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    Clinical Trial Results:
    A phase 3, multicenter, randomized, double-blind, parallel assignment study to assess the efficacy and safety of reparixin in pancreatic islet transplantation.

    Summary
    EudraCT number
    		 2011-006201-10
    Trial protocol
    		 CZ   GB   SE   IT  
    Global end of trial date
    09 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Apr 2018
    First version publication date
    28 Apr 2018
    Other versions
    Summary report(s)
    		 CSR summary report v 1.0 - 09 Nov 2017

    Trial information

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    Trial identification
    Sponsor protocol code
    REP0211
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01817959
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND - USA participated in the study: 15,194
    Sponsors
    Sponsor organisation name
    Dompé farmaceutici S.p.A
    Sponsor organisation address
    Via Santa Lucia, 6, Milan, Italy, 20122
    Public contact
    Project Development Direction, Dompe' spa, +39 0258383500, info@dompe.it
    Scientific contact
    Project Development Direction, Dompe' spa, +39 0258383500, info@dompe.it
    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
    09 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this clinical trial is to assess whether reparixin leads to improved transplant outcome as measured by glycaemic control following intra-hepatic infusion of pancreatic islets in T1D patients. The safety of reparixin in the specific clinical setting will be also evaluated.
    Protection of trial subjects
    There was a Data Monitoring Committee (DMC). There were 6 meetings from DMC committee. The trial sites were monitored by WCT monitors according to ICH GCP guidelines and WCT SOPs. At each monitoring visit, progress of the trial was assessed and discussed with the investigator; completed CRFs were checked for completeness and accuracy and were compared to the original subject records and/or source documents; signed ICFs were inspected; and the trial supplies were examined. Independent auditing was conducted by both Dompé and WCT’s Quality Assurance Department according to the SOPs of both.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Oct 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 13
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Czech Republic: 9
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    United States: 12
    Worldwide total number of subjects
    51
    EEA total number of subjects
    39
    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)
    49
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Competitive recruitment was chosen to increase the speed of recruitment and to account for any difference in transplant rate among trial sites. However, each site was strongly encouraged to recruit the planned number of subjects in order to provide “within site” results for balanced treatment groups.

    Pre-assignment
    Screening details
    		 Potential study patients were identified whilst on the centre transplant waiting list. Consented patients (consent signed within 3 months prior to screening) underwent confirmatory screening for the study within maximum 3 days prior to the 1st transplant. BP, HR, body weight (kg) and height (m) was be measured, blood samples were taken.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    The trial was blinded to subjects, investigators, and sponsor. As the concentrated Reparixin solution has a pale yellow color compared with placebo, any pharmacist preparing the sterile i.v. bags with solutions for treatment could not be blinded. The solutions used for treatment were indistinguishable from each other once prepared. Individual treatment codes were provided in sealed envelopes to the Pharmacist (or designee) and to the Investigator (one set each).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Reparixin arm
    Arm description
    		 Patients received reparixin at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hrs)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Reparixin
    Investigational medicinal product code
    DF1681Y
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Reparixin at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hrs) The dosing solution (if reparixin, 11mg/mL) was administered as a continuous i.v. infusion into a (high flow) central vein, by an infusion pump adequate to provide reliable infusion rates, as per treatment schedule. Infusion of the Investigational Product will start approximately 12hrs (allowed range 6-18hrs) before the anticipated time when each islet infusion is started. The Investigator will identify the time to start study drug administration. The pump rate will be adjusted to provide an infusion rate of approximately 0.25mL/kg/hour. Actual infusion rate (mL/hour), adjusted to body weight

    Arm title
    		 Placebo
    Arm description
    		 Patients received placebo for 7 days (168 hours) at the same flow rate (mL/kg body weight/hour) used for reparixin
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dosing solution of Placebo was administered as a continuous i.v. infusion into a (high flow) central vein at the same flow rate (mL/kg body weight/hour) used for reparixin; infusion was started approximately 12hrs (6-18hrs) before each pancreatic islet infusion and continued for 7 days (168 hours)

    Number of subjects in period 1 [1]
    		Reparixin arm Placebo
    Started
    29
    19
    Completed
    25
    16
    Not completed
    4
    3
         Total withdrawals
    4
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: There's a discrepancy on the total number of patients enrolled (51) and the ones who received IMP (48). There were 3 subject enrolled in the trial who withdrew prior to receiving the IMP for the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 48 48
    Age categorical
    Units: Subjects
        Age 18- 70
    		 48 48
    Gender categorical
    Units: Subjects
        Female
    		 29 29
        Male
    		 19 19

