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    Clinical Trial Results:
    HYDROXYCHLOROQUINE FOR PREVENTION OF ABNORMAL GLUCOSE TOLERANCE AND DIABETES IN INDIVIDUALS AT-RISK FOR TYPE 1 DIABETES MELLITUS

    Summary
    EudraCT number
    		 2018-000659-42
    Trial protocol
    		 SE   GB   IT   FI  
    Global end of trial date
    01 Nov 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Aug 2024
    First version publication date
    03 Aug 2024
    Other versions
    Summary report(s)
    		 TN-22 Hydroxychloroquine in Stage 1 Type 1 Diabetes Final Study Report

    Trial information

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    Trial identification
    Sponsor protocol code
    TN-22
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    TrialNet
    Sponsor organisation address
    3650 Spectrum Blvd , Tampa, United States, 33612
    Public contact
    Erica Perri, TrialNet Coordinating Center, 1 8133969543, Erica.Perri@epi.usf.edu
    Scientific contact
    Dr. Kevan Herold, Yale University , 1 203-785-6507, Kevan.Herold@yale.edu
    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
    15 Mar 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Nov 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Nov 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the efficacy, safety and mode of action of hydroxychloroquine to prevent progression from Stage 1 to Stage 2 or Stage 3 of T1D. The primary objective is to determine whether intervention with hydroxychloroquine will prevent or delay the progression from Stage 1 (normal glucose tolerance) to Stage 2 (abnormal glucose tolerance) or Stage 3 (clinically overt T1D).
    Protection of trial subjects
    The DSMB met regularly during the study and reviewed safety and related information.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Aug 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
    Australia: 20
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    United States: 227
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    Italy: 2
    Worldwide total number of subjects
    273
    EEA total number of subjects
    6
    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)
    147
    Adolescents (12-17 years)
    95
    Adults (18-64 years)
    31
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Potential study participants may be identified through the TrialNet Pathway to Prevention Study, although prior participation is not required.

    Pre-assignment
    Screening details
    		 A pre-screening visit may be required if diabetes-related autoantibody status needs to be assessed by a TrialNet contracted laboratory. Autoantibody-positive individuals are then further evaluated with the performance of OGTTs, additional blood tests, detailed medical history, and physical exam.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Hydroxychloroquine
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hydroxychloroquine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The target dose is 5 mg/kg/day (actual body weight), up to a maximum of 400mg/day, of hydroxychloroquine. The dose was chosen based on demonstrated safety and efficacy in other human autoimmune diseases. Dose by body weight will be calculated in 100mg increments and will be equivalent to ≤ 5 mg/kg/day averaged over a one-week period.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The target dose is 5 mg/kg/day (actual body weight), up to a maximum of 400mg/day, of placebo. The dose was chosen based on demonstrated safety and efficacy in other human autoimmune diseases. Dose by body weight will be calculated in 100mg increments and will be equivalent to ≤ 5 mg/kg/day averaged over a one-week period.

    Number of subjects in period 1
    		Hydroxychloroquine Placebo
    Started
    183
    90
    Completed
    168
    77
    Not completed
    15
    13
         Consent withdrawn by subject
    10
    10
         Lost to follow-up
    5
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Hydroxychloroquine
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Hydroxychloroquine Placebo Total
    Number of subjects
    		 183 90 273
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 96 51 147
        Adolescents (12-17 years)
    		 69 26 95
        Adults (18-64 years)
    		 18 13 31
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 11.7 (8.3 to 15.6) 10.9 (8.2 to 15.7) -
    Gender categorical
    Units: Subjects
        Female
    		 61 33 94
        Male
    		 122 57 179

    End points

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    End points reporting groups
    Reporting group title
    Hydroxychloroquine
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Change From Treatment Assignment Glucose Tolerance to Abnormal Glucose Tolerance or Diabetes

