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    Clinical Trial Results:
    Hyperbaric Oxygen for the Prevention of Osteoradionecrosis (HOPON): A Randomised Controlled Trial of Hyperbaric Oxygen to prevent Osteoradionecrosis of the Irradiated Mandible.

    Summary
    EudraCT number
    		 2007-006225-27
    Trial protocol
    		 GB  
    Global end of trial date
    24 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 May 2019
    First version publication date
    31 May 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SP000283141
    Additional study identifiers
    ISRCTN number
    		 ISRCTN39634732
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Liverpool
    Sponsor organisation address
    765 Brownlow Hill, Liverpool, United Kingdom, L69 7ZX
    Public contact
    Clinical Trials Information, Cancer Research UK Liverpool Cancer Trials Unit, 0044 01517948938, lctu@liverpool.ac.uk
    Scientific contact
    Clinical Trials Information, Cancer Research UK Liverpool Cancer Trials Unit, 0044 01517948938, lctu@liverpool.ac.uk
    Sponsor organisation name
    Aintree University Hospitals NHS Foundation Trust
    Sponsor organisation address
    Longmoor Lane, Liverpool, United Kingdom, L9 7AL
    Public contact
    Clinical Trials Information, Cancer Research UK Liverpool Cancer Trials Unit , 0044 0151 7948938, lctu@liverpool.ac.uk
    Scientific contact
    Clinical Trials Information, Cancer Research UK Liverpool Cancer Trials Unit , 0044 0151 7948938, lctu@liverpool.ac.uk
    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
    22 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jan 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Questions in a number of key areas are addressed by this trial: 1. Incidence of ORN: what is the incidence of ORN following ‘at risk’ procedures, and how is this affected by the use of prophylactic HBO? 2. Outcome of ORN: what proportion of ORN cases progress to the most serious outcomes, and how is this influenced by the use of prophylactic HBO? 3. Morbidity of HBO: measurement of adverse events in treatment arm related to HBO therapy. 4. Cost effectiveness: what is the financial justification for prophylactic HBO in this setting? 5. Oral rehabilitation: how is osseointegrated implant retention affected by HBO independent of any effect on the incidence if ORN? 6. Late follow up of MBS (Minor Bone Spicules) to assess risk of further deterioration for patients with MBS (see Appendix 11) 7. Late follow up of implant survival: How many implants were lost since completing the HOPON assessments? (See Appendix 12).
    Protection of trial subjects
    Central and on-site monitoring was conducted to help protect patients and to monitor performance relating to trial procedures, trial intervention administration and laboratory/data collection processes. A risk assessment was carried out to determine the level of monitoring required, and subsequently a monitoring plan was developed to document how and when monitoring is conducted and to what extent. Patient safety was also monitored via LCTU pharmacovigilance procedures (reporting and review of adverse event data) and by an ISDMC. A Trial Management Group regularly reviewed central monitoring reports and advised accordingly. Serious adverse events were followed-up until resolution or death. Annual safety reports were submitted to the national regulatory authorities.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Sep 2008
    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: 141
    Country: Number of subjects enrolled
    Denmark: 3
    Worldwide total number of subjects
    144
    EEA total number of subjects
    144
    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)
    105
    From 65 to 84 years
    39
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The HOPON trial recruited 144 patients across 17 centres across England, Wales and Denmark between 24/09/2008 and 16/11/2016.

