E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Osteoradionecrosis (ORN) of the irradiated mandible; the most feared complication of radiotherapy for head and neck cancer. |
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E.1.1.1 | Medical condition in easily understood language |
If you have head and neck cancer, you may have radiotherapy. Sometimes this treatment can damage your jaw bone (you have ‘osteoradionecrosis’ or ‘ORN’). |
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E.1.1.2 | Therapeutic area | Diseases [C] - Mouth and tooth diseases [C07] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064658 |
E.1.2 | Term | Osteonecrosis of jaw |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | 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). |
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E.2.2 | Secondary objectives of the trial |
Secondary Outcomes:
1. The diagnosis of osteoradionecrosis at 3 and 12 months (in the same way as the 6 month outcome)
2. Severity of cases of diagnosed osteoradionecrosis, according to Notani grade
3. Pain: patient questionnaire at baseline, 3, 6 and 12 months
4. 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)
5. Implant survival and outcome of MBS
Safety Outcomes:
1. Adverse events in HBO arm related to hyperbaric oxygen treatment
2. 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.
3. New Diagnosis of cancer, either recurrent or new site within 12 months following surgery |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Anticipated translational research facilitated by collection of EDTA blood samples for genotyping for patients in both arms of the HOPON trial.
Blood collection will be arranged at the time of surgery in both HBO and non-HBO arms of the trial for all patients. |
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E.3 | Principal inclusion criteria |
1. Age > 18 years
2. Prior history of external beam radiotherapy (dose > 50Gy) to mandible or prior history of brachytherapy with equivalent radiation dose as above.
3. No evidence of cancer recurrence
4. New diagnosis of condition requiring surgery to mandible (commonest examples but not limited to: dental extraction, implant placement, surgical tooth, cyst or osteosynthesis plate removal)
5. Patient has read and understood information leaflet and is willing to be randomised.
6. Patient competent to consent and psychologically / physically fit for HBO.
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E.4 | Principal exclusion criteria |
1. Known contraindications to HBO:
a. Lung disease: Chronic obstructive airways disease; bullous lung disease, acute or chronic pulmonary infection; uncontrolled asthma, untreated pneumothorax
b. Middle ear disease; previous middle ear operations, eustachian tube dysfunction or recurrent attacks of vertigo
2. Prior hyperbaric oxygen therapy
3. Prior diagnosis of osteoradionecrosis of the mandible
4. Previous surgery for osteoradionecrosis
5. Any history of systemic bisphosphonate therapy, pentoxyphylline or tocopherol.
6. Pregnancy
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Outcome:
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). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary endpoint will be evaluated at six months following surgery. |
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E.5.2 | Secondary end point(s) |
Secondary Outcomes:
1. The diagnosis of osteoradionecrosis at 3 and 12 months (in the same way as the 6 month outcome)
2. Severity of cases of diagnosed osteoradionecrosis, according to Notani grade
3. Pain: patient questionnaire at baseline, 3, 6 and 12 months
4. 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)
5. Implant survival and outcome of MBS
Safety Outcomes:
1. Adverse events in HBO arm related to hyperbaric oxygen treatment
2. 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.
3. New Diagnosis of cancer, either recurrent or new site within 12 months following surgery |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Diagnosis of ORN and at 3 and 12 months following surgery
2. Severity of ORN at 3, 6 and 12 months.
3. Pain Assessment at 3, 6 and 12 months.
4. Quality of Life at 3, 6 and 12 months.
5. Adverse Events at 3, 6 and 12 months
6.Admissions, operations, complications at 3, 6 and 12 months.
7. Mortality (any time in study)
8. 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.
9. New Diagnosis of cancer, either recurrent or new site within 12 months following surgery
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Standard treatment with oral antibiotics and mouthwash |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 30 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial is defined as the last visit of the last patient randomised on to the trial. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 9 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 9 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |