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    Clinical Trial Results:
    Hyperbaric oxygen treatment of mandibular osteoradionecrosis. A randomized clinical trial.

    Summary
    EudraCT number
    		 2007-007842-36
    Trial protocol
    		 DK   SE   GB  
    Global end of trial date
    31 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jan 2020
    First version publication date
    28 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DAHANCA-21
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00760682
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Copenhagen University Hospital
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen , Denmark, DK-2100 Copenhagen
    Public contact
    Lone Forner , Copenhagen University Hospital , +45 26396440, loneforner@outlook.dk
    Scientific contact
    Lone Forner , Copenhagen University Hospital , +45 26396440, loneforner@outlook.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
    01 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Nov 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of hyperbaric oxygen treatment on mandibular osteoradionecrosis and secondary endpoints xerostomia, hypersalivation, trismus, dysphagia, pain, BMI and quality of life. Only primary endpoints have been finally analyzed. An important information about the trial is the inclusion of data of a separate Dutch study. The Dutch participants are not recruited in the DAHANCA-21 trial, but in the Dutch trial NWHHT 2009-1. Due to slow recruitment in both trials, it was decided to share the data after termination of the studies. It must therefore be emphasized that no Dutch participants were recruited into DAHANCA-21, but the pooled data are presented in this report.
    Protection of trial subjects
    Following measures were made to minimise pain and distress: Thorough information prior to giving consent and thorough care taken to ensure that participants were comfortable with participation throughout the study. Patients were informed that they were entitled to leave the study without giving any reason for this. The treatment they were assigned to was not painful but potentially stressful because it took place in a closed compartment, the hyperbaric chamber. Participants were informed that a hyperbaric tender would be able to get into the chamber within 20 seconds. It was possible to speak to the tenders surveilling the chamber from outside. Participants were informed that there would at all times be a tender outside the chamber to watch what was going on inside the chamber. Participants were encouraged to share experiences and adress treatment-related stress to assigned doctors and to the investigator. Annual safety reports were submitted to the national regulatory authorities
    Background therapy
    		 Hyperbaric oxygen is 100% oxygen delivered in a mask or a hood while decompressing the hyperbaric chamber to approximately 2.4 ATA, corresponding to diving at 14-15 meters. Decompression lead to a greater delivery of the oxygen into the body. There is currently insufficient evidence of an effect of hyperbaric oxygen on osteoradionecrosis (radiotherapy-induced bone tissue necrosis)
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 2008
    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
    Netherlands: 20
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    Denmark: 51
    Worldwide total number of subjects
    97
    EEA total number of subjects
    97
    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)
    70
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment periods from June 1st, 2008 to August 1st, 2017.

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 97
    Number of subjects completed
    		 97

    Period 1
    Period 1 title
    Randomisation
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This is an open-label due to the different schedules of treatment administration

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Hyperbaric oxygen and surgery
    Arm description
    		 In Arm 1, participants were allocated to 30 preoperative and 10 postoperative exposures to hyperbaric oxygen consisting of inhaling 100% oxygen from a hood while decompressed to 2.4 ATA. Surgical procedure includes surgical removal of necrotic mandibular bone
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hyperbaric oxygen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Inhalation use
    Dosage and administration details
    30 preoperative and 10 postoperative exposures at 2.4 ATA pressurisation

    Arm title
    		 Surgery
    Arm description
    		 Surgical removal of necrotic mandibular bone
    Arm type
    		 Standard care, comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Hyperbaric oxygen and surgery Surgery
    Started
    46
    51
    Completed
    46
    51
    Period 2
    Period 2 title
    Therapy
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Trial is open labelled

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Hyperbaric oxygen and surgery
    Arm description
    		 In Arm 1, participants were allocated to 30 preoperative and 10 postoperative exposures to hyperbaric oxygen consisting of inhaling 100% oxygen from a hood while decompressed to 2.4 ATA. Surgical procedure includes surgical removal of necrotic mandibular bone
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hyperbaric oxygen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Inhalation use
    Dosage and administration details
    30 preoperative and 10 postoperative exposures at 2.4 ATA pressurisation

