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    Clinical Trial Results:
    A Phase I/II Open Label Study Evaluating the Safety and Efficacy of Gene Therapy of the β-Hemoglobinopathies (Sickle Cell Disease and β-Thalassemia Major) by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo with a Lentiviral β-A-T87Q-Globin Vector (LentiGlobin® BB305 Drug Product)

    Summary
    EudraCT number
    		 2012-000695-42
    Trial protocol
    		 FR  
    Global end of trial date
    26 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Sep 2019
    First version publication date
    07 Sep 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HGB-205
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02151526
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    bluebird bio, Inc
    Sponsor organisation address
    60 Binney Street, Cambridge, Massachusetts, United States, 02142
    Public contact
    Study Medical Director, bluebird bio. Inc, +31 30 310 04 50, medinfo@bluebirdbio.com
    Scientific contact
    Study Medical Director, bluebird bio. Inc, +31 30 310 04 50, medinfo@bluebirdbio.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001665-PIP02-17
    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
    26 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Feb 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the safety, tolerability, and success of engraftment with LentiGlobin BB305 Drug Product after conditioning with Busilvex (busulfan IV) in subjects with severe sickle cell disease (SCD) or transfusion dependent β-thalassemia (TDT).
    Protection of trial subjects
    All monitoring visits were conducted according to the International Conference on Harmonisation (ICH) and Good Clinical Practice (GCP) guidelines to ensure protocol adherence, quality of data, compliance with regulatory requirements, and continued adequacy of the study site and its facilities. PIP was available only for SCD subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jun 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 7
    Worldwide total number of subjects
    7
    EEA total number of subjects
    7
    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)
    0
    Adolescents (12-17 years)
    4
    Adults (18-64 years)
    3
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at a single site in France in between 07 June 2013 (First subject signed informed consent) to 26 February 2019 (Last subject last visit).

    Pre-assignment
    Screening details
    		 A total of 7 subjects were enrolled and completed the study. 3 had Sickle Cell Disease (SCD) and 4 had transfusion-dependent β-thalassemia (TDT).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LentiGlobin BB305 Drug Product for SCD
    Arm description
    		 Following myeloablative conditioning with a dose (dose may be adjusted as per protocol) of 3.2 milligram per kilogram per day (mg/kg/day) busulfan intravenous (IV) for 4 consecutive days and subsequent daily monitoring of busulfan levels until no busulfan was detected, a single dose of greater than or equal to (> or =) 2.0×10^6 CD34+ cells/kg LentiGlobin BB305 Drug Product was administered to subjects with sickle cell disease (SCD) by IV infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LentiGlobin BB305 Drug Product
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    LentiGlobin BB305 drug product was administered by intravenous (IV) infusion.

    Arm title
    		 LentiGlobin BB305 Drug Product for TDT
    Arm description
    		 Following myeloablative conditioning with a dose (dose may be adjusted as per protocol) of 3.2 mg/kg/day busulfan Intravenous (IV) for 4 consecutive days and subsequent daily monitoring of busulfan levels until no busulfan was detected, a single dose of > or =3.0 × 10^6 CD34+ cells/kg LentiGlobin BB305 Drug Product was administered to subjects with transfusion-dependent β-thalassemia (TDT) by IV infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LentiGlobin BB305 Drug Product
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    LentiGlobin BB305 drug product was administered by intravenous (IV) infusion.

    Number of subjects in period 1
    		LentiGlobin BB305 Drug Product for SCD LentiGlobin BB305 Drug Product for TDT
    Started
    3
    4
    Completed
    3
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LentiGlobin BB305 Drug Product for SCD
    Reporting group description
    		 Following myeloablative conditioning with a dose (dose may be adjusted as per protocol) of 3.2 milligram per kilogram per day (mg/kg/day) busulfan intravenous (IV) for 4 consecutive days and subsequent daily monitoring of busulfan levels until no busulfan was detected, a single dose of greater than or equal to (> or =) 2.0×10^6 CD34+ cells/kg LentiGlobin BB305 Drug Product was administered to subjects with sickle cell disease (SCD) by IV infusion.

