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    Clinical Trial Results:
    A randomized, double-blinded placebo-controlled, paralleled designed, investigator sponsored study of the effect of the GLP-1 receptor agonist liraglutide on beta-cell function in C-peptide positive type 1 diabetic patients.

    Summary
    EudraCT number
    		 2014-005174-11
    Trial protocol
    		 SE  
    Global end of trial date
    01 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Oct 2022
    First version publication date
    20 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    U1111-1166-6923
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02617654
    WHO universal trial number (UTN)
    		 U1111-1166-6923
    Sponsors
    Sponsor organisation name
    Uppsala University Hospital
    Sponsor organisation address
    Sjukhusvägen, Uppsala, Sweden, 751 85
    Public contact
    Department of Special Medicine. Unit of Endocrinology & Diabetology, Uppsala University Hospital, +46 186110000, mms@akademiska.se
    Scientific contact
    Department of Special Medicine. Unit of Endocrinology & Diabetology, Uppsala University Hospital, +46 186110000, mms@akademiska.se
    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
    16 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jun 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect of 52 weeks of treatment with liraglutide 1.8 mg/day, compared to placebo, on stimulated C-peptide concentrations in patients with long-standing type 1 diabetes (T1D) and residual insulin production.
    Protection of trial subjects
    At each visit a full safety profile was obtained by asking for discomfort and side effects combined with laboratory safety assessments. Study personnel was available to be contacted by study subjects between study visits if necessary. Before each of the study procedures were carried out, the study personnel explained the procedure to the study subject as to make the subject aware of the procedure. When necessary, topical anesthetics were used prior to blood sampling as per clinical practice, in order to minimize discomfort related to the procedure. Besides, patients participating in the study were covered by the Swedish Patient Insurance and the Swedish Pharmaceutical Insurance.
    Background therapy
    		 Insulin treatment by either pump or multiple daily injection regimen as per clinical practice (standard of care for patients with Type1 diabetes) was allowed in both arms during the study. Concomitant medication which may interfere with glucose regulation other than insulin treatment was not allowed during the study, leading to study subject withdrawal.
    Evidence for comparator
    		 Glucagon-like peptide 1 (GLP-1) plays a key role in limiting postprandial glucose excursions by stimulating insulin secretion, inhibiting glucagon release and delaying gastric emptying. Other putative effects of GLP-1 are increased insulin sensitivity and, at least in rodents, trophic effects on beta-cells. GLP-1 receptor analogs (GLP-1RA) are today successfully used for treatment of type 2 diabetes (T2D). These drugs have also been tested in clinical trials on C-peptide negative T1D patients, showing a decrease in glycaemic excursions, exogenous insulin doses and HbA1c. GLP-1RA stimulates beta-cell neogenesis in rodents and specifically liraglutide has shown some potency for human beta-cell regeneration in vitro. In contrast to its rodent counterparts, human beta-cell regeneration in adults has been hard to achieve. However, there is a clear age-dependent responsiveness in the capacity of human beta-cell mass to expand, with beta-cells of younger individuals still having plasticity up to approximately 30 years of age. Clinically, GLP-1RAs are commonly used in the treatment of adults with T2D in the elderly, thereby having a less plastic beta-cell population as part of the disease pathogenesis. Noteworthy, in head-to-head clinical trials in T2D patients liraglutide treatment has been superior or equal to other GLP-1RAs with regard to efficacy to decrease HbA1c. Recently it has been shown that many patients have remaining beta-cells with residual measurable C-peptide concentrations in blood even several decades after diagnosis. This implies that some beta-cells may be resistant to destruction, that the immune attack has stopped or that beta-cell regeneration continues. To our knowledge, the long-term effect of liraglutide on C-peptide positive T1D patients has not yet been studied. We aim to investigate the possibility to expand beta-cell mass in young individuals with T1D and remaining beta- cell mass function by liraglutide.
    Actual start date of recruitment
    01 Oct 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 18
    Worldwide total number of subjects
    18
    EEA total number of subjects
    18
    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)
    18
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited from the population of T1D patients at Uppsala University Hospital (Sweden) or referral hospitals. All subjects received both oral and written information and signed informed consent prior to study-specific screening procedures. The trial was initiated on 15-11-2015 and the first patient (FPFV) was included on 08-02-2016.

    Pre-assignment
    Screening details
    		 Female and male adults between 18-30 years of age with clinical diagnose of T1D for 5 or more years and hb1c between 45 and 75 mmol/mol and fasting plasma C-peptide >1.5 pmol/L. 88 patients screened and 70 excluded. 66 patients did not meet inclusion criteria, 4 declined to participate. Main reason was c-peptide (49) or hba1c (13) out of range.

    Pre-assignment period milestones
    Number of subjects started
    		 18
    Number of subjects completed
    		 18

    Period 1
    Period 1 title
    On-treatment week 0-52
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    After randomization, a patient identification number was assigned to each study subjects in consecutive order. This identification number corresponds to specific batch of study drug, either liraglutide and placebo. Batch number were blinded by the MAH. Double-blinding was achieved as both liraglutide and placebo were labelled and packed identically by the MAH. The injection pens were identical and the study subjects were instructed to inject the same volume of active substance or placebo.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Liraglutide Arm
    Arm description
    		 Treatment with IMP liraglutide during 52 weeks. Initial titration phase 6 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Victoza (liraglutide)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Solution for injection , Subcutaneous use
    Dosage and administration details
    Subjects will initiate treatment with a dose of 0.6 mg during 2 weeks, increase to a dose of 1.2 mg for 2 weeks and then finally increase to 1.8 mg for 48 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Treatment with placebo during 52 weeks. Initial titration phase 6 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Liraglutide-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Solution for injection , Subcutaneous use
    Dosage and administration details
    Subjects initiated treatment with a dose of 0.6 mg during 2 weeks, increase to a dose of 1.2 mg for 2 weeks and then finally increase to 1.8 mg for 48 weeks, same dose as for Liraglutide.

    Number of subjects in period 1
    		Liraglutide Arm Placebo
    Started
    10
    8
    Completed
    8
    8
    Not completed
    2
    0
         Adverse event, non-fatal
    2
    -
    Period 2
    Period 2 title
    Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    See period 2

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Liraglutide-Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Liraglutide-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Solution for injection , Subcutaneous use
    Dosage and administration details
    Subjects will initiate treatment with a dose of 0.6 mg during 2 weeks, increase to a dose of 1.2 mg for 2 weeks and then finally increase to 1.8 mg for 48 weeks.

    Arm title
    		 Liraglutide
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Victoza (liraglutide)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Solution for injection , Subcutaneous use
    Dosage and administration details
    Subjects will initiate treatment with a dose of 0.6 mg during 2 weeks, increase to a dose of 1.2 mg for 2 weeks and then finally increase to 1.8 mg for 48 weeks.

    Number of subjects in period 2
    		Liraglutide-Placebo Liraglutide
    Started
    8
    8
    Completed
    8
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Liraglutide Arm
    Reporting group description
    		 Treatment with IMP liraglutide during 52 weeks. Initial titration phase 6 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Treatment with placebo during 52 weeks. Initial titration phase 6 weeks.