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    End point title
    		 Change From Treatment Assignment Glucose Tolerance to Abnormal Glucose Tolerance or Diabetes
    End point description
    The primary outcome is the time in months from random treatment assignment to the development of confirmed abnormal glucose tolerance or clinical diabetes.
    End point type
    Primary
    End point timeframe
    Glucose tolerance is measured every 6 months for up to 4 years
    End point values
    		 Hydroxychloroquine Placebo
    Number of subjects analysed
    168
    83
    Units: Number of Subjects Analyzed
        number (not applicable)
    168
    83
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    The primary outcome is the time in months from random treatment assignment to the development of confirmed abnormal glucose tolerance or clinical diabetes.
    Comparison groups
    Hydroxychloroquine v Placebo
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.032 [1]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.61
    Notes
    [1] - The hazard ratio for the time development of AGT (Hydroxychloroquine vs. placebo) was 0.95 in two years (95% confidence interval, 0.56 to 1.61; P = non-significant by adjusted Cox proportional-hazards model).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Duration of study from screening to last visit encompassing each participant's duration of time in the study no more than 4 years with an average duration prior to study termination of 23.9 months.
    Adverse event reporting additional description
    Adverse Events were defined using the Common Terminology Criteria for Adverse Events (CTCAE)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Hydroxychloroquine
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Hydroxychloroquine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 183 (2.73%)
    1 / 90 (1.11%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylaxis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychosis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Hydroxychloroquine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    125 / 183 (68.31%)
    61 / 90 (67.78%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 90 (1.11%)
         occurrences all number
    1
    1
    Skin papilloma
         subjects affected / exposed
    0 / 183 (0.00%)
    3 / 90 (3.33%)
         occurrences all number
    0
    3
    Surgical and medical procedures
    Surgical and medical procedures - Other
         subjects affected / exposed
    10 / 183 (5.46%)
    3 / 90 (3.33%)
         occurrences all number
    12
    4
    General disorders and administration site conditions
    Fever hallucinations
         subjects affected / exposed
    5 / 183 (2.73%)
    0 / 90 (0.00%)
         occurrences all number
    7
    0
    Flu like symptoms
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 90 (1.11%)
         occurrences all number
    2
    1
    General disorders and administration site conditions
         subjects affected / exposed
    3 / 183 (1.64%)
    4 / 90 (4.44%)
         occurrences all number
    3
    5
    Pain
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 90 (0.00%)
         occurrences all number
    2
    0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    2 / 183 (1.09%)
    2 / 90 (2.22%)
         occurrences all number
    2
    2
    Anaphylaxis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Autoimmune disorder
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders - Other
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Dysmenorrhea
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 90 (1.11%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Allergic Rhinitis
         subjects affected / exposed
    5 / 183 (2.73%)
    2 / 90 (2.22%)
         occurrences all number
    5
    2
    Bronchospasm
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    6 / 183 (3.28%)
    2 / 90 (2.22%)
         occurrences all number
    6
    2
    Dyspnea
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 90 (0.00%)
         occurrences all number
    4
    0
    Nasal congestion
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 90 (1.11%)
         occurrences all number
    2
    1
    Pleuritic pain
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders - Other
         subjects affected / exposed
    6 / 183 (3.28%)
    3 / 90 (3.33%)
         occurrences all number
    6
    6
    Sinus disorder
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Sleep apnea
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Sore throat
         subjects affected / exposed
    2 / 183 (1.09%)
    3 / 90 (3.33%)
         occurrences all number
    2
    4
    Wheezing
         subjects affected / exposed
    3 / 183 (1.64%)
    1 / 90 (1.11%)
         occurrences all number
    4
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 90 (0.00%)
         occurrences all number
    3
    0
    Insomnia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Psychiatric disorders - Other
         subjects affected / exposed
    4 / 183 (2.19%)
    9 / 90 (10.00%)
         occurrences all number
    5
    4
    Depression
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Psychosis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Suicide attempt
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 90 (0.00%)
         occurrences all number
    2
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 90 (0.00%)
         occurrences all number
    4
    0
    Creatine increased
         subjects affected / exposed
    4 / 183 (2.19%)
    0 / 90 (0.00%)
         occurrences all number
    4
    0
    Investigations - Other
         subjects affected / exposed
    6 / 183 (3.28%)
    3 / 90 (3.33%)
         occurrences all number
    6
    3
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    32 / 183 (17.49%)
    26 / 90 (28.89%)
         occurrences all number
    56
    41
    Weight gain
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Weight loss
         subjects affected / exposed
    3 / 183 (1.64%)
    1 / 90 (1.11%)
         occurrences all number
    3
    1
    White blood cell decreased
         subjects affected / exposed
    4 / 183 (2.19%)
    4 / 90 (4.44%)
         occurrences all number
    4
    5
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 90 (1.11%)
         occurrences all number
    1
    1
    Fall
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 90 (0.00%)
         occurrences all number
    4
    0
    Fracture
         subjects affected / exposed
    8 / 183 (4.37%)
    3 / 90 (3.33%)
         occurrences all number
    8
    3
    Injury, poisoning and procedural complications - Other
         subjects affected / exposed
    8 / 183 (4.37%)
    5 / 90 (5.56%)
         occurrences all number
    19
    5
    Venous injury
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Cardiac disorders
    Cardiac Disorders
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Concentration impairment
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    5 / 183 (2.73%)
    3 / 90 (3.33%)
         occurrences all number
    7
    4
    Nervous system disorders - Other
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 90 (0.00%)
