells transplantation. However, approximately 1/3 of patients will not show blood count improvement after ATG/CsA. General experience and small pilot studies have suggested that such patients may benefit from further immunosuppression. Furthermore, analysis of our own clinical data suggest that patients with poor blood count responses to a single course of ATG, even when transfusion-independence is achieved, have a markedly worse prognosis than patients with robust hematologic improvement. The management of such cases is uncertain.

This study will enroll patients who are either refractory to h-ATG (continued severe pancytopenia) or who have only modest improvement in blood counts (weak hematologic responders) to receive a further immunosuppressive therapy, delivered either as rabbit ATG (Thymoglobulin, r-ATG) or a humanized monoclonal antibody to T-cells, alemtuzumab (Campath-1H ). Primary endpoint will be response rate at 3 months defined as no longer meeting criteria for severe aplastic anemia. Relapse, robustness of hematopoietic recovery at 3 months, survival and clonal evolution to paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia and acute leukemia will be the secondary endpoints.


Condition Intervention Phase
Aplastic Anemia
Drug: Campath-1H
Drug: r-ATG
Drug: CsA
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Trial of Immunosuppression in Aplastic Anemia Patients With Refractory Pancytopenia or Suboptimal Hematologic Response After h-ATG/CsA Treatment

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • No Longer Meeting Criteria for Severe Aplastic Anemia. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Secondary Endpoints Will Include: Relapse; Clonal Evolution to Myelodysplastic Syndrome (MDS), Paroxysmal Nocturnal Hemoglobinuria (PNH) or Acute Leukemia [ Time Frame: months/years ] [ Designated as safety issue: No ]

Enrollment: 54
Study Start Date: July 2003
Study Completion Date: March 2015
Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: r-ATG /cyclosporine
A randomized trial of rabbit anti-thymocyte globulin (r-ATG)/ cyclosporine (CsA) versus Campath-1H in aplastic anemia patients with refractory pancytopenia or suboptimal hematological response after horse ATG treatment. Subjects who receive rabbit ATG/ CsA will be given rabbit ATG 3.5mg/kg/day for 5 days and CsA 10mg/kg/day orally twice daily for 6 months (15mg/kg/day for children under 12 yrs. Subjects who receive Campath-1H will receive an intravenous infusion for 10 days. Adult subjects will receive 10mg/day (children:0.2mg/kg/day).
Drug: r-ATG
Rabbit ATG 3.5mg/kg/day for consecutive 5 days
Other Name: Rabbit Anti-Thymoglobulin
Drug: CsA
CsA 10mg/kg/day orally twice daily for 6 months (15mg/kg/day for children under 12 yrs.
Other Name: Cyclosporine
Experimental: Alemtuzumab (Campath-1H)
A randomized trial of rabbit anti-thymocyte globulin (ATG)/ cyclosporine (CsA) versus Campath-1H in aplastic anemia patients with refractory pancytopenia or suboptimal hematological response after horse ATG treatment. Subjects who receive rabbit ATG/ CsA will be given rabbit ATG 3.5mg/kg/day for 5 days and CsA 10mg/kg/day orally twice daily for 6 months (15mg/kg/day for children under 12 yrs. Subjects who receive Campath-1H will receive an intravenous infusion for 10 days. Adult subjects will receive 10mg/day (children:0.2mg/kg/day).
Drug: Campath-1H
Campath-1H IV 10 days. Adults:10mg/day (children:0.2mg/kg/day).
Other Name: Alemtuzumab

Detailed Description:

Severe aplastic anemia, characterized by pancytopenia and a hypocellular bone marrow, is effectively treated by immunosuppressive therapy, usually a combination of antithymocyte globulin (ATG) and cyclosporine (CsA). Survival rates following this regimen are equivalent to those achieved with allogeneic stem cells transplantation. However, approximately 1/3 of patients will not show blood count improvement after ATG/CsA. General experience and small pilot studies have suggested that such patients may benefit from further immunosuppression. Furthermore, analysis of our own clinical data suggest that patients with poor blood count responses to a single course of ATG, even when transfusion-independence is achieved, have a markedly worse prognosis than patients with robust hematologic improvement. The management of such cases is uncertain.

This study will enroll patients who are either refractory to h-ATG (continued severe pancytopenia) or who have only modest improvement in blood counts (weak hematologic responders) to receive further immunosuppressive therapy, delivered either as rabbit ATG (Thymoglobulin , r-ATG) or a humanized monoclonal antibody to T-cells, alemtuzumab (Campath-1H ). Primary endpoint will be response rate at 6 months defined as no longer meeting criteria for severe aplastic anemia. Relapse, robustness of hematopoietic recovery at 6 months, survival and clonal evolution to paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia and acute leukemia will be the secondary endpoints.

  Eligibility

Ages Eligible for Study:   2 Years and older   (Child, Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Severe aplastic anemia confirmed at NIH by:

Bone marrow cellularity less than 30% (excluding lymphocytes)

At least two of the following:

Absolute neutrophil count less than 500/microL;

Platelet count less than 20,000/ microL;

Reticulocyte count less than 60,000/ microL.

Severe aplastic anemia refractory to prior course(s) of h-ATG/CsA defined after 3 months from treatment with less or equal to 4 years from receiving h-ATG.

OR

Suboptimal response to initial immunosuppression with h-ATG/CsA as defined by platelet and reticulocyte count less than 50,000 /microL at 3 months.

Age greater than or equal to 2 years of age

EXCLUSION CRITERIA:

Diagnosis of Fanconi anemia.

Evidence of a clonal disorder on cytogenetics. Patients with super severe neutropenia (ANC less than 200/microL) will not be excluded initially if results of cytogenetics are not available or pending. If evidence of a clonal disorder is later identified, the subject will go off study.

Prior treatment courses with rabbit ATG or high dose cyclophosphamide (200 mg/kg or equivalent).

Infection not adequately responding to appropriate therapy.

Underlying immunodeficiency state including seropositivity for HIV.

Failure to discontinue the herbal supplements Echinacea purpurea or Usnea barbata (Old Man's Beard) within two weeks of enrollment.

Previous hypersensitivity to Campath-1H or its components.

Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient s ability to tolerate protocol therapy or that death within 7-10 days is likely.

Potential subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects will not be eligible.

Serum creatinine greater than 2.5 mg/dL.

Current pregnancy or lactation or unwillingness to take contraceptives.

Inability to understand the investigational nature of the study or give informed consent.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00065260

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Danielle M Townsley, M.D. National Heart, Lung, and Blood Institute (NHLBI)
  More Information

Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Danielle Townsley, M.D., NHLBI Hematologist, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00065260     History of Changes
Other Study ID Numbers: 030249  03-H-0249 
Study First Received: July 18, 2003
Results First Received: February 3, 2016
Last Updated: February 3, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
Alemtuzumab (Campath-1H)
Rabbit ATG
Severe Aplastic Anemia
Cyclosporine
Thrombocytopenia
Leukopenia
Neutropenia
Autoimmunity
Relapse
Anemia

Additional relevant MeSH terms:
Anemia
Anemia, Aplastic
Hematologic Diseases
Bone Marrow Diseases
Cyclosporins
Cyclosporine
Antilymphocyte Serum
Alemtuzumab
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents
Calcineurin Inhibitors
Antineoplastic Agents

ClinicalTrials.gov processed this record on September 23, 2016