Severe Aplastic AnemiaPhase 2NCT00001964
Combination Therapy of Severe Aplastic Anemia
A Phase 2 study testing Cyclosporine A, ATG and MMF in people with Severe Aplastic Anemia, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
Trial summary
This study will test the safety and effectiveness of a combination of three drugs in treating severe aplastic anemia and preventing its recurrence. Two drugs used in this trial ATG and cyclosporine are standard combination therapy for aplastic anemia. Read more about this study
- Who is it for?
- Ages 1 year to 99 years
- Conditions the study is for
- Severe Aplastic Anemia
- What is being tested?
- Cyclosporine A, ATG and MMF
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 104 participants
- Where
- 1 siteUnited States
- Study dates
- 17 Mar 2000to 12 May 2015
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 99 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Only patients with SAA will be admitted, defined as:
- Bone marrow cellularity less than 30%.
- At least two of the following blood count findings: absolute granulocyte count less than 500/mm(3); platelet count less than 20,000/mm(3); reticulocyte count less than 60,000/mm(3).
- Age greater than or equal to 1 years.
- Weight greater than 12 kg.
Who cannot join
- Serum creatinine greater than 2 mg/dl or estimated creatinine clearance less than 40 ml/min.
- Underlying carcinoma, recent history of radiation or chemotherapy.
- Current pregnancy or unwillingness to be treated with oral contraceptives.
- Inability to comprehend the investigational nature of the study.
- Moribund status or concurrent hepatic, renal, cardiac, neurologic, or metabolic disease of such severity that death within 7 to 10 days is likely.
- Evidence of other etiology than AA for bone marrow failure, including positive clastogenic stress cytogenetic assay for Fanconi anemia and marrow chromosome abnormalities typical of myelodysplasia.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Treatment of Severe Aplastic Anemia With Combined Immunosuppression: Antithymocyte Globulin (ATG) and Cyclosporine A (CSA), and Mycophenolate Mofetil (MMF)
This study will test the safety and effectiveness of a combination of three drugs in treating severe aplastic anemia and preventing its recurrence. Two drugs used in this trial ATG and cyclosporine are standard combination therapy for aplastic anemia. This study will try to improve this therapy in three ways: 1) by altering the drug regimen to allow the drugs to work better; 2) by reducing the risk of kidney damage; and 3) by adding a third drug mycophenolate mofetil to try to prevent disease relapse.
Patients with severe aplastic anemia who do not have a suitable bone marrow donor or who decline bone marrow transplantation may participate in this study. Patients will have a skin test for ATG allergy, chest X-ray, blood test, and bone marrow aspiration before treatment begins. ATG will then be started, infused through a vein continuously for 4 days. Ten days after ATG is stopped, cyclosporine treatment will begin, taken twice a day by mouth in either liquid or capsule form and will continue for 6 months. Also, in the first 2 weeks of treatment, patients will be given a full dose of corticosteroid (prednisone) to prevent serum sickness that could develop as a side effect of ATG therapy. The dosage will be decreased after that. Mycophenolate will be started at the same time as ATG, in two daily doses by mouth, and will continue for 18 months.
Patients will be hospitalized at the beginning of the study. During this time, blood will be drawn at 3-week intervals and a bone marrow examination will be repeated 3 months after treatment has begun. Additional tests, including X-rays may be required. After hospital discharge, patients will be followed on an outpatient basis at 3-month intervals. The patients own physician will perform blood tests weekly and kidney and liver function tests every 2 weeks during cyclosporine therapy. Transfusions may be required initially.
Read the detailed description
Severe acquired aplastic anemia (SAA) has a poor prognosis if untreated. Bone marrow transplantation is available to only a minority of patients due to lack of a matched sibling donor, advanced age of the patient, or cost. Clinical studies at NIH and elsewhere have demonstrated excellent response rates and improved survival with immunosuppressive treatments. Laboratory data implicate underlying cytotoxic T-lymphocyte-mediated suppression of hematopoiesis as the likely proximal cause of disease in most patients. In earlier clinical protocols we treated SAA with cyclosporine A (CSA) (86-H-0007), antithymocyte globulin (ATG) (87-H-0124), and combined ATG and CSA (90-H-0146). While intensive immunosuppression is most effective, relapse is common and some patients also develop second hematologic complications like myelodysplasia. In this protocol, we modify our regimen by delaying the introduction of cyclosporine to promote ATG tolerizing effects and adding mycophenolate mofetil (MMF), a new agent that, like ATG may be relatively specific for activated lymphocytes, in an effort to reduce the high relapse rate.