         occurrences all number
    2
    0
    Paresthesia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Presyncope
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 90 (0.00%)
         occurrences all number
    2
    0
    Syncope
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 90 (0.00%)
         occurrences all number
    2
    0
    Vasovagal reaction
         subjects affected / exposed
    4 / 183 (2.19%)
    1 / 90 (1.11%)
         occurrences all number
    6
    0
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    4 / 183 (2.19%)
    0 / 90 (0.00%)
         occurrences all number
    5
    0
    Lymph node pain
         subjects affected / exposed
    1 / 183 (0.55%)
    3 / 90 (3.33%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    ear pain
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    hearing impaired
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Middle ear inflammation
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    vertigo
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    2
    0
    Eye disorders
    Blurred vision
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Eye Disorders
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 90 (1.11%)
         occurrences all number
    6
    1
    Vision decreased
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 183 (1.09%)
    2 / 90 (2.22%)
         occurrences all number
    2
    2
    Bloating
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    1
    Diarrhea
         subjects affected / exposed
    5 / 183 (2.73%)
    1 / 90 (1.11%)
         occurrences all number
    5
    1
    Esophagitis
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 90 (2.22%)
         occurrences all number
    0
    0
    Flatulence
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 90 (0.00%)
         occurrences all number
    2
    0
    Gastritis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Gastroesophageal reflux disease
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
         subjects affected / exposed
    3 / 183 (1.64%)
    4 / 90 (4.44%)
         occurrences all number
    3
    5
    Nausea
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 90 (0.00%)
         occurrences all number
    3
    0
    Toothache
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    1
    1
    Vomiting
         subjects affected / exposed
    6 / 183 (3.28%)
    0 / 90 (0.00%)
         occurrences all number
    6
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    3 / 183 (1.64%)
    2 / 90 (2.22%)
         occurrences all number
    3
    2
    Rash acneiform
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    5
    0
    Rash maculo-papular
         subjects affected / exposed
    5 / 183 (2.73%)
    0 / 90 (0.00%)
         occurrences all number
    5
    0
    kin and subcutaneous tissue disorders - Other
         subjects affected / exposed
    16 / 183 (8.74%)
    5 / 90 (5.56%)
         occurrences all number
    19
    7
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Renal and urinary disorders - Other
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Urinary frequency
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Endocrine disorders
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 90 (1.11%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Avascular necrosis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Back pain
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 90 (2.22%)
         occurrences all number
    0
    2
    Bone pain
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 90 (1.11%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorder - Other
         subjects affected / exposed
    6 / 183 (3.28%)
    1 / 90 (1.11%)
         occurrences all number
    8
    1
    Neck pain
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 90 (1.11%)
         occurrences all number
    1
    1
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Bronchial infection
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Esophageal infection
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Eye infection
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Gum infection
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Herpes simplex reactivation
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 90 (0.00%)
         occurrences all number
    4
    0
    Infections and infestations - Other
         subjects affected / exposed
    29 / 183 (15.85%)
    13 / 90 (14.44%)
         occurrences all number
    33
    14
    Nail infection
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Otitis media
         subjects affected / exposed
    4 / 183 (2.19%)
    5 / 90 (5.56%)
         occurrences all number
    4
    5
    Penile infection
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 90 (2.22%)
         occurrences all number
    0
    2
    Pharyngitis
         subjects affected / exposed
    3 / 183 (1.64%)
    4 / 90 (4.44%)
         occurrences all number
    3
    4
    Sinusitis
         subjects affected / exposed
    11 / 183 (6.01%)
    5 / 90 (5.56%)
         occurrences all number
    13
    5
    Skin infection
         subjects affected / exposed
    3 / 183 (1.64%)
    1 / 90 (1.11%)
         occurrences all number
    3
    1
    Soft tissue infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Tooth infection
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 90 (1.11%)
         occurrences all number
    1
    1
    Upper respiratory infection
         subjects affected / exposed
    16 / 183 (8.74%)
    7 / 90 (7.78%)
         occurrences all number
    21
    10
    Wound infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 90 (1.11%)
         occurrences all number
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    3 / 183 (1.64%)
    3 / 90 (3.33%)
         occurrences all number
    3
    6
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (0.00%)
         occurrences all number
    1
    0
    Hyponatremia
         subjects affected / exposed
    4 / 183 (2.19%)
    3 / 90 (3.33%)
         occurrences all number
    4
    3
    Metabolism and nutrition disorders - Other
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 90 (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
    25 Feb 2019
    Investigator emergent unmasking is permitted without the need for approval by TrialNet administration. Inclusion of lang auge that permits different consenting requirements based off of local regulatory requirements.
    22 Mar 2021
    Removal of TN01 participation as entry criteria. Addition of pregnancy or breastfeeding exclusion criteria for clarity. OGTT window correction for clarity. Change in stopping criteria was implemented and implemented site-wide for consistency across all sites. Addition of a -2 pre-screening visit for those needing testing for autoantibodies.

    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.
    Interim analysis completed prompted the DSMB's decision to terminate the protocol early limiting the originally planned follow up period for participants.
    For support, Contact us.
    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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