Back to resultsA Study Evaluating the Efficacy and Safety of the LentiGlobin® BB305 Drug Product in Participants With Transfusion-Dependent β-Thalassemia
Primary Purpose
Beta-Thalassemia
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
LentiGlobin BB305 Drug Product
Sponsored by
About this trial
This is an interventional treatment trial for Beta-Thalassemia
Eligibility Criteria
Inclusion Criteria:
• Participants less than or equal to (<=) 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 other then β0 (e.g., β+, βE, βC) on at least one β-globin gene (HBB) allele.
- 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.
- 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.
Sites / Locations
- UCSF Benioff Children's Hospital Oakland
- Ann & Robert H. Lurie Children's Hospital of Chicago
- Children's Hospital of Philadelphia
- Hopital d'enfants de la Timone
- Hannover Medical School
- University of Heidelberg
- General Hospital of Thessaloniki 'G.Papanikolaou'
- IRCCS Ospedale Pediatrico Babino Gesu
- University College London Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
LentiGlobin BB305 Drug Product
Arm Description
LentiGlobin BB305 Drug Product (autologous CD34+ cell-enriched population that contains cells transduced with LentiGlobin BB305 lentiviral vector encoding human βA-T87Q-globin)
Outcomes
Primary Outcome Measures
Proportion of Participants who meet the Definition of Transfusion Independence (TI)
TI is defined as greater than or equal to (>=) 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.
Secondary Outcome Measures
Proportion of Participants who meet the Definition of Transfusion Independence (TI) at Month 24
Duration of Transfusion Independence (TI)
Time From Drug Product Infusion to Achievement of Transfusion Independence (TI)
Average Weighted Hemoglobin (Hb) During Transfusion Independence (TI)
Proportion of Participants who meet the Definition of Transfusion Reduction (TR)
TR is defined as demonstration of a 60 percent (%) reduction in the annualized volume of pRBC transfusion requirements (in milliliter per kilogram [mL/kg]) in the post-treatment time period from 12 Months post-drug product infusion through Month 24 compared to the annualized mL/kg pRBC transfusion requirement during the 24 months prior to study enrollment
Proportion of Participants with At Least 50%, 60%, 75%, 90% or 100% Reduction in the Annualized pRBCs Transfusion
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.
Annualized Number of pRBC Transfusions
Annualized number of pRBC transfusions from 12 months post-drug product infusion through Month 24 compared to the annualized number of transfusions during the 24 months prior to enrollment.
Annualized Volume of pRBC Transfusions
Annualized volume of pRBC transfusions from 12 months post-drug product infusion through Month 24 compared to the annualized volume of transfusions during the 24 months prior to enrollment.
Time From Drug Product Infusion to Last pRBC Transfusion
Time From Last pRBC Transfusion to 24 Months
Weighted Average Nadir Hemoglobin (Hb)
Weighted average nadir Hb during the 24 months prior to enrollment compared to weighted average nadir Hb from 12 months post-drug product infusion through the Month 24 Visit.
Unsupported Total Hb Levels Over Time
Unsupported Total Hb Levels (>=10 g/dL, >=11 g/dL, >=12 g/dL, >=13 g/dL, and >=14 g/dL)
Proportion of Participants Who Have Not Received Chelation Therapy for At Least 6 Months Following Drug Product Infusion
Time From Last Iron Chelation Use to Last Follow-up
Proportion of Participants Using Therapeutic Phlebotomy and Annualized Frequency of Phlebotomy
Change From Baseline in Liver Iron Content by Magnetic Resonance Imaging (MRI)
Change From Baseline in Cardiac T2 on MRI
Change From Baseline in Serum Ferritin
Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale (GCS) Score
PedsQL GCS is designed to measure health-related quality of life in pediatric participants and adolescents (2 to 18 years of age). It encompasses 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), and Teens (13-18 years). Depending on the participant's age, the questionnaire may be completed by parent/caregiver as appropriate. For the Toddler group, the PedsQL GCS consist of 21 items, using a 5-point Likert scale (0 to 4); for all other groups, the PedsQL GCS consist of 23 items, with a 3-point Likert scale (0, 2, 4) for the young pediatric, and a 5-point Likert scale for the pediatric and teens groups. Scores are transformed on a scale from 0 to 100 where 0=100, 1=75, 2=50, 3=25, and 4=0. Higher scores indicate improved quality of life.
