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    Clinical Trial Results:
    A Phase 3 Single Arm Study Evaluating the Efficacy and Safety of Gene Therapy in Subjects with Transfusion-dependent β-Thalassemia, who do not have a β0/β0 Genotype, by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo with a Lentiviral βA-T87Q-Globin Vector in Subjects ≤50 Years of Age

    Summary
    EudraCT number
    2015-004122-33
    Trial protocol
    IT   DE   GR   GB   FR  
    Global end of trial date
    31 Mar 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Oct 2022
    First version publication date
    04 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HGB-207
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02906202
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bluebird bio, Inc.
    Sponsor organisation address
    455 Grand Union Blvd, Somerville, United States, MA 02145
    Public contact
    Clinical Trials Operations, bluebird bio, Inc., 001 3394999300, clinicaltrials@bluebirdbio.com
    Scientific contact
    Clinical Trials Operations, bluebird bio, Inc., 001 3394999300, clinicaltrials@bluebirdbio.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001665-PIP01-14
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Mar 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary purpose of the study was to evaluate the efficacy of treatment with LentiGlobin BB305 Drug Product (betibeglogene autotemcel) in subjects less than or equal to (<=) 50 of age with transfusion-dependent β-thalassemia (TDT), who do not have β0/β0 genotype at the β-globin (HBB) gene.
    Protection of trial subjects
    This study was performed in accordance with Title 21, United States (US) Code of Federal Regulations (CFR) Parts 50, 54, 56, and 312 Subpart D; the International Council for Harmonisation (ICH) Guideline on Good Clinical Practice (GCP; E6); and the ethical principles outlined in the Declaration of Helsinki; and/or, where applicable, the European Directive 2001/20/EC relating to implementation of GCP in the conduct of clinical trials on medicinal products for human use and Directive 2005/28/EC on GCP for investigational medicinal products for human use.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Aug 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    13 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Thailand: 2
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    United States: 9
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Italy: 7
    Worldwide total number of subjects
    24
    EEA total number of subjects
    9
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    8
    Adolescents (12-17 years)
    6
    Adults (18-64 years)
    10
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 9 centers from 08 August 2016 to 31 March 2022.

    Pre-assignment
    Screening details
    A total of 24 subjects were enrolled, of which 23 subjects aged <= 50 years were treated of LentiGlobin BB305 Drug Product.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    LentiGlobin BB305 Drug Product
    Arm description
    Subjects <= 50 years of age received a single intravenous (IV) infusion of LentiGlobin BB305 Drug Product at a dose of >= 5.0 × 10^6 CD34+ cells/kilogram (kg) following myeloablative conditioning with busulfan (termed the Transplant population). As appropriate, data are analysed at times based on Intent-to-Treat (ITT) population which included all 24 subjects who initiated any study procedures, beginning with mobilization by G-CSF and/or plerixafor.
    Arm type
    Experimental

    Investigational medicinal product name
    LentiGlobin BB305 Drug Product
    Investigational medicinal product code
    Other name
    betibeglogene autotemcel, beti-cel
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a single IV infusion of >=5.0 x 10^6 CD34+ cells/kg of LentiGlobin BB305 Drug Product.

    Number of subjects in period 1
    LentiGlobin BB305 Drug Product
    Started
    24
    Completed
    23
    Not completed
    1
         Discontinued after mobilization due to pregnancy
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall study (overall period)
    Reporting group description
    Subjects <= 50 years of age received a single intravenous (IV) infusion of LentiGlobin BB305 Drug Product at a dose of >= 5.0 × 10^6 CD34+ cells/kilogram (kg) following myeloablative conditioning with busulfan (termed the Transplant population). As appropriate, data are analysed at times based on Intent-to-Treat (ITT) population which included all 24 subjects who initiated any study procedures, beginning with mobilization by G-CSF and/or plerixafor.

    Reporting group values
    Overall study (overall period) Total
    Number of subjects
    24 24
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    15.0 (4 to 34) -
    Gender categorical
    Units: Subjects
        Female
    13 13
        Male
    11 11
    Race
    Units: Subjects
        Asian
    14 14
        White
    8 8
        Other
    2 2
        American Indian or Alaska Native
    0 0
        Black or African American
    0 0
        Native Hawaiian or Other Pacific Islander
    0 0
        Not Provided
    0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    1 1
        Not Hispanic or Latino
    22 22
        Not Provided
    1 1

    End points

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    End points reporting groups
    Reporting group title
    LentiGlobin BB305 Drug Product
    Reporting group description
    Subjects <= 50 years of age received a single intravenous (IV) infusion of LentiGlobin BB305 Drug Product at a dose of >= 5.0 × 10^6 CD34+ cells/kilogram (kg) following myeloablative conditioning with busulfan (termed the Transplant population). As appropriate, data are analysed at times based on Intent-to-Treat (ITT) population which included all 24 subjects who initiated any study procedures, beginning with mobilization by G-CSF and/or plerixafor.

    Primary: Percentage of Subjects who Meet the Definition of Transfusion Independence (TI)

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    End point title
    Percentage of Subjects who Meet the Definition of Transfusion Independence (TI) [1]
    End point description
    TI was defined as a weighted average hemoglobin (Hb) >= 9 grams per deciliter (g/dL) without any packed red blood cell (pRBC) transfusions for a continuous period of >= 12 months at any time during the study after drug product infusion. Transplant Population (TP) included all subjects who received beti-cel. Subjects evaluable for TI are defined as subjects who have achieved TI, will not achieve TI in their parent study, or completed their parent study.
    End point type
    Primary
    End point timeframe
    From 14 to 24 months post-transplant
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were performed; no inferential statistical analyses were performed.
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    23
    Units: percentage of subjects
        number (confidence interval 95%)
    91.3 (72.0 to 98.9)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who Meet the Definition of Transfusion Independence (TI) at Month 24

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    End point title
    Percentage of Subjects who Meet the Definition of Transfusion Independence (TI) at Month 24
    End point description
    TI was defined as a weighted average hemoglobin (Hb) >= 9 grams per deciliter (g/dL) without any packed red blood cell (pRBC) transfusions for a continuous period of >= 12 months at any time during the study after drug product infusion. Percentage of subjects who met the definition of TI at Month 24 were evaluated. TP included all subjects who received beti-cel. Subjects evaluable for TI are defined as subjects who have achieved TI, will not achieve TI in their parent study, or completed their parent study.
    End point type
    Secondary
    End point timeframe
    At Month 24 post-transplant
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    23
    Units: percentage of subjects
        number (confidence interval 95%)
    91.3 (72.0 to 98.9)
    No statistical analyses for this end point

    Secondary: Duration of Transfusion Independence (TI)

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    End point title
    Duration of Transfusion Independence (TI)
    End point description
    Duration of TI was calculated as the time from the start of TI (i.e. first Hb >=9 with no transfusions in the preceding 60 days) up to the last available Hb at which the TI criteria are still met using Kaplan-Meier methodology. Duration of TI from start of TI up to Month 24 months was reported. TP included all subjects who received beti-cel. Subjects evaluable for TI are defined as subjects who have achieved TI, will not achieve TI in their parent study, or completed their parent study.
    End point type
    Secondary
    End point timeframe
    From start of TI up to Month 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    23
    Units: months
        median (full range (min-max))
    20.50 (18.2 to 22.5)
    No statistical analyses for this end point

    Secondary: Time From Drug Product Infusion to Achievement of Transfusion Independence (TI)

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    End point title
    Time From Drug Product Infusion to Achievement of Transfusion Independence (TI)
    End point description
    Time from drug product infusion to achievement of TI was calculated as the time from drug product infusion to the first hemoglobin at which a subject can be declared as TI (that is to 'start of TI + >= 12 months', dependent on Hb lab schedule). TP included all subjects who received beti-cel. Here, “number of subjects analysed” signifies those subjects who achieved TI.
    End point type
    Secondary
    End point timeframe
    From 14 months post-drug product infusion through Month 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    21
    Units: months
        median (full range (min-max))
    15.51 (14.8 to 19.4)
    No statistical analyses for this end point

    Secondary: Weighted Average Hemoglobin (Hb) During Transfusion Independence (TI)

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    End point title
    Weighted Average Hemoglobin (Hb) During Transfusion Independence (TI)
    End point description
    Weighted Hb was defined as an average area under the curve where the Hb closest but within 3 days prior to a transfusion was used as the Hb. Weighted average Hb during TI from 2 months post-drug product infusion through the Month 24 was reported. TP included all subjects who received beti-cel. Here, “number of subjects analysed” signifies those subjects who achieved TI.
    End point type
    Secondary
    End point timeframe
    From 60 days after the last pRBC transfusion through Month 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    21
    Units: grams per deciliter (g/dL)
        arithmetic mean (standard deviation)
    11.473 ± 1.0395
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who had a Reduction of At least 50%, 60%, 75%, 90% or 100% in the Annualized pRBCs Transfusion Volume

