A Study Evaluating the Efficacy and Safety of the LentiGlobin® BB305 Drug Product in Participants With Transfusion-Dependent β-Thalassemia, Who do Not Have a β0/β0 Genotype

Study Overview
=================
Brief Summary
-----------------
This is a single-arm, multi-site, single-dose, Phase 3 study in 23 participants less than or equal to (<=) 50 years of age with transfusion-dependent β-thalassemia (TDT), also known as β-thalassemia major, who do not have a β0 mutation at both alleles of the hemoglobin β (HBB) gene. The study will evaluate the efficacy and safety of autologous hematopoietic stem cell transplantation (HSCT) using LentiGlobin BB305 Drug Product.

Official Title
-----------------
A Phase 3 Single Arm Study Evaluating the Efficacy and Safety of Gene Therapy in Subjects With Transfusion-dependent β-Thalassemia, Who do Not Have a β0/β0 Genotype, by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With a Lentiviral βA-T87Q-Globin Vector in Subjects ≤50 Years of Age

Conditions
-----------------
Beta-Thalassemia

Intervention / Treatment
-----------------
* Genetic: LentiGlobin BB305 Drug Product


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants <= 50 years of age at the time of consent or assent (as applicable), and able to provide written consent (adults, or legal guardians, as applicable) or assent (adolescents or children). Provided that the Data Monitoring Committee (DMC) has approved enrolling participants younger than 5 years of age, participants younger than 5 years of age may be enrolled if they weigh a minimum of 6 kilograms (kg) and are reasonably anticipated to be able to provide at least the minimum number of cells required to initiate the manufacturing process. Diagnosis of TDT with a history of at least 100 milliliter per kilogram per year (mL/kg/year) of pRBCs in the 2 years preceding enrollment (all participants), or be managed under standard thalassemia guidelines with >= 8 transfusions of pRBCs per year in the 2 years preceding enrollment (participants >= 12 years). Clinically stable and eligible to undergo (HSCT). Treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records, including transfusion history. Exclusion Criteria: Presence of a mutation characterized as β0 mutation at both alleles of the β-globin gene HBB. Positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 and HIV-2), hepatitis B virus (HBV), or hepatitis C (HCV). A white blood cell (WBC) count less than (<) 3×10^9/Liter (L), and/or platelet count < 100×10^9/L not related to hypersplenism. Uncorrected bleeding disorder. Any prior or current malignancy. Immediate family member with a known Familial Cancer Syndrome. Prior HSCT. Advanced liver disease. A cardiac T2* < 10 ms by MRI. Any other evidence of severe iron overload that, in the Investigator's opinion, warrants exclusion. Participation in another clinical study with an investigational drug within 30 days of Screening. Any other condition that would render the participant ineligible for HSCT, as determined by the attending transplant physician or investigator. Prior receipt of gene therapy. Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile participant. A known and available Human leukocyte antigen (HLA) matched family donor. Any contraindications to the use of granulocyte colony stimulating factor (G-CSF) and 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.

