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

NCT00944749 | Completed Phase 2 Results

• 2 other identifiers: 09018309-H-0183
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• 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. Objectives: \- 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. Eligibility: \- 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. Design:
• 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.

Conditions

Anemia, Aplastic; Anemia, Hypoplastic

Keywords

H- ATG; Anti -Thymocyte Globulin; Lymphocyte Immune Globulin; Aplastic Anemia

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Complete Response at 3 Months.

  The primary endpoint was hematologic response at 3 months, defined as no longer meeting criteria for Severe Aplastic Anemia (SAA) defined as bone marrow cellularity of less than 30% and severe pancytopenia with at least two of the following peripheral blood count criteria: (i) absolute neutrophil count less than 0.5×109/L; (ii) absolute reticulocyte count less than 60×109/L; and (iii) platelet count less than 20×109/L. A complete response was defined as absolute neutrophil count (ANC) above 1.0×109/L, Hgb \> 10 g/dL, and platelet count \> 100×109/L. A partial response was defined as a hematologic response that was not sufficient for a complete response.

  3-months

• Number of Participants With Complete Response at 3 Months.

  The primary endpoint was hematologic response at 3 months, defined as no longer meeting criteria for Severe Aplastic Anemia (SAA). A complete response was defined as absolute neutrophil count (ANC) above 1.0×109/L, Hgb \> 10 g/dL, and platelet count \> 100×109/L. A partial response was defined as a hematologic response that was not sufficient for a complete response. In subjects with a non-robust hematologic response at 3 months, improvement in one or more of the listed peripheral blood parameter (a,b,c) were recorded as a response: a) ANC - if baseline ANC below 0.5×109/L, increase in ANC by \> 0.3×109/L, if baseline ANC above 0.5×109/L, any increase in ANC by \> 0.5×109/L of blood; (b) platelets - if baseline platelet count \< 50×109/L, any increase in platelet count by \> 20×109/L of blood; c) hemoglobin - any increase in hemoglobin by 1.5 g/dl of blood in transfusion-independent patients and in absolute reticulocyte count to \> 60×109/L of blood in transfusion-dependent patients.

  3 months

Study Arms (1)

Single Arm

EXPERIMENTAL

Drug: h-ATG (ATGAM ); Drug: Cyclosporine (Gengraf )

Interventions

h-ATG (ATGAM ) DRUG

Single Arm

Cyclosporine (Gengraf ) DRUG

Single Arm

Eligibility Criteria

• Age: 2 Years - 82 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosed with SAA characterized by:
• Bone marrow cellularity \< 30% (excluding lymphocytes)
• At least two of the following:
• i. Absolute neutrophil count \<500/ microL
• ii. Platelet count \<20,000/ microL
• iii. Reticulocyte count \<60,000/ microL
• 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
• Age greater than or equal to 2 years of age

You may not qualify if:

• 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.
• 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.
• Patients who received prior course(s) of alemtuzumab will not be excluded.
• Infection not adequately responding to appropriate therapy
• HIV seropositivity
• 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.
• Subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects will not be eligible
• Serum creatinine \> 2.5 mg/dL
• Current pregnancy, breast-feeding or unwillingness to refrain from pregnancy if of child bearing potential
• Inability to understand the investigational nature of the study or give informed consent

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• Mendez G Jr, Russell E. Gastrointestinal varices: percutaneous transheptic therapeutic embolization in 54 patients. AJR Am J Roentgenol. 1980 Nov;135(5):1045-50. doi: 10.2214/ajr.135.5.1045.

  PMID: 6778145 BACKGROUND

• Maciejewski JP, Selleri C, Sato T, Anderson S, Young NS. Increased expression of Fas antigen on bone marrow CD34+ cells of patients with aplastic anaemia. Br J Haematol. 1995 Sep;91(1):245-52. doi: 10.1111/j.1365-2141.1995.tb05277.x.

  PMID: 7577642 BACKGROUND

• Risitano AM, Maciejewski JP, Green S, Plasilova M, Zeng W, Young NS. In-vivo dominant immune responses in aplastic anaemia: molecular tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 sequencing. Lancet. 2004 Jul 24-30;364(9431):355-64. doi: 10.1016/S0140-6736(04)16724-X.

  PMID: 15276395 BACKGROUND

• Zaimoku Y, Patel BA, Adams SD, Shalhoub R, Groarke EM, Lee AAC, Kajigaya S, Feng X, Rios OJ, Eager H, Alemu L, Quinones Raffo D, Wu CO, Flegel WA, Young NS. HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia. Blood. 2021 Dec 30;138(26):2799-2809. doi: 10.1182/blood.2021012895.

  PMID: 34724566 DERIVED

• Scheinberg P, Townsley D, Dumitriu B, Scheinberg P, Weinstein B, Rios O, Wu CO, Young NS. Horse antithymocyte globulin as salvage therapy after rabbit antithymocyte globulin for severe aplastic anemia. Am J Hematol. 2014 May;89(5):467-9. doi: 10.1002/ajh.23669. Epub 2014 Mar 7.

  PMID: 24415649 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Anemia, Aplastic

Interventions

Antilymphocyte Serum; Cyclosporine; Cyclosporins

Condition Hierarchy (Ancestors)

Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Failure Disorders; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides

Results Point of Contact

• Title: Dr Danielle Townsley
• Organization: National Heart Lung and Blood Institute

townsleydm@nhlbi.nih.gov

301-402-3477

Study Officials

• Danielle M Townsley, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 22, 2009
• First Posted: July 23, 2009
• Study Start: August 31, 2009
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2016
• Last Updated: March 23, 2021
• Results First Posted: February 23, 2017

Record last verified: 2020-09

Locations

US (1)