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    Clinical Trial Results:
    Patient-controlled sedation with propofol versus combined sedation during bronchoscopy – a randomized controlled trial

    Summary
    EudraCT number
    		 2015-005274-38
    Trial protocol
    		 SE  
    Global end of trial date
    09 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Dec 2021
    First version publication date
    26 Dec 2021
    Other versions
    Summary report(s)
    		 Published article

    Trial information

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    Trial identification
    Sponsor protocol code
    BRONSE
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03357393
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Universitetssjukhuset i Linköping
    Sponsor organisation address
    Universitetssjukhuset, Linköping, Sweden, 58185
    Public contact
    Universitetssjukhuset i Linköping, Region Östergötland, lena.nilsson@regionostergotland.se
    Scientific contact
    Universitetssjukhuset i Linköping, Region Östergötland, lena.nilsson@regionostergotland.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
    03 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    We hypothesise that the use of propofol patient controlled sedation for outpatient bronchoscopy will be a safe and well accepted procedure by patients and bronchoscopists, and increase the amount of patients ready for discharge after two hours, compared with sedation using midazolam and morphine.
    Protection of trial subjects
    If patient is randomized to sedation with PCS the nurse anaesthetist will give additional thorough information and instructions how to operate the PCS device before premedication is administrated and the bronchoscopy begins. A nurse anaesthetist is present during the whole procedure until sedation level OAA/S 5 is reached, thereafter and before procedure a pulmonary nurse is present. Bronchoscopist and anaesthesiologist are available via telephone and/or pager and can be present within a few minutes. All of the drugs are administered by routes and given in doses in accordance with approval from the Swedish Medical Products Agency. The personnel involved in the procedure are all familiar with the use of the drugs being studied. During the procedure the anaesthesiologist is available for consultation via telephone and will be informed before sedation and bronschoscopy procedure begins. Furthermore the anaesthesiologist is available within minutes if call is made to anaesthesiologist pager. Before bronchoscopy is initiated (one hour after premedication) the patient is encouraged to start using the PCS until the patient feel comfortable. At the same time local anaesthetic is administrated nasally and pharyngeally depending on type of bronchoscopy and during the procedure local anaesthetic is administrated with a spray-as- you-go technique to anaesthetize vocal cords and trachea. During the procedure the bronchoscopist may request additional medication to achieve deeper sedation and/or pain relief due to a need that the patient has to be completely still during specially demanding and potentially dangerous parts of the procedure. If requested, the sedation is deepened with additional midazolam (if group MM) by nurse anaesthetist or by awaiting the PCS to deliver additional requests from the patient (if group MP or GP). If pain relief is needed additional topical anaesthetics is administrated by bronchoscopist and/or alfentanil (rescue).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 150
    Worldwide total number of subjects
    150
    EEA total number of subjects
    150
    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)
    53
    From 65 to 84 years
    95
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted following the principles of the amended Declaration of Helsinki at the Department of Pulmonary Medicine, Linköping University Hospital, from April 2016 to May 2017.

    Pre-assignment
    Screening details
    		 Exclusion criteria:positive pregnancy test, contraindication for the study drugs, functional disability, and cognitive impairment or language difficulties). 185 screened. 35 excluded (cancelled FB, 17 declined to participate, 3 contraindication, 5 cognitive disability, 3 personnel not available, 2 exclusion note missing)

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The bronchoscopist was blinded to the premedication, and it was administered by the bronchoscopic team.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control group
    Arm description
    		 Morphine-scopolamine/midazolam (NCS)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Morphine-scopolamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Morphine-scopolamine by age (18 to 54 y, 1.0 mL; 55 to 65 y, 0.75 mL; above 65 y, 0.5mL),

    Investigational medicinal product name
    Midazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Initial dose of 1.25mg of midazolam and, when necessary, repeated doses of 1.25mg, according to the type of procedure or bronchoscopist request.

    Arm title
    		 Intervention group (PCS-MS)
    Arm description
    		 Morphine-scopolamine/propofol (PCS)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Morphine-scopolamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Morphine-scopolamine by age (18 to 54 y, 1.0 mL; 55 to 65 y, 0.75 mL; above 65 y, 0.5mL),

    Investigational medicinal product name
    Propofol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Concentrate for solution for infusion
    Dosage and administration details
    By pressing a button, patients could self-administer a bolus of 5mg of propofol (0.5 mL) without lockout periods. The delivery time was ∼8 seconds, with an estimated maximum of 35mg of propofol/min if the patient were to repeatedly press the button for boluses.

    Arm title
    		 Intervention group (PCS-G)
    Arm description
    		 Glycopyrrolate/propofol (PCS)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glycopyrrolate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Glycopyrronium 0.2mg.

    Investigational medicinal product name
    Propofol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Concentrate for solution for infusion
    Dosage and administration details
    By pressing a button, patients could self-administer a bolus of 5mg of propofol (0.5 mL) without lockout periods. The delivery time was ∼8 seconds, with an estimated maximum of 35mg of propofol/min if the patient were to repeatedly press the button for boluses.

    Number of subjects in period 1
    		Control group Intervention group (PCS-MS) Intervention group (PCS-G)
    Started
    50
    50
    50
    Completed
    50
    50
    50

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Control group
    Reporting group description
    		 Morphine-scopolamine/midazolam (NCS)

    Reporting group title
    Intervention group (PCS-MS)
    Reporting group description
    		 Morphine-scopolamine/propofol (PCS)

    Reporting group title
    Intervention group (PCS-G)
    Reporting group description
    		 Glycopyrrolate/propofol (PCS)

    Primary: Discharge Assessment Using PADSS After 2 Hours Number of Patients Reaching PADSS Score 10 After 2 Hours

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    End point title
    		 Discharge Assessment Using PADSS After 2 Hours Number of Patients Reaching PADSS Score 10 After 2 Hours
    End point description
    ost Anaesthetic Discharge Scoring System (PADSS).A measurement of the PADSS score is done by pulmonary nurse every 15 min after bronchoscopy is finished (when bronchoscope is removed) for 2 hours. The PADSS is used to clinically assess if the patient is ready to be discharged after anaesthesia/sedation and consist of five criteria: vital signs, ambulation, nausea and/or vomiting, pain and surgical bleeding. Each criterion is given a score ranging from 0 to 2. Only patients who achieve a total score of 10 are considered ready for discharge after 2 hours.
    End point type
    Primary
    End point timeframe
    2 hours after bronchoscopy is finished
    End point values
    		 Control group Intervention group (PCS-MS) Intervention group (PCS-G)
    Number of subjects analysed
    50
    50
    50
    Units: Participants
    19
    30
    45
    Statistical analysis title
    		 Planned comparison PCS-MS vs PCS-G
    Comparison groups
    Intervention group (PCS-MS) v Intervention group (PCS-G)
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05
    Method
    		 Planned comparison
    Confidence interval
    Notes
    [1] - The groups were compared using a planned comparison. First, the control group was compared with the combined 2 PCS groups. Second, the PCS-MS group was compared with the PCS-G Group.
    Statistical analysis title
    		 Planned comparison Control vs PCS-MS/PCS-G
    Comparison groups
    Control group v Intervention group (PCS-MS) v Intervention group (PCS-G)
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.05
    Method
    		 Planned comparison
    Confidence interval
    Notes
    [2] - The groups were compared using a planned comparison. First, the control group was compared with the combined 2 PCS groups. Second, the PCS-MS group was compared with the PCS-G Group.

    Secondary: Assessment of Self-rated Patient Questionaries' Using S-PSR

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    End point title
    		 Assessment of Self-rated Patient Questionaries' Using S-PSR
    End point description
    Post-discharge Surgical Recovery Scale (S-PSR) The modified Swedish version S-PSR is based on the "Post-discharge Surgical Recovery Scale" and is a 14-item questionnaire to assess the recovery post-discharge regarding the patients' health status and activity (see further appendix 2). Each item is rated using a semantic differential scale and the total sum is multiplied by 100. The possible range is 10-100, with higher score indicating a more favourable postoperative recovery.
    End point type
    Secondary
    End point timeframe
    The assessment is done by the patient at home (or at ward if pro-longed hospital stay is necessary) in the evening on the day of bronchoscopy. It takes approximately 2 minutes to complete the questionnaire.
    End point values
    		 Control group Intervention group (PCS-MS) Intervention group (PCS-G)
    Number of subjects analysed
    50
    50
    50
    Units: Units on a scale
        median (full range (min-max))
    55 (36 to 77)
    56 (43 to 73)
    54 (41 to 100)
    No statistical analyses for this end point

    Secondary: Quality of Recovery (QoR-23)

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    End point title
    		 Quality of Recovery (QoR-23)
    End point description
    Modified version of Quality of Recovery (QoR-23) Minimum value 23. Maximum value 115. A higher score indicate a better quality of recovery. The questionnaire "Quality of Recovery" (QoR-23) is a 23 item questionnaire to assess recovery after day surgery regarding the patients' emotional state, physical comfort and physical independence (see further appendix 4). Each item is rated on a five-point scale (1-5) and the scores are summed.
    End point type
    Secondary
    End point timeframe
    The assessment is done by the patient at home (or at ward if pro-longed hospital stay is necessary) in the morning the day after bronchoscopy. It takes less than 1 minute to complete the assessment.
    End point values
    		 Control group Intervention group (PCS-MS) Intervention group (PCS-G)
    Number of subjects analysed
    50
    50
    50
    Units: Score on a scale
        median (full range (min-max))
    100 (61 to 112)
    102 (60 to 115)
    100 (63 to 115)
    No statistical analyses for this end point

    Secondary: Patients' Satisfaction Using a Likert-type Scale

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    End point title
    		 Patients' Satisfaction Using a Likert-type Scale
    End point description
    overall satisfaction with the procedure using the Likert-type scale (1. Very dissatisfied, 2. Dissatisfied, 3. Neither satisfied nor dissatisfied, 4. Satisfied, 5. Very satisfied). The patient may comment any cause which made the satisfaction score high or low and if the patient would like to receive the same method of sedation during a future bronchoscopy.
    End point type
    Secondary
    End point timeframe
    After patient has recovered after bronchoscopy and before discharge home, estimated period of time 0-24 hours.
    End point values
    		 Control group Intervention group (PCS-MS) Intervention group (PCS-G)
    Number of subjects analysed
    50
    50
    50
    Units: Units on a scale
        median (full range (min-max))
    5 (2 to 5)
    5 (4 to 5)
    5 (4 to 5)
    No statistical analyses for this end point

    Secondary: Bronchoscopist Evaluation Using a Likert-type Scale

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    End point title
    		 Bronchoscopist Evaluation Using a Likert-type Scale
    End point description
    The bronchoscopist assess their perception of cough, bronchial secretion respectively circumstances for a smooth performance of the bronchoscopy of procedure using the Likert-type scale (1. Very dissatisfied, 2. Dissatisfied, 3. Neither satisfied nor dissatisfied, 4. Satisfied, 5. Very satisfied).
    End point type
    Secondary
    End point timeframe
    Directly after completion of the procedure.
    End point values
    		 Control group Intervention group (PCS-MS) Intervention group (PCS-G)
    Number of subjects analysed
    50
    50
    50
    Units: Units on a scale
        median (full range (min-max))
    5 (2 to 5)
    4 (1 to 5)
    4 (2 to 5)
    No statistical analyses for this end point

    Secondary: Level of Sedation Using the Observer's Assessment of Alertness/Sedation (OAA/S) Scale

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    End point title
    		 Level of Sedation Using the Observer's Assessment of Alertness/Sedation (OAA/S) Scale
    End point description
    Level of sedation is assessed every 5th minute during the procedure by the nurse anaesthetist using The Observer's Assessment of Alertness/Sedation (OAA/S) scale whereby a higher score represent a lighter sedation. Below is the scale descriped, Observation/score: Responds readily to name spoken in normal tone/5 Lethargic response to name spoken in normal tone/4 Responds only after name is called loudly and/or repeatedly/3 Responds only after mild prodding or shaking/2 Does not respond to mild prodding or shaking/1
    End point type
    Secondary
    End point timeframe
    Assessement are done every 5th minute from procedure start until end of procedure (extraction of bronchoscope), estimated period of time 0-60 minutes.
    End point values
    		 Control group Intervention group (PCS-MS) Intervention group (PCS-G)
    Number of subjects analysed
    50
    50
    50
    Units: Units on a scale
        median (full range (min-max))
    3 (1 to 4)
    2 (1 to 4)
    2 (1 to 4)
    No statistical analyses for this end point

    Other pre-specified: Number of Participants With Interventions Performed

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    End point title
    		 Number of Participants With Interventions Performed
    End point description
    Number of participants with interventions performed to maintain cardiovascular (if atropine or ephidrine has been given) and respiratory stability (if assisted ventilation, chin lift or painful stimulation has been performed). Assesed every five minutes during the procedure.
    End point type
    Other pre-specified
    End point timeframe
    From procedure start until end of procedure (extraction of bronchoscope), estimated period of time 0-60 minutes.
    End point values
    		 Control group Intervention group (PCS-MS) Intervention group (PCS-G)
    Number of subjects analysed
    50
    50
    50
    Units: Participants
    1
    4
    3
    No statistical analyses for this end point

    Other pre-specified: Arterial Oxygen Saturation (SpO2)

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    End point title
    		 Arterial Oxygen Saturation (SpO2)
    End point description
    Outcome Measure Data Reported for participants SpO2 < 90%
    End point type
    Other pre-specified
    End point timeframe
    Every five minutes during the procedure (from procedure start until end of procedure (extraction of bronchoscope), , estimated period of time 0-60 minutes, and thereafter after the procedure every 15 minutes until PADSS score ≥9 or maximum 4 hours.
    End point values
    		 Control group Intervention group (PCS-MS) Intervention group (PCS-G)
    Number of subjects analysed
    50
    50
    50
    Units: Participants
    4
    4
    7
    No statistical analyses for this end point

    Other pre-specified: Respiratory Rate Per Minute (RR)

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    End point title
    		 Respiratory Rate Per Minute (RR)
    End point description
    Outcome Measure Data Reported for participants RR<8 breaths/min
    End point type
    Other pre-specified
    End point timeframe
    Every five minutes during the procedure (from procedure start until end of procedure (extraction of bronchoscope), , estimated period of time 0-60 minutes, and thereafter after the procedure every 15 minutes until PADSS score ≥9 or maximum 4 hours.
    End point values
    		 Control group Intervention group (PCS-MS) Intervention group (PCS-G)
    Number of subjects analysed
    50
    50
    50
    Units: Participants
    4
    6
    2
    No statistical analyses for this end point

    Other pre-specified: Non-invasive Blood Pressure (NIBP)

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    End point title
    		 Non-invasive Blood Pressure (NIBP)
    End point description
    Outcome Measure Data Reported for participants NIBP <90mmHg
    End point type
    Other pre-specified
    End point timeframe
    Every five minutes during the procedure (from procedure start until end of procedure (extraction of bronchoscope), , estimated period of time 0-60 minutes, and thereafter after the procedure every 15 minutes until PADSS score ≥9 or maximum 4 hours.
    End point values
    		 Control group Intervention group (PCS-MS) Intervention group (PCS-G)
    Number of subjects analysed
    50
    50
    50
    Units: Participants
    2
    2
    2
    No statistical analyses for this end point

    Other pre-specified: Heart Rate (Beats Per Minute, HR)

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    End point title
    		 Heart Rate (Beats Per Minute, HR)
    End point description
    Outcome Measure Data Reported for participants HR<40 beats/min
    End point type
    Other pre-specified
    End point timeframe
    Every five minutes during the procedure (from procedure start until end of procedure (extraction of bronchoscope), , estimated period of time 0-60 minutes, and thereafter after the procedure every 15 minutes until PADSS score ≥9 or maximum 4 hours.
    End point values
    		 Control group Intervention group (PCS-MS) Intervention group (PCS-G)
    Number of subjects analysed
    50
    50
    50
    Units: Participants
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start preparation for bronchospcpy (first drug given) to completing the questionnary QoR-23 on the day after procedure
    Adverse event reporting additional description
    In the incident report the following grading is used to rate the severity of an incidence: Mild = aware of the symptoms but they are tolerable Moderate = symptoms partially affect daily activities Severe = symptoms significantly affect daily activities The investigator assesses the relationship between the incidence and the study, as defined:
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Clinic specific
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Control group
    Reporting group description
    		 -

    Reporting group title
    Intervention group (PCS-MS)
    Reporting group description
    		 -

    Reporting group title
    Intervention group (PCS-G)
    Reporting group description
    		 -

    Serious adverse events
    		 Control group Intervention group (PCS-MS) Intervention group (PCS-G)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Overnight admission
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Control group Intervention group (PCS-MS) Intervention group (PCS-G)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 50 (6.00%)
    6 / 50 (12.00%)
    2 / 50 (4.00%)
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    2
    General disorders and administration site conditions
    Dizziness
         subjects affected / exposed
    3 / 50 (6.00%)
    6 / 50 (12.00%)
    0 / 50 (0.00%)
         occurrences all number
    6
    12
    0
    Fever
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31478938
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