    End points

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    End points reporting groups
    Reporting group title
    Reparixin arm
    Reporting group description
    		 Patients received reparixin at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hrs)

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received placebo for 7 days (168 hours) at the same flow rate (mL/kg body weight/hour) used for reparixin

    Primary: Area Under the Curve (AUC) for the serum C-peptide level during the first 2 hours of an MMTT, normalized by the number of Islet Equivalent (IEQ)/kg -Day 365+/-14 after the last islet infusion

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    End point title
    		 Area Under the Curve (AUC) for the serum C-peptide level during the first 2 hours of an MMTT, normalized by the number of Islet Equivalent (IEQ)/kg -Day 365+/-14 after the last islet infusion
    End point description
    The C-peptide AUC normalized by IEQ/kg will be analyzed at day 365+14 after the last islet infusion. Analysis of variance will be used, including terms for treatment, centre and treatment per centre interaction. The importance of the treatment by center interaction will be investigated but if this is not significant at the 10% level, this term will be excluded from the final model. If a center by treatment interaction is detected, alternative methods of presentation will be explored. Treatment effect will be compared using a two-sided 0.0025 level Student’s t test (statistical significance adjusted for one pivotal trial). Considering the nature of the variable, there are no reasonable substitutions of missing data that would not introduce a bias in the interpretation of the results. /-14 after the last islet infusion
    End point type
    Primary
    End point timeframe
    Day 365+/-14 after the last islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    27
    18
    Units: ng/ml
        arithmetic mean (standard error)
    0.234 ± 0.05
    0.207 ± 0.033
    Attachments
    		 Untitled (Filename: Table 14.2.1.1.doc)
    Statistical analysis title
    		 Primary analysis model
    Statistical analysis description
    The primary efficacy endpoint was analysed by analysis of variance (ANOVA) including terms for treatment, centre and treatment-by-centre interaction. Centres that recruited less than four subjects were pooled and counted as a single centre for analysis purposes. If the treatment-by-centre interaction was not significant at the 10% level, the term was to be excluded from the final model. If the interaction term was significant at the 10% level, alternative methods of presentation were explored
    Comparison groups
    Reparixin arm v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≥ 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Area Under the Curve (AUC) for the serum C-peptide level during the first 2 hours of an MMTT, normalized by the number of Islet Equivalent (IEQ)/kg - Day 75+/-5 after the 1st islet infusion

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    End point title
    		 Area Under the Curve (AUC) for the serum C-peptide level during the first 2 hours of an MMTT, normalized by the number of Islet Equivalent (IEQ)/kg - Day 75+/-5 after the 1st islet infusion
    End point description
    The C-peptide AUC normalized by IEQ/kg will be analyzed at day 75+5 post the 1st islet infusion. Analysis of variance will be used, including terms for treatment, centre and treatment per centre interaction. The importance of the treatment by center interaction will be investigated but if this is not significant at the 10% level, this term will be excluded from the final model. If a center by treatment interaction is detected, alternative methods of presentation will be explored. Treatment effect will be compared using a two-sided 0.0025 level Student’s t test (statistical significance adjusted for one pivotal trial). Considering the nature of the variable, there are no reasonable substitutions of missing data that would not introduce a bias in the interpretation of the results. /-14 after the last islet infusion
    End point type
    Primary
    End point timeframe
    Day 75+/-5 after the 1st islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    27
    18
    Units: ng/ml
        arithmetic mean (standard error)
    0.247 ± 0.042
    0.231 ± 0.049
    Attachments
    		 Untitled (Filename: Table 14.2.1.1.doc)
    Statistical analysis title
    		 Primary analysis model
    Statistical analysis description
    The primary efficacy endpoint was analysed by analysis of variance (ANOVA) including terms for treatment, centre and treatment-by-centre interaction. Centres that recruited less than four subjects were pooled and counted as a single centre for analysis purposes. If the treatment-by-centre interaction was not significant at the 10% level, the term was to be excluded from the final model. If the interaction term was significant at the 10% level, alternative methods of presentation were explored
    Comparison groups
    Reparixin arm v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≥ 0.05
    Method
    		 ANOVA
    Confidence interval

