Interventions

Medication group – 4 weeks of ‘pre-treatment’ therapy to reduce inflammation, infection and pain consisting of 2 g daily of Amoxicillin+Clavulanic acid 875/125 mg (1 g morning and night), 50 mg Fluconazole daily (morning), 16 mg prednisolone daily (morning) taken orally by the patient. ‘Therapeutic phase’ then commences immediately and consists of 5 days dosing of 800 mg pentoxifylline (400 mg morning and night) and 1000 IU vitamin E (morning) (Monday to Friday) taken orally by the patient. If the patient deteriorates (defined as a negative change or worsening in either Notani or Lyons score at follow-up by consultant) then add clodronate 1600 mg daily (orally morning, Monday to Friday, tablet to be swallowed intact and not crushed per clinical pharmacists involved with the trial) for a minimum of 6 months but up to 18 months if the patient has stable ORN and is not deteriorating further (defined as an ongoing negative change in either Notani or Lyons score for two consecutive appointments 1 month apart). If the patient experiences any pain or infection then 1 g ciprofloxacin (500 mg morning and night) and prednisolone 16 mg (morning) orally on the remaining 2 days (Saturday and Sunday) can be added to help resolve symptoms for as long as the patient is symptomatic, if this fails to be effective then a short course of 7 days per week therapy of either the same steroid or antibiotic will be added to help alleviate symptoms, this will be recorded against the patients data for the trial. Patients that have fully healed (defined by complete mucosal coverage of the boney defect excepting minor bone spicules of less than 20 mm² present for 6 months or more and that have no ongoing pain) will continue to take the medication and be reviewed up to the 18-month follow-up point at which time they will cease. Patients that are not fully healed will also continue to take the medication and be reviewed up to the 18-month follow-up point at which time a decision will be made in conjunction with their treating consultant about whether to continue with the medication or to offer an alternative treatment. Note will be made in the final analysis about what the patient decides.

HBO group—4 weeks of ‘pre-treatment’ therapy as above. ‘Therapeutic phase’ incorporates HBO therapy prescribed for each patient based on Marx’s protocol of 30 dives at 2.4 atm for 90 min per dive, the treatment will be monitored and administered by specialist physicians who are not part of the trial team in a dedicated HBO unit and will be the same for all patients in the HBO arm. If the patient has healed after this treatment (defined by complete mucosal coverage of the boney defect excepting minor bone spicules of less than 20 mm² present for 6 months or more and that have no ongoing pain) then they will be reviewed as per the protocol time points to 18 months after which they will undergo normal follow-up according to established oral and maxillofacial unit protocols. If the patient still has exposed bone meeting Notani grade 1 scoring criteria then they will undergo a surgical procedure to remove the exposed bone and then a further 10 dives of HBO at 2.4 atm for 90 min per dive again as per Marx’ protocol.3 If the patient experiences pain or infection during the course of treatment then appropriate medical treatment will be prescribed according to the same protocol outlined in the medication intervention but without the addition of any of: pentoxifylline, tocopherol or clodronate.

For this pilot study, we will recruit eight patients per treatment arm (figure 1). demonstrates the planned enrolment and randomisation. As we are not testing a hypothesis the initial descriptive results on efficacy of the two treatment arms will be used to determine an adequately powered sample size for a larger clinical trial. Assessors and investigators will be blinded to the treatment that the study participants receive. Clinical photographs will be taken in a dedicated room and de-identified prior to being assessed, radiographs will also be de-identified but coupled with the matching photographs for the purposes of assessment and scoring via the modified Notani and Lyons classifications. Investigators will remain blinded during the data collection phase and during the analysis other than knowing which group NUMBER the participants were assigned to and the patients unique identifier number for the purposes of comparing the two treatments against defined primary and secondary outcome measures and ensuring that the correct imaging results are matched against the correct photographs for the external assessors.

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Figure 1

Planned enrolment CONSORT diagram. CONSORT, Consolidated Standards of Reporting Trials; HBO, hyperbaric oxygen.

Objectives

• To describe time to complete healing in patients treated with PENTOCLO vs HBO using an accepted clinical and radiographic scoring system.

• To describe the rate of improvement in patients treated with PENTOCLO vs HBO using an accepted clinical and radiographic scoring system.

• To describe the rates of failure of treatment in patients treated with PENTOCLO vs HBO using an accepted clinical and radiographic scoring system.

Outcomes

• Primary outcome—successful healing, improvement or worsening of ORN of the mandible.

• Secondary outcome—complications that arise from treatment.

Primary outcome will be measured by two blinded independent assessors in the following way:

• Successful healing will primarily be defined by complete mucosal coverage and absence of pain over the previously involved area. In the event of partial healing or worsening a Notani and Lyons score will be assigned with Notani score taking precedence in the event of a discrepancy between the two scores. For the purposes of this study Minor bone spicules of less than 20 mm² present for 6 months or more that remain after treatment with no radiographic abnormalities will be considered fully healed and not Notani grade 1.10

• Clinical photographs of the intra-oral status of the tissues will be taken with a standard flash by trained clinical photographers at the tertiary hospital, these photographs will be de-identified and printed out with the unique identifier number sticker on them. An authorised Maxillofacial registrar not participating in the trial or the clinical team but who is aware of the methodology and which patients are on the trial will be asked to select, de-identify, add the unique identifier sticker and print out the most recent CT still images or panoramic radiographs that demonstrate the largest extent of the boney defect by the treating consultant at each visit. The two sets of images will then be combined and double checked by the trial investigators and then provided to the independent assessors. If the patients have trismus and cannot have clinical photographs taken then a digital intra-oral scanner will be used with measurements of the mucosal defect made using the images. If the patients have absolute trismus and cannot open their mouth at all then soft tissue windows on the most recent CT scan will be used to measure the defect. Images will show the boney and soft tissue defect for each patient that has ORN. The independent assessors will then be asked to review the clinical photographs and radiographic images and assign a Notani and Lyons score which are the validated scoring systems for ORN chosen to be used in this study.10–12 This will be done for each patient presented to the assessors shortly after the various different time points for follow-up for each patient. The treating consultant will also have access to the clinical photographs and radiographic images for the purposes of assigning a score to track the patients progress for follow-up. The scores assigned by the independent assessors will be collated in an excel spreadsheet and kept with the patients unique identifier number to track their progress through the study.

Secondary outcome will be measured in the following way:

• A record will be kept by the treating consultant of any serious adverse events that  are reported throughout the treatment. A serious adverse event will be defined as per the U.S. Food and Drug Administration.13 Other complications such as worsening of the patient’s condition will be recorded by the treating consultant and these will be de-identified and made known to the lead investigator to be recorded against the patient’s data for the study.

Inclusion criteria

• Patients diagnosed with grade 1 Notani score ORN by an Oral and Maxillofacial surgeon, ORN will be defined as “an area of exposed devitalized irradiated bone that fails to heal over a period of 3 to 6 months in the absence of local neoplastic disease’14 and is greater than 20 mm² in size.10

• Patients that are able to give informed consent.

Exclusion criteria

• Patients that have spontaneously healing ORN.

• Patients that have undergone previous treatment for ORN (PENTO, HBO or surgery).

• Patients that are unable to give informed consent.

• Patients that are pregnant at the time of therapy.

• Patients that have received previous anti-resorptive or anti-angiogenic medications.

• Patients requiring further surgical management for their head and neck cancer during the study period.

• Patients diagnosed with ORN requiring surgery as first line management (Notani grade 2 or 3  or those with grade 1  who have an acute infection which requires surgical curettage).

• Patients who are unable to be randomised either because they cannot swallow medication or because they cannot undergo HBO therapy (eg, they have optic neuritis, chronic obstructive pulmonary disease or congenital pulmonary blebs).

Descriptive statistics will be calculated and summarised to define the time-point during follow-up at which the patient is completely healed or in the event of improvement without complete healing at 18 months, descriptive statistics (estimates of the mean, SD and 95% CIs, for each treatment group for continuous measurements and proportions in each treatment group for categorical variables) will be used to quantify the degree of improvement for each patient within both groups. Patients worsening while on the trial will be analysed up to the point at which they were removed from the treatment they were originally assigned to. At the conclusion of the trial all participants will be included in an intention to treat analysis. The results of this study will be used to inform the numbers of participants needed for each trial arm in a large multicentre controlled trial that will follow.

Figure 2 demonstrates the follow-up schedule for the patients recruited to the study. Each participant will be commenced on ‘pre-treatment’ immediately after their initial appointment to minimise the time spent waiting and decrease any pain or infection that they may have.

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Figure 2

Timeline describing the planned follow-up for each patient after the initial ‘screening’ visit where the treating consultant will collect baseline data. ORN, osteoradionecrosis.

Patient and consumer involvement

Patients and consumer representatives have had input into the trial design via the ethics committee that has given approval for this study. The committee has several patient and consumer representatives among its constituents. We have planned to disseminate the results of the study to the trial participants via their indicated preferred method of contact which will be a part of the information collected at their initial appointment with the treating consultant Oral and Maxillofacial Surgeon. We have also planned to include a patient representative on the data monitoring committee that will form part of the large multi-centre controlled trial to follow this pilot study.

Ethics and dissemination

Any modification of the protocol during the study will need to be agreed by the research team, if this involves the collection of data, patient treatment, safety or data analysis this will be communicated to the Co-ordinating principal investigator who will then disseminate the information to the relevant parties, for example if the change in protocol requires participants to be notified then the clinical pharmacy team who are holding the master list will be notified by the CPI and they will then go about notifying each of the participants via the agreed format which the participant will indicate on their PICF. In the case of investigative staff requiring notification of protocol changes, this will be communicated with the team and if required then re-training or re-writing of protocol forms and an ethics amendment will be sought via the institutional ethics committee, this will need to take place prior to any further data collection occurring.

Personal information will be collected on a secure form (electronic or paper) that will be stored in the Tertiary hospital site record of the patient. The investigative team will be notified that there is new data by the collecting unit and this data will be retrieved electronically via a secure and encrypted connection to the data source. Once data analysis begins all data for the trial will be stored on secure servers for the duration of the analysis and for a period of 5 years after this according to Health department protocols

Once trial data has been analysed the outcome of the trial will be communicated via the participants preferred mode of contact, clinicians will be informed of the outcome of the trial via a dedicated meeting that will be held at the participating site. Data will be written up and published in peer-reviewed journals regardless of outcome in the trial and presented at national and international meetings of clinicians interested in the area of research ORN.