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    Clinical Trial Results:
    Phase I/II, historical controlled, open-label, non-randomised, single-centre trial to assess the safety and efficacy of EF1αS-ADA lentiviral vector mediated gene modification of autologus CD34+ cells from ADA-deficient individuals

    Summary
    EudraCT number
    		 2010-024253-36
    Trial protocol
    		 GB  
    Global end of trial date
    23 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jul 2020
    First version publication date
    09 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    10MI29
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01380990
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 GTAC reference: GTAC178
    Sponsors
    Sponsor organisation name
    Great Ormond Street Hospital for Children NHS Foundation Trust
    Sponsor organisation address
    30 Guilford Street, London, United Kingdom, WC1N 1EH
    Public contact
    Dr Claire Booth, UCL Institute of Child Health, +44 207 905 2198, C.Booth@ucl.ac.uk
    Scientific contact
    Dr Claire Booth, UCL Institute of Child Health, +44 207 905 2198, C.Booth@ucl.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001974-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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Dec 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study were to assess the safety and efficacy of EFS-ADA LV-mediated gene therapy (OTL-101*) for the treatment of ADA-SCID subjects
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines, the general principles indicated in the Declaration of Helsinki, and all applicable regulatory requirements. Prior to initiation at each study center, the study protocol was reviewed by an Independent Ethics Committee (IEC). All subjects were to provide written informed consent prior to entering the study and before initiation of any study-related procedure (including administration of investigational product). The investigator was responsible for explaining the benefits and risks of participation in the study to each subject or the subject’s legally acceptable representative and for obtaining written informed consent.
    Background therapy
    		 Busulfan was administered intravenously as a single non-myeloablative dose prior to administration of OTL-101*. The dose of Busulfan was according to weight of the individual subject and was based on European Society for Blood and Marrow Transplantation (EBMT) guidelines for Busulfan dosing in children and a recent publication (Bartelink et al., 2012). All subjects were receiving PEG-ADA Enzyme Replacement Therapy (ERT) prior to study participation. PEG-ADA ERT was continued until 1 month (+/- 6 days) post infusion of genetically modified cells. PEG-ADA ERT was restarted if after 180 days there was no evidence of genetically modified cell engraftment and/or failure of T cell recovery. PEG-ADA ERT could be restarted at the PI’s discretion prior to that time point on clinical grounds (e.g. in the event of infections or delayed T cell reconstitution).
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    15 Nov 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Regulatory reason
    Long term follow-up duration
    		 12 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    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)
    28
    Children (2-11 years)
    7
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    0
    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 the UK between 20-Nov-2012 (First Patient First Visit) and 23-Dec-2019 (Last Patient Last Visit, Compassionate Use)

    Pre-assignment
    Screening details
    		 10 subjects were treated with OTL-101* on study. 10 additional patients were treated with OTL-101* within the protocol under a Great Ormond Street Hospital (GOSH) Specials Licence, constituting the compassionate use program (CUP). 16 patients treated with hematopoietic stem cell transplant (HSCT) at GOSH, constituting the historical control group.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Gene Therapy
    Arm description
    		 Infusion of autologous EFS-ADA LV CD34+ cells
    Arm type
    		 Experimental

    Investigational medicinal product name
    Autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo using the EFS-ADA lentiviral vector (LV)
    Investigational medicinal product code
    OTL-101*
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received OTL-101* following harvest of CD34+ hematopoietic stem and progenitor cell (HSPCs) from leukapheresis or BM and successful transduction and release of OTL-101*. The dose for each subject consisted of at least 0.5 x 10e6 CD34+ cells/kg of body weight. If the total infusion dose for OTL-101* was confirmed to be <0.5 x 10e6 CD34+ cells/kg, it was intended that OTL-101* be administered, followed by the back-up cells. The subject would have been withdrawn from the study.

    Arm title
    		 Historical Control Group
    Arm description
    		 Historical data from a database of ADA-SCID patients treated with allogeneic HSCT from GOSH was collected as comparator group
    Arm type
    		 Haematopoietic Stem Cell Transplantation

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Gene Therapy Historical Control Group
    Started
    20
    16
    Completed
    19
    15
    Not completed
    1
    1
         Treatment Failure
    1
    -
         Death
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Gene Therapy
    Reporting group description
    		 Infusion of autologous EFS-ADA LV CD34+ cells

    Reporting group title
    Historical Control Group
    Reporting group description
    		 Historical data from a database of ADA-SCID patients treated with allogeneic HSCT from GOSH was collected as comparator group

    Reporting group values
    		 Gene Therapy Historical Control Group Total
    Number of subjects
    		 20 16 36
    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)
    		 14 14 28
        Children (2-11 years)
    		 5 2 7
        Adolescents (12-17 years)
    		 1 0 1
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: months
        median (full range (min-max))
    		 11.6 (4 to 193) 13.5 (1 to 118) -
    Gender categorical
    Units: Subjects
        Female
    		 8 0 8
        Male
    		 12 0 12
        Not Reported
    		 0 16 16
    Subject analysis sets

    Subject analysis set title
    HSCT Controls without MRD
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The primary efficacy population from the HSCT historical control cohort comprises ADA-SCID patients without a medically eligible MRD who were treated with HSCT at GOSH from 2000 to 2016. An MRD refers to either a matched sibling or family donor.