    Reporting group title
    LentiGlobin BB305 Drug Product for TDT
    Reporting group description
    		 Following myeloablative conditioning with a dose (dose may be adjusted as per protocol) of 3.2 mg/kg/day busulfan Intravenous (IV) for 4 consecutive days and subsequent daily monitoring of busulfan levels until no busulfan was detected, a single dose of > or =3.0 × 10^6 CD34+ cells/kg LentiGlobin BB305 Drug Product was administered to subjects with transfusion-dependent β-thalassemia (TDT) by IV infusion.

    Reporting group values
    		 LentiGlobin BB305 Drug Product for SCD LentiGlobin BB305 Drug Product for TDT Total
    Number of subjects
    		 3 4 7
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 2 2 4
        Adults (18-64 years)
    		 1 2 3
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 2 2 4
        Male
    		 1 2 3

    End points

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    End points reporting groups
    Reporting group title
    LentiGlobin BB305 Drug Product for SCD
    Reporting group description
    		 Following myeloablative conditioning with a dose (dose may be adjusted as per protocol) of 3.2 milligram per kilogram per day (mg/kg/day) busulfan intravenous (IV) for 4 consecutive days and subsequent daily monitoring of busulfan levels until no busulfan was detected, a single dose of greater than or equal to (> or =) 2.0×10^6 CD34+ cells/kg LentiGlobin BB305 Drug Product was administered to subjects with sickle cell disease (SCD) by IV infusion.

    Reporting group title
    LentiGlobin BB305 Drug Product for TDT
    Reporting group description
    		 Following myeloablative conditioning with a dose (dose may be adjusted as per protocol) of 3.2 mg/kg/day busulfan Intravenous (IV) for 4 consecutive days and subsequent daily monitoring of busulfan levels until no busulfan was detected, a single dose of > or =3.0 × 10^6 CD34+ cells/kg LentiGlobin BB305 Drug Product was administered to subjects with transfusion-dependent β-thalassemia (TDT) by IV infusion.

    Primary: Number of Treated Subjects With Successful Neutrophil and Platelet Engraftment

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    End point title
    		 Number of Treated Subjects With Successful Neutrophil and Platelet Engraftment [1]
    End point description
    Neutrophil engraftment was defined as the first of absolute neutrophil count (ANC) > or = 0.5 × 10^9/ liter (L) for 3 consecutive days (or 3 consecutive measurements done on separate days), after a post-transplant value less than [<] 0.5 × 10^9/L). Platelet engraftment was defined as the first of 3 consecutive platelet values > or =20 × 10^9/L for subjects with TDT and values > or =50 × 10^9/L for subjects with SCD obtained on different days with no platelet transfusions administered for 7 days immediately preceding and during the evaluation period. The day of engraftment is the first day of the 3 consecutive platelet measurements. This endpoint was evaluated in the Transplant Population (TP), which included all subjects in the intent-to-treat (ITT) population who underwent LentiGlobin BB305 Drug Product infusion.
    End point type
    Primary
    End point timeframe
    From time of drug product infusion through Month 24 visit
    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 for SCD LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    3
    4
    Units: Number of Subjects
        Subjects with Neutrophil Engraftment
    3
    4
        Subjects with Platelet Engraftment
    3
    4
    No statistical analyses for this end point

    Primary: Time to Successful Neutrophil and Platelet Engraftment

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    End point title
    		 Time to Successful Neutrophil and Platelet Engraftment [2]
    End point description
    Neutrophil engraftment was defined as the first of ANC > or = 0.5 × 10^9/ liter (L) for 3 consecutive days (or 3 consecutive measurements done on separate days), after a post-transplant value < 0.5 × 10^9/L). Platelet engraftment was defined as the first of 3 consecutive platelet values > or =20 × 10^9/L for subjects with TDT and values > or =50 × 10^9/L for subjects with SCD obtained on different days with no platelet transfusions administered for 7 days immediately preceding and during the evaluation period. The day of engraftment is the first day of the 3 consecutive platelet measurements. This endpoint was evaluated in the Transplant Population (TP).
    End point type
    Primary
    End point timeframe
    From time of drug product infusion through Month 24 visit
    Notes
    [2] - 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 for SCD LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    3
    4
    Units: Days
    median (full range (min-max))
        Time to neutrophil engraftment
    32 (27 to 38)
    16.5 (14 to 29)
        Time to platelet engraftment
    51 (39 to 92)
    23 (20 to 26)
    No statistical analyses for this end point

