E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040644 |
E.1.2 | Term | Sickle cell disease |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of treatment with LentiGlobin BB305 Drug Product in subjects with sickle cell disease (SCD). |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety of treatment with LentiGlobin BB305 Drug Product in subjects with SCD |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have a diagnosis of SCD, with either βS/βS, βS/β0 or βS/β+ 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). |
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E.4 | Principal 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
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of subjects meeting Globin Response criteria 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: a. Weighted average HbAT87Q percentage of total Hb* ≥30% AND b. Weighted average total Hb* increase of ≥3 g/dL compared to baseline total Hb* OR weighted average total Hb* ≥10 g/dL -total Hb is the non-transfused total Hb; it is HbS + HbF + HbA2 + HbAT87Q
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-24 months post-transplant |
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E.5.2 | Secondary end point(s) |
•Percent of subjects reaching a 75% reduction in annualized severe vaso-occlusive events (sVOE-75) in the 24 months after drug product administration compared to the 24 months prior to Informed Consent. •Weighted average non-transfused total Hb •Weighted average HbS percentage of non-transfused total Hb •Weighted average HbS percentage of non-transfused total Hb ≤70%, ≤60%, ≤50% •Weighted average HbAT87Q percentage of non-transfused total Hb •Weighted average non-HbS percentage of non-transfused total Hb •Average and median of non-transfused total Hb over time •Average and median of HbS percentage of non-transfused total Hb over time •Average and median of HbAT87Q percentage of non-transfused total Hb over time •Average and median of non-HbS percentage of non-transfused total Hb over time •Change from baseline in absolute reticulocyte count •Change from baseline in percent reticulocytes •Change from baseline in percent erythrocytes •Change from baseline in total bilirubin •Change from baseline in haptoglobin •Change from baseline in lactate dehydrogenase •Change from baseline in iron •Change from baseline in ferritin •Change from baseline in transferrin saturation •Change from baseline in liver iron content •Change from baseline in cardiac iron content (if assessed at baseline) •Change from baseline in erythropoietin •Change from baseline in serum transferrin receptor •Change in the annualized number of severe VOEs in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent. •Change in the annualized number of VOEs in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent •Proportion of subjects achieving severe VOE-complete resolution (sVOE-CR) Defined as complete resolution of severe VOEs between 6 months and 24 months after drug product administration •Proportion of subjects achieving reduction in the annualized number of severe VOEs of at least 90% in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent. •Change from baseline in annualized frequency transfusions •Change from baseline in volume of packed red blood cell (pRBC) transfusions •Change from baseline in cerebral vasculature and prior brain parenchymal injury As measured by cerebral MRA/MRI in all subjects, and transcranial doppler (TCD) for subjects ≤16 years old at Informed Consent •Change from baseline in bone mineral density (BMD) evaluation using dual x-ray (DXA) absorptiometry •Proportion of subjects with the development of osteonecrosis in new joints needing any specific therapeutic procedure •Proportion of subjects with new or worsening retinopathy complications needing any specific therapeutic procedure •Proportion of subjects with new or worsening severe leg ulcers needing wound care specialized follow-up •Change from baseline in proteinuria •Change from baseline in microalbuminuria •Change from baseline in estimated glomerular filtration rate (eGFR) •Change from baseline in cardiac-pulmonary function via echocardiogram •Change from baseline in cardiac-pulmonary function via pulmonary function test •Change from baseline in cardiac-pulmonary function via brain natriuretic peptide •Change from baseline in meters walked during 6-minute walk test •Change from baseline in annualized number of hospital admissions •Change from baseline in annualized number of total days hospitalized •Change from baseline in patient-reported quality of life, as measured by Patient Reported Outcomes Measurement Information System-57 (PROMIS-57) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
France |
Germany |
Italy |
Netherlands |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 3 |