Severe Aplastic AnemiaPhase 2NCT02979873
Sirolimus (Rapamune ) for Relapse Prevention in People With Severe Aplastic Anemia Responsive to Immunosuppressive Therapy
A Phase 2 study testing Sirolimus in people with Severe Aplastic Anemia, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
Trial summary
Background: People with severe aplastic anemia (SAA) do not make enough red and white blood cells, and/or platelets. Their body's immune system stops the bone marrow from making these cells. Immunosuppression (IST) with anti-thymocyte globulin (ATG) and cyclosporine (CSA) leads to better blood counts. Read more about this study
- Who is it for?
- Ages 2 to 99 years
- Conditions the study is for
- Severe Aplastic Anemia
- What is being tested?
- Sirolimus
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 84 participants
- Where
- 1 siteUnited States
- Study dates
- 19 Dec 2016to 30 Jun 2030
- Phase
- Phase 2
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 2 to 99 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Age greater than or equal to 2 years old
- Weight greater than 12 kg
- Previous diagnosis of SAA by bone marrow biopsy and cytogenetics, treated with lymphodepleting therapy ATG, cyclophosphamide or alemtuzumab that included cyclosporine. The lymphodepleting therapy must have been administered at least 12 months prior.
- Continuous treatment with cyclosporine for the previous 6 months (excluding minor dose delays not exceeding more than 30 days).
- Evidence of a hematologic response to an lymphodepletion-based regimen as evidence of at least two of the following:
- Absolute neutrophil count greater than or equal to 500/uL
- Platelet count greater than or equal to 20,000/uL (without transfusion support)
- Absolute reticulocyte count greater than or equal to 60,000/uL (or hemoglobin 10 gm/dL without transfusion support)
Who cannot join
- Evidence of relapse of aplastic anemia due to cyclosporine withdrawal during the previous 6 months.
- Prior use of sirolimus or other mTOR inhibitor within 12 weeks of study entry
- Myelodysplastic syndrome or acute myeloid leukemia, according to WHO diagnostic criteria (if baseline BM consistent with MDS after enrollment, patients will be considered ineligible and immediately exit the study, and the subject can be replaced with another subject)
- Patients that are on CYP3A4 inhibitors and cannot replace these medications with other equivalent medications for the period of study: protease inhibitors (ritonavir, indinavir, nelfinavir, saquinavir), some macrolide antibiotics (clarithromycin, telithromycin, erythromycin), azole anti-fungals (fluconazole, itraconazole, ketoconazole), metroclopramide, felodipine, nifedipine, carbamazepine, phenobarbital, grapefruit juice and St. John's Wort.
- Anaphylactic or hypersensitivity reaction to sirolimus
- Patients with infections not adequately responding to appropriate therapy as evidenced by persistence of a clear source of infection that, in the view of the investigator, would preclude safe treatment with sirolimus.
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- Current pregnancy, or unwillingness to take oral contraceptives or use the barrier methods of birth control or practice abstinence to refrain from pregnancy if of childbearing potential during the course of the study 8. Lactating women, due to the potentially harmful effects on the nursing child.
- Patients who have received live vaccines within the past 30 days
- Patients with cancer who are actively receiving chemotherapeutic treatment or who take drugs with hematological effects such as thrombopoietin receptor agonists (such as eltrombopag), granulocyte-colony stimulating factor or erythroid stimulating agents.
- Moribund status such that death within 7 to 10 days is likely. Comorbidities of such severity that in the view of the Investigator it would likely preclude the patient's ability to tolerate sirolimus.
- Inability to understand the investigational nature of the study or to give informed consent or without a legally authorized representative or surrogate that can provide informed consent.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
Official title: A Randomized Trial of Sirolimus (Rapamune(R)) for Relapse Prevention in Patients With Severe Aplastic Anemia Responsive to Immunosuppressive Therapy
Background:
People with severe aplastic anemia (SAA) do not make enough red and white blood cells, and/or platelets. Their body's immune system stops the bone marrow from making these cells. Immunosuppression (IST) with anti-thymocyte globulin (ATG) and cyclosporine (CSA) leads to better blood counts. But when cyclosporine is stopped, the disease may return in 1 in 3 people. The drug sirolimus (SRL) may help by suppressing the immune system to prevent the return of aplastic anemia.