    Primary: Incidence of Transplant Related Mortality

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    End point title
    		 Incidence of Transplant Related Mortality [3]
    End point description
    This is the safety endpoint related to mortality. Transplant related mortality was defined as any death occurring in the study post drug product infusion deemed related to the transplant by the investigator. This endpoint was evaluated in the Transplant Population (TP).
    End point type
    Primary
    End point timeframe
    From screening through 365 days post-transplant
    Notes
    [3] - 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 for SCD LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    3
    4
    Units: Number of Subjects
    0
    0
    No statistical analyses for this end point

    Primary: Overall Survival

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    End point title
    		 Overall Survival [4]
    End point description
    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 subject was still alive. Subjects who survived throughout the study were reported in this endpoint. This endpoint was evaluated in the ITT population, which consisted of all subjects who initiated any study procedures, beginning with mobilization (by granulocyte-colony stimulating factor [G-CSF] with or without plerixafor), or bone marrow harvest.
    End point type
    Primary
    End point timeframe
    From time of drug product infusion through Month 24 visit
    Notes
    [4] - 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 for SCD LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    3
    4
    Units: Number of Subjects
    3
    4
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Vector-Derived Replication-Competent Lentivirus (RCL)

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    End point title
    		 Percentage of Subjects With Vector-Derived Replication-Competent Lentivirus (RCL) [5]
    End point description
    Blood samples were analyzed for detection of RCL using RCL co-culture assay. This endpoint was evaluated in the ITT population.
    End point type
    Primary
    End point timeframe
    From time of drug product infusion through Month 24 visit
    Notes
    [5] - 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 for SCD LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    3
    4
    Units: Percentage of subjects
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Primary: Number of Treated Subjects With (>) 30 Percent (%) Contribution of an Individual Clone As Per Integration Site Analysis (ISA)

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    End point title
    		 Number of Treated Subjects With (>) 30 Percent (%) Contribution of an Individual Clone As Per Integration Site Analysis (ISA) [6]
    End point description
    Clonal dominance was defined as an ISA result greater than (>) 90% of the total IS at any time and a vector copy number (VCN) > or =0.3, or an initial ISA result of > 30% of the total IS with a VCN > or =0.3 followed by a result > 30% and less than or equal to (< or =)90% at first repeat and a result > 50% at second repeat. This endpoint was evaluated in the Transplant Population (TP).
    End point type
    Primary
    End point timeframe
    From time of drug product infusion through Month 24 visit
    Notes
    [6] - 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 for SCD LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    3
    4
    Units: Number of Subjects
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) [7]
    End point description
    An AE was any untoward medical occurrence associated with the use of a drug in subjects, whether or not considered drug related. An AE may include a change in physical signs, symptoms, and/or clinically significant laboratory change occurring in any phase of a clinical study. This definition includes inter-current illnesses or injuries, and exacerbation of pre-existing conditions. An SAE was any AE, occurring at any dose and regardless of causality, that resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or was considered an important medical event that may jeopardize the subject and may require medical or surgical intervention to prevent an outcome listed previously. The number of subjects with AEs and SAEs was evaluated. This endpoint was evaluated in the ITT population.
    End point type
    Primary
    End point timeframe
    From date of Informed Consent up to Month 24 visit
    Notes
    [7] - 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 for SCD LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    3
    4
    Units: Number of Subjects
        Number of Subjects with any Adverse Event
    3
    4
        Number of Subjects with any Serious Adverse Event
    3
    3
    No statistical analyses for this end point

    Secondary: Percentage of Treated TDT Subjects Who Achieved Transfusion independence (TI)

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    End point title
    		 Percentage of Treated TDT Subjects Who Achieved Transfusion independence (TI) [8]
    End point description
    TI was defined as a weighted average hemoglobin (Hb) > or =9 grams per deciliter (g/dL) without any pRBC transfusions for a continuous period of > or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when subjects achieve a Hb > or =9 g/dL with no transfusions in the preceding 60 days. This endpoint was evaluated in the TDT Transplant Population (TP).
    End point type
    Secondary
    End point timeframe
    From time of drug product infusion through Month 24 visit
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Transfusion Independence (TI) was only evaluated in TDT subjects.
    End point values
    		 LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    4
    Units: Percentage of subjects
        number (not applicable)
    75
    No statistical analyses for this end point