- Conditions
- Severe Aplastic Anemia
- Being tested
- Cyclosporine A, ATG, MMF
- Keywords
- Hematopoiesis, Bone Marrow Failure, Aplastic Anemia
- Medical subject headings
- Anemia, Aplastic, Bone Marrow Failure Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Cyclosporine ADrug
Cyclosporine A
ATGDrug
ATG
MMFDrug
MMF
| Study group | Role | What they receive |
|---|---|---|
| single arm | Experimental | ATG 40 mg/kg/d for 4 d; CsA 2 weeks after at 12 mg/kg/d for 6 months. MMF starting on first day of ATG at 600 mg/m2 twice daily for 18 months Receives: Drug: Cyclosporine A; Drug: ATG; Drug: MMF |
| single arm 2 | Experimental | ATG at 40 mg/kg/day for 4 days; MMF at 600 mg/m2 twice daily for 18 months and CsA at 12 mg/kg/day for 6 months starting 2 weeks after ATG and MMF Receives: Drug: Cyclosporine A; Drug: ATG; Drug: MMF |
What is being measured
The primary outcome is the main question the study is designed to answer.
reduction in 24-month relapse
reduction in 24-month relapse
Measured: 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jan 2000 (estimated)
- Study start17 Mar 2000
- Primary completion9 Dec 2003
- Study completion12 May 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Severe Aplastic AnemiaStudies of the same condition, open and under way.
- More trials run by National Heart, Lung, and Blood Institute (NHLBI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 104 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Neal S Young, M.D., Principal investigator, National Heart, Lung, and Blood Institute (NHLBI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00001964
- Sponsor's protocol ID
- 000032
- Other IDs
- 00-H-0032
- Status last verified
- Mar 2021
- First submitted
- 18 Jan 2000
- Last updated
- 16 Mar 2021
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Young NS. Acquired aplastic anemia. JAMA. 1999 Jul 21;282(3):271-8. doi: 10.1001/jama.282.3.271. No abstract available.
PubMed 10422997Young 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.
PubMed 9134878Nimer SD, Ireland P, Meshkinpour A, Frane M. An increased HLA DR2 frequency is seen in aplastic anemia patients. Blood. 1994 Aug 1;84(3):923-7.
PubMed 8043874Zaimoku 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.
PubMed 34724566
Study at a glance
From the registry record, last updated by the sponsor on 16 Mar 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment of Severe Aplastic Anemia With Combined Immunosuppression: Antithymocyte Globulin (ATG) and Cyclosporine A (CSA), and Mycophenolate Mofetil (MMF)
- ClinicalTrials.gov ID
- NCT00001964
- Acronym / sponsor ID
- 000032
- Conditions
- Severe Aplastic Anemia
- Keywords
- Hematopoiesis, Bone Marrow Failure, Aplastic Anemia
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 104 participants (actual)
- Lead sponsor
- National Heart, Lung, and Blood Institute (NHLBI)US National Institutes of Health
- Study start
- 17 Mar 2000
- Primary completion
- 9 Dec 2003 (actual)
- Study completion
- 12 May 2015 (actual)
- First posted
- 19 Jan 2000 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will test the safety and effectiveness of a combination of three drugs in treating severe aplastic anemia and preventing its recurrence. Two drugs used in this trial ATG and cyclosporine are standard combination therapy for aplastic anemia. This study will try to improve this therapy in three ways: 1) by altering the drug regimen to allow the drugs to work better; 2) by reducing the risk of kidney damage; and 3) by adding a third drug mycophenolate mofetil to try to prevent disease relapse.
Patients with severe aplastic anemia who do not have a suitable bone marrow donor or who decline bone marrow transplantation may participate in this study. Patients will have a skin test for ATG allergy, chest X-ray, blood test, and bone marrow aspiration before treatment begins. ATG will then be started, infused through a vein continuously for 4 days. Ten days after ATG is stopped, cyclosporine treatment will begin, taken twice a day by mouth in either liquid or capsule form and will continue for 6 months. Also, in the first 2 weeks of treatment, patients will be given a full dose of corticosteroid (prednisone) to prevent serum sickness that could develop as a side effect of ATG therapy. The dosage will be decreased after that. Mycophenolate will be started at the same time as ATG, in two daily doses by mouth, and will continue for 18 months.
