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ICH GCP | Clinical Trials Registry

A Randomized Trial of a Novel Immunosuppressive Combination of ATG, CsA and Sirolimus (Rapamune) vs a Slow Taper Cyclosporine Regimen in Subjects With Severe Aplastic Anemia

Improving Immunosuppressive Treatment for Patients With Severe Aplastic Anemia



Sponsors

Lead Sponsor

 National Heart, Lung, and Blood Institute (NHLBI)


Source

National Institutes of Health Clinical Center (CC)

Oversight Info

Is Fda Regulated Drug

Yes

Is Fda Regulated Device

No


Brief Summary

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized by pancytopenia and a hypocellular bone marrow. Allogeneic bone marrow transplantation and immunosuppressive treatment with anti-thymocyte globulin (ATG) and cyclosporine (CsA) have dramatically changed the natural course of this illness, with 5 year survival of 75% in patients undergoing either treatment. Since most patients are not suitable candidates for hematopoietic stem cell transplantation (HSCT) due to advanced age or lack of a histocompatible sibling, efforts at NHLBI have focused on improving immunosuppression treatment in order to improve response rates, survival, and to decrease relapse. In our experience of 122 patients treated at NHLBI with the combination of ATG and cyclosporine, one quarter to one third did not respond; about 50% of responders relapsed; and 5 year survival was correlated with the robustness in blood cell count improvement at 3 months (reticulocyte or platelet count greater than or equal to 50,000 /uL). Why some patients do not respond initially while others relapse is unclear. Autoreactive T cells may be resistant to the effect of ATG/CsA (nonresponders), while in others residual autoreactive T cells expand post-treatment leading to hematopoietic stem cell destruction and recurrent pancytopenia (relapse). Therefore, novel immunosuppressive regimens to increase response rates and hematologic recovery at 3 months and to decrease relapse rates are needed. An ongoing NHLBI trial, which is close to completing accrual, has added mycophenolate mofetil (MMF) for a total of 18 months to standard ATG + CsA in an attempt to reduce the relapse rate after cyclosporine is discontinued. Preliminary results have been disappointing, with no marked reduction in relapse among patients who received MMF. Sirolimus (rapamycin, Rapamune , RAPA) is a novel immunosuppressive agent, which acts synergistically with cyclosporine by blocking T cell activation through CsA-resistant pathways. The potentiation of the combination of CsA-RAPA has been established in vitro and in the clinical setting, mainly in islet cell and solid organ transplantation. The significant increase in response rate seen with the addition of CsA to ATG indicated that an inhibitory effect on T lymphocytes is important in blocking autoreactive T cells in aplastic anemia. The combination of CsA-RAPA may further block activated autoreactive T cells and therefore lead to improved response rates (and survival) and decreased relapse rates. This prospective randomized phase II study will investigate two different immunosuppressive regimens in patients with severe aplastic anemia who have not received prior immunosuppressive therapy. One arm will receive ATG + CsA in addition to sirolimus for 6 months, and the second arm will receive standard ATG + CsA for 6 months followed by a slow taper of CsA with a 25% dose reduction every 3 months for the subsequent 18 months. This trial will determine the effectiveness of sirolimus in patients with aplastic anemia as well as the role of a cyclosporine taper in preventing relapses. Primary endpoint will be no longer meeting criteria for severe aplastic anemia while secondary endpoints are relapse, robustness of hematologic recovery at 3 months, survival, clonal evolution to PNH, myelodysplasia and acute leukemia. 10/11/2005. The Sirolimus (Rapamune) arm of the trial was stopped for lack of efficacy. The study will continue as a single arm study to establish if slow taper of CsA prevents relapse rates after initial standard treatment with ATG followed by CsA for six months.

Detailed Description

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized by pancytopenia and a hypocellular bone marrow. Allogeneic bone marrow transplantation and immunosuppressive treatment with anti-thymocyte globulin (ATG) and cyclosporine (CsA) have dramatically changed the natural course of this illness, with 5 year survival of 75% in patients undergoing either treatment. Since most patients are not suitable candidates for hematopoietic stem cell transplantation (HSCT) due to advanced age or lack of a histocompatible sibling, efforts at NHLBI have focused on improving immunosuppression treatment in order to improve response rates, survival, and to decrease relapse. In our experience of 122 patients treated at NHLBI with the combination of ATG and cyclosporine, one quarter to one third did not respond; about 50% of responders relapsed; and 5 year survival was correlated with the robustness in blood cell count improvement at 3 months (reticulocyte or platelet count greater than or equal to 50,000 /uL). Why some patients do not respond initially while others relapse is unclear. Autoreactive T cells may be resistant to the effect of ATG/CsA (nonresponders), while in others residual autoreactive T cells expand post-treatment leading to hematopoietic stem cell destruction and recurrent pancytopenia (relapse). Therefore, novel immunosuppressive regimens to increase response rates and hematologic recovery at 3 months and to decrease relapse rates are needed. An ongoing NHLBI trial, which is close to completing accrual, has added mycophenolate mofetil (MMF) for a total of 18 months to standard ATG + CsA in an attempt to reduce the relapse rate after cyclosporine is discontinued. Preliminary results have been disappointing, with no marked reduction in relapse among patients who received MMF. Sirolimus (rapamycin, Rapamune , RAPA) is a novel immunosuppressive agent, which acts synergistically with cyclosporine by blocking T cell activation through CsA-resistant pathways. The potentiation of the combination of CsA-RAPA has been established in vitro and in the clinical setting, mainly in islet cell and solid organ transplantation. The significant increase in response rate seen with the addition of CsA to ATG indicated that an inhibitory effect on T lymphocytes is important in blocking autoreactive T cells in aplastic anemia. The combination of CsA-RAPA may further block activated autoreactive T cells and therefore lead to improved response rates (and survival) and decreased relapse rates. This prospective randomized phase II study will investigate two different immunosuppressive regimens in patients with severe aplastic anemia who have not received prior immunosuppressive therapy. One arm will receive ATG + CsA in addition to sirolimus for 6 months, and the second arm will receive standard ATG + CsA for 6 months followed by a slow taper of CsA with a 25% dose reduction every 3 months for the subsequent 18 months. This trial will determine the effectiveness of sirolimus in patients with aplastic anemia as well as the role of a cyclosporine taper in preventing relapses. Primary endpoint will be no longer meeting criteria for severe aplastic anemia while secondary endpoints are relapse, robustness of hematologic recovery at 3 months, survival, clonal evolution to PNH, myelodysplasia and acute leukemia. 10/11/2005. The Sirolimus (Rapamune) arm of the trial was stopped for lack of efficacy. The study will continue as a single arm study to establish if slow taper of CsA prevents relapse rates after initial standard treatment with ATG followed by CsA for six months. 3/2/2006. The protocol was closed to new accrual.