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    End point title
    Percentage of Subjects who had a Reduction of At least 50%, 60%, 75%, 90% or 100% in the Annualized pRBCs Transfusion Volume
    End point description
    Percentage of subjects with a reduction in the annualized mL/kg pRBCs transfused from 12 months post-drug product infusion through Month 24 (approximately a 12-month period) of at least 50%, 60%, 75%, 90% or 100% compared to the annualized mL/kg pRBC transfusion requirement during the 24 months prior to enrollment. TP included all subjects who received beti-cel.
    End point type
    Secondary
    End point timeframe
    12 months post-drug product infusion through Month 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    23
    Units: percentage of subjects
    number (not applicable)
        Reduction at >= 50%
    95.7
        Reduction at >= 60%
    91.3
        Reduction at >= 75%
    91.3
        Reduction at >= 90%
    91.3
        Reduction at 100%
    91.3
    No statistical analyses for this end point

    Secondary: Annualized Volume of pRBC Transfusions

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    End point title
    Annualized Volume of pRBC Transfusions
    End point description
    Annualized volume of pRBC transfusions from 12 months post-drug product infusion through Month 24 was reported. TP included all subjects who received beti-cel.
    End point type
    Secondary
    End point timeframe
    From 12 months post-drug product infusion through Month 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    23
    Units: milliliter/kilogram/year (mL/kg/year)
        arithmetic mean (standard deviation)
    11.607 ± 40.2964
    No statistical analyses for this end point

    Secondary: Time from Drug Product Infusion to Last pRBC Transfusion

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    End point title
    Time from Drug Product Infusion to Last pRBC Transfusion
    End point description
    Time from drug product infusion to last pRBC transfusion was reported. TP included all subjects who received beti-cel.
    End point type
    Secondary
    End point timeframe
    From start of drug product infusion up to Month 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    23
    Units: months
        median (full range (min-max))
    0.953 (0.46 to 23.98)
    No statistical analyses for this end point

    Secondary: Time From Last pRBC Transfusion to the Month 24

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    End point title
    Time From Last pRBC Transfusion to the Month 24
    End point description
    Time From Last pRBC Transfusion to the Month 24 was reported. TP included all subjects who received beti-cel.
    End point type
    Secondary
    End point timeframe
    From last pRBC Transfusion up to Month 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    23
    Units: months
        median (full range (min-max))
    23.228 (0.07 to 26.64)
    No statistical analyses for this end point

    Secondary: Weighted Average Nadir Hemoglobin (Hb)

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    End point title
    Weighted Average Nadir Hemoglobin (Hb)
    End point description
    The weighted average nadir Hb was defined as the most recent Hb prior to each pRBC transfusion, on the day of transfusion or within 3 days and, if there was a period of more than 60 days without transfusion, all Hb records between Day 61 and last follow-up or next transfusion (inclusive) was included. The weighted average nadir Hb during the period of 12 months post-drug product infusion to Month 24 was compared to the weighted average nadir Hb during the 24 months prior to enrollment. TP included all subjects who received beti-cel.
    End point type
    Secondary
    End point timeframe
    12 months post-drug product infusion through Month 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    23
    Units: g/dL
        arithmetic mean (standard deviation)
    9.546 ± 0.7007
    No statistical analyses for this end point

    Secondary: Unsupported Total Hb Levels at Month 6, 9, 12, 18 and 24

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    End point title
    Unsupported Total Hb Levels at Month 6, 9, 12, 18 and 24
    End point description
    Unsupported total Hb level was defined as the total Hb measurement level without any acute or chronic pRBC transfusions within 60 days prior to the measurement date. TP consisted of subjects who received LentiGlobin BB305 Drug Product infusion. Here, “number of subjects analysed” signifies those subjects who were evaluable for this endpoint and “n” signifies those subjects who were evaluable at specific timepoint.
    End point type
    Secondary
    End point timeframe
    At Month 6, 9, 12, 18 and 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    22
    Units: g/dL
    arithmetic mean (standard deviation)
        At Month 6 (n=22)
    11.24 ± 1.249
        At Month 9 (n=22)
    11.22 ± 1.138
        At Month 12 (n=21)
    11.45 ± 1.314
        At Month 18 (n=19)
    11.80 ± 1.167
        At Month 24 (n=20)
    11.77 ± 1.224
    No statistical analyses for this end point

    Secondary: Number of Subjects with Unsupported Total Hb Levels (>=10 g/dL, >=11 g/dL, >=12 g/dL, >=13 g/dL, and >=14 g/dL) at Months 6, 9, 12, 18 and 24

