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

Osteoradionecrosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06055257
• Other study ID #: pending
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: May 1, 2024
• Est. completion date: November 2025

Study information

• Verified date: March 2024
• Source: Sunnybrook Health Sciences Centre
• Contact: Ben Safa, MD
• Phone: 416-480-4864
• Email: ben.safa[@]sunnybrook.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 24
• Est. completion date: November 2025
• Est. primary completion date: October 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Osteoradionecrosis
• Osteoradionecrosis of Jaw

Intervention

Drug:
• 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.
• 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).

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Sunnybrook Health Sciences Centre

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Quality of Life questionnaire	Assessed using EQ-5D-5L questionnaire	Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)
Other	Xerostomia severity	Assessed using Xerostomia Inventory and/or Clinical Oral Dryness Score	Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)
Other	Opioid usage	Medications and dosages (oral morphine equivalents) currently being taken by participants at each scheduled follow-up	Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)
Other	ORN Pain	Assessed using Numerical Rating Scale (NRS) patient to rate their pain on scale of 0-10 where 0 is no pain and 10 is the worst pain imaginable	Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)
Primary	Recruitment and adherence to protocol (process)	Recruitment of two subjects per month on average over 12 months	Pilot study (including 12-month follow-up)
Primary	Recruitment and adherence to protocol (process)	At least 70% of all eligible patients are recruited	Pilot study (including 12-month follow-up)
Primary	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)
Primary	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)
Primary	Recruitment and adherence to protocol (process)	80% 12-month follow-up rate (20/24)	Pilot study (including 12-month follow-up)
Primary	Feasibility (resource) - Time	Investigators to keep logs of time required to perform study related work	Pilot study (including 12-month follow-up)
Primary	Feasibility (resource) - Cost	Cost of study including research support and healthcare resource costs per patient	Pilot study (including 12-month follow-up)
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)