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    Clinical Trial Results:
    A Phase 1/2, Open-Label Safety and Dose-Finding Study of Adeno-Associated Virus (AAV) Serotype 8 (AAV8)-Mediated Gene Transfer of Glucose-6-Phosphatase (G6Pase) in Adults with Glycogen Storage Disease Type Ia (GSDIa)

    Summary
    EudraCT number
    		 2016-003023-30
    Trial protocol
    		 ES   NL  
    Global end of trial date
    02 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    401GSDIA01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03517085
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ultragenyx Pharmaceutical Inc.
    Sponsor organisation address
    60 Leveroni Court, Novato, United States, California 94949
    Public contact
    Patient Advocacy, Ultragenyx Pharmaceutical, Inc., +1 415 756-8657, Trialrecruitment@ultragenyx.com
    Scientific contact
    Medical Information, Ultragenyx Pharmaceutical, Inc., +1 888 756-8657, medinfo@ultragenyx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    02 Nov 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to determine the safety of single doses of DTX401, including the incidence of dose-limiting toxicities (DLTs) at each dose level.
    Protection of trial subjects
    The trial was designed, conducted, recorded, and reported in accordance with the principles established by the 18th World Medical Association General Assembly (Helsinki, 1964) and subsequent amendments and clarifications adopted by the General Assemblies. The investigators made every effort to ensure that the study was conducted in full conformance with Helsinki principles, International Council for Harmonization (ICH) Good Clinical Practice (GCP) guidelines, current Food and Drug Administration (FDA) regulations, EU Clinical Trial Directive 2001/20/EC, and local ethical and regulatory requirements. Each investigator was thoroughly familiar with the appropriate administration and potential risks of administration of the study drug, as described in the protocol and Investigator’s Brochure, prior to the initiation of the study. The method of obtaining and documenting informed consent and the contents of the informed consent form (ICF) complied with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of Human Subjects,” the Health Insurance Portability and Accountability Act regulations, and all other applicable regulatory requirements. Investigators were responsible for preparing the ICF and submitting it to the Sponsor for approval prior to submission to the Institutional Review Board (IRB). All ICFs were written in regional language and contained the minimum elements for consent as mandated by the ICH guidelines. An IRB-approved ICF was provided by the Sponsor prior to initiation of the study. Investigators obtained signed written informed consent from each potential study subject prior to the conduct of any study procedures and after the methods, objectives, requirements, and potential risks of the study were fully explained to each potential subject. Consent for participation could be withdrawn at any time for any reason by the subject.
    Background therapy
    		 During the study, participants were administered oral prednisone or prednisolone as a reactive ( Cohorts 1 and 2; 6 weeks, at a starting dose of 40 mg/day, after ALT elevation), optimized reactive (Cohort 3; 7 weeks, at a starting dose of 60 mg/day, after ALT elevation), or prophylactic (Cohort 4; 8 weeks, at a starting dose of 60 mg/day, starting on Day 1) regimen to manage alanine aminotransferase (ALT) elevation.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 May 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United States: 8
    Country: Number of subjects enrolled
    Canada: 1
    Worldwide total number of subjects
    12
    EEA total number of subjects
    3
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    12
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Eligible participants were enrolled sequentially into 4 cohorts of 3 participants each and received a single intravenous (IV) infusion of DTX401, with steroids (prednisone/prednisolone) to manage alanine aminotransferase (ALT) elevation.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DTX401 Cohort 1
    Arm description
    		 DTX401 Dose 1 (2.0 × 10^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after ALT elevation)
    Arm type
    		 Experimental

    Investigational medicinal product name
    DTX401
    Investigational medicinal product code
    Other name
    AAV8G6PC, Pariglasgene brecaparvovec
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    DTX401 administered as a single peripheral intravenous (IV) infusion

    Arm title
    		 DTX401 Cohort 2
    Arm description
    		 DTX401 Dose 2 (6.0 × 10^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after ALT elevation)
    Arm type
    		 Experimental

    Investigational medicinal product name
    DTX401
    Investigational medicinal product code
    Other name
    AAV8G6PC, Pariglasgene brecaparvovec
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    DTX401 administered as a single peripheral intravenous (IV) infusion

