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    Clinical Trial Results:
    A phase 2, multicentre, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of 400 mg twice a day oral ladarixin in patients with new-onset type 1 diabetes.

    Summary
    EudraCT number
    		 2014-003968-20
    Trial protocol
    		 IT   DE   BE  
    Global end of trial date
    15 May 2019

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MEX0114
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02814838
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dompé Farmaceutici S.p.A.
    Sponsor organisation address
    Via Santa Lucia, 6, Milano, Italy, 20122
    Public contact
    Clinical Development, Dompé Farmaceutici S.p.A., Dompé Farmaceutici S.p.A., +39 02583831, info@dompe.com
    Scientific contact
    Clinical Development, Dompé Farmaceutici S.p.A., Dompé Farmaceutici S.p.A., +39 02583831, info@dompe.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
    03 Apr 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this clinical trial is to investigate whether ladarixin has sufficient activity (preservation of β-cell function and slow-down of the progression of T1D) to warrant its further development (proof of concept trial).
    Protection of trial subjects
    The study was conducted in accordance with the protocol, the ethical principles derived from international guidelines including the Declaration of Helsinki and applicable International Council for Harmonisation (ICH) E6 (R2) Good Clinical Practice (GCP) Guidelines and applicable laws and regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Aug 2016
    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
    Belgium: 31
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Italy: 27
    Worldwide total number of subjects
    76
    EEA total number of subjects
    76
    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)
    76
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment was to be competitive among the study centres, until the planned number of pts were enrolled. Competitive recruitment was chosen to increase the speed of recruitment and to account for any difference among study centres in the rate and timing of patient referral. Each centre recruited pts as rapidly as possible up to a max of 21 pts.

    Pre-assignment
    Screening details
    		 At Screening, from enrolment to randomisation, the patient’s past medical history, disease-specific clinical information and date of first insulin administration were to be recorded. The screening includes the assessment of the baseline values.

    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, Carer
    Blinding implementation details
    This was a randomised, double-blind, placebo-controlled study and the Investigator, study centre staff, patients, Sponsor and designee were blinded to treatment assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ladarixin - ITT/SAF
    Arm description
    		 Ladarixin was administered as oral capsules at a dose of 400 mg (2 capsules) BID, for a total daily dose of 800 mg, for 3 cycles of 14 days on/14 days off.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ladarixin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The study treatment consisted of 400 mg of ladarixin (2 oral capsules) BID, for a total daily dose of 800 mg, for 3 cycles of 14 days on/14 days off. The 2 daily doses were to be administered with a glass of water at about 12-hour intervals (morning and evening; ideally between 8.30/9.30 and 20.30/21.30) and at least 2 hours from breakfast or dinner.

    Arm title
    		 Placebo - ITT/SAF
    Arm description
    		 Matching placebo capsules were administered in the same manner as the test product: 2 oral capsules BID, for 3 cycles of 14 days on/14 days off.
    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
    Matching placebo capsules were administered in the same manner as the test product. More specifically, the placebo was administered orally (2 capsules) BID for 3 cycles of 14 days on/14 days off. The 2 daily doses were to be administered with a glass of water at about 12-hour intervals (morning and evening; ideally between 8.30/9.30 and 20.30/21.30) and at least 2 hours from breakfast or dinner.

    Number of subjects in period 1
    		Ladarixin - ITT/SAF Placebo - ITT/SAF
    Started
    50
    26
    Completed
    48
    25
    Not completed
    2
    1
         Consent withdrawn by subject
    1
    1
         The pt missed 3 agreed dates for the final visit
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ladarixin - ITT/SAF
    Reporting group description
    		 Ladarixin was administered as oral capsules at a dose of 400 mg (2 capsules) BID, for a total daily dose of 800 mg, for 3 cycles of 14 days on/14 days off.

    Reporting group title
    Placebo - ITT/SAF
    Reporting group description
    		 Matching placebo capsules were administered in the same manner as the test product: 2 oral capsules BID, for 3 cycles of 14 days on/14 days off.

