OZOCLO_MUCOSITIS: a New Protocol for Prevention of Oral Mucositis

Phase 4

• Conditions: Mucositis (MeSH Unique ID: D052016); Stomatitis (MeSH Unique ID: D013280)
• Interventions: Drug: 3. chlorhexidine 0,2% - mouthwash; Drug: 4. sodium bicarbonate 5% solution - mouthwash; Drug: 1. alpha acid lipoic - tables; Drug: 2. ozonated oil - mouthwash

• Registration Number: NCT05211622
• Lead Sponsor: University of Palermo

Brief Summary

Oral mucositis (OM) is a significant side effect of cytotoxic anti-cancer chemotherapy and HN radiotherapy. CT-associated OM (CT-OM). It is the ulcerative phase that is most painful and associated with poor health outcomes. The sequelae of CT-OM, which include pain, odyno/dys-phagia, dysgeusia, decreased oral intake and systemic infection, frequently require treatment delays, interruptions, and discontinuations that not only negatively impact the quality of life but also tumor control and survivorship. To date, OM management is aimed to control symptoms through topical or systemic analgesics and topical application of barrier agents to cover injured mucosa as a salve or ointment. According to the recent MASCC/ISOO Clinical Practice Guidelines for the Management of Mucositis Secondary to Cancer Therapy, no guideline was possible regarding the use of saline or sodium bicarbonate rinses in the prevention or treatment of OM-CT in patients undergoing cancer therapy because of limited data.

Ozone at low medical concentration, not included in MASCC guidelines, will be generally proven to induce a mild activation of protective anti-oxidant pathways, thus exerting therapeutic effects in many inflammatory diseases.

Aim: to evaluate the effectiveness of a new protocol OZOCLO (alpha-lipoic acid, ozonated oil, and chlorhexidine \[CHX\] mouthwash) compared to sodium bicarbonate solution (Oral Basic Care- OBC) or chlorhexidine (CHX) mouthwash alone or to a binomial administration (AAL-OZ) of systemic alpha-lipoic acid and topical ozonated oil to reduce the incidence of OM (primary aim) and/or to postpone the beginning of oral mucositis (OM) and to reduce OM severity (secondary aims).

Detailed Description

Oral mucositis (OM) is a significant side effect of cytotoxic anti-cancer chemotherapy and HN radiotherapy. CT-associated OM (CT-OM) begins in the submucosa and becomes clinically on the surface about 4 days after infusion: typical primary manifestations are erythema, mucosal atrophy, and sensitivity. The process continues to deteriorate mucosae, and ulceration occurs a few days later, peaking at 2 weeks and persisting for 1-2 weeks after which it typically resolves spontaneously. It is the ulcerative phase that is most painful and associated with poor health outcomes. The sequelae of CT-OM, which include pain, odyno/dys-phagia, dysgeusia, decreased oral intake and systemic infection, frequently require treatment delays, interruptions, and discontinuations that not only negatively impact the quality of life but also tumor control and survivorship. To date, OM management is aimed to control symptoms through topical or systemic analgesics and topical application of barrier agents to cover injured mucosa as a salve or ointment. Although the investigators reviewed a large body of evidence, there are still, clinical settings for which there is no recommended intervention. According to the recent MASCC/ISOO Clinical Practice Guidelines for the Management of Mucositis Secondary to Cancer Therapy, no guideline was possible regarding the use of saline or sodium bicarbonate rinses in the prevention or treatment of OM-CT in patients undergoing cancer therapy because of limited data. Despite the limited data available for both saline and sodium bicarbonate, the panel recognizes that these are inert, bland rinses that increase oral clearance, which may help maintain oral hygiene and improve patient comfort. Also, CHX is indicated because of concurrent oral infection and OM, it is acceptable to use it for the oral infection.

Ozone at low medical concentration, not included in MASCC guidelines, will be generally proven to induce a mild activation of protective anti-oxidant pathways, thus exerting therapeutic effects in many inflammatory diseases.

Aim: to evaluate the effectiveness of a new protocol OZOCLO (alpha-lipoic acid, ozonated oil, and chlorhexidine \[CHX\] mouthwash) compared to sodium bicarbonate solution (Oral Basic Care- OBC) or chlorhexidine (CHX) mouthwash alone or to a binomial administration (AAL-OZ) of systemic alpha-lipoic acid and topical ozonated oil to reduce the incidence of OM (primary aim) and/or to postpone the beginning of oral mucositis (OM) and to reduce OM severity (secondary aims).