    Arm title
    		 DTX401 Cohort 3
    Arm description
    		 DTX 401 Dose 2 (6.0 × 10^12 GC/kg) with an optimized reactive steroid regimen (7 weeks, at a starting dose of 60 mg/day, after ALT elevation)
    Arm type
    		 Experimental

    Investigational medicinal product name
    DTX401
    Investigational medicinal product code
    Other name
    AAV8G6PC, Pariglasgene brecaparvovec
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    DTX401 administered as a single peripheral intravenous (IV) infusion

    Arm title
    		 DTX401 Cohort 4
    Arm description
    		 DTX401 Dose 2 (6.0 × 10^12 GC/kg) with a prophylactic steroid regimen (8 weeks, at a starting dose of 60 mg/day, starting on Day 1)
    Arm type
    		 Experimental

    Investigational medicinal product name
    DTX401
    Investigational medicinal product code
    Other name
    AAV8G6PC; Pariglasgene brecaparvovec
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    DTX401 administered as a single peripheral intravenous (IV) infusion

    Number of subjects in period 1
    		DTX401 Cohort 1 DTX401 Cohort 2 DTX401 Cohort 3 DTX401 Cohort 4
    Started
    3
    3
    3
    3
    Completed
    3
    3
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DTX401 Cohort 1
    Reporting group description
    		 DTX401 Dose 1 (2.0 × 10^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after ALT elevation)

    Reporting group title
    DTX401 Cohort 2
    Reporting group description
    		 DTX401 Dose 2 (6.0 × 10^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after ALT elevation)

    Reporting group title
    DTX401 Cohort 3
    Reporting group description
    		 DTX 401 Dose 2 (6.0 × 10^12 GC/kg) with an optimized reactive steroid regimen (7 weeks, at a starting dose of 60 mg/day, after ALT elevation)

    Reporting group title
    DTX401 Cohort 4
    Reporting group description
    		 DTX401 Dose 2 (6.0 × 10^12 GC/kg) with a prophylactic steroid regimen (8 weeks, at a starting dose of 60 mg/day, starting on Day 1)

    Reporting group values
    		 DTX401 Cohort 1 DTX401 Cohort 2 DTX401 Cohort 3 DTX401 Cohort 4 Total
    Number of subjects
    		 3 3 3 3 12
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45.3 ± 15.3 29.7 ± 10.1 26.0 ± 13.9 25.0 ± 5.2 -
    Gender categorical
    Units: Subjects
        Female
    		 1 0 2 1 4
        Male
    		 2 3 1 2 8
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 1 0 0 1
        Not Hispanic or Latino
    		 3 2 3 3 11
    Race
    Units: Subjects
        White
    		 3 3 3 3 12
    Controlled Fasting Challenge: Time to First Hypoglycemic Event [
    Time (in hours) to first hypoglycemic event (defined as glucose < 54 mg/dL [< 3.0 mmol/L]) during a controlled fasting challenge.
    Units: hours
        arithmetic mean (standard deviation)
    		 4.4 ± 0.9 4.5 ± 1.4 2.3 ± 1.2 2.5 ± 0.9 -

    End points

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    End points reporting groups
    Reporting group title
    DTX401 Cohort 1
    Reporting group description
    		 DTX401 Dose 1 (2.0 × 10^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after ALT elevation)

    Reporting group title
    DTX401 Cohort 2
    Reporting group description
    		 DTX401 Dose 2 (6.0 × 10^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after ALT elevation)

    Reporting group title
    DTX401 Cohort 3
    Reporting group description
    		 DTX 401 Dose 2 (6.0 × 10^12 GC/kg) with an optimized reactive steroid regimen (7 weeks, at a starting dose of 60 mg/day, after ALT elevation)

    Reporting group title
    DTX401 Cohort 4
    Reporting group description
    		 DTX401 Dose 2 (6.0 × 10^12 GC/kg) with a prophylactic steroid regimen (8 weeks, at a starting dose of 60 mg/day, starting on Day 1)

    Primary: Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs)