    Secondary: The proportion of insulin-independent patients at timeframe day 365+14 after last islet infusion

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    End point title
    		 The proportion of insulin-independent patients at timeframe day 365+14 after last islet infusion
    End point description
    The proportion of insulin-independent patients at timeframe day 365+14 after last islet infusion
    End point type
    Secondary
    End point timeframe
    Day 365+14 after last islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    27
    18
    Units: Subjects
    8
    5
    Attachments
    		 Untitled (Filename: Table 14.2.2.1.doc)
    Statistical analysis title
    		 Fisher exact test
    Comparison groups
    Reparixin arm v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 ≥ 0.05
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 4.93
    Variability estimate
    Standard deviation
    Notes
    [1] - If a primary analysis model could not fit, a Fisher's exact test was used instead.

    Secondary: The proportion of patients who achieve and maintain an HbA1c <7.0% (or o reduction in HbA1c > 2%) AND are free of severe hypoglycaemic events

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    End point title
    		 The proportion of patients who achieve and maintain an HbA1c <7.0% (or o reduction in HbA1c > 2%) AND are free of severe hypoglycaemic events
    End point description
    The proportion of patients who achieve and maintain an HbA1c <7.0% (or o reduction in HbA1c > 2%) AND are free of severe hypoglycaemic events at day 365+14 after the last islet infusion
    End point type
    Secondary
    End point timeframe
    Day 365+14 after the last islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    27
    18
    Units: Subjects
    10
    8
    Attachments
    		 Untitled (Filename: Table 14.2.3.1.doc)
    Statistical analysis title
    		 Secondary analysis model
    Statistical analysis description
    The data at Day 75±5 (both transplants) and Day 365±14 (last transplant) were analysed via logistic regression models with factors for treatment and pooled centre. The odds ratio for treatment effect were presented with the associated 95% CIs.
    Comparison groups
    Reparixin arm v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≥ 0.05
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 2.66
    Variability estimate
    Standard deviation

    Secondary: The number of patients not allocated to a 2nd infusion because insulin-independent after the 1st infusion

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    End point title
    		 The number of patients not allocated to a 2nd infusion because insulin-independent after the 1st infusion
    End point description
    The number of patients not allocated to a 2nd infusion because insulin-independent after the 1st infusion
    End point type
    Secondary
    End point timeframe
    day 365+14 after the 1st islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    27
    18
    Units: Subjects
    4
    0
    Attachments
    		 Untitled (Filename: Table 14.2.4.doc)
    Statistical analysis title
    		 Fisher exact test
    Statistical analysis description
    If a primary analysis model could not fit, a Fisher's exact test was used instead.
    Comparison groups
    Reparixin arm v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≥ 0.05
    Method
    		 Fisher exact
    Parameter type
    		 Yes/No
    Point estimate
    0.1383
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 1

    Secondary: Cumulative number of severe hypoglycaemic events

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    End point title
    		 Cumulative number of severe hypoglycaemic events
    End point description
    Cumulative number of severe hypoglycaemic events at day 365+14 after the last islet infusion
    End point type
    Secondary
    End point timeframe
    day 365+14 after the last islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    27
    18
    Units: Events
    11
    7
    Attachments
    		 Untitled (Filename: Table 14.2.5.1.doc)
    No statistical analyses for this end point

    Secondary: Change in average daily insulin requirements (absolute and % decrease from pre-transplant levels)

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    End point title
    		 Change in average daily insulin requirements (absolute and % decrease from pre-transplant levels)
    End point description
    Change in average daily insulin requirements (absolute and % decrease from pre-transplant levels) at day 75+5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion
    End point type
    Secondary
    End point timeframe
    day 75+5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    27 [2]
    18 [3]
    Units: IU/kg/day
    0
    0
    Attachments
    		 Untitled (Filename: Table 14.2.6.1.doc)
    Notes
    [2] - Multiple values, please check attached table for actual values
    [3] - Multiple values, please check attached table for actual values
    Statistical analysis title
    		 Secondary ANCOVA analysis
    Statistical analysis description
    The data at Day 75±5 (both transplants) and Day 365±14 after the last islet infusion were analysed via analysis of covariance (ANCOVA) with factors for treatment and centre and pre-dose value as a covariate. Least squares adjusted mean values for each treatment group were presented, together with the difference in least squares means. The 95% CI for the difference in least square means were estimated using the mean square error from the ANCOVA.
    Comparison groups
    Reparixin arm v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≥ 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.056
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.042
         upper limit
    		 0.154
    Variability estimate
    Standard error of the mean

    Secondary: HbA1c % (absolute and % decrease from pre-transplant levels)

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    End point title
    		 HbA1c % (absolute and % decrease from pre-transplant levels)
    End point description
    HbA1c % (absolute and % decrease from pre-transplant levels) at Day 75+5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion
    End point type
    Secondary
    End point timeframe
    Day 75+5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    27 [4]
    18 [5]
    Units: HbA1c %
        number (not applicable)
    0
    0
    Attachments
    		 Untitled (Filename: Table 14.2.7.1.doc)
    Notes
    [4] - Multiple values, please check attached table for actual values
    [5] - Multiple values, please check attached table for actual values
    Statistical analysis title
    		 Secondary ANCOVA analysis
    Statistical analysis description
    The data at Day 75±5 (both transplants) and Day 365±14 after the last islet infusion were analysed via analysis of covariance (ANCOVA) with factors for treatment and centre and pre-dose value as a covariate. Least squares adjusted mean values for each treatment group were presented, together with the difference in least squares means. The 95% CI for the difference in least square means were estimated using the mean square error from the ANCOVA.
    Comparison groups
    Reparixin arm v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≥ 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 0.93
    Variability estimate
    Standard error of the mean

    Secondary: Basal (fasting) and 0 to 120 min time course of glucose, C-peptide and insulin derived from the MMTT

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    End point title
    		 Basal (fasting) and 0 to 120 min time course of glucose, C-peptide and insulin derived from the MMTT
    End point description
    Basal (fasting) and 0 to 120 min time course of glucose, C-peptide and insulin derived from the MMTT at 75+5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion
    End point type
    Secondary
    End point timeframe
    Day 75+5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    27 [6]
    18 [7]
    Units: IEQ/kg; ng/ml; minutes
        number (not applicable)
    0
    0
    Attachments
    		 Untitled (Filename: Table 14.2.8.5.doc)
    Notes
    [6] - Multiple values, please check attached table for actual values
    [7] - Multiple values, please check attached table for actual values
    No statistical analyses for this end point

    Secondary: β-cell function as assessed by β-score and Transplant Estimated Function (TEF)

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    End point title
    		 β-cell function as assessed by β-score and Transplant Estimated Function (TEF)
    End point description
    β-cell function as assessed by β-score and Transplant Estimated Function (TEF) at day 75+5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion
    End point type
    Secondary
    End point timeframe
    Day 75+5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    27 [8]
    18 [9]
    Units: β-score and TEF
        number (not applicable)
    0
    0
    Attachments
    		 Untitled (Filename: Table 14.2.11.1.doc)
    Notes
    [8] - Multiple values, please check attached table for actual values
    [9] - Multiple values, please check attached table for actual values
    Statistical analysis title
    		 Secondary analysis - ANOVA
    Statistical analysis description
    beta cell function variables were analysed via ANOVA with factors for treatment and centre. Least squares adjusted mean values for each treatment group were presented, together with the difference in least squares means. The 95% CI for the difference in least square means were estimated using the mean square error from the ANOVA.
    Comparison groups
    Reparixin arm v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≥ 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.97
         upper limit
    		 0.8
    Variability estimate
    Standard error of the mean

    Secondary: The proportion of insulin-independent patients at timeframe day 75+5 after the 1st islet infusion

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    End point title
    		 The proportion of insulin-independent patients at timeframe day 75+5 after the 1st islet infusion
    End point description
    The proportion of insulin-independent patients at timeframe day 75+5 after the 1st islet infusion
    End point type
    Secondary
    End point timeframe
    Day 75+5 after the 1st islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    27
    18
    Units: Subjects
    5
    1
    Attachments
    		 Untitled (Filename: Table 14.2.2.1.doc)
    Statistical analysis title
    		 Fisher exact test
    Comparison groups
    Reparixin arm v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 ≥ 0.05
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 4.93
    Variability estimate
    Standard deviation
    Notes
    [10] - If a primary analysis model could not fit, a Fisher's exact test was used instead.

    Secondary: The proportion of insulin-independent patients at timeframe day 75+5 after the 2nd islet infusion

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    End point title
    		 The proportion of insulin-independent patients at timeframe day 75+5 after the 2nd islet infusion
    End point description
    The proportion of insulin-independent patients at timeframe day 75+5 after the 2nd islet infusion
    End point type
    Secondary
    End point timeframe
    Day 75+5 after the 2nd islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    27
    18
    Units: Subjects
    5
    8
    Attachments
    		 Untitled (Filename: Table 14.2.2.1.doc)
    Statistical analysis title
    		 Fisher exact test
    Comparison groups
    Reparixin arm v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 ≥ 0.05
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 4.93
    Variability estimate
    Standard deviation
    Notes
    [11] - If a primary model could not fit, a Fisher's exact test was used instead

    Other pre-specified: Incidence and severity of Adverse Events and Serious Adverse Events

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    End point title
    		 Incidence and severity of Adverse Events and Serious Adverse Events
    End point description
    Incidence and severity of Adverse Events and Serious Adverse Events throughout the study up to day 365+14 after last islet infusion. All AEs will be coded using the most up-to-date version at the time of database lock of the MedDRA and will be presented by primary system organ class and preferred term. AEs will be presented in terms of the incidence, severity and relationship to the study drug, overall and by body system and preferred term. SAEs will be presented in the same way.
    End point type
    Other pre-specified
    End point timeframe
    Throughout the study up to day 365+14 after last islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    29 [12]
    19 [13]
    Units: Event
    0
    0
    Attachments
    		 Untitled (Filename: Table 14.3.2.doc)
    Untitled (Filename: Table 14.3.5.doc)
    Notes
    [12] - Multiple values, please check attached table for actual values
    [13] - Multiple values, please check attached table for actual values
    No statistical analyses for this end point

    Other pre-specified: Standard laboratory tests including hematology, clinical chemistry

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    End point title
    		 Standard laboratory tests including hematology, clinical chemistry
    End point description
    Standard laboratory tests including hematology, clinical chemistry at preinfusion hospital admission and post-infusion hospital discharge Standard laboratory tests including hematology (hematocrit, hemoglobin, red blood cells, platelets, white blood cells, differential white blood cells count), clinical chemistry (sodium, potassium, serum creatinine, blood urea nitrogen, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and coagulation (prothrombin time (PT), partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT)) Results for each laboratory test at screening and hospital discharge will be assessed as being below the lower limit of the normal range, within the normal range or above the upper limit of the normal range.
    End point type
    Other pre-specified
    End point timeframe
    Preinfusion hospital admission and post-infusion hospital discharge
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    29 [14]
    19 [15]
    Units: Various
        number (not applicable)
    0
    0
    Attachments
    		 Untitled (Filename: Table 14.3.9.doc)
    Untitled (Filename: Table 14.3.10.doc)
    Untitled (Filename: Table 14.3.11.1.doc)
    Untitled (Filename: Table 14.3.11.2.doc)
    Untitled (Filename: Table 14.3.12.doc)
    Untitled (Filename: Table 14.3.13.doc)
    Untitled (Filename: Table 14.3.14.1.doc)
    Untitled (Filename: Table 14.3.14.2.doc)
    Untitled (Filename: Table 14.3.14.3.doc)
    Untitled (Filename: Table 14.3.15.doc)
    Untitled (Filename: Table 14.3.16.doc)
    Untitled (Filename: Table 14.3.17.doc)
    Untitled (Filename: Table 14.3.18.doc)
    Notes
    [14] - Multiple values, please check attached table for actual values
    [15] - Multiple values, please check attached table for actual values
    No statistical analyses for this end point

    Other pre-specified: Vital signs

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    End point title
    		 Vital signs
    End point description
    Vital signs at each time point and the change in vital signs from screening will be presented using descriptive statistics
    End point type
    Other pre-specified
    End point timeframe
    Pre-infusion hospital admission and post-infusion hospital discharge
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    29 [16]
    19 [17]
    Units: Various
        number (not applicable)
    0
    0
    Attachments
    		 Untitled (Filename: Table 14.3.19.doc)
    Untitled (Filename: Table 14.3.20.doc)
    Untitled (Filename: Table 14.3.21.doc)
    Notes
    [16] - Multiple values, please check attached table for actual values
    [17] - Multiple values, please check attached table for actual values
    No statistical analyses for this end point

    Other pre-specified: ALT/AST, PT/PTT, fibrin degradation products (XDPs) or D-dimer, C-reactive protein (CRP)

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    End point title
    		 ALT/AST, PT/PTT, fibrin degradation products (XDPs) or D-dimer, C-reactive protein (CRP)
    End point description
    ALT/AST, PT/PTT, XDP and CRP will be summarized for each of the 6 days post-transplant and (ALT/AST) for day 75+5 post-transplant. The proportion of patients with ALT/AST below or within normal range, up to 3x ULN or above 3x ULN will also be presented.
    End point type
    Other pre-specified
    End point timeframe
    All daily up to day 6 after the 1st and 2nd islet infusion; ALT/AST also on day 75+5 after the 1st and 2nd islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    29 [18]
    19 [19]
    Units: Various
        number (not applicable)
    0
    0
    Attachments
    		 Untitled (Filename: Table 14.3.9.doc)
    Untitled (Filename: Table 14.3.10.doc)
    Untitled (Filename: Table 14.3.11.1.doc)
    Untitled (Filename: Table 14.3.11.2.doc)
    Untitled (Filename: Table 14.3.12.doc)
    Untitled (Filename: Table 14.3.13.doc)
    Untitled (Filename: Table 14.3.14.1.doc)
    Untitled (Filename: Table 14.3.14.2.doc)
    Untitled (Filename: Table 14.3.14.3.doc)
    Untitled (Filename: Table 14.3.15.doc)
    Notes
    [18] - Multiple values, please check attached table for actual values
    [19] - Multiple values, please check attached table for actual values
    No statistical analyses for this end point

    Other pre-specified: Auto-antibodies (GAD, IA-2, optional: ZnT8)

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    End point title
    		 Auto-antibodies (GAD, IA-2, optional: ZnT8)
    End point description
    Auto-antibody, anti-HLA antibodies, chemokines/cytokines and coagulation/complement activation markers will be presented using appropriate descriptive statistics, by treatment group.
    End point type
    Other pre-specified
    End point timeframe
    Pre-infusion hospital admission, day 6/7 and day 75+5 after the 1st and 2nd islet infusion and day 365+14 after the last islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    27 [20]
    18 [21]
    Units: Subjects
    0
    0
    Attachments
    		 Untitled (Filename: Table 14.2.13.1.doc)
    Notes
    [20] - Multiple values, please check attached table for actual values
    [21] - Multiple values, please check attached table for actual values
    No statistical analyses for this end point

    Other pre-specified: Anti-HLA antibodies

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    End point title
    		 Anti-HLA antibodies
    End point description
    Auto-antibody, anti-HLA antibodies, chemokines/cytokines and coagulation/complement activation markers will be presented using appropriate descriptive statistics, by treatment group.
    End point type
    Other pre-specified
    End point timeframe
    Pre-infusion hospital admission, day 6/7 and day 75+5 after the 1st and 2nd islet infusion and day 365+14 after the last islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    27 [22]
    18 [23]
    Units: Subjects
    0
    0
    Attachments
    		 Untitled (Filename: Table 14.2.16.doc)
    Notes
    [22] - Multiple values, please check attached table for actual values
    [23] - Multiple values, please check attached table for actual values
    No statistical analyses for this end point

    Other pre-specified: Time course of inflammatory chemokines/cytokines as assessed by serum level of CXCL8, CCL2 (MCP-1), CCL3, CCL4, CXCL10 (IP-10), CXCL9 (MIG), IL-6, IL-10 & Time course of serum microRNA-375 (miR-375)

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    End point title
    		 Time course of inflammatory chemokines/cytokines as assessed by serum level of CXCL8, CCL2 (MCP-1), CCL3, CCL4, CXCL10 (IP-10), CXCL9 (MIG), IL-6, IL-10 & Time course of serum microRNA-375 (miR-375)
    End point description
    Auto-antibody, anti-HLA antibodies, chemokines/cytokines and coagulation/complement activation markers will be presented using appropriate descriptive statistics, by treatment group.
    End point type
    Other pre-specified
    End point timeframe
    preinfusion hospital admission and 6, 12, 24, 72, 120 and 168hrs after the 1st and 2nd islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    27
    18
    Units: Various
        number (not applicable)
    9
    7
    Attachments
    		 Untitled (Filename: Table 14.2.1.1.doc)
    Untitled (Filename: Table 14.2.18.doc)
    Untitled (Filename: Table 14.2.19.doc)
    Untitled (Filename: Table 14.2.20.doc)
    Untitled (Filename: Table 14.2.21.doc)
    Untitled (Filename: Table 14.2.22.doc)
    Untitled (Filename: Table 14.2.23.doc)
    Untitled (Filename: Table 14.2.24.doc)
    Untitled (Filename: Table 14.2.26.doc)
    Statistical analysis title
    		 Exploratory ANCOVA analysis
    Statistical analysis description
    For each of the above variables, the AUC0-168 after each transplant were analysed via ANCOVA of ranked transformed data with factors for treatment and centre and pre-transplant value as a covariate. The 95% Hodges-Lehmann CI for the difference between treatments were estimated using PROC NPAR1WAY in SAS using the Higher Level (HL) option. The within treatment distribution-free 95% CIs for the medians were estimated using the CIQUANTDF (alpha=.05) option within PROC UNIVARIATE in SAS.
    Comparison groups
    Reparixin arm v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≥ 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.94
         upper limit
    		 5.55
    Variability estimate
    Standard error of the mean

    Other pre-specified: Time-course of coagulation/complement activation markers as assessed by blood level of C3a, sC5b-9, Thrombin-antithrombin complexes (TAT), D-dimer (inclusive of markers of PMN/monocyte activation)

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    End point title
    		 Time-course of coagulation/complement activation markers as assessed by blood level of C3a, sC5b-9, Thrombin-antithrombin complexes (TAT), D-dimer (inclusive of markers of PMN/monocyte activation)
    End point description
    Auto-antibody, anti-HLA antibodies, chemokines/cytokines and coagulation/complement activation markers will be presented using appropriate descriptive statistics, by treatment group.
    End point type
    Other pre-specified
    End point timeframe
    pre-infusion hospital admission and 1, 6, 12, 24, 72, 120 and 168hrs after the 1st and 2nd islet infusion
    End point values
    		 Reparixin arm Placebo
    Number of subjects analysed
    27 [24]
    18 [25]
    Units: Various
        number (not applicable)
    0
    0
    Attachments
    		 Untitled (Filename: Table 14.2.27.doc)
    Untitled (Filename: Table 14.2.28.doc)
    Untitled (Filename: Table 14.2.29.doc)
    Untitled (Filename: Table 14.2.30.doc)
    Untitled (Filename: Table 14.2.31.doc)
    Untitled (Filename: Table 14.2.32.doc)
    Notes
    [24] - Multiple values, please check attached table for actual values
    [25] - Multiple values, please check attached table for actual values
    Statistical analysis title
    		 Exploratory ANCOVA analysis
    Statistical analysis description
    For each of the above variables, the AUC0-168 after each transplant were analysed via ANCOVA of ranked transformed data with factors for treatment and centre and pre-transplant value as a covariate. The 95% Hodges-Lehmann CI for the difference between treatments were estimated using PROC NPAR1WAY in SAS using the HL option. The within treatment distribution-free 95% CIs for the medians were estimated using the CIQUANTDF (alpha=.05) option within PROC UNIVARIATE in SAS.
    Comparison groups
    Reparixin arm v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≥ 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    -10.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.57
         upper limit
    		 19.95
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    - seven calendar days after becoming aware of the information if the event is fatal or life threatening; and - fifteen calendar days after becoming aware of the information if the event is neither fatal nor life threatening
    Adverse event reporting additional description
    Dompé was to submit a complete report in respect of ADR information that included an assessment of the importance and implication of any findings made within 8 days after having informed the Competent Authority.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Reparixin
    Reporting group description
    		 Subjects who received Reparixin at a dose of 2.772 mg/kg body weight/hour for 7 days 

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects who received Placebo at a dose of 2.772 mg/kg body weight/hour for 7 days 

    Serious adverse events
    		 Reparixin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 29 (58.62%)
    12 / 19 (63.16%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Implant site haemorrhage
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Puncture site haemorrhage
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Alloimmunisation
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant rejection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    HLA marker trial positive
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panel-reactive antibody increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complications of transplant surgery
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Diabetic neuropathy
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 19 (15.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic haematoma
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Localised infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ketosis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Reparixin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 29 (100.00%)
    18 / 19 (94.74%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Dizziness
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Hypertension
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 19 (0.00%)
         occurrences all number
    4
    0
    Hypotension
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Catheter site pain
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 19 (10.53%)
         occurrences all number
    4
    2
    Chest discomfort
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Chills
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Generalised oedema
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Implant site haemorrhage
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 19 (5.26%)
         occurrences all number
    5
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    3 / 29 (10.34%)
    5 / 19 (26.32%)
         occurrences all number
    4
    6
    Vessel puncture site erythema
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    Nasal congestion
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 19 (15.79%)
         occurrences all number
    1
    4
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Blood pressure decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Heart rate increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Liver function test increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Portal vein pressure increased
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    Weight increased
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Head injury
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Incision site pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Post procedural haematoma
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Procedural pain
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 19 (5.26%)
         occurrences all number
    3
    2
    Wound dehiscence
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Blood magnesium decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Bradycardia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Tachycardia
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 19 (5.26%)
         occurrences all number
    3
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    8 / 29 (27.59%)
    7 / 19 (36.84%)
         occurrences all number
    11
    9
    Migraine
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 19 (10.53%)
         occurrences all number
    1
    2
    Syncope
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Tremor
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Emotional distress
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 19 (10.53%)
         occurrences all number
    2
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 19 (5.26%)
         occurrences all number
    6
    3
    Leukopenia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Neutropenia
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 19 (10.53%)
         occurrences all number
    1
    2
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Vitreous floaters
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 29 (20.69%)
    9 / 19 (47.37%)
         occurrences all number
    6
    9
    Abdominal pain upper
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 19 (10.53%)
         occurrences all number
    1
    2
    Constipation
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    Diarrhoea
         subjects affected / exposed
    5 / 29 (17.24%)
    3 / 19 (15.79%)
         occurrences all number
    7
    3
    Lip oedema
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Lip swelling
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    10 / 29 (34.48%)
    10 / 19 (52.63%)
         occurrences all number
    15
    15
    Peritoneal haemorrhage
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Stomatitis
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    Vomiting
         subjects affected / exposed
    6 / 29 (20.69%)
    5 / 19 (26.32%)
         occurrences all number
    7
    7
    Hepatobiliary disorders
    Hepatic haemorrhage
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Erythema
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 19 (10.53%)
         occurrences all number
    2
    2
    Rash
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Skin exfoliation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Back pain
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 19 (10.53%)
         occurrences all number
    3
    3
    Joint swelling
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Muscular weakness
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 19 (5.26%)
         occurrences all number
    3
    1
    Neck pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Infections and infestations
    Coccidioidomycosis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Fluid retention
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 19 (0.00%)
         occurrences all number
    5
    0
    Hypervolaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    5 / 29 (17.24%)
    3 / 19 (15.79%)
         occurrences all number
    6
    5
    Hypokalaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jul 2012
    Protocol amendment 1: the wording for AEs and SAEs recording were corrected in protocol section 8.2 in order to clarify recording period and keep consistency with Appendix 4 of the protocol.
    13 Dec 2013
    Protocol version No. 2 dated 13 December 2013 included updates to: clinical data section, overall study design (study timelines), objectives and endpoints, exclusion criteria, investigation product section (other treatments), study procedure and assessments and finally administrative details It also included the changes introduced by previous amendment No. 1 and country-specific amendments No. 2 and 3. Country-specific amendment No. 2 created to address specific requirements from Swedish regulatory authority, is applicable to the Swedish sites only. Similarly, Amendment No. 3 issued upon specific requirements from the FDA, considering that islet allo-transplant is a research procedure in the US, is applicable to the US site only. Therefore, additional exclusion criteria and procedures, as well as stopping rules, are meant to comply with these specific IND requirements; consequently introduced by amendment no. 3, are applicable to the US site only. All country-specific procedures are clearly identified in the revised protocol (version No. 2 dated 13 December 2013). Some other minor corrections to the protocol and clarification with regard to some items were also included.

    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.
    Sample size was based on feasibility and might have been too low to detect treatment differences. Similarly, unbalanced patient distribution across sites and site-specific differences in the population/procedures, might have affected overall 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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