    Pre-assignment
    Screening details
    		 144 of the 256 patients screened were recruited to the study. Patients provided consent and then screening assessments were performed to determine eligibility prior to randomisation into standard or hyperbaric treatment arms.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard care plus HBO
    Arm description
    		 Standard care plus 20 Hyperbaric Oxygen (HBO) treatments prior to surgery followed by a further 10 HBO treatments. HBO complies with dive table RN66.
    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
    20 pre-operation HBO dives and 10 Post operation HBO dives

    Arm title
    		 Standard preoperative care
    Arm description
    		 Pre- and post- operative chlorohexidine mouthwash 0.2% – 10ml washed around the mouth for around 1 minute and spat out, three times daily for 5 days post-operatively; antibiotic cover pre-and post-operatively.
    Arm type
    		 Standard management arm

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Standard care plus HBO Standard preoperative care
    Started
    72
    72
    Completed
    72
    72
    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
    		 Standard care plus HBO
    Arm description
    		 Standard care plus 20 Hyperbaric Oxygen (HBO) treatments prior to surgery followed by a further 10 HBO treatments. HBO complies with dive table RN66.
    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
    20 pre-operation HBO dives and 10 Post operation HBO dives

    Arm title
    		 Standard preoperative care
    Arm description
    		 Pre- and post- operative chlorohexidine mouthwash 0.2% – 10ml washed around the mouth for around 1 minute and spat out, three times daily for 5 days post-operatively; antibiotic cover pre-and post-operatively.
    Arm type
    		 Standard management arm

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Standard care plus HBO Standard preoperative care
    Started
    72
    72
    Completed
    55
    66
    Not completed
    17
    6
         Withdrew during/after HBO before surgery
    3
    -
         Withdrew before HBO
    14
    -
         Withdrew before surgery
    -
    6
    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
    		 Standard care plus HBO
    Arm description
    		 Standard care plus 20 Hyperbaric Oxygen (HBO) treatments prior to surgery followed by a further 10 HBO treatments. HBO complies with dive table RN66.
    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
    20 pre-operation HBO dives and 10 Post operation HBO dives

    Arm title
    		 Standard preoperative care
    Arm description
    		 Pre- and post- operative chlorohexidine mouthwash 0.2% – 10ml washed around the mouth for around 1 minute and spat out, three times daily for 5 days post-operatively; antibiotic cover pre-and post-operatively.
    Arm type
    		 Standard management arm

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		Standard care plus HBO Standard preoperative care
    Started
    55
    66
    Completed
    44
    51
    Not completed
    11
    15
         Withdrew after surgery
    11
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard care plus HBO
    Reporting group description
    		 Standard care plus 20 Hyperbaric Oxygen (HBO) treatments prior to surgery followed by a further 10 HBO treatments. HBO complies with dive table RN66.

    Reporting group title
    Standard preoperative care
    Reporting group description
    		 Pre- and post- operative chlorohexidine mouthwash 0.2% – 10ml washed around the mouth for around 1 minute and spat out, three times daily for 5 days post-operatively; antibiotic cover pre-and post-operatively.

    Reporting group values
    		 Standard care plus HBO Standard preoperative care Total
    Number of subjects
    		 72 72 144
    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)
    		 57.9 ± 11.3 57.6 ± 11.1 -
    Gender categorical
    Units: Subjects
        Female
    		 53 53 106
        Male
    		 19 19 38
    Smoking
    Units: Subjects
        Smoking - Never
    		 23 23 46
        Smoking - Past
    		 31 33 64
        Smoking-Current
    		 14 15 29
        Smoking - Not recorded
    		 4 1 5
    Alcohol
    Units: Subjects
        Alcohol - Never
    		 5 4 9
        Alcohol - Past
    		 6 12 18
        Alcohol - Current
    		 33 34 67
        Alcohol - Not recorded
    		 28 22 50
    R/Therapy dose (mean)
    Units: Gy
        arithmetic mean (standard deviation)
    		 63.5 ± 10.3 62.3 ± 9.4 -
    Radiotherapy duration
    Units: Weeks
        arithmetic mean (standard deviation)
    		 6.2 ± 1.6 6 ± 1.7 -

    End points

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    End points reporting groups
    Reporting group title
    Standard care plus HBO
    Reporting group description
    		 Standard care plus 20 Hyperbaric Oxygen (HBO) treatments prior to surgery followed by a further 10 HBO treatments. HBO complies with dive table RN66.

    Reporting group title
    Standard preoperative care
    Reporting group description
    		 Pre- and post- operative chlorohexidine mouthwash 0.2% – 10ml washed around the mouth for around 1 minute and spat out, three times daily for 5 days post-operatively; antibiotic cover pre-and post-operatively.
    Reporting group title
    Standard care plus HBO
    Reporting group description
    		 Standard care plus 20 Hyperbaric Oxygen (HBO) treatments prior to surgery followed by a further 10 HBO treatments. HBO complies with dive table RN66.

    Reporting group title
    Standard preoperative care
    Reporting group description
    		 Pre- and post- operative chlorohexidine mouthwash 0.2% – 10ml washed around the mouth for around 1 minute and spat out, three times daily for 5 days post-operatively; antibiotic cover pre-and post-operatively.
    Reporting group title
    Standard care plus HBO
    Reporting group description
    		 Standard care plus 20 Hyperbaric Oxygen (HBO) treatments prior to surgery followed by a further 10 HBO treatments. HBO complies with dive table RN66.

    Reporting group title
    Standard preoperative care
    Reporting group description
    		 Pre- and post- operative chlorohexidine mouthwash 0.2% – 10ml washed around the mouth for around 1 minute and spat out, three times daily for 5 days post-operatively; antibiotic cover pre-and post-operatively.

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Following discussion with the TSC Chair and DMC Statistician it was decided that the primary analyses will be performed on a “per protocol-like” basis, analysing only patients who received surgery according to the treatment group originally allocated. This will be supported by sensitivity analyses

    Primary: Primary Endpoint

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    End point title
    		 Primary Endpoint
    End point description
    The presence of osteoradionecrosis at 6 months after surgery defined according to the Chief Investigator’s revised criteria (see appendix 9 of protocol), as determined by blinded central review of Clinical photograph, Radiography and PI assessment (see algorithm, appendix 10 of protocol)
    End point type
    Primary
    End point timeframe
    The presence of osteoradionecrosis at 6 months after surgery.
    End point values
    		 Standard care plus HBO Standard preoperative care Per Protocol
    Number of subjects analysed
    47
    53
    100
    Units: Patients
    3
    3
    6
    Statistical analysis title
    		 Mucosal Healing at 6 months
    Comparison groups
    Standard care plus HBO v Standard preoperative care
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 8.92
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.06

    Secondary: Mucosal Healing at 3 months

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    End point title
    		 Mucosal Healing at 3 months
    End point description
    End point type
    Secondary
    End point timeframe
    The presence of ORN at 3 months follow-up
    End point values
    		 Standard care plus HBO Standard preoperative care
    Number of subjects analysed
    45
    55
    Units: Patients
    9
    12
    Statistical analysis title
    		 Mucosal Healing at 3 months
    Comparison groups
    Standard care plus HBO v Standard preoperative care
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 2.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.56

    Secondary: Mucosal Healing at 12 months

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    End point title
    		 Mucosal Healing at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months follow-up
    End point values
    		 Standard care plus HBO Standard preoperative care
    Number of subjects analysed
    46
    50
    Units: Patients
    5
    6
    Statistical analysis title
    		 Mucosal Healing at 12 months
    Comparison groups
    Standard care plus HBO v Standard preoperative care
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 3.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.79

    Secondary: Severity of Osteoradionecrosis

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    End point title
    		 Severity of Osteoradionecrosis
    End point description
    End point type
    Secondary
    End point timeframe
    6 months follow-up
    End point values
    		 Standard care plus HBO Standard preoperative care
    Number of subjects analysed
    50
    57
    Units: Patients
        Notani G1
    7
    7
        Notani G2
    1
    0
        Notani G3
    0
    2
    No statistical analyses for this end point