    Reporting group values
    		 Ladarixin - ITT/SAF Placebo - ITT/SAF Total
    Number of subjects
    		 50 26 76
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 50 26 76
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 27.6 ± 7.06 26.8 ± 6.35 -
    Gender categorical
    Units: Subjects
        Female
    		 21 10 31
        Male
    		 29 16 45

    End points

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    End points reporting groups
    Reporting group title
    Ladarixin - ITT/SAF
    Reporting group description
    		 Ladarixin was administered as oral capsules at a dose of 400 mg (2 capsules) BID, for a total daily dose of 800 mg, for 3 cycles of 14 days on/14 days off.

    Reporting group title
    Placebo - ITT/SAF
    Reporting group description
    		 Matching placebo capsules were administered in the same manner as the test product: 2 oral capsules BID, for 3 cycles of 14 days on/14 days off.

    Primary: 2-hour area under the curve (AUC) of C-peptide Response to the Mixed Meal Tolerance Test (MMTT) at week 13

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    End point title
    		 2-hour area under the curve (AUC) of C-peptide Response to the Mixed Meal Tolerance Test (MMTT) at week 13
    End point description
    C-peptide level is a widely used measure of pancreatic beta-cell function. The MMTT is one of the methods for its estimation. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each follow-up visit on weeks 13±1, 26±2, and 52±2. All the AUC analyses were based on actual rather than scheduled timings and were calculated using the trapezoidal rule. If the actual time was not recorded, the scheduled time was used instead.
    End point type
    Primary
    End point timeframe
    Follow-up at Week 13±1
    End point values
    		 Ladarixin - ITT/SAF Placebo - ITT/SAF
    Number of subjects analysed
    49
    26
    Units: log (x+1)
        arithmetic mean (standard deviation)
    4.026 ± 0.4852
    3.886 ± 0.7446
    Statistical analysis title
    		 Ladarixin vs Placebo
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.3303
    Method
    		 Student's t test for unpaired samples
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.14
         upper limit
    		 0.42
    Notes
    [1] - Transformed AUC was analyzed with Student t-test for unpaired data using PROC TTEST within SAS® to compare Ladarixin and placebo groups. The estimated treatment difference between Ladarixin and placebo was also presented together with the corresponding 95% confidence interval.

    Secondary: 2-hour AUC of C-peptide Response to the Mixed Meal Tolerance Test (MMTT) at weeks 26 and 52

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    End point title
    		 2-hour AUC of C-peptide Response to the Mixed Meal Tolerance Test (MMTT) at weeks 26 and 52
    End point description
    C-peptide level is a widely used measure of pancreatic beta-cell function. The MMTT is one of the methods for its estimation. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each follow-up visit on weeks 13±1, 26±2, and 52±2. All the AUC analyses were based on actual rather than scheduled timings and were calculated using the trapezoidal rule. If the actual time was not recorded, the scheduled time was used instead.
    End point type
    Secondary
    End point timeframe
    Follow-ups at Weeks 26±2 and 52±2
    End point values
    		 Ladarixin - ITT/SAF Placebo - ITT/SAF
    Number of subjects analysed
    47 [2]
    25
    Units: Log (x+1)
    arithmetic mean (standard deviation)
        Week 26
    3.9351 ± 0.51710
    3.8076 ± 0.76473
        Week 52
    3.6371 ± 0.75222
    3.6380 ± 0.81268
    Notes
    [2] - n=47 at week 26 and n=46 at week 52
    Statistical analysis title
    		 Ladarixin vs placebo at FUP week 26
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.517
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.0984
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2028
         upper limit
    		 0.3995
    Notes
    [3] - The comparisons between groups on 2-hour AUC C-peptide efficacy endpoint was carried-out using a mixed linear model where the log(x+1) transformed 2-hour AUC C-peptide was the dependent variable, while treatment group, visit, treatment by visit interaction were the fixed factors of the model and patient will be the random effect. An unstructured covariance matrix for each patient is considered and the Kenward-Roger adjustment is used for the degrees of freedom.
    Statistical analysis title
    		 Ladarixin vs placebo at FUP week 52
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.7999
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    -0.0486
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4294
         upper limit
    		 0.3322
    Notes
    [4] - The comparisons between groups on 2-hour AUC C-peptide efficacy endpoint was carried-out using a mixed linear model where the log(x+1) transformed 2-hour AUC C-peptide was the dependent variable, while treatment group, visit, treatment by visit interaction were the fixed factors of the model and patient will be the random effect. An unstructured covariance matrix for each patient is considered and the Kenward-Roger adjustment is used for the degrees of freedom.

