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    Clinical Trial Results:
    Oxygen therapy for cluster headache. A mask comparison trial. A single-blinded, placebo-controlled, crossover study.

    Summary
    EudraCT number
    		 2011-006182-18
    Trial protocol
    		 DK  
    Global end of trial date
    06 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Aug 2016
    First version publication date
    12 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    15.12.12
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01589588
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Danish Headache Center
    Sponsor organisation address
    nordre ringvej 57, glostrup, Denmark, 2600
    Public contact
    Mads Barloese, Danish Headache Center, 45 38632062, GLO-hovedpine@regionh.dk
    Scientific contact
    Mads Barloese, Danish Headache Center, 45 38632062, GLO-hovedpine@regionh.dk
    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
    06 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Feb 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study will investigate the possible difference in treatment effect between three different oxygen delivery systems in the acute treatment of cluster headaches
    Protection of trial subjects
    All adverse events throughout the study will be recorded. All adverse events will be categorized as serious or non-serious, expected or not expected and the relationship with masks and treatment and placebo given. In assessing whether an adverse reaction expected or not expected we will use the product resume of Airapy and Oxygen AGA. The experiment is reported to the GCP-unit Region capital as follows with announced and unannounced visits. The trial is blind. A key so that it can always be seen what treatment the patient has received when. If the patient experiences unpleasant side-effects of one of the masks he can use his usual attack treatment after 15 minutes. The trial takes place in a hospital where there is immediate access to medical expertise. It is possible to immediately unblinding of the study using randomiseringsnøglen located at trial site. Conducted a clinical report form (CRF) for each patient throughout the study. This is designed according GCP unit guidelines
    Background therapy
    		 preventive medication was stable one week pror to inclusion and during the trial. Patients were allowed rescue medication after 15 minutes of trial theraphy,
    Evidence for comparator
    		 High flow oxygen is known to relief patients within 15 minutes (cohen 2009) and a small open label study showed that DVO migth be more efficiant than high flow oxygen, rozen 2011
    Actual start date of recruitment
    01 Feb 2012
    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
    Denmark: 57
    Worldwide total number of subjects
    57
    EEA total number of subjects
    57
    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)
    57
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 We included 57 CH patients from the Danish Headache Center, a tertiary headache center, between June 2012 and December 2014. Hereof, 31 CH patients also participated in an inpatient sleep study (Project ID: H-2-2012-016). Twenty-six CH-patients participated only in the mask comparison trial.

    Pre-assignment
    Screening details
    		 The inclusion criteria were age between 18 and 65 years; CH diagnosis according to International Classification of Headache Disorders, second edition (ICHD-II) criteria ; regular attack and cluster frequency for at least two years; average attack frequency of two to eight attacks per day prior to inclusion; cluster duration of more than two weeks;

    Pre-assignment period milestones
    Number of subjects started
    		 57
    Number of subjects completed
    		 10 [1]

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 not enough attacks: 45
    Reason: Number of subjects
    		 latex allergy: 1
    Reason: Number of subjects
    		 Protocol deviation: 1
    Notes
    [1] - The number of subjects reported to be in the pre-assignment period is not consistent with the number starting period 1. It is expected that the number completing the pre-assignment period are also present in the arms in period 1.
    Justification: 57 patients were enrolled. 42 patients had attacks. The trial is 4 way cross over.
    Period 1
    Period 1 title
    baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    Patinets were blinded for gastype and not masktype. Author MB generated the random sequence with the Microsoft Excel SLUMP function. The list was kept in the trial master file during the trial. Blinding of the mask type currently used was deemed impossible but patients were blinded to the contents of the gas cylinders. The gas cylinders were exactly the same size and covered with black plastic wrapping during the trial. A sticker with the numbers 1–4 distinguished the cylinders

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 DVO Demand valve oxygen
    Arm description
    		 Demand Valve oxygen
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Conoxia,
    Investigational medicinal product code
    Other name
    Oxygen, 100%
    Pharmaceutical forms
    Gas and solvent for dispersion for injection/infusion
    Routes of administration
    Inhalation use
    Dosage and administration details
    accodring to RR and TV

    Arm title
    		 Optimask
    Arm description
    		 Optimask
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Conoxia,
    Investigational medicinal product code
    Other name
    Oxygen, 100%
    Pharmaceutical forms
    Gas and solvent for dispersion for injection/infusion
    Routes of administration
    Inhalation use
    Dosage and administration details
    15 L/min

    Arm title
    		 Simple Mask
    Arm description
    		 Simple mask
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Conoxia,
    Investigational medicinal product code
    Other name
    Oxygen, 100%
    Pharmaceutical forms
    Gas and solvent for dispersion for injection/infusion
    Routes of administration
    Inhalation use
    Dosage and administration details
    15 L/min

    Arm title
    		 Placebo
    Arm description
    		 Place with DVO
    Arm type
    		 Placebo

    Investigational medicinal product name
    AIRAPY
    Investigational medicinal product code
    Other name
    eq air
    Pharmaceutical forms
    Gas and solvent for dispersion for injection/infusion
    Routes of administration
    Inhalation use
    Dosage and administration details
    Accodring to RR and TV

    Number of subjects in period 1
    		DVO Demand valve oxygen Optimask Simple Mask Placebo
    Started
    31
    32
    28
    11
    Completed
    31
    32
    28
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    baseline
    Reporting group description
    		 57 patients included in trial