    Secondary: Pain

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    End point title
    		 Pain
    End point description
    End point type
    Secondary
    End point timeframe
    6 Months Follow-up
    End point values
    		 Standard care plus HBO Standard preoperative care Standard care plus HBO Standard preoperative care
    Number of subjects analysed
    67
    69
    51
    54
    Units: Patients
        median (inter-quartile range (Q1-Q3))
    0.063 (0.011 to 0.234)
    0.074 (0.02 to 0.389)
    0.02 (0 to 0.106)
    0.03 (0.011 to 0.21)
    No statistical analyses for this end point

    Secondary: Quality of Life

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    End point title
    		 Quality of Life
    End point description
    End point type
    Secondary
    End point timeframe
    6 months follow-up
    End point values
    		 Standard care plus HBO Standard preoperative care Standard care plus HBO Standard preoperative care
    Number of subjects analysed
    71
    71
    55
    50
    Units: Patients
        arithmetic mean (standard error)
    60 ± 2.8
    58.8 ± 2.7
    54.2 ± 3.4
    59.6 ± 3.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs that occur within 28 days following the last dose of trial treatment will be reported.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Standard care plus HBO
    Reporting group description
    		 Standard care plus 20 Hyperbaric Oxygen (HBO) treatments prior to surgery followed by a further 10 HBO treatments. HBO complies with dive table RN66.

    Reporting group title
    Standard preoperative care
    Reporting group description
    		 Pre- and post- operative chlorohexidine mouthwash 0.2% – 10ml washed around the mouth for around 1 minute and spat out, three times daily for 5 days post-operatively; antibiotic cover pre-and post-operatively.

