Long-term Follow-up of Subjects With Transfusion-Dependent β-Thalassemia (TDT) Treated With Ex Vivo Gene Therapy

• ClinicalTrials.gov Identifier: NCT02633943
• Recruitment Status: Active, not recruiting
• First Posted: December 17, 2015
• Last Update Posted: May 6, 2023
• Sponsor: bluebird bio
• Information provided by (Responsible Party): bluebird bio

Study Description

Brief Summary:

This is a multi-center, long-term safety and efficacy follow-up study for subjects with transfusion-dependent β-thalassemia (TDT) who have been treated with ex vivo gene therapy drug product in bluebird bio-sponsored parent clinical studies. After completing the parent clinical study (approximately 2 years), eligible subjects will be followed for an additional 13 years for a total of 15 years post-drug product infusion. No investigational drug product will be administered in the study.

Condition or disease	Intervention/treatment
Transfusion-dependent Beta-Thalassemia	Other: Safety and efficacy assessments

Study Design

• Study Type: Observational
• Actual Enrollment: 66 participants
• Observational Model: Case-Only
• Time Perspective: Prospective
• Official Title: Long-term Follow-up of Subjects With Transfusion-Dependent β-Thalassemia (TDT) Treated With Ex Vivo Gene Therapy Using Autologous Hematopoietic Stem Cells Transduced With a Lentiviral Vector
• Actual Study Start Date: January 2014
• Estimated Primary Completion Date: November 2035
• Estimated Study Completion Date: November 2035

Groups and Cohorts

Group/Cohort	Intervention/treatment
Subjects with Transfusion-Dependent β-Thalassemia; Subjects treated with ex vivo gene therapy product in an applicable bluebird bio-sponsored clinical trial who agree to participate in this long-term follow-up study	Other: Safety and efficacy assessments; Vector copy number (VCN) measurement, safety evaluations, disease-specific assessments, and assessments to monitor for long-term effects of autologous transplant

Outcome Measures

Primary Outcome Measures :

1. The number of subjects with malignancies [ Time Frame: Up to 15 years post-drug product infusion ]
2. The number of subjects with immune-related AEs [ Time Frame: Up to 15 years post-drug product infusion ]
3. The number of subjects with new or worsening hematologic disorders [ Time Frame: Up to 15 years post-drug product infusion ]
4. The number of subjects with new or worsening neurologic disorders [ Time Frame: Up to 15 years post-drug product infusion ]

Secondary Outcome Measures :

