Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| 03-H-0249 |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| r-ATG /cyclosporine | Experimental | 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). |
|
| Alemtuzumab (Campath-1H) | Experimental | 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Campath-1H | Drug | Campath-1H IV 10 days. Adults:10mg/day (children:0.2mg/kg/day). |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Percentage of Cumulative Incidence of Relapse in Participants |
Not provided
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.
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Danielle M Townsley, M.D. | National Heart, Lung, and Blood Institute (NHLBI) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | 20892 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 9134878 | Background | Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med. 1997 May 8;336(19):1365-72. doi: 10.1056/NEJM199705083361906. No abstract available. | |
| 4909449 | Background | Mathe 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. doi: 10.1136/bmj.2.5702.131. |
| Label | URL |
|---|---|
| NIH Clinical Center Detailed Web Page | View source |
Not provided
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | 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). 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. |
| FG001 | 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). Campath-1H: Campath-1H IV 10 days. Adults:10mg/day (children:0.2mg/kg/day). |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | 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). 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | 1 patient was not evaluable at 6 months in the alemtuzumab arm because of a single early death from infectious complications | Posted | Number | participants | 6 months |
|
3 years
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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). 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| infection | Immune system disorders | CTCAE (2.0) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| infection | Blood and lymphatic system disorders | CTCAE (2.0) | Non-systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Bhavisha Patel | NIH NHLBI | 301.402.3477 | bhavisha.patel@nih.gov |
Not provided
| ID | Term |
|---|---|
| D000741 | Anemia, Aplastic |
| D013921 | Thrombocytopenia |
| D007970 | Leukopenia |
| D009503 | Neutropenia |
| D001327 | Autoimmune Diseases |
| D012008 | Recurrence |
| D000740 | Anemia |
| ID | Term |
|---|---|
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D000080983 | Bone Marrow Failure Disorders |
| D001855 | Bone Marrow Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D000074323 | Alemtuzumab |
| D016572 | Cyclosporine |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| r-ATG | Drug | Rabbit ATG 3.5mg/kg/day for consecutive 5 days |
|
|
| CsA | Drug | CsA 10mg/kg/day orally twice daily for 6 months (15mg/kg/day for children under 12 yrs. |
|
|
Percentage of cumulative incidence of relapse of disease in participants |
| 3 year |
| 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 |
| 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 |
| 7985721 | Background | 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. doi: 10.1097/00000441-199412000-00005. |
| 22067384 | Derived | Scheinberg P, Nunez O, Weinstein B, Scheinberg P, Wu CO, Young NS. Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia. Blood. 2012 Jan 12;119(2):345-54. doi: 10.1182/blood-2011-05-352328. Epub 2011 Nov 8. |
| BG001 | 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). Campath-1H: Campath-1H IV 10 days. Adults:10mg/day (children:0.2mg/kg/day). |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | 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). Campath-1H: Campath-1H IV 10 days. Adults:10mg/day (children:0.2mg/kg/day). |
|
|
| 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 | 1 patient was not evaluable at 6 months in the alemtuzumab arm because of a single early death from infectious complications | Posted | Count of Participants | Participants | 6 months |
|
|
|
| Secondary | Percentage of Cumulative Incidence of Relapse in Participants | Percentage of cumulative incidence of relapse of disease in participants | 1 participants was not evaluable at 6 months in the alemtuzumab arm because of a single early death from infectious complications. | Posted | Number | percentage of cumulative incidence | 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. | 1 participant was not evaluable at 6 months in the alemtuzumab arm because of a single early death from infectious complications | Posted | Number | Percentage of Cumulative Incidence | 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 | 1 patient was not evaluable at 6 months in the alemtuzumab arm because of a single early death from infectious complications | Posted | Number | 95% Confidence Interval | percentage of participants | 3 months and 6 months |
|
|
|
| 9 |
| 27 |
| 7 |
| 27 |
| 7 |
| 27 |
| EG001 | 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). Campath-1H: Campath-1H IV 10 days. Adults:10mg/day (children:0.2mg/kg/day). | 4 | 27 | 12 | 27 | 12 | 27 |
Not provided
Not provided
Not provided
| D001791 | Blood Platelet Disorders |
| D000095542 | Cytopenia |
| D007960 | Leukocyte Disorders |
| D000380 | Agranulocytosis |
| D007154 | Immune System Diseases |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D003524 | Cyclosporins |
| D010456 | Peptides, Cyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
| D010455 | Peptides |