- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01745120
A Study Evaluating the Safety and Efficacy of the LentiGlobin BB305 Drug Product in β-Thalassemia Major Participants
April 16, 2019 updated by: bluebird bio
A Phase 1/2 Open Label Study Evaluating the Safety and Efficacy of Gene Therapy in Subjects With β-Thalassemia Major by Transplantation of Autologous CD34+ Cells Transduced Ex Vivo With a Lentiviral βA-T87Q-Globin Vector (LentiGlobin® BB305 Drug Product)
This is a non-randomized, open label, multi-site, single-dose, phase 1/2 study in up to 18 participants (including at least 3 adolescents between 12 and 17 years of age, inclusive) with β-thalassemia major.
The study will evaluate the safety and efficacy of autologous hematopoietic stem cell transplantation (HSCT) using LentiGlobin BB305 Drug Product [autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human βA-T87Q-globin gene].
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Detailed Description
Subject participation for this study will be 2 years.
Subjects who enroll in this study will be asked to participate in a subsequent long-term follow up study that will monitor the safety and efficacy of the treatment they receive for up to 13 years post-transplant.
Study Type
Interventional
Enrollment (Actual)
19
Phase
- Phase 2
- Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Sydney, Australia
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Bangkok, Thailand
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California
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Los Angeles, California, United States
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Oakland, California, United States
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Illinois
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Chicago, Illinois, United States
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Pennsylvania
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Philadelphia, Pennsylvania, United States
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
12 years to 35 years (Child, Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion criteria:
- Participants between 12 and 35 years of age, inclusive, at the time of consent/assent, and able to provide written consent/assent, if applicable.
- Diagnosis of β-thalassemia major and a history of at least 100 mL/kg/year of pRBCs or ≥8 transfusions of pRBCs per year for the prior 2 years.
- Eligible for allogeneic bone marrow transplant.
- Treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records, including transfusion history.
Exclusion criteria:
- Positive for presence of human immunodeficiency virus type 1 or 2 (HIV 1 and HIV 2).
- A white blood cell (WBC) count <3 × 10^9/L, and / or platelet count <100 × 10^9/L if not due to hypersplenism.
- Uncorrected bleeding disorder.
- Any prior or current malignancy or myeloproliferative or immunodeficiency disorder.
- 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).
- Receipt of an allogeneic transplant.
- Advanced liver disease, including persistent aspartate transaminase (AST), alanine transaminase (ALT), or total bilirubin value >3 × the upper limit of normal, liver biopsy demonstrating cirrhosis, extensive bridging fibrosis, or active hepatitis.
- Kidney disease with a calculated creatinine clearance <30% normal value.
- Uncontrolled seizure disorder.
- Diffusion capacity of carbon monoxide (DLco) <50% of predicted (corrected for hemoglobin).
- A cardiac T2* <10 ms by magnetic resonance imaging (MRI).
- Any other evidence of severe iron overload that, in the Investigator's opinion, warrants exclusion.
- Clinically significant pulmonary hypertension, as defined by the requirement for ongoing pharmacologic treatment or the consistent or intermittent use of supplemental home oxygen.
- Participation in another clinical study with an investigational drug within 30 days of Screening.
- Any prior or current malignancy or myeloproliferative disorder.
- Prior receipt of gene therapy.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: LentiGlobin BB305 Drug Product
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Transplant of autologous hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Percentage of Participants With Sustained Production of >=2.0 Grams Per Deciliter (g/dL) of Hemoglobin A (HbA) Containing βA-T87Q-globin (HbAT87Q) for the Six Months Between Month 18 and Month 24
Time Frame: Month 18 to Month 24
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Percentage of participants with sustained production of >=2.0 grams per deciliter (g/dL) of hemoglobin A (HbA) containing βA-T87Q-globin (HbAT87Q) for 6 months (Month 18 to Month 24) was reported.
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Month 18 to Month 24
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Percentage of Participants Who Achieved Transfusion Independence (TI)
Time Frame: From time of drug product infusion up to 24 months
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TI was defined as a weighted average hemoglobin (Hb) >= 9 g/dL without any packed red blood cells (pRBC) transfusions for a continuous period of >=12 months at any time during the study after LentiGlobin BB305 Drug Product infusion.