    Subject analysis set title
    HSCT Controls with MRD
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Secondary efficacy population for comparison comprise ADA-SCID patients with an MRD treated with HSCT at GOSH from 2000 to 2016

    Subject analysis set title
    All HSCT Controls
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Complete HSCT historical control group consisting of ADA-SCID patients with any type of donor treated with HSCT at GOSH from 2000 to 2016 (referred to as the All HSCT Controls group)

    Subject analysis set title
    OTL-101* On-Study Subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The primary efficacy population for analysis consists of the on-study OTL-101*-treated subjects.

    Subject analysis set title
    OTL-101* On-Study and CUP Subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The safety population consists of all OTL-101*-treated subjects (on-study and CUP). The secondary efficacy population consists of all OTL-101*-treated subjects (on-study and CUP).

    Subject analysis sets values
    		 HSCT Controls without MRD HSCT Controls with MRD All HSCT Controls OTL-101* On-Study Subjects OTL-101* On-Study and CUP Subjects
    Number of subjects
    5
    11
    16
    10
    20
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    4
    10
    14
    9
    14
        Children (2-11 years)
    1
    1
    2
    1
    5
        Adolescents (12-17 years)
    0
    0
    0
    0
    1
        Adults (18-64 years)
    0
    0
    0
    0
    0
        From 65-84 years
    0
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    0
    Age continuous
    Units: months
        median (full range (min-max))
    17.0 (12 to 118)
    4.0 (1 to 37)
    13.5 (1 to 118)
    10.2 (7 to 64)
    11.6 (4 to 193)
    Gender categorical
    Units: Subjects
        Female
    4
    8
        Male
    6
    12
        Not Reported
    5
    11
    16
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Gene Therapy
    Reporting group description
    		 Infusion of autologous EFS-ADA LV CD34+ cells

    Reporting group title
    Historical Control Group
    Reporting group description
    		 Historical data from a database of ADA-SCID patients treated with allogeneic HSCT from GOSH was collected as comparator group

    Subject analysis set title
    HSCT Controls without MRD
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The primary efficacy population from the HSCT historical control cohort comprises ADA-SCID patients without a medically eligible MRD who were treated with HSCT at GOSH from 2000 to 2016. An MRD refers to either a matched sibling or family donor.

    Subject analysis set title
    HSCT Controls with MRD
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Secondary efficacy population for comparison comprise ADA-SCID patients with an MRD treated with HSCT at GOSH from 2000 to 2016

    Subject analysis set title
    All HSCT Controls
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Complete HSCT historical control group consisting of ADA-SCID patients with any type of donor treated with HSCT at GOSH from 2000 to 2016 (referred to as the All HSCT Controls group)

    Subject analysis set title
    OTL-101* On-Study Subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The primary efficacy population for analysis consists of the on-study OTL-101*-treated subjects.

    Subject analysis set title
    OTL-101* On-Study and CUP Subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The safety population consists of all OTL-101*-treated subjects (on-study and CUP). The secondary efficacy population consists of all OTL-101*-treated subjects (on-study and CUP).

    Primary: Overall Survival (OS) of subjects treated with Investigational Medicinal Product (IMP) (1 year)

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    End point title
    		 Overall Survival (OS) of subjects treated with Investigational Medicinal Product (IMP) (1 year) [1]
    End point description
    Overall survival is defined as the proportion of subjects alive at 12 months
    End point type
    Primary
    End point timeframe
    12 months
    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: If there was at least 1 event in each group, it was planned to use the log rank test to compare the difference in survival curves between each OTL-101* treatment groups and each of the HSCT control groups. However, as there was no event in any group at 12 months, this analysis was not carried out.
    End point values
    		 HSCT Controls without MRD HSCT Controls with MRD All HSCT Controls OTL-101* On-Study Subjects OTL-101* On-Study and CUP Subjects
    Number of subjects analysed
    5
    11
    16
    10
    20
    Units: percent
    number (confidence interval 95%)
        Proportion surviving at 12 months (95% CI)
    100 (47.82 to 100)
    100 (71.51 to 100)
    100 (79.41 to 100)
    100 (69.15 to 100)
    100 (83.16 to 100)
    No statistical analyses for this end point

    Primary: Event-free survival (EvFS) of subjects treated with Investigational Medicinal Product (IMP) (1 year)

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    End point title
    		 Event-free survival (EvFS) of subjects treated with Investigational Medicinal Product (IMP) (1 year) [2]
    End point description
    Event-free survival is defined as the proportion of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue allogenic Hematopoietic Stem Cell Transplant (HSCT), or death.
    End point type
    Primary
    End point timeframe
    12 months
    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: If there was at least 1 event in each group, it was planned to use the log rank test to compare the difference in survival curves between each OTL-101* treatment groups and each of the HSCT control groups. However, as there was no event in any group at 12 months, this analysis was not carried out.
    End point values
    		 HSCT Controls without MRD HSCT Controls with MRD All HSCT Controls OTL-101* On-Study Subjects OTL-101* On-Study and CUP Subjects
    Number of subjects analysed
    5
    11
    16
    10
    20
    Units: percent
    number (confidence interval 95%)
        Proportion event-free at 12 months (95% CI)
    100 (47.82 to 100)
    100 (71.51 to 100)
    100 (79.41 to 100)
    100 (69.15 to 100)
    100 (83.16 to 100)
    No statistical analyses for this end point

    Primary: Comparison of OS of subjects treated with IMP with those of patients treated with allogeneic HSCT (1 year)

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    End point title
    		 Comparison of OS of subjects treated with IMP with those of patients treated with allogeneic HSCT (1 year) [3]
    End point description
    Difference in OS of historical control group, "HSCT Controls without MRD", "HSCT Controls with MRD" and "All HSCT Controls group", compared to subjects treated with OTL-101* in the "OTL-101* On-Study" group and "OTL-101* On-Study and CUP Subjects" group.
    End point type
    Primary
    End point timeframe
    12 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: If there was at least 1 event in each group, it was planned to use the log rank test to compare the difference in survival curves between each OTL-101* treatment groups and each of the HSCT control groups. However, as there was no event in any group at 12 months, this analysis was not carried out.
    End point values
    		 HSCT Controls without MRD HSCT Controls with MRD All HSCT Controls
    Number of subjects analysed
    5
    11
    16
    Units: percent
    number (not applicable)
        Difference from OTL-101* on-study subjects
    0
    0
    0
        Difference from OTL-101* on-study and CUP subjects
    0
    0
    0
    No statistical analyses for this end point

    Primary: Vector copy number (VCN) in Granulocyte fraction (Neutrophils)

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    End point title
    		 Vector copy number (VCN) in Granulocyte fraction (Neutrophils) [4]
    End point description
    Engraftment of transduced cells was assessed using vector gene marking in Granulocytes (Neutrophils)
    End point type
    Primary
    End point timeframe
    36 months
    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: As VCN was assessed for the gene therapy arm only, there is no comparator and so formal statistical analysis could not be performed.
    End point values
    		 OTL-101* On-Study Subjects OTL-101* On-Study and CUP Subjects
    Number of subjects analysed
    9 [5]
    18 [6]
    Units: copies/cell
    median (full range (min-max))
        Granulocytes fraction (Neutrophils)
    0.240 (0.15 to 0.79)
    0.280 (0.03 to 1.60)
    Notes
    [5] - 9/10 subjects evaluated for granulocytes at Month 36
    [6] - 18/20 subjects evaluated for granulocytes at Month 36
    No statistical analyses for this end point

    Primary: Vector copy number (VCN) in Peripheral Blood mononuclear cells (PBMCs)

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    End point title
    		 Vector copy number (VCN) in Peripheral Blood mononuclear cells (PBMCs) [7]
    End point description
    Engraftment of transduced cells was assessed using vector gene marking in PBMCs
    End point type
    Primary
    End point timeframe
    36 months
    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: As VCN was assessed for the gene therapy arm only, there is no comparator and so formal statistical analysis could not be performed.
    End point values
    		 OTL-101* On-Study Subjects OTL-101* On-Study and CUP Subjects
    Number of subjects analysed
    9 [8]
    18 [9]
    Units: copies/cell
    median (full range (min-max))
        PBMCs
    0.600 (0.20 to 1.67)
    0.625 (0.20 to 1.67)
    Notes
    [8] - 9/10 subjects evaluated for PBMCs at Month 36
    [9] - 18/20 subjects evaluated for PBMCs at Month 36
    No statistical analyses for this end point

