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

NCT06055257 | Recruiting Phase 3

• 1 other identifier: pending
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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.

Conditions

Osteoradionecrosis; Osteoradionecrosis of Jaw; Osteoradionecrosis of the Mandible

Keywords

Osteoradionecrosis; ORN; PENtoxifylline, TOcopherol and CLOdronate; PENTOCLO; Hyperbaric Oxygen Therapy; HBOT; Head and Neck Cancer; Radiation Therapy

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (6)

• Recovery from ORN at one-year follow-up

  12-month follow-up

• 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)

• 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)

• 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)

• 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)

Other Outcomes (4)

• Quality of Life questionnaire

  Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)

• Xerostomia severity

  Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)

• Opioid usage

  Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)

Study Arms (2)

Group 1 (Control)

PLACEBO COMPARATOR

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

Group 2 (Intervention)

EXPERIMENTAL

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)

Interventions

modified PENTOCLO (mPENTOCLO) 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.

Also known as: PENtoxyphylline, TOcopherol, and CLOdronate

Group 2 (Intervention)

sham mPENTOCLO 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).

Also known as: Placebo

Group 1 (Control)

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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))
• 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

Sponsors & Collaborators

• Sunnybrook Health Sciences Centre: lead

Study Sites (1)

Sunnybrook Health Sciences Centre

Toronto, Ontario, M4N3M5, Canada

RECRUITING

MeSH Terms

Conditions

Osteoradionecrosis; Head and Neck Neoplasms

Interventions

Pentoxifylline; Tocopherols; Clodronic Acid

Condition Hierarchy (Ancestors)

Radiation Injuries; Wounds and Injuries; Neoplasms by Site; Neoplasms

Intervention Hierarchy (Ancestors)

Theobromine; Xanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Vitamin E; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals

Study Officials

• Ben Safa, MD

  Sunnybrook Health Sciences Centre

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ben Safa, MD

CONTACT

416-480-4864; ben.safa@sunnybrook.ca

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: One unblinded clinician will be required for management of side effects and dose adjustments of pentoxifylline and clodronate as required in the event of side effects or intolerance. However, all other participants including, patients, assessors, research team and data analysts will be blinded to group allocation. At standard follow-up examination, imaging and photographs will be taken and de-identified and then presented to a blinded oral and maxillofacial surgeon for EBA calculation and to a blinded radiologist for allocation of Notani classification grade.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Prospective, pilot, double blind, randomized (stratified to ORN stage), controlled trial

Study Record Dates

• First Submitted: September 6, 2023
• First Posted: September 26, 2023
• Study Start: January 16, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: September 12, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: This is a pilot trial and full inferential analysis will not be conducted until completion of the full trial. As such, data will be available following publication of the primary results of the subsequent full trial.
• Access Criteria: Data and supporting information will be made available following reasonable request directly to study PI.

Locations

CA (1)