1. βA-T87Q-globin expression [ Time Frame: Up to 15 years post-drug product infusion ]
   Median (min, max) βA-T87Q-globin expression
2. Proportion of subjects treated with beti-cel who achieved Transfusion Independence (TI) [ Time Frame: Up to 15 years post-drug product infusion ]
   Proportion of subjects who achieved TI, defined as a weighted average Hb ≥ 9 g/dL without any packed red blood cell (pRBC) transfusions for a continuous period of ≥ 12 months at any time after drug product infusion in parent study and/or Study LTF-303
3. Proportion of subjects treated with beti-cel who achieved Transfusion Independence at yearly timepoints [ Time Frame: Up to 15 years post-drug product infusion ]
   Proportion of subjects treated with beti-cel who achieved TI at yearly timepoints including Year 5, Year 10, and Year 15 post-drug product infusion, and at last follow-up
4. Time from drug product infusion to achievement of Transfusion Independence (in parent study or Study LTF-303) [ Time Frame: Up to 15 years post-drug product infusion ]
5. Duration of Transfusion Independence [ Time Frame: Up to 15 years post-drug product infusion ]
6. Weighted average Hb during Transfusion Independence [ Time Frame: Up to 15 years post-drug product infusion ]
7. Reduction in annualized pRBC transfusion volume (among subjects who achieved TI), from 6 months post-drug product infusion (parent study) through last follow-up [ Time Frame: Up to 15 years post-drug product infusion ]
   Characterization of Transfusion Reduction based on reduction in annualized pRBC transfusion volume (mL/kg/year) from 6 months post-drug product infusion (parent study) through last follow-up of at least 50%, 60%, 75%, 90%, or 100% as compared to the annualized pRBC transfusion volume during the 2 years prior to parent study enrollment
8. Annualized pRBC transfusion volume, from 6 months post-drug product infusion (parent study) through last follow-up [ Time Frame: Up to 15 years post-drug product infusion ]
   Characterization of Transfusion Reduction based on annualized pRBC transfusion volume (mL/kg/year from 6 months post-drug product infusion (parent study) through last follow-up as compared to the annualized pRBC transfusion requirements during the 2 years prior to parent study enrollment
9. pRBC transfusion frequency, from 6 months post-drug product infusion (parent study) through last follow-up [ Time Frame: Up to 15 years post-drug product infusion ]
   Characterization of Transfusion Reduction based on annualized pRBC frequency (number/year) from 6 months post-drug product infusion (parent study) through last follow-up as compared to the annualized pRBC transfusion requirements during the 2 years prior to parent study enrollment
10. Time from drug product infusion to last pRBC transfusion (in parent study or Study LTF-303) [ Time Frame: Up to 15 years post-drug product infusion ]
11. Time from last pRBC transfusion (in parent study or Study LTF-303) to last follow-up [ Time Frame: Up to 15 years post-drug product infusion ]
12. Weighted average nadir Hb from 6 months post-drug product infusion (parent study) through last follow-up [ Time Frame: Up to 15 years post-drug product infusion ]
    Weighted average nadir Hb from 6 months post-drug product infusion (parent study) through last follow-up as compared to the weighted average nadir Hb during the 2 years prior to parent study enrollment
13. Unsupported total Hb levels over time through last follow-up [ Time Frame: Up to 15 years post-drug product infusion ]
    Unsupported total Hb level is defined as the total Hb measurement level without any acute or chronic pRBC transfusions within 60 days prior to the measurement date.
14. Proportion of subjects with unsupported total Hb levels ≥ 10 g/dL over time through last follow-up, including Year 5, Year 10, and Year 15 [ Time Frame: Up to 15 years post-drug product infusion ]
15. Proportion of subjects with unsupported total Hb levels ≥ 11 g/dL over time through last follow-up, including Year 5, Year 10, and Year 15 [ Time Frame: Up to 15 years post-drug product infusion ]
16. Proportion of subjects with unsupported total Hb levels ≥ 12 g/dL over time through last follow-up, including Year 5, Year 10, and Year 15 [ Time Frame: Up to 15 years post-drug product infusion ]
17. Proportion of subjects with unsupported total Hb levels ≥ 13 g/dL over time through last follow-up, including Year 5, Year 10, and Year 15 [ Time Frame: Up to 15 years post-drug product infusion ]
18. Proportion of subjects with unsupported total Hb levels ≥ 14 g/dL over time through last follow-up, including Year 5, Year 10, and Year 15 [ Time Frame: Up to 15 years post-drug product infusion ]
19. Liver iron content (LIC) by magnetic resonance imaging (MRI)/Superconducting Quantum Interference Device (SQUID) over time at yearly timepoints through last follow-up [ Time Frame: Up to 15 years post-drug product infusion ]
20. Change from parent study baseline in LIC by MRI/SQUID over time at yearly timepoints through last follow-up [ Time Frame: Up to 15 years post-drug product infusion ]
21. Cardiac T2* by MRI over time at yearly timepoints through last follow-up [ Time Frame: Up to 15 years post-drug product infusion ]
22. Change from parent study baseline in cardiac T2* by MRI over time at yearly timepoints through last follow-up [ Time Frame: Up to 15 years post-drug product infusion ]
23. Serum ferritin over time at yearly timepoints through last follow-up [ Time Frame: Up to 15 years post-drug product infusion ]
24. Change from parent study baseline in serum ferritin over time at yearly timepoints through last follow-up [ Time Frame: Up to 15 years post-drug product infusion ]
25. Number of subjects who stopped iron chelation post-DP infusion [ Time Frame: Up to 15 years post-drug product infusion ]
    Defined as subjects who stopped iron chelation or never restarted chelation after DP infusion.
26. Number of subjects who stopped iron chelation for at least 6 months post-drug product infusion [ Time Frame: Up to 15 years post-drug product infusion ]
27. Time from stopping chelation to last follow-up [ Time Frame: Up to 15 years post-drug product infusion ]
    Among subjects that never restart chelation after DP infusion.
28. Proportion of subjects using phlebotomy therapy post-drug product infusion [ Time Frame: Up to 15 years post-drug product infusion ]
29. Annualized frequency of phlebotomy therapy usage [ Time Frame: Up to 15 years post-drug product infusion ]
    Annualized frequency of phlebotomy therapy usage is defined as the number of procedures per year, calculated from DP infusion through last follow-up.
30. Reticulocyte counts over time at yearly timepoints through last follow-up [ Time Frame: Up to 15 years post-drug product infusion ]
31. Change from Baseline in reticulocyte counts at yearly timepoints through last follow-up [ Time Frame: 15 years post-drug product infusion ]
    Baseline defined as value closest, but prior to, conditioning in parent study.
32. Proportion of subject with nucleated RBC over time at yearly timepoints through last follow-up [ Time Frame: Up to 15 years post-drug product infusion ]
33. Change from Baseline in patient reported outcome (PRO) as assessed by Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale (GCS) Score [ Time Frame: 5 years post-drug product infusion ]
34. Change from Baseline in PRO as assessed by EuroQol-5D Youth version (EQ-5D-Y) [ Time Frame: 5 years post-drug product infusion ]
35. Change from Baseline in PRO as assessed by EuroQol-5D (EQ-5D-3L) [ Time Frame: 5 years post-drug product infusion ]
36. Change From Baseline in PRO as assessed by Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Questionnaire Score [ Time Frame: 5 years post-drug product infusion ]
37. Change from Baseline in PRO as assessed by Short Form-36 Health Survey (SF-36) [ Time Frame: 5 years post-drug product infusion ]

