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    Clinical Trial Results:
    The pain relieving effect of nitrous oxide during bone marrow aspiration and biopsy - a placebo-controlled and randomized trial

    Summary
    EudraCT number
    		 2012-004285-18
    Trial protocol
    		 FI  
    Global end of trial date
    20 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Dec 2021
    First version publication date
    13 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    00002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Helsinki and Uusimaa Hospital District
    Sponsor organisation address
    Haartmaninkatu 4, Helsinki, Finland, 00029
    Public contact
    Per Rosenberg, Helsingin yliopisto, +358 9471 72 510,
    Scientific contact
    Per Rosenberg, Helsingin yliopisto, +358 9471 72 510,
    Sponsor organisation name
    Helsinki University Hospital
    Sponsor organisation address
    Haartmaninkatu 4, Helsinki, Finland, 00029
    Public contact
    Anna-Maria Kuivalainen, Helsinki and Uusimaa Hospital District, Helsinki University Hospital, anna-maria.kuivalainen@helsinki.fi
    Scientific contact
    Anna-Maria Kuivalainen, Helsinki and Uusimaa Hospital District, Helsinki University Hospital, anna-maria.kuivalainen@helsinki.fi
    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
    30 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this study was to find out if inhalation of a 50% mixture of N2O and oxygen is effective in relieving procedural pain in adults during bone maarow aspiration and/or biopsy compared to 50% oxygen.
    Protection of trial subjects
    The ethics committee of Helsinki and Uusimaa Hospital District approved the study protocol before the start of the trial (Diary number 323/13/03/01/2012). The ethical principles of Helsinki declaration were followed during every step of the clinical trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 May 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Finland: 70
    Worldwide total number of subjects
    70
    EEA total number of subjects
    70
    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)
    46
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Adult outpatients from the Division of Haematology undergoing bone marrow aspiration and/or biopsy were considered for inclusion. Patients were interviewed and screened for predetermined exclusion criteria before enrollment.

    Pre-assignment
    Screening details
    		 144 patients were considered for randomization. 74 patients were excluded and 70 patients were randomized.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nitrous oxide arm
    Arm description
    		 Patients receiving 50% mixture of nitrous oxide and oxygen
    Arm type
    		 Experimental

    Investigational medicinal product name
    50% mixture of nitrous oxide and oxygen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Medicinal gas, compressed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Patients started inhalation when the procedure was about to begin. After 2-3 minutes of inhalation, procedure was started. Patients inhaled countinuously throughout the procedure. After the procedure was completed, inhalation was stopped.

    Arm title
    		 Placebo arm
    Arm description
    		 Patients receiving 50% oxygen arm
    Arm type
    		 Placebo

    Investigational medicinal product name
    50% oxygen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Medicinal gas, compressed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Patients started inhalation when the procedure was about to begin. After 2-3 minutes of inhalation, procedure was started. Patients inhaled continuously throughout the procedure. After the procedure, patients stopped inhalation.

    Number of subjects in period 1
    		Nitrous oxide arm Placebo arm
    Started
    35
    35
    Completed
    35
    35

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nitrous oxide arm
    Reporting group description
    		 Patients receiving 50% mixture of nitrous oxide and oxygen

    Reporting group title
    Placebo arm
    Reporting group description
    		 Patients receiving 50% oxygen arm

    Reporting group values
    		 Nitrous oxide arm Placebo arm Total
    Number of subjects
    		 35 35 70
    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)
    		 58 ± 13 60 ± 12 -
    Gender categorical
    Units: Subjects
        Female
    		 19 14 33
        Male
    		 16 21 37

    End points

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    End points reporting groups
    Reporting group title
    Nitrous oxide arm
    Reporting group description
    		 Patients receiving 50% mixture of nitrous oxide and oxygen

    Reporting group title
    Placebo arm
    Reporting group description
    		 Patients receiving 50% oxygen arm

    Primary: Pain during procedure

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    End point title
    		 Pain during procedure
    End point description
    End point type
    Primary
    End point timeframe
    Pain during bone marrow aspiration and/or biopsy procedure
    End point values
    		 Nitrous oxide arm Placebo arm
    Number of subjects analysed
    35
    35
    Units: Pain in NRS
    median (full range (min-max))
        Local anaesthetic infiltration
    3 (0 to 7)
    3 (1 to 8)
        Puncture
    3 (0 to 9)
    3 (0 to 8)
        Aspiration
    4 (0 to 10)
    4 (0 to 9)
        Biopsy
    3.5 (0 to 10)
    3.5 (0 to 10)
    Statistical analysis title
    		 Statistical analysis
    Statistical analysis description
    The normality of the variables was assessed with the Shapiro–Wilk test. Ordinal regression analysis stratified by phase of the procedure was used to analyse the differences in pain felt during BMAB in both groups.
    Comparison groups
    Nitrous oxide arm v Placebo arm
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of study treatment until end of follow-up interview on the following day.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    		 Patients receiving 50% mixture of nitrous oxide and oxygen

    Reporting group title
    Placebo arm
    Reporting group description
    		 Patients receiving 50% oxygen

    Serious adverse events
    		 Treatment arm Placebo arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 35 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment arm Placebo arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 35 (14.29%)
    4 / 35 (11.43%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 35 (14.29%)
    2 / 35 (5.71%)
         occurrences all number
    5
    2
    Headache
         subjects affected / exposed
    0 / 35 (0.00%)
    3 / 35 (8.57%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0

    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/29911602
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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