Read more
Objective:
To evaluate and compare the usefulness of SRL in preventing aplastic anemia from returning after cyclosporine is stopped, compared with stopping cyclosporine alone.
Eligibility:
- People ages 2 and older with SAA who:
- Have responded to IST and continue to take cyclosporine
- Are not taking drugs with hematologic effects
Study Design:
Participants will be screened with:
- Medical history, physical exam, blood and urine tests, bone marrow biopsy and aspirate.
Participants will be randomly assigned to a group. All will stop cyclosporine. Group 1 will take sirolimus by mouth at the same time each day for 12 weeks with close monitoring. Group 2 will not receive the study drug but will be monitored closely (Observation arm).
Participants will have clinical tests for the first 3 months:
- Weekly blood test Monthly fasting blood test
- For group 1, measurements of sirolimus in the blood every 1-2 weeks
Participants will have clinic visits at 3 months, 12 months, and annually for 5 years after the study starts. They may have another visit if their SAA returns.
Read the detailed description
- Most SAA ensues from immune-mediated destruction of hematopoietic stem and progenitor cells.
- Immunosuppression is the definitive treatment of patients with SAA who are not candidates for immediate hematopoietic stem cell transplantation.
- Horse ATG combined with the calcineurin inhibitor, CSA, remains standard as first-line immunosuppressive therapy (IST).
- Hematologic responses to transfusion independence occur in about two thirds of patients with standard IST and in 80-90% of patients treated with IST in combination with the growth factor eltrombopag.
- About 30% to 40% of patients relapse after discontinuation of CSA. Many achieve disease control after the reinitiation of CSA, but remain CSA dependent indefinitely.
- Evidence from mouse models of bone marrow failure indicates that conversion from cyclosporine to the mTOR inhibitor,SRL, results in immune tolerance which can endure the eventual withdrawal of SRL.
- We hypothesize that CSA to SRL conversion will significantly decrease the relapse rate after immunosuppressive therapy for SAA.
- This study will investigate the safety and efficacy of SRL for preventing relapse in patients -previously treated with IST who remain on CSA. The primary endpoint is rate of relapse at 2 years following conversion from CSA to SRL, versus stopping CSA.
- Biological sampling of peripheral blood and bone marrow aspirates during treatment will be used to investigate changes to lymphocyte phenotypes and cytokine profiles.
- Conditions
- Severe Aplastic Anemia
- Being tested
- Sirolimus
- Keywords
- Rapamycin, Relapse Prevention, Immune Tolerance, Sirolimus
- Medical subject headings
- Anemia, Aplastic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SirolimusDrug
Also called Rapamune
Sirolimus will be administered orally once daily for 12 weeks. Adults will receive a 6 mg loading dose on Day 1, followed by 2 mg daily. Pediatric participants <40 kg will receive a 3 mg/m^2 loading dose, followed by 1 mg/m^2 daily; those >13 years and <40 kg will be dosed based on body surface area. Doses will be adjusted to maintain trough levels of 5-15 ng/mL. The loading and/or maintenance dose may be reduced at the investigator's discretion in elderly patients (>65 years), those with hepatic impairment, significant comorbidities, or when receiving concomitant medications with known sirolimus interactions.
| Study group | Role | What they receive |
|---|---|---|
| Sirolimus | Experimental | Participants with prior response to immunosuppressive therapy will discontinue cyclosporine and initiate sirolimus administered orally once daily for 12 weeks. Adults will receive a 6 mg loading dose on Day 1 followed by 2 mg daily. Pediatric participants <40 kg will receive a 3 mg/m² loading dose followed by 1 mg/m² daily; those >13 years and <40 kg will be dosed based on body surface area. Doses will be adjusted to maintain target trough levels of 5-15 ng/mL, with reductions permitted at the investigator's discretion for elderly patients (>65 years), those with hepatic impairment, significant comorbidities, or concomitant medications with known sirolimus interactions. Receives: Drug: Sirolimus |
| Observation | No intervention | Participants with prior response to immunosuppressive therapy will discontinue cyclosporine with no additional therapy. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Rate of Relapse
Rate of relapse as defined by either of the following occurring after enrollment:
- Decline in blood counts meeting Camitta criteria for severe aplastic anemia, confirmed by at least two complete blood counts (CBCs) within 14 days; or
- Investigator-assessed decline in one or more blood cell lineages not attributable to another clinical cause, characterized by a rapid drop or progressive decline on at least two consecutive measurements, and confirmed by independent review from two blinded investigators.