    Secondary: Percent change from Baseline of 2-hour AUC of C-peptide response to the MMTT

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    End point title
    		 Percent change from Baseline of 2-hour AUC of C-peptide response to the MMTT
    End point description
    Assessment of percent change is a method to evaluate a response regardless of basal condition. All the AUC analyses were based on actual rather than scheduled timings and were calculated using the trapezoidal rule. If the actual time was not recorded, the scheduled time was used instead.
    End point type
    Secondary
    End point timeframe
    Follow-ups at Weeks 13±1, 26±2 and 52±2
    End point values
    		 Ladarixin - ITT/SAF Placebo - ITT/SAF
    Number of subjects analysed
    49 [5]
    25 [6]
    Units: percentage
    arithmetic mean (standard deviation)
        Week 13
    5.7818 ± 36.74477
    -6.0734 ± 38.22179
        Week 26
    -0.8701 ± 42.93044
    -13.7347 ± 37.41900
        Week 52
    -22.2532 ± 38.84672
    -24.2215 ± 42.67277
    Notes
    [5] - n=49 at week 13; n=47 at week 26; n=46 at week 52
    [6] - n=25 at week 13 and n=24 at weeks 26 and 52
    Statistical analysis title
    		 Ladarixin vs placebo at week 13
    Statistical analysis description
    Analysis is based on a linear mixed model with percent change from baseline of 2-hour AUC of C-peptide as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect. The baseline value of 2-hour AUC C-peptide is included in the model as covariate.
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2224
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    12.0411
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.3823
         upper limit
    		 31.4644
    Statistical analysis title
    		 Ladarixin vs placebo at week 26
    Statistical analysis description
    Analysis is based on a linear mixed model with percent change from baseline of 2-hour AUC of C-peptide as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect. The baseline value of 2-hour AUC C-peptide is included in the model as covariate.
    Comparison groups
    Placebo - ITT/SAF v Ladarixin - ITT/SAF
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3931
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    8.4803
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.0935
         upper limit
    		 28.0541
    Statistical analysis title
    		 Ladarixin vs placebo at week 52
    Statistical analysis description
    Analysis is based on a linear mixed model with percent change from baseline of 2-hour AUC of C-peptide as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect. The baseline value of 2-hour AUC C-peptide is included in the model as covariate.
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7664
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    -2.9502
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.5476
         upper limit
    		 16.6473

    Secondary: C-peptide AUC(15 to 120 mins) above fasting value

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    End point title
    		 C-peptide AUC(15 to 120 mins) above fasting value
    End point description
    This parameter is a measure of pancreatic response to stimulus independent from any background (fasting) glycemic control. All the AUC analyses were based on actual rather than scheduled timings and were calculated using the trapezoidal rule. If the actual time was not recorded, the scheduled time was used instead. The means are all "adjusted means".
    End point type
    Secondary
    End point timeframe
    Follow-ups at Weeks 13±1 26±2 and 52±2
    End point values
    		 Ladarixin - ITT/SAF Placebo - ITT/SAF
    Number of subjects analysed
    50
    26
    Units: logaritm (x+1)
    arithmetic mean (confidence interval 95%)
        week 13
    3.3736 (3.1730 to 3.5742)
    3.2334 (2.9568 to 3.5100)
        week 26
    3.2419 (3.0186 to 3.4652)
    3.0649 (2.7562 to 3.3735)
        week 52
    2.9733 (2.7150 to 3.2316)
    2.9282 (2.5720 to 3.2844)
    Statistical analysis title
    		 Ladarixin vs placebo - week 13
    Statistical analysis description
    Comparison at week 13
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.4163
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.1402
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2015
         upper limit
    		 0.4819
    Notes
    [7] - Analysis is based on a linear mixed model for repeated measures with log(AUC(15-120 minutes)+1) of C-peptide above fasting value as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.
    Statistical analysis title
    		 Ladarixin vs placebo - week 26
    Statistical analysis description
    Comparison at week 26
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.3575
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.177
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2039
         upper limit
    		 0.558
    Notes
    [8] - Analysis is based on a linear mixed model for repeated measures with log(AUC(15-120 minutes)+1) of C-peptide above fasting value as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.
    Statistical analysis title
    		 Ladarixin vs placebo - week 52
    Statistical analysis description
    Comparison at week 52
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.8386
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.0451
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3948
         upper limit
    		 0.4851
    Notes
    [9] - Analysis is based on a linear mixed model for repeated measures with log(AUC(15-120 minutes)+1) of C-peptide above fasting value as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.

    Secondary: AUC(0-2h) of C-peptide MMTT in patients with screening C-peptide < median value

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    End point title
    		 AUC(0-2h) of C-peptide MMTT in patients with screening C-peptide < median value
    End point description
    A subgroup analysis of efficacy endpoints by fasting C-peptide at Screening was performed. The reported data specifically refers to fasting C-peptide at Screening <median value. All the AUC analyses were based on actual rather than scheduled timings and were calculated using the trapezoidal rule. If the actual time was not recorded, the scheduled time was used instead.
    End point type
    Secondary
    End point timeframe
    Follow-up at Weeks 13±1, 26±2, and 52±2. VERIFICARE SORGENTE DATI CON D'AFFONCHIO
    End point values
    		 Ladarixin - ITT/SAF Placebo - ITT/SAF
    Number of subjects analysed
    26 [10]
    11 [11]
    Units: log(x+1)
    arithmetic mean (standard deviation)
        Week 13
    3.8085 ± 0.45692
    3.4543 ± 0.86632
        Week 26
    3.8202 ± 0.48142
    3.3178 ± 0.91906
        Week 52
    3.3796 ± 0.68616
    3.1562 ± 0.97130
    Notes
    [10] - n=26 wk 13 n=25 wk 26 n=24 wk 52
    [11] - n=11 wk 13 n=10 wk 26 n=10 wk 52
    Statistical analysis title
    		 Ladarixin vs Placebo - Week 13
    Statistical analysis description
    Transformed AUC was analyzed with Student t-test for unpaired data using PROC TTEST within SAS® to compare Ladarixin and placebo groups. The estimated treatment difference between Ladarixin and placebo was also presented together with the corresponding 95% confidence interval.
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1114
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.354
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.75
    Statistical analysis title
    		 Ladarixin vs Placebo - Week 26
    Statistical analysis description
    Transformed AUC was analyzed with Student t-test for unpaired data using PROC TTEST within SAS® to compare Ladarixin and placebo groups. The estimated treatment difference between Ladarixin and placebo was also presented together with the corresponding 95% confidence interval.
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0411
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.502
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.98
    Statistical analysis title
    		 Ladarixin vs Placebo - Week 52
    Statistical analysis description
    Transformed AUC was analyzed with Student t-test for unpaired data using PROC TTEST within SAS® to compare Ladarixin and placebo groups. The estimated treatment difference between Ladarixin and placebo was also presented together with the corresponding 95% confidence interval.
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4506
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.223
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 0.82

    Secondary: AUC(15-120) of C-peptide MMTT above fasting value in patients with screening C-peptide < median value

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    End point title
    		 AUC(15-120) of C-peptide MMTT above fasting value in patients with screening C-peptide < median value
    End point description
    A subgroup analysis of efficacy endpoints by fasting C-peptide at Screening was performed. The reported data specifically refers to fasting C-peptide at Screening <median value. All the AUC analyses were based on actual rather than scheduled timings and were calculated using the trapezoidal rule. If the actual time was not recorded, the scheduled time was used instead.
    End point type
    Secondary
    End point timeframe
    Follow-up at Weeks 13±1, 26±2, and 52±2.
    End point values
    		 Ladarixin - ITT/SAF Placebo - ITT/SAF
    Number of subjects analysed
    26 [12]
    11 [13]
    Units: log(x+1)
    arithmetic mean (standard deviation)
        Week 13
    3.1590 ± 0.56135
    2.7959 ± 1.07745
        Week 26
    27.7841 ± 15.10337
    18.6842 ± 15.46837
        Week 52
    2.7993 ± 0.82214
    19.9415 ± 16.95597
    Notes
    [12] - n=26 wk 13 n=25 wk 26 n=24 wk 52
    [13] - n=11 wk 13 n=10 wk 26 n=10 wk 52
    Statistical analysis title
    		 Ladarixin vs Placebo - Week 13
    Statistical analysis description
    Analysis is based on a linear mixed model for repeated measures with log(AUC(15-120 minutes)+1) of C-peptide above fasting value as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1847
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.3631
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1817
         upper limit
    		 0.908
    Statistical analysis title
    		 Ladarixin vs Placebo - Week 26
    Statistical analysis description
    Analysis is based on a linear mixed model for repeated measures with log(AUC(15-120 minutes)+1) of C-peptide above fasting value as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.031
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.6304
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.0609
         upper limit
    		 1.1998
    Statistical analysis title
    		 Ladarixin vs Placebo - Week 52
    Statistical analysis description
    Analysis is based on a linear mixed model for repeated measures with log(AUC(15-120 minutes)+1) of C-peptide above fasting value as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6299
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.1639
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5202
         upper limit
    		 0.8479

    Secondary: Proportion of patients with HbA1c <7% and absence of episodes of severe hypoglycaemia from the previous visit

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    End point title
    		 Proportion of patients with HbA1c <7% and absence of episodes of severe hypoglycaemia from the previous visit
    End point description
    This parameter integrates overal glycemic control (HbA1c) with requirement of as low insulin dose as to avoid hypoglycemia. Proportion is reported as percentage of patients, despite the measure type indicated is "number". Events per patient are calculated from the date of randomisation.
    End point type
    Secondary
    End point timeframe
    Follow-up at Weeks 13±1, 26±2, and 52±2.
    End point values
    		 Ladarixin - ITT/SAF Placebo - ITT/SAF
    Number of subjects analysed
    49 [14]
    25 [15]
    Units: percentage
    number (confidence interval 95%)
        Week 13
    90.0 (78.19 to 96.67)
    73.1 (52.21 to 88.43)
        Week 26
    78.0 (64.4 to 88.47)
    50.0 (29.93 to 70.07)
        Week 52
    62.0 (47.17 to 75.35)
    53.8 (33.37 to 73.41)
    Notes
    [14] - n=49 wk 13 n=48 wk 26 n=47 wk 52
    [15] - n=25 wk 13 n=24 wk 26 n=25 wk 52
    Statistical analysis title
    		 Ladarixin vs Placebo - Week 13
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0779
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Ladarixin vs Placebo - Week 26
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0248
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Ladarixin vs Placebo - Week 52
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4504
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Proportion of patients with HbA1c <7% and absence of episodes of severe hypoglycaemia from the previous visit in patients with screening C-peptide < median value

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    End point title
    		 Proportion of patients with HbA1c <7% and absence of episodes of severe hypoglycaemia from the previous visit in patients with screening C-peptide < median value
    End point description
    A severe hypoglycaemic event was defined as an event with one of the following symptoms: memory loss, confusion, uncontrollable behaviour, irrational behaviour, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms”, in which the patient was unable to treat him/herself and which was associated with either a blood glucose level <54 mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration. Proportion is reported as percentage of patients, despite the measure type indicated is "number". Events per patient are calculated from the date of randomisation.
    End point type
    Secondary
    End point timeframe
    Follow-up at Weeks 13±1, 26±2, and 52±2.
    End point values
    		 Ladarixin - ITT/SAF Placebo - ITT/SAF
    Number of subjects analysed
    26 [16]
    11 [17]
    Units: Percentage
    number (confidence interval 95%)
        Week 13
    88.5 (69.85 to 97.55)
    63.6 (30.79 to 89.07)
        Week 26
    88.5 (69.85 to 97.55)
    36.4 (10.93 to 69.21)
        Week 52
    65.4 (44.33 to 82.79)
    45.5 (16.75 to 76.62)
    Notes
    [16] - n=26 wk 13 n=25 wk 26 n=25 wk 52
    [17] - n=11 wk 13 n=9 wk 26 n=19 wk 52
    Statistical analysis title
    		 Ladarixin vs Placebo - Week 13
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.163
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Ladarixin vs Placebo - Week 26
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0074
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Ladarixin vs Placebo - Week 52
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4437
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Average (previous 3 days) insulin requirement

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    End point title
    		 Average (previous 3 days) insulin requirement
    End point description
    Insulin requirement was averaged over the previous 3 days.
    End point type
    Secondary
    End point timeframe
    Follow-up at Weeks 13±1, 26±2, and 52±2.
    End point values
    		 Ladarixin - ITT/SAF Placebo - ITT/SAF
    Number of subjects analysed
    47 [18]
    26 [19]
    Units: IU/kg/day
    arithmetic mean (standard deviation)
        Week 13
    0.270 ± 0.1355
    0.310 ± 0.1955
        Week 26
    0.334 ± 0.2624
    0.369 ± 0.2114
        Week 52
    0.374 ± 0.2105
    0.439 ± 0.2349
    Notes
    [18] - n= 47 at weeks 13 and 26 n=46 at week 52
    [19] - n= 26 at week 13; n=25 at weeks 26 and 52
    Statistical analysis title
    		 Ladarixin vs placebo - week 13
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.2225
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    -0.048
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1257
         upper limit
    		 0.0298
    Notes
    [20] - Analysis is based on a linear mixed model for repeated measures with Daily Insulin Requirement (IU/kg/day) as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.
    Statistical analysis title
    		 Ladarixin vs placebo - week 26
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.551
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    -0.0369
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1596
         upper limit
    		 0.0858
    Notes
    [21] - Analysis is based on a linear mixed model for repeated measures with Daily Insulin Requirement (IU/kg/day) as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.
    Statistical analysis title
    		 Ladarixin vs placebo - week 52
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.2501
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    -0.063
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1712
         upper limit
    		 0.0453
    Notes
    [22] - Analysis is based on a linear mixed model for repeated measures with Daily Insulin Requirement (IU/kg/day) as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.

    Secondary: Glycated haemoglobin (HbA1c) levels

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    End point title
    		 Glycated haemoglobin (HbA1c) levels
    End point description
    HbA1c is a standard measure of glycemic control in diabetes, that reflects peak blood glucose levels reached in the past 2-3 months.
    End point type
    Secondary
    End point timeframe
    Follow-ups at Weeks 13±1, 26±2 and 52±2
    End point values
    		 Ladarixin - ITT/SAF Placebo - ITT/SAF
    Number of subjects analysed
    49 [23]
    25 [24]
    Units: percentage
    arithmetic mean (standard deviation)
        week 13
    6.18 ± 0.735
    6.37 ± 0.838
        week 26
    6.41 ± 1.200
    6.65 ± 1.138
        week 52
    6.86 ± 1.482
    6.65 ± 1.122
    Notes
    [23] - n=49 at week 13 n=48 at week 26 n=47 at week 52
    [24] - n=25 at week 13 n=24 at week 26 n=25 at week 52
    Statistical analysis title
    		 Ladarixin vs Placebo - week 13
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.6252
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    -0.1494
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7514
         upper limit
    		 0.4526
    Notes
    [25] - Analysis is based on a linear mixed model for repeated measures with HbA1c (%) as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.
    Statistical analysis title
    		 Ladarixin vs Placebo - week 26
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.366
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    -0.2804
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8904
         upper limit
    		 0.3297
    Notes
    [26] - Analysis is based on a linear mixed model for repeated measures with HbA1c (%) as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.
    Statistical analysis title
    		 Ladarixin vs Placebo - week 52
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.5026
    Method
    		 Mixed models analysis
    Parameter type
    		 adjusted mean difference
    Point estimate
    -0.2063
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3992
         upper limit
    		 0.8118
    Notes
    [27] - Analysis is based on a linear mixed model for repeated measures with HbA1c (%) as dependent variable, treatment, visit and treatment by visit interaction as fixed effects and patient as random effect.

    Secondary: Proportion of patients maintaining a residual β-cell function

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    End point title
    		 Proportion of patients maintaining a residual β-cell function
    End point description
    Maintenance of a residual ß-cell function is defined as at least one MMTT C-peptide value > 0.2 nmol/L. Proportion is reported as Percentage of patients, despite the measure type indicated is "number".
    End point type
    Secondary
    End point timeframe
    Follow-ups at Weeks 13±1, 26±2 and 52±2
    End point values
    		 Ladarixin - ITT/SAF Placebo - ITT/SAF
    Number of subjects analysed
    49 [28]
    26 [29]
    Units: Percentage
    number (confidence interval 95%)
        Week 13
    96.0 (86.29 to 99.51)
    88.5 (69.85 to 97.55)
        Week 26
    86.0 (73.26 to 94.18)
    84.6 (65.13 to 95.64)
        Week 52
    78.0 (64.04 to 88.47)
    76.9 (56.35 to 91.03)
    Notes
    [28] - n=49 at week 13 n=46 at week 26 n=45 at week 52
    [29] - n=26 at week 13 n=25 at week 26 n=25 at week 52
    Statistical analysis title
    		 Ladarixin vs placebo - week 13
    Statistical analysis description
    Percentages are calculated relative to the number of patients in ITT population
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1171
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Ladarixin vs placebo - week 26
    Statistical analysis description
    Percentages are calculated relative to the number of patients in ITT population
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6586
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Ladarixin vs placebo - week 52
    Statistical analysis description
    Percentages are calculated relative to the number of patients in ITT population
    Comparison groups
    Ladarixin - ITT/SAF v Placebo - ITT/SAF
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5056
    Method
    		 Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were recorded and reported in the CRF from enrolment through patient’s participation in the study (last planned visit or early withdrawal date)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Ladarixin SAF
    Reporting group description
    		 Safety analysis set (SAF) was defined as all patients in the Randomized Analysis Set (RND) who received any study treatment

    Reporting group title
    Placebo SAF
    Reporting group description
    		 Safety analysis set (SAF) was defined as all patients in the Randomized Analysis Set (RND) who received any study treatment

    Serious adverse events
    		 Ladarixin SAF Placebo SAF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 26 (3.85%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental disorder
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (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: 2%
    Non-serious adverse events
    		 Ladarixin SAF Placebo SAF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 50 (74.00%)
    21 / 26 (80.77%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Diabetes mellitus management
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Tooth extraction
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Injection site reaction
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    6 / 50 (12.00%)
    2 / 26 (7.69%)
         occurrences all number
    7
    3
    Sensation of foreign body
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Drug hypersensitivity
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    3
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Dysmenorrhoea
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Nipple inflammation
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Increased viscosity of upper respiratory secretion
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Oropharyngeal pain
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 26 (0.00%)
         occurrences all number
    5
    0
    Vocal cord inflammation
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Emotional distress
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Insomnia
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Blood iron decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Eosinophil count decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Glycosylated haemoglobin increased
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Haemoglobin increased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Vitamin D decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Alcohol poinsoning
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Joint injury
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Ligament sprain
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Limb injury
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Muscle injury
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Skin wound
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Sunburn
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Headache
         subjects affected / exposed
    14 / 50 (28.00%)
    6 / 26 (23.08%)
         occurrences all number
    20
    8
    Migrane
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Eosinophilia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    lymphadenopathy
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Lymphocytosis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    Neutropenia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Polycythaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Ear pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 26 (7.69%)
         occurrences all number
    4
    2
    Constipation
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Dental caries
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2
    Dyspepsia
         subjects affected / exposed
    6 / 50 (12.00%)
    0 / 26 (0.00%)
         occurrences all number
    9
    0
    Dysphagia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Faeces hard
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Hyperchlorhydria
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 26 (11.54%)
         occurrences all number
    4
    4
    Odynophagia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Pancreatitis chronic
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Toothache
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Vomiting
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Alopecia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Rash
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Back pain
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    3
    Muscle spasms
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Osteoarthritis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Cystitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Eye infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Folliculitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 26 (11.54%)
         occurrences all number
    1
    3
    Gingivitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Infected bite
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Influenza
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    Laryngitis
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    2
    Oral herpes
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Pharyngitis
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Sinusitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    Tinea pedis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Tooth abscess
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    Viral infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    13 / 50 (26.00%)
    4 / 26 (15.38%)
         occurrences all number
    19
    6
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 26 (3.85%)
         occurrences all number
    7
    2
    Iron deficiency
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 26 (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? 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.
    No limitations or caveats are applicable to this summary of the results
    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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