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Sickle Cell DiseasePhase 2NCT04018937

Early Human Leukocyte Antigen (HLA) Matched Sibling Hematopoietic Stem Cell Transplantation

A Phase 2 study testing Alemtuzumab, Fludarabine and Melphalan in people with Sickle Cell Disease, run by Emory University at 15 sites in 2 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

This study aims to enroll 58 pre-adolescent (<13 years) pediatric participants with sickle cell disease (SCD) who have a pre-adolescent sibling bone marrow donor. All participants will go through a pre-transplant evaluation to find out if there are health problems that will keep them from being able to receive the… Read more about this study

Who is it for?
Ages 2 to 13 years
Conditions the study is for
Sickle Cell Disease
What is being tested?
Alemtuzumab, Fludarabine and Melphalan
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
43 participants
Where
15 sitesin 2 countries
Study dates
22 Mar 2019to Nov 2026
Phase
Phase 2
Are there results?
Not yet: the study is under way

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 13 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • Patients must be at least 2 years and less than 13 years old and have a sickle hemoglobinopathy.
  • Patient must have an HLA identical sibling donor who is less than 13 years old. Sibling donors must not have any form of SCD. It is acceptable for the donor to carry a hemoglobinopathy trait.
  • Patients must meet criteria for symptomatic SCD as defined below.
  • Severe disease:
  • Previous clinical stroke, defined as a neurological deficit lasting longer than 24 hours plus new finding on head CT or brain MRI/MRA.
  • Progressive silent cerebral infarction, as evidenced by serial MRI scans that demonstrate the development of a succession of lesions (at least two temporally discreet lesions, each measuring at least 3 mm in greatest dimension on the most recent brain MRI/MRA) or the enlargement of a single lesion, initially measuring at least 3 mm). Lesions must be visible on T2-weighted MRI sequences.
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  • Abnormal TCD testing (confirmed elevated velocities in any single vessel of TAMMV > 200 cm/sec for non-imaging TCD)
  • Significant vasculopathy on MRA (greater than 50% stenosis of > 2 arterial segments or complete occlusion of any single arterial segment).
  • Frequent (at least 3 per year for preceding 2 years) painful vaso-occlusive episodes (defined as episode lasting at least 4 hours and requiring hospitalization or outpatient treatment with parenteral opioids). If patient is on hydroxyurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 2 years prior to the start of hydroxyurea.
  • Recurrent (at least 3 in lifetime) acute chest syndrome events which have necessitated erythrocyte transfusion therapy.
  • Any combination of at least 3 acute chest syndrome episodes and vaso-occlusive pain episodes (defined as above) yearly for 3 years. If patient is on hydroxyurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 3 years prior to the start of hydroxyurea.
  • Less severe disease: to qualify as having less severe disease, patients must not meet criteria for severe disease and must have one of the following:
  • Asymptomatic cerebrovascular disease, as evidenced by one the following: Silent cerebral infarction with at least one lesion measuring at least 3 mm in one dimension that is visible on two planes on the most recent brain MRI, or, cerebral arteriopathy, as evidenced by conditional TCD (TAMMV>170cm/sec but <200cm/sec) on two separate scans >2 weeks apart). If patient has a conditional TCD, then a brain MRI/MRA to evaluate for vasculopathy is required.
  • 2 or more painful vaso-occlusive episodes (in lifetime) requiring hospitalization or outpatient treatment with parenteral opioids.
  • 2 or more episodes of acute chest syndrome (in lifetime) irrespective of SCD modifying therapy administered.
  • Any combination of at least 3 acute chest syndrome episodes and vaso-occlusive pain episodes (defined as above, lifetime).
  • Patients with HbSS and HbSβ°thalassemia who have no clinical complications of their sickle cell disease and do not meet the criteria for less severe or severe disease.
  • Participant's parent or legal guardian must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
  • Patient must have been evaluated and parent(s)/legal guardian, and the patient as age appropriate as determined by the treating center, adequately counseled regarding treatment options for SCD by a pediatric hematologist.
  • Co-enrollment on STAR Project Sickle Cure (PSC) study is required for sites that are activated and participating in the study.

