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    Clinical Trial Results:
    A phase I/II study evaluating safety and efficacy of autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene for the treatment of patients affected by transfusion dependent beta-thalassemia

    Summary
    EudraCT number
    		 2014-004860-39
    Trial protocol
    		 IT  
    Global end of trial date
    25 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Oct 2020
    First version publication date
    15 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TIGET-BTHAL
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02453477
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ospedale San Raffaele
    Sponsor organisation address
    Via Olgettina 60, Milan, Italy, 20132
    Public contact
    TIGET Clinical Trial Office (TCTO), OSPEDALE SAN RAFFAELE, tcto@hsr.postcert.it
    Scientific contact
    San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), OSPEDALE SAN RAFFAELE, tcto@hsr.postcert.it
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001933-PIP01-16
    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 Jul 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Nov 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To evaluate the safety and tolerability of autologous CD34+ cell enriched fraction that contains Hematopoietic Stem Cells (HSC) transduced with Lentiviral Vector (LV) encoding the beta-globin gene in pediatric and adult patients with transfusion dependent beta-thalassemia following a reduced toxicity conditioning regimen. 2. To evaluate the efficacy of autologous CD34+ cell enriched fraction that contains Hematopoietic Stem Cells (HSC) transduced with Lentiviral Vector (LV) encoding the beta-globin gene in pediatric and adult patients with transfusion dependent beta-thalassemia following a reduced toxicity conditioning regimen.
    Protection of trial subjects
    The study was conducted in accordance with the protocol, consistent to ICH-GCP and applicable local regulatory requirements. The written informed consent with a declaration of data privacy was signed and dated by the subject or by the subject's legally acceptable representative. For pediatric subjects or subjects unable to give free consent to the trial, subject's parents or subject's legally acceptable representative signed the informed consent. An independent Data Safety Monitoring Board (DSMB) was assigned to monitor the trial. Long-term follow-up will be conducted under a separate protocol.
    Background therapy
    		 Regular red blood cell transfusions and iron chelator therapy
    Evidence for comparator
    		 No acceptable comparator therapy was available.
    Actual start date of recruitment
    29 May 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 6 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 10
    Worldwide total number of subjects
    10
    EEA total number of subjects
    10
    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)
    4
    Adolescents (12-17 years)
    3
    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 enrolled subjects aged ≥3 and <65 years with a diagnosis of Transfusion dependent beta-thalassemia (TDBT) (any genotype). Enrolment started with adult subjects. The ensuing enrolment of older children, and then of younger children, was conducted after Data Safety Monitoring Board (DSMB) approval for both of these age groups.

    Pre-assignment
    Screening details
    		 The conditions required by the clinical protocol for subject inclusion/exclusion were assessed during the screening phase.

    Period 1
    Period 1 title
    OTL-300 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was a single-arm open-label study.

    Arms
    Arm title
    		 OTL-300
    Arm description
    		 Each subject received the Advanced therapy investigational medicinal product (ATIMP), OTL-300 (autologous CD34+ cell enriched fraction containing HSPC transduced with the GLOBE LVV encoding for the beta-globin gene), on a single occasion via intraosseous infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    OTL-300 (autologous CD34+ cell enriched fraction)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intraosseous use
    Dosage and administration details
    5 x 10e6 CD34+ cells/kg, with a minimum dose of 2 x 10e6 CD34+ cells/kg and a maximum dose of 20 x 10e6 CD34+ cells/kg, depending on the yield of cells.

    Number of subjects in period 1 [1]
    		OTL-300
    Started
    9
    ATIMP infusion/Ly infusion
    9
    Completed
    9
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Ten subjects have been enrolled in the study. Nine subjects received the conditioning regimen, received the OTL-300 infusion, and completed the 2-year study. One younger child discontinued the study after PBSC mobilization and transduction, and did not receive the conditioning regimen or the OTL-300 infusion.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    OTL-300
    Reporting group description
    		 All patients were affected by transfusion dependent beta-thalassemia. Enrolment started with adult subjects. The ensuing enrolment of older children, and then of younger children, was conducted after DSMB approval for both of these age groups. Ten subjects underwent Peripheral blood stem cell (PBSC) mobilization and harvest: four younger children, three older children, and three adults. Nine subjects received the conditioning regimen, received the OTL-300 infusion, and completed the 2-year study; these subjects comprised the modified Intention-to-Treat (mITT) Population. One younger child discontinued the study after PBSC mobilization and transduction, and did not receive the conditioning regimen or the OTL-300 infusion. Mean age in the mITT Population was 5.7 years for younger children, 13.5 years for older children, and 33.8 years for adult subjects. The majority of subjects were male (66.7%) and all subjects were White.

    Reporting group values
    		 OTL-300 Total
    Number of subjects
    		 9 9
    Age categorical
    Units: Subjects
        Younger children (3-7 years)
    		 3 3
        Older children (8-17 years)
    		 3 3
        Adults (≥18 years)
    		 3 3
    Age continuous
    Units: years
        median (full range (min-max))
    		 17.64 (4.6 to 35.7) -
    Gender categorical
    Units: Subjects
        Female
    		 3 3
        Male
    		 6 6
    Subject analysis sets

    Subject analysis set title
    mITT Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    mITT Population comprised of subjects received mobilization + conditioning + OTL-300 and completed the 2-year study.

    Subject analysis sets values
    		 mITT Population
    Number of subjects
    9
    Age categorical
    Units: Subjects
        Younger children (3-7 years)
    3
        Older children (8-17 years)
    3
        Adults (≥18 years)
    3
    Age continuous
    Units: years
        median (full range (min-max))
    17.64 (4.6 to 35.7)
    Gender categorical
    Units: Subjects
        Female
    3
        Male
    6

    End points

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    End points reporting groups
    Reporting group title
    OTL-300
    Reporting group description
    		 Each subject received the Advanced therapy investigational medicinal product (ATIMP), OTL-300 (autologous CD34+ cell enriched fraction containing HSPC transduced with the GLOBE LVV encoding for the beta-globin gene), on a single occasion via intraosseous infusion.

    Subject analysis set title
    mITT Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    mITT Population comprised of subjects received mobilization + conditioning + OTL-300 and completed the 2-year study.

    Primary: Overall survival

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    End point title
    		 Overall survival [1]
    End point description
    Overall survival of all nine subjects in the mITT Population at the end of the 24-month follow up.
    End point type
    Primary
    End point timeframe
    Day 1 -2 Years
    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: No statistical analysis has been specified for this endpoint as it is a single arm study with no comparator.
    End point values
    		 OTL-300
    Number of subjects analysed
    9
    Units: percent
    number (confidence interval 95%)
        Proportion surviving at end of follow-up
    100 (66.37 to 100)
        Kaplan-Meier estimate of survival
    100 (100 to 100)
    No statistical analyses for this end point

    Primary: Achievement of hematological engraftment

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    End point title
    		 Achievement of hematological engraftment [2]
    End point description
    Hematological engraftment was defined as neutrophil count >500/mm^3 and platelets >20,000/mm^3 on three consecutive blood counts (in the absence of transfusions).
    End point type
    Primary
    End point timeframe
    by Day +60 from OTL-300 infusion
    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: No statistical analysis has been specified for this endpoint as it is a single arm study with no comparator.
    End point values
    		 OTL-300
    Number of subjects analysed
    9
    Units: Percentage
    number (confidence interval 95%)
        Hematological engraftment (%)
    100 (70.1 to 100)
    No statistical analyses for this end point

    Primary: Exposure to OTL-300 Infusion

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    End point title
    		 Exposure to OTL-300 Infusion [3]
    End point description
    Exposure to OTL-300 Infusion was defined by the mean number of CD34+ cells infused, mean transduction efficiency and mean VCN.
    End point type
    Primary
    End point timeframe
    0–24 months
    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: No statistical analysis has been specified for this endpoint as it is a single arm study with no comparator.
    End point values
    		 OTL-300
    Number of subjects analysed
    9
    Units: Percent/cells
    arithmetic mean (standard deviation)
        CD34+ cells [x 10^6/kg]
    18.99 ( 1.182 )
        Transduction efficiency [%]
    59.4 ( 10.74 )
        VCN [copies/cell]
    0.93 ( 0.269 )
    No statistical analyses for this end point

