Assessing the Efficacy of a Carbamide Peroxide Mouthwash for Oral Wound Healing, Oral Hygiene and Xerostomia Relief

A Randomized Placebo-Controlled Clinical Trial Assessing the Efficacy of a Carbamide Peroxide Mouthwash for Oral Wound Healing, Postoperative Symptoms, Xerostomia Relief, and Oral Hygiene Following Diagnostic Biopsy of Minor Labial Salivary Glands for Sjögren's Syndrome Investigation

The aim of this study is to evaluate the efficacy and safety of a carbamide peroxide mouthwash regarding oral wound healing, postoperative symptoms, xerostomia (dry mouth) and oral hygiene improvement. Study participants have reported dry mouth and are scheduled for a diagnostic biopsy of minor labial salivary glands to investigate Sjögren's Syndrome, following consultation with their rheumatologist. This is a standardized diagnostic procedure that leads to healing by primary intention (i.e. wound edges are closely re-approximated with sutures).

Researchers are comparing this mouthwash with a placebo (a look-and-taste-alike substance that contains no active ingredients) to see if it is helpful with healing of wounds in the mouth and associated symptoms, improving dry mouth and/or oral hygiene. Carbamide peroxide breaks down to hydrogen peroxide and urea and shows antiseptic and antimicrobial properties and it might help with the parameters to be assessed. Participants randomly get the carbamide peroxide mouthwash or the placebo one to use for 14 days after the biopsy. The investigators will not know which one they are providing as the bottles will be identical.

Oral wound healing, postoperative symptoms (such as pain, eating and speech difficulties), oral hygiene (dental plaque and gingival inflammation), improvement of dry mouth and quality of life are assessed during a 14-day period after the biopsy. Participants are required to visit the clinic three times, one for the initial consultation and the biopsy, one at 7 days and one at 14 days after the biopsy. They are asked to fill in some questionnaires, while certain procedures (such as measuring saliva) and assessments (like evaluating the dental plaque and gingival inflammation) take place. During the first week they, also, keep a diary of their symptoms, as instructed.

This is a prospective, randomized, triple-blind, placebo-controlled clinical trial and post-market clinical follow-up (PMCF) study, expected to last approximately 12 months. All procedures/visits/examinations are taking place in the Oral Medicine and Pathology Clinic at the School of Dentistry, National and Kapodistrian University of Athens, Greece. Participants with reported dry mouth are scheduled for a diagnostic biopsy of minor labial salivary glands to investigate Sjögren's Syndrome, following consultation with their rheumatologist. This is a standardized diagnostic procedure that leads to healing by primary intention. After checking if they comply with the study's criteria, they are informed about the study and the biopsy procedure (including possible complications) and they sign the Ιnformed Consent Form.

All biopsies are obtained from the lower lip with a 12 - 15 mm linear incision. After blunt dissection of the borders, 5-7 lobules of minor salivary glands are removed by dissection with the scalpel or a curved mosquito forceps and the use of tweezers. Attention is paid not to injure nerve branches or vessels. Adequate hemostasis is achieved by manual pressure, and the incision is closed by simple interrupted non-absorbable 4/0 silk sutures at equal distances. Participants are instructed to have cold, soft diet for the day and use ice packs externally for 1-2 hours after the procedure. Use of 500mg paracetamol up to 3 times is permitted for day 0. Following their normal oral hygiene routine (brushing and toothpaste) is suggested.

Subsequently, they are assigned randomly in a 1:1 ratio to receive either a carbamide peroxide mouthwash or a placebo comparator, i.e. a look-alike substance that lacks active ingredients. Both participants and investigators are masked. Follow-up examinations are conducted at 7 and 14 days. On day 7 the sutures are cut.

The evaluation includes:

• oral wound healing (primary intention) assessed by scores (primary outcome)

and secondarily:

• oral wound healing via measuring the incision/wound length
• postoperative symptoms (such as pain, eating and speech difficulties)
• quality of life assessed by a questionnaire
• improvement of dry mouth through subjective and objective measurements
• oral hygiene via plaque and gingival indices.

All data are anonymized and the outcome assessors are masked.

The mouthwash used in the experinmental/test group is a Class IIa, CE-marked (Conformité Européenne) medical device. This mouthwash contains hydrogen carbamide that breaks down to hydrogen peroxide and urea. Hydrogen peroxide has antiseptic and antimicrobial properties, as well the ability to mechanically clean affected areas by producing an oxygenated foam, while urea shares antiseptic and antimicrobial abilities as well and can enhance the pH of the oral cavity. These substances have been used in wound healing either in skin or intraorally, as well as in oral hygiene for a long time. However, to date, no clinical trial examining the use of a hydrogen carbamide/peroxide product in oral wound healing, postoperative symptoms or dry mouth has been reported. Published clinical studies on the control of dental plaque and periodontal inflammation exhibit partially conflicting results.

Inclusion criteria

1. Age >18 years
2. Patients requiring lower lip salivary gland biopsy for investigation of Sjögren's syndrome
3. Patients with subjective dry mouth, i.e. who have recorded ≥30mm in at least one of the first 4 questions of the VAS (Visual Analogue Scale) questionnaire according to Pai et al, 2001
4. Able to use the study products (rinse - swish and spit)
5. Agreeing to abstain from the use of any products for xerostomia other than the products provided by the study.
6. Patients who are legally competent and able to understand the information about the study, have been informed of the nature, scope and utility of the study, voluntarily agree to participate and have signed the consent form.

Exclusion criteria

1. Age <18 years
2. Total number of teeth in the oral cavity <10
3. Existence of orthodontic appliances
4. Current use of bleaching trays
5. Presence or history of oral malignant lesions
6. Existence of viral or other infections of the oral cavity or pathology that could interfere with the primary outcomes of the study (e.g. oral vesicobullous disorders)
7. Currently undergoing and/or has received radiation therapy to the head or neck (including radioactive iodine therapy)
8. Currently receiving or has received within the previous 12 months chemotherapy and/or targeted therapies for any malignancy
9. History of acute myocardial infarction and/or vascular stroke during the last 6 months
10. Patients with poor glycemic control (HbA1c ≥ 7% within the previous 3 months according to American Diabetes Association (ADA) recommendations), uncontrolled type I or II diabetes mellitus or other systemic diseases known to affect oral wound healing
11. Use of antibiotics in the last 1 month prior to biopsy or conditions requiring antibiotic prophylaxis
12. Use of any antimicrobial mouthwash in the last 1 month before the biopsy
13. Concurrent immunocompromised status and/or use of immunosuppressant medications (e.g. corticosteroids) and steroid inhalers or nasal sprays within the last 1 month prior to enrollment
14. Use of sialagogues
15. Heavy smokers (those who smoke greater than or equal to 25 cigarettes per day) and tobacco chewers or users of tobacco pouches
16. Received dental treatment during the period included in the study
17. Malnutrition
18. Alcohol abuse and (illicit) drug use disorders
19. Pregnancy or lactation/nursing/breast feeding
20. Known allergy to any of the ingredients of the study products
21. Inability to provide informed consent
22. Participation in another study of an investigational product or device until the primary endpoint is met
23. Other medical condition that, in the opinion of the investigator, may be causing the patient's non-compliance with the clinical investigation plan or confusion in interpreting the data