Patients will be hospitalized at the beginning of the study. During this time, blood will be drawn at 3-week intervals and a bone marrow examination will be repeated 3 months after treatment has begun. Additional tests, including X-rays may be required. After hospital discharge, patients will be followed on an outpatient basis at 3-month intervals. The patients own physician will perform blood tests weekly and kidney and liver function tests every 2 weeks during cyclosporine therapy. Transfusions may be required initially.
Detailed description
Severe acquired aplastic anemia (SAA) has a poor prognosis if untreated. Bone marrow transplantation is available to only a minority of patients due to lack of a matched sibling donor, advanced age of the patient, or cost. Clinical studies at NIH and elsewhere have demonstrated excellent response rates and improved survival with immunosuppressive treatments. Laboratory data implicate underlying cytotoxic T-lymphocyte-mediated suppression of hematopoiesis as the likely proximal cause of disease in most patients. In earlier clinical protocols we treated SAA with cyclosporine A (CSA) (86-H-0007), antithymocyte globulin (ATG) (87-H-0124), and combined ATG and CSA (90-H-0146). While intensive immunosuppression is most effective, relapse is common and some patients also develop second hematologic complications like myelodysplasia. In this protocol, we modify our regimen by delaying the introduction of cyclosporine to promote ATG tolerizing effects and adding mycophenolate mofetil (MMF), a new agent that, like ATG may be relatively specific for activated lymphocytes, in an effort to reduce the high relapse rate.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| single arm | Experimental | Drug: Cyclosporine A, Drug: ATG, Drug: MMFATG 40 mg/kg/d for 4 d; CsA 2 weeks after at 12 mg/kg/d for 6 months. MMF starting on first day of ATG at 600 mg/m2 twice daily for 18 months |
| single arm 2 | Experimental | Drug: Cyclosporine A, Drug: ATG, Drug: MMFATG at 40 mg/kg/day for 4 days; MMF at 600 mg/m2 twice daily for 18 months and CsA at 12 mg/kg/day for 6 months starting 2 weeks after ATG and MMF |
Who may qualify
- Ages
- 1 year to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (5 listed)
- Bone marrow cellularity less than 30%.
- At least two of the following blood count findings: absolute granulocyte count less than 500/mm(3); platelet count less than 20,000/mm(3); reticulocyte count less than 60,000/mm(3).
- Age greater than or equal to 1 years.
- Weight greater than 12 kg.
Key exclusion criteria (6 listed)
- Serum creatinine greater than 2 mg/dl or estimated creatinine clearance less than 40 ml/min.
- Underlying carcinoma, recent history of radiation or chemotherapy.
- Current pregnancy or unwillingness to be treated with oral contraceptives.
- Inability to comprehend the investigational nature of the study.
- Moribund status or concurrent hepatic, renal, cardiac, neurologic, or metabolic disease of such severity that death within 7 to 10 days is likely.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Cyclosporine ACyclosporine A | Drug | single arm, single arm 2 |
| ATGATG | Drug | single arm, single arm 2 |
| MMFMMF | Drug | single arm, single arm 2 |
Primary outcome
reduction in 24-month relapse
Time frame: 24 months
reduction in 24-month relapse
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Mar 2021.
- Background: PubMed 10422997Young NS. Acquired aplastic anemia. JAMA. 1999 Jul 21;282(3):271-8. doi: 10.1001/jama.282.3.271. No abstract available.
- Background: PubMed 9134878Young 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.
- Background: PubMed 8043874Nimer SD, Ireland P, Meshkinpour A, Frane M. An increased HLA DR2 frequency is seen in aplastic anemia patients. Blood. 1994 Aug 1;84(3):923-7.
- Derived from this study: PubMed 34724566Zaimoku 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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Neal S Young, M.D. principal investigator
National Heart, Lung, and Blood Institute (NHLBI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Cyclosporine A, ATG and MMF in people with Severe Aplastic Anemia, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
reduction in 24-month relapse (time frame: 24 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00001964, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Mar 2021.