Study Timeline

• Status Verified: 2021-12
• Study First Submitted: 2021-12-14
• Study First Submitted QC: 2022-01-26
• Last Update Submitted: 2022-01-26
• Study First Posted: 2022-01-27
• Last Update Posted: 2022-01-27
• Study Start: 2022-03-10
• Primary Completion: 2022-12-31
• Study Completion: 2023-01-10

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 80

Inclusion Criteria

• Aged 18-80 years

• Planned to receive conventional chemotherapy such as:

  • CMF (cyclophosphamide (Endoxan), methotrexate, 5-FU))
  • Standard AC+T regimen (doxorubicin (Adriamycin)), cyclophosphamide (Endoxan), Taxane [paclitaxel (Taxol) or docetaxel (Taxotere)) or any combination of two or more components (e.g., ACT, TAC, TA, AT, AC)
  • ABVD (doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine)
  • FOLFIRI (irinotecan, 5-FU, leucovorin)
  • Any other 5-FU-based regimen

• Planned to receive at conventional new generation targeted agents (tyrosine-kinase inhibitors or monoclonal antibodies) such as cetuximab, axitinib, bevacizumab, sunitinib, and sorafenib, temsirolimus, everolimus, vemurafenib, dabrafenib.

• Be willing and able to complete all study-related activities

• Properly obtained written informed consent

Exclusion Criteria

• Receiving any oxaliplatin-containing chemotherapy regimen, such as FOLFOX
• Concurrent radiotherapy
• Unable or unwilling to complete study assessments
• Concurrent participation in another interventional clinical study or use of another investigational agent within 30 days before randomization
• Any other clinical or psychiatric condition or prior therapy that, in the opinion of the investigator, would make the patient unsuitable for the study or unable to comply with the protocol
• Chronic use of opioid analgesics

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Group III, CHX	3. chlorhexidine 0,2% - mouthwash	• Group III, CHX Chlorhexidine 0,2% - mouthwash (1 minute- three times/die after oral hygiene, possibly) from five days after the beginning of chemotherapy and for subsequent 2 weeks
Group I, OZOCLO	3. chlorhexidine 0,2% - mouthwash	• Group I, OZOCLO 1. alpha acid lipoic - 600 mg/die per os from 7 days before the beginning of chemotherapy and continue for other 4 days 2. ozonated oil - mouthwash (1 minute- three times/die after oral hygiene, possibly) from the beginning of chemotherapy and for 2 weeks 3. chlorhexidine 0,2% - mouthwash (1 minute- three times/die after oral hygiene, possibly) from five days after the beginning of chemotherapy and for subsequent 2 weeks
Group II, OBC	4. sodium bicarbonate 5% solution - mouthwash	• Group II, OBC Sodium bicarbonate 5% solution - mouthwash (1 minute- three times/die after oral hygiene, possibly) from the beginning of chemotherapy and for 3 weeks
Group IV, AAL-OZ	1. alpha acid lipoic - tables	• Group IV, AAL-OZ 1. alpha acid lipoic - 600 mg/die per os from 7 days before the beginning of chemotherapy and continue for other 4 days 2. ozonated oil - mouthwash (1 minute- three times/die after oral hygiene, possibly) from the beginning of chemotherapy and for 2 weeks
Group IV, AAL-OZ	2. ozonated oil - mouthwash	• Group IV, AAL-OZ 1. alpha acid lipoic - 600 mg/die per os from 7 days before the beginning of chemotherapy and continue for other 4 days 2. ozonated oil - mouthwash (1 minute- three times/die after oral hygiene, possibly) from the beginning of chemotherapy and for 2 weeks
Group I, OZOCLO	1. alpha acid lipoic - tables	• Group I, OZOCLO 1. alpha acid lipoic - 600 mg/die per os from 7 days before the beginning of chemotherapy and continue for other 4 days 2. ozonated oil - mouthwash (1 minute- three times/die after oral hygiene, possibly) from the beginning of chemotherapy and for 2 weeks 3. chlorhexidine 0,2% - mouthwash (1 minute- three times/die after oral hygiene, possibly) from five days after the beginning of chemotherapy and for subsequent 2 weeks
Group I, OZOCLO	2. ozonated oil - mouthwash	• Group I, OZOCLO 1. alpha acid lipoic - 600 mg/die per os from 7 days before the beginning of chemotherapy and continue for other 4 days 2. ozonated oil - mouthwash (1 minute- three times/die after oral hygiene, possibly) from the beginning of chemotherapy and for 2 weeks 3. chlorhexidine 0,2% - mouthwash (1 minute- three times/die after oral hygiene, possibly) from five days after the beginning of chemotherapy and for subsequent 2 weeks

Primary Outcome Measures

Name	Time	Method
Change of OM incidence	7th, 14th, and the 21st day after application of the interventions	In order to demonstrate whether the new protocol OZOCLO determines change of the incidence of OM compared to sodium bicarbonate solution (OBC) or chlorhexidine (CHX) mouthwash alone or the binomial AAL-OZ combination, in patients treated with chemotherapy regimens.

Secondary Outcome Measures

Name	Time	Method
Delay onset of OM	7th, 14th, and the 21st day after application of the interventions	In order to determine whether the new protocol OZOCLO determines a delay of onset for OM, considering that it currently begins at 7th day, compared to sodium bicarbonate solution (OBC) or chlorhexidine (CHX) mouthwash alone or a binomial administration of systemic alpha-lipoic acid and topical ozonated oil.