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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT01745120
Registration number
NCT01745120
Ethics application status
Date submitted
6/12/2012
Date registered
7/12/2012
Date last updated
8/05/2019
Titles & IDs
Public title
A Study Evaluating the Safety and Efficacy of the LentiGlobin BB305 Drug Product in ß-Thalassemia Major Participants
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Scientific title
A Phase 1/2 Open Label Study Evaluating the Safety and Efficacy of Gene Therapy in Subjects With ß-Thalassemia Major by Transplantation of Autologous CD34+ Cells Transduced Ex Vivo With a Lentiviral ßA-T87Q-Globin Vector (LentiGlobin® BB305 Drug Product)
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Secondary ID [1]
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HGB-204
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
ß-thalassemia Major
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Condition category
Condition code
Blood
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Haematological diseases
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Blood
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Other blood disorders
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Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Other interventions - LentiGlobin BB305 Drug Product
Experimental: LentiGlobin BB305 Drug Product -
Other interventions: LentiGlobin BB305 Drug Product
Transplant of autologous hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector.
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Intervention code [1]
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Other interventions
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Percentage of Participants With Sustained Production of >=2.0 Grams Per Deciliter (g/dL) of Hemoglobin A (HbA) Containing ßA-T87Q-globin (HbAT87Q) for the Six Months Between Month 18 and Month 24
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Assessment method [1]
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Percentage of participants with sustained production of >=2.0 grams per deciliter (g/dL) of hemoglobin A (HbA) containing ßA-T87Q-globin (HbAT87Q) for 6 months (Month 18 to Month 24) was reported.
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Timepoint [1]
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Month 18 to Month 24
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Primary outcome [2]
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Percentage of Participants Who Achieved Transfusion Independence (TI)
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Assessment method [2]
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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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Timepoint [2]
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From time of drug product infusion up to 24 months
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Secondary outcome [1]
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Percentage of Participants Who Achieved Transfusion Independence (TI) at Month 18 and Month 24
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Assessment method [1]
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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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Timepoint [1]
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Month 18, Month 24
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Secondary outcome [2]
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Duration of Transfusion Independence (TI)
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Assessment method [2]
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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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Timepoint [2]
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From time of drug product infusion up to 24 months
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Secondary outcome [3]
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Time From LentiGlobin BB305 Drug Product Infusion to Last pRBC Transfusion Prior to Achieving Transfusion Independence (TI)
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Assessment method [3]
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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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Timepoint [3]
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From time of drug product infusion up to 24 months
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Secondary outcome [4]
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Time From LentiGlobin BB305 Drug Product Infusion to Achieving Transfusion Independence (TI)
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Assessment method [4]
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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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Timepoint [4]
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From time of drug product infusion up to 24 months
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Secondary outcome [5]
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Weighted Average Hemoglobin (Hb) During Period of Transfusion Independence (TI)
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Assessment method [5]
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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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Timepoint [5]
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From time of drug product infusion up to 24 months
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Secondary outcome [6]
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Percentage Change From Baseline in Annualized Number of Packed Red Blood Cells (pRBC) Transfusions at Month 24
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Assessment method [6]
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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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Timepoint [6]
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Baseline, Month 24
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Secondary outcome [7]
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Percentage Change From Baseline in Average Annual Packed Red Blood Cells (pRBC) Transfusion Volume at Month 24
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Assessment method [7]
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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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Timepoint [7]
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Baseline, Month 24
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Secondary outcome [8]
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Weighted Average Nadir Hemoglobin (Hb)
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Assessment method [8]
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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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Timepoint [8]
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Baseline, Month 6 to Month 24
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Secondary outcome [9]
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Number of Participants With Successful Neutrophil Engraftment
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Assessment method [9]
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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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Timepoint [9]
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From time of drug product infusion up to 24 months
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Secondary outcome [10]
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Time to Neutrophil Engraftment
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Assessment method [10]
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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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Timepoint [10]
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From time of drug product infusion up to 24 months
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Secondary outcome [11]
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Number of Participants With Successful Platelet Engraftment
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Assessment method [11]
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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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Timepoint [11]
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From time of drug product infusion up to 24 months
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Secondary outcome [12]
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Time to Platelet Engraftment
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Assessment method [12]
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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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Timepoint [12]
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From time of drug product infusion up to 24 months
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Secondary outcome [13]
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Transplant-related Mortality
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Assessment method [13]
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Transplant-related mortality was determined by the investigator (any deaths considered related to the transplant.)
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Timepoint [13]
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Through 100 and 365 days post-LentiGlobin BB305 Drug Product infusion
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Secondary outcome [14]
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Overall Survival
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Assessment method [14]
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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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Timepoint [14]
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From time of drug product infusion up to 24 months
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Secondary outcome [15]
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Percentage of Participants Detected With Replication-competent Lentivirus (RCL)
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Assessment method [15]
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Blood samples were analyzed for detection of RCL using RCL co-culture assay.
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Timepoint [15]
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From time of drug product infusion up to 24 months
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Secondary outcome [16]
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Number of Participants With Integration Site Analysis (ISA) With >30% Clonal Contribution
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Assessment method [16]
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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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Timepoint [16]
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From time of drug product infusion up to 24 months
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Secondary outcome [17]
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Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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Assessment method [17]
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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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Timepoint [17]
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From signing of informed consent to 24 months after the drug product infusion
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Eligibility
Key inclusion criteria
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 ß-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.
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Minimum age
12
Years
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Maximum age
35
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1/Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/08/2013
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
21/02/2018
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Sample size
Target
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Accrual to date
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Final
19
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Recruitment in Australia
Recruitment state(s)
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Recruitment hospital [1]
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- Sydney
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Recruitment postcode(s) [1]
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- Sydney
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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Country [2]
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United States of America
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State/province [2]
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Illinois
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Country [3]
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United States of America
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State/province [3]
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Pennsylvania
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Country [4]
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Thailand
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State/province [4]
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Bangkok
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
bluebird bio
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
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 ß-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 ßA-T87Q-globin gene].
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Trial website
https://clinicaltrials.gov/ct2/show/NCT01745120
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Mohammed Asmal, MD
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Address
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bluebird bio
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01745120
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