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

Primary Purpose

Osteoradionecrosis, Osteoradionecrosis of Jaw, Osteoradionecrosis of the Mandible

Status
Not yet recruiting
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
modified PENTOCLO (mPENTOCLO)
sham mPENTOCLO
Sponsored by
Sunnybrook Health Sciences Centre
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Osteoradionecrosis focused on measuring Osteoradionecrosis, ORN, PENtoxifylline, TOcopherol and CLOdronate, PENTOCLO, Hyperbaric Oxygen Therapy, HBOT, Head and Neck Cancer, Radiation Therapy

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Placebo Comparator

    Experimental

    Arm Label

    Group 1 (Control)

    Group 2 (Intervention)

    Arm Description

    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.

    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.

    Outcomes

    Primary Outcome Measures

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

    Secondary Outcome Measures

    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.
    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.
    Improvement and failure rates in patients treated in each group using an accepted clinical and radiographic scoring system:
    Exposed bone area (EBA)
    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
    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
    Complications that arise from treatment
    Complications related to HBOT and/or mPENTOCLO, as defined in product monographs and study protocol.

    Full Information

    First Posted
    September 6, 2023
    Last Updated
    September 19, 2023
    Sponsor
    Sunnybrook Health Sciences Centre
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    1. Study Identification

    Unique Protocol Identification Number
    NCT06055257
    Brief Title
    Combination Therapy: Hyperbaric Oxygen and PENTOCLO for Treatment of Osteoradionecrosis of the Mandible
    Official Title
    Combination Therapy: Hyperbaric Oxygen and PENTOCLO for Treatment of Osteoradionecrosis of the Mandible, a Pilot Randomized Control Trial
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    September 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    October 2023 (Anticipated)
    Primary Completion Date
    October 2025 (Anticipated)
    Study Completion Date
    November 2025 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Sunnybrook Health Sciences Centre

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No

    5. Study Description

    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    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

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Model Description
    Prospective, pilot, double blind, randomized (stratified to ORN stage), controlled trial
    Masking
    ParticipantInvestigatorOutcomes Assessor
    Masking Description
    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.
    Allocation
    Randomized
    Enrollment
    24 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Group 1 (Control)
    Arm Type
    Placebo Comparator
    Arm Description
    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.
    Arm Title
    Group 2 (Intervention)
    Arm Type
    Experimental
    Arm Description
    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.
    Intervention Type
    Drug
    Intervention Name(s)
    modified PENTOCLO (mPENTOCLO)
    Other Intervention Name(s)
    PENtoxyphylline, TOcopherol, and CLOdronate
    Intervention Description
    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
    Intervention Name(s)
    sham mPENTOCLO
    Other Intervention Name(s)
    Placebo
    Intervention Description
    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).
    Primary Outcome Measure Information:
    Title
    Recruitment and adherence to protocol (process)
    Description
    Recruitment of two subjects per month on average over 12 months
    Time Frame
    Pilot study (including 12-month follow-up)
    Title
    Recruitment and adherence to protocol (process)
    Description
    At least 70% of all eligible patients are recruited
    Time Frame
    Pilot study (including 12-month follow-up)
    Title
    Recruitment and adherence to protocol (process)
    Description
    More than 80% of all recruited subjects complete 60 sessions of HBOT (20/24)
    Time Frame
    Pilot study (including 12-month follow-up)
    Title
    Recruitment and adherence to protocol (process)
    Description
    More than 80% of patients in mPENTOCLO group complete mPENTOCLO protocol (10/12)
    Time Frame
    Pilot study (including 12-month follow-up)
    Title
    Recruitment and adherence to protocol (process)
    Description
    80% 12-month follow-up rate (20/24)
    Time Frame
    Pilot study (including 12-month follow-up)
    Title
    Feasibility (resource) - Time
    Description
    Investigators to keep logs of time required to perform study related work
    Time Frame
    Pilot study (including 12-month follow-up)
    Title
    Feasibility (resource) - Cost
    Description
    Cost of study including research support and healthcare resource costs per patient
    Time Frame
    Pilot study (including 12-month follow-up)
    Secondary Outcome Measure Information:
    Title
    Recovery from ORN at one-year follow-up
    Description
    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 Frame
    12-month follow-up
    Title
    Time required to achieve recovery in patients
    Description
    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.
    Time Frame
    Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)
    Title
    Improvement and failure rates in patients treated in each group using an accepted clinical and radiographic scoring system:
    Description
    Exposed bone area (EBA)
    Time Frame
    Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)
    Title
    Improvement and failure rates in patients treated in each group using an accepted clinical and radiographic scoring system:
    Description
    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
    Time Frame
    Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)
    Title
    Improvement and failure rates in patients treated in each group using an accepted clinical and radiographic scoring system:
    Description
    Late Effects Normal Tissue Task Force-Subjective, Objective, Management and Analytic (LENT-SOMA) score
    Time Frame
    Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)
    Title
    Complications that arise from treatment
    Description
    Complications related to HBOT and/or mPENTOCLO, as defined in product monographs and study protocol.
    Time Frame
    Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)
    Other Pre-specified Outcome Measures:
    Title
    Quality of Life questionnaire
    Description
    Assessed using EQ-5D-5L questionnaire
    Time Frame
    Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)
    Title
    Xerostomia severity
    Description
    Assessed using Xerostomia Inventory and/or Clinical Oral Dryness Score
    Time Frame
    Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)
    Title
    Opioid usage
    Description
    Medications and dosages (oral morphine equivalents) currently being taken by participants at each scheduled follow-up
    Time Frame
    Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)
    Title
    ORN Pain
    Description
    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
    Time Frame
    Assessed at each scheduled follow-up (4 weeks, 5/6 weeks, and 3, 6, 9 and 12 months)

    10. Eligibility

    Sex
    All
    Accepts Healthy Volunteers
    No
    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 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)
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Ben Safa, MD
    Phone
    416-480-4864
    Ext
    61307
    Email
    ben.safa@sunnybrook.ca
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Ben Safa, MD
    Organizational Affiliation
    Sunnybrook Health Sciences Centre
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    De-identified participant-level data will be made available upon reasonable request to study PI following publication of full trial results.
    IPD Sharing 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.
    IPD Sharing Access Criteria
    Data and supporting information will be made available following reasonable request directly to study PI.

    Learn more about this trial

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

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