    Primary: Vector copy number (VCN) in CD3+ T Cells

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    End point title
    		 Vector copy number (VCN) in CD3+ T Cells [10]
    End point description
    Engraftment of transduced cells was assessed using vector gene marking in CD3+ T Cells
    End point type
    Primary
    End point timeframe
    36 months
    Notes
    [10] - 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: As VCN was assessed for the gene therapy arm only, there is no comparator and so formal statistical analysis could not be performed.
    End point values
    		 OTL-101* On-Study Subjects OTL-101* On-Study and CUP Subjects
    Number of subjects analysed
    8 [11]
    17 [12]
    Units: copies/cell
    median (full range (min-max))
        CD3+ T cells
    1.065 (0.84 to 1.59)
    1.160 (0.30 to 4.61)
    Notes
    [11] - 8/10 subjects evaluated for CD3+ T Cells at Month 36
    [12] - 17/20 subjects evaluated for CD3+ T Cells at Month 36
    No statistical analyses for this end point

    Primary: Vector copy number (VCN) in CD19+ B Cells

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    End point title
    		 Vector copy number (VCN) in CD19+ B Cells [13]
    End point description
    Engraftment of transduced cells was assessed using vector gene marking in CD19+ B Cells
    End point type
    Primary
    End point timeframe
    36 months
    Notes
    [13] - 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: As VCN was assessed for the gene therapy arm only, there is no comparator and so formal statistical analysis could not be performed.
    End point values
    		 OTL-101* On-Study Subjects OTL-101* On-Study and CUP Subjects
    Number of subjects analysed
    9 [14]
    17 [15]
    Units: copies/cell
    median (full range (min-max))
        CD19+ B cells
    0.880 (0.68 to 1.77)
    1.190 (0.68 to 3.75)
    Notes
    [14] - 9/10 subjects evaluated for CD19+ B Cells at Month 36
    [15] - 17/20 subjects evaluated for CD19+ B Cells at Month 36
    No statistical analyses for this end point

    Primary: Change from Baseline in CD3+ T cell counts (3 years)

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    End point title
    		 Change from Baseline in CD3+ T cell counts (3 years) [16]
    End point description
    Immune reconstitution was assessed by change in CD3+ T Cell counts over time.
    End point type
    Primary
    End point timeframe
    36 months
    Notes
    [16] - 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: Change in CD3+ T Cell counts was assessed for the gene therapy arm only. As this is a single group, there is no comparator and so statistical analysis could not be performed.
    End point values
    		 OTL-101* On-Study Subjects OTL-101* On-Study and CUP Subjects
    Number of subjects analysed
    7 [17]
    16 [18]
    Units: 10e9/L
    median (full range (min-max))
        CD3+ T Cells Change from Baseline
    1.060 (0.59 to 1.47)
    1.090 (-0.49 to 1.47)
    Notes
    [17] - Change from Baseline data available for 7/10 subjects
    [18] - Change from Baseline data available for 16/20 subjects
    No statistical analyses for this end point

    Primary: ADA activity in erythrocytes

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    End point title
    		 ADA activity in erythrocytes [19]
    End point description
    ADA enzyme activity was assessed as a measure of successful engraftment of genetically modified HSPCs, as it marks sustained gene expression from the normal ADA transgene.
    End point type
    Primary
    End point timeframe
    36 months
    Notes
    [19] - 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: Formal statistical analysis was not performed, data was analysed using descriptive statistics.
    End point values
    		 HSCT Controls without MRD HSCT Controls with MRD All HSCT Controls OTL-101* On-Study Subjects OTL-101* On-Study and CUP Subjects
    Number of subjects analysed
    4 [20]
    7 [21]
    11 [22]
    9 [23]
    18 [24]
    Units: nmol/h/mg
    median (full range (min-max))
        ADA Activity
    86.5 (39 to 115)
    1.0 (0 to 27)
    23.0 (0 to 115)
    638.0 (220 to 3038)
    490.5 (27 to 3038)
    Notes
    [20] - Data available for 4/5 subjects at "Over 30 Months post HSCT"
    [21] - Data available for 7/11 subjects at "Over 30 Months post HSCT"
    [22] - Data available for 11/16 subjects at "Over 30 Months post HSCT"
    [23] - Data available for 9/10 subjects at 36 months
    [24] - Data available for 18/20 subjects at 36 months
    No statistical analyses for this end point