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    End point title
    		 Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs) [1]
    End point description
    An AE is defined as any untoward medical occurrence, regardless of its causal relationship to study product. An SAE is defined as any event that: results in death; is immediately life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; or an important medical event, in the opinion of the investigator. The relationship to study drug was categorized as unrelated, possible, probable or definite. A DLT is defined as any AE/SAE ≥ Grade 3 that is considered by the Investigator and/or Sponsor to be related to DTX401, based on the Nation Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 or later version. Per protocol, SAEs that occurred > 30 days after EOS or Early withdrawal visit, did not need to be reported unless Investigator considered them related to study product.
    End point type
    Primary
    End point timeframe
    AEs Prior to Dosing: From signing the informed consent form (ICF) to first dose of study drug. TEAEs: From first dose of study drug through the End of Study (EOS)/Early Withdrawal visit (up to Week 52) plus 30 days.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented per protocol.
    End point values
    		 DTX401 Cohort 1 DTX401 Cohort 2 DTX401 Cohort 3 DTX401 Cohort 4
    Number of subjects analysed
    3
    3
    3
    3
    Units: participants
        AE started prior to dosing
    1
    1
    2
    2
        Any TEAE
    3
    3
    3
    3
        Related TEAE
    3
    3
    3
    3
        Serious TEAE
    2
    1
    1
    0
        Serious related TEAE
    0
    0
    0
    0
        Grade 3 or 4 TEAE
    0
    0
    1
    0
        Dose-limiting toxicity
    0
    0
    0
    0
        TEAE leading to study discontinuation
    0
    0
    0
    0
        TEAE leading to death
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Time to First Hypoglycemic Event Over Time

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    End point title
    		 Change From Baseline in Time to First Hypoglycemic Event Over Time
    End point description
    The change from baseline in time (in hours) to first hypoglycemic event (defined as glucose < 54 mg/dL [< 3.0 mmol/L]) during a controlled fasting challenge at 12, 24, and 52 weeks after IV administration of DTX401. A positive change from baseline is favorable. n=participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 52
    End point values
    		 DTX401 Cohort 1 DTX401 Cohort 2 DTX401 Cohort 3 DTX401 Cohort 4
    Number of subjects analysed
    3
    3
    3
    3 [2]
    Units: hours
    arithmetic mean (standard deviation)
        Change at Week 12; n=3, 3, 3, 0
    3.3 ± 2.0
    1.7 ± 0.6
    1.4 ± 0.8
    99999 ± 99999
        Change at Week 24; n=3, 3, 3, 1
    4.3 ± 4.2
    0.5 ± 0.6
    0.7 ± 1.7
    0.3 ± 999999
        Change at Week 52; n=3, 3, 2, 3
    4.2 ± 2.2
    -1.8 ± 1.7
    -0.6 ± 0.1
    3.6 ± 2.7
    Notes
    [2] - 99999=NA (no participants assessed); 999999=NA (1 participant assessed)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug (treatment emergent adverse events) through the End of Study/Early Withdrawal visit (up to Week 52) plus 30 days.
    Adverse event reporting additional description
    Per protocol, serious events that occurred > 30 days after EOS or Early withdrawal visit, did not need to be reported unless Investigator considered them related to study product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    DTX401 Cohort 1
    Reporting group description
    		 DTX401 Dose 1 (2.0 × 10^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after ALT elevation)

    Reporting group title
    DTX401 Cohort 2
    Reporting group description
    		 DTX401 Dose 2 (6.0 × 10^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after ALT elevation)

    Reporting group title
    DTX401 Cohort 3
    Reporting group description
    		 DTX401 Dose 2 (6.0 × 10^12 GC/kg) with an optimized reactive steroid regimen (7 weeks, at a starting dose of 60 mg/day, after ALT elevation)

    Reporting group title
    DTX401 Cohort 4
    Reporting group description
    		 DTX401 Dose 2 (6.0 × 10^12 GC/kg) with a prophylactic steroid regimen (8 weeks, at a starting dose of 60 mg/day, starting on Day 1)