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    End point title
    Number of Subjects with Unsupported Total Hb Levels (>=10 g/dL, >=11 g/dL, >=12 g/dL, >=13 g/dL, and >=14 g/dL) at Months 6, 9, 12, 18 and 24
    End point description
    The number of subjects with unsupported total Hb levels (>=10 g/dL, >=11 g/dL, >=12 g/dL, >=13 g/dL, and >=14 g/dL) meeting the thresholds were reported at at Months 6, 9, 12, 18 and 24. TP included all subjects who received beti-cel. Here, “number of subjects analysed” signifies those subjects who were evaluable for this endpoint and “n” signifies those subjects who were evaluable at specific timepoint. Subjects were evaluable if they had an unsupported total Hb measurement at the specific timepoint, where 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.
    End point type
    Secondary
    End point timeframe
    At Month 6, 9, 12, 18 and 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    22
    Units: subjects
        At Month 6 (>=10 g/dL) (n=22)
    17
        At Month 6 (>=11 g/dL) (n=22)
    15
        At Month 6 (>=12 g/dL) (n=22)
    7
        At Month 6 (>=13 g/dL) (n=22)
    1
        At Month 6 (>=14 g/dL) (n=22)
    0
        At Month 9 (>=10 g/dL) (n=22)
    20
        At Month 9 (>=11 g/dL) (n=22)
    14
        At Month 9 (>=12 g/dL) (n=22)
    5
        At Month 9 (>=13 g/dL) (n=22)
    1
        At Month 9 (>=14 g/dL) (n=22)
    0
        At Month 12 (>=10 g/dL) (n=21)
    18
        At Month 12 (>=11 g/dL) (n=21)
    14
        At Month 12 (>=12 g/dL) (n=21)
    10
        At Month 12 (>=13 g/dL) (n=21)
    1
        At Month 12 (>=14 g/dL) (n=21)
    0
        At Month 18 (>=10 g/dL) (n=19)
    18
        At Month 18 (>=11 g/dL) (n=19)
    15
        At Month 18 (>=12 g/dL) (n=19)
    8
        At Month 18 (>=13 g/dL) (n=19)
    4
        At Month 18 (>=14 g/dL) (n=19)
    0
        At Month 24 (>=10 g/dL) (n=20)
    18
        At Month 24 (>=11 g/dL) (n=20)
    14
        At Month 24 (>=12 g/dL) (n=20)
    10
        At Month 24 (>=13 g/dL) (n=20)
    5
        At Month 24 (>=14 g/dL) (n=20)
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Have Not Received Chelation Therapy for At Least 6 Months Following Drug Product Infusion

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    End point title
    Percentage of Subjects Who Have Not Received Chelation Therapy for At Least 6 Months Following Drug Product Infusion
    End point description
    Percentage of subjects who have not received chelation therapy for at least 6 months following drug product infusion were reported. TP included all subjects who received beti-cel.
    End point type
    Secondary
    End point timeframe
    Up to Month 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    23
    Units: percentage of subjects
        number (not applicable)
    43.5
    No statistical analyses for this end point

    Secondary: Time from Last Iron Chelation Use to Last Follow-up

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    End point title
    Time from Last Iron Chelation Use to Last Follow-up
    End point description
    Time from last iron chelation use to last follow-up to 24 months was reported. TP included all subjects who received beti-cel. Here, “number of subjects analysed” signifies those subjects who were evaluable for this endpoint. Subjects were evaluable for this endpoint if they had not received iron chelation therapy for at least 6 months following drug product infusion.
    End point type
    Secondary
    End point timeframe
    Up to Month 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    10
    Units: months
        median (full range (min-max))
    23.56 (17.6 to 24.6)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who Used Therapeutic Phlebotomy Post DP infusion

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    End point title
    Percentage of Subjects who Used Therapeutic Phlebotomy Post DP infusion
    End point description
    Therapeutic phlebotomy could be used in lieu of chelation in subjects who had Hb consistently >= 11 g/dL and who were no longer receiving regular transfusions, at the discretion of the investigator. Percentage of subjects who used therapeutic phlebotomy post DP infusion for up to Month 24 were reported. TP included all subjects who received beti-cel.
    End point type
    Secondary
    End point timeframe
    Up to Month 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    23
    Units: percentage of subjects
        number (not applicable)
    30.4
    No statistical analyses for this end point

    Secondary: Change From Baseline in liver Iron Concentration by Magnetic Resonance Imaging (MRI)

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    End point title
    Change From Baseline in liver Iron Concentration by Magnetic Resonance Imaging (MRI)
    End point description
    Change From Baseline in liver Iron Content by Magnetic Resonance Imaging (MRI) at Months 12 and 24 were reported.TP included all subjects who received beti-cel. Here, “number of subjects analysed” signifies those subjects who were evaluable for this endpoint. Subjects were evaluable for this endpoint if they had available liver iron content measurements at baseline and at the applicable follow-up timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12 and 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    22
    Units: milligrams per gram (mg/g)
    arithmetic mean (standard deviation)
        At Month 12
    2.490 ± 4.1546
        At Month 24
    0.494 ± 3.9957
    No statistical analyses for this end point

