Award Title: RAPTOR: Randomised Controlled Trial of PENTOCLO in Mandibular Osteoradionecrosis
Funder: Medical Research Council

Abstract: Most treatments for head and neck cancer include radiotherapy, and despite advances in planning and doses, this leaves survivors at risk of significant late effects. One of the most severe complications is osteo-radio-necrosis ‘bone death caused by irradiation’. This can affect any bone or cartilage in the head and neck but is commonest in the lower jaw. ORN is characterized by exposure and crumbling of the jaw, severe pain, repeated infections, weight loss, restricted mouth opening, difficulty in chewing, and disfigurement._x000D_
Existing treatments include:_x000D_
i. supportive & conservative methods: long-term antibiotics, antiseptic mouthwash and painkillers_x000D_
ii. surgery, which may be curative but is risky, complex and has unpredictable outcomes._x000D_
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Some studies of osteoradionecrosis suggest that a combination of three medications (pentoxyphylline, tocopherol, and clodronate: PENTOCLO) may be capable of complete resolution without surgery. Healing in this way is through lifting off of the dead bone fragments leaving intact skin underneath. Some research suggests that just over half of patients get benefit, but this has yet to been proved, particularly in comparison with other treatments_x000D_
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This trial proposes to compare PENTOCLO medications against standard supportive medications such as antibiotics, mouthwash and painkillers. Patients will be selected at random for either of the two treatments for at least a year. The trial will also carefully measure pain, side-effects, the need for antibiotics and the instances where deterioration forces the need to resort to surgery instead._x000D_
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Discussion with patients during trial design has resulted in an increased emphasis within the protocol for collection of information on patients’ pain and other symptoms, and particularly in providing a ‘safety-net’ for those patients who are deteriorating. As a result, at 3-monthly clinic visits, patients will report their symptoms (pain, eating, mouth-opening, swelling) every 15 days via their smart device using an App.

Lay Abstract: Research question_x000D_
RAPTOR aims to establish the value of the repurposed drug combination Pentoxifylline, Tocopherol & Clodronate (termed PENTOCLO) in treating osteoradionecrosis (ORN) of the mandible._x000D_
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Background_x000D_
Osteoradionecrosis is a well-recognized and feared complication following curative treatment of head and neck cancer with radiotherapy.  There are no medical treatments with high level evidence to support their use and many patients deteriorate to the point where they need multiple hospital admissions, destructive removal of all necrotic bone and complex jaw and facial reconstruction. A combination of three repurposed drugs: pentoxifylline, tocopherol and clodronate has been suggested as being able to heal ORN in the majority of cases but requires at least 12 months treatment.  In successful cases it has stopped disease progression, improved symptoms and facilitated the exfoliation of necrotic bone. There have, to date, been no randomized trials, or trials making a comparison of PENTOCLO against control treatments, but single arm studies have been encouraging._x000D_
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Aims and objectives_x000D_
The aim of RAPTOR is to compare standard supportive care (SSC) against SSC plus PENTOCLO, measuring time-to-healing as primary endpoint.  The secondary endpoints are to measure patient symptoms, quality of life, SOMA, extent of necrotic bone, mandibular preservation rate._x000D_
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Methods_x000D_
RAPTOR is an unblinded randomised controlled trial where patients in the control arm receive standard supportive care dependent on symptoms including antibiotics, analgesia and antiseptic mouthwash.  In the treatment arm, patients additionally receive PENTOCLO and both arms are assessed at clinic visits every 3 months.  Blinded remote assessment of primary and secondary endpoints are supported by clinical photographs. Rich data on patients’ symptom burden are collected remotely using a dedicated App every 15 days throughout the trial._x000D_
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Timelines for delivery_x000D_
Following 6-months set up time, the trial will be opened with the aid of the national maxillofacial trainee collaborative (MTREC) which we believe may greatly facilitate recruitment. 15 sites will be selected, and recruitment is expected to take 24 months for a total study length of 48 months._x000D_
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Anticipated impact and dissemination_x000D_
For the first time, the activity of PENTOCLO will be robustly compared with a control group and these results will form the basis of future treatment decisions and / or to inform the necessity for a larger phase III trial in jaw osteoradionecrosis. The trial will also explore the use of an App to collect ePROM data which will inform its suitability for other trial applications.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS;MUSCULOSKELETAL