    Reporting group values
    		 Liraglutide Arm Placebo Total
    Number of subjects
    		 10 8 18
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 10 8 18
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 24.0 ( 3.5 ) 24.6 ( 3.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 3 5
        Male
    		 8 5 13
    Insulin treatment at baseline
    Insulin treatment modality at baseline as per clinical practice. MDI (multiple daily injection) and subcutaneous insulin pump.
    Units: Subjects
        MDI
    		 9 4 13
        Insulin Pump
    		 1 4 5
    Retinopathy
    Diabetes retinopathy status at baseline
    Units: Subjects
        Yes
    		 2 2 4
        No
    		 8 6 14
    GAD
    GAD antibody status at baseline
    Units: Subjects
        Positive
    		 6 5 11
        Negative
    		 4 2 6
        Not Recorded
    		 0 1 1
    IA-2
    IA-2 antibody status at baseline
    Units: Subjects
        Positive
    		 7 5 12
        Negative
    		 3 3 6
        Not Recorded
    		 0 0 0
    HbA1c
    Glycated haemoglobin at baseline
    Units: mol/L
        arithmetic mean (standard deviation)
    		 54.3 ( 7.4 ) 59.9 ( 8.1 ) -
    Weight
    Weight at baseline
    Units: Kg
        arithmetic mean (standard deviation)
    		 75.9 ( 7.5 ) 76.7 ( 15.3 ) -
    BMI
    Body Mass Index at baseline
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 24.4 ( 2.8 ) 25.7 ( 3.7 ) -
    Fasting C-peptide
    Fasting C-peptide concentration at baseline
    Units: pmol/L
        arithmetic mean (standard deviation)
    		 48.1 ( 37.9 ) 25.3 ( 45.8 ) -
    Insulin dose at baseline
    Units: U/kg
        arithmetic mean (standard deviation)
    		 0.57 ( 0.14 ) 0.66 ( 0.22 ) -
    Age at onset of diabetes
    Units: years
        arithmetic mean (standard deviation)
    		 14.0 ( 2.4 ) 15.6 ( 4.7 ) -
    Duration of T1D
    Units: years
        arithmetic mean (standard deviation)
    		 10.0 ( 4.8 ) 9.0 ( 3.5 ) -

    End points

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    End points reporting groups
    Reporting group title
    Liraglutide Arm
    Reporting group description
    		 Treatment with IMP liraglutide during 52 weeks. Initial titration phase 6 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Treatment with placebo during 52 weeks. Initial titration phase 6 weeks.
    Reporting group title
    Liraglutide-Placebo
    Reporting group description
    		 -

    Reporting group title
    Liraglutide
    Reporting group description
    		 -

    Primary: ∆-change in C-peptide AUC after 52 weeks

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    End point title
    		 ∆-change in C-peptide AUC after 52 weeks
    End point description
    The Area Under the Curve (AUC) change in plasma C-peptide concentration in response to a standardized mixed meal tolerance test (MMTT) after completion of one year of treatment with liraglutide.
    End point type
    Primary
    End point timeframe
    Week 0 (start of treatment) Week 52 (treatment stop)
    End point values
    		 Liraglutide Arm Placebo
    Number of subjects analysed
    8 [1]
    8
    Units: pmol/l x min
        arithmetic mean (standard deviation)
    -1103 ( 4194 )
    -283 ( 4423 )
    Attachments
    		 Untitled (Filename: Delta C-peptide AUC w52-w0.pdf)
    Notes
    [1] - 2 subjects discontinued during the titration phase due to adverse events.
    Statistical analysis title
    		 T-test of change in C-peptide AUC w52-w0
    Statistical analysis description
    Student’s unpaired two-tailed t-test
    Comparison groups
    Liraglutide Arm v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7091
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -820.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5442
         upper limit
    		 3801
    Variability estimate
    Standard error of the mean
    Dispersion value
    2155

    Secondary: ∆- change in C-peptide AUC w52-w6

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    End point title
    		 ∆- change in C-peptide AUC w52-w6
    End point description
    The Area Under the Curve (AUC) change in plasma C-peptide concentration in response to a standardized mixed meal tolerance test (MMTT) comparing week 52 and week 6, after the titration period.
    End point type
    Secondary
    End point timeframe
    week 6 (end of IMP titration) week 52 (end of treatment)
    End point values
    		 Liraglutide Arm Placebo
    Number of subjects analysed
    8
    8
    Units: pmol/l x min
        arithmetic mean (standard deviation)
    -4548 ( 7682 )
    1479 ( 4861 )
    Attachments
    		 Untitled (Filename: Delta C-peptide AUC w52-w6.pdf)
    Statistical analysis title
    		 Unpaired t-test
    Statistical analysis description
    Secondary endpoints will be evaluated as ∆-changes using Student’s unpaired two-tailed t-test
    Comparison groups
    Liraglutide Arm v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0818
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6027
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12920
         upper limit
    		 866.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    3214

    Secondary: ∆-change in C-peptide AUC w65-w0

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    End point title
    		 ∆-change in C-peptide AUC w65-w0
    End point description
    ∆-change in C-peptide AUC between the MMTT three months after cessation of treatment and that after the run-in period
    End point type
    Secondary
    End point timeframe
    Week 65 (end of follow-up) Week 0 (treatment start)
    End point values
    		 Liraglutide Arm Placebo
    Number of subjects analysed
    8
    8
    Units: pmol/l x min
        arithmetic mean (standard deviation)
    -4447 ( 5545 )
    -796 ( 2399 )
    Attachments
    		 Untitled (Filename: Delta C-peptide AUC w65-w0.pdf)
    Statistical analysis title
    		 T-test ∆-change in C-peptide AUC w65-w0
    Statistical analysis description
    Secondary endpoints were evaluated as ∆-changes using Student’s unpaired two-tailed t-test.
    Comparison groups
    Liraglutide Arm v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1094
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3651
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8233
         upper limit
    		 929.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    2136

    Secondary: ∆- change in HbA1c w52-w0

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    End point title
    		 ∆- change in HbA1c w52-w0
    End point description
    End point type
    Secondary
    End point timeframe
    week 52 (treatment stop) week 0 (start of treatment)
    End point values
    		 Liraglutide Arm Placebo
    Number of subjects analysed
    8
    8
    Units: mmol/mol
        arithmetic mean (standard deviation)
    0.25 ( 5.092 )
    0.5 ( 6.047 )
    Attachments
    		 Untitled (Filename: Delta HbA1c w52-w0.pdf)
    Statistical analysis title
    		 T-test ∆- change in HbA1c w52-w0
    Statistical analysis description
    Secondary endpoints were evaluated as ∆-changes using Student’s unpaired two-tailed t-test.
    Comparison groups
    Placebo v Liraglutide Arm
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.93
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.245
         upper limit
    		 5.745
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.795

    Secondary: ∆- change in HbA1c w52-w6

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    End point title
    		 ∆- change in HbA1c w52-w6
    End point description
    ∆- change in HbA1c between after one year and after 6 weeks of treatment
    End point type
    Secondary
    End point timeframe
    week 52 (treatment stop) week 6 (end of titration period)
    End point values
    		 Liraglutide Arm Placebo
    Number of subjects analysed
    8
    8
    Units: mmol/mol
        arithmetic mean (standard deviation)
    3.50 ( 4.44 )
    4.625 ( 4.627 )
    Attachments
    		 Untitled (Filename: Delta HbA1c w52-w6.pdf)
    Statistical analysis title
    		 T-test ∆- change in HbA1c w52-w6
    Statistical analysis description
    ∆- change in HbA1c between after one year and after 6 weeks of treatment
    Comparison groups
    Liraglutide Arm v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6275
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.125
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.988
         upper limit
    		 3.738
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.267

    Secondary: ∆- change in HbA1c w65-w0

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    End point title
    		 ∆- change in HbA1c w65-w0
    End point description
    ∆- change in HbA1c between three months after the cessation of treatment and after the run-in period
    End point type
    Secondary
    End point timeframe
    week 65 (end of follow-up) week 0 (treatment start)
    End point values
    		 Liraglutide Arm Placebo
    Number of subjects analysed
    8
    8
    Units: mmol/mol
        arithmetic mean (standard deviation)
    2.875 ( 7.754 )
    2.125 ( 6.312 )
    Attachments
    		 Untitled (Filename: Delta HbA1c w65-w0.pdf)
    Statistical analysis title
    		 T-test ∆- change in HbA1c w65-w0
    Statistical analysis description
    ∆- change in HbA1c between three months after the cessation of treatment and after the run-in period
    Comparison groups
    Liraglutide Arm v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.835
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.832
         upper limit
    		 8.332
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.535

    Secondary: ∆- change in insulin dose w52-w0

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    End point title
    		 ∆- change in insulin dose w52-w0
    End point description
    ∆- change in exogenous insulin doses between after one year and after the run-in period
    End point type
    Secondary
    End point timeframe
    week 52 (treatment stop) week 0 (start of treatment)
    End point values
    		 Liraglutide Arm Placebo
    Number of subjects analysed
    8
    7 [2]
    Units: U/kg/24h
        arithmetic mean (standard deviation)
    -0.025 ( 0.057 )
    -0.054 ( 0.104 )
    Attachments
    		 Untitled (Filename: Delta Insulin dose w52-w0.pdf)
    Notes
    [2] - w52 measurement missing in one subject
    Statistical analysis title
    		 T-test ∆- change in insulin dose w52-w0
    Statistical analysis description
    Secondary endpoints were evaluated as ∆-changes using Student’s unpaired two-tailed t-test.
    Comparison groups
    Liraglutide Arm v Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.506
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.029
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.063
         upper limit
    		 0.121
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.042

    Secondary: ∆- change in insulin dose w52-w6

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    End point title
    		 ∆- change in insulin dose w52-w6
    End point description
    ∆- change in exogenous insulin doses between after one year and after 6 weeks of treatment
    End point type
    Secondary
    End point timeframe
    week 52 (end of treatment) week 6 (end of titration period)
    End point values
    		 Liraglutide Arm Placebo
    Number of subjects analysed
    8
    7 [3]
    Units: U/kg/24h
        arithmetic mean (standard deviation)
    0.147 ( 0.084 )
    -0.094 ( 0.089 )
    Attachments
    		 Untitled (Filename: Delta Insulin dose w52-w6.pdf)
    Notes
    [3] - Week 52 measurement missing in one patient
    Statistical analysis title
    		 T-test ∆- change in insulin dose w52-w6
    Comparison groups
    Liraglutide Arm v Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.241
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.145
         upper limit
    		 0.338
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.044

    Secondary: ∆- change in insulin dose w65-w0

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    End point title
    		 ∆- change in insulin dose w65-w0
    End point description
    ∆- change in exogenous insulin doses between three months after the cessation of treatment and after the run-in period.
    End point type
    Secondary
    End point timeframe
    week 65 (end of follow-up) week 0 (treatment start)
    End point values
    		 Liraglutide Arm Placebo
    Number of subjects analysed
    7 [4]
    8
    Units: U/kg/24h
        arithmetic mean (standard deviation)
    0.0357 ( 0.102 )
    -0.046 ( 0.138 )
    Attachments
    		 Untitled (Filename: Delta Insulin dose w65-w0.pdf)
    Notes
    [4] - Measurement at week 65 missing for 1 patient
    Statistical analysis title
    		 T-test ∆- change in insulin dose w65-w0
    Statistical analysis description
    Secondary endpoints were evaluated as ∆-changes using Student’s unpaired two-tailed t-test
    Comparison groups
    Liraglutide Arm v Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.22
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.081
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.055
         upper limit
    		 0.219
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.063

    Secondary: ∆- change in glucose variability w52-w0

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    End point title
    		 ∆- change in glucose variability w52-w0
    End point description
    ∆- change in glucose variability between after one year and after the run-in period
    End point type
    Secondary
    End point timeframe
    week 52 (end of treatment) week 0 (treatment start)
    End point values
    		 Liraglutide Arm Placebo
    Number of subjects analysed
    7
    7
    Units: mmol/l
        arithmetic mean (standard deviation)
    0.525 ( 0.573 )
    -0.034 ( 0.913 )
    Attachments
    		 Untitled (Filename: Delta Glucose Variability w52-w0.pdf)
    Statistical analysis title
    		 T-test ∆- change in glucose varibility w52-w0
    Statistical analysis description
    Secondary endpoints were evaluated as ∆-changes using Student’s unpaired two-tailed t-test
    Comparison groups
    Liraglutide Arm v Placebo
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1947
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.328
         upper limit
    		 1.448
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.407