    Secondary: Change From Baseline in Cardiac T2* on MRI

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    End point title
    Change From Baseline in Cardiac T2* on MRI
    End point description
    Change From Baseline in Cardiac T2* on MRI at baseline, month 12 and 24 was reported. TP included all subjects who received beti-cel. Here, “number of subjects analysed” signifies those subjects who were evaluable for this endpoint and “n” signifies those subjects who were evaluable at specific timepoint. Subjects were evaluable for this endpoint if they had available cardiac T2* measurements at baseline and at the applicable follow-up timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12 and 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    21
    Units: milliseconds
    arithmetic mean (standard deviation)
        At Month 12 (n=19)
    -1.0 ± 5.93
        At Month 24 (n=21)
    -1.6 ± 7.42
    No statistical analyses for this end point

    Secondary: Change From Baseline in Serum Ferritin at Months 12 and 24

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    End point title
    Change From Baseline in Serum Ferritin at Months 12 and 24
    End point description
    Serum ferritin was commonly used for an indirect estimation of body iron stores. Although sensitive, it is not specific for iron overload as it can be elevated in a variety of infectious and inflammatory states, and in the presence of cytolysis. Change from baseline in serum ferritin at months 12 and 24 was reported. TP included all subjects who received beti-cel. Subjects were evaluable for this endpoint if they had available serum ferritin measurements at baseline and at the applicable follow-up timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12 and 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    23
    Units: picomole per Liter (pmol/L)
    arithmetic mean (standard deviation)
        At Month 12 (n=22)
    167.3 ± 1887.67
        At Month 24 (n=23)
    -1163.8 ± 2435.58
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Total Scores at Months 12 and 24

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    End point title
    Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Total Scores at Months 12 and 24
    End point description
    PedsQL GCS designed to measure health-related quality of life in pediatric and adolescents (2 to 18 years). It encompassed 4 dimensions of functioning (physical [8 items], emotional [5 items], social [5 items], school [3 items]). Age groups: Toddler (2-4 years), Young pediatric (5-7 years), Pediatric (8-12 years), Teens (13-18 years). Depending on subject's age, questionnaire was completed by parent/caregiver as appropriate. For Toddler group, consisted of 21 items, using a 5-point Likert scale (0 to 4); for all other groups, consisted of 23 items, with a 3-point Likert scale (0, 2, 4) for young pediatric, a 5-point Likert scale for pediatric and teens groups. All scores were transformed on a scale from 0 to 100 where 0=100, 1=75, 2=50, 3=25, and 4=0. Higher scores means improved quality of life. TP population. Here, “number of subjects analysed” signifies those subjects who were evaluable for this endpoint and “n” signifies those subjects who were evaluable at specific timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12 and 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    14
    Units: score on a scale
    arithmetic mean (standard deviation)
        Parent total score: Change at Month 12 (n=12)
    8.76 ± 12.071
        Parent total score: Change at Month 24 (n=14)
    6.03 ± 9.753
        Patient total score: Change at Month 12 (n=11)
    6.82 ± 16.079
        Patient total score: Change at Month 24 (n=12)
    9.96 ± 16.997
    No statistical analyses for this end point

    Secondary: Change From Baseline in EuroQol Quality of Life 5-Dimension Youth Scale (EQ-5D-Y) VAS Health Status at Months 12 and 24

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    End point title
    Change From Baseline in EuroQol Quality of Life 5-Dimension Youth Scale (EQ-5D-Y) VAS Health Status at Months 12 and 24
    End point description
    EQ-5D was validated, standardized, generic instrument that is most widely used preference based health related quality of life questionnaire in cost effectiveness and health technologies assessment. EQ-5D-Y was a version of instrument specifically developed and validated for use by youths aged 12 through 17 years. Components assess level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, anxiety and depression. Score scale for each domain scored on 3-level scale from 1 (“I have no problems/pain/anxiety/worry”) to 3 (“I have a lot of problems/pain/anxiety/worry”). Respondents used EQ vertical, graduated Visual Analogue Scale (VAS) health status to rate their own health between 0 ( worst) and 100 ( best health state he/she can imagine). TP population. Here, “number of subjects analysed” signifies those subjects who were evaluable for this endpoint and “n” signifies those subjects who were evaluable at specific timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12 and 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    7
    Units: score on a scale
    arithmetic mean (standard deviation)
        Health State: Change at Month 12 (n=6)
    15.8 ± 20.60
        Health State: Change at Month 24 (n=7)
    20.9 ± 18.86
    No statistical analyses for this end point

    Secondary: Change From Baseline in EuroQol-5D (EQ-5D) Heath Status Score

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    End point title
    Change From Baseline in EuroQol-5D (EQ-5D) Heath Status Score
    End point description
    EQ-5D was standardised measure of health status for combined EQ-5D-Y and EQ-5D-3L dimension. EQ-5D-3L consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS) which are summed up. EQ-5D-3L and EQ-5D-Y descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Score scale for each domain scored on a 3-level scale from 1 (“I have no problems/pain/anxiety/worry”) to 3 (“I have a lot of problems/pain/anxiety/worry”). Health state of EQ-5D score was calculated based on responses to 5 dimensions, providing a single value on scale from less than 0 (where 0 is a health state equivalent to death; negative values are valued as worse than death) to 1 (perfect health), with higher scores indicates better health utility. The TP population. Here, “number of subjects analysed” signifies those subjects who were evaluable for this endpoint and “n” signifies those subjects who were evaluable at specific timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12 and 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    16
    Units: score on a scale
    arithmetic mean (standard deviation)
        Health state: Change at Month 12 (n=15)
    10.5 ± 15.92
        Health state: Change at Month 24 (n=16)
    14.6 ± 17.14
    No statistical analyses for this end point

    Secondary: Change From Baseline in Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Total Score

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    End point title
    Change From Baseline in Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Total Score
    End point description
    FACT-BMT assessed bone marrow transplant related concerns. Total score was sum of sub-scale scores for 5 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, Functional Well-Being, and Bone Marrow Transplantation Subscale. Each item scored on a 5-point Likert scale based on subject agreement with each statement: 0 for "not at all," 1 for "a little bit," 2 for "somewhat," 3 for "quite a bit," and 4 for "very much. After taking into account reverse scores for questions constructed in negative form, subscale score for each domain was calculated by multiplying sum of item scores by number of items in subscale, then dividing by number of items answered. Total score was sum of subscale total added together and ranges from 0-148. Higher the score, better the quality of life. TP population. Here, “number of subjects analysed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12 and 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    9
    Units: score on a scale
    arithmetic mean (standard deviation)
        Total Score: Change at Month 12 (n=9)
    3.78 ± 16.994
        Total Score: Change at Month 24 (n=9)
    2.15 ± 13.695
    No statistical analyses for this end point

    Secondary: Change From Baseline in Short Form-36 Health Survey (SF-36), Version 2, Acute (Physical and Mental Component Summary Scores) at Months 12 and 24

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    End point title
    Change From Baseline in Short Form-36 Health Survey (SF-36), Version 2, Acute (Physical and Mental Component Summary Scores) at Months 12 and 24
    End point description
    SF-36 was generic quality-of-life instrument, consisted of 36 items, were aggregated into 8 multi-item scales (physical functioning [1=yes, limited a lot to 3=no, not limited at all], role-physical [1=all of time to 5=none of time], bodily pain [1=very severe to 6=none], general health [1=poor to 5=excellent], vitality [1=none of time to 5=all of time], social functioning [1=all of time: to 5=none of time], role emotional [1=all of time to 5=none of time] and mental health [1=all of time to 5=none of the time]). Four domains comprised physical component summary (PCS) score (physical functioning, role-physical, bodily pain, general health) and remaining 4 domains comprised mental component summary (MCS) score (vitality, social functioning, role-emotional, mental health). TP population. Here, “number of subjects analysed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12 and 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    9
    Units: score on a scale
    arithmetic mean (standard deviation)
        Physical Component: Change at Month 12 (n=9)
    0.80 ± 4.838
        Physical Component: Change at Month 24 (n=9)
    0.82 ± 3.672
        Mental Component: Change at Month 12 (n=9)
    1.88 ± 8.201
        Mental Component: Change at Month 24 (n=9)
    0.93 ± 10.805
    No statistical analyses for this end point

    Secondary: Annualized Phlebotomy Therapy Usage Following Drug Product Infusion

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    End point title
    Annualized Phlebotomy Therapy Usage Following Drug Product Infusion
    End point description
    Annualized phlebotomy therapy usage (number of procedures per year, calculated from DP infusion through last follow-up) were reported. TP included all subjects who received beti-cel. Here, “number of subjects analysed” signifies those subjects who received therapeutic phlebotomy.
    End point type
    Secondary
    End point timeframe
    Up to Month 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    7
    Units: number of procedures per year
        arithmetic mean (standard deviation)
    6.29 ± 4.786
    No statistical analyses for this end point

    Secondary: Annualized Number of pRBC Transfusions

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    End point title
    Annualized Number of pRBC Transfusions
    End point description
    Annualized number of pRBC transfusions from 12 months post-drug product infusion through Month 24 were reported. TP consisted of subjects who received LentiGlobin BB305 Drug Product infusion.
    End point type
    Secondary
    End point timeframe
    From 12 months post-drug product infusion through Month 24
    End point values
    LentiGlobin BB305 Drug Product
    Number of subjects analysed
    23
    Units: number of pRBC transfusions
        arithmetic mean (standard deviation)
    0.95 ± 3.195
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of informed consent up to Month 24
    Adverse event reporting additional description
    ITT population included all subjects who initiated any study procedures, beginning with mobilization by G-CSF and/or plerixafor.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    LentiGlobin BB305 Drug Product
    Reporting group description
    Subjects <= 50 years of age received a single IV infusion of LentiGlobin BB305 Drug Product at a dose of >= 5.0 × 10^6 CD34+ cells/kg following myeloablative conditioning with busulfan (termed the Transplant population). As appropriate, data are analysed at times based on Intent-to-Treat (ITT) population which included all 24 subjects who initiated any study procedures, beginning with mobilization by G-CSF and/or plerixafor.

    Serious adverse events
    LentiGlobin BB305 Drug Product
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 24 (58.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Venoocclusive liver disease
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    LentiGlobin BB305 Drug Product
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 24 (100.00%)
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Chest pain
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    5
    Fatigue
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    5
    Mucosal inflammation
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Pain
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Pyrexia
         subjects affected / exposed
    12 / 24 (50.00%)
         occurrences all number
    21
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    3
    Cough
         subjects affected / exposed
    10 / 24 (41.67%)
         occurrences all number
    13
    Dyspnoea
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    4
    Epistaxis
         subjects affected / exposed
    10 / 24 (41.67%)
         occurrences all number
    18
    Hypoxia
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Oropharyngeal pain
         subjects affected / exposed
    5 / 24 (20.83%)
         occurrences all number
    5
    Pharyngeal inflammation
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    4
    Rhinitis allergic
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Rhinorrhoea
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Nasal congestion
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Insomnia
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    4
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 24 (37.50%)
         occurrences all number
    15
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 24 (25.00%)
         occurrences all number
    9
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Blood magnesium decreased
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    4
    Blood bilirubin increased
         subjects affected / exposed
    5 / 24 (20.83%)
         occurrences all number
    6
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Procedural pain
         subjects affected / exposed
    11 / 24 (45.83%)
         occurrences all number
    16
    Skin abrasion
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    3
    Transfusion reaction
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 24 (41.67%)
         occurrences all number
    12
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    17 / 24 (70.83%)
         occurrences all number
    43
    Febrile neutropenia
         subjects affected / exposed
    8 / 24 (33.33%)
         occurrences all number
    8
    Leukocytosis
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    3
    Leukopenia
         subjects affected / exposed
    13 / 24 (54.17%)
         occurrences all number
    38
    Lymphopenia
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    5
    Neutropenia
         subjects affected / exposed
    18 / 24 (75.00%)
         occurrences all number
    52
    Thrombocytopenia
         subjects affected / exposed
    24 / 24 (100.00%)
         occurrences all number
    78
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    9 / 24 (37.50%)
         occurrences all number
    15
    Abdominal pain upper
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Anal fissure
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Anal haemorrhage
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Anal inflammation
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    7 / 24 (29.17%)
         occurrences all number
    8
    Diarrhoea
         subjects affected / exposed
    9 / 24 (37.50%)
         occurrences all number
    13
    Dyspepsia
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    6
    Gingival bleeding
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Nausea
         subjects affected / exposed
    14 / 24 (58.33%)
         occurrences all number
    25
    Stomatitis
         subjects affected / exposed
    18 / 24 (75.00%)
         occurrences all number
    35
    Vomiting
         subjects affected / exposed
    16 / 24 (66.67%)
         occurrences all number
    36
    Hepatobiliary disorders
    Venoocclusive liver disease
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    8 / 24 (33.33%)
         occurrences all number
    9
    Pigmentation disorder
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Pruritus
         subjects affected / exposed
    7 / 24 (29.17%)
         occurrences all number
    9
    Rash
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    4
    Skin hyperpigmentation
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Skin hypopigmentation
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Skin ulcer
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Back pain
