Combination Therapy: Hyperbaric Oxygen and PENTOCLO for Treatment of Osteoradionecrosis of the Mandible

Study Overview
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Brief Summary
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Radiation is commonly used to treat cancer in the head and neck, however, this can lead to a serious complication called osteoradionecrosis (ORN), where there is necrotic (dead) open bone inside or outside of the mouth. This complication is difficult to treat, involves large healthcare costs, and can have devastating effects on quality of life. Two common adjuncts used in treatment of ORN are hyperbaric oxygen therapy (HBOT), which may requires up to 60 treatments at a specialized clinic where patients are treated with high concentrations of oxygen using special chambers, and a less complex option called PENTOCLO which involves treating patients with several antibiotics followed by a combination of other oral medications taken for at least 1 year. This pilot study will be guide the design of a definitive trial to examine if the combination of HBOT and a modified PENTOCLO protocol together is better than the current standard treatment of HBOT alone. Outcomes will include pain, side effects and the need for surgery in patients with ORN. Specifically, the results of this small, pilot study will help to inform the design of a future larger study.

Detailed Description
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Osteoradionecrosis (ORN) of the mandible is a potentially devastating complication which can occur following radiation therapy for head and neck cancers. ORN is difficult to treat using standard methods, and is associated with high healthcare costs and potentially dire impacts on quality of life. In addition to conservative measures (e.g. antibiotics, local irrigation, oral care) and surgical management, there are two established adjuvant treatments for ORN: hyperbaric oxygen therapy (HBOT) and an oral regimen called PENTOCLO, which consists of pre-treatment with oral antibiotics followed by prolonged treatment with a combination of PENtoxifylline, TOcopherol (Vitamin E) and CLOdronate. This will be the first study to investigate the potential benefits of combining HBOT and a modified PENTOCLO regimen for treatment of ORN. This study is a prospective, pilot, open label, outcome blinded, randomized controlled trial where participants with a confirmed diagnosis of mandibular ORN will be randomized (1:1 in blocks of 4, stratified by ORN stage) to receive either the standard HBOT treatment or HBOT plus a modified PENTOCLO regimen. The primary objective of this pilot trial is to determine feasibility of a larger definitive trial by assessing recruitment, adherence to the interventional protocol, ability to achieve 12 months follow up, feasibility of completing outcome measures, and study costs (including research support and healthcare resources costs per patient). Clinical outcomes including improvement or worsening of ORN of the mandible after 12-month treatment will also be assessed. Participants will be followed for 12 months from the start of treatment, with follow-ups at 4 weeks, 5/6 weeks, and 3, 6, 9, and 12 months to assess pain scores, ORN characteristics, quality of life and adverse events.

Official Title
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Combination Therapy: Hyperbaric Oxygen and PENTOCLO for Treatment of Osteoradionecrosis of the Mandible, a Pilot Randomized Control Trial

Conditions
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Osteoradionecrosis, Osteoradionecrosis of Jaw, Osteoradionecrosis of the Mandible

Intervention / Treatment
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* Drug: modified PENTOCLO (mPENTOCLO)
* Drug: sham mPENTOCLO


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of mandibular ORN after completion of radiotherapy ORN will be defined as an area of exposed devitalized irradiated bone (> 20 mm2); minor bone spicules (MBS) (< 20 mm2) in the absence of radiographic abnormality, will be considered clinically insignificant Has no contraindications for undergoing hyperbaric oxygen therapy as assessed by a Hyperbaric Physician, and is willing to commit the time to undergo 60 sessions Exclusion Criteria: Inability to give informed consent Previous treatment for ORN (PENTOCLO, HBOT or surgery) Major surgical procedure planned (more extensive than sequestrectomy) Severe trismus and inability to obtain intraoral photographs Contraindications for HBOT: pneumothorax, bullous disease, uncontrolled hypertension, uncontrolled epilepsy, claustrophobia Contraindications to mPENTOCLO: inability to swallow medication; pregnancy or lactating; allergy to any study drug; currently on oral anticoagulants; hemorrhagic/coagulation disorder; Vitamin K deficiency; active unresolved cardiac disease; severe liver or kidney disease (CrCl < 30 mL/min)
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, pilot, double blind, randomized (stratified to ORN stage), controlled trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Group 1 (Control)<br>Standard of care treatment for ORN consisting of conservative measures (e.g. local irrigation, antiseptic mouthwash) and approximately 60 hyperbaric oxygen therapy (HBOT) treatments (90 minute exposures at 2.4 ATA each, scheduled Monday to Friday for 12 weeks - i.e., 5 treatments per week). At the conclusion of the study and at the discretion of the clinical team, patients randomized to the control group with residual disease may be considered for the mPENTOCLO protocol. Simultaneously, the 4-week mPENTOCLO pre-treatment phase will be started (as defined in the intervention section), followed by a sham/placebo mPENTOCLO treatment phase for a total of 12 months. | Drug: sham mPENTOCLO<br>* 4-week pre-treatment phase consisting of 2 g daily of Amoxicillin+Clavulanic acid 875/125 mg (1 g morning and night), 1 g ciprofloxacin (500 mg morning and night) and 50 mg Fluconazole daily (morning), taken orally by the patient. This is followed by an additional 11 months (12 months total) of sham treatment phase (placebo).<br>* Other names: Placebo;|
| Experimental: Group 2 (Intervention)<br>Standard of care treatment as described for the control group (conservative measures and 60 HBOT treatments). Simultaneously, a comprehensive oral regimen (mPENTOCLO) will be started, including a 4-week pre-treatment phase followed by a treatment phase for a total of 12 months, as defined in the Intervention section. | Drug: modified PENTOCLO (mPENTOCLO)<br>* 4-week pre-treatment phase consisting of 2 g daily of Amoxicillin+Clavulanic acid 875/125 mg (1 g morning and night), 1 g ciprofloxacin (500 mg morning and night) and 50 mg Fluconazole daily (morning), taken orally by the patient. This is followed by an additional 11 months (12 months total) treatment phase consisting of 800 mg pentoxifylline (400 mg morning and night) and 800 IU tocopherol (400 IU morning and night) taken orally 5 days per week (Monday to Friday with no medications on Saturday and Sunday). If the patient deteriorates (i.e., worsening of ORN T 6 or 9-month follow-up) then clodronate 1600 mg once daily (Monday to Friday) for the rest of the study period will be added.<br>* Other names: PENtoxyphylline, TOcopherol, and CLOdronate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recruitment and adherence to protocol (process) | Recruitment of two subjects per month on average over 12 months | Pilot study (including 12-month follow-up) | 
| Recruitment and adherence to protocol (process) | At least 70% of all eligible patients are recruited | Pilot study (including 12-month follow-up) | 
| Recruitment and adherence to protocol (process) | More than 80% of all recruited subjects complete 60 sessions of HBOT (20/24) | Pilot study (including 12-month follow-up) | 
| Recruitment and adherence to protocol (process) | More than 80% of patients in mPENTOCLO group complete mPENTOCLO protocol (10/12) | Pilot study (including 12-month follow-up) | 
| Recruitment and adherence to protocol (process) | 80% 12-month follow-up rate (20/24) | Pilot study (including 12-month follow-up) | 
| Feasibility (resource) - Time | Investigators to keep logs of time required to perform study related work | Pilot study (including 12-month follow-up) | 
| Feasibility (resource) - Cost | Cost of study including research support and healthcare resource costs per patient | Pilot study (including 12-month follow-up) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recovery from ORN at one-year follow-up | Proportion of patients reaching recovery within the study period in each group. Recovery will be defined as the absence of pain, pathologic fracture, and cutaneous fistula; exposed bone area (EBA) less than 20 mm2; and by evidence of stabilization or regression on radiographic findings (Notani classification score). Minor bone spicules of less than 20 mm2 that have no ongoing pain, and no radiographic abnormalities will be considered fully healed and not Notani grade 1. | 12-month follow-up | 
| Time required to achieve recovery in patients | Difference in time required to reach recovery in each group. Recovery will be defined as the absence of pain, pathologic fracture, and cutaneous fistula; exposed bone area (EBA) less than 20 mm2; and by evidence of stabilization or regression on radiographic findings (Notani classification score). Minor bone spicules of less than 20 mm2 that have no ongoing pain, and no radiographic abnormalities will be considered fully healed and not Notani grade 1. | Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months) | 
| Improvement and failure rates in patients treated in each group using an accepted clinical and radiographic scoring system: | Exposed bone area (EBA) | Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months) | 
| Improvement and failure rates in patients treated in each group using an accepted clinical and radiographic scoring system: | Notani Classification Score I ORN confined to dentoalveolar bone II ORN limited to dentoalveolar bone or mandible above the inferior dental canal, or both III ORN involving the mandible below the inferior dental canal, or pathological fracture, or skin fistula | Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months) | 
| Improvement and failure rates in patients treated in each group using an accepted clinical and radiographic scoring system: | Late Effects Normal Tissue Task Force-Subjective, Objective, Management and Analytic (LENT-SOMA) score | Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months) | 
| Complications that arise from treatment | Complications related to HBOT and/or mPENTOCLO, as defined in product monographs and study protocol. | Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteoradionecrosis, ORN, PENtoxifylline, TOcopherol and CLOdronate, PENTOCLO, Hyperbaric Oxygen Therapy, HBOT, Head and Neck Cancer, Radiation Therapy