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    Clinical Trial Results:
    Vasopressin vs Noradrenaline as Initial therapy in Septic Shock

    Summary
    EudraCT number
    		 2011-005363-24
    Trial protocol
    		 GB  
    Global end of trial date
    03 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Jun 2017
    First version publication date
    21 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRO1888
    Additional study identifiers
    ISRCTN number
    		 ISRCTN20769191
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    Exhibition Road, London, United Kingdom, SW7 2AZ
    Public contact
    Prof Anthony Gordon, Imperial College London, +44 (0)20 3313 0657, anthony.gordon@imperial.ac.uk
    Scientific contact
    Prof Anthony Gordon, Imperial College London, +44 (0)20 3313 0657, anthony.gordon@imperial.ac.uk
    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
    20 Nov 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main aims of the trial are 1. To assess if vasopressin reduces kidney dysfunction compared to noradrenaline when used as the initial treatment in the management of septic shock in adult patients. 2. To assess if there is an interaction between vasopressin and steroids in the management of septic shock in adult patients.
    Protection of trial subjects
    All patients were treated in an intensive care unit with constant 1:1 nursing care to ensure safety and comfort, and minimise any distress.
    Background therapy
    		 In order to ensure that patients are treated as early as possible we will compare vasopressin to noradrenaline as the first line vasopressor in the management of septic shock, after adequate fluid resuscitation to maintain mean arterial blood pressure has been achieved. As international guidelines only suggest corticosteroids for cases of septic shock that are poorly responsive to fluids and vasopressors, patients will only be prescribed corticosteroids once higher doses of vasopressin or noradrenaline are required. Other management of septic shock, including use of inotropes (e.g. dobutamine) will be at the treating physician's discretion, based on the international 'Surviving Sepsis' guidelines. All other drugs (other than vasopressors) should be prescribed as clinically indicated. High volume haemofiltration for the management of sepsis (i.e. RRT not to treat kidney failure) should not be used.
    Evidence for comparator
    		 The rationale for the current study is that evidence to date suggests that vasopressin may prevent renal dysfunction in septic shock when used early, and that vasopressin may interact with corticosteroids. A 2011 Cochrane review concluded “There is not sufficient evidence that any one of the investigated vasopressors is clearly superior over others”. There are six randomised controlled trials of vasopressin in adults with septic shock. The majority of these trials were small proof-of-principle studies that used physiological variables as the primary outcome and only 150 patients in total have been studied in five of these trials. In all studies the use of vasopressin allowed a reduction in the dose of conventional catecholamines required to maintain blood pressure. In one study vasopressin also increased cardiac index, and combined vasopressin and norepinephrine infusion improved gastrointestinal perfusion as assessed by gastric tonometry. Another important finding in one study was that vasopressin infusion doubled urine output and increased creatinine clearance by the end of the 4-hour study period. For corticosteroids a 2009 Cochrane review reported that prolonged low-dose corticosteroid treatment led to better outcomes (RR 0.84 95%CI 0.72-0.97, p=0.02, for 28-day mortality). Another review in 2009 found a similar beneficial effect of low dose steroids However the decrease in mortality was confined to the more severely ill patients. A sub-group analysis from the VASST study reported a statistically significant interaction between vasopressin / noradrenaline treatment and corticosteroid treatment (interaction statistic p=0.008). The combination of vasopressin and steroids led to a significantly lower mortality compared to noradrenaline plus steroids (35.9% v 44.7% respectively, p=0.03) and less organ dysfunction demonstrated by more days alive and free from shock, ventilation and renal failure.
    Actual start date of recruitment
    09 Feb 2013
    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
    United Kingdom: 409
    Worldwide total number of subjects
    409
    EEA total number of subjects
    409
    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)
    190
    From 65 to 84 years
    199
    85 years and over
    20

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted in multiple general adult ICUs within the UK with a target of recruiting 412 patients to include 400 patients in the final analysis. The first patient was recruited on 09/02/2013 and the last patient was recruited on 06/05/2015, with a maximum follow up of 28 days in ICU.

    Pre-assignment
    Screening details
    		 All patients who were clinically judged to have septic shock were screened against the inclusion and exclusion criteria to be eligible for the study. A total of 2237 patients were screened in the study between 05/02/2013 and 07/05/2015

    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, Carer, Assessor
    Blinding implementation details
    Ampoules of vasopressin, noradrenaline and hydrocortisone phosphate were masked by overlabeling on the body and neck of normal drug ampoules. Matching placebo ampoules (0.9% saline) were manufactured to provide dummies for all active drugs.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vasopressin + hydrocortisone
    Arm description
    		 Vasopressin + hydrocortisone
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vasopressin
    Investigational medicinal product code
    ATC code: H01BA01
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received vasopressin titrated up to 0.06 U/min via a central venous catheter to maintain the target mean arterial pressure (MAP). The protocol recommended a MAP of 65 to 75 mm Hg, but this could be altered by the treating physician if clinically indicated.

    Investigational medicinal product name
    Hydrocortisone Phosphate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    50mg given as intravenous bolus once vasopressin dose at 0.06 Units/min. Administered 6hrly

    Arm title
    		 Vasopressin + placebo
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vasopressin
    Investigational medicinal product code
    ATC code: H01BA01
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received vasopressin titrated up to 0.06 U/min via a central venous catheter to maintain the target mean arterial pressure (MAP). The protocol recommended a MAP of 65 to 75 mm Hg, but this could be altered by the treating physician if clinically indicated.

    Arm title
    		 Noradrenaline + hydrocortisone
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Hydrocortisone Phosphate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    50mg given as intravenous bolus once vasopressin dose at 0.06 Units/min. Administered 6hrly

    Investigational medicinal product name
    Noradrenaline
    Investigational medicinal product code
    ATC code: C01CA03
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Noradrenaline titrated up to 12mcg/min via a central venous catheter to maintain the target mean arterial pressure (MAP). The protocol recommended a MAP of 65 to 75 mm Hg, but this could be altered by the treating physician if clinically indicated.

    Arm title
    		 Noradrenaline + placebo
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Noradrenaline
    Investigational medicinal product code
    ATC code: C01CA03
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Noradrenaline titrated up to 12mcg/min via a central venous catheter to maintain the target mean arterial pressure (MAP). The protocol recommended a MAP of 65 to 75 mm Hg, but this could be altered by the treating physician if clinically indicated.

    Number of subjects in period 1
    		Vasopressin + hydrocortisone Vasopressin + placebo Noradrenaline + hydrocortisone Noradrenaline + placebo
    Started
    101
    104
    101
    103
    Completed
    100
    104
    101
    103
    Not completed
    1
    0
    0
    0
         Consent withdrawn by subject
    1
    -
    -
    -

    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
    		 409 409
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 66 (54 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 171 171
        Male
    		 238 238
    APACHE II score
    Acute Physiology and Chronic Health Evaluation (range 0-72, a higher score corresponds to more severe illness and a higher risk of death)
    Units: None
        median (inter-quartile range (Q1-Q3))
    		 24 (19 to 30) -

    End points

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    End points reporting groups
    Reporting group title
    Vasopressin + hydrocortisone
    Reporting group description
    		 Vasopressin + hydrocortisone

    Reporting group title
    Vasopressin + placebo
    Reporting group description
    		 -

    Reporting group title
    Noradrenaline + hydrocortisone
    Reporting group description
    		 -

    Reporting group title
    Noradrenaline + placebo
    Reporting group description
    		 -

    Primary: Survivors with no renal failure

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    End point title
    		 Survivors with no renal failure [1]
    End point description
    28-day Survivors who never developed kidney failure
    End point type
    Primary
    End point timeframe
    Over 28 days in ICU
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was a single primary endpoint, the distribution of renal failure free days (days alive and free of renal failure) between groups. This was tested statistically. The survivors with no renal failure is simply another way to display this part of the primary endpoint analysis but is not a separate primary outcome and therefore doesn't require a separate statistical test.
    End point values
    		 Vasopressin + hydrocortisone Vasopressin + placebo Noradrenaline + hydrocortisone Noradrenaline + placebo
    Number of subjects analysed
    81
    84
    77
    80
    Units: People
        No Kidney failure
    46
    48
    46
    47
    No statistical analyses for this end point

    Primary: Kidney failure free days

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    End point title
    		 Kidney failure free days [2]
    End point description
    In those who had kidney failure, died, or both at any time.
    End point type
    Primary
    End point timeframe
    Over 28 days after randomisation
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was a single primary endpoint, the distribution of renal failure free days (days alive and free of renal failure) between groups. This was tested statistically. The Kidney failure free days is simply another way to display this part of the primary endpoint analysis but is not a separate primary outcome and therefore doesn't require a separate statistical test.
    End point values
    		 Vasopressin + hydrocortisone Vasopressin + placebo Noradrenaline + hydrocortisone Noradrenaline + placebo
    Number of subjects analysed
    54
    56
    55
    56
    Units: Days
        median (inter-quartile range (Q1-Q3))
    5 (0 to 23)
    12 (1 to 25)
    13 (0 to 25)
    14 (1 to 24)
    No statistical analyses for this end point

    Secondary: Rate of renal replacement therapy

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    End point title
    		 Rate of renal replacement therapy
    End point description
    End point type
    Secondary
    End point timeframe
    Over 28 days in ICU
    End point values
    		 Vasopressin + hydrocortisone Vasopressin + placebo Noradrenaline + hydrocortisone Noradrenaline + placebo
    Number of subjects analysed
    101
    104
    101
    103
    Units: People
        Yes
    29
    23
    32
    40
    No statistical analyses for this end point

    Secondary: 28-day mortality rate

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    End point title
    		 28-day mortality rate
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Vasopressin + hydrocortisone Vasopressin + placebo Noradrenaline + hydrocortisone Noradrenaline + placebo
    Number of subjects analysed
    100
    104
    101
    103
    Units: People
        Dead
    33
    30
    29
    27
        Alive
    67
    74
    72
    76
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Fatal or life threatening SAEs should be reported on the day that the local site is aware of the event (within 24 hours).
    Adverse event reporting additional description
    Clinical outcomes from sepsis are exempt from adverse event reporting, unless the investigator deems the event to be related to the administration of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Vasopressin + hydrocortisone
    Reporting group description
    		 Vasopressin + hydrocortisone

    Reporting group title
    Vasopressin + placebo
    Reporting group description
    		 -

    Reporting group title
    Noradrenaline + hydrocortisone
    Reporting group description
    		 -

    Reporting group title
    Noradrenaline + placebo
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: As all patients included in the trial were critically ill by definition then it is very difficult to define what is an adverse event as they will have abnormal blood results and physiological signs as part of their underlying illness. Therefore the trial focused only on serious adverse events only, as the priority safety analysis.
    Serious adverse events
    		 Vasopressin + hydrocortisone Vasopressin + placebo Noradrenaline + hydrocortisone Noradrenaline + placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 101 (8.91%)
    13 / 104 (12.50%)
    11 / 101 (10.89%)
    6 / 103 (5.83%)
         number of deaths (all causes)
    33
    30
    29
    27
         number of deaths resulting from adverse events
    4
    5
    4
    1
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    4 / 101 (3.96%)
    7 / 104 (6.73%)
    2 / 101 (1.98%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    1 / 5
    4 / 7
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 104 (0.00%)
    0 / 101 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
    Additional description: Life-threatening arrhythmia
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 104 (0.00%)
    1 / 101 (0.99%)
    4 / 103 (3.88%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    4 / 101 (3.96%)
    3 / 104 (2.88%)
    2 / 101 (1.98%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    1 / 1
    0 / 1
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 104 (0.00%)
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Pupil fixed
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 104 (0.00%)
    0 / 101 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Mesenteric vascular insufficiency
         subjects affected / exposed
    2 / 101 (1.98%)
    3 / 104 (2.88%)
    4 / 101 (3.96%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 2
    1 / 1
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 104 (0.96%)
    0 / 101 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 104 (0.00%)
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 104 (0.96%)
    0 / 101 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Infections and infestations
    Secondary transmission
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 104 (0.00%)
    1 / 101 (0.99%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Vasopressin + hydrocortisone Vasopressin + placebo Noradrenaline + hydrocortisone Noradrenaline + placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 101 (0.00%)
    0 / 104 (0.00%)
    0 / 101 (0.00%)
    0 / 103 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jul 2012
    Changes made to the quantity of IMP: (i) Decreased maximum limit of study drug 1 from 9mls/hr to 4.5ml/s (ii) Increased quantity of study drug 1 in one small ampoule from 1ml to 2ml, increasing the total quantity of study drug 1 from 5mls to 10mls (iii) Reduced the quantity of 5% dextrose from 45mls to 40mls (iv) Infusion of study drug 1 to start at 1ml/hr instead of 2ml/hr Supply of study drug 1 – to be supplied as 3 ampoules/vials (2ml and 2x4ml) to contain Vasopressin (40U)/Noradrenaline (8mg), instead of 2 ampoules/vials (1ml and 4ml) to contain Vasopressin (20U)/Noradrenaline (4mg). Change in the number of vials being supplied for the first 3 days per patient – from 15 vials in each of the 3 packs to 9 vials in each of the 3 packs.
    27 Oct 2014
    Change in the manufacturer of placebo to match all IMPs - from Northwick Park Hospital to South Davon Healthcare NHS Foundation Trust.

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27483065
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