    Serious adverse events
    		 Standard care plus HBO Standard preoperative care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 58 (32.76%)
    13 / 72 (18.06%)
         number of deaths (all causes)
    7
    5
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Investigations - Other, specify
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Other: Malignant Neoplasm
         subjects affected / exposed
    8 / 58 (13.79%)
    5 / 72 (6.94%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 6
    0 / 5
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Vascular disorders - Other, specify
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Neuralgia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Other: ear barotrauma
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hearing impaired
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Other: uterine Bleeding
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other: post-op hypoventilation & acidosis
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis of jaw
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorder - Other, specify
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations - Other, specify
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other: jaw ORN and associated infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Standard care plus HBO Standard preoperative care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 58 (48.28%)
    17 / 72 (23.61%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    4 / 58 (6.90%)
    1 / 72 (1.39%)
         occurrences all number
    5
    1
    Teratoma
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    death
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    0
    2
    PATIENT ADMITTED TO HOSPICE FOR PALLIATIVE CARE
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    Bronchial carcinoma
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    endovascular repair for pre existing abdominal aortic aneurysm
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Pain
    Additional description: PAIN R MANDIBLE - UNDIAGNOSED CAUSE HOSPITALISATION FOR ACUTE FACIAL PAIN LEFT MANDIBLE
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 72 (4.17%)
         occurrences all number
    2
    3
    Fatigue
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Uterine bleeding episode leading to hysteroscopy and biopsy
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    PULMONARY OEDEMA:FAILED EXTUBATION
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    POST OP HYPOVENTILATION/ACIDOSIS
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 72 (2.78%)
         occurrences all number
    1
    2
    INPATIENT EPISODE TO REPAIR SUSTAINED FACIAL INJURIES
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    OXYGEN TOXICITY CONVULSION
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences all number
    2
    0
    SEVERE PAIN FROM NERVE TO SCAPULA WITH PARESTHESIA OF HEMIPLEGIA ON THE RIGHT SIDE
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    SLight CVA
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    OTIC BAROTRAUMA
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 72 (0.00%)
         occurrences all number
    3
    0
    EPISTAXIS DURING DECOMPRESSION
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences all number
    2
    0
    Eye disorders
    RESIDUAL DEFECT IN VISUAL FIELD OF RIGHT EYE
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences all number
    2
    0
    SUBCONJUCTIVAL HAEMORRHAGE
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    Dysphagia
    Additional description: DYSPHAGIA AND SUBSEQUENT ADMISSION FOR PEGTUBE PLACEMENT
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    EXTRACTION LL5 (XLA WITH SEDATION)
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    Endocrine disorders
    BLOCKED PAROTID DUCT L SIDE
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    NECROTIC MANDIBULAR BONE EXPOSURE REQUIRING SURGICAL INTERVENTION
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    INFECTED CHIN DRAINAGE
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    INFECTED SOCKET
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    Helicobacter infection
    Additional description: PATIENT HOSPITALISED WITH VARIOUS SYMPTOMS AND DIAGNOSED WITH HELCOBACTER PYLORI - COLIFORM CHEST INFECTION AND VERTEBRAE WEDGE FRACTURES T12 TO L4
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    INTRA ORAL INFECTION
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    Chest infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 72 (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
    16 Jun 2008
    Protocol updated to version 2.0, 16 April 2008 after MREC and NCRN review, and included alterations to the Patient Information Sheet, GP letter and Consent form (which are included as appendices in the protocol and as separate documents and pdf files on the disk), typographical errors in the protocol, and amendments to the protocol. Also, Protocol version 1.0 detailed a gingival biopsy that was to be performed and tissue samples collected as part of a sub study. This is no longer the case and only blood will be collected from patients.
    28 Nov 2008
    Protocol updated to version 3.0, 04/11/2008 to include the following: Volume of blood collected changed from 5ml to 6ml as there are no 5ml blood collection vaccutainers on the market. General updates made to the protocol to make it easier to read, some addresses changes, site contact details added.
    27 Jan 2010
    Protocol updated to version 4.0, 09/12/2009 to cover the following: 1. Added list of abbreviations 2. Additional recruiting centres 3. Additional text added to the main inclusion criteria to clarify the evidence of cancer recurrence 4. Exclusion criteria clarified in the event of patient becoming pregnant 5. Primary and secondary outcome measures reworded for clarity 6. General updates made throughout the protocol to make it easier to read
    02 Jul 2010
