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β-thalassemia MajorPhase 1/2NCT01745120

A Study Evaluating the Safety and Efficacy of the LentiGlobin BB305 Drug Product in β-Thalassemia Major Participants

A Phase 1/2 study testing LentiGlobin BB305 Drug Product in people with β-thalassemia Major, run by Genetix Biotherapeutics Inc. at 6 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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 β-thalassemia major. Read more about this study

Who is it for?
Ages 12 to 35 years
Conditions the study is for
β-thalassemia Major
What is being tested?
LentiGlobin BB305 Drug Product
Could I receive a placebo?
No, everyone receives an active treatment
How many people
19 participants
Where
6 sitesin 3 countries
Study dates
Aug 2013to 21 Feb 2018
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 12 to 35 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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.

Who cannot join

  • 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.
Show all 16Show fewer
  • 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.

Trial locations and contacts

6 sites in 3 countries.

6 sites in 3 countries

United States4 sites
  • Study site

    Chicago, Illinois

  • Study site

    Los Angeles, California

  • Study site

    Oakland, California

  • Study site

    Philadelphia, Pennsylvania

Other trials in United States

Australia1 site
  • Study site

    Sydney

Other trials in Australia

Thailand1 site
  • Study site

    Bangkok

Other trials in Thailand

About this study

Official title: 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].

Read the 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.

Being tested
LentiGlobin BB305 Drug Product
Keywords
gene therapy, β thalassemia, hemoglobin, anemia, CD34
Medical subject headings
Anemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LentiGlobin BB305 Drug ProductGenetic

    Transplant of autologous hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector.

Study groups in NCT01745120
Study groupRoleWhat they receive
LentiGlobin BB305 Drug ProductExperimentalNot described
Receives: Genetic: LentiGlobin BB305 Drug Product

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    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.

    Measured: Month 18 to Month 24

  2. Percentage of Participants Who Achieved Transfusion Independence (TI)

    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.

    Measured: From time of drug product infusion up to 24 months

Secondary outcomes (17)
  1. Percentage of Participants Who Achieved Transfusion Independence (TI) at Month 18 and Month 24

    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.

    Measured: Month 18, Month 24

  2. Duration of Transfusion Independence (TI)

    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.

    Measured: From time of drug product infusion up to 24 months

  3. Time From LentiGlobin BB305 Drug Product Infusion to Last pRBC Transfusion Prior to Achieving Transfusion Independence (TI)

    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.

    Measured: From time of drug product infusion up to 24 months

  4. Time From LentiGlobin BB305 Drug Product Infusion to Achieving Transfusion Independence (TI)

    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.

    Measured: From time of drug product infusion up to 24 months

  5. Weighted Average Hemoglobin (Hb) During Period of Transfusion Independence (TI)

    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.

    Measured: From time of drug product infusion up to 24 months

  6. Percentage Change From Baseline in Annualized Number of Packed Red Blood Cells (pRBC) Transfusions at Month 24

    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.

    Measured: Baseline, Month 24

  7. Percentage Change From Baseline in Average Annual Packed Red Blood Cells (pRBC) Transfusion Volume at Month 24

    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.

    Measured: Baseline, Month 24

  8. Weighted Average Nadir Hemoglobin (Hb)

    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.

    Measured: Baseline, Month 6 to Month 24

  9. Number of Participants With Successful Neutrophil Engraftment

    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.

    Measured: From time of drug product infusion up to 24 months

  10. Time to Neutrophil Engraftment

    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.

    Measured: From time of drug product infusion up to 24 months

  11. Number of Participants With Successful Platelet Engraftment

    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.

    Measured: From time of drug product infusion up to 24 months

  12. Time to Platelet Engraftment

    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.

    Measured: From time of drug product infusion up to 24 months

  13. Transplant-related Mortality

    Transplant-related mortality was determined by the investigator (any deaths considered related to the transplant.)

    Measured: Through 100 and 365 days post-LentiGlobin BB305 Drug Product infusion

  14. Overall Survival

    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.

    Measured: From time of drug product infusion up to 24 months

  15. Percentage of Participants Detected With Replication-competent Lentivirus (RCL)

    Blood samples were analyzed for detection of RCL using RCL co-culture assay.

    Measured: From time of drug product infusion up to 24 months

  16. Number of Participants With Integration Site Analysis (ISA) With >30% Clonal Contribution

    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.

    Measured: From time of drug product infusion up to 24 months

  17. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

    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.

    Measured: From signing of informed consent to 24 months after the drug product infusion

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Dec 2012 (estimated)
  2. Study startAug 2013
  3. Primary completion8 Feb 2018
  4. Study completion21 Feb 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
19 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01745120
Sponsor's protocol ID
HGB-204
Status last verified
Apr 2019
First submitted
6 Dec 2012
Last updated
8 May 2019
Data monitoring committee
Yes

Publications

  • Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, Ribeil JA, Hongeng S, Magrin E, Schiller GJ, Payen E, Semeraro M, Moshous D, Lefrere F, Puy H, Bourget P, Magnani A, Caccavelli L, Diana JS, Suarez F, Monpoux F, Brousse V, Poirot C, Brouzes C, Meritet JF, Pondarre C, Beuzard Y, Chretien S, Lefebvre T, Teachey DT, Anurathapan U, Ho PJ, von Kalle C, Kletzel M, Vichinsky E, Soni S, Veres G, Negre O, Ross RW, Davidson D, Petrusich A, Sandler L, Asmal M, Hermine O, De Montalembert M, Hacein-Bey-Abina S, Blanche S, Leboulch P, Cavazzana M. Gene Therapy in Patients with Transfusion-Dependent beta-Thalassemia. N Engl J Med. 2018 Apr 19;378(16):1479-1493. doi: 10.1056/NEJMoa1705342.

    PubMed 29669226

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing LentiGlobin BB305 Drug Product in people with β-thalassemia Major, run by Genetix Biotherapeutics Inc. at 6 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 May 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in United States, Australia, Thailand. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 8 May 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01745120, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 May 2019.

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