OZOCLO_MUCOSITIS: a New Protocol for Prevention of Oral Mucositis

Study Overview
=================
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).

Official Title
-----------------
OZOCLO: a Randomized Clinical Trial for Prevention of Oral Mucositis

Conditions
-----------------
Mucositis (MeSH Unique ID: D052016), Stomatitis (MeSH Unique ID: D013280)

Intervention / Treatment
-----------------
* Drug: 1. alpha acid lipoic - tables
* Drug: 2. ozonated oil - mouthwash
* Drug: 3. chlorhexidine 0,2% - mouthwash
* Drug: 4. sodium bicarbonate 5% solution - mouthwash


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Patients will be randomly using a table of random numbers (allocation ratio 1:1:1:1). Arm I, OZOCLO alpha acid lipoic - 600 mg/die per os from 7 days before the beginning of chemotherapy and for other 4 die ozonated oil - mouthwash (1 minute- three times/die) for 2 weeks chlorhexidine 0,2% - mouthwash (1 minute- three times/die) from five days after the beginning and for other 2 weeks Arm II, OBC Sodium bicarbonate 5% solution - mouthwash (1 minute- three times/die) for 3 weeks Arm III, CHX Chlorhexidine 0,2% - mouthwash (1 minute- three times/die) from five days after the beginning and for other 2 weeks Arm IV, AAL-OZ alpha acid lipoic - 600 mg/die per os from 7 days before the beginning and continue for other 4 die ozonated oil - mouthwash (1 minute- three times/die) from the beginning and for 2 weeks Every interventional arm will be conducted by the patient at home according to indications and will monitored at 8th, 15th, and the 21st day
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I, OZOCLO<br>• Group I, OZOCLO alpha acid lipoic - 600 mg/die per os from 7 days before the beginning of chemotherapy and continue for other 4 days ozonated oil - mouthwash (1 minute- three times/die after oral hygiene, possibly) from the beginning of chemotherapy and for 2 weeks 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 | Drug: 1. alpha acid lipoic - tables<br>* 600 mg/die per os from 7 days before the beginning of chemotherapy and continue for other 4 days<br>* Other names: alpha acid lipoic - tables;Drug: 2. ozonated oil - mouthwash<br>* 1 minute- three times/die after oral hygiene, possibly, from the beginning of chemotherapy and for 2 weeks<br>* Other names: ozonated oil - mouthwash;Drug: 3. chlorhexidine 0,2% - mouthwash<br>* 1 minute- three times/die after oral hygiene, possibly, from five days after the beginning of chemotherapy and for subsequent 2 weeks<br>* Other names: chlorhexidine 0,2% - mouthwash;|
| Placebo Comparator: Group II, OBC<br>• 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 | Drug: 4. sodium bicarbonate 5% solution - mouthwash<br>* 1 minute- three times/die after oral hygiene, possibly, from the beginning of chemotherapy and for 3 weeks<br>* Other names: sodium bicarbonate 5% solution - mouthwash;|
| Active Comparator: Group III, CHX<br>• 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 | Drug: 3. chlorhexidine 0,2% - mouthwash<br>* 1 minute- three times/die after oral hygiene, possibly, from five days after the beginning of chemotherapy and for subsequent 2 weeks<br>* Other names: chlorhexidine 0,2% - mouthwash;|
| Active Comparator: Group IV, AAL-OZ<br>• Group IV, AAL-OZ alpha acid lipoic - 600 mg/die per os from 7 days before the beginning of chemotherapy and continue for other 4 days ozonated oil - mouthwash (1 minute- three times/die after oral hygiene, possibly) from the beginning of chemotherapy and for 2 weeks | Drug: 1. alpha acid lipoic - tables<br>* 600 mg/die per os from 7 days before the beginning of chemotherapy and continue for other 4 days<br>* Other names: alpha acid lipoic - tables;Drug: 2. ozonated oil - mouthwash<br>* 1 minute- three times/die after oral hygiene, possibly, from the beginning of chemotherapy and for 2 weeks<br>* Other names: ozonated oil - mouthwash;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of OM incidence | 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. | 7th, 14th, and the 21st day after application of the interventions | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delay onset of OM | 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. | 7th, 14th, and the 21st day after application of the interventions |