Change From Baseline in EuroQol-5D (Youth version) (EQ-5D-Y)
EQ-5D-Y health questionnaire is a participant answered questionnaire scoring 5 dimensions - mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ-5D total score ranges from 0 (worst health state) to 1 (perfect health state) and 1 reflects the best outcome.
Change From Baseline in EuroQol-5D (EQ-5D)
The EQ-5D provides a descriptive profile and index value for health status. The questionnaire measures 5 dimensions of health status: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each dimension, there are 5 levels of response: no problems, slight problems, moderate problems, severe problems, and unable to do/extreme problems.
Change From Baseline in Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Questionnaire Score
The FACT-BMT assesses bone marrow transplant related concerns. The total score is the 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. Within each domain, a 5-point Likert-type scale (from 0-4) is used to measure the responses for each question. After taking into account reverse scores for questions constructed in a negative form, the subscale score for each domain is calculated by multiplying the sum of the item scores by the number of items in the subscale, then dividing by the number of items answered. The final score for FACT-BMT ranges from 0 to 148. Higher scores indicate better quality of life.
Change From Baseline in Short Form-36 Health Survey (SF-36), Version 2
SF-36 is a generic quality-of-life instrument that had been widely used to assess HRQL of participants. Generic instruments were used in general populations to assess a wide range of domains applicable to a variety of health states, conditions, and diseases. The SF-36 consisted of 36 items that 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 the time to 5=none of the time], bodily pain [1=very severe to 6=none], general health [1=poor to 5=excellent], vitality [1=none of the time to 5=all of the time], social functioning [1=all of the time: to 5=none of the time], role emotional [1=all of the time to 5=none of the time] and mental health [1=all of the time to 5=none of the time]), with scores ranged from 0 to 100. Higher scores indicating better HRQL.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03207009
Brief Title
A Study Evaluating the Efficacy and Safety of the LentiGlobin® BB305 Drug Product in Participants With Transfusion-Dependent β-Thalassemia
Official Title
A Phase 3 Single Arm Study Evaluating the Efficacy and Safety of Gene Therapy in Subjects With Transfusion-dependent β-Thalassemia by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With a Lentiviral βA-T87Q-Globin Vector in Subjects ≤50 Years of Age
Study Type
Interventional
2. Study Status
Record Verification Date
February 2022
Overall Recruitment Status
Completed
Study Start Date
June 8, 2017 (Actual)
Primary Completion Date
November 15, 2022 (Actual)
Study Completion Date
November 15, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
bluebird bio
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This is a single-arm, multi-site, single-dose, Phase 3 study in approximately 18 participants less than or equal to (<=) 50 years of age with transfusion-dependent β-thalassemia (TDT), who have a β0/β0, β0/IVS-I-110, or IVS-I-110/IVS-I-110 genotype. The study will evaluate the efficacy and safety of autologous hematopoietic stem cell transplantation (HSCT) using LentiGlobin BB305 Drug Product.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Beta-Thalassemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Actual)
8. Arms, Groups, and Interventions
Arm Title
LentiGlobin BB305 Drug Product
Arm Type
Experimental
Arm Description
LentiGlobin BB305 Drug Product (autologous CD34+ cell-enriched population that contains cells transduced with LentiGlobin BB305 lentiviral vector encoding human βA-T87Q-globin)
Intervention Type
Genetic
Intervention Name(s)
LentiGlobin BB305 Drug Product
Other Intervention Name(s)
betibeglogene autotemcel
Intervention Description
LentiGlobin BB305 Drug Product is administered by IV infusion following myeloablative conditioning with busulfan.
Primary Outcome Measure Information:
Title
Proportion of Participants who meet the Definition of Transfusion Independence (TI)
Description
TI is defined as greater than or equal to (>=) 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.
Time Frame
From 12 to 24 months post-transplant
Secondary Outcome Measure Information:
Title
Proportion of Participants who meet the Definition of Transfusion Independence (TI) at Month 24
Time Frame
At Month 24 post-transplant
Title
Duration of Transfusion Independence (TI)
Time Frame
Up to 24 months post-transplant
Title
Time From Drug Product Infusion to Achievement of Transfusion Independence (TI)
Time Frame
From 12 to 24 months post-transplant
Title
Average Weighted Hemoglobin (Hb) During Transfusion Independence (TI)
Time Frame
From 12 to 24 months post-transplant
Title
Proportion of Participants who meet the Definition of Transfusion Reduction (TR)
Description
TR is defined as demonstration of a 60 percent (%) reduction in the annualized volume of pRBC transfusion requirements (in milliliter per kilogram [mL/kg]) in the post-treatment time period from 12 Months post-drug product infusion through Month 24 compared to the annualized mL/kg pRBC transfusion requirement during the 24 months prior to study enrollment
Time Frame
From 12 to 24 months post-transplant
Title
Proportion of Participants with At Least 50%, 60%, 75%, 90% or 100% Reduction in the Annualized pRBCs Transfusion
Description
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.
Time Frame
From 12 to 24 months post-transplant
Title
Annualized Number of pRBC Transfusions
Description
Annualized number of pRBC transfusions from 12 months post-drug product infusion through Month 24 compared to the annualized number of transfusions during the 24 months prior to enrollment.
Time Frame
From 12 to 24 months post-transplant
Title
Annualized Volume of pRBC Transfusions
Description
Annualized volume of pRBC transfusions from 12 months post-drug product infusion through Month 24 compared to the annualized volume of transfusions during the 24 months prior to enrollment.
Time Frame
From 12 to 24 months post-transplant
Title
Time From Drug Product Infusion to Last pRBC Transfusion
Time Frame
Up to 24 months post-transplant
Title
Time From Last pRBC Transfusion to 24 Months
Time Frame
Up to 24 months post-transplant
Title
Weighted Average Nadir Hemoglobin (Hb)
Description
Weighted average nadir Hb during the 24 months prior to enrollment compared to weighted average nadir Hb from 12 months post-drug product infusion through the Month 24 Visit.
Time Frame
From 12 to 24 months post-transplant
Title
Unsupported Total Hb Levels Over Time
Time Frame
At Month 6, 9, 12, 18 and 24
Title
Unsupported Total Hb Levels (>=10 g/dL, >=11 g/dL, >=12 g/dL, >=13 g/dL, and >=14 g/dL)
Time Frame
At Month 6, 12, 18 and 24
Title
Proportion of Participants Who Have Not Received Chelation Therapy for At Least 6 Months Following Drug Product Infusion
Time Frame
From 6 to 24 months
Title
Time From Last Iron Chelation Use to Last Follow-up
Time Frame
Up to 24 months
Title
Proportion of Participants Using Therapeutic Phlebotomy and Annualized Frequency of Phlebotomy
Time Frame
Up to 24 months
Title
Change From Baseline in Liver Iron Content by Magnetic Resonance Imaging (MRI)
Time Frame
Baseline, Month 12 and 24
Title
Change From Baseline in Cardiac T2 on MRI
Time Frame
Baseline, Month 12 and 24
Title
Change From Baseline in Serum Ferritin
Time Frame
Baseline, Month 12 and 24
Title
Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale (GCS) Score
Description
PedsQL GCS is designed to measure health-related quality of life in pediatric participants and adolescents (2 to 18 years of age). It encompasses 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), and Teens (13-18 years). Depending on the participant's age, the questionnaire may be completed by parent/caregiver as appropriate. For the Toddler group, the PedsQL GCS consist of 21 items, using a 5-point Likert scale (0 to 4); for all other groups, the PedsQL GCS consist of 23 items, with a 3-point Likert scale (0, 2, 4) for the young pediatric, and a 5-point Likert scale for the pediatric and teens groups. Scores are transformed on a scale from 0 to 100 where 0=100, 1=75, 2=50, 3=25, and 4=0. Higher scores indicate improved quality of life.
Time Frame
Baseline, Month 12 and 24
Title
Change From Baseline in EuroQol-5D (Youth version) (EQ-5D-Y)
Description
EQ-5D-Y health questionnaire is a participant answered questionnaire scoring 5 dimensions - mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ-5D total score ranges from 0 (worst health state) to 1 (perfect health state) and 1 reflects the best outcome.
Time Frame
Baseline, Month 12 and 24
Title
Change From Baseline in EuroQol-5D (EQ-5D)
Description
The EQ-5D provides a descriptive profile and index value for health status. The questionnaire measures 5 dimensions of health status: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each dimension, there are 5 levels of response: no problems, slight problems, moderate problems, severe problems, and unable to do/extreme problems.
Time Frame
Baseline, Month 12 and 24
Title
Change From Baseline in Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Questionnaire Score
Description
The FACT-BMT assesses bone marrow transplant related concerns. The total score is the 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. Within each domain, a 5-point Likert-type scale (from 0-4) is used to measure the responses for each question. After taking into account reverse scores for questions constructed in a negative form, the subscale score for each domain is calculated by multiplying the sum of the item scores by the number of items in the subscale, then dividing by the number of items answered. The final score for FACT-BMT ranges from 0 to 148. Higher scores indicate better quality of life.
Time Frame
Baseline, Month 12 and 24
Title
Change From Baseline in Short Form-36 Health Survey (SF-36), Version 2
Description
SF-36 is a generic quality-of-life instrument that had been widely used to assess HRQL of participants. Generic instruments were used in general populations to assess a wide range of domains applicable to a variety of health states, conditions, and diseases. The SF-36 consisted of 36 items that 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 the time to 5=none of the time], bodily pain [1=very severe to 6=none], general health [1=poor to 5=excellent], vitality [1=none of the time to 5=all of the time], social functioning [1=all of the time: to 5=none of the time], role emotional [1=all of the time to 5=none of the time] and mental health [1=all of the time to 5=none of the time]), with scores ranged from 0 to 100. Higher scores indicating better HRQL.
Time Frame
Baseline, Month 12 and 24
10. Eligibility
Sex
All
Minimum Age & Unit of Time
0 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
• Participants less than or equal to (<=) 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 other then β0 (e.g., β+, βE, βC) on at least one β-globin gene (HBB) allele.
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.
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Himal L Thakar, MD
Organizational Affiliation
bluebird bio
Official's Role
Study Director
Facility Information:
Facility Name
UCSF Benioff Children's Hospital Oakland
City
Oakland
State/Province
California
ZIP/Postal Code
94609
Country
United States
Facility Name
Ann & Robert H. Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Hopital d'enfants de la Timone
City
Marseille
ZIP/Postal Code
13385
Country
France
Facility Name
Hannover Medical School
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Facility Name
University of Heidelberg
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
General Hospital of Thessaloniki 'G.Papanikolaou'
City
Thessaloníki
Country
Greece
Facility Name
IRCCS Ospedale Pediatrico Babino Gesu
City
Rome
Country
Italy
Facility Name
University College London Hospital
City
London
Country
United Kingdom
12. IPD Sharing Statement
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A Study Evaluating the Efficacy and Safety of the LentiGlobin® BB305 Drug Product in Participants With Transfusion-Dependent β-Thalassemia
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