Ages Eligible for Study
-----------------
Minimum Age: 0 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LentiGlobin BB305 Drug Product<br>Participants aged less than or equal to (<=) 50 years received a single intravenous (IV) infusion of LentiGlobin BB305 Drug Product at a dose of greater than or equal to (>=) 5.0*10^6 CD34 plus (+) cells per kilogram (cells/kg) following myeloablative conditioning with busulfan (termed the Transplant population). | Genetic: LentiGlobin BB305 Drug Product<br>* LentiGlobin BB305 Drug Product is administered by IV infusion following myeloablative conditioning with busulfan.<br>* Other names: betibeglogene autotemcel;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Meet the Definition of Transfusion Independence (TI) | TI was defined as a weighted average hemoglobin (Hb) >= 9 grams per deciliter (g/dL) without any packed red blood cell (pRBC) transfusions for a continuous period of >= 12 months at any time during the study after drug product infusion. | From 14 to 24 months post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Meet the Definition of Transfusion Independence (TI) at Month 24 | TI was defined as a weighted average hemoglobin (Hb) >= 9 grams per deciliter (g/dL) without any packed red blood cell (pRBC) transfusions for a continuous period of >= 12 months at any time during the study after drug product infusion. Percentage of participants who met the definition of TI at Month 24 were evaluated | At Month 24 post-transplant | 
| Duration of Transfusion Independence (TI) | Duration of TI was calculated as the time from the start of TI (that is (i.e.), first Hb >=9 with no transfusions in the preceding 60 days) up to the last available Hb at which the TI criteria are still met using Kaplan-Meier methodology. Duration of TI from start of TI up to Month 24 months was reported. | From start of TI up to Month 24 | 
| Time From Drug Product Infusion to Achievement of Transfusion Independence (TI) | Time from drug product infusion to achievement of TI was calculated as the time from drug product infusion to the first hemoglobin at which a participant can be declared as TI (that is to 'start of TI + >= 12 months', dependent on Hb lab schedule). | From 14 months post-drug product infusion through Month 24 | 
| Weighted Average Hemoglobin (Hb) During Transfusion Independence (TI) | Weighted average Hb was defined as the weighted average of Hb values without any pRBC transfusions in the proceeding 60 days. The ratio of the time between two Hb values and the time between the first and the last Hb values was used as the weight for calculation. | From 60 days after the last pRBC transfusion through Month 24 | 
| Percentage of Participants Who Had a Reduction of At Least 50%, 60%, 75%, 90% or 100% in the Annualized pRBCs Transfusion Volume | Percentage of participants reduction in the annualized mL/kg pRBCs transfused from 12 months post-drug product infusion through Month 24 (approximately a 12-month period) of at least 50%, 60%, 75%, 90% or 100% compared to the annualized mL/kg pRBC transfusion requirement during the 24 months prior to enrollment. | 12 months post-drug product infusion through Month 24 | 
| Annualized Number of pRBC Transfusions | Annualized number of pRBC transfusions from 12 months post-drug product infusion through Month 24 were reported. | From 12 months post-drug product infusion through Month 24 | 
| Annualized Volume of pRBC Transfusions | Annualized volume of pRBC transfusions from 12 months post-drug product infusion through Month 24 was reported. | From 12 months post-drug product infusion through Month 24 | 
| Time From Drug Product Infusion to Last pRBC Transfusion | Time from drug product infusion to last pRBC transfusion was reported. | From start of drug product infusion up to Month 24 | 
| Time From Last pRBC Transfusion to Month 24 | Time From Last pRBC Transfusion to Month 24 was reported. | From last pRBC Transfusion up to Month 24 (actual maximum time frame of up to approximately 27 months due to visit window) | 
| Weighted Average Nadir Hemoglobin (Hb) | The weighted average nadir Hb was defined as the most recent Hb prior to each pRBC transfusion, on the day of transfusion or within 3 days and, if there was a period of more than 60 days without transfusion, all Hb records between Day 61 and last follow-up or next transfusion (inclusive) was included. The weighted average nadir Hb during the period of 12 months post-drug product infusion to Month 24 was compared to the weighted average nadir Hb during the 24 months prior to enrollment. | 12 months post-drug product infusion through Month 24 | 
| Unsupported Total Hb Levels at Month 6, 9, 12, 18 and 24 | Unsupported total Hb level was defined as the total Hb measurement level without any acute or chronic pRBC transfusions within 60 days prior to the measurement date. | At Month 6, 9, 12, 18 and 24 | 
| Number of Participants With Unsupported Total Hb Levels (>=10 g/dL, >=11 g/dL, >=12 g/dL, >=13 g/dL, and >=14 g/dL) at Months 6, 9, 12, 18 and 24 | The number of participants with unsupported total Hb levels (>=10 g/dL, >=11 g/dL, >=12 g/dL, >=13 g/dL, and >=14 g/dL) meeting the thresholds were reported at at Months 6, 9, 12, 18 and 24. Participants were evaluable if they had an unsupported total Hb measurement at the specific timepoint, where unsupported total Hb level is defined as the total Hb measurement level without any acute or chronic pRBC transfusions within 60 days prior to the measurement date. | At Month 6, 9, 12, 18 and 24 | 
| Percentage of Participants Who Have Not Received Chelation Therapy for At Least 6 Months Following Drug Product Infusion | Percentage of participants who have not received chelation therapy for at least 6 months following drug product infusion were reported. | Up to Month 24 | 
| Time From Last Iron Chelation Use to Last Follow-up | Time from last iron chelation use to last follow-up to 24 months was reported. Participants were evaluable for this outcome if they had not received iron chelation therapy for at least 6 months following drug product infusion. | Time from last iron chelation up to Month 24 (actual maximum time frame of up to approximately 27 months due to visit window) | 