    Protocol updated to version 5.0, 07/05/2010 to cover the following: 1. Details of recruitment of another 150 patients over the next three years followed by one year of follow up added. 2. References to phase II trial and potential phase III trial removed. 3. Trial end date changed. 4. Trial Steering Committee members updated. 5. Statistical and analytical details amended for phase III. 6. GP letter updated (removed reference to Feasibility study as is now phase III). 7. Additional trial sites added (University Hospital of Wales, Worcestershire Royal Hospital, University 8. Hospital Coventry and Warwickshire, Midlands Diving Chamber). 9. Principal Investigator in Leeds replaced. 10. Additional Secondary Endpoint 11. Other minor corrections.
    04 Oct 2012
    Protocol updated to version 6.0, 28/06/2012 to cover the following: 1. Typographical corrections 2. Additional expertise added in the form of a clinical oncologist, lecturer in medical oncology and an additional lay member. 3. Contact details for research team members updated 4. Protocol version 5 stated that for patients who had missed 3 or less HBO dives, they would have extra dives added on at the end to make sure that they had the full 30 HBO dives. The new version allows for any amount of HBO dives to have been missed (not just 3 or less) which will then be added on to the end of their treatment to ensure the full amount of dives have been given. This amendment has been advised by the HOPON TSC on 03/10/11. It also reaffirms that patients will be followed up as per protocol. 5. This text has been removed based on the advice of the HOPON TSC on 03/10/11. Patients who have missed 4 or more HBO sessions will continue to receive HBO treatment and follow up as per protocol. 6. Contact Numbers for the Centres and Investigators updated. Details for Leeds, Guy’s, Plymouth, Cardiff and Aberdeen, corrected.
    14 Jun 2013
    Protocol updated to version 7.0, 25/04/2013 to cover the following: 1. Trial duration extended for patient recruitment. Previously it was May 2010 – May 2014. But it was updated to May 2014 – Feb 2018. 2. The total number of patients to be randomised will slightly increase from 200 to 221 to adjust for increased drop-out rate. 3. Reference Safety Information details added for information on relevant SmPC for trial IMP. 4. Annual recruitment, total recruitment and duration of recruitment amended to reflect the changes detailed above. 5. Site removed from list of participating sites as site is to be closed out (site closure already approved by MREC) 6. Site details added and name of Principal Investigators updated as were not present in previous version of protocol.
    24 Mar 2016
    Protocol updated to version 8.0, 26/11/2015 to cover the following: Change to the Primary Outcome measures. The presence of osteoradionecrosis at 6 months after surgery defined according to the Chief Investigator’s revised criteria (see appendix 9), as determined by blinded central review of Clinical photograph, Radiography and PI assessment (see algorithm, appendix 10). Change in Title and address of the Chief Investigator and change of Trial Coordinator details throughout the protocol Change in email address of Mr Gerry Robertson (TSC Chair) Removal of a Trial Steering Committee member Change to the Secondary Outcome measures: 8.1.2. Secondary Outcomes: The diagnosis of osteoradionecrosis at 3 and 12 months (in the same way as the 6 month outcome) Severity of cases of diagnosed osteoradionecrosis, according to Notani grade Pain: patient questionnaire at baseline, 3, 6 and 12 months Quality of life (QoL): following randomisation, and at 3, 6 and 12 months following surgery (as determined by a modified University of Washington Head and Neck QoL questionnaire - Appendix 6) 8.1.3. Safety Outcomes: Adverse events in HBO arm related to hyperbaric oxygen treatment The number and proportion of patients with hospital admissions, operations and complications (e.g. major bleeding, sepsis or mortality) occurring within 12 months post-surgery. New Diagnosis of cancer, either recurrent or new site within 12 months following surgery Change to section 10.7 Randomisation Code List An update to Website for checking and downloading current versions of the SMPC: https://lakemedelsverket.se/LMF/?q=oxygen Update to section 13.1. Quality control Update to section 18. Statistical Considerations – this has been extensively revised and re-written so no concise summary is possible. Update to protocol for Change in the Principal Investigators at different sites Addition of New References to the protocol
    08 Feb 2017
    Protocol updated to version 9.0, 11/01/2017 to cover the following: 1. Minor Bone Spicules. Following clarification of the endpoints earlier in 2016, and changes to the protocol subsequently approved by HOPON trial governance committees, REC and MHRA, these changes were subject to external peer review and have recently been published: Refining the definition of mandibular osteoradionecrosis in clinical trials: The cancer research UK HOPON trial (Hyperbaric Oxygen for the Prevention of Osteoradionecrosis). Shaw R, Tesfaye B, Bickerstaff M, Silcocks P, Butterworth C. Oral Oncol. 2017 Jan;64:73-77. doi: 10.1016/j.oraloncology.2016.12.002. At the most recent meeting of the HOPON Trial Steering Committee, it was decided that in order to properly implement the endpoints, the protocol required additional amendments with the aim of follow up of secondary endpoints for Minor Bone Spicules (MBS). (Only relevant for those patients who have MBS at the 12 month endpoint). This is in order to assess the risk of further deterioration for patients with MBS, and hence the validity of the current assumption that these patients do not in fact have osteoradionecrosis, instead having slightly delayed but otherwise normal and complete healing. 2. Implant retention. (Only relevant for those patients for whom eligibility was placement of dental implants) To analyse the effect of HBO on implant retention in the irradiated mandible. This outcome was in fact included within previous protocols, and the original approvals, but owing to an oversight on our behalf had been excluded from appropriate follow up arrangements. We now seek to properly address this secondary endpoint as originally intended.

    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/30851351
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