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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT00065260
Other study ID # 030249
Secondary ID 03-H-0249
Status Completed
Phase Phase 2
First received
Last updated
Start date November 6, 2003
Est. completion date February 5, 2016

Study information

Verified date June 2021
Source National Institutes of Health Clinical Center (CC)
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

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.


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.


Recruitment information / eligibility

Status Completed
Enrollment 54
Est. completion date February 5, 2016
Est. primary completion date December 29, 2010
Accepts healthy volunteers No
Gender All
Age group 2 Years and older
Eligibility - 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.

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Campath-1H
Campath-1H IV 10 days. Adults:10mg/day (children:0.2mg/kg/day).
r-ATG
Rabbit ATG 3.5mg/kg/day for consecutive 5 days
CsA
CsA 10mg/kg/day orally twice daily for 6 months (15mg/kg/day for children under 12 yrs.

Locations

Country Name City State
United States National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda Maryland

Sponsors (1)

Lead Sponsor Collaborator
National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Mathé G, Amiel JL, Schwarzenberg L, Choay J, Trolard P, Schneider M, Hayat M, Schlumberger JR, Jasmin C. Bone marrow graft in man after conditioning by antilymphocytic serum. Br Med J. 1970 Apr 18;2(5702):131-6. — View Citation

Stein RS, Means RT Jr, Krantz SB, Flexner JM, Greer JP. Treatment of aplastic anemia with an investigational antilymphocyte serum prepared in rabbits. Am J Med Sci. 1994 Dec;308(6):338-43. — View Citation

Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med. 1997 May 8;336(19):1365-72. Review. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Primary Participants no Longer Meeting Criteria for Severe Aplastic Anemia. Number of participants no longer meeting the criteria for severe aplastic anemia as measured by response to treatment at 6 months 6 months
Secondary Number of Participants With Robust Hematologic Recovery With Reticulocyte or Platelet Count Number of participants with robust hematologic recovery with reticulocyte or platelet count = 50,000/uL 6 months
Secondary Percentage of Cumulative Incidence of Relapse in Participants Percentage of cumulative incidence of relapse of disease in participants 3 year
Secondary Percentage of Cumulative Incidence of Clonal Evolution in Participants Percent of cumulative incidence of clonal evolution in participants to either paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia or acute leukemia. 3 years
Secondary Percentage of Participants no Longer Meeting Criteria for Severe Aplastic Anemia. Percentage of participants no longer meeting the criteria for severe aplastic anemia as measured by response to treatment 3 months and 6 months
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