Camitta Criteria (SAA)
SAA is defined by bone marrow hypocellularity (typically <25% cellularity, or 25-50% with <30% hematopoietic cells) plus at least two of the following:
- Absolute neutrophil count (ANC) <500/µL
- Platelet count <20,000/µL
- Absolute reticulocyte count <20,000/µL (or corrected reticulocyte count <1%) Very severe aplastic anemia: same criteria, but ANC <200/µL.
Measured: 24 months (+/- 60 days)
Secondary outcomes (5)
Median Days to Relapse
Median Days to Relapse
Relapse is defined by either of the following occurring after enrollment:
- Decline in blood counts meeting Camitta criteria for severe aplastic anemia, confirmed by at least two complete blood counts (CBCs) within 14 days; or
- Investigator-assessed decline in one or more blood cell lineages not attributable to another clinical cause, characterized by a rapid drop or progressive decline on at least two consecutive measurements, and confirmed by independent review from two blinded investigators.
Camitta Criteria
Severe aplastic anemia is defined by bone marrow hypocellularity (typically <25% cellularity, or 25-50% with <30% hematopoietic cells) plus at least two of the following:
- Absolute neutrophil count (ANC) <500/µL
- Platelet count <20,000/µL
- Absolute reticulocyte count <20,000/µL (or corrected reticulocyte count <1%)
Very severe aplastic anemia: same criteria, but ANC <200/µL.
Measured: Up to 24 Months (+/- 60 days)
Safety and Tolerability
Safety and tolerability of sirolimus.
Measured: 3 mo
Time to Relapse
Time to relapse at any time assessed before and after 24 months.
Relapse is defined by either of the following occurring after enrollment:
Decline in blood counts meeting Camitta criteria for severe aplastic anemia, confirmed by at least two complete blood counts (CBCs) within 14 days; or Investigator-assessed decline in one or more blood cell lineages not attributable to another clinical cause, characterized by a rapid drop or progressive decline on at least two consecutive measurements, and confirmed by independent review from two blinded investigators.
Camitta Criteria
Severe aplastic anemia is defined by bone marrow hypocellularity (typically <25% cellularity, or 25-50% with <30% hematopoietic cells) plus at least two of the following:
Absolute neutrophil count (ANC) <500/µL Platelet count <20,000/µL Absolute reticulocyte count <20,000/µL (or corrected reticulocyte count <1%) Very severe aplastic anemia: same criteria, but ANC <200/µL.
Measured: Up to 5 years
Rate of Relapse
Rate of relapse at any time assessed before and after 24 months.
Relapse is defined by either of the following occurring after enrollment:
Decline in blood counts meeting Camitta criteria for severe aplastic anemia, confirmed by at least two complete blood counts (CBCs) within 14 days; or Investigator-assessed decline in one or more blood cell lineages not attributable to another clinical cause, characterized by a rapid drop or progressive decline on at least two consecutive measurements, and confirmed by independent review from two blinded investigators.
Camitta Criteria
Severe aplastic anemia is defined by bone marrow hypocellularity (typically <25% cellularity, or 25-50% with <30% hematopoietic cells) plus at least two of the following:
Absolute neutrophil count (ANC) <500/µL Platelet count <20,000/µL Absolute reticulocyte count <20,000/µL (or corrected reticulocyte count <1%) Very severe aplastic anemia: same criteria, but ANC <200/µL.
Measured: Up to 5 years
Rate of Clonal Evolution
Rate of clonal evolution to new cytogenetic abnormalities, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or rate of expansion of paroxysmal nocturnal hemoglobinuria clones.
Measured: Up to 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Dec 2016 (estimated)
- Study start19 Dec 2016
- Primary completion4 Sep 2025
- Study completion30 Jun 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- 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
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 84 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Bhavisha A Patel, M.D., Principal investigator, National Heart, Lung, and Blood Institute (NHLBI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02979873
- Sponsor's protocol ID
- 170019
- Other IDs
- 17-H-0019
- Status last verified
- Sep 2026
- First submitted
- 1 Dec 2016
- Last updated
- 6 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes