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    Clinical Trial Results:
    Impact of preoperative midazolam on outcome of elderly patients: a multicenter randomised controlled trial

    Summary
    EudraCT number
    		 2016-004555-79
    Trial protocol
    		 DE  
    Global end of trial date
    24 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 May 2022
    First version publication date
    25 May 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    16-115
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03052660
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    RWTH Aachen University represented by the Rector himself, represented by the Dean of the Medical Faculty
    Sponsor organisation address
    Pauwelsstraße 30, Aachen, Germany, 52074
    Public contact
    Center for Translational and Clinical Research Aachen (CTC-A), Uniklinik RWTH Aachen, +49 24180092, ctc-a-spoqs@ukaachen.de
    Scientific contact
    Center for Translational and Clinical Research Aachen (CTC-A), Uniklinik RWTH Aachen, +49 24180092, ctc-a-spoqs@ukaachen.de
    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
    26 Jan 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jun 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    We aim to assess, if placebo administration compared to preoperative administration of midazolam in elderly patients is different in regard to the global postoperative patient satisfaction.
    Protection of trial subjects
    Since Midazolam is a preoperatively, routinely used medication in surgical patients, no specific measures have been necessary to protect trial subjects. Study-specific baseline tests were not expected to have an influence on patients stresslevel.
    Background therapy
    		 Patients have been recruited consecutively during the preoperative anaesthesia consultation in the clinical routine. Anaesthesia has been conducted according to the clinical routine, including the kind of anaesthesia as well as administered drugs. An additional application of benzodiazepines was not desired, but left to the discretion of the attending anaesthetist, who was blinded to the allocation treatment. Surgical procedures were performed according to the patients disease/needs. Pre- and postoperative care, including monitoring of vital signs, administration of medication and doctor's visits, has been conducted following the hospitals standard operating procedures (SOPs).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Oct 2017
    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
    Germany: 607
    Worldwide total number of subjects
    607
    EEA total number of subjects
    607
    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)
    0
    From 65 to 84 years
    607
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients have been recruited during the preoperative anaesthesia consultation in the clinical routine. Each participating centre recruited as many patients as possible. Recruitment started 17.10.2017. Site 001 recruited 120, Site 002 40, site 003 33, site 004 48, site 005 26, site 006 34, site 007 88, site 008 81 and site 009 137 patients.

    Pre-assignment
    Screening details
    		 All screened patients (including the screening failures and enrolled patients) have been documented in a screening/ enrollment log. The screening number has been coded independently from the randomization number with 3 digits. Of overall 3605 screened patients, 616 patients were enrolled in the trial.

    Period 1
    Period 1 title
    Visit 0
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Midazolam group (Baseline visit)
    Arm description
    		 Patients, meeting all inclusion and none exclusion criteria, will be randomly assigned to either receive 3.75 mg midazolam 30-45 minutes before surgery .
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dormicum
    Investigational medicinal product code
    IMP 1
    Other name
    Midazolam
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage of 3.75mg midazolam (halved 7.5mg tablet) was chosen according to the recommendation to reduce the dosage for elderly patients, which is described in the SmPC. Furthermore, it complies with the clinical routine in many German hospitals (including the participating centres) to use this reduced dosage in elderly patients. According to the clinical routine, the patients will receive the drug 30-45 minutes before the surgery.

    Arm title
    		 Placebo group (Baseline visit)
    Arm description
    		 The patients in the placebo group received a placebo capsule 30-45 minutes before surgery
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients, meeting all inclusion and none exclusion criteria, will be randomly assigned to either receive 3.75 mg midazolam or placebo.

    Number of subjects in period 1
    		Midazolam group (Baseline visit) Placebo group (Baseline visit)
    Started
    304
    303
    Completed
    304
    303
    Period 2
    Period 2 title
    Visit 1 - surgery day, pre-operative
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Midazolam group (surgery day, pre-operative)
    Arm description
    		 Patients receive 3.75 mg midazolam 30-45 minutes before surgery.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dormicum
    Investigational medicinal product code
    IMP 1
    Other name
    Midazolam
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    3.75mg midazolam (hard) capsule, oral use

    Arm title
    		 Placebo group (surgery day, pre-operative)
    Arm description
    		 Patients receive a placebo capsule 30-45 minutes before surgery.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    placebo (hard) capsule, oral use

    Number of subjects in period 2
    		Midazolam group (surgery day, pre-operative) Placebo group (surgery day, pre-operative)
    Started
    304
    303
    Completed
    304
    303
    Period 3
    Period 3 title
    Visit 2 - surgery day intra-operative
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Midazolam group (surgery day intra-operative)
    Arm description
    		 No IMP administration
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dormicum
    Investigational medicinal product code
    IMP 1
    Other name
    Midazolam
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    None

    Arm title
    		 Placebo group (surgery day intra-operative)
    Arm description
    		 No placebo administration.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    None

    Number of subjects in period 3
    		Midazolam group (surgery day intra-operative) Placebo group (surgery day intra-operative)
    Started
    304
    303
    Completed
    304
    303
    Period 4
    Period 4 title
    Visit 3 - surgery day post-operative
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Midazolam group (surgery day post-operative)
    Arm description
    		 No IMP administration.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dormicum
    Investigational medicinal product code
    IMP 1
    Other name
    Midazolam
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    None

    Arm title
    		 Placebo group (surgery day post-operative)
    Arm description
    		 No placebo administration
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    None

    Number of subjects in period 4
    		Midazolam group (surgery day post-operative) Placebo group (surgery day post-operative)
    Started
    304
    303
    Completed
    304
    303
    Period 5
    Period 5 title
    Visit 4 - post-operative day 1
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Midazolam group (post-operative day 1)
    Arm description
    		 No IMP administration
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dormicum
    Investigational medicinal product code
    IMP 1
    Other name
    Midazolam
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    None

    Arm title
    		 Placebo group (post-operative day 1)
    Arm description
    		 No placebo administration.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    None

    Number of subjects in period 5
    		Midazolam group (post-operative day 1) Placebo group (post-operative day 1)
    Started
    304
    303
    Completed
    304
    303
    Period 6
    Period 6 title
    Visit 5 - post-operative day 30
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Midazolam group (post-operative day 30)
    Arm description
    		 No IMP administration.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dormicum
    Investigational medicinal product code
    IMP 1
    Other name
    Midazolam
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    None

    Arm title
    		 Placebo group (post-operative day 30)
    Arm description
    		 No placebo administration.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    None

    Number of subjects in period 6
    		Midazolam group (post-operative day 30) Placebo group (post-operative day 30)
    Started
    304
    303
    Completed
    304
    303

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Midazolam group (Baseline visit)
    Reporting group description
    		 Patients, meeting all inclusion and none exclusion criteria, will be randomly assigned to either receive 3.75 mg midazolam 30-45 minutes before surgery .

    Reporting group title
    Placebo group (Baseline visit)
    Reporting group description
    		 The patients in the placebo group received a placebo capsule 30-45 minutes before surgery

    Reporting group values
    		 Midazolam group (Baseline visit) Placebo group (Baseline visit) Total
    Number of subjects
    		 304 303 607
    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
        arithmetic mean (standard deviation)
    		 71.5 ( 4.37 ) 72.3 ( 4.43 ) -
    Gender categorical
    Units: Subjects
        Female
    		 106 124 230
        Male
    		 198 179 377
    Physical status (ASA)
    Units: Subjects
        type I
    		 12 11 23
        type II
    		 200 198 398
        type III
    		 91 92 183
        type IV
    		 1 2 3
    Smoking status
    Units: Subjects
        smoker
    		 25 25 50
        Ex-smoker
    		 103 109 212
        Non-smoker
    		 176 169 345
    Medical history - Diabetes
    Units: Subjects
        yes
    		 62 50 112
        no
    		 242 253 495
    Medical history - Arterial hypertension
    Units: Subjects
        yes
    		 198 208 406
        no
    		 106 95 201
    Medical history - Adipositas
    Units: Subjects
        yes
    		 168 171 339
        no
    		 136 132 268
    Medical history - Hypercholesterolemia
    Units: Subjects
        yes
    		 79 81 160
        no
    		 225 222 447
    Medical history - Chronic heart disease
    Units: Subjects
        yes
    		 41 34 75
        no
    		 263 269 532
    Medical history - Pulmonary disease
    Units: Subjects
        yes
    		 21 25 46
        no
    		 283 278 561
    Medical history - Renal disease
    Units: Subjects
        yes
    		 33 37 70
        no
    		 271 266 537
    Medical history - Cerebrovascular disease
    Units: Subjects
        yes
    		 19 18 37
        no
    		 285 285 570
    Medical history - Malignant disease
    Units: Subjects
        yes
    		 114 135 249
        no
    		 190 168 358
    Medical history - previous surgery
    Units: Subjects
        yes
    		 254 258 512
        no
    		 50 45 95
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 171.92 ( 9.11 ) 170.54 ( 9.27 ) -
    Body mass index (BMI)
    Units: kg / cm²
        arithmetic mean (standard deviation)
    		 27.195 ( 4.632 ) 27.192 ( 4.403 ) -
    Hemoglobin
    Units: g / dl
        arithmetic mean (standard deviation)
    		 13.822 ( 1.719 ) 13.665 ( 1.729 ) -
    Haematocrit
    Units: percentage
        arithmetic mean (standard deviation)
    		 40.431 ( 4.705 ) 40.106 ( 4.881 ) -
    Albumin
    Units: g / dl
        arithmetic mean (standard deviation)
    		 4.354 ( 0.358 ) 4.219 ( 0.432 ) -
    Creatinine
    Units: mg / dl
        arithmetic mean (standard deviation)
    		 1.062 ( 0.861 ) 1.063 ( 0.861 ) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Midazolam group (Baseline visit)
    Reporting group description
    		 Patients, meeting all inclusion and none exclusion criteria, will be randomly assigned to either receive 3.75 mg midazolam 30-45 minutes before surgery .

    Reporting group title
    Placebo group (Baseline visit)
    Reporting group description
    		 The patients in the placebo group received a placebo capsule 30-45 minutes before surgery
    Reporting group title
    Midazolam group (surgery day, pre-operative)
    Reporting group description
    		 Patients receive 3.75 mg midazolam 30-45 minutes before surgery.

    Reporting group title
    Placebo group (surgery day, pre-operative)
    Reporting group description
    		 Patients receive a placebo capsule 30-45 minutes before surgery.
    Reporting group title
    Midazolam group (surgery day intra-operative)
    Reporting group description
    		 No IMP administration

    Reporting group title
    Placebo group (surgery day intra-operative)
    Reporting group description
    		 No placebo administration.
    Reporting group title
    Midazolam group (surgery day post-operative)
    Reporting group description
    		 No IMP administration.

    Reporting group title
    Placebo group (surgery day post-operative)
    Reporting group description
    		 No placebo administration
    Reporting group title
    Midazolam group (post-operative day 1)
    Reporting group description
    		 No IMP administration

    Reporting group title
    Placebo group (post-operative day 1)
    Reporting group description
    		 No placebo administration.
    Reporting group title
    Midazolam group (post-operative day 30)
    Reporting group description
    		 No IMP administration.

    Reporting group title
    Placebo group (post-operative day 30)
    Reporting group description
    		 No placebo administration.

    Subject analysis set title
    Men (Midazolam group)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in the midazolam group with male gender

    Subject analysis set title
    Men (Placebo group)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in the placebo group with male gender.

    Subject analysis set title
    Women (Midazolam group)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in the midazolam group with female gender.

    Subject analysis set title
    Women (Placebo group)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in the placebo group with female gender.

    Subject analysis set title
    Patients without frailty (Midazolam group)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in the midazolam group without frailty (assessment includes medical history, laboratory values, history of falls, the Mini-Cog and timed "Up & Go" test

    Subject analysis set title
    Patients without frailty (Placebo group)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in the placebo group without frailty (assessment includes medical history, laboratory values, history of falls, the Mini-Cog and timed "Up & Go" test

    Subject analysis set title
    Patients with frailty (Midazolam group)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in the midazolam group with frailty (assessment includes medical history, laboratory values, history of falls, the Mini-Cog and timed "Up & Go" test

    Subject analysis set title
    Patients with frailty (Placebo group)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in the placebo group with frailty (assessment includes medical history, laboratory values, history of falls, the Mini-Cog and timed "Up & Go" test

    Subject analysis set title
    Patients without anxiety (Midazolam group)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in the midazolam group without anxiety (APAIS-Score ≤ 12)

    Subject analysis set title
    Patients without anxiety (Placebo group)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in the placebo group without anxiety (APAIS-Score ≤ 12)

    Subject analysis set title
    Patients with anxiety (Midazolam group)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in the midazolam group with anxiety (APAIS-Score > 12)

    Subject analysis set title
    Patients with anxiety (Placebo group)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in the placebo group with anxiety (APAIS-Score > 12)

    Primary: Global patient satisfaction

    		 Close Top of page
    End point title
    		 Global patient satisfaction
    End point description
    End point type
    Primary
    End point timeframe
    post-operative day 1
    End point values
    		 Midazolam group (post-operative day 1) Placebo group (post-operative day 1) Men (Midazolam group) Men (Placebo group) Women (Midazolam group) Women (Placebo group) Patients without frailty (Midazolam group) Patients without frailty (Placebo group) Patients with frailty (Midazolam group) Patients with frailty (Placebo group) Patients without anxiety (Midazolam group) Patients without anxiety (Placebo group) Patients with anxiety (Midazolam group) Patients with anxiety (Placebo group)
    Number of subjects analysed
    304 [1]
    303 [2]
    198 [3]
    179 [4]
    106 [5]
    124
    298 [6]
    298 [7]
    6
    5
    258 [8]
    242 [9]
    46 [10]
    61
    Units: none
        arithmetic mean (standard deviation)
    43.33 ( 9.95 )
    43.83 ( 10.41 )
    43.89 ( 10.580 )
    44.36 ( 10.862 )
    42.27 ( 8.565 )
    43.07 ( 9.713 )
    43.43 ( 9.965 )
    43.84 ( 10.492 )
    38.53 ( 8.174 )
    43.33 ( 2.150 )
    43.67 ( 10.082 )
    43.61 ( 10.603 )
    41.38 ( 8.963 )
    44.68 ( 9.633 )
    Notes
    [1] - 3 missing data
    [2] - 2 missing data
    [3] - 1 missing data
    [4] - 2 missing data
    [5] - 2 missing data
    [6] - 3 missing data
    [7] - 2 missing data
    [8] - 1 missing data
    [9] - 2 missing data
    [10] - 2 missing data
    Statistical analysis title
    		 Treatment effect
    Comparison groups
    Midazolam group (post-operative day 1) v Placebo group (post-operative day 1)
    Number of subjects included in analysis
    607
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.447
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 1.1
    Statistical analysis title
    		 Treatment effect among men
    Comparison groups
    Men (Midazolam group) v Men (Placebo group)
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.353
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 1.6
    Statistical analysis title
    		 Treatment effect among women
    Comparison groups
    Women (Midazolam group) v Women (Placebo group)
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.986
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 1.6
    Statistical analysis title
    		 Treatment effect among patients without frailty
    Comparison groups
    Patients without frailty (Midazolam group) v Patients without frailty (Placebo group)
    Number of subjects included in analysis
    596
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.493
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 1.1
    Statistical analysis title
    		 Treatment effect among patients with frailty
    Comparison groups
    Patients with frailty (Midazolam group) v Patients with frailty (Placebo group)
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.541
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -19.2
         upper limit
    		 10.2
    Statistical analysis title
    		 Treatment effect among patients without anxiety
    Comparison groups
    Patients without anxiety (Midazolam group) v Patients without anxiety (Placebo group)
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.0326
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 1.7
    Statistical analysis title
    		 Treatment effect among patients with anxiety
    Comparison groups
    Patients with anxiety (Placebo group) v Patients with anxiety (Midazolam group)
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.033
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -6.8
         upper limit
    		 0.8

    Secondary: Assessment of preoperative anxiety

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    End point title
    		 Assessment of preoperative anxiety
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Midazolam group (Baseline visit) Placebo group (Baseline visit)
    Number of subjects analysed
    304
    303
    Units: none
        arithmetic mean (standard deviation)
    8.339 ( 4.0 )
    8.802 ( 4.36 )
    No statistical analyses for this end point

    Secondary: IADL score

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    End point title
    		 IADL score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline & POD 30
    End point values
    		 Midazolam group (Baseline visit) Placebo group (Baseline visit) Midazolam group (post-operative day 30) Placebo group (post-operative day 30)
    Number of subjects analysed
    303 [11]
    301 [12]
    280 [13]
    276 [14]
    Units: none
        arithmetic mean (standard deviation)
    8.974 ( 2.806 )
    8.894 ( 2.733 )
    10.114 ( 4.175 )
    10.355 ( 4.512 )
    Notes
    [11] - 1 missing data
    [12] - 2 missing data
    [13] - 23 missing data
    [14] - 25 missing data
    No statistical analyses for this end point

    Secondary: SBT Score

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    End point title
    		 SBT Score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, POD 1 & POD 30
    End point values
    		 Midazolam group (Baseline visit) Placebo group (Baseline visit) Midazolam group (post-operative day 1) Placebo group (post-operative day 1) Midazolam group (post-operative day 30) Placebo group (post-operative day 30)
    Number of subjects analysed
    304
    303
    299 [15]
    296 [16]
    282 [17]
    277 [18]
    Units: none
        arithmetic mean (standard deviation)
    3.178 ( 3.431 )
    3.274 ( 3.448 )
    2.221 ( 3.365 )
    2.176 ( 3.124 )
    1.734 ( 2.876 )
    1.845 ( 2.993 )
    Notes
    [15] - 5 missing data
    [16] - 7 missing data
    [17] - 22 missing data
    [18] - 26 missing data
    No statistical analyses for this end point

    Secondary: Confusion Assessment Method CAM

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    End point title
    		 Confusion Assessment Method CAM
    End point description
    End point type
    Secondary
    End point timeframe
    post-operative day 1
    End point values
    		 Midazolam group (post-operative day 1) Placebo group (post-operative day 1)
    Number of subjects analysed
    304
    303
    Units: subjects
        positive
    1
    3
        negative
    301
    300
        no data
    2
    0
    No statistical analyses for this end point

    Secondary: Change in perioperative condition of well-being - extubation

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    End point title
    		 Change in perioperative condition of well-being - extubation
    End point description
    End point type
    Secondary
    End point timeframe
    shortly after extubation compared to Baseline
    End point values
    		 Midazolam group (surgery day intra-operative) Placebo group (surgery day intra-operative)
    Number of subjects analysed
    269 [19]
    262 [20]
    Units: none
        arithmetic mean (standard deviation)
    -0.8104 ( 30.75 )
    -1.7023 ( 31.12 )
    Notes
    [19] - 35 missing data
    [20] - 41 missing data
    No statistical analyses for this end point

    Secondary: Change in perioperative condition of pain - extubation

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    End point title
    		 Change in perioperative condition of pain - extubation
    End point description
    End point type
    Secondary
    End point timeframe
    directly after extubation compared to Baseline
    End point values
    		 Midazolam group (surgery day intra-operative) Placebo group (surgery day intra-operative)
    Number of subjects analysed
    280 [21]
    277 [22]
    Units: none
        arithmetic mean (standard deviation)
    -9.139 ( 32.74 )
    -11.032 ( 30.61 )
    Notes
    [21] - 24 missing data
    [22] - 26 missing data
    No statistical analyses for this end point

    Secondary: Change in perioperative condition of sleeping - POD 1

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    End point title
    		 Change in perioperative condition of sleeping - POD 1
    End point description
    End point type
    Secondary
    End point timeframe
    post-operative day 1 compared to Baseline
    End point values
    		 Midazolam group (post-operative day 1) Placebo group (post-operative day 1)
    Number of subjects analysed
    301 [23]
    300 [24]
    Units: none
        arithmetic mean (standard deviation)
    -17.58 ( 35.13 )
    -15.42 ( 36.05 )
    Notes
    [23] - 3 missing data
    [24] - 3 missing data
    No statistical analyses for this end point

    Secondary: Patient cooperation

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    End point title
    		 Patient cooperation
    End point description
    End point type
    Secondary
    End point timeframe
    directly before surgery
    End point values
    		 Midazolam group (surgery day intra-operative) Placebo group (surgery day intra-operative)
    Number of subjects analysed
    299 [25]
    295 [26]
    Units: none
        arithmetic mean (standard deviation)
    96.02 ( 14.77 )
    96.02 ( 13.96 )
    Notes
    [25] - 5 missing data
    [26] - 8 missing data
    No statistical analyses for this end point

    Secondary: Amount of patients with rescue midazolam application

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    End point title
    		 Amount of patients with rescue midazolam application
    End point description
    End point type
    Secondary
    End point timeframe
    during surgery
    End point values
    		 Midazolam group (surgery day intra-operative) Placebo group (surgery day intra-operative)
    Number of subjects analysed
    304
    303
    Units: subjects
        yes
    2
    0
        no
    301
    303
        no data
    1
    0
    No statistical analyses for this end point

    Secondary: Time to extubation

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    End point title
    		 Time to extubation
    End point description
    End point type
    Secondary
    End point timeframe
    during surgery
    End point values
    		 Midazolam group (surgery day intra-operative) Placebo group (surgery day intra-operative)
    Number of subjects analysed
    302 [27]
    299 [28]
    Units: min
        arithmetic mean (standard deviation)
    10.007 ( 6.853 )
    9.201 ( 6.251 )
    Notes
    [27] - 2 missing data
    [28] - 4 missing data
    No statistical analyses for this end point

    Secondary: change in EQ 5D-5L

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    End point title
    		 change in EQ 5D-5L
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline & POD 30
    End point values
    		 Midazolam group (post-operative day 30) Placebo group (post-operative day 30)
    Number of subjects analysed
    281 [29]
    277 [30]
    Units: none
        arithmetic mean (standard deviation)
    0.0396 ( 0.2398 )
    0.0223 ( 0.2435 )
    Notes
    [29] - 23 missing data
    [30] - 26 missing data
    No statistical analyses for this end point

    Secondary: Change in perioperative condition of well-being - surgery

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    End point title
    		 Change in perioperative condition of well-being - surgery
    End point description
    End point type
    Secondary
    End point timeframe
    after surgery compared to Baseline
    End point values
    		 Midazolam group (surgery day intra-operative) Placebo group (surgery day intra-operative)
    Number of subjects analysed
    289 [31]
    285 [32]
    Units: none
        arithmetic mean (standard deviation)
    -5.734 ( 28.64 )
    -9.189 ( 28.90 )
    Notes
    [31] - 15 missing data
    [32] - 18 missing data
    No statistical analyses for this end point

    Secondary: Change in perioperative condition of well-being - POD 1

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    End point title
    		 Change in perioperative condition of well-being - POD 1
    End point description
    End point type
    Secondary
    End point timeframe
    post-operative day 1 compared to Baseline
    End point values
    		 Midazolam group (post-operative day 1) Placebo group (post-operative day 1)
    Number of subjects analysed
    301 [33]
    299 [34]
    Units: none
        arithmetic mean (standard deviation)
    -0.6279 ( 24.53 )
    -2.8127 ( 22.82 )
    Notes
    [33] - 3 missing data
    [34] - 4 missing data
    No statistical analyses for this end point

    Secondary: Change in perioperative condition of pain - surgery

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    End point title
    		 Change in perioperative condition of pain - surgery
    End point description
    End point type
    Secondary
    End point timeframe
    after surgery compared to Baseline
    End point values
    		 Midazolam group (surgery day intra-operative) Placebo group (surgery day intra-operative)
    Number of subjects analysed
    299 [35]
    296 [36]
    Units: none
        arithmetic mean (standard deviation)
    0.1438 ( 34.11 )
    0.2939 ( 36.18 )
    Notes
    [35] - 5 missing data
    [36] - 7 missing data
    No statistical analyses for this end point

    Secondary: Change in perioperative condition of pain - POD 1

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    End point title
    		 Change in perioperative condition of pain - POD 1
    End point description
    End point type
    Secondary
    End point timeframe
    post-operative day 1 compared to Baseline
    End point values
    		 Midazolam group (post-operative day 1) Placebo group (post-operative day 1)
    Number of subjects analysed
    301 [37]
    301 [38]
    Units: none
        arithmetic mean (standard deviation)
    -3.993 ( 31.67 )
    -1.166 ( 32.62 )
    Notes
    [37] - 3 missing data
    [38] - 2 missing data
    No statistical analyses for this end point

    Secondary: Mortality

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    End point title
    		 Mortality
    End point description
    End point type
    Secondary
    End point timeframe
    post-operative day 30
    End point values
    		 Midazolam group (post-operative day 30) Placebo group (post-operative day 30)
    Number of subjects analysed
    304
    303
    Units: subjects
        alive
    298
    295
        dead
    0
    2
        no data
    6
    6
    No statistical analyses for this end point

    Secondary: new-onset of serious cardiac or pulmonary complications, acute stroke, or acute kidney injury

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    End point title
    		 new-onset of serious cardiac or pulmonary complications, acute stroke, or acute kidney injury
    End point description
    End point type
    Secondary
    End point timeframe
    post-operative day 30
    End point values
    		 Midazolam group (post-operative day 30) Placebo group (post-operative day 30)
    Number of subjects analysed
    304
    303
    Units: subjects
        yes
    6
    10
        no
    291
    283
        no data
    7
    10
    No statistical analyses for this end point

    Secondary: Longer-term outcome after 30 days (new-onset complications)

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    End point title
    		 Longer-term outcome after 30 days (new-onset complications)
    End point description
    End point type
    Secondary
    End point timeframe
    post-operative day 30
    End point values
    		 Midazolam group (post-operative day 30) Placebo group (post-operative day 30)
    Number of subjects analysed
    6
    10
    Units: subjects
        cardiac complications
    1
    5
        pulmonary complications
    3
    2
        acute stroke
    0
    2
        acute kidney injury
    2
    1
    No statistical analyses for this end point

    Secondary: Length of stay in hospital

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    End point title
    		 Length of stay in hospital
    End point description
    End point type
    Secondary
    End point timeframe
    post-operative day 30
    End point values
    		 Midazolam group (post-operative day 30) Placebo group (post-operative day 30)
    Number of subjects analysed
    301 [39]
    302 [40]
    Units: days
        arithmetic mean (standard deviation)
    6.791 ( 5.363 )
    6.798 ( 5.201 )
    Notes
    [39] - 3 missing data
    [40] - 1 missing data
    No statistical analyses for this end point

    Secondary: Length of stay in Intensive Care Unit

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    End point title
    		 Length of stay in Intensive Care Unit
    End point description
    End point type
    Secondary
    End point timeframe
    post-operative day 30
    End point values
    		 Midazolam group (post-operative day 30) Placebo group (post-operative day 30)
    Number of subjects analysed
    301 [41]
    302 [42]
    Units: days
        arithmetic mean (standard deviation)
    0.1561 ( 1.003 )
    0.2947 ( 1.911 )
    Notes
    [41] - 3 missing data
    [42] - 1 missing data
    No statistical analyses for this end point

    Secondary: Frailty - Mini-Cog

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    End point title
    		 Frailty - Mini-Cog
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Midazolam group (Baseline visit) Placebo group (Baseline visit)
    Number of subjects analysed
    302 [43]
    300 [44]
    Units: points
        arithmetic mean (standard deviation)
    3.553 ( 1.447 )
    3.487 ( 1.460 )
    Notes
    [43] - 2 missing data
    [44] - 3 missing data
    No statistical analyses for this end point

    Secondary: Frailty - Timed up and go test

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    End point title
    		 Frailty - Timed up and go test
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Midazolam group (Baseline visit) Placebo group (Baseline visit)
    Number of subjects analysed
    247 [45]
    258 [46]
    Units: sec
        arithmetic mean (standard deviation)
    11.530 ( 6.290 )
    11.671 ( 6.103 )
    Notes
    [45] - 57 missing data
    [46] - 45 missing data
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    30 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 none
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Midazolam group
    Reporting group description
    		 Patients, meeting all inclusion and none exclusion criteria, will be randomly assigned to either receive 3.75 mg midazolam 30-45 minutes before surgery .

    Reporting group title
    Placebo group
    Reporting group description
    		 The patients in the placebo group received a placebo capsule 30-45 minutes before surgery

    Serious adverse events
    		 Midazolam group Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 304 (1.97%)
    13 / 303 (4.29%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant tumor
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Iatrogenic injury of esophagus and trachea
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iatrogenic ureteral injury
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post-operative bleeding
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hematoma abdominal wall
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 303 (0.33%)
         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
    1 / 304 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac decompensation
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 303 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypertension
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Stroke
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 303 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Midazolam group Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    264 / 304 (86.84%)
    251 / 303 (82.84%)
    Injury, poisoning and procedural complications
    Extravasation of colloids
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 303 (0.33%)
         occurrences all number
    0
    1
    Vascular disorders
    Bleeding
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 303 (0.00%)
         occurrences all number
    1
    0
    Collapse
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 303 (0.33%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 303 (0.33%)
         occurrences all number
    0
    1
    Hypothermia
         subjects affected / exposed
    7 / 304 (2.30%)
    0 / 303 (0.00%)
         occurrences all number
    7
    0
    Cardiac disorders
    Arrythmia
         subjects affected / exposed
    2 / 304 (0.66%)
    3 / 303 (0.99%)
         occurrences all number
    3
    5
    Bradycardia
         subjects affected / exposed
    62 / 304 (20.39%)
    63 / 303 (20.79%)
         occurrences all number
    64
    65
    Hypertension
         subjects affected / exposed
    34 / 304 (11.18%)
    34 / 303 (11.22%)
         occurrences all number
    38
    37
    Hypotension
         subjects affected / exposed
    229 / 304 (75.33%)
    222 / 303 (73.27%)
         occurrences all number
    250
    241
    Hypovolaemia
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 303 (0.33%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    7 / 304 (2.30%)
    6 / 303 (1.98%)
         occurrences all number
    7
    7
    Nervous system disorders
    Agitation
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 303 (0.66%)
         occurrences all number
    0
    2
    Central anticholinergic syndrome
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 303 (0.33%)
         occurrences all number
    0
    1
    delayed awakening
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 303 (0.00%)
         occurrences all number
    1
    0
    Delirium
         subjects affected / exposed
    3 / 304 (0.99%)
    3 / 303 (0.99%)
         occurrences all number
    3
    3
    Drowsiness
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 303 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    5 / 304 (1.64%)
    5 / 303 (1.65%)
         occurrences all number
    5
    5
    Numbness occipital right side
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 303 (0.00%)
         occurrences all number
    2
    0
    post-operative cognitive dysfunction
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 303 (0.66%)
         occurrences all number
    0
    2
    post-operative nausea and vomitting
         subjects affected / exposed
    17 / 304 (5.59%)
    14 / 303 (4.62%)
         occurrences all number
    18
    14
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 303 (0.00%)
         occurrences all number
    2
    0
    Hemoglobin drop
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 303 (0.00%)
         occurrences all number
    1
    0
    Hypoxemia
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 303 (0.00%)
         occurrences all number
    1
    0
    Lymphocele
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 303 (0.33%)
         occurrences all number
    0
    1
    Desaturation
         subjects affected / exposed
    25 / 304 (8.22%)
    21 / 303 (6.93%)
         occurrences all number
    26
    24
    General disorders and administration site conditions
    Shivering
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 303 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Anaphylaxis
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 303 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 303 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 303 (0.33%)
         occurrences all number
    0
    1
    Bronchospasm
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 303 (0.00%)
         occurrences all number
    3
    0
    Respiratory insufficiency
         subjects affected / exposed
    3 / 304 (0.99%)
    0 / 303 (0.00%)
         occurrences all number
    3
    0
    Thoracic rigidity
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 303 (0.33%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Laryngospasm
         subjects affected / exposed
    2 / 304 (0.66%)
    1 / 303 (0.33%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Apr 2019
    change of sponsor name

    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
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