Clinical study to assess the efficacy and safety of gene therapy for the treatment of Sickle Cell Disease

Phase 1

Conditions: Sickle Cell Disease
MedDRA version: 21.0Level: PTClassification code 10040644Term: Sickle cell diseaseSystem Organ Class: 10010331 - Congenital, familial and genetic disorders
Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Registration Number: EUCTR2019-000331-63-GB

Lead Sponsor: bluebird bio, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: A

Sex: All

Target Recruitment: 35

Inclusion Criteria

1. Have a diagnosis of SCD, with either ßS/ßS, ßS/ß0 or ßS/ß+ genotype.
2. Be =2 and =50 years of age at time of consent.
3. Weigh a minimum of 6 kg.
4. Have a Karnofsky performance status of =60 (=16 years of age) or a Lansky performance status of =60 (<16 years of age).
5. Be treated and followed for at least the past 24 months prior to Informed Consent in medical center(s) that maintained detailed records on sickle cell disease history.
6. Have severe manifestations of SCD. i.e. in the setting of appropriate supportive care measures (e.g., pain management plan), have experienced at least 4 severe VOEs in the 24 months prior to informed consent as defined below. 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 a =24 -hour hospital or emergency room (ER) observation unit visit or at least 2 visits to a day unit or ER over 72 hours with both visits requiring intravenous treatment. 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.
7. Have either experienced HU failure at any point in the past or must have intolerance to HU (intolerance is defined as the patient being unable to continue to take HU per PI judgment).
Are the trial subjects under 18? yes
Number of subjects for this age range: 20
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 15
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

1. Applicable to subjects <18 years of age only: Availability of a willing, matched human leukocyte antigen (HLA)-identical sibling HSC donor.
2. Severe cerebral vasculopathy, defined by any history of: overt ischemic or hemorrhagic stroke, abnormal transcranial Doppler (>200 cm/sec based on central read) requiring chronic transfusion, occlusion or stenosis in the circle of Willis, or presence of Moyamoya disease.
3. 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 -2 (HTLV-2), active syphilis.
4. Clinically significant, active bacterial, viral, fungal, or parasitic infection
5. Advanced liver disease, such as
a. clear evidence of liver cirrhosis, active hepatitis or significant fibrosis (based on MRI or liver biopsy)
b. liver iron concentration =15 mg/g unless liver biopsy shows no evidence of cirrhosis, active hepatitis or significant fibrosis
6. Inadequate bone marrow function, as defined by an absolute neutrophil count of <1×10^9/L (<0.5×10^9/L for subjects on hydroxyurea treatment) or a platelet count <100×10^9/L.
7. 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.
8. Patients needing therapeutic anticoagulation treatment during the period of conditioning through platelet engraftment
9. Unable to receive red blood cell (RBC) transfusion.
10. Prior receipt of an allogeneic HSC transplant.
11. Prior receipt of gene therapy.
12. Any prior or current malignancy or immunodeficiency disorder, except previously treated, non-life threatening, cured tumors such as squamous cell carcinoma of the skin.
13. Immediate family member with a known or suspected Familial Cancer Syndrome.
14. Pregnancy, or breastfeeding in a postpartum female, or absence of adequate contraception for fertile subjects.
15. Any other condition that would render the subject ineligible for HSCT.
16. Participation in another clinical study with an investigational drug within 30 days of screening

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the efficacy of treatment with LentiGlobin BB305 Drug Product in subjects with sickle cell disease (SCD).;Secondary Objective: To evaluate the safety of treatment with LentiGlobin BB305 Drug Product in subjects with SCD;Primary end point(s): Proportion of subjects meeting Globin Response criteria<br>Subjects must meet the below criteria for a continuous period of at least 6 months after drug product infusion in order to be considered having achieved Globin response:<br>a. Weighted average HbAT87Q percentage of total Hb* =30% AND<br>b. Weighted average total Hb* increase of =3 g/dL compared to baseline total Hb* OR weighted average total Hb* =10 g/dL<br> -total Hb is the non-transfused total Hb; it is HbS + HbF + HbA2 + HbAT87Q<br>;Timepoint(s) of evaluation of this end point: 1-24 months post-transplant

Secondary Outcome Measures

Name	Time	Method

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