    Primary: Polyclonal engraftment

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    End point title
    		 Polyclonal engraftment [4]
    End point description
    Polyclonality of hematopoiesis was defined as >1000 unique integration sites retrieved from peripheral blood and/or bone marrow cells when available.
    End point type
    Primary
    End point timeframe
    Polyclonal engraftment evaluated by integration analysis at 6, 12, 18, 24 months after OTL-300 infusion.
    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: No statistical analysis has been specified for this endpoint as it is a single arm study with no comparator.
    End point values
    		 OTL-300
    Number of subjects analysed
    9
    Units: Percent
    median (confidence interval 95%)
        6 months
    100 (70.1 to 100)
        12 months
    88.9 (56.5 to 98.0)
        18 months
    77.8 (45.3 to 93.7)
        24 months
    100 (70.1 to 100)
        Any time
    100 (70.1 to 100)
    No statistical analyses for this end point

    Primary: Transfusion Independence

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    End point title
    		 Transfusion Independence [5]
    End point description
    Transfusion independence was defined as less than or equal to one transfusion in the previous 6 months.
    End point type
    Primary
    End point timeframe
    Transfusion independence at 12 and 24 months after OTL-300 infusion.
    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: No statistical analysis has been specified for this endpoint as it is a single arm study with no comparator.
    End point values
    		 OTL-300
    Number of subjects analysed
    9
    Units: percent
    number (confidence interval 95%)
        Transfusion Independence (Overall)/12 months/N=9
    55.6 (26.7 to 81.1)
        Transfusion Independence (Overall)/24 months/N=9
    44.4 (18.9 to 73.3)
        Transfusion Independence (3–7 yrs)/12 months/N=3
    66.7 (20.8 to 93.9)
        Transfusion Independence (3–7 yrs)/24 months/N=3
    66.7 (20.8 to 93.9)
        Transfusion Independence (8–17 yrs)/12 months/N=3
    66.7 (20.8 to 93.9)
        Transfusion Independence (8–17 yrs)/24 months/N=3
    66.7 (20.8 to 93.9)
        Transfusion Independence (≥18 yrs)/12 months/N=3
    33.3 (6.1 to 79.2)
        Transfusion Independence (≥18 yrs)/24 months/N=3
    0 (0 to 56.1)
    No statistical analyses for this end point

    Primary: Achievement of adequate Hb in transfusion independent subjects

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    End point title
    		 Achievement of adequate Hb in transfusion independent subjects [6]
    End point description
    Achievement of adequate hemoglobin in transfusion independent subjects defined as Hb >9 g/dL (adult) or >10 g/dL (child).
    End point type
    Primary
    End point timeframe
    Achievement of adequate hemoglobin in transfusion independent subjects measured at 9, 12, 18 and 24 months.
    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: No statistical analysis has been specified for this endpoint as it is a single arm study with no comparator.
    End point values
    		 OTL-300
    Number of subjects analysed
    9
    Units: percent
    number (not applicable)
        Adequate Hb level (3-7 yrs)/12 months/N=2
    0
        Adequate Hb level (3-7 yrs)/24 months/N=2
    0
        Adequate Hb level (8-17 yrs)/12 months/N=2
    100
        Adequate Hb level (8-17 yrs)/24 months/N=2
    100
        Adequate Hb level (>=18 yrs)/12 months/N=1
    0
        Adequate Hb level (>=18 yrs)/24 months/N=0
    0
    No statistical analyses for this end point