    Primary: Reduction in deoxyadenosine triphosphate (dATP) in erythrocytes

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    End point title
    		 Reduction in deoxyadenosine triphosphate (dATP) in erythrocytes [25]
    End point description
    Decreased dATP levels coincide with increased ADA enzyme activity, detoxification was used as a marker of correction of the defective ADA gene. The threshold for detoxification was <100 µmol/L.
    End point type
    Primary
    End point timeframe
    36 months
    Notes
    [25] - 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: Formal statistical analysis was not performed, data was analysed using descriptive statistics.
    End point values
    		 HSCT Controls without MRD HSCT Controls with MRD All HSCT Controls OTL-101* On-Study Subjects OTL-101* On-Study and CUP Subjects
    Number of subjects analysed
    1 [26]
    6 [27]
    7 [28]
    7 [29]
    15 [30]
    Units: umol/L
    median (full range (min-max))
        dATP
    0.0 (0 to 0)
    114.0 (23 to 192)
    90.0 (0 to 192)
    50.0 (50 to 50)
    50.0 (50 to 50)
    Notes
    [26] - Data available for 1/5 subjects at "Over 30 Months post HSCT"
    [27] - Data available for 6/11 subjects at "Over 30 Months post HSCT"
    [28] - Data available for 7/16 subjects at "Over 30 Months post HSCT"
    [29] - Data available for 7/10 subjects at Month 36
    [30] - Data available for 15/20 subjects at Month 36
    No statistical analyses for this end point

    Primary: Analysis of the frequency of vector integration into known protooncogenes (3 years)

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    End point title
    		 Analysis of the frequency of vector integration into known protooncogenes (3 years) [31]
    End point description
    Vector Integration Site Analysis (VISA) allowed determination of the distribution of vector integration sites in each subject’s genome, as well as the relative clonal abundance. VISA was to be considered abnormal for a subject if, in 2 or more instances during the course of follow-up, a single integration site was found to represent >30% of the total integration sites detected.
    End point type
    Primary
    End point timeframe
    36 months
    Notes
    [31] - 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: Vector integration analysis was assessed for the gene therapy arm only. As this is a single group, there is no comparator and so statistical analysis could not be performed.
    End point values
    		 OTL-101* On-Study Subjects OTL-101* On-Study and CUP Subjects
    Number of subjects analysed
    10
    20
    Units: percent
    number (not applicable)
        No. instances of integration >30% total sites
    0
    0
    No statistical analyses for this end point

    Primary: Comparison of EvFS of subjects treated with IMP with those of patients treated with allogeneic HSCT (1 year)

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    End point title
    		 Comparison of EvFS of subjects treated with IMP with those of patients treated with allogeneic HSCT (1 year) [32]
    End point description
    Difference in EvFS of historical control group, "HSCT Controls without MRD", "HSCT Controls with MRD" and "All HSCT Controls group", compared to subjects treated with OTL-101* in the "OTL-101* On-Study" group and "OTL-101* On-Study and CUP Subjects" group.
    End point type
    Primary
    End point timeframe
    12 months
    Notes
    [32] - 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: If there was at least 1 event in each group, it was planned to use the log rank test to compare the difference in survival curves between each OTL-101* treatment groups and each of the HSCT control groups. However, as there was no event in any group at 12 months, this analysis was not carried out.
    End point values
    		 HSCT Controls without MRD HSCT Controls with MRD All HSCT Controls
    Number of subjects analysed
    5
    11
    16
    Units: percent
    number (not applicable)
        Difference from OTL-101* on-study subjects
    0
    0
    0
        Difference from OTL-101* on-study and CUP subjects
    0
    0
    0
    No statistical analyses for this end point

    Primary: Change from Baseline in CD3+ T cell counts (1 year)

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    End point title
    		 Change from Baseline in CD3+ T cell counts (1 year)
    End point description
    Immune reconstitution was assessed by change in CD3+ T Cell counts over time.
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 OTL-101* On-Study Subjects OTL-101* On-Study and CUP Subjects
    Number of subjects analysed
    8
    17
    Units: 10e9/L
    geometric mean (confidence interval 95%)
        Adjusted Mean (95% CI)
    3.58 (1.64 to 7.83)
    3.18 (1.98 to 5.10)
    Statistical analysis title
    		 MMRM Analysis of OTL-101* On-Study at M12
    Statistical analysis description
    MMRM Analysis of Change from Baseline to Month 12 in Log-Transformed CD3+ T Cell count (OTL-101*) for "OTL-101* on-study subjects" group
    Comparison groups
    OTL-101* On-Study Subjects v OTL-101* On-Study and CUP Subjects
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    P-value
    		 = 0.002
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [33] - Model includes fixed effects for visit and Baseline, subject as random effect, with compound symmetry covariance structure. Observations with a value of 0 were imputed as 0.01. Model analyses log transformed data, so the adjusted mean refers to the geometric mean ratio between Month 12 and Baseline.
    Statistical analysis title
    		 MMRM Analysis of OTL-101* On-Study/CUP at M12
    Statistical analysis description
    MMRM Analysis of Change from Baseline to Month 12 in Log-Transformed CD3+ T Cell count (OTL-101*) for "OTL-101* on-study and CUP subjects" group
    Comparison groups
    OTL-101* On-Study and CUP Subjects v OTL-101* On-Study Subjects
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other [34]
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [34] - Model includes fixed effects for visit and Baseline, subject as random effect, with compound symmetry covariance structure. Observations with a value of 0 were imputed as 0.01. Model analyses log transformed data, so the adjusted mean refers to the geometric mean ratio between Month 12 and Baseline.