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Bone pain
         subjects affected / exposed
    5 / 24 (20.83%)
         occurrences all number
    6
    Pain in extremity
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    5
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Folliculitis
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    4
    Gingivitis
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Molluscum contagiosum
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Nasopharyngitis
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    4
    Pneumonia
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Rhinitis
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 24 (25.00%)
         occurrences all number
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 24 (20.83%)
         occurrences all number
    9
    Fluid overload
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Hypocalcaemia
         subjects affected / exposed
    5 / 24 (20.83%)
         occurrences all number
    7
    Hypokalaemia
         subjects affected / exposed
    6 / 24 (25.00%)
         occurrences all number
    7
    Hypomagnesaemia
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    4
    Hypophosphataemia
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2016
    Protocol Amendment Version 1.3: • Original protocol submitted to Health Authorities for regulatory approval.
    05 Jan 2017
    Protocol Amendment Version 2.0: • Included changes from country specific protocol Version 1.6 • Added study cohort of subjects <12 years of age and increased the number of subjects in the study as a result of this added cohort
    19 Jun 2018
    Protocol Amendment Version 3.0: • Updated secondary efficacy endpoints to include weighted average Hb during TI, transfusion volume from Month 12 through Month 24, and total Hb levels. All these data were already collected as part of the study and used to calculate other endpoints. • Corrected secondary efficacy endpoint of characterization of TR to be assessed for all subjects, not just for subjects who don’t achieve TI • Corrected description of pharmacodynamic endpoint of βA-T87Q-globin expression • Removed requirement for repeating bone marrow aspiration as risks outweigh the benefits • Added requirement of prophylaxis with ursodeoxycholic acid (preferred) or defibrotide is required before initiation of conditioning to help prevent the occurrence of VOD/SOS. • Adjusted the target busulfan AUC, added recommendation for q6h dosing regimen for children and adolescents to avoid higher peak concentrations of busulfan, to reduce potential incidence of VOD/SOS • Clarified that SUSARs associated with the use of plerixafor will also be reported • Clarified planned interim analyses and primary endpoint failure definition • Updated baseline value for laboratory parameters to the most recent assessment prior to mobilization • Updated safety analysis of AEs time periods (e.g. collection modified in relation to each subject’s time to NE rather than a specified day post drug product infusion)
    05 Apr 2019
    Protocol Amendment Version 4.0: • Included changes from country specific protocol Version 3.1 • Updated secondary efficacy endpoint to include time from drug product infusion to achievement of TI • Clarified that the volume and number of transfusions will be annualized for the period from 12 months post-drug product infusion, rather than from Month 12 through Month 24. • Moved parameter of ‘time from last pRBC transfusion to Month 24’ under characterization of TR to be assessed for all subjects, and not just for subjects achieving TI • Updated secondary efficacy endpoint to calculate weighted average nadir Hb to more accurately capture Hb levels over time. • Updated secondary efficacy endpoint to analyze unsupported total Hb compared to total Hb to reduce the contribution of transfused pRBCs to total Hb assessments. • Updated parameters for the secondary efficacy endpoints of characterization of use of iron chelation therapies, including adding the use of phlebotomy to more accurately capture iron removal strategies. • Re-categorized quality of life (QoL) parameters as secondary endpoints instead of exploratory efficacy endpoints. • Updated efficacy endpoint of ‘correlations of pre-treatment variables with response’ to remove β/α globin ratio as an example of pre-treatment variables and to add peripheral blood, VCN, and HbAT87Q as examples of response parameters. • Updated endpoint on measures of health resource utilization to clarify it is measuring annualized number of transfusions and annualized corresponding parameters, to remove iron chelation usage assessment, and to measure number of days hospitalized from Month 12 through Month 24. • Added efficacy endpoint of length of in-patient stay from initiation of conditioning to discharge. • Added additional safety endpoint to characterize the incidence of acute and chronic graft-versus-host disease (GVHD) to ensure that any occurrence of GVHD is adequately assessed in this study.
    06 Oct 2020
    Protocol Amendment Version 5.0: • Updated the assessment of clonal predominance to be based on frequency of clones with LVV insertions rather than on frequency of individual LVV insertion sites. • Separated the safety endpoint for insertional oncogenesis and clonal predominance into two endpoints, with insertional oncogenesis as a secondary endpoint and clonal predominance as an exploratory endpoint. Designated the remaining safety endpoints as secondary endpoints. • Added text to provide guidelines around study procedures impacted by force of nature events and analysis of assessments impacted by the COVID-19 pandemic. • Added text to indicate that clinical work-up for unexpected blood test results may be performed. • Clarified that SAEs that start between completion of the parent study and enrollment in long-term follow-up Study LTF-303 will be recorded in the HGB-207 SAE report form. • Following regulatory correspondence, added text to extend the time period for follow-up of newborns
    10 Jun 2021
    .Protocol Amendment Version 6.0: • Updated clinical work-up criteria, procedure and follow-up describing Integration Site Analysis. • Optional archival and genetic testing on Bone Marrow samples. Updated schedule of events

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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