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    Clinical Trial Results:
    PROLOGUES - Prehospital lowering of glucose in Stroke

    Summary
    EudraCT number
    		 2011-002780-16
    Trial protocol
    		 SE  
    Global end of trial date
    31 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Apr 2021
    First version publication date
    07 Apr 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    8.4
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Karolinska Institutet
    Sponsor organisation address
    17177, Stockholm, Sweden,
    Public contact
    David Nathanson, Karolinska Institutet Södersjukhuset, 46 86163449, david.nathanson@sodersjukhuset.se
    Scientific contact
    David Nathanson, Karolinska Institutet Södersjukhuset, 46 86163449, david.nathanson@sodersjukhuset.se
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to investigate whether Exenatide given in a pre-hospital setting lowers blood glucose levels 4 h after injection, in patients with symptoms of a cerebrovascular lesion.
    Protection of trial subjects
    The study was approved by the Central Ethics Committee of Sweden (Ref. No. Ö 6‐2012). Written informed consent was obtained in the ambulance from all participants. Study physician (ML) was on call around the clock for consultations throughout the study period.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 19
    Worldwide total number of subjects
    19
    EEA total number of subjects
    19
    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)
    7
    From 65 to 84 years
    9
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was open for inclusion between May 2013 and May 2018 and was stopped due to slow inclusion. The study center was Södersjukhuset in Stockholm, Sweden.

    Pre-assignment
    Screening details
    		 Patients transported to hospital by ambulance with symptoms of stroke and hyperglycemia were considered eligible. Inclusion criteria: ≥1 point on the FAST test28 (Face Arm Speech Time), symptoms of stroke with a duration <6 hours, capillary plasma glucose 8‐15 mmol/L, age ≥18 and signed informed consent.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control
    Arm description
    		 The control group received standard care for hyperglycemia (ie, insulin treatment at hospital). Patients in the control group received no study treatment in the ambulance. However, no insulin was administrated during the study period as the criterion for insulin treatment was not met for any individual. Patients were kept fasting the first 4 hours to achieve stable and comparable conditions. Venous samples were collected before treatment and after 4 and 24 hours. Capillary glucose measurements were made every hour for the first 4 hours, then every 4 hours until end of study. Total study period was 24 hours.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    No insulin was administrated during the study period as the criterion for insulin treatment was not met for any individual.

    Arm title
    		 Exenatide
    Arm description
    		 Patients in the exenatide group received a single subcutaneous injection of 10 μg exenatide in the ambulance en‐route to hospital. Patients were kept fasting the first 4 hours to achieve stable and comparable conditions. Venous samples were collected before treatment and after 4 and 24 hours. Capillary glucose measurements were made every hour for the first 4 hours, then every 4 hours until end of study. Total study period was 24 hours.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Exenatide
    Investigational medicinal product code
    SUB21818
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients received a single subcutaneous injection of 10 μg exenatide.

    Number of subjects in period 1
    		Control Exenatide
    Started
    11
    8
    Completed
    11
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control
    Reporting group description
    		 The control group received standard care for hyperglycemia (ie, insulin treatment at hospital). Patients in the control group received no study treatment in the ambulance. However, no insulin was administrated during the study period as the criterion for insulin treatment was not met for any individual. Patients were kept fasting the first 4 hours to achieve stable and comparable conditions. Venous samples were collected before treatment and after 4 and 24 hours. Capillary glucose measurements were made every hour for the first 4 hours, then every 4 hours until end of study. Total study period was 24 hours.

    Reporting group title
    Exenatide
    Reporting group description
    		 Patients in the exenatide group received a single subcutaneous injection of 10 μg exenatide in the ambulance en‐route to hospital. Patients were kept fasting the first 4 hours to achieve stable and comparable conditions. Venous samples were collected before treatment and after 4 and 24 hours. Capillary glucose measurements were made every hour for the first 4 hours, then every 4 hours until end of study. Total study period was 24 hours.

    Reporting group values
    		 Control Exenatide Total
    Number of subjects
    		 11 8 19
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 3 4 7
        From 65-84 years
    		 5 4 9
        85 years and over
    		 3 0 3
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 80 (63 to 89) 71 (54 to 82) -
    Gender categorical
    Units: Subjects
        Female
    		 5 4 9
        Male
    		 6 4 10
    Discharge diagnosis
    Units: Subjects
        Ischemic stroke
    		 9 4 13
        Hemorrhagic stroke
    		 0 2 2
        Non‐stroke
    		 2 2 4
    BMI
    Units: kg/m2
        median (inter-quartile range (Q1-Q3))
    		 26.4 (23.2 to 31.7) 27.2 (21.6 to 29.5) -
    cP‐glucose
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 9.6 (9.0 to 10.8) 9.6 (8.4 to 10.6) -
    vP‐glucose
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 9.4 (7.9 to 11.2) 8.8 (6.9 to 10.9) -
    Systolic blood pressure
    Units: mm Hg
        median (inter-quartile range (Q1-Q3))
    		 165 (130 to 190) 150 (124 to 175) -
    Diastolic blood pressure
    Units: mm Hg
        median (inter-quartile range (Q1-Q3))
    		 89 (80 to 100) 80 (76 to 98) -
    Heart rate
    Units: Heart rate
        median (inter-quartile range (Q1-Q3))
    		 88 (72 to 90) 80 (68 to 89) -
    NIHSS
    NIHSS, National Institutes of Health Stroke Scale
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 1 (0 to 4) 4.5 (1 to 8) -

    End points

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    End points reporting groups
    Reporting group title
    Control
    Reporting group description
    		 The control group received standard care for hyperglycemia (ie, insulin treatment at hospital). Patients in the control group received no study treatment in the ambulance. However, no insulin was administrated during the study period as the criterion for insulin treatment was not met for any individual. Patients were kept fasting the first 4 hours to achieve stable and comparable conditions. Venous samples were collected before treatment and after 4 and 24 hours. Capillary glucose measurements were made every hour for the first 4 hours, then every 4 hours until end of study. Total study period was 24 hours.

    Reporting group title
    Exenatide
    Reporting group description
    		 Patients in the exenatide group received a single subcutaneous injection of 10 μg exenatide in the ambulance en‐route to hospital. Patients were kept fasting the first 4 hours to achieve stable and comparable conditions. Venous samples were collected before treatment and after 4 and 24 hours. Capillary glucose measurements were made every hour for the first 4 hours, then every 4 hours until end of study. Total study period was 24 hours.

    Primary: vP‐glucose 4 h

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    End point title
    		 vP‐glucose 4 h
    End point description
    vP‐glucose = venous plasma glucose.
    End point type
    Primary
    End point timeframe
    4 hours after injection of exenatide.
    End point values
    		 Control Exenatide
    Number of subjects analysed
    11
    8
    Units: mmol/L
        arithmetic mean (standard deviation)
    7.0 ( 1.9 )
    7.6 ( 1.6 )
    Statistical analysis title
    		 Difference in vP‐glucose at 4 h
    Statistical analysis description
    Difference in vP‐glucose at 4 h between control and exenatide.
    Comparison groups
    Control v Exenatide
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.56
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: cP‐glucose 4 h

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    End point title
    		 cP‐glucose 4 h
    End point description
    cP‐glucose = capillary plasma glucose.
    End point type
    Primary
    End point timeframe
    4 hours after injection of exenatide.
    End point values
    		 Control Exenatide
    Number of subjects analysed
    11
    8
    Units: mmol/L
        arithmetic mean (standard deviation)
    6.5 ( 1.5 )
    7.3 ( 2.0 )
    Statistical analysis title
    		 Difference in cP‐glucose at 4 h
    Statistical analysis description
    Difference in cP‐glucose at 4 h between control and exenatide.
    Comparison groups
    Control v Exenatide
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.62
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: AUC 0‐4 h

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    End point title
    		 AUC 0‐4 h
    End point description
    End point type
    Primary
    End point timeframe
    AUC of glucose during the first 4 hours after injection.
    End point values
    		 Control Exenatide
    Number of subjects analysed
    11
    8
    Units: glu × h
        arithmetic mean (standard deviation)
    32.9 ( 6.2 )
    33.7 ( 9.6 )
    Statistical analysis title
    		 Difference AUC 0-4 h
    Statistical analysis description
    Difference in total glucose exposure measured with AUC.
    Comparison groups
    Control v Exenatide
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.93
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: AUC 0‐24 h

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    End point title
    		 AUC 0‐24 h
    End point description
    End point type
    Primary
    End point timeframe
    AUC of glucose during the total study period of 24 hours after injection.
    End point values
    		 Control Exenatide
    Number of subjects analysed
    11
    8
    Units: glu × h
        arithmetic mean (standard deviation)
    184.3 ( 41 )
    186.8 ( 40 )
    Statistical analysis title
    		 Difference AUC 0-24 h
    Statistical analysis description
    Difference in total glucose exposure measured with AUC.
    Comparison groups
    Control v Exenatide
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Total study period, it was 24 hours.
    Adverse event reporting additional description
    No specific dictionary was used and frequency threshold was not indicated in the protocol. Reporting of adverse events was done continuously for each patient, it was a non-blinded study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 No specific was used
    Dictionary version
    n/a
    Reporting groups
    Reporting group title
    Control
    Reporting group description
    		 -

    Reporting group title
    Exenatide
    Reporting group description
    		 -

    Serious adverse events
    		 Control Exenatide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Control Exenatide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 8 (12.50%)
    Gastrointestinal disorders
    Nausea and vomiting
    Additional description: That participant suffered from basilar thrombosis and had vomited before inclusion.
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2013
    Inclusion of patients with previously known metformin‐treated type 2 diabetes.
    12 Mar 2014
    Widening of glucose inclusion criteria from 10‐15 mmol/L to 9‐15 mmol/L.
    31 May 2016
    Widening of glucose inclusion criteria from 9‐15 mmol/L to 8‐15 mmol/L.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The limited sample size warrants some caution in interpretation of the lack of adverse events as a lower frequency than 35% cannot be expected to be detected.33 Another limitation is the short follow‐up of 24 hours.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31518433
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