    Reporting group values
    		 baseline Total
    Number of subjects
    		 57 57
    Age categorical
    mean 45 years, range 21-65
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 57 57
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Age (years
    Units: years
        arithmetic mean (full range (min-max))
    		 45 (21 to 65) -
    Gender categorical
    gender
    Units: Subjects
        Female
    		 15 15
        Male
    		 42 42
    Chronic or episodic type
    Chronic=CCH Episodic=ECH
    Units: Subjects
        CCH
    		 26 26
        ECH
    		 31 31

    End points

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    End points reporting groups
    Reporting group title
    DVO Demand valve oxygen
    Reporting group description
    		 Demand Valve oxygen

    Reporting group title
    Optimask
    Reporting group description
    		 Optimask

    Reporting group title
    Simple Mask
    Reporting group description
    		 Simple mask

    Reporting group title
    Placebo
    Reporting group description
    		 Place with DVO

    Primary: Two-point reduction on a five-point rating scale

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    End point title
    		 Two-point reduction on a five-point rating scale
    End point description
    The primary endpoint was a two-point reduction on a five-point rating scale within 15 minutes (min).
    End point type
    Primary
    End point timeframe
    15 minutes
    End point values
    		 DVO Demand valve oxygen Optimask Simple Mask Placebo
    Number of subjects analysed
    31
    32
    28
    11
    Units: effekt/no effect
        Effect
    16
    14
    11
    5
        No effect
    15
    18
    17
    6
    Attachments
    		 Untitled (Filename: FIGUR 4.xlsx)
    Statistical analysis title
    		 logistic reg
    Comparison groups
    Optimask v Simple Mask v DVO Demand valve oxygen v Placebo
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.411 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Confidence interval
    Notes
    [1] - After 15 min of therapy, the percentage of patients that were either pain free or had a two-point decrease on the five-point rating scale was 40%, 44% and 52% on the SM, OM and DVO, respectively (Figure 4). We completed a logistic analysis of all attacks for the primary outcome regarding pain relief within 15 min of oxygen therapy, but could not show any significant differences (p = 0.411).
    [2] - non sig

    Secondary: Mask preference

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    End point title
    		 Mask preference [3]
    End point description
    Only patients who tried all three mask types.
    End point type
    Secondary
    End point timeframe
    no time frame
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: We only included patient in this analysis who had tried all three mask types
    End point values
    		 DVO Demand valve oxygen Optimask Simple Mask
    Number of subjects analysed
    21
    21
    21
    Units: procentage
        first preference.
    62
    33
    5
    Statistical analysis title
    		 patient preference
    Comparison groups
    Simple Mask v Optimask v DVO Demand valve oxygen
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.001 [5]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [4] - The majority of the CH patients preferred DVO (62%) and only 5% preferred the SM (p < 0.001). The remaining 33% favored the OM (p = 0.061, compared to DVO) (Table 3). Only patients who tried all three mask types were included in this analysis (n = 21).
    [5] - significant

    Post-hoc: First attack Analysis

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    End point title
    		 First attack Analysis [6]
    End point description
    We tested for informative drop-out by means of a logistic regression model for the risk of more than one attack with respect to the mask used during the first attack. In addition, we tested the association between the mask used during the first attack and completion of the crossover study by logistic regression. To eliminate the possible carry-over effect, we conducted a post hoc comparative cross-sectional analysis, where only the first treated attack was included. Since this was the first attack, the randomization was intact and the risk of bias was minimized.
    End point type
    Post-hoc
    End point timeframe
    15 min
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: we only included the first attack, not the second, third or fouth. This was due to risk of unequal distribution and to short a wash out period.
    End point values
    		 DVO Demand valve oxygen Optimask Simple Mask
    Number of subjects analysed
    15
    14
    13
    Units: effect, no-effect
        effect
    9
    3
    3
        no effect
    6
    11
    10
    Statistical analysis title
    		 first attack
    Statistical analysis description
    The analysis of the first attack contains 42 CH attacks (Figure 3). The DVO was significantly better than the OM at treating the CH attacks on the five-point rating scale at 15 min with an OR of 5.5 (p = 0.042). The DVO was borderline better than the SM with an OR of 5.0 (p = 0.056). There was no difference between SM and OM (p = 0.918). Pooling the data and comparing the DVO to both SM and OM, the DVO is significantly better (p = 0.018).
    Comparison groups
    DVO Demand valve oxygen v Optimask v Simple Mask
    Number of subjects included in analysis
    42
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.018
    Method
    		 Regression, Logistic
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    14 days
    Adverse event reporting additional description
    Four adverse events happened after the trial, including one serious, but all were assessed to be unrelated to oxygen therapy.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 gcp manual
    Dictionary version
    1.0
    Reporting groups
    Reporting group title
    total population
    Reporting group description
    		 only 42 patients received trial therapy.

    Serious adverse events
    		 total population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 42 (2.38%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    thropping chest pain
    Additional description: One patient developed throbbing chest pain one week after oxygen inhalation but the cardiac follow-up was negative (ECG, tropnins and heart CT).
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 total population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 42 (7.14%)
    General disorders and administration site conditions
    Influenza
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    nose bleed
    Additional description: nosebleed one week after inhalation
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    increase in headache frequency
    Additional description: increased frequency. Interpreted as normal fluctuation of disease
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Nov 2013
    Inclusion of more patients and extension of trial period.

    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.
    patients did not suffer from four attacks and therefor the cross over is not complete and a peer protocol analysis is not possible.
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