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Protocol Details

A Phase 1 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo with the LentiGlobinA BB305 Lentiviral Vector in Subjects with Severe Sickle Cell Disease

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts




Sponsoring Institute

National Heart, Lung and Blood Institute (NHLBI)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 12
Max Age: 50

Referral Letter Required


Population Exclusion(s)

Pregnant Women and Fetuses;
Adults who are or may become unable to consent

Special Instructions

Currently Not Provided


Stem Cell Transplant;
Sickle Cell Disease;
Gene Therapy

Recruitment Keyword(s)



Sickle Cell Disease

Investigational Drug(s)

LentiGlobin BB305 Drug Product

Investigational Device(s)



Drug: LentiGlobin BB305 Drug Product
Drug: Anti-seizure prophylaxis
Procedure/Surgery: Bone marrow harvest
Drug: Busulfan
Drug: plerixafor

Supporting Site

National Heart, Lung and Blood InstituteNational Heart, Lung, and Blood Institute


- Sickle cell disease (SCD) is a red blood cell disease. It is caused by a gene that produces an abnormal hemoglobin. Researchers want to see if removing stem cells from a person s bone marrow, adding the correct gene, and returning them back to the person helps symptoms of SCD.


- To evaluate how well and safely stem cell transplant with gene-modified stem cells treats sickle cell disease.


- Adults at least 18 years old with SCD.


- Participants will be screened with:

- Physical exam

- Blood, urine, heart, and breathing tests

- 6-minute walk

- Brain, liver, and heart scan

- They may have liver tissue removed with a needle.

- Visit 1: While participants are under general anesthesia:

- A needle will collect stem cells from bone marrow at each hipbone.

- They may have a small rubber tube (central line) threaded through the skin, into a large vein.

- The stem cells will be changed in a lab.

- Visit 2: Participants will be in the hospital about 5 6 weeks. They will have frequent physical exams and blood tests.

- They will get a chemotherapy drug through the central line for 4 days.

- Participants will then receive the changed stem cells through the central line.

- They will stay in a protective environment and take medicines to prevent infections.

- Participants will be have 11 follow-up visits for 2 years after the procedure. Screening tests will be repeated at some visits.

- Study doctors will maintain long-term contact with participants.

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Subjects must:

1. Be greater than or equal to 12 years of age and less than or equal to 5 years of age at time of consent.

2. Have a diagnosis of SCD, with either BetaS/BetaS or BetaS/Beta0 or BetaS/Beta + genotype.

3. Have severe SCD. i.e., in the setting of appropriate supportive care measures for SCD (e.g., pain management plan, HU) have experienced severe VOEs as defined below: at least 4 episodes requiring hospital inpatient admission in the 24 months prior to informed consent. Exception: priapism does not require hospital admission but does require a medical facility visit; 4 priapism episodes that require a visit to a medical facility (without inpatient

admission) are sufficient to meet criterion.

For the purposes of this study, a severe VOE is defined as an event with no medically determined cause other than a vaso-occlusion requiring hospital inpatient admission over 24 hours and including:

-a. an episode of acute pain with no medically determined cause other than a vasoocclusive event requiring admission over 24 hours

-b. Acute chest syndrome, defined by an acute event with pneumonia-like symptoms (e.g., chest pain, fever [>38.5 (Infinite)C], tachypnea, wheezing or cough, findings upon lung

auscultation,) and the presence of a new pulmonary infiltrate consistent with ACS.

-c. Acute hepatic sequestration, defined by a sudden increase in liver size associated with pain in the right upper quadrant, abnormal results of liver-function test not due to biliary tract disease, and reduction in Hb concentration by at least 2 g/dL below the baseline value

-d. Acute splenic sequestration, defined as sudden enlargement of the spleen and reduction in Hb concentration by at least 2 g/dL below the baseline value

-e. Acute priapism: defined as a sustained, unwanted painful erection lasting more than 2 hours and requiring care at a medical facility (with or without hospitalization).

4. Have a Karnofsky performance status of greater than or equal to 60 (greater than or equal to 16 years of age) or a Lansky performance status of greater than or equal to 60 (<16 years of age).

5. Have either experienced HU failure at any point in the past (defined as >1 VOE or greater than or equal to 1 ACS after taking HU for at least 3 months) or must have intolerance to HU (defined as inability to be maintained on an adequate dose of HU due to marrow suppression or severe drug-induced toxicity [e.g. gastrointestinal distress, fatigue]).

6. Have been treated and followed for at least the past 24 months in medical center(s) that maintained detailed records on SCD history, e.g., incidence of VOEs and severe VOEs, aplastic crises,

infectious complications, SCD-related chronic complications, SCD-related surgery, pRBC transfusions (including volume and units of pRBCs, associated pre- transfusion HbS values and post-transfusion

AEs [including allo-immunization]), SCD specific treatment history (HU, iron overload, and chelation history), and use of pain medication.


Subjects are excluded if they meet any of the following criteria.

1. Positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 or HIV-2), hepatitis B, hepatitis C, human T-lymphotrophic virus-1 (HTLV-1) or HTLV-2, syphilis (RPR), toxoplasmosis, Trypanosoma cruzi, or West Nile Virus. (Note that subjects who have been vaccinated against hepatitis B [hepatitis B surface antibody-positive] who are negative for other markers of prior hepatitis B infection [e.g., negative for hepatitis B core antibody] are eligible. Subjects with past exposure to HBV [HBc Ab positive and/or HBe Ab positive] are also eligible for the study provided they are negative for HBV DNA. Subjects who are positive for anti-hepatitis C antibody are eligible as long as they have a negative hepatitis C viral load.

2. Clinically significant, active bacterial, viral, fungal, or parasitic infection, as determined by the Investigator e.g., active relapsing malaria.

3. Inadequate bone marrow function, as defined by an absolute neutrophil count of less than 1000/ l (less than 500/microliter for subjects on hydroxyurea treatment) or a platelet count<120,000/ L

(without hypersplenism).

4. Any history of severe cerebral vasculopathy: defined by overt or hemorrhagic stroke; abnormal transcranial Doppler [greater than or equal to 200 cm/sec] needing chronic transfusion; or occlusion or stenosis in the polygon of Willis; or presence of Moyamoya disease

5. Baseline oxygen saturation <90% without supplemental oxygen (excluding periods of SCD crisis, severe anemia or infection).

6. Baseline carbon monoxide diffusing capacity (DLCO) less than 40% (corrected for Hb) in the absence of infection.

7. Baseline left ventricular ejection fraction (LVEF) less than 40%.

8. Clinically significant pulmonary hypertension at Baseline, as defined by the requirement for ongoing pharmacologic treatment or the consistent or intermittent use of supplemental home oxygen.

9. Baseline estimated glomerular filtration rate (eGFR) less than 70 mL/min/1.73 m2, as determined using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (see

10. Advanced liver disease, defined as:

-a. Persistent aspartate transaminase, alanine transaminase, or direct bilirubin value >3(SqrRoot) the upper limit of normal (ULN), or

-b. Baseline prothrombin time or partial thromboplastin time >1.5(SqrRoot) ULN, suspected of arising from liver disease, or

-c. Magnetic Resonance Imaging (MRI) of the liver demonstrating clear evidence of cirrhosis, or

-d. MRI findings suggestive of active hepatitis, significant fibrosis, inconclusive evidence of cirrhosis, or liver iron concentration greater than or equal to 15 mg/g require follow-up liver biopsy in subjects greater than or equal to 18 years of age. In subjects <18 years of age, these MRI findings are exclusionary, unless in the opinion of the Investigator, a liver biopsy could provide additional data to confirm eligibility and would be safe to perform. If a liver biopsy is performed based on MRI findings, any evidence of cirrhosis, bridging fibrosis, or significant active hepatitis will be exclusionary.

11. For subjects who have history of iron overload or serum ferritin levels >1000 ng/mL, a cardiac MRI is required. Cardiac T2* <10 ms results in exclusion.

12. Contraindication to anesthesia.

13. Any contraindications to the use of plerixafor during the mobilization of hematopoietic stem cells and any contraindications to the use of busulfan and any other medicinal products required during the myeloablative conditioning, including hypersensitivity to the active substances or to any of the excipients

14. Any prior or current malignancy or immunodeficiency disorder, except previously treated, non-life threatening, cured tumors such as squamous cell carcinoma of the skin.

15. Prior receipt of an allogeneic transplant.

16. Immediate family member with a known or suspected Familial Cancer Syndrome (including but not limited to hereditary breast and ovarian cancer syndrome, hereditary non-polyposis colorectal cancer syndrome, and familial adenomatous polyposis).

17. Diagnosis of significant psychiatric disorder of the subject that, in the Investigator s judgement, could seriously impede the ability to participate in the study.

18. Pregnancy, or breastfeeding in a postpartum female, or absence of adequate contraception for fertile subjects. Females of child-bearing potential must agree to use a medically acceptable method of birth control such as oral contraceptive, intrauterine device, barrier and spermicide, or contraceptive implant/injection from Screening through at least 6 months after drug product infusion. Male subjects must agree to use effective contraception (including condoms) from Screening through at least 6 months after drug product infusion.

19. Participation in another clinical study with an investigational drug within 30 days of screening.

20. Prior receipt of gene therapy.

21. Receipt of erythropoietin within the 60 days prior to hematopoietic stem cell harvest.

22. An assessment by the Investigator that the subject or parents/caregivers (as required) will not comply with the study procedures outlined in the study protocol

23. Patients needing curative anticoagulation therapy during the period of conditioning through platelet engraftment (patients on prophylactic doses of anticoagulants are eligible).

24. Unable to receive RBC transfusion

25. Any other condition that would render the subject ineligible for HSCT, as determined by the attending transplant physician

26. Applicable to subjects <18 years of age only: Availability of a willing, matched HLA identical sibling hematopoietic cell donor.

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Not Provided

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Principal Investigator

Referral Contact

For more information:

John F. Tisdale, M.D.
National Heart, Lung and Blood Institute (NHLBI)
BG 10 RM 9N112
(301) 402-6497

Wynona Coles
National Heart, Lung and Blood Institute (NHLBI)
National Institutes of Health
Building 10
Room 4-5350
10 Center Drive
Bethesda, Maryland 20892
(301) 402-2104

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: 1-866-411-1010

Clinical Trials Number:


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