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A Study Evaluating the Safety and Efficacy of bb1111 in Severe Sickle Cell Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02140554
Recruitment Status : Active, not recruiting
First Posted : May 16, 2014
Last Update Posted : August 2, 2021
Sponsor:
Information provided by (Responsible Party):
bluebird bio

Tracking Information
First Submitted Date  ICMJE May 14, 2014
First Posted Date  ICMJE May 16, 2014
Last Update Posted Date August 2, 2021
Actual Study Start Date  ICMJE August 2014
Estimated Primary Completion Date May 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 16, 2020)
sVOE-CR [ Time Frame: 6-18 months post-transplant ]
Proportion of subjects achieving complete resolution of severe vaso-occlusive events, between 6 months and 18 months after drug product infusion
Original Primary Outcome Measures  ICMJE
 (submitted: May 14, 2014)
Safety [ Time Frame: 1-24 months post-transplant ]
Safety will be evaluated by the following:
  • success and kinetics of hematopoietic stem cell (HSC) engraftment
  • incidence of treatment related mortality
  • incidence of mortality through 2 years after drug product infusion
  • detection of vector derived replication competent lentivirus (RCL) in any subject
  • characterization of events of insertional mutagenesis leading to malignancy
  • monitoring of laboratory parameters and frequency and severity of clinical AEs, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 16, 2020)
  • Proportion of Subjects achieving Globin Response [ Time Frame: 6-24 months post-transplant ]
    Globin Response, defined as meeting the following criteria for a continuous period of at least 6 months after drug product infusion:
    1. Weighted average HbAT87Q percentage of non-transfused total Hb ≥30% AND
    2. Weighted average non-transfused total Hb increase of ≥3 g/dL compared to baseline total Hb OR weighted average non-transfused total Hb ≥10 g/dL
  • Proportion of subjects who meet the definition of Globin Response at Month 24 [ Time Frame: Month 24 post-transplant ]
  • Duration of Globin Response [ Time Frame: 6-24 months post-transplant ]
  • Weighted average non-transfused total Hb [ Time Frame: Month 6, 12, 18, and 24 post-transplant ]
  • Weighted average HbS percentage of non-transfused total Hb [ Time Frame: Month 6, 12, 18, and 24 post-transplant ]
  • Weighted average HbS percentage of non-transfused total Hb ≤ 70%, ≤ 60%, ≤ 50% [ Time Frame: Month 6, 12, 18, and 24 post-transplant ]
  • Weighted average HbAT87Q percentage of non-transfused total Hb [ Time Frame: Month 6, 12, 18, and 24 post-transplant ]
  • Weighted average non-HbS percentage of non-transfused total Hb [ Time Frame: Month 6, 12, 18, and 24 post-transplant ]
  • Average and median of non-transfused total Hb over time [ Time Frame: Through Month 24 post-transplant ]
  • Average and median of HbS percentage of non-transfused total Hb over time [ Time Frame: Through Month 24 post-transplant ]
  • Average and median of HbAT87Q percentage of non-transfused total Hb over time [ Time Frame: Through Month 24 post-transplant ]
  • Average and median of non-HbS percentage of non-transfused total Hb over time [ Time Frame: Through Month 24 post-transplant ]
  • Change from baseline in hemolysis markers [ Time Frame: Through Month 24 post-transplant ]
  • Change from baseline in markers of iron stores [ Time Frame: Through Month 24 post-transplant ]
  • Change from baseline in annualized frequency and volume of packed red blood cell (pRBC) transfusions [ Time Frame: 6 - 24 months post-transplant ]
  • Change from baseline in markers of stress erythropoiesis [ Time Frame: Through Month 24 post-transplant ]
  • Change in the annualized number of vaso-occlusive events (VOEs) in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent [ Time Frame: Through Month 24 post-transplant ]
  • sVOE-CR24 [ Time Frame: 6-24 months post-transplant ]
