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Horse ATG/CsA in Aplastic Anemia Patients Unresponsive to or With a Suboptimal Response to Rabbit ATG/CsA Treatment

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ) Identifier:
First received: July 22, 2009
Last updated: August 31, 2016
Last verified: March 2016


  • Severe plastic anemia can lead to problems with bone marrow platelet production and result in low blood platelet counts, which require frequent platelet transfusions to improve blood clotting.
  • A standard treatment for SAA involves injections of rabbit-antithymocyte globulin (r-ATG). r-ATG is developed by injecting horses with a type of human white blood cells called thymocytes. The horse's immune system reacts against these cells and makes antibodies that can destroy them. These antibodies are collected and purified to make r-ATG. Horses can also be used for this procedure to make horse-antithymocyte globulin (h-ATG).
  • h-ATG is approved by the Food and Drug Administration for the treatment of aplastic anemia. h-ATG is a standard first-line method to treat aplastic anemia, but researchers do not know how effective it is in patients who were first treated unsuccessfully with r-ATG.


- To evaluate the effectiveness and safety of horse-ATG (with cyclosporine) in increasing blood counts and reducing the need for transfusions in aplastic anemia patients who have failed to respond to prior immunosuppressive treatment with rabbit-ATG and cyclosporine.


- Patients 2 years of age and older who have consistently low blood platelet counts related to aplastic anemia that has not responded to conventional treatment with rabbit-ATG.


  • After initial screening, medical history, and blood tests, patients will be admitted to the inpatient unit at the National Institutes of Health Clinical Center. Researchers will perform a skin test with h-ATG to check for allergic or other adverse reaction.
  • After the skin test, h-ATG will be given into a vein continuously over 4 days.
  • Cyclosporine will also be given to improve the response rate of ATG treatment. Treatment with cyclosporine will start the same day as the h-ATG, either in liquid or capsule form, and continued for 6 months. The dose of cyclosporine will be monitored and adjusted based on blood levels and signs of side effects in the kidney and liver.
  • To prevent or treat infections that may result from cyclosporine s effect on the immune system, patients will also take inhaled or capsule doses of pentamidine.
  • After the study is completed, patients will have followup evaluations every 3 months, 6 months, and annually for 5 years. Evaluations will include blood samples and periodic bone marrow biopsies.

Condition Intervention Phase
Anemia, Aplastic
Anemia, Hypoplastic
Drug: h-ATG (ATGAM )
Drug: Cyclosporine (Gengraf )
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Horse ATG/CsA in Aplastic Anemia Patients Unresponsive to or With a Suboptimal Response to Rabbit ATG/CsA Treatment

Resource links provided by NLM:

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

Primary Outcome Measures:
  • Changes in absolute neutrophil count, platelet count, reticulocyte count at 3-months. [ Time Frame: 3-months ]

Secondary Outcome Measures:
  • Time to relapse, changes in cytogenetics, time to death.

Enrollment: 23
Study Start Date: July 2009
Estimated Study Completion Date: December 2020
Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Detailed Description:

Severe aplastic anemia (SAA), 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 benefit from further immunosuppression. Furthermore, analysis of our own clinical data suggests that patients with minimal 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 majority of the experience in the US and worldwide has been with horse ATG (h-ATG) plus CsA as initial therapy in SAA. Rabbit ATG (r-ATG) plus CsA has been employed successfully in about 1/3 of cases in those who are refractory to initial h-ATG/CsA (current NHLBI Protocol 03-H-0249). In recent years, h-ATG and r-ATG have been used interchangeably in treatment-naive patients, and initial therapy with r-ATG/CsA is now frequent in the US and the only option in Europe and Japan, where h-ATG is no longer available. An active NHLBI randomized study is comparing the efficacy of h- and r-ATG as initial therapy in SAA, and the results from a recently completed interim analysis suggest that the hematologic response rate ultimately may not be comparable between these two agents (Protocol 06-H-0034). There is no published report on the outcome of repeat immunosuppressive therapy in those patients refractory to initial r-ATG/CsA, and thus the management of these patients is uncertain. We therefore propose this study of h-ATG/CsA in SAA patients who are refractory or have a suboptimal response to r-ATG.

The primary endpoint will be the response rate at 3 months where response is defined as no longer meeting criteria for SAA.

The primary objective is to evaluate the effectiveness (response rate) at 3 months of a second course of immunosuppression with h-ATG/CsA in subjects refractory to or with a suboptimal response to a course of r-ATG/CsA or cyclophosphamide at least 3 months post treatment.

Secondary objectives include robustness of hematologic recovery, relapse, response rate at 6 months, clonal evolution and overall survival.

The primary endpoint will be changes in absolute neutrophil count, platelet count, reticulocyte count at 3 months.

Secondary endpoints will include time to relapse, changes in cytogenetics, time to death.


Ages Eligible for Study:   2 Years to 82 Years   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
  • All patients 2 years old or over with SAA who have failed initial immunosuppression with r-ATG/CsA and are not candidates for a matched sibling marrow transplantation will be considered for enrollment. Patients who have a suitable matched sibling donor will be referred for consideration of allogeneic bone marrow transplantation. Patients not willing to undergo transplantation will be considered for enrollment. Eligibility will be determined on another screening Hematology Branch protocol (97-H-0041) or another active Hematology branch protocol. The time between determination of eligibility and signing consent to participate on this protocol and initiate treatment on this protocol will not exceed 90 days.


  1. Diagnosed with SAA characterized by:

    1. Bone marrow cellularity < 30% (excluding lymphocytes)
    2. At least two of the following:

    i. Absolute neutrophil count <500/ microL

    ii. Platelet count <20,000/ microL

    iii. Reticulocyte count <60,000/ microL

  2. Failure to respond to an initial course of r-ATG/CsA or cyclophosphamide at least 3 months post-treatment or a suboptimal response to initial therapy defined by both platelet and reticulocyte count < 50,000 /microL at 3 months post-treatment
  3. Age greater than or equal to 2 years of age


  1. Diagnosis of Fanconi anemia. Patients with very severe neutropenia (ANC < 200 /microL) will not be excluded initially if results of Fanconi anemia testing are not available or pending. If evidence of Fanconi anemia is later identified, the subject will go off study.
  2. Evidence of a clonal disorder on cytogenetics. Patients with very severe neutropenia (ANC < 200/uL) 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.
  3. Patients who received prior course(s) of alemtuzumab will not be excluded.
  4. Infection not adequately responding to appropriate therapy
  5. HIV seropositivity
  6. 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.
  7. Subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects will not be eligible
  8. Serum creatinine > 2.5 mg/dL
  9. Current pregnancy, breast-feeding or unwillingness to refrain from pregnancy if of child bearing potential
  10. Inability to understand the investigational nature of the study or give informed consent
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Please refer to this study by its identifier: NCT00944749

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)
Principal Investigator: Danielle M Townsley, M.D. National Heart, Lung, and Blood Institute (NHLBI)
  More Information

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: National Heart, Lung, and Blood Institute (NHLBI) Identifier: NCT00944749     History of Changes
Other Study ID Numbers: 090183  09-H-0183 
Study First Received: July 22, 2009
Last Updated: August 31, 2016

Keywords provided by National Institutes of Health Clinical Center (CC):
Anti -Thymocyte Globulin
Lymphocyte Immune Globulin
Aplastic Anemia

Additional relevant MeSH terms:
Anemia, Aplastic
Hematologic Diseases
Bone Marrow Diseases
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 processed this record on February 20, 2017