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

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    End point title
    		 Weighted Average Hemoglobin (Hb) During Period of Transfusion Independence (TI) [9]
    End point description
    TI was defined as a weighted average hemoglobin (Hb) > or =9 grams per deciliter (g/dL) without any pRBC transfusions for a continuous period of > or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when subjects achieve a Hb > or =9 g/dL with no transfusions in the preceding 60 days. This endpoint was evaluated in the TDT Transplant Population (TP) that reached TI.
    End point type
    Secondary
    End point timeframe
    From time of drug product infusion through Month 24 visit
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Transfusion Independence (TI) was only evaluated in TDT subjects.
    End point values
    		 LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    3
    Units: grams per deciliter
        median (full range (min-max))
    11.3 (10.6 to 13.1)
    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) [10]
    End point description
    TI was defined as a weighted average Hb > or =9 grams per deciliter (g/dL) without any pRBC transfusions for a continuous period of > or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when subjects achieve a Hb > or =9 g/dL with no transfusions in the preceding 60 days. To meet the initial TI criteria, the weighted Hb must be > or =9 g/dL at the end of the 12-month period, to remain in the TI state beyond the 12-month period, the treated subject needs to maintain a weighted Hb of > or =9 g/dL from that point forward, without receiving a pRBC transfusion. This endpoint reports the duration of TI and was evaluated in the TDT Transplant Population (TP) that reached TI.
    End point type
    Secondary
    End point timeframe
    From time of drug product infusion through Month 24 visit
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Transfusion Independence (TI) was only evaluated in TDT subjects.
    End point values
    		 LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    3
    Units: Month
        median (full range (min-max))
    21.7 (21.2 to 21.8)
    No statistical analyses for this end point

    Secondary: Time From LentiGlobin BB305 Drug Product Infusion to Last Packed Red Blood Cells (pRBC) Transfusion Prior to Achieving Transfusion Independence (TI)

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    End point title
    		 Time From LentiGlobin BB305 Drug Product Infusion to Last Packed Red Blood Cells (pRBC) Transfusion Prior to Achieving Transfusion Independence (TI) [11]
    End point description
    TI was defined as a weighted average Hb > or =9 grams per deciliter (g/dL) without any pRBC transfusions for a continuous period of > or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when subjects achieve a Hb > or =9 g/dL with no transfusions in the preceding 60 days. To meet the initial TI criteria, the weighted Hb must be > or =9 g/dL at the end of the 12-month period, to remain in the TI state beyond the 12-month period, the treated subject needs to maintain a weighted Hb of > or =9 g/dL from that point forward, without receiving a pRBC transfusion. This endpoint reports the time from infusion to the last pRBC transfusion prior to achieving TI and was evaluated in the TDT Transplant Population (TP) that reached TI.
    End point type
    Secondary
    End point timeframe
    From time of drug product infusion through Month 24 visit
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Transfusion Independence (TI) was only evaluated in TDT subjects.
    End point values
    		 LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    3
    Units: Days
        median (full range (min-max))
    11 (5 to 13)
    No statistical analyses for this end point

    Secondary: Time from LentiGlobin BB305 Drug Product Infusion to Achieving Transfusion Independence (TI)

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    End point title
    		 Time from LentiGlobin BB305 Drug Product Infusion to Achieving Transfusion Independence (TI) [12]
    End point description
    TI was defined as a weighted average Hb > or =9 grams per deciliter (g/dL) without any pRBC transfusions for a continuous period of > or =12 months at any time during the study after drug product infusion, where calculation of time period of TI starts when subjects achieve a Hb > or =9 g/dL with no transfusions in the preceding 60 days. To meet the initial TI criteria, the weighted Hb must be > or =9 g/dL at the end of the 12-month period, to remain in the TI state beyond the 12-month period, the treated subject needs to maintain a weighted Hb of > or =9 g/dL from that point forward, without receiving a pRBC transfusion. This endpoint reports the time from infusion to achievement of TI and was reported in the TDT Transplant Population (TP) that reached TI.
    End point type
    Secondary
    End point timeframe
    From time of drug product infusion through Month 24 visit
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Transfusion Independence (TI) was only evaluated in TDT subjects.
    End point values
    		 LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    3
    Units: Month
        median (full range (min-max))
    14.9 (14.9 to 15.6)
    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) [13]
    End point description
    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 was used as the Hb nadir. Hb values on the day of the transfusion were considered for nadir calculations. This endpoint was evaluated in the TDT Transplant Population (TP).
    End point type
    Secondary
    End point timeframe
    From 6 months post-drug product infusion through Month 24 visit
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Weighted Average Nadir Hemoglobin (Hb) was evaluated only in TDT subjects.
    End point values
    		 LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    4
    Units: grams per deciliter (g/dL)
        median (full range (min-max))
    11 (8.5 to 13.2)
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline in Annualized Packed Red Blood Cell (pRBC) Transfusion Volume

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    End point title
    		 Percentage Change From Baseline in Annualized Packed Red Blood Cell (pRBC) Transfusion Volume
    End point description
    Percent change from baseline in the average annual transfusion volume from 6 months post-drug product infusion through last visit were reported. This endpoint was evaluated in the Transplant Population (TP).
    End point type
    Secondary
    End point timeframe
    Baseline, From 6 months post-drug product infusion through Month 24 visit
    End point values
    		 LentiGlobin BB305 Drug Product for SCD LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    3
    4
    Units: percent change in Annualized pRBC volume
        median (full range (min-max))
    -100.0 (-100.0 to 90.0)
    -100.0 (-100.0 to -100.0)
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline in Annualized Number of Packed Red Blood Cell (pRBC) Transfusions

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    End point title
    		 Percentage Change From Baseline in Annualized Number of Packed Red Blood Cell (pRBC) Transfusions
    End point description
    Frequency of pRBC transfusions (number per year) from 6 months post-drug product infusion through last visit were reported. This endpoint was evaluated in the Transplant Population (TP).
    End point type
    Secondary
    End point timeframe
    Baseline, From 6 months post-drug product infusion through Month 24 visit
    End point values
    		 LentiGlobin BB305 Drug Product for SCD LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    3
    4
    Units: percentage change in pRBC transfusion
        median (full range (min-max))
    -100.0 (-100.0 to -1.9)
    -100.0 (-100.0 to -100.0)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Vaso-Occlusive Crisis (VOC) and/or Acute Chest Syndrome (ACS) Events Post Drug Product Infusion

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    End point title
    		 Number of Subjects with Vaso-Occlusive Crisis (VOC) and/or Acute Chest Syndrome (ACS) Events Post Drug Product Infusion [14]
    End point description
    Number of VOCs, ACS, and vaso-occlusive events (VOEs; which included both VOC and ACS) through 24 months after drug product infusion, compared to 2 years prior to enrollment. This endpoint was evaluated in ITT population.
    End point type
    Secondary
    End point timeframe
    From time of drug product infusion through Month 24 visit
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: VOC and/or ACS events were only evaluable in SCD subjects
    End point values
    		 LentiGlobin BB305 Drug Product for SCD
    Number of subjects analysed
    3 [15]
    Units: Number of Subjects
        Vaso-Occlusive Crisis (VOC)
    1
        Acute Chest Syndrome (ACS)
    1
    Notes
    [15] - Events of VOC and ACS were from same subject
    No statistical analyses for this end point

    Secondary: Therapeutic Globin Expression Measured by Hb Containing β^A -T87Q Globin (HbA^T87Q) in Peripheral Blood

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    End point title
    		 Therapeutic Globin Expression Measured by Hb Containing β^A -T87Q Globin (HbA^T87Q) in Peripheral Blood
    End point description
    Therapeutic globin expression was measured by HbA^T87Q in peripheral blood and the ratio of alpha(α)- globin to all beta (β)-like-globins. The relative amount of each globin produced by a subject (including βA^A-T87Q globin) was determined in peripheral blood throughout the study. This endpoint was evaluated in the Transplant Population (TP).
    End point type
    Secondary
    End point timeframe
    From time of drug product infusion through Month 24 visit
    End point values
    		 LentiGlobin BB305 Drug Product for SCD LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    3
    4
    Units: gram/deciliter (g/dL)
        arithmetic mean (standard deviation)
    2.947 ( 2.4415 )
    8.287 ( 1.5758 )
    No statistical analyses for this end point

    Secondary: Vector Copy Number (VCN) in Peripheral Blood

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    End point title
    		 Vector Copy Number (VCN) in Peripheral Blood
    End point description
    LentiGlobin BB305 lentiviral vector (LVV) transduction efficiency was measured by VCN. The presence of vector sequences in the genomic DNA of cells is detected using quantitative polymerase chain reaction (qPCR), and results were expressed as VCN. This endpoint was evaluated in the Transplant Population (TP).
    End point type
    Secondary
    End point timeframe
    From time of drug product infusion through Month 24 visit
    End point values
    		 LentiGlobin BB305 Drug Product for SCD LentiGlobin BB305 Drug Product for TDT
    Number of subjects analysed
    3
    4
    Units: copies per diploid genome (c/dg)
        arithmetic mean (standard deviation)
    0.898 ( 1.1655 )
    1.796 ( 1.3665 )
    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 through Month 24 visit
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    LentiGlobin BB305 Drug Product for SCD
    Reporting group description
    		 Following myeloablative conditioning with a dose (dose may be adjusted as per protocol) of 3.2 milligram per kilogram per day (mg/kg/day) busulfan intravenous (IV) for 4 consecutive days and subsequent daily monitoring of busulfan levels until no busulfan was detected, a single dose of > or = 2.0×10^6 CD34+ cells/kg LentiGlobin BB305 Drug Product was administered to subjects with SCD by IV infusion.

    Reporting group title
    LentiGlobin BB305 Drug Product for TDT
    Reporting group description
    		 Following myeloablative conditioning with a dose (dose may be adjusted as per protocol) of 3.2 mg/kg/day busulfan Intravenous (IV) for 4 consecutive days and subsequent daily monitoring of busulfan levels until no busulfan was detected, a single dose of greater than or equal to > or =3.0 × 10^6 CD34+ cells/kg LentiGlobin BB305 Drug Product was administered to subjects with transfusion-dependent β-thalassemia (TDT) by IV infusion.