    Primary: Transfusion Frequency

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    End point title
    		 Transfusion Frequency [7]
    End point description
    Reduction in transfusion frequency from baseline.
    End point type
    Primary
    End point timeframe
    Baseline transfusion frequency is presented for the 6-month period from Month -7 to Month -1. Post-treatment transfusion frequency is presented for the last 6 months of the study (Month 19 to Month 24).
    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: Application of Poisson generalized linear mixed-model repeated measures was used to compare transfusion frequency after OTL-300 infusion with Pre-Treatment. Comparing 19 to 24 months vs. Pre-Treatment for the overall population (N=9), this indicated a significant decrease in Least Squares Mean annualized transfusion frequency (ratio versus Pre-Treatment = 0.13; p<0.001).
    End point values
    		 OTL-300
    Number of subjects analysed
    9
    Units: Annualized Transfusion Frequency
    median (full range (min-max))
        Transfusion Frequency (Overall)/Pre-treatment/N=9
    19.96 (14.0 to 33.9)
        Transfusion Frequency (Overall)/19–24 months/N=9
    10.19 (0 to 24.4)
        Transfusion Frequency (3–7 yrs)/Pre-treatment/N=3
    17.96 (14.0 to 25.9)
        Transfusion Frequency (3–7 yrs)/19–24 months/N=3
    0 (0 to 12.6)
        Transfusion Frequency (8–17 yrs)/Pre-treatment/N=3
    19.96 (18.0 to 22.0)
        Transfusion Frequency (8–17 yrs)/19–24 months/N=3
    0 (0 to 20.5)
        Transfusion Frequency (≥18 yrs)/Pre-treatment/N=3
    27.94 (18.0 to 33.9)
        Transfusion Frequency (≥18 yrs)/19–24 months/N=3
    11.85 (10.2 to 24.4)
    No statistical analyses for this end point

    Primary: Transfusion Volume

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    End point title
    		 Transfusion Volume [8]
    End point description
    Reduction in annualised transfusion volume from baseline.
    End point type
    Primary
    End point timeframe
    Baseline transfusion volume is presented for the 6-month period from Month -7 to Month -1. Post-treatment transfusion volume is presented for the last 6 months of the study (Month 19 to Month 24).
    Notes
    [8] - 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: Application of Poisson generalized linear mixed-model repeated measures was used to compare transfusion volume after OTL-300 infusion with Pre-Treatment. Comparing 19 to 24 months vs. Pre-Treatment for the overall population (N=9), this indicated a significant decrease in Least Squares Mean annualized transfusion volume (ratio versus Pre-Treatment = 0.02; p<0.001).
    End point values
    		 OTL-300
    Number of subjects analysed
    9
    Units: Annualized Transfusion Volume mL/kg/year
    median (full range (min-max))
        Transfusion Volume (Overall)/Pre-treatment/N=9
    257.41 (190.4 to 346.4)
        Transfusion Volume (Overall)/ 19–24 months/N=9
    85.99 (0 to 237.9)
        Transfusion Volume (3–7 yrs)/Pre-treatment/N=3
    297.56 (190.4 to 346.4)
        Transfusion Volume (3–7 yrs)/ 19–24 months/N=3
    0 (0 to 231.8)
        Transfusion Volume (8–17 yrs)/Pre-treatment/N=3
    248.48 (239.6 to 257.4)
        Transfusion Volume (8–17 yrs)/19–24 months/N=3
    0 (0 to 234.4)
        Transfusion Volume (≥18 yrs)/Pre-treatment/N=3
    266.51 (196.8 to 285.9)
        Transfusion Volume (≥18 yrs)/19–24 months/N=3
    93.22 (86.0 to 237.9)
    No statistical analyses for this end point

    Primary: Engraftment of genetically corrected cells in bone marrow

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    End point title
    		 Engraftment of genetically corrected cells in bone marrow [9]
    End point description
    Adequate engraftment is defined as a vector copy number (VCN) >= 0.15 assessed on bone marrow erythroid cells (both CD36+ and glycophorin-A+).
    End point type
    Primary
    End point timeframe
    From 6 months to 24 months
    Notes
    [9] - 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: No statistical analysis has been specified for this endpoint as it is a single arm study with no comparator.
    End point values
    		 OTL-300
    Number of subjects analysed
    9
    Units: percent
    number (confidence interval 95%)
        Engraftment (Overall)/6 months/N=9
    100 (70.1 to 100)
        Engraftment (Overall)/12 months/N=9
    77.8 (45.3 to 93.7)
        Engraftment (Overall)/24 months/N=9
    77.8 (45.3 to 93.7)
        Engraftment (3-7 yrs)/6 months/N=3
    100 (43.9 to 100)
        Engraftment (3-7 yrs)/12 months/N=3
    66.7 (20.8 to 93.9)
        Engraftment (3-7 yrs)/24 months/N=3
    66.7 (20.8 to 93.9)
        Engraftment (8-17 yrs)/6 months/N=3
    100 (43.9 to 100)
        Engraftment (8-17 yrs)/12 months/N=3
    66.7 (20.8 to 93.9)
        Engraftment (8-17 yrs)/24 months/N=3
    66.7 (20.8 to 93.9)
        Engraftment (>=18 yrs)/6 months/N=3
    100 (43.9 to 100)
        Engraftment (>=18 yrs)/12 months/N=3
    100 (43.9 to 100)
        Engraftment (>=18 yrs)/18 months/N=3
    100 (43.9 to 100)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of mobilization until Month 24.
    Adverse event reporting additional description
    All AEs were identified using Medical Dictionary for Regulatory Activities (MedDRA version 21.1) terms and for each event the following parameters were recorded: intensity or severity (see below); onset date; stop date; causality assessment with study drug (related/not related); action taken; outcome.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    OTL-300
    Reporting group description
    		 -