    Proportion of subjects achieving complete resolution of severe VOEs between 6 months and 24 months after drug product infusion
  • VOE-CR24 [ Time Frame: 6-24 months post-transplant ]
    Proportion of subject achieving complete resolution of VOEs between 6 months and 24 months after drug product infusion
  • VOE-CR [ Time Frame: 6-18 months post-transplant ]
    Proportion of subjects achieving complete resolution of VOEs between 6 months and 18 months after drug product infusion
  • sVOE-75 [ Time Frame: Through Month 24 post-transplant ]
    Proportion of subjects achieving a 75% reduction in annualized severe VOEs in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent
  • Change in the annualized number of severe VOEs in the 24 months after drug product infusion as compared to the 24 months prior to informed consent [ Time Frame: Through Month 24 post-transplant ]
  • Change from baseline in renal function as measured by eGFR [ Time Frame: Through Month 24 post-transplant ]
  • Change from baseline in cardiac-pulmonary function via echocardiogram (tricuspid regurgitant jet velocity [TRJV], LVEF) [ Time Frame: Through Month 24 post-transplant ]
  • Change from baseline in cardiac-pulmonary function via pulmonary function tests [ Time Frame: Through Month 24 post-transplant ]
  • Change from baseline in meters walked during 6-minute walk test [ Time Frame: Through Month 24 post-transplant ]
  • Change from baseline in annualized hospital admissions [ Time Frame: From post-transplant hospital discharge to Month 24 post-transplant ]
  • Change from baseline in annualized total days hospitalized [ Time Frame: From post-transplant hospital discharge to Month 24 post-transplant ]
  • Change from baseline in patient-reported quality of life, as measured by Patient Reported Outcomes Measurement Information System (PROMIS) [ Time Frame: Month 3, 6, 12, 18, and 24 post-transplant ]
Original Secondary Outcome Measures  ICMJE
 (submitted: May 14, 2014)
Clinical efficacy will be evaluated by comparing the frequency of clinical events secondary to sickle cell disease [ Time Frame: 1-24 months post-transplant ]
Efficacy will be evaluated by the following:
  • severe vaso-occlusive crisis (VOC). A severe VOC is defined as an episode of pain lasting more than 2 hours severe enough to require care at a medical facility. Priapism that lasts more than 2 hours and requires care at a medical facility is considered a severe VOC
  • acute chest syndrome events, defined as an acute event with pneumonia like symptoms and the presence of a new pulmonary infiltrate
  • strokes or transient ischemic attacks
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study Evaluating the Safety and Efficacy of bb1111 in Severe Sickle Cell Disease
Official Title  ICMJE A Phase 1/2 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With the LentiGlobin BB305 Lentiviral Vector in Subjects With Severe Sickle Cell Disease
Brief Summary This is a non-randomized, open label, multi-site, single dose, Phase 1/2 study in approximately 50 adults and adolescents with severe SCD. The study will evaluate hematopoietic stem cell (HSC) transplantation (HSCT) using bb1111 (also known as LentiGlobin BB305 Drug Product for SCD).
Detailed Description Subject participation for this study will be 2 years post-transplant. 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 an additional 13 years for a total of 15 years post-drug product infusion.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Sickle Cell Disease
Intervention  ICMJE Genetic: bb1111
bb1111 is administered by IV infusion following myeloablative conditioning with busulfan.
Other Names:
  • LentiGlobin BB305 Drug Product for SCD
  • autologous CD34+ cell-enriched population from patients with SCD that contains HSCs transduced with BB305 lentiviral vector encoding the βA-T87Q-globin gene, suspended in cryopreservation solution
Study Arms  ICMJE
  • Experimental: Group A