Eligibility Criteria

• Ages Eligible for Study: 0 Years to 50 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Subjects with transfusion-dependent β-thalassemia who have been treated with ex vivo gene therapy product in bluebird bio-sponsored clinical studies

Criteria

Inclusion Criteria:

• Provision of written informed consent for this study by subjects, or as applicable, subject's parent(s)/legal guardian(s)
• Treated with drug product for therapy of transfusion-dependent β-thalassemia in a bluebird bio-sponsored clinical study

Exclusion Criteria:

• There are no exclusion criteria for this study

Contacts and Locations

Locations

United States, California

Oakland, California, United States

United States, Illinois

Chicago, Illinois, United States

United States, Maryland

Bethesda, Maryland, United States

United States, New York

New York, New York, United States

United States, Pennsylvania

Philadelphia, Pennsylvania, United States

United States, South Carolina

Charleston, South Carolina, United States

Australia

Sydney, Australia

France

Marseille, France

Paris, France

Germany

Hannover, Germany

Heidelberg, Germany

Greece

Thessaloníki, Greece

Italy

Rome, Italy

Thailand

Bangkok, Thailand

United Kingdom

London, United Kingdom

Sponsors and Collaborators

bluebird bio

Investigators

• Study Director: Himal L Thakar, MD; bluebird bio, Inc.

More Information

Additional Information:

HGB-204 Clinicaltrials.gov 

HGB-205 Clinicaltrials.gov 

HGB-207 Clinicaltrials.gov 

HGB-212 Clinicaltrials.gov 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Magrin E, Semeraro M, Hebert N, Joseph L, Magnani A, Chalumeau A, Gabrion A, Roudaut C, Marouene J, Lefrere F, Diana JS, Denis A, Neven B, Funck-Brentano I, Negre O, Renolleau S, Brousse V, Kiger L, Touzot F, Poirot C, Bourget P, El Nemer W, Blanche S, Treluyer JM, Asmal M, Walls C, Beuzard Y, Schmidt M, Hacein-Bey-Abina S, Asnafi V, Guichard I, Poiree M, Monpoux F, Touraine P, Brouzes C, de Montalembert M, Payen E, Six E, Ribeil JA, Miccio A, Bartolucci P, Leboulch P, Cavazzana M. Long-term outcomes of lentiviral gene therapy for the beta-hemoglobinopathies: the HGB-205 trial. Nat Med. 2022 Jan;28(1):81-88. doi: 10.1038/s41591-021-01650-w. Epub 2022 Jan 24.

• Responsible Party: bluebird bio
• ClinicalTrials.gov Identifier: NCT02633943
• Other Study ID Numbers: LTF-303
• First Posted: December 17, 2015
• Last Update Posted: May 6, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Bluebird bio is committed to transparency and appropriately de-identified subject-level datasets and supporting documents may be shared after all participants have completed study participation and following attainment of applicable marketing approvals associated with a given study and consistent with criteria established by bluebird bio and/or industry best practices to maintain the privacy of study participants. For enquiries, please contact us at datasharing@bluebirdbio.com.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Thalassemia; beta-Thalassemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn