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

Phase 3

Not yet recruiting

• Conditions: Osteoradionecrosis of the Mandible; Osteoradionecrosis of Jaw; Osteoradionecrosis
• Interventions: Drug: sham mPENTOCLO; Drug: modified PENTOCLO (mPENTOCLO)

• Registration Number: NCT06055257
• Lead Sponsor: Sunnybrook Health Sciences Centre

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2023-09-06
• Study First Submitted QC: 2023-09-19
• Study First Posted: 2023-09-26
• Status Verified: 2024-03
• Last Update Submitted: 2024-04-02
• Last Update Posted: 2024-04-04
• Study Start: 2024-05-01
• Primary Completion: 2025-10
• Study Completion: 2025-11

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 24

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
• Negative Human Chronic Gonadotropin (hCG) screening test at baseline (for female patients of reproductive age not practicing medically acceptable methods of birth control (e.g., hormonal contraceptives, implants, injectables, intrauterine device (IUD), intrauterine system (IUS), vasectomy and bilateral tubal ligation)
• Baseline in-date ECG (within 60 days prior to enrolment)
• Age ≥ 18

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)
• Known QT prolongation as documented on an in-date ECG (within 60 days prior to enrolment)
• Currently on other drugs known to prolong the QT interval (e.g., erythromycin, cisapride, astemizole, pimozide or quinidine)
• History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin-clavulanate
• Moderate to severe liver disease (due potential for drug induced liver dysfunction)
• History of myasthenia gravis
• Patients with a history of nontraumatic tendon disorders or have experienced nontraumatic tendinitis or tendon rupture
• Patients who have previously experienced peripheral neuropathy due to exposure to antibiotics
• Smokers, high alcohol intake (average of >2 standard drinks per day), sepsis, severe undernourishment and severe immunodeficiency conditions (e.g. HIV, autoimmune disease, immune-compromised)
• Persistent or recurrent cancer and active neoplastic pathology will be excluded
• Patients with documented Vitamin K deficiency
• Patients taking additional Vitamin E
• Patients who have received previous anti-resorptive or anti-angiogenic medications
• Patients diagnosed with retinitis pigmentosa
• Patients diagnosed with clinically significant anemia

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 1 (Control)	sham mPENTOCLO	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.
Group 2 (Intervention)	modified PENTOCLO (mPENTOCLO)	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.

Primary Outcome Measures

Name	Time	Method
Recruitment and adherence to protocol (process)	Pilot study (including 12-month follow-up)	80% 12-month follow-up rate (20/24)
Feasibility (resource) - Time	Pilot study (including 12-month follow-up)	Investigators to keep logs of time required to perform study related work
Feasibility (resource) - Cost	Pilot study (including 12-month follow-up)	Cost of study including research support and healthcare resource costs per patient

Secondary Outcome Measures

Name	Time	Method
Recovery from ORN at one-year follow-up	12-month 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.
Time required to achieve recovery in patients	Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)	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.
Improvement and failure rates in patients treated in each group using an accepted clinical and radiographic scoring system:	Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)	Late Effects Normal Tissue Task Force-Subjective, Objective, Management and Analytic (LENT-SOMA) score
Complications that arise from treatment	Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)	Complications related to HBOT and/or mPENTOCLO, as defined in product monographs and study protocol.