Who cannot join

  • Bridging (portal to portal) fibrosis or cirrhosis of the liver.
  • Parenchymal lung disease stemming from SCD or other process defined as a diffusing capacity of the lungs for carbon monoxide (DLCO; corrected for hemoglobin) or forced vital capacity of less than 45% of predicted. Children unable to perform pulmonary function testing will be excluded if they require daytime oxygen supplementation.
  • Renal dysfunction with an estimated glomerular filtration rate (GFR) < 50% of predicted normal for age.
  • Cardiac dysfunction with shortening fraction < 25%.
  • Neurologic impairment other than hemiplegia, defined as full-scale intelligence quotient (IQ) of less than or equal to 70, quadriplegia or paraplegia, or inability to ambulate.
  • Lansky functional performance score < 70%.
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  • Patient is HIV infected.
  • Donor is HIV infected.
  • Patient with unspecified chronic toxicity serious enough to detrimentally affect the patient's capacity to tolerate HSCT.
  • Patient's parent(s) or legal guardian is unable to understand the nature and the risks inherent in the HSCT process.
  • History of lack of adherence with medical care that would jeopardize transplant course.
  • Donor who for psychological, physiologic, or medical reasons is unable to tolerate a bone marrow harvest or receive general anesthesia.
  • Active viral, bacterial, fungal or protozoal infection.
  • Patients with viral upper respiratory tract infections should be asymptomatic for at least 7 days prior to enrollment. PCR testing for respiratory viruses (nasopharyngeal sample) should be negative at the start of the conditioning regimen. Exceptions may be made in patients with prolonged carriage (repeatedly positive over many weeks) of rhinovirus. These exceptions should be discussed with and approved by both study co-chairs and STAR Medical Director.

Trial locations and contacts

15 sites in 2 countries.

15 sites in 2 countries

United States13 sites

  • Children's Healthcare of Altanta

    Atlanta, Georgia, 30322

  • Children's Hospital of Alabama

    Birmingham, Alabama, 35233

  • Dana-Farber Cancer Institute/Boston Children's Hospital

    Boston, Massachusetts, 02215

  • University of North Carolina Medical Center

    Chapel Hill, North Carolina, 27514

  • Atrium Health Levine Cancer Institute

    Charlotte, North Carolina, 28204

  • University of Chicago

    Chicago, Illinois, 60637

  • Hackensack University Medical Center

    Hackensack, New Jersey, 07601

  • Riley Children's Health/Indiana University

    Indianapolis, Indiana, 46202

  • Yale University, Yale Cancer Center

    New Haven, Connecticut, 06520

  • Children's Hospital of Philadelphia

    Philadelphia, Pennsylvania, 19104

  • Phoenix Children's

    Phoenix, Arizona, 85016

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • Children's National Hospital

    Washington D.C., District of Columbia, 20010

Other trials in United States

Canada2 sites

  • Centre Hospitalier Universitaire Sainte-Justine

    Montreal, Quebec

  • Cancercare Manitoba/Winnipeg Children's Hospital

    Winnipeg, Manitoba

Other trials in Canada

About this study

Official title: Early HLA Matched Sibling Hematopoietic Stem Cell Transplantation for Children With Sickle Cell Disease: A Sickle Transplant Advocacy and Research Alliance (STAR) Trial

This study aims to enroll 58 pre-adolescent (<13 years) pediatric participants with sickle cell disease (SCD) who have a pre-adolescent sibling bone marrow donor. All participants will go through a pre-transplant evaluation to find out if there are health problems that will keep them from being able to receive the transplant. It usually takes 2 to 3 months to complete the pre-transplant evaluation and make the arrangements for the transplant. Once they are found to be eligible for transplant, participants will be admitted to the hospital and will start transplant conditioning. Conditioning is the chemotherapy and other medicines given to prepare them to receive donor cells. It prevents the immune system from rejecting donor cells. Conditioning will start 21 days before transplant. Once they complete conditioning, participants will receive the bone marrow transplant. After the transplant, participants will stay in the hospital for 4-6 weeks. After they leave the hospital, participants will be followed closely in the clinic. Outpatient treatment and frequent clinic visits usually last 6 to 12 months. Routine medical care includes at least a yearly examination for many years after transplant by doctors and nurses familiar with sickle cell disease and transplant. The researchers will collect and study information about participants for 2 years after transplant.

Read the detailed description

The use of HLA matched sibling donor (MSD) hematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD) is evolving. Because of the low risk for graft versus host disease (GVHD) associated with younger age, HSCT is increasingly being performed prior to adolescence. The use of less gonadotoxic reduced intensity regimens (RIC) are more commonly be utilized to lessen the risk for infertility. Finally, with the recognition that most children, even those who have asymptomatic to relatively mild courses, will develop debilitating morbidities as adults and ultimately suffer an early death, HSCT is being offered to children across a wider spectrum of SCD severity. Long reserved for severely affected children, HSCT is being performed for a growing number of less severely affected children, as well as children without disease manifestation.

This trial is designed to prospectively assess HSCT under these conditions. Eligibility will be limited to children less than 13 years of age who have an HLA MSD. SCD severity criteria will be broadened to include less severely affected children as well as those who are severely affected. A RIC regimen - fludarabine, alemtuzumab and melphalan (FAM) - will be employed. For GVHD prophylaxis, all patients will receive a calcineurin inhibitor and short course methotrexate.

This study has the following two specific aims:

Specific Aim #1: To prospectively assess the safety and efficacy of HSCT using FAM conditioning in children with SCD of varying severity who are under 13 years of age.

Specific Aim #2: To address current gaps in our understanding of the long-term effects of HSCT in children with SCD, by longitudinally assessing sickle cell related cerebrovascular disease, sickle cell related nephropathy and health related quality of life.

Being tested
Alemtuzumab, Fludarabine, Melphalan, Cyclosporine, Tacrolimus
Keywords
Pediatrics, Hematopoietic stem cell transplantation, HLA matched sibling
Medical subject headings
Anemia, Sickle Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AlemtuzumabDrug

    Also called Campath

    Alemtuzumab will be administered by either subcutaneous (SQ) injection or IV. A test dose of alemtuzumab, 3 mg, is administered on the first day. If the test dose is tolerated, administration of three treatment doses will begin within 24 hours. The three treatment doses will be administered on consecutive days. On the first day, 10 mg/m2 will be given, 15 mg/m^2 the second and 20 mg/m^2 the third. Alemtuzumab will be started between Days -22 and -20, but all doses (test dose and three treatment doses) should be completed by Day -18.

  • FludarabineDrug

    Also called Fludara, FLU

    Fludarabine will be administered at 30 mg/m^2 IV daily for five days (Days -7 to -3).

  • MelphalanDrug

    Also called Alkeran, Evomela

    Melphalan will be administered at 140 mg/m^2 IV on Day -3 following fludarabine administration.

  • CyclosporineDrug

    Also called Gengraf, Neoral, CsA

    For GVHD prophylaxis, calcineurin inhibitor (cyclosporine or tacrolimus) administration will commence no later than Day -2 (at least 36 hours before the stem cell infusion). Cyclosporine doses will be adjusted to maintain a level of 150-300 nanograms per milliliter (ng/ml) by mass spectrometry.

  • TacrolimusDrug

    Also called Prograf, FK-506

    For GVHD prophylaxis, calcineurin inhibitor (cyclosporine or tacrolimus) administration will commence no later than Day -2 (at least 36 hours before the stem cell infusion). Tacrolimus doses will be adjusted to maintain a level of 8-15 ng/ml.

  • MethotrexateDrug

    Also called MTX, Trexall, amethopterin

    For GVHD prophylaxis, methotrexate will be given intravenously at a dose of 15 milligrams per square meter (mg/m^2) on day 1 and a dose of 10 mg/m^2 on days 3, 6 and 11. Dosing shall be based on actual weight.

Study groups in NCT04018937
Study groupRoleWhat they receive
Reduced Intensity Conditioning with FAMExperimentalChildren with SCD will received reduced intensity conditioning with fludarabine, alemtuzumab and melphalan (FAM) during HSCT with a HLA matched sibling donor. For GVHD prophylaxis, all patients will receive a calcineurin inhibitor (cyclosporine or tacrolimus) and short course methotrexate.
Receives: Drug: Alemtuzumab; Drug: Fludarabine; Drug: Melphalan; Drug: Cyclosporine; Drug: Tacrolimus; Drug: Methotrexate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Immune Suppression-free, Rejection-free Survival

    Immune suppression-free, rejection-free survival is defined as rejection-free survival off all systemic immunosuppressive agents. Participants who are off systemic immune suppression by 2-years post-transplant will be considered as being immune suppression free.

    Measured: Year 2

Secondary outcomes (15)

  1. Regimen-Related Toxicity

    Regimen-Related Toxicity (RRT) will be scored according to the Bearman scale. Major RRT, defined as grade 4 (causing death) in any organ system or grade 3 for pulmonary, cardiac, renal, oral mucosal, neurologic or hepatic, will be recorded. The assessment for RRT will be carried out on day 42 post-transplant.

    Measured: Day 42

  2. Number of Neurological Complications

    Neurological complications will be defined as any one of the following: seizures, intracranial hemorrhage, infarctive stroke (clinical or sub-clinical), and/or encephalopathy, including posterior reversible encephalopathy syndrome (PRES).

    Measured: Up to Year 2

  3. Neutrophil Recovery

    Neutrophil recovery is defined as the first of 3 consecutive days following the nadir that the absolute neutrophil count is at least 500/µl.

    Measured: Up to Year 2

  4. Platelet Recovery

    Platelet recovery is defined as the first day that the platelet count is at least 50,000/µl without a transfusion in the preceding 7 days.

    Measured: Up to Year 2

  5. Graft Rejection

    This endpoint will be met when donor engraftment fails to occur as evidenced by lack of neutrophil recovery or donor chimerism (5% donor derived cells on chimerism testing; for sorted testing, at least 5% of both lineages must be donor derived). This endpoint will also be met when there is initial donor engraftment but donor chimerism is lost.

    Measured: Up to Year 2

  6. Sustained Donor Engraftment

    This endpoint will be met when the patient is off all immune suppression (or is still on immune suppression as treatment for GVHD) by one year, has normal marrow function, has no acute signs of SCD and has at least 5% donor derived cells on chimerism testing (for sorted testing at least 5% of both lineages must be donor derived). This endpoint will be assessed through 2 years.

    Measured: Year 2

  7. Cytomegalovirus (CMV) Viremia

    CMV Viremia will be defined as the occurrence of a positive polymerase chain reaction (PCR) test prior to day 180.

    Measured: Day 180

  8. CMV Invasive Disease

    CMV invasive disease will be defined in accordance with the Blood and Marrow Transplant Clinical Trials Network Manual of Procedures.

    Measured: Up to Year 2

  9. Post-transplant Lymphoproliferative Disorder

    Post-transplant lymphoproliferative disorder will be defined in accordance with the Blood and Marrow Transplant Clinical Trials Network Manual of Procedures.

    Measured: Up to Year 2

  10. Other Infections

    Other Infections will be defined in accordance with the Blood and Marrow Transplant Clinical Trials Network Manual of Procedures.

    Measured: Up to Year 2

  11. Early Onset Acute GVHD

    Early onset (before day 100) acute GVHD (including all grades, and stratified by grades) will be assessed according to the Blood and Marrow Transplant Clinical Trials Network Manual of Procedures using the NIH consensus criteria.

    Measured: Day 100

  12. Late Onset Acute GVHD

    Late onset (after day 100) acute GVHD will be assessed according to the Blood and Marrow Transplant Clinical Trials Network Manual of Procedures using the NIH consensus criteria.

    Measured: Up to Year 2

  13. Chronic GVHD

    Chronic GVHD will be assessed according to the Blood and Marrow Transplant Clinical Trials Network Manual of Procedures using the NIH consensus criteria.

    Measured: Up to Year 2

  14. Rejection-free Survival

    Rejection-free survival is defined as survival with sustained engraftment.

    Measured: Up to Year 2

  15. Overall Survival

    Overall survival is defined as survival with or without rejection.

    Measured: Up to Year 2

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Jul 2019
  2. Study start22 Mar 2019
  3. Primary completionNov 2026 (estimated)
  4. Study completionNov 2026 (estimated)

Resources

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
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
43 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04018937
Sponsor's protocol ID
IRB00093513
Other IDs
2025P011044
Status last verified
Sep 2026
First submitted
10 Jul 2019
Last updated
24 Sep 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Leonard A, Furstenau D, Abraham A, Darbari DS, Nickel RS, Limerick E, Fitzhugh C, Hsieh M, Tisdale JF. Reduction in vaso-occlusive events following stem cell transplantation in patients with sickle cell disease. Blood Adv. 2023 Jan 24;7(2):227-234. doi: 10.1182/bloodadvances.2022008137.

    PubMed 36240296

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Alemtuzumab, Fludarabine and Melphalan in people with Sickle Cell Disease, run by Emory University at 15 sites in 2 countries.

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 20 inclusion and 14 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: under way, not looking for participants, as of the sponsor's last update on 24 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 15 sites in United States, Canada. 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?

This study is still under way. Results are not available in the source record yet.

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?

Immune Suppression-free, Rejection-free Survival (time frame: Year 2). 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 NCT04018937, which also lists 1 linked publication.

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 24 Sep 2026.

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