Percentage of participants who achieved TI from time of drug product infusion up to 24 months was reported.
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From time of drug product infusion up to 24 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Percentage of Participants Who Achieved Transfusion Independence (TI) at Month 18 and Month 24
Time Frame: Month 18, Month 24
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TI was defined as a weighted average Hb >= 9 g/dL without any pRBC transfusions for a continuous period of >= 12 months at any time during the study after LentiGlobin BB305 Drug Product infusion.
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Month 18, Month 24
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Duration of Transfusion Independence (TI)
Time Frame: From time of drug product infusion up to 24 months
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TI was defined as a weighted average Hb >= 9 g/dL without any pRBC transfusions for a continuous period of >= 12 months at any time during the study after LentiGlobin BB305 Drug Product infusion.
Time period of TI will start when participants achieve a Hb >= 9 g/dL with no transfusions in the preceding 60 days.
Duration of TI was calculated as the time from the start of TI (i.e.
first Hb >= 9 g/dL with no transfusions in the preceding 60 days) up to the last available Hb at which the TI criteria are still met.
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From time of drug product infusion up to 24 months
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Time From LentiGlobin BB305 Drug Product Infusion to Last pRBC Transfusion Prior to Achieving Transfusion Independence (TI)
Time Frame: From time of drug product infusion up to 24 months
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TI was defined as a weighted average Hb >= 9 g/dL without any pRBC transfusions for a continuous period of >= 12 months at any time during the study after LentiGlobin BB305 Drug Product infusion.
Time From LentiGlobin BB305 Drug Product Infusion to last pRBC transfusion prior to achieving TI was reported.
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From time of drug product infusion up to 24 months
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Time From LentiGlobin BB305 Drug Product Infusion to Achieving Transfusion Independence (TI)
Time Frame: From time of drug product infusion up to 24 months
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TI was defined as a weighted average Hb >= 9 g/dL without any pRBC transfusions for a continuous period of >= 12 months at any time during the study after LentiGlobin BB305 Drug Product infusion.
Time from drug product infusion to initial achievement of TI was calculated as the time from drug product infusion to the first Hb at which a participant can be declared as TI.
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From time of drug product infusion up to 24 months
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Weighted Average Hemoglobin (Hb) During Period of Transfusion Independence (TI)
Time Frame: From time of drug product infusion up to 24 months
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The weighted average Hb is an average area under the curve during the period of TI, from the start of TI when the Hb is first >= 9 g/dL with no transfusions in the preceding 60 days to the last available Hb at which the TI criteria are still met.
TI was defined as a weighted average Hb >= 9 g/dL without any pRBC transfusions for a continuous period of >= 12 months at any time during the study after LentiGlobin BB305 Drug Product infusion.
Weighted average Hb during the period of TI was reported.
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From time of drug product infusion up to 24 months
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Percentage Change From Baseline in Annualized Number of Packed Red Blood Cells (pRBC) Transfusions at Month 24
Time Frame: Baseline, Month 24
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The annualized number of pRBC transfusions over the 2 year period prior to drug product infusion was compared to the annualized number of pRBC transfusions during the Month 6 to Month 24 period post drug product infusion and the percentage change was reported.
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Baseline, Month 24
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Percentage Change From Baseline in Average Annual Packed Red Blood Cells (pRBC) Transfusion Volume at Month 24
Time Frame: Baseline, Month 24
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The annualized volume of pRBC transfusions over the 2 year period prior to drug product infusion was compared to the annualized volume of pRBC transfusions in the Month 6 to Month 24 period post drug product Infusion and the percentage change from baseline was reported.
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Baseline, Month 24
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Weighted Average Nadir Hemoglobin (Hb)
Time Frame: Baseline, Month 6 to Month 24
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Weighted average Hb nadir was defined as an average area under the curve where the Hb closest but within 3 days prior to a transfusion is used as the Hb nadir.
If there is a period of more than 60 days without a pRBC transfusion, all Hb records between Day 61 and day of last visit or next transfusion (inclusive) were also considered as nadirs.
The weighted average nadir Hb during the period of Month 6 to Month 24 was compared to the weighted average nadir Hb during the 2 years prior to enrollment.