    Subjects will have rescue cells collected by bone marrow harvest, and will receive treatment of bb1111 manufactured with autologous CD34+ hematopoietic stem cells (HSCs) collected by bone marrow harvest transduced with BB305 lentiviral vector encoding the human beta-A-T87Q globin gene.

    *No Longer Recruiting

    Intervention: Genetic: bb1111
  • Experimental: Group B

    Group B1:

    Subjects will have rescue cells collected by bone marrow harvest, and will receive treatment of bb1111 manufactured with autologous CD34+ hematopoietic stem cells (HSCs) collected by bone marrow harvest transduced with BB305 lentiviral vector encoding the human beta-A-T87Q globin gene.

    *No Longer Recruiting

    Group B2:

    Plerixafor mobilization and apheresis will be used for collection of rescue cells and exploratory manufacturing development. Subjects will receive treatment of bb1111 manufactured with autologous CD34+ hematopoietic stem cells (HSCs) collected by bone marrow harvest transduced with BB305 lentiviral vector encoding the human beta-A-T87Q globin gene.

    *No Longer Recruiting

    Intervention: Genetic: bb1111
  • Experimental: Group C
    Plerixafor mobilization and apheresis will be used for collection of rescue cells, and subjects will receive treatment of bb1111 manufactured with autologous CD34+ hematopoietic stem cells (HSCs) collected by plerixafor mobilization and apheresis transduced with BB305 lentiviral vector encoding the human beta-A-T87Q globin gene.
    Intervention: Genetic: bb1111
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: November 7, 2018)
50
Original Estimated Enrollment  ICMJE
 (submitted: May 14, 2014)
8
Estimated Study Completion Date  ICMJE December 2023
Estimated Primary Completion Date May 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Be ≥12 and ≤50 of age at time of consent.
  2. Diagnosis of sickle cell disease (SCD), with either βS/βS or βS/β0 or βS/β+ genotype.
  3. Have severe SCD. i.e., in the setting of appropriate supportive care measures for SCD (e.g.,pain management plan) have experienced at least 4 severe VOEs in the 24 months prior to informed consent.

    For the purposes of this study, a severe VOE is defined as an event with no medically determined cause other than a vaso-occlusion, requiring a ≥ 24-hour hospital or Emergency Room (ER) observation unit visit or at least 2 visits to a day unit or ER over 72 hours with both visits requiring intravenous treatment. Exception: priapism does not require hospital admission but does require a medical facility visit; 4 priapism episodes that require a visit to a medical facility (without inpatient admission) are sufficient to meet criterion.

  4. Karnofsky performance status of ≥ 60 (≥16 years of age) or a Lansky performance status of ≥60 (<16 years of age).
  5. Have either experienced hydroxyurea (HU) failure at any point in the past or must have intolerance to HU (defined as patient being unable to continue to take HU per PI judgement).
  6. Have been treated and followed for at least the past 24 months prior to Informed Consent in medical center(s) that maintained detailed records on SCD history.

Exclusion Criteria:

  1. Positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 and HIV-2), hepatitis B virus (HBV), or hepatitis C (HCV).
  2. Clinically significant and active bacterial, viral, fungal, or parasitic infection.
  3. Inadequate bone marrow function, as defined by an absolute neutrophil count of < 1000/µL (< 500/µL for subjects on HU treatment) or a platelet count < 120,000/µL (without hypersplenism).
  4. Any history of severe cerebral vasculopathy: defined by overt or hemorrhagic stroke; abnormal transcranial Doppler [≥200 cm/sec] needing chronic transfusion; or occlusion or stenosis in the polygon of Willis; or presence of Moyamoya disease. Subjects with radiologic evidence of silent infarction in the absence of any of the above criteria would still be eligible
  5. Advanced liver disease, defined as:

    1. Persistent aspartate transaminase, alanine transaminase, or direct bilirubin value >3× the upper limit of normal (ULN), or
    2. Baseline prothrombin time or partial thromboplastin time >1.5× ULN, suspected of arising from liver disease, or
    3. Magnetic Resonance Imaging (MRI) of the liver demonstrating clear evidence of cirrhosis, or
    4. MRI findings suggestive of active hepatitis, significant fibrosis, inconclusive evidence of cirrhosis, or liver iron concentration ≥15 mg/g require follow-up liver biopsy in subjects ≥18 years of age. In subjects <18 years of age, these MRI findings are exclusionary, unless in the opinion of the Investigator, a liver biopsy could provide additional data to confirm eligibility and would be safe to perform. If a liver biopsy is performed based on MRI findings, any evidence of cirrhosis, bridging fibrosis, or significant active hepatitis will be exclusionary.
  6. Any contraindications to the use of 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.
  7. Any prior or current malignancy or immunodeficiency disorder, except previously treated, non-life threatening, cured tumors such as squamous cell carcinoma of the skin.
  8. Prior receipt of an allogeneic transplant.
  9. Immediate family member with a known or suspected Familial Cancer Syndrome.
  10. Diagnosis of significant psychiatric disorder of the subject that, in the Investigator's judgment, could seriously impede the ability to participate in the study.
  11. Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile subjects.
  12. Participation in another clinical study with an investigational drug within 30 days of Screening.
  13. Prior receipt of gene therapy.
  14. Patients needing curative anticoagulation therapy during the period of conditioning through platelet engraftment (patients on prophylactic doses of anticoagulants are eligible).
  15. Unable to receive RBC transfusion.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years to 50 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02140554
Other Study ID Numbers  ICMJE HGB-206
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party bluebird bio
Study Sponsor  ICMJE bluebird bio
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Richard Colvin, MD bluebird bio, Inc.
PRS Account bluebird bio
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP