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    Clinical Trial Results:
    An open label, randomised controlled feasibility pilot study to evaluate whether nasal fentanyl alone and in combination with buccal midazolam give better symptom control to dying patients when compared with standard as needed medication

    Summary
    EudraCT number
    		 2013-005009-30
    Trial protocol
    		 GB  
    Global end of trial date
    26 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Nov 2021
    First version publication date
    13 Nov 2021
    Other versions
    Summary report(s)
    		 Quantitative Results
    Qualitative Paper

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    13/057/GHT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02009306
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ClinicalTrials.gov Identifier: NCT02009306, South Central-Berkshire Research Ethics Committee: 13/SC/0636
    Sponsors
    Sponsor organisation name
    Gloucestershire Hospitals NHS Foundation Trust
    Sponsor organisation address
    Leadon House, Gloucestershire Royal Hospital, Gloucester, United Kingdom, GL1 3NN
    Public contact
    Paul Perkins, Gloucestershire Hospitals NHS Foundation Trust and, +44 01242 230199, paul.perkins@suerydercare.org
    Scientific contact
    Paul Perkins, Gloucestershire Hospitals NHS Foundation Trust and, +44 01242 230199, paul.perkins@suerydercare.org
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    We want to see how best to carry out a clinical trial to find out whether a medication known as fentanyl (given through the nose) given together with another medication known as midazolam (given through the lining of the mouth) are better (i.e. more effective) and faster at controlling the pain and agitation for patients dying in a hospice. The goal will be to use these medications for patients dying at home, leading to fewer nursing visits and lower healthcare costs. We will assess the following:- 1. What is the time taken to control symptoms? 2. Did the patients need additional oral or injection medications? 3. How safe are the two medication when given together? This is a pilot study meaning that we do not expect to have all answers to our research questions. It is to allow us to design a trial to confirm the trends we see in this trial.
    Protection of trial subjects
    Patients could receive rescue as needed medication
    Background therapy
    		 Background symptom relieving medication
    Evidence for comparator
    		 Standard care (subcutaneous injections delivered by staff) - not great evidence for this standard care
    Actual start date of recruitment
    01 Dec 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
    United Kingdom: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    0
    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)
    10
    From 65 to 84 years
    9
    85 years and over
    1

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Recruitment from December 2016 to Feb 2018 in UK

    Pre-assignment
    Screening details
    		 Inclusion criteria: • Hospice in-patients 18 - 99 years old. • Diagnosed with terminal cancer with an estimated prognosis of 1-2 weeks. • Have carer/family member who would be willing to give the study medication to the patient AND likely to be at the hospice at least 25% of the time.

    Period 1
    Period 1 title
    Titration
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nasal fentanyl and buccal midazolam
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    PecFent
    Investigational medicinal product code
    EU/1/10/644/001
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Patients will be titrated with PecFent and Epistatus. Efficacy of study drug will be determined 30 minutes after administration. A dose is deemed effective if the symptom is controlled AND there are no intolerable side effects. If symptom control is achieved that dose will be administered as the effective treatment dose. If symptom control is not achieved the patient will be administered a different dose on the PecFent or Epistatus titration schedule next time a dose of study drug is given: • Next dose up if inadequate pain relief • Next dose down if intolerable side effects If patient has 2 consecutive doses of study drug at effective treatment dose followed by inadequate symptom relief consider: • Giving next dose up on titration schedules if inadequate symptom relief • Giving next dose down on titration schedules if intolerable side effects • Patient stops trial PecFent Titration - 100 mcg, 200mcg, 400mcg, 800mcg

    Investigational medicinal product name
    Epistatus
    Investigational medicinal product code
    M11
    Other name
    Pharmaceutical forms
    Oromucosal liquid
    Routes of administration
    Buccal use
    Dosage and administration details
    Patients will be titrated with PecFent and Epistatus. Efficacy of study drug will be determined 30 minutes after administration. A dose is deemed effective if the symptom is controlled AND there are no intolerable side effects. If symptom control is achieved that dose will be administered as the effective treatment dose. If symptom control is not achieved the patient will be administered a different dose on the PecFent or Epistatus titration schedule next time a dose of study drug is given: • Next dose up if inadequate pain relief • Next dose down if intolerable side effects If patient has 2 consecutive doses of study drug at effective treatment dose followed by inadequate symptom relief consider: • Giving next dose up on titration schedules if inadequate symptom relief • Giving next dose down on titration schedules if intolerable side effects • Patient stops trial Epistatus Titration: 2.5, 5, 7.5, 10mg

    Arm title
    		 Standard as needed medication
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Diamorphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    When the oral route becomes problematic it is standard practice for SANM to be administered via subcutaneous injection. Subcutaneous SANM will include: • Opioids for pain or dyspnoea o Diamorphine o Oxycodone o Fentanyl The breakthrough dose of opioid is calculated according to the 24 hour background dose as is standard practice. Often it is 1/6th of the oral equivalent 24 hour dose although this can sometimes be different19. • Benzodiazepine and / or anti-psychotic for agitation o Midazolam, usually 2.5 – 5mg o Levomepromazine, usually 6.25 – 25mg o Haloperidol, usually 0.5 – 5mg • Anti-emetic for nausea o Cyclizine, 50mg o Metoclopramide, 10mg o Haloperidol, usually 0.5 – 5mg o Levomepromazine, usually 6.25 – 25mg • Anti-secretory drug for respiratory secretions o Glycopyrronium, 200 – 400 mcg o Hyoscine butylbromide, 20mg o Hyoscine hydrobromide, 400 – 600mcg

    Investigational medicinal product name
    Midazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    When the oral route becomes problematic it is standard practice for SANM to be administered via subcutaneous injection. Subcutaneous SANM will include: • Opioids for pain or dyspnoea o Diamorphine o Oxycodone o Fentanyl The breakthrough dose of opioid is calculated according to the 24 hour background dose as is standard practice. Often it is 1/6th of the oral equivalent 24 hour dose although this can sometimes be different19. • Benzodiazepine and / or anti-psychotic for agitation o Midazolam, usually 2.5 – 5mg o Levomepromazine, usually 6.25 – 25mg o Haloperidol, usually 0.5 – 5mg • Anti-emetic for nausea o Cyclizine, 50mg o Metoclopramide, 10mg o Haloperidol, usually 0.5 – 5mg o Levomepromazine, usually 6.25 – 25mg • Anti-secretory drug for respiratory secretions o Glycopyrronium, 200 – 400 mcg o Hyoscine butylbromide, 20mg o Hyoscine hydrobromide, 400 – 600mcg

    Investigational medicinal product name
    Oxycodone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    1/6th of total daily oxycodone SC dose up to hourly PRN SC

    Investigational medicinal product name
    Glycopyrronium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    200 - 400 mcg PRN SC up to hourly

    Investigational medicinal product name
    Fentanyl
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    25 - 50 mcg PRN SC up to hourly

    Investigational medicinal product name
    Levomepromazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    6.25 - 25 mg PRN SC up to hourly

    Investigational medicinal product name
    Haloperidol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    0.5 - 5 mg PRN SC up to hourly

    Investigational medicinal product name
    Hyoscine hydrobromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    200 - 400 mcg PRN SC up to hourly

    Investigational medicinal product name
    Hyoscine butylbromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    200 - 400 mcg PRN SC up to hourly

    Arm title
    		 Buccal Midazolam alone
    Arm description
    		 In July 2017 the study team discussed a possible change to the study protocol. The study was recruiting on target but the 2 stage methodology meant that patients were not living long enough to receive Epistatus. Patients had to be titrated on PecFent before they could receive Epistatus. It was recognised that: • The objective of this study is to evaluate the feasibility of a bigger study. • The acceptability of administration of Epistatus for terminally ill patients and their families / carers is an important outcome for the study. It was agreed that it would be more likely for the study to be able to collect useful feasibility data if a third observational arm could be added to the open label randomised control trial arms. Patients in this arm would receive Epistatus alone as the only experimental drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Epistatus
    Investigational medicinal product code
    M11
    Other name
    Pharmaceutical forms
    Nasal spray, Oromucosal liquid
    Routes of administration
    Nasal use
    Dosage and administration details
    For agitation, buccal Epistatus will be given instead of subcutaneous midazolam. The Epistatus doses will be administered in time intervals not less than 4 hours. If patient has agitation AND pain, they will be given: • Standard analgesia for pain if agitation is assessed as likely to be secondary to pain • Standard analgesia for pain and Epistatus buccally if pain and agitation are assessed as likely to be separate Effectiveness of the dose will be assessed at 30 minutes post-dose. If deemed ineffective the following action should be taken: • Consideration of administration of injection of opioid and benzodiazepine. • Consideration of medical review. Epistatus Titration: 2.5, 5, 7.5, 10mg

    Number of subjects in period 1
    		Nasal fentanyl and buccal midazolam Standard as needed medication Buccal Midazolam alone
    Started
    9
    9
    2
    Completed
    6
    9
    2
    Not completed
    3
    0
    0
         Patient died before receiving study drug
    1
    -
    -
         Lack of efficacy
    2
    -
    -
    Period 2
    Period 2 title
    Maintenance
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nasal fentanyl and buccal midazolam
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    PecFent
    Investigational medicinal product code
    EU/1/10/644/001
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Nasal use
    Dosage and administration details
    Patients will be titrated with PecFent and Epistatus. Efficacy of study drug will be determined 30 minutes after administration. A dose is deemed effective if the symptom is controlled AND there are no intolerable side effects. If symptom control is achieved that dose will be administered as the effective treatment dose. If symptom control is not achieved the patient will be administered a different dose on the PecFent or Epistatus titration schedule next time a dose of study drug is given: • Next dose up if inadequate pain relief • Next dose down if intolerable side effects If patient has 2 consecutive doses of study drug at effective treatment dose followed by inadequate symptom relief consider: • Giving next dose up on titration schedules if inadequate symptom relief • Giving next dose down on titration schedules if intolerable side effects • Patient stops trial PecFent Titration - 100 mcg, 200mcg, 400mcg, 800mcg

    Investigational medicinal product name
    Epistatus
    Investigational medicinal product code
    M11
    Other name
    Pharmaceutical forms
    Oromucosal liquid
    Routes of administration
    Buccal use
    Dosage and administration details
    Patients will be titrated with PecFent and Epistatus. Efficacy of study drug will be determined 30 minutes after administration. A dose is deemed effective if the symptom is controlled AND there are no intolerable side effects. If symptom control is achieved that dose will be administered as the effective treatment dose. If symptom control is not achieved the patient will be administered a different dose on the PecFent or Epistatus titration schedule next time a dose of study drug is given: • Next dose up if inadequate pain relief • Next dose down if intolerable side effects If patient has 2 consecutive doses of study drug at effective treatment dose followed by inadequate symptom relief consider: • Giving next dose up on titration schedules if inadequate symptom relief • Giving next dose down on titration schedules if intolerable side effects • Patient stops trial Epistatus Titration: 2.5, 5, 7.5, 10mg

    Arm title
    		 Standard as needed medication
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Diamorphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    When the oral route becomes problematic it is standard practice for SANM to be administered via subcutaneous injection. Subcutaneous SANM will include: • Opioids for pain or dyspnoea o Diamorphine o Oxycodone o Fentanyl The breakthrough dose of opioid is calculated according to the 24 hour background dose as is standard practice. Often it is 1/6th of the oral equivalent 24 hour dose although this can sometimes be different19. • Benzodiazepine and / or anti-psychotic for agitation o Midazolam, usually 2.5 – 5mg o Levomepromazine, usually 6.25 – 25mg o Haloperidol, usually 0.5 – 5mg • Anti-emetic for nausea o Cyclizine, 50mg o Metoclopramide, 10mg o Haloperidol, usually 0.5 – 5mg o Levomepromazine, usually 6.25 – 25mg • Anti-secretory drug for respiratory secretions o Glycopyrronium, 200 – 400 mcg o Hyoscine butylbromide, 20mg o Hyoscine hydrobromide, 400 – 600mcg

    Investigational medicinal product name
    Midazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    When the oral route becomes problematic it is standard practice for SANM to be administered via subcutaneous injection. Subcutaneous SANM will include: • Opioids for pain or dyspnoea o Diamorphine o Oxycodone o Fentanyl The breakthrough dose of opioid is calculated according to the 24 hour background dose as is standard practice. Often it is 1/6th of the oral equivalent 24 hour dose although this can sometimes be different19. • Benzodiazepine and / or anti-psychotic for agitation o Midazolam, usually 2.5 – 5mg o Levomepromazine, usually 6.25 – 25mg o Haloperidol, usually 0.5 – 5mg • Anti-emetic for nausea o Cyclizine, 50mg o Metoclopramide, 10mg o Haloperidol, usually 0.5 – 5mg o Levomepromazine, usually 6.25 – 25mg • Anti-secretory drug for respiratory secretions o Glycopyrronium, 200 – 400 mcg o Hyoscine butylbromide, 20mg o Hyoscine hydrobromide, 400 – 600mcg

    Investigational medicinal product name
    Oxycodone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    1/6th of total daily oxycodone SC dose up to hourly PRN SC

    Investigational medicinal product name
    Glycopyrronium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    200 - 400 mcg PRN SC up to hourly

    Investigational medicinal product name
    Fentanyl
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    25 - 50 mcg PRN SC up to hourly

    Investigational medicinal product name
    Levomepromazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    6.25 - 25 mg PRN SC up to hourly

    Investigational medicinal product name
    Haloperidol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    0.5 - 5 mg PRN SC up to hourly

    Investigational medicinal product name
    Hyoscine hydrobromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    200 - 400 mcg PRN SC up to hourly

    Investigational medicinal product name
    Hyoscine butylbromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    200 - 400 mcg PRN SC up to hourly

    Arm title
    		 Epistatus alone
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Epistatus
    Investigational medicinal product code
    M11
    Other name
    Pharmaceutical forms
    Oromucosal liquid
    Routes of administration
    Buccal use
    Dosage and administration details
    For agitation, buccal Epistatus will be given instead of subcutaneous midazolam. The Epistatus doses will be administered in time intervals not less than 4 hours. If patient has agitation AND pain, they will be given: • Standard analgesia for pain if agitation is assessed as likely to be secondary to pain • Standard analgesia for pain and Epistatus buccally if pain and agitation are assessed as likely to be separate Effectiveness of the dose will be assessed at 30 minutes post-dose. If deemed ineffective the following action should be taken: • Consideration of administration of injection of opioid and benzodiazepine. • Consideration of medical review. Epistatus Titration: 2.5, 5, 7.5, 10mg

    Number of subjects in period 2
    		Nasal fentanyl and buccal midazolam Standard as needed medication Epistatus alone
    Started
    6
    9
    2
    Completed
    6
    9
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nasal fentanyl and buccal midazolam
    Reporting group description
    		 -

    Reporting group title
    Standard as needed medication
    Reporting group description
    		 -

    Reporting group title
    Buccal Midazolam alone
    Reporting group description
    		 In July 2017 the study team discussed a possible change to the study protocol. The study was recruiting on target but the 2 stage methodology meant that patients were not living long enough to receive Epistatus. Patients had to be titrated on PecFent before they could receive Epistatus. It was recognised that: • The objective of this study is to evaluate the feasibility of a bigger study. • The acceptability of administration of Epistatus for terminally ill patients and their families / carers is an important outcome for the study. It was agreed that it would be more likely for the study to be able to collect useful feasibility data if a third observational arm could be added to the open label randomised control trial arms. Patients in this arm would receive Epistatus alone as the only experimental drug.

    Reporting group values
    		 Nasal fentanyl and buccal midazolam Standard as needed medication Buccal Midazolam alone Total
    Number of subjects
    		 9 9 2 20
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 4 6 0 10
        From 65-84 years
    		 5 3 2 10
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Male
    		 5 0 2 7
        Female
    		 4 9 0 13

    End points

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    End points reporting groups
    Reporting group title
    Nasal fentanyl and buccal midazolam
    Reporting group description
    		 -

    Reporting group title
    Standard as needed medication
    Reporting group description
    		 -

    Reporting group title
    Buccal Midazolam alone
    Reporting group description
    		 In July 2017 the study team discussed a possible change to the study protocol. The study was recruiting on target but the 2 stage methodology meant that patients were not living long enough to receive Epistatus. Patients had to be titrated on PecFent before they could receive Epistatus. It was recognised that: • The objective of this study is to evaluate the feasibility of a bigger study. • The acceptability of administration of Epistatus for terminally ill patients and their families / carers is an important outcome for the study. It was agreed that it would be more likely for the study to be able to collect useful feasibility data if a third observational arm could be added to the open label randomised control trial arms. Patients in this arm would receive Epistatus alone as the only experimental drug.
    Reporting group title
    Nasal fentanyl and buccal midazolam
    Reporting group description
    		 -

    Reporting group title
    Standard as needed medication
    Reporting group description
    		 -

    Reporting group title
    Epistatus alone
    Reporting group description
    		 -

    Primary: Time to symptom control from when medication needed

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    End point title
    		 Time to symptom control from when medication needed
    End point description
    End point type
    Primary
    End point timeframe
    Patients in experimental arm who had been successfully titrated
    End point values
    		 Nasal fentanyl and buccal midazolam Standard as needed medication
    Number of subjects analysed
    6
    9
    Units: Minutes
        median (inter-quartile range (Q1-Q3))
    20 (17.5 to 29)
    30 (25 to 38)
    Statistical analysis title
    		 Quantitative outcome analysis
    Statistical analysis description
    Quantitative outcome measures was undertaken using Stata v.15. Descriptive statistics were used to characterise the cohort. Multiple imputation by chain equations procedure in Stata25 was used to obtain twenty imputed datasets. The median time with interquartile range are reported for the main outcome measures.
    Comparison groups
    Nasal fentanyl and buccal midazolam v Standard as needed medication
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.5 [1]
    Method
    		 Not appropriate
    Confidence interval
    Notes
    [1] - Small feasibility study - not appropriate to look for significance in results

    Secondary: Time from medication needed to onset of symptom control

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    End point title
    		 Time from medication needed to onset of symptom control
    End point description
    End point type
    Secondary
    End point timeframe
    Patients in experimental arm who have been successfully titrated.
    End point values
    		 Nasal fentanyl and buccal midazolam Standard as needed medication
    Number of subjects analysed
    6
    9
    Units: Minutes
        median (inter-quartile range (Q1-Q3))
    10 (9 to 16)
    20 (16 to 30)
    No statistical analyses for this end point

    Secondary: Time from medication given to administration of next breakthrough medication

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    End point title
    		 Time from medication given to administration of next breakthrough medication
    End point description
    End point type
    Secondary
    End point timeframe
    Patients in experimental arm who have been successfully titrated.
    End point values
    		 Nasal fentanyl and buccal midazolam Standard as needed medication
    Number of subjects analysed
    6
    9
    Units: Minutes
        median (inter-quartile range (Q1-Q3))
    380 (142.5 to 694)
    275 (152.5 to 537)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    While patients participating in the study
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Nasal fentanyl and buccal midazolam
    Reporting group description
    		 -

    Reporting group title
    Standard as needed medication
    Reporting group description
    		 -

    Reporting group title
    Buccalmidazolam alone
    Reporting group description
    		 -

    Serious adverse events
    		 Nasal fentanyl and buccal midazolam Standard as needed medication Buccalmidazolam alone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    3
    6
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Product issues
    Incorrect dose administered
    Additional description: A patient received four times the dose of nasal fentanyl they should have. We classified this as a serious adverse event. The patient was more sleepy after having the wrong dosage but was otherwise unharmed.
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Nasal fentanyl and buccal midazolam Standard as needed medication Buccalmidazolam alone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 9 (11.11%)
    0 / 1 (0.00%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 9 (11.11%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jul 2017
    which are needed: 1. To recruit up to 10 hospice in-patients into a study where they can receive Epistatus for agitation. The study will have different inclusion criteria to the main study and its conduct will not affect that of the main study. 2. Dr Jo Leonardi-Bee, Associate Professor in Medical Statistics and Independent Statistician Member of the TSG has suggested some rewording for the study objectives to make it clear that this is a feasibility study and the primary outcomes are about evaluating the feasibility of a larger study. 3. We would like to alter the titration and frequency of Epistatus. It has become clear from feedback from nursing staff that it is very unusual to give benzodiazepines half hourly (although they are often prescribed as such). We have reduced the frequency to hourly. We have also introduced another titration step of 7.5mg as it would be unusual to jump straight from 5mg to 10mg. 4. We have updated the membership of the TSG. 5. We have written some clearer guidance in conjunction with nursing staff administering trial drugs.

    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/32376759
    http://www.ncbi.nlm.nih.gov/pubmed/33766820
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