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Comparing Therapies for the Treatment of Severe Aplastic Anemia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
ClinicalTrials.gov Identifier:
NCT00001626
First received: November 3, 1999
Last updated: November 4, 2014
Last verified: October 2014
  Purpose

Severe Aplastic Anemia (SAA) is a rare and very serious blood disorder in which the bone marrow stops producing the cells which make up blood; red blood cells, white blood cells, and platelets.

Researchers believe this is caused by an autoimmune reaction, a condition in which the natural defense system of the body begins attacking itself. In SAA the immune system begins attacking the bone marrow. Red blood cells are responsible for carrying oxygen to all of the organ systems in the body, and low numbers (anemia) can cause difficulty breathing and fatigue. Platelets are responsible for normal blood clotting and low numbers can result in easy bruising and bleeding which can be deadly. White blood cells are responsible for fighting infections, and low numbers of these can lead to frequent infections, the most common cause of death in patients with aplastic anemia.

SAA can be treated by bone marrow transplant (BMT) or by drugs designed to slow down the immune system (immunosuppressants). BMT can be successful, but it requires a donor with matched bone marrow, making this therapy available only to a few patients. BMT with unmatched bone marrow can fail and cause dangerous side effects.

Presently, the two drugs used to treat SAA by slowing down the immune system (immunosuppression) are antithymocyte globulin (ATG) and cyclosporin A (CSA). When used in combination these two drugs can improve most patients condition. However, one third of the patients who respond to this therapy experience a relapse of SAA. In addition, some patients treated with ATG/CSA can later develop other disorders of the blood.

Recently, researchers have found that another immunosuppressive drug called cyclophosphamide, has been successful at treating patients with SAA. In addition, patients treated with cyclophosphamide do not experience relapses or develop other disorders of the blood.

In this study researchers would like to compare the combinations of antithymocyte globulin (ATG) and cyclosporin A (CSA) to cyclophosphamide and cyclosporin A (CSA) for the treatment of SAA.


Condition Intervention Phase
Aplastic Anemia
Hematologic Disease
Drug: Antithymocyte globulin & amp; Cyclosporin A
Drug: Cyclophosphamide & amp; Cyclosporin A
Phase 3

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 Antithymocyte Globulin and Cyclosporine Versus Cyclophosphamide and Cyclosporine in the Treatment of Severe Aplastic Anemia

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Compare the sustained response proportions among patients with SAA treated with immunosuppressive therapy with either ATG/CSA or high dose cyclophosphamide and CSA. [ Time Frame: 12 weeks. ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Overall and event-free survival rate. [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Enrollment: 33
Study Start Date: May 1997
Study Completion Date: March 2008
Primary Completion Date: September 2002 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
1 hour intravenous infusion of 50 mg/kg of cyclophosphamide daily for 4 days as an alternative immunosuppressive agent for treatment of severe aplastaic anemia.
Drug: Cyclophosphamide & amp; Cyclosporin A
1 hour IV infusion of 50 mg/kg daily for 4 days
Active Comparator: 2
40 mg/kg of ATG daily for 4 days as immunosuppressive agent for treatment of severe aplastic anemia
Drug: Antithymocyte globulin & amp; Cyclosporin A
40 mg/kg daily for 4 days

Detailed Description:

Severe aplastic anemia (SAA) is a disorder with a poor prognosis if untreated. Current accepted therapeutic strategies include bone marrow transplantation (BMT) and immunosuppression, both offering cure or amelioration in the majority of patients. Although BMT is successful using human leukocyte antigen (HLA) matched sibling bone marrow, the 25% probability of finding an HLA identical sibling within a family renders this approach available to only a minority of patients. BMT utilizing HLA-matched, unrelated donors carries a high risk of treatment failure along with considerable toxicity. While combined immunosuppression with both antithymocyte globulin (ATG) and cyclosporine A (CSA) produces hematologic improvement in most patients, relapse is common, occurring in about a third of responders. Late evolution of aplastic anemia to other serious hematologic disorders is a significant problem following successful treatment with ATG/CSA with paroxysmal nocturnal hemoglobinuria (PNH) occurs in approximately 13%, myelodysplasia in about 10%, and acute leukemia in about 7%. Recently, results of immunosuppression in SAA with another potent immunosuppressive agent, cyclophosphamide, were reported in 10 patients. In this small group, the overall response rate was similar to that seen with ATG/CSA, but relapse and late clonal disease were not seen during a median follow-up of greater than 10 years. In the larger randomized trial proposed here, we will compare sustained hematologic response rates to either conventional immunosuppression with ATG/CSA or high dose cyclophosphamide and CSA. Secondary endpoints include response duration, event free survival, and overall survival.

  Eligibility

Ages Eligible for Study:   15 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Severe aplastic anemia confirmed at NIH by:

  1. Bone marrow cellularity less than thirty percent (excluding lymphocytes).
  2. At least two of the following:

Absolute neutrophil count less that 500/mm(3);

Platelet count less than 20,000/mm(3);

Reticulocyte count less than 60,000/mm(3).

EXCLUSION CRITERIA:

Serum creatinine greater than to 2.5 mg/dl.

Cardiac ejection fraction less than 45% by MUGA.

Underlying carcinoma (except local cervical, basal cell, squamous cell or melanoma).

Current pregnancy or unwilling to take oral contraceptives.

Diagnosis of Fanconi anemia or other congenital bone marrow failure syndromes.

Evidence of a clonal disorder on cytogenetics.

HIV positivity.

Inability to understand the investigational nature of the study.

Patients who are moribund or have hepatic, renal, cardiac, metabolic or other concurrent diseases of such severity that death within 7-10 days is likely.

Previous treatment with ATG, or cyclophosphamide.

  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: NCT00001626

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

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
ClinicalTrials.gov Identifier: NCT00001626     History of Changes
Other Study ID Numbers: 970117, 97-H-0117
Study First Received: November 3, 1999
Last Updated: November 4, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Cytopenia
Randomized
Immunosuppression
Severe Aplastic Anemia

Additional relevant MeSH terms:
Anemia
Anemia, Aplastic
Hematologic Diseases
Bone Marrow Diseases
Antilymphocyte Serum
Cyclophosphamide
Cyclosporine
Cyclosporins
Immunosuppressive Agents
Alkylating Agents
Anti-Infective Agents
Antifungal Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 24, 2014