    Secondary: ∆- change in glucose varibility w52-w6

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    End point title
    		 ∆- change in glucose varibility w52-w6
    End point description
    ∆- change in glucose variability between after one year and after 6 weeks of treatment
    End point type
    Secondary
    End point timeframe
    week 52 (end of treatment) week 6 (end of titration period)
    End point values
    		 Liraglutide Arm Placebo
    Number of subjects analysed
    8
    8
    Units: mmol/l
        arithmetic mean (standard deviation)
    0.701 ( 0.749 )
    -0.366 ( 1.105 )
    Attachments
    		 Untitled (Filename: Delta Glucose Variability w52-w6.pdf)
    Statistical analysis title
    		 T-test ∆- change in glucose varibility w52-w6
    Statistical analysis description
    Secondary endpoints were evaluated as ∆-changes using Student’s unpaired two-tailed t-test.
    Comparison groups
    Liraglutide Arm v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0402
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.068
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.055
         upper limit
    		 2.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.472

    Secondary: ∆- change in glucose varibility w65-w0

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    End point title
    		 ∆- change in glucose varibility w65-w0
    End point description
    ∆- change in glucose variability between three months after the cessation of treatment and after the run-in period.
    End point type
    Secondary
    End point timeframe
    week 65 (end of follow-up) week 0 (start of treatment)
    End point values
    		 Liraglutide Arm Placebo
    Number of subjects analysed
    7
    7
    Units: mmol/l
        arithmetic mean (standard deviation)
    0.440 ( 0.587 )
    0.12 ( 1.063 )
    Attachments
    		 Untitled (Filename: Delta Glucose Variability w65-W0.pdf)
    Statistical analysis title
    		 T-test ∆- change in glucose varibility w65-w0
    Statistical analysis description
    Secondary endpoints were evaluated as ∆-changes using Student’s unpaired two-tailed t-test.
    Comparison groups
    Liraglutide Arm v Placebo
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4989
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.679
         upper limit
    		 1.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.458

    Secondary: ∆- change in QoL (DTSQ) week 0-52

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    End point title
    		 ∆- change in QoL (DTSQ) week 0-52
    End point description
    ∆- change in assessment of QoL between after one year of treatment and after the run-in period. Assessment was done by means of the DTSQ test (Diabetes treatment satisfaction questionnaire)
    End point type
    Secondary
    End point timeframe
    week 0 (treatment start) week 52 (end of treatment)
    End point values
    		 Liraglutide Arm Placebo
    Number of subjects analysed
    8
    8
    Units: points
        arithmetic mean (standard deviation)
    2.875 ( 5.768 )
    -0.1250 ( 4.051 )
    Attachments
    		 Untitled (Filename: Delta DTSQ w52-w0.pdf)
    Statistical analysis title
    		 T-test ∆- change in QoL (DTSQ) week 0-52
    Comparison groups
    Liraglutide Arm v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2486
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.345
         upper limit
    		 8.345
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.492

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment: week 0 (start of treatment) through week 52 (end of treatment)
    Adverse event reporting additional description
    Assessment of adverse events by a study nurse or physician was done at each study visit under the treatment period. Study subjects received a diary and were instructed to document adverse events and other happenings during the study period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Liraglutide Arm
    Reporting group description
    		 Treatment with IMP liraglutide during 52 weeks. Initial titration phase 6 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Treatment with placebo during 52 weeks. Initial titration phase 6 weeks.

    Serious adverse events
    		 Liraglutide Arm Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Liraglutide Arm Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 8 (87.50%)
    7 / 8 (87.50%)
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    7 / 8 (87.50%)
    7 / 8 (87.50%)
         occurrences all number
    24
    24

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    The trial planned to randomize 50 patients. 88 patients were assessed for eligibility but 70 did not meet inclusion criteria. Thus, the sponsor took the decision to discontinue further subject recruitment after the inclusion of 18 patients.
    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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