    Reporting group title
    Total
    Reporting group description
    		 DTX401 Dose 1 (2.0 × 10^12 GC/kg) or DTX401 Dose 2 (6.0 × 10^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after ALT elevation), an optimized reactive steroid regimen (7 weeks, at a starting dose of 60 mg/day, after ALT elevation), or a prophylactic steroid regimen (8 weeks, at a starting dose of 60 mg/day, starting on Day 1)

    Serious adverse events
    		 DTX401 Cohort 1 DTX401 Cohort 2 DTX401 Cohort 3 DTX401 Cohort 4 Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    4 / 12 (33.33%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Lactic Acidosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic Disorder
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 DTX401 Cohort 1 DTX401 Cohort 2 DTX401 Cohort 3 DTX401 Cohort 4 Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    12 / 12 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Chills
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Face Oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    1
    1
    2
    Hunger
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Thirst
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Immune system disorders
    Food Allergy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Hypersensitivity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    0
    2
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Prostatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Oropharyngeal Pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    1
    0
    3
    Rhinorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Upper Respiratory Tract Congestion
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Anxiety
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    3 / 12 (25.00%)
         occurrences all number
    1
    0
    1
    1
    3
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    1
    0
    2
    Libido Increased
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    0
    0
    2
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    6 / 12 (50.00%)
         occurrences all number
    0
    2
    3
    7
    12
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    3
    0
    3
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    4 / 12 (33.33%)
         occurrences all number
    1
    4
    1
    0
    6
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Blood Glucose Fluctuation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    0
    2
    Blood Uric Acid Increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Heart Rate Increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Hepatic Enzyme Increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    2
    0
    3
    Liver Function Test Increased
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    5
    1
    0
    0
    6
    Weight Decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Injury, poisoning and procedural complications
    Arthropod Bite
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Foot Fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Muscle Strain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Stoma Site Discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Headache
         subjects affected / exposed
    3 / 3 (100.00%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    8 / 12 (66.67%)
         occurrences all number
    8
    5
    4
    1
    18
    Hypoaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Migraine
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Blood and lymphatic system disorders
    Iron Deficiency Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Polycythaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Abdominal Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    1
    0
    2
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    5 / 12 (41.67%)
         occurrences all number
    1
    3
    2
    0
    6
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    1
    0
    2
    Gastrointestinal Disorder
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Malabsorption
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Mouth Ulceration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Nausea
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    4 / 12 (33.33%)
         occurrences all number
    1
    2
    2
    0
    5
    Toothache
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    5 / 12 (41.67%)
         occurrences all number
    1
    3
    3
    0
    7
    Hepatobiliary disorders
    Hepatic Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Alopecia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Dermatitis Acneiform
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Hair Growth Abnormal
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Rash
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    1
    2
    0
    0
    3
    Skin Striae
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Skin Ulcer
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    3 / 12 (25.00%)
         occurrences all number
    1
    0
    1
    1
    3
    Proteinuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    1
    0
    2
    Endocrine disorders
    Adrenal Insufficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Adrenal Suppression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Glucocorticoid Deficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    2
    0
    1
    0
    3
    Back Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Gouty Arthritis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Joint Noise
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Muscle Spasms
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    2
    0
    1
    0
    3
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Pain In Extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Plantar Fasciitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Infections and infestations
    Abdominal Wall Infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Covid-19