    Arm title
    		 Surgery
    Arm description
    		 Surgical removal of necrotic mandibular bone
    Arm type
    		 Standard care, comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Hyperbaric oxygen and surgery Surgery
    Started
    46
    51
    Completed
    36
    40
    Not completed
    10
    11
         Consent withdrawn by subject
    6
    5
         Cancer recurrence
    2
    1
         Death
    -
    1
         Surgery not needed
    -
    1
         Lost to follow-up
    2
    3
    Period 3
    Period 3 title
    Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Trial is open label

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Hyperbaric oxygen and surgery
    Arm description
    		 In Arm 1, participants were allocated to 30 preoperative and 10 postoperative exposures to hyperbaric oxygen consisting of inhaling 100% oxygen from a hood while decompressed to 2.4 ATA. Surgical procedure includes surgical removal of necrotic mandibular bone
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hyperbaric oxygen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Inhalation use
    Dosage and administration details
    30 preoperative and 10 postoperative exposures at 2.4 ATA pressurisation

    Arm title
    		 Surgery
    Arm description
    		 Surgical removal of necrotic mandibular bone
    Arm type
    		 Standard care, comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		Hyperbaric oxygen and surgery Surgery
    Started
    36
    40
    Completed
    26
    34
    Not completed
    10
    6
         Cancer recurrence
    -
    2
         Death
    4
    2
         Ear problems in HBO chamber
    1
    -
         Surgery not needed
    1
    -
         Lost to follow-up
    2
    2
         Protocol deviation
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Hyperbaric oxygen and surgery
    Reporting group description
    		 In Arm 1, participants were allocated to 30 preoperative and 10 postoperative exposures to hyperbaric oxygen consisting of inhaling 100% oxygen from a hood while decompressed to 2.4 ATA. Surgical procedure includes surgical removal of necrotic mandibular bone

    Reporting group title
    Surgery
    Reporting group description
    		 Surgical removal of necrotic mandibular bone

    Reporting group values
    		 Hyperbaric oxygen and surgery Surgery Total
    Number of subjects
    		 46 51 97
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 32 38 70
        From 65-84 years
    		 14 13 27
        85 years and over
    		 0 0 0
        Adults (>17 years)
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 59 (48 to 78) 60 (49 to 80) -
    Gender categorical
    Units: Subjects
        Female
    		 9 10 19
        Male
    		 37 41 78
    Subject analysis sets

    Subject analysis set title
    Analysis of the effect of hyperbaric oxygen on ORN
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    While DAHANCA-21 was ongoing, recruitment was slow. At the time of initiation of DAHANCA-21, a similar trial was initiated in the Netherlands, the NWHHT 2009-1 trial. It was considered to join these trials from the beginning, but because both trials were ready to start at this time, it was decided to keep in touch and exchange experiences. After a few years, it became clear that recruitment was slow, and it was decided to include the Dutch data material in DAHANCA-21. Overall, 20 Dutch participants were included. 10 completed their participation, and further one participant was included in the intention-to-treat analysis. 60 participants completed the study, while another five were considered eligible for the intention-to-treat analysis. Of these 65, only 54 was from the DAHANCA-21 recruitment group, while the remaining 11 were Dutch.

    Subject analysis sets values
    		 Analysis of the effect of hyperbaric oxygen on ORN
    Number of subjects
    60
    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)
    70
        From 65-84 years
    27
        85 years and over
    0
        Adults (>17 years)
    0
    Age continuous
    Units: years
        median (full range (min-max))
    60 (48 to 80)
    Gender categorical
    Units: Subjects
        Female
    10
        Male
    55

    End points

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    End points reporting groups
    Reporting group title
    Hyperbaric oxygen and surgery
    Reporting group description
    		 In Arm 1, participants were allocated to 30 preoperative and 10 postoperative exposures to hyperbaric oxygen consisting of inhaling 100% oxygen from a hood while decompressed to 2.4 ATA. Surgical procedure includes surgical removal of necrotic mandibular bone

    Reporting group title
    Surgery
    Reporting group description
    		 Surgical removal of necrotic mandibular bone
    Reporting group title
    Hyperbaric oxygen and surgery
    Reporting group description
    		 In Arm 1, participants were allocated to 30 preoperative and 10 postoperative exposures to hyperbaric oxygen consisting of inhaling 100% oxygen from a hood while decompressed to 2.4 ATA. Surgical procedure includes surgical removal of necrotic mandibular bone

    Reporting group title
    Surgery
    Reporting group description
    		 Surgical removal of necrotic mandibular bone
    Reporting group title
    Hyperbaric oxygen and surgery
    Reporting group description
    		 In Arm 1, participants were allocated to 30 preoperative and 10 postoperative exposures to hyperbaric oxygen consisting of inhaling 100% oxygen from a hood while decompressed to 2.4 ATA. Surgical procedure includes surgical removal of necrotic mandibular bone

    Reporting group title
    Surgery
    Reporting group description
    		 Surgical removal of necrotic mandibular bone

    Subject analysis set title
    Analysis of the effect of hyperbaric oxygen on ORN
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    While DAHANCA-21 was ongoing, recruitment was slow. At the time of initiation of DAHANCA-21, a similar trial was initiated in the Netherlands, the NWHHT 2009-1 trial. It was considered to join these trials from the beginning, but because both trials were ready to start at this time, it was decided to keep in touch and exchange experiences. After a few years, it became clear that recruitment was slow, and it was decided to include the Dutch data material in DAHANCA-21. Overall, 20 Dutch participants were included. 10 completed their participation, and further one participant was included in the intention-to-treat analysis. 60 participants completed the study, while another five were considered eligible for the intention-to-treat analysis. Of these 65, only 54 was from the DAHANCA-21 recruitment group, while the remaining 11 were Dutch.

    Primary: Osteoradionecrosis

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    End point title
    		 Osteoradionecrosis
    End point description
    Osteoradionecrosis was evaluated on a scale from 0-4 based on the grading system Common Toxicity Criteria of Adverse Event version 3.0
    End point type
    Primary
    End point timeframe
    1 year
    End point values
    		 Hyperbaric oxygen and surgery Surgery Hyperbaric oxygen and surgery Surgery Hyperbaric oxygen and surgery Surgery Analysis of the effect of hyperbaric oxygen on ORN
    Number of subjects analysed
    26
    34
    26
    34
    26
    34
    60
    Units: Osteoradionecrosis disease grades 0-4
    26
    34
    26
    34
    26
    34
    60
    Statistical analysis title
    		 Osteoradionecrosis at 1 year follow-up
    Statistical analysis description
    Multivariate analysis
    Comparison groups
    Hyperbaric oxygen and surgery v Surgery
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19 [1]
    Method
    		 Multivariate analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2
    Confidence interval
         level
    		 96%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 6.3
    Notes
    [1] - No statistically significant difference was found in the intent-to-treat analysis between ORN patients having received either HBO+surgery or HBO alone

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events could be assessed at any time point with in the study period of 1 year
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1
    Reporting groups
    Reporting group title
    HBO + standard care
    Reporting group description
    		 -

    Reporting group title
    Standard care
    Reporting group description
    		 -

    Serious adverse events
    		 HBO + standard care Standard care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 46 (4.35%)
    2 / 51 (3.92%)
         number of deaths (all causes)
    4
    3
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Head hitting hyperbaric chamber door
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected hematoma of lower limb
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected reconstruction plate leading to sinuitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 HBO + standard care Standard care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 51 (0.00%)
    Ear and labyrinth disorders
    Ear problems during pressurization i hyperbaric chamber
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 51 (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? Yes
    Date
    Amendment
    09 Mar 2010
    Addition of centres in Bradford and Cardiff. Changes to monitoring plan. Investigator of Aarhus centre was changed.
    06 Mar 2011
    Addition of centres in Stockholm, Chichester/Portsmouth, Gdansk and Valencia. Exclusion of centre in Rome. Extension of approval date until April 30, 2015.
    29 Nov 2012
    Addition: Possibility for adding airbreaks to the protocol treatment for individual hyperbaric units
    26 Feb 2014
    Extension of approval date
    06 May 2015
    Addition of Midlands as centre
    21 Apr 2016
    Addition of Leeds, London and Hull as centres. Extension of approval date

    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.
    The planned number of 114 observations was not achieved.
    For support, Contact us.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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