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

NCT ID: NCT06055257

Last Updated: 2025-09-12

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-01-16
• Study Completion Date: 2027-12-31

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.

Conditions

Osteoradionecrosis; Osteoradionecrosis of Jaw; Osteoradionecrosis of the Mandible

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Group 1 (Control)

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 Type: PLACEBO_COMPARATOR

sham mPENTOCLO

Intervention Type: DRUG

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).

Group 2 (Intervention)

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.

Group Type: EXPERIMENTAL

modified PENTOCLO (mPENTOCLO)

Intervention Type: DRUG

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.

Interventions

modified PENTOCLO (mPENTOCLO)

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.

Intervention Type: DRUG

sham mPENTOCLO

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).

Intervention Type: DRUG

Other Intervention Names

PENtoxyphylline, TOcopherol, and CLOdronate; Placebo

Eligibility Criteria

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) are excluded. Patients with the QTc prolongation associated with a correctable cause (e.g., electrolyte imbalance or drug-induced), and corrected QTc prior to enrolment into the study as documented on 12 lead ECG will be eligible for inclusion
• Patients requiring concurrent use of medications known to significantly prolong the QT interval with a high risk of clinical impact (e.g., erythromycin, cisapride, astemizole, pimozide or quinidine) are excluded unless safe discontinuation or substitution of these medications is feasible prior to initiation of the study
• Patients on medication with a potential but low risk of QTc prolongation (e.g., ondansetron, SSRIs) may be included if a post-initiation ECG conducted within 24-48 hours of starting ciprofloxacin or fluconazole confirms that there is no significant QTc prolongation
• History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin-clavulanate
• Moderate to severe active liver disease (class B or C Pugh-Child Score) or active liver disease with significant acute elevation of LFT values
• History of myasthenia gravis
• Patients with a history of nontraumatic tendon disorders with severe functional impairment (i.e., significant swelling of the affected tendon, or partial tendon tear documented on clinical examination or imaging)
• 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 with concomitant prescription of anti-resorptive or anti-angiogenic medications (e.g. risedronate, alendronate, aIbandronate, zoledronic acid, pamidronate, etidronate or prescription of denosusamab, etc.)
• Patients diagnosed with retinitis pigmentosa
• Patients diagnosed with clinically significant anemia

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sunnybrook Health Sciences Centre

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ben Safa, MD

Role: PRINCIPAL_INVESTIGATOR

Sunnybrook Health Sciences Centre

Locations

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

Site Status: RECRUITING

Countries

Canada

Central Contacts

Ben Safa, MD

Role: CONTACT

ben.safa@sunnybrook.ca

416-480-4864 ext. 61307

Facility Contacts

Ben Safa

Role: primary

ben.safa@sunnybrook.ca

416 480 4864

Other Identifiers

pending

Identifier Type: -

Identifier Source: org_study_id