Overall Status

Completed

Start Date

2003-05-23

Completion Date

2015-09-08

Primary Completion Date

2005-11-15

Phase

Phase 2

Study Type

Interventional

Primary Outcome

Measure

Time Frame

Hematologic recovery in patients with severe aplastic anemia treated with a novel immunosuppressive combination of ATG, CsA and sirolimus.
2 yrs

Enrollment

77

Condition

 Severe Aplastic Anemia

Intervention

Intervention Type

Drug

Intervention Name

 cyclosporine

Arm Group Label

ATG+CsA+RA

ATG+CsA



Intervention Type

Drug

Intervention Name

 Rapamune

Arm Group Label

ATG+CsA+RA


Intervention Type

Drug

Intervention Name

 ATG

Arm Group Label

ATG+CsA+RA

ATG+CsA




Eligibility

Criteria

- INCLUSION CRITERIA: Severe aplastic anemia confirmed at NIH by: 1. . Bone marrow cellularity less than 30% (excluding lymphocytes) 2. . At least two of the following: Absolute neutrophil count less than 500/ uL; Platelet count less than 20,000/ uL; Absolute reticulocyte count less than 60,000/ uL Age greater than or equal to 2 years old Weight greater than 12 kg EXCLUSION CRITERIA: Serum creatinine greater than 2.5 mg/dL Underlying carcinoma (except local cervical, basal cell, squamous cell) Prior immunosuppressive therapy with ATG, ALG, or high dose cyclophospamide. Current pregnancy or lactation or unwillingness to take oral contraceptives or use an effective method of birth control. Diagnosis of Fanconi anemia or other congenital bone marrow failure syndromes Evidence of a clonal disorder on cytogenetics. Patients with super severe neutropenia (ANC less than 200/uL) will not be excluded if results of cytogenetics are not available or pending. Underlying immunodeficiency state including seropositivity for HIV Inability to understand the investigational nature of the study or give informed consent 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.

Gender

All

Minimum Age

2 Years

Maximum Age

110 Years

Healthy Volunteers

No


Overall Official

Last Name

Role

Affiliation

Neal S Young, M.D.
Principal Investigator
National Heart, Lung, and Blood Institute (NHLBI)

Location

Facility

National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda Maryland 20892 United States

Location Countries

Country

United States


Verification Date

2018-07-25

Lastchanged Date

N/A

Firstreceived Date

N/A

Responsible Party

Responsible Party Type

Sponsor


Keywords

 Bone Marrow Failure,  Cyclosporine,  Anti Thymocyte Globulin,  Severe Aplastic Anemia

Has Expanded Access

No

Condition Browse

 Anemia,  Anemia, Aplastic

Secondary Id

03-H-0193

Number Of Arms

2

Intervention Browse

Mesh Term

Cyclosporins

Cyclosporine

Immunosuppressive Agents

Sirolimus

Everolimus



Arm Group

Arm Group Label

ATG+CsA+RA

Arm Group Type

Experimental

Description

ATG+CsA+RAPA for 6 months


Arm Group Label

ATG+CsA

Arm Group Type

Experimental

Description

ATG+CsA for 6 months followed by a slow CsA taper in the subsequent 18 months



Firstreceived Results Date

N/A

Reference

Citation

Bacigalupo A, Brand R, Oneto R, Bruno B, Socié G, Passweg J, Locasciulli A, Van Lint MT, Tichelli A, McCann S, Marsh J, Ljungman P, Hows J, Marin P, Schrezenmeier H. Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy--The European Group for Blood and Marrow Transplantation experience. Semin Hematol. 2000 Jan;37(1):69-80. Review.

PMID

10676912


Citation

Young NS. Acquired aplastic anemia. Ann Intern Med. 2002 Apr 2;136(7):534-46. Review.

PMID

11926789


Citation

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

PMID

9134878



Firstreceived Results Disposition Date

N/A

Study Design Info

Allocation

Randomized

Intervention Model

Parallel Assignment

Primary Purpose

Treatment

Masking

None (Open Label)


Study First Submitted

May 23, 2003

Study First Submitted Qc

May 23, 2003

Study First Posted

May 26, 2003

Last Update Submitted

August 11, 2018

Last Update Submitted Qc

August 11, 2018

Last Update Posted

August 14, 2018


ClinicalTrials.gov processed this data on August 31, 2018

Conditions

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Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied. Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase

Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions that study is seeking to answer:

In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.

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