    Serious adverse events
    		 LentiGlobin BB305 Drug Product for SCD LentiGlobin BB305 Drug Product for TDT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 4 (75.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Sickle cell anaemia with crisis
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute chest syndrome
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LentiGlobin BB305 Drug Product for SCD LentiGlobin BB305 Drug Product for TDT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    4 / 4 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Hypotension
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Xerosis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Puncture site pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    Pyrexia
         subjects affected / exposed
    3 / 3 (100.00%)
    4 / 4 (100.00%)
         occurrences all number
    8
    5
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Catheter site pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Feeling cold
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Hypothermia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Injection site inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Premature menopause
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Lung disorder
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Restrictive pulmonary disease
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    Disturbance in attention
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 4 (75.00%)
         occurrences all number
    3
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 4 (75.00%)
         occurrences all number
    3
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    1
    2
    Staphylococcus test positive
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Aspergillus test positive
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Catheter site pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Congenital, familial and genetic disorders
    Dolichocolon
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Presyncope
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Tremor
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    3 / 3 (100.00%)
    4 / 4 (100.00%)
         occurrences all number
    3
    4
    Neutropenia
         subjects affected / exposed
    3 / 3 (100.00%)
    4 / 4 (100.00%)
         occurrences all number
    4
    4
    Anaemia
         subjects affected / exposed
    3 / 3 (100.00%)
    4 / 4 (100.00%)
         occurrences all number
    15
    5
    Leukocytosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Sickle cell anaemia with crisis
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 4 (0.00%)
         occurrences all number
    7
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 3 (66.67%)
    4 / 4 (100.00%)
         occurrences all number
    4
    6
    Vomiting
         subjects affected / exposed
    3 / 3 (100.00%)
    2 / 4 (50.00%)
         occurrences all number
    5
    3
    Nausea
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 4 (75.00%)
         occurrences all number
    4
    4
    Diarrhoea
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 4 (75.00%)
         occurrences all number
    4
    3
    Stomatitis
         subjects affected / exposed
    3 / 3 (100.00%)
    4 / 4 (100.00%)
         occurrences all number
    3
    7
    Anal fissure
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Colitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Lip dry
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Gastrointestinal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Odynophagia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Anal inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 3 (100.00%)
    4 / 4 (100.00%)
         occurrences all number
    3
    4
    Melanoderma
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    2
    2
    Pruritus generalised
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Skin lesion
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Petechiae
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    Bone pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Bronchitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Genital candidiasis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Tooth abscess
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Wound infection fungal
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Mastitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Oral herpes
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    1
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Apr 2012
    Original: Enrollment in Study HGB 205 began.
    05 Oct 2012
    Version 2: Enrollment of subjects with severe SCD and cerebral vasculopathy was made contingent upon approval by ANSM, the Comité de protection des personnes (CPP), and the Comité de Surveillance (CDS) after review of safety and efficacy data from >or=2 SCD subjects without cerebral vasculopathy treated with LentiGlobin BB305 Drug Product in this study. Hematologic abnormalities considered a direct consequence of the conditioning regimen were to be reported.
    23 Sep 2013
    Version 3: Clarified that approval for enrollment of subjects with severe SCD and cerebral vasculopathy is the jurisdiction of the Comité de Surveillance. Clarified that ovarian tissue grafting potentially may be offered to subjects under the context of biomedical research. Busulfan range corrected for units and dosing regimen (changed from 'range 800 to 1100 micrometer per minute (µM/min)' to 'Area Under Curve (AUC) range 800 to 1100 µM*min for a q6 hour dosing regimen, or 3200 to 4400 µM*min for a daily dosing regimen') Increased monitoring of physical examinations, CBCs, and vital signs during apheresis
    07 Jul 2014
    Version 4: Staggering altered from 3 subjects observed for 2 months to 2 subjects observed for 3 months, as longer observation of initial subjects felt to give more safety information than shorter observation of more subjects. Washout definition changed from "there must be a minimum of 4 busulfan washout days" to "until no busulfan is detected for at least 2 consecutive days", as considered sufficient for HSC safety.
    15 Dec 2014
    Version 5.1: Increased the frequency of HPLC globin analyses to provide better kinetics. Added erythropoietin tests, erythroblast counts, and exploratory bone marrow cellularity studies to help evaluate erythropoiesis; a new set of exploratory tests for sickle cell disease (SCD) to assist in evaluating the efficacy of treatment on this disease; new immunology testing to provide more safety data. Removed VCN and globin chain analysis in BFU Es in blood and bone marrow, as VCN in peripheral blood adequate to monitor persistence; removed RCL and ISA time points not recommended by regulatory authorities. Clarified that additional cell collection procedures may be allowed in the event of drug product release-testing failure.
    26 Aug 2015
    Version 6: The stipulation that safety and efficacy data from at least 2 SCD subjects without cerebral vasculopathy treated with LentiGlobin BB305 Drug Product be available in Study HGB-205 specifically was removed because bluebird bio has another ongoing study with LentiGlobin BB305 in subjects with severe SCD in the USA (Study HGB-206), and the required safety and efficacy data pre-specified to allow enrollment of SCD subjects with cerebral vasculopathy will be available collectively from the 2 ongoing studies (HGB-205 and HGB-206). The amount and duration of data required from these 2 trials to allow enrollment of SCD subjects with cerebral vasculopathies in this study remained at the discretion of the CDS.
    19 May 2016
    Version 7: Adjusted the acceptable busulfan range (from AUC 800 to 1100 µM*min to 1000 to 1300 µM*min for an every 6 hour dosing regimen, and from AUC 3200 to 4400 µM*min to 4000 to 5200 µM*min for a daily dosing regimen) based on clinical experience that increased busulfan exposure assists in achieving improved efficacy outcomes. Increased the minimum cell number for the dose from 1.5 × 10^6 CD34+ cells/kg to 2.0 × 10^6 CD34+ cells/kg when bone marrow is used as the cell source, as well as increased the number of bone marrow harvests that may be performed to up to 3 bone marrow harvests, based on clinical experience suggesting that doses above the current minimum may promote a better clinical response, and on acceptable clinical safety observed during bone marrow harvests in this study to date, for subjects with SCD.

    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.
    PIP was available only for SCD subjects.
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