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Folliculitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Gastrointestinal Infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Gastrointestinal Viral Infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Hordeolum
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    1
    0
    2
    Oral Candidiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Sinobronchitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    1
    0
    0
    2
    Tinea Pedis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    1
    1
    1
    0
    3
    Urinary Tract Infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Viral Infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    4 / 12 (33.33%)
         occurrences all number
    0
    2
    2
    5
    9
    Hyperlipidaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    1
    0
    2
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    3 / 12 (25.00%)
         occurrences all number
    2
    0
    0
    5
    7
    Hypoglycaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    4 / 12 (33.33%)
         occurrences all number
    1
    2
    2
    3
    8
    Lactic Acidosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Vitamin D Deficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Dec 2017
    • Lactate testing was removed (except during the controlled fasting challenge). • It was updated that subjects would be dosed at a minimum of 2 weeks (14 days) apart. • Anti-G6Pase antibody testing was added as an exploratory objective and endpoint and as a safety assessment. • The Week 2 visit was removed and an outpatient visit was added at Day 13. • Exclusion criterion #8 was updated to exclude subjects based on the presence of, or history of treatment for, hepatitis B or hepatitis C. • Previous genotyping results could be used to satisfy entry criteria. • The definition of a dose-limiting toxicity was added. • Sample size justification was added.
    02 Mar 2018
    • Instructions for treating hypoglycemia after the controlled fasting challenge were added.
    18 Feb 2019
    • The stopping criteria for the controlled fasting challenge was updated to include symptoms of hypoglycemia. • An exploratory objective and endpoint were added to assess the impact of DTX401 on morning glucose levels. Corresponding assessments and analyses were added. • A Morning Glucose Level worksheet was added. • Use of cornstarch was updated from other analyses to efficacy analyses.
    10 Sep 2019
    • The dosing interval for subjects after Cohort 2 was decreased to ≥1 week. • The starting dose for reactive steroids was increased from 40 to 60 mg/day. • The criterion for initiating steroids was modified to an increase in ALT compared to baseline or recently drawn levels. • Language was added to allow consideration of steroid regimen modification if a subject’s ALT levels do not normalize during the steroid taper. • The target carbohydrate range of the prefasting challenge dinner meal was decreased to 15–20 g, and the prefasting challenge cornstarch dose was decreased to 5 g. • Blood sample collection for measurement of glucose and lactate levels was added at the beginning of the fasting challenge to provide baseline levels. • Symptoms of hypoglycemia was removed as a fasting challenge stopping criterion. • Fasting challenge data to be captured in the eCRF was updated. • Continuous glucose monitoring was added. • The exploratory study objective and endpoint related to morning glucose level were modified to glucose level (due to the addition of continuous glucose monitoring). • Measurement of lipid levels was added on the morning before the fasting challenge. • Measurement of cortisol, fatty acid, glucagon, insulin, and ketone levels was added at the beginning and end of the fasting challenge. • Measurement of cortisol levels was added ~1 week before the Week 12 visit. • The interval for liver function testing was decreased. • Health-related quality of life assessments were added at Weeks 24 and 52. • The Screening Period was increased from 42 to 56 days. • The frequency of assessing prescribed diet/cornstarch and diet/cornstarch intake was increased to weekly. • Measurement of weight was added at Weeks 6, 12, 24, and 36. Magnetic resonance imaging was moved from safety assessments to efficacy assessments.
    28 Oct 2019
    • Cohort 4 was added to assess a prophylactic oral steroid regimen for the prevention of vector-induced hepatitis after DTX401 administration. • Language was added to clarify that prescribed diet and diet intake should be assessed during scheduled study visits and, if possible, on a weekly basis for the duration of the study. • Language was added to clarify that prescribed cornstarch (or equivalent) and cornstarch (or equivalent) intake should be assessed during scheduled study visits and, if possible, on a weekly basis for the duration of the study. • Language was added to clarify that the CRM model would estimate the MTD of DTX401 regardless of the steroid approach used, reactive vs prophylactic.
    16 Feb 2021
    • The definition of euglycemia for the end of the controlled fasting challenge changed from ≥ 60 mg/dL (≥ 3.33 mmol/L) to ≥ 54 mg/dL (≥ 3.0 mmol/L). • The following changes were made to the controlled fasting challenge: o CFC assessment was removed at Week 6 and optional at Week 12. o The composition of the dinner meal was updated to a personalized meal. o The prefasting cornstarch dose was updated to match the subject’s most recent cornstarch prescription and timing after dinner. o Assessments at the beginning and end of the challenge were updated. o A final sample was added 30 minutes after the challenge. o Capillary glucose measurement was added. • Week 6 was changed to an outpatient visit. Week 12 was changed from inpatient to outpatient (if the subject was still receiving prednisone at the time). • A new section was added to address the COVID-19 pandemic. • The definition of dose-limiting toxicity was revised to include events based on the Sponsor’s evaluation of relatedness to DTX401, as well as the Investigator’s. • A sample for ACTH assessment was added 1 week before the Week 12 visit.

    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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