    Secondary: OS of subjects treated with IMP with those of patients treated with allogeneic HSCT (3 years)

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    End point title
    		 OS of subjects treated with IMP with those of patients treated with allogeneic HSCT (3 years)
    End point description
    Overall survival is defined as the proportion of subjects alive at 36 months
    End point type
    Secondary
    End point timeframe
    36 months
    End point values
    		 HSCT Controls without MRD HSCT Controls with MRD All HSCT Controls OTL-101* On-Study Subjects OTL-101* On-Study and CUP Subjects
    Number of subjects analysed
    5
    11
    16
    10
    20
    Units: percent
    number (confidence interval 95%)
        Proportion surviving at 36 months (95% CI)
    100 (47.82 to 100)
    88.89 (51.75 to 99.72)
    92.86 (66.13 to 99.82)
    100 (66.37 to 100)
    100 (82.35 to 100)
    No statistical analyses for this end point

    Secondary: EvFS of subjects treated with IMP with those of patients treated with allogeneic HSCT (3 years)

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    End point title
    		 EvFS of subjects treated with IMP with those of patients treated with allogeneic HSCT (3 years)
    End point description
    Event-free survival is defined as the proportion of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue allogenic Hematopoietic Stem Cell Transplant (HSCT), or death.
    End point type
    Secondary
    End point timeframe
    36 months
    End point values
    		 HSCT Controls without MRD HSCT Controls with MRD All HSCT Controls OTL-101* On-Study Subjects OTL-101* On-Study and CUP Subjects
    Number of subjects analysed
    5
    11
    16
    10
    20
    Units: percent
    number (confidence interval 95%)
        Proportion event-free at 36 months (95% CI)
    80.00 (28.36 to 99.49)
    60.00 (26.24 to 87.84)
    66.67 (38.38 to 88.18)
    90.00 (55.50 to 99.75)
    95.00 (75.13 to 99.87)
    Statistical analysis title
    		 HSCT without MRD & OTL 101* on-study
    Statistical analysis description
    Comparison of "HSCT Controls without MRD" and "OTL-101* on-study subjects" groups
    Comparison groups
    OTL-101* On-Study Subjects v HSCT Controls without MRD
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.645
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 HSCT without MRD & OTL 101* on-study/CUP
    Statistical analysis description
    Comparison of "HSCT Controls without MRD" and "OTL-101* on-study and CUP subjects" groups
    Comparison groups
    HSCT Controls without MRD v OTL-101* On-Study and CUP Subjects
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.299
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 HSCT with MRD & OTL 101* on-study
    Statistical analysis description
    Comparison of "HSCT Controls with MRD" and "OTL-101* on-study subjects" groups
    Comparison groups
    OTL-101* On-Study Subjects v HSCT Controls with MRD
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 HSCT with MRD & OTL 101* on-study/CUP
    Statistical analysis description
    Comparison of "HSCT Controls with MRD" and "OTL-101* on-study and CUP subjects" groups
    Comparison groups
    HSCT Controls with MRD v OTL-101* On-Study and CUP Subjects
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.028
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 All HSCT & OTL 101* on-study
    Statistical analysis description
    Comparison of "All HSCT Controls" and "OTL-101* on-study subjects" groups
    Comparison groups
    All HSCT Controls v OTL-101* On-Study Subjects
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.259
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 All HSCT & OTL 101* on-study/CUP
    Statistical analysis description
    Comparison of "All HSCT Controls" and "OTL-101* on-study and CUP subjects" groups
    Comparison groups
    All HSCT Controls v OTL-101* On-Study and CUP Subjects
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.044
    Method
    		 Logrank
    Confidence interval

    Secondary: Comparison of OS of subjects treated with IMP with those of patients treated with allogeneic HSCT (3 years)

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    End point title
    		 Comparison of OS of subjects treated with IMP with those of patients treated with allogeneic HSCT (3 years)
    End point description
    Difference in OS of historical control group, "HSCT Controls without MRD", "HSCT Controls with MRD" and "All HSCT Controls group", compared to subjects treated with OTL-101* in the "OTL-101* On-Study" group and "OTL-101* On-Study and CUP Subjects" group.
    End point type
    Secondary
    End point timeframe
    36 months
    End point values
    		 HSCT Controls without MRD HSCT Controls with MRD All HSCT Controls
    Number of subjects analysed
    5
    11
    16
    Units: percent
    number (confidence interval 95%)
        Difference in OS from OTL-101* on-study subjects
    0 (0 to 0)
    11.11 (-22.41 to 48.25)
    7.14 (-28.10 to 34.23)
        Difference from OTL-101* on-study and CUP subjects
    0 (0 to 0)
    11.11 (-10.1 to 48.25)
    7.14 (-12.91 to 33.87)
    No statistical analyses for this end point

    Secondary: Comparison of EvFS of subjects treated with IMP with those of patients treated with allogeneic HSCT (3 years)

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    End point title
    		 Comparison of EvFS of subjects treated with IMP with those of patients treated with allogeneic HSCT (3 years)
    End point description
    Difference in EvFS of historical control group, "HSCT Controls without MRD", "HSCT Controls with MRD" and "All HSCT Controls group", compared to subjects treated with OTL-101* in the "OTL-101* On-Study" group and "OTL-101* On-Study and CUP Subjects" group.
    End point type
    Secondary
    End point timeframe
    36 months
    End point values
    		 HSCT Controls without MRD HSCT Controls with MRD All HSCT Controls
    Number of subjects analysed
    5
    11
    16
    Units: percent
    number (confidence interval 95%)
        Difference from OTL-101* on-study subjects
    10.00 (-32.05 to 61.97)
    30.00 (-10.72 to 65.87)
    23.33 (-15.24 to 54.59)
        Difference from OTL-101* on-study and CUP subjects
    15.00 (-13.70 to 63.54)
    35.00 (2.29 to 68.45)
    28.33 (2.04 to 56.36)
    No statistical analyses for this end point

    Secondary: Infection Rate

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    End point title
    		 Infection Rate
    End point description
    The infections of interest in this study were severe infections or opportunistic infectious episodes, defined as infections requiring hospitalization or prolonging hospitalization and/or documented infections by opportunistic pathogens.
    End point type
    Secondary
    End point timeframe
    36 months
    End point values
    		 HSCT Controls without MRD HSCT Controls with MRD All HSCT Controls OTL-101* On-Study Subjects OTL-101* On-Study and CUP Subjects
    Number of subjects analysed
    5
    11
    16
    10
    20
    Units: per person per year
    number (not applicable)
        Severe infection rate
    0.13
    0.17
    0.16
    0.14
    0.14
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from the time of participant consent to end of trial
    Adverse event reporting additional description
    Adverse events were analysed from OTL-101* administration to end of trial
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    OTL-101* On-Study and CUP Subjects
    Reporting group description
    		 -

    Reporting group title
    OTL-101* On-Study Subjects
    Reporting group description
    		 The safety population for analysis consists of the on-study OTL-101*-treated subjects.

    Serious adverse events
    		 OTL-101* On-Study and CUP Subjects OTL-101* On-Study Subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 20 (55.00%)
    7 / 10 (70.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 20 (30.00%)
    5 / 10 (50.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Bone marrow failure
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Immune reconstitution inflammatory syndrome
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 10 (20.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 10 (30.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transmission of an infectious agent via product
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Weight gain poor
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 OTL-101* On-Study and CUP Subjects OTL-101* On-Study Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 20 (100.00%)
    10 / 10 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma of skin
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Skin papilloma
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Pallor
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 20 (45.00%)
    4 / 10 (40.00%)
         occurrences all number
    16
    9
    Developmental delay
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Infusion site erythema
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Catheter site erythema
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Chest pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Hypothermia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Mucosal inflammation
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Hypermetropia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Amblyopia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Astigmatism
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Strabismus
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Immune reconstitution inflammatory syndrome
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Reproductive system and breast disorders
    Testicular swelling
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 20 (55.00%)
    4 / 10 (40.00%)
         occurrences all number
    19
    6
    Epistaxis
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Rhinorrhoea
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    4
    0
    Wheezing
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Bronchial disorder
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Pharyngeal oedema
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Sapovirus test positive
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    2
    Norovirus test positive
         subjects affected / exposed
    4 / 20 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    4
    1
    Adenovirus test positive
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Weight decreased
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Enterococcus test positive
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Acinetobacter test positive
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Influenza A virus test positive
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Morganella test positive
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Aspiration bone marrow abnormal
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Chest x-ray abnormal
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Computerised tomogram thorax abnormal
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Cytomegalovirus test positive
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Epstein-Barr virus test positive
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    Human metapneumovirus test positive
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Human rhinovirus test positive
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Respirovirus test positive
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Staphylococcus test positive
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Streptococcus test positive
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Hypophagia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 20 (15.00%)
    2 / 10 (20.00%)
         occurrences all number
    3
    2
    Skin abrasion
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Thermal burn
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Congenital, familial and genetic disorders
    Combined immunodeficiency
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Preauricular cyst
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Gross motor delay
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Hypotonia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Speech disorder developmental
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Dizziness
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    7 / 20 (35.00%)
    3 / 10 (30.00%)
         occurrences all number
    9
    3
    Thrombocytopenia
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Lymphopenia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Bone marrow failure
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Febrile neutropenia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Motion sickness
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Deafness neurosensory
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 10 (20.00%)
         occurrences all number
    2
    2
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    9 / 20 (45.00%)
    4 / 10 (40.00%)
         occurrences all number
    13
    5
    Diarrhoea
         subjects affected / exposed
    10 / 20 (50.00%)
    3 / 10 (30.00%)
         occurrences all number
    15
    4
    Constipation
         subjects affected / exposed
    3 / 20 (15.00%)
    3 / 10 (30.00%)
         occurrences all number
    3
    3
    Abdominal pain
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    Mouth ulceration
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Abdominal distension
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Dental caries
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Gastritis
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Oral mucosal erythema
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Stomatitis
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Tongue discolouration
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Nausea
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Proctitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    7 / 20 (35.00%)
    5 / 10 (50.00%)
         occurrences all number
    8
    6
    Rash
         subjects affected / exposed
    7 / 20 (35.00%)
    3 / 10 (30.00%)
         occurrences all number
    10
    5
    Alopecia
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Dry skin
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    Blood blister
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Dermatitis atopic
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Eczema
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Exfoliative rash
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Dermatitis acneiform
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Petechiae
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Skin lesion
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Azotaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    9 / 20 (45.00%)
    5 / 10 (50.00%)
         occurrences all number
    15
    9
    Viral upper respiratory tract infection
         subjects affected / exposed
    7 / 20 (35.00%)
    4 / 10 (40.00%)
         occurrences all number
    12
    7
    Otitis media
         subjects affected / exposed
    3 / 20 (15.00%)
    2 / 10 (20.00%)
         occurrences all number
    4
    2
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 10 (20.00%)
         occurrences all number
    2
    2
    Metapneumovirus infection
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 10 (20.00%)
         occurrences all number
    2
    2
    Viral rash
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 10 (20.00%)
         occurrences all number
    2
    2
    Ear infection
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    2
    Device related infection
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    1
    Hand-foot-and-mouth disease
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Influenza
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Varicella
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 10 (0.00%)
         occurrences all number
    5
    0
    Staphylococcal infection
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Adenovirus infection
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Bronchiolitis
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Impetigo
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Laryngitis
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Tinea capitis
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Tinea infection
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Bronchitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Haemophilus infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Herpes zoster
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Weight gain poor
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    1
    Abnormal loss of weight
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Dehydration
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Feeding intolerance
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Hypercalcaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Metabolic acidosis
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Decreased appetite
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Oct 2012
    Changed busulfan dosage from 4 mg/kg IV to a weight-adjusted dosage after a change to EBMT guidelines for busulfan dosing in children Changed to continue PEG-ADA ERT until after the re-infusion of gene modified cells based on data from a recently published murine study and promising data from 2 patients treated on a compassionate basis
    18 Dec 2013
    Clarified inclusion criterion for patients >5 years of age
    06 May 2014
    Clarified procedure timing of BM harvest versus leukapheresis and storage of back-up cells Corrected to allow a back-up BM harvest to be collected 3 months before gene therapy in cases where this was necessary Clarified that inclusion criterion for subjects based on age was <5 years OR >5 years with preserved thymic function Removed exclusion criterion for evidence of infection with HIV-1&2, hepatitis B, HCV Amended GCSF dose for mobilization Changed monitoring of CD34+ cell counts from Day 4 to Day 5 Removed sequential dosing Added statistical analysis plan for the study Removed Treg analysis before gene therapy Corrected an error in follow-up time points
    29 Sep 2015
    Updated trial summary flow charts to better reflect the instructions in text Amended leukapheresis procedure to 1-2 days Clarified window of PEG-ADA ERT withdrawal Clarified inclusion criteria around age Harmonized and clarified primary and secondary objectives and endpoints Clarified withdrawal of cotrimoxazole concomitant medication Inserted flexibility on GCSF dosing Removed “ADA expression” from testing after infusion Corrected OTL-101* volume bag Removed some tests to monitor immunological reconstitution as they were not needed to demonstrate objectives and required too large a blood draw Created a more detailed subject monitoring schedule Clarified that OTL-101* cell dose specifications were based on CD34+ cells Moved reporting of AEs from patient notes to the CRF
    05 Aug 2016
    Changed trial personnel Added historical HSCT control group Moved from paper CRFs to eCRFs Updated monitoring
    16 Mar 2017
    Rewrote primary and secondary objectives and corresponding endpoints Added the CUP group
    28 Jun 2017
    Updated the schedule of assessment relating to immune reconstitution.

    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.
    Not applicable
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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