| Percentage of Participants Who Used Therapeutic Phlebotomy Post Drug Product (DP) Infusion | Therapeutic phlebotomy could be used in lieu of chelation in participants who had Hb consistently >= 11 g/dL and who were no longer receiving regular transfusions, at the discretion of the investigator. Percentage of participants who used therapeutic phlebotomy post DP infusion for up to Month 24 were reported. | Up to Month 24 | 
| Annualized Phlebotomy Therapy Usage Following Drug Product Infusion | Annualized phlebotomy therapy usage (number of procedures per year, calculated from DP infusion through last follow-up) were reported. | Up to Month 24 | 
| Change From Baseline in Liver Iron Concentration by Magnetic Resonance Imaging (MRI) | Change From Baseline in liver Iron Content by Magnetic Resonance Imaging (MRI) at Months 12 and 24 were reported. | Baseline, Months 12 and 24 | 
| Change From Baseline in Cardiac T2* on MRI | Change From Baseline in Cardiac T2* on MRI at baseline, Month 12 and 24 was reported. | Baseline, Months 12 and 24 | 
| Change From Baseline in Serum Ferritin at Months 12 and 24 | Serum ferritin was commonly used for an indirect estimation of body iron stores. Although sensitive, it is not specific for iron overload as it can be elevated in a variety of infectious and inflammatory states, and in the presence of cytolysis. Change from baseline in serum ferritin at Months 12 and 24 was reported. | Baseline, Months 12 and 24 | 
| Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Total Scores at Months 12 and 24 | PedsQL GCS designed to measure health-related quality of life in pediatric and adolescents (2 to 18 years). It encompassed 4 dimensions of functioning (physical [8 items], emotional [5 items], social [5 items], school [3 items]). Age groups: Toddler (2-4 years), Young pediatric (5-7 years), Pediatric (8-12 years), Teens (13-18 years). The questionnaire was also completed by parent/caregiver to assess parents' perceptions of their children's quality of life. The Toddler group consisted of 21 items, using a 5-point Likert scale (0 to 4); all other groups consisted of 23 items, with a 3-point Likert scale (0, 2, 4) for young pediatric, a 5-point Likert scale for pediatric and teens groups. All reported scores were transformed on a scale from 0 to 100 for each domain where 0=100, 1=75, 2=50, 3=25, and 4=0. Higher scores correspond with higher quality of life. | Baseline, Months 12 and 24 | 
| Change From Baseline in EuroQol Quality of Life 5-Dimension Youth Scale (EQ-5D-Y) VAS Health Status at Months 12 and 24 | EQ-5D is a validated, standardized, generic instrument that was most widely used preference based health related quality of life questionnaire in cost effectiveness and health technologies assessment. EQ-5D-Y was a version of instrument specifically developed and validated for use by youths aged 12 through 17 years. The EQ-5D-Y visual analog scale (VAS) consisted of a 20-cm vertical VAS, with anchors of 0 (worst imaginable health state) and 100 (best imaginable health state). Respondents were asked to rate their own health state today by drawing a line from a box containing these words to the point on the scale that they felt most accurately reflected their current health state. The VAS was reported (raw data) on a scale of 0-100 where 0= death and 100= perfect health. Higher scores equated to better outcomes. | Baseline, Months 12 and 24 | 
| Change From Baseline in EuroQol Quality of Life 5-Dimension Adult Scale (EQ-5D-3L) VAS Heath Status Score at Months 12 and 24 | EQ-5D is a validated, standardized, generic instrument that was most widely used preference based health related quality of life (HRQoL) questionnaire in cost effectiveness and health technologies assessment. Participants age >=18 at time of informed consent were eligible to complete the EQ-5D-3L which is a visual analog scale (VAS) which consists of a 20-cm vertical VAS, with anchors of 0 (worst imaginable health state) and 100 (best imaginable health state). Respondents were asked to rate their own health state today by drawing a line from a box containing these words to the point on the scale that they feel most accurately reflects their current health state. | Baseline, Months 12 and 24 | 
| Change From Baseline in Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Questionnaire Score | FACT-BMT is assessed bone marrow transplant related quality of life in adults. It. Total score was sum of sub-scale scores for 5 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, Functional Well-Being, and Bone Marrow Transplantation Subscale. Each item scored on a 5-point Likert scale based on participant agreement with each statement: 0 for not at all, 1 for a little bit, 2 for somewhat, 3 for quite a bit, and 4 for very much. Reported scores were transformed as follows: After taking into account reverse scores for questions constructed in negative form, subscale score for each domain was calculated by multiplying sum of item scores by number of items in subscale, then dividing by number of items answered. Total score was sum of subscale total added together and ranges from 0-148. Higher scores corresponded with higher quality of life. | Baseline, Months 12 and 24 | 
| Change From Baseline in Short Form-36 Health Survey (SF-36), Version 2, Acute (Physical and Mental Component Summary Scores) at Months 12 and 24 | SF-36 was designed to measure health-related quality of life in adults. The instrument consisted of 36 items, were aggregated into 8 multi-item scales (physical functioning [1=yes, limited a lot to 3=no, not limited at all], role-physical [1=all of time to 5=none of time], bodily pain [1=very severe to 6=none], general health [1=poor to 5=excellent], vitality [1=none of time to 5=all of time], social functioning [1=all of time: to 5=none of time], role emotional [1=all of time to 5=none of time] and mental health [1=all of time to 5=none of the time]). Four domains comprised physical component summary (PCS) score (physical functioning, role-physical, bodily pain, general health) and remaining 4 domains comprised mental component summary (MCS) score (vitality, social functioning, role-emotional, mental health). Reported summary scores were transformed on a scale from 0 to 100. Higher scores corresponded with higher quality of life. | Baseline, Months 12 and 24 |