    Serious adverse events
    		 OTL-300
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 9 (44.44%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mycobacterium fortuitum infection
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 9 (11.11%)
         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
    		 OTL-300
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 9 (55.56%)
         occurrences all number
    9
    Asthenia
         subjects affected / exposed
    4 / 9 (44.44%)
         occurrences all number
    5
    Oedema peripheral
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    7
    Axillary pain
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Catheter site erythema
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Catheter site pain
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Influenza like illness
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Injection site pain
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Injection site swelling
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Perineal erythema
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Testicular pain
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    3 / 9 (33.33%)
         occurrences all number
    5
    Epistaxis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Hiccups
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Nasal turbinate hypertrophy
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    2
    Psychiatric disorders
    Panic attack
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    2
    Investigations
    Liver iron concentration increased
         subjects affected / exposed
    3 / 9 (33.33%)
         occurrences all number
    3
    Weight increased
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Blood creatinine increased
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    2
    Enterobacter test positive
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Liver iron concentration abnormal
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Staphylococcus test positive
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Urine protein/creatinine ratio increased
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Vitamin B12 decreased
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Joint injury
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Limb injury
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    2
    Post procedural fever
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Procedural pain
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 9 (33.33%)
         occurrences all number
    4
    Dysaesthesia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Syncope
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    5 / 9 (55.56%)
         occurrences all number
    5
    Lymphopenia
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Coagulopathy
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Lymphadenopathy
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Neutropenia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    6 / 9 (66.67%)
         occurrences all number
    7
    Diarrhoea
         subjects affected / exposed
    5 / 9 (55.56%)
         occurrences all number
    7
    Abdominal pain
         subjects affected / exposed
    4 / 9 (44.44%)
         occurrences all number
    8
    Abdominal pain upper
         subjects affected / exposed
    3 / 9 (33.33%)
         occurrences all number
    5
    Nausea
         subjects affected / exposed
    3 / 9 (33.33%)
         occurrences all number
    4
    Constipation
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Gingival bleeding
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Cholelithiasis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Hepatitis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Jaundice
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash erythematous
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Drug eruption
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Erythema
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Nodular rash
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Petechiae
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Rash pruritic
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 9 (33.33%)
         occurrences all number
    9
    Bone pain
         subjects affected / exposed
    3 / 9 (33.33%)
         occurrences all number
    3
    Arthralgia
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Spinal pain
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    2
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    3 / 9 (33.33%)
         occurrences all number
    3
    Influenza
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    3
    Pharyngitis
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Conjunctivitis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Folliculitis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Helicobacter infection
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Human bocavirus infection
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Nasal herpes
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    3
    Nasopharyngitis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Oral herpes
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Periorbital infection
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Salmonellosis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Streptococcal infection
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Streptococcal sepsis
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    4 / 9 (44.44%)
         occurrences all number
    4
    Folate deficiency
         subjects affected / exposed
    2 / 9 (22.22%)
         occurrences all number
    2
    Diabetes mellitus
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Hyperferritinaemia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    2
    Hypokalaemia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 9 (11.11%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Nov 2015
    The planned assessment of globin expression by high performance liquid chromatography was removed due to the closure of the bioanalytical laboratory.
    10 May 2016
    • The conditioning regimen for Group 3 (aged 3–7 years) was modified to be the same as Group 2 (aged 8–17 years). This change was implemented before any subjects in Group 3 were treated. • Inclusion of two additional research endpoints (#2 and #3 in Section 8.2.3).

    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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