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Baseline, Month 6 to Month 24
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Number of Participants With Successful Neutrophil Engraftment
Time Frame: From time of drug product infusion up to 24 months
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Neutrophil engraftment was defined as achieving 3 consecutive absolute neutrophil count (ANC) >= 0.5 × 10^9/L on different days after a post-transplant value of < 0.5 × 10^9/L within 42 days after drug product infusion.
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From time of drug product infusion up to 24 months
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Time to Neutrophil Engraftment
Time Frame: From time of drug product infusion up to 24 months
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Time to neutrophil engraftment was defined as the time to the first of 3 consecutive absolute neutrophil count (ANC) >= 0.5 × 10^9/L obtained on different days after a post-transplant value of < 0.5 × 10^9/L.
The Day of neutrophil engraftment is the first day of the 3 consecutive measurements, where Day 1 is the day of drug product infusion.
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From time of drug product infusion up to 24 months
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Number of Participants With Successful Platelet Engraftment
Time Frame: From time of drug product infusion up to 24 months
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Platelet engraftment was defined as achieving 3 consecutive platelet values >= 20 × 10^9/L on different days after a post-transplant value of < 20 × 10^9/L, while no platelet transfusions administered for 7 days immediately preceding and during the evaluation period.
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From time of drug product infusion up to 24 months
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Time to Platelet Engraftment
Time Frame: From time of drug product infusion up to 24 months
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Time to platelet engraftment was defined as achieving of first 3 consecutive platelet values >= 20 × 10^9/L obtained on different days after a post-transplant value of < 20 × 10^9/L, while no platelet transfusions administered for 7 days immediately preceding and during the evaluation period.
The day of platelet engraftment is the first day of the 3 consecutive measurements, where Day 1 is the day of drug product infusion.
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From time of drug product infusion up to 24 months
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Transplant-related Mortality
Time Frame: Through 100 and 365 days post-LentiGlobin BB305 Drug Product infusion
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Transplant-related mortality was determined by the investigator (any deaths considered related to the transplant.)
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Through 100 and 365 days post-LentiGlobin BB305 Drug Product infusion
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Overall Survival
Time Frame: From time of drug product infusion up to 24 months
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Overall survival was defined as time from date of LentiGlobin BB305 Drug Product infusion (Day 1) to date of death.
Overall survival was censored at the date of last visit if the participant was still alive.
Percentage of participants who survived throughout the study were reported.
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From time of drug product infusion up to 24 months
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Percentage of Participants Detected With Replication-competent Lentivirus (RCL)
Time Frame: From time of drug product infusion up to 24 months
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Blood samples were analyzed for detection of RCL using RCL co-culture assay.
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From time of drug product infusion up to 24 months
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Number of Participants With Integration Site Analysis (ISA) With >30% Clonal Contribution
Time Frame: From time of drug product infusion up to 24 months
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Linear amplification-mediated polymerase chain reaction (LAM-PCR) coupled with next generation sequencing and subsequent (semi-) automated data mining allowed high-throughput analysis of vector integration site (IS) in blood cells from treated participants at multiple time points.
ISs detected in peripheral blood cells at early time points generally were due to the expansion of transduced short-term progenitor stem cell clones, and gradually shift to include sites detected due to expansion of transduced long-term stem cell clones.
An efficient transduction procedure was anticipated to give rise to a polyclonal population in the participant, reflected by the detection of multiple IS.
Additionally, ISA allowed monitoring of the relative contribution of individual clones over time.
Number of participants who had IS that contributed to >=30% of the total clones at any time was used as a first step to investigating whether clonal dominance was achieved.
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From time of drug product infusion up to 24 months
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Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame: From signing of informed consent to 24 months after the drug product infusion
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An AE was defined as any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
A SAE was any AE, occurring at any dose and regardless of causality that: results in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect.
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From signing of informed consent to 24 months after the drug product infusion
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Investigators
- Study Director: Mohammed Asmal, MD, bluebird bio
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
August 1, 2013
Primary Completion (Actual)
February 8, 2018
Study Completion (Actual)
February 21, 2018
Study Registration Dates
First Submitted
December 6, 2012
First Submitted That Met QC Criteria
December 6, 2012
First Posted (Estimate)
December 7, 2012
Study Record Updates
Last Update Posted (Actual)
May 8, 2019
Last Update Submitted That Met QC Criteria
April 16, 2019
Last Verified
April 1, 2019
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- HGB-204
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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