A randomised clinical trial to assess maintenance of gingival health by a novel gel to foam dentifrice containing 0.1%w/w o-cymen-5-ol, 0.6%w/w zinc chloride

ORIGINAL ARTICLE

International Dental Journal 2011; 61 (Suppl. 3): 13–20 doi: 10.1111/j.1875-595X.2011.00044.x

A randomised clinical trial to assess maintenance of gingival health by a novel dentifrice containing 0.1%w⁄w o-cymen-5-ol and 0.6%w⁄w zinc chloride Ashish Kakar1, Evelyn E. Newby2, Kanupriya Kakar1, Siddhartha Ghosh3, Darren Targett2 and Mary Lynn Bosma2 1 Global Health Research Group, New Delhi, India; 2GlaxoSmithKline Consumer Healthcare, Weybridge, UK; 3GlaxoSmithkline Asia Private Ltd., Gurgaon, India.

Objectives: To assess the ability of 0.1%w ⁄ w o-cymen-5-ol ⁄ 0.6%w ⁄ w zinc chloride dentifrice to maintain gingival health compared to a sodium fluoride control dentifrice. Design: Following a baseline examination, subjects went through a regimen to bring them to a high level of gingival health. This included a professional prophylaxis supported by oral hygiene instruction prior to commencing study treatment. Subjects brushed twice daily for 12 weeks with either the test or control dentifrice. Examinations for gingival inflammation (MGI), bleeding and plaque were performed after 6 and 12 weeks. Results: 224 subjects were included in the efficacy analysis. Relative to the sodium fluoride ⁄ silica control dentifrice group the o-cymen-5-ol ⁄ zinc chloride dentifrice exhibited statistically significant reductions (p < 0.0001) in MGI, bleeding and plaque of 12.3%, 18.5% and 13.2% respectively after six weeks and 38.1%, 37.8% and 24.2% after 12 weeks. Conclusion: The results of the present clinical study demonstrate that the use of the 0.1%w ⁄ w o-cymen-5-ol ⁄ 0.6%w ⁄ w zinc chloride dentifrice over a 12 week period provides a statistically significant benefit in maintaining gingival health compared to a sodium fluoride control dentifrice. Key words: Dentifrice, gingival health, zinc chloride

Gingivitis is a commonly occurring gingival disease characterised by accumulation of bacterial plaque leading to reversible inflammation along the gingival margin. If left untreated, gingivitis may lead to the more serious irreversible disease periodontitis. It is recognised that the presence of dental plaque is a precursor to gingivitis and that gingivitis can be significantly reversed through adequate control of dental plaque1. It is widely accepted that keeping the teeth free of dental plaque by a thorough oral hygiene regimen is key to maintaining oral health2–4. However, removing sufficient dental plaque mechanically simply by brushing, particularly from those sites in the mouth which are less accessible with a toothbrush is technically difficult and time consuming. The introduction of antimicrobial ingredients in oral care products to help control dental plaque is now widespread5,6. Such agents including triclosan, zinc salts and stannous are discussed in reviews by Brading and Marsh7, Eley8 and further by Pizzey9. The most effective means of controlling dental plaque is through professional dental prophylaxis. This has been ª 2011 FDI World Dental Federation

shown to be highly effective in reducing gingivitis10. Sturzenberger11 reported that the greatest effect of a dental prophylaxis on gingivitis can be observed 7 to 10 days after treatment, following this gingivitis increased with the recurrence of dental plaque. In healthy patients, the typical time period between dental cleanings is six months. It is highly desirable to have products that will help to maintain the healthy state obtained from professional dental cleanings between these visits. Typically, evaluation of efficacy of over the counter antigingivitis toothpastes is carried out in studies where subjects undergo a dental prophylaxis at baseline and then immediately start to use the study treatment12–14. The effect of the dental prophylaxis itself during these studies is unknown as comparisons are made relative to baseline (pre-prophylaxis) gingivitis scores without separately evaluating the effect of the prophylaxis. In order to truly assess the ability of a dentifrice to maintain the level of gingival health obtained from dental prophylaxis, it is important to utilise a clinical study design where subjects are first brought to their optimum gingival health prior to commencing study 13

Kakar et al. treatment. Other researchers have utilised clinical study designs which employed a ‘pre-experimental phase’ where subjects were brought to an improved level of gingival health prior to study treatment. Svatun15,16 demonstrated that a dentifrice containing zinc citrate was able to maintain gingival health to a greater extent than a control dentifrice in student nurses over a one year period. The study design employed a dental prophylaxis at baseline followed by a 4-week preexperimental phase of oral hygiene instruction to bring subjects to a pre-determined level of gingival health based on number of bleeding sites. Gordon17 compared Listerine antiseptic mouthrinse to an essential oil free mouthrinse vehicle control and water in a nine month maintenance of gingival health clinical study. The study design employed a four week pre-experimental phase where subjects underwent multiple dental prophylaxes to optimise their gingival health prior to treatment. The findings of this study indicated that Listerine antiseptic mouthrinse significantly reduced the development of plaque at 1, 3, 6 and 9 months and the development of gingivitis at nine months as compared to its vehicle control or water rinses. Gordon did not observe a significant difference between the test and control mouthrinses in gingivitis until the nine month visit despite an earlier study by Lamster13 which had shown a significant effect on gingivitis after 1, 3 and 6 months for the same product. Gordon hypothesised that this was due the low levels of gingivitis from the preexperimental phase in their study compared to the study of Lamster. Despite the slightly different approaches to obtaining improved gingival health through a preexperimental phase, both Svatun and Gordon observed a significant improvement in their studies compared to baseline prior to commencing treatment. The objectives of this clinical study were to assess the ability of a dentifrice containing 0.1%w ⁄ w o-cymen-5ol and 0.6%w.w zinc chloride (ZnCl2) to maintain gingival health following a 14 day pre-experimental phase of dental prophylaxis and oral hygiene instruction prior to study treatment compared to a regular sodium fluoride ⁄ silica based dentifrice. In addition the ability of the test dentifrice to control dental plaque was also assessed. The unique combination of o-cymen-5-ol and zinc chloride has resulted in a spectrum of antimicrobial activity greater than for each of the ingredients alone9. The product was used twice daily and assessments of gingival inflammation, bleeding and plaque were conducted after six and 12 weeks. MATERIALS AND METHODS Study design This was a single centre, examiner blind, two arm, parallel group, randomised and stratified clinical study 14

in healthy adult volunteers conducted at Global Health Research Group, New Delhi, India to assess the ability of a dentifrice containing 0.1%w ⁄ w o-cymen-5-ol and 0.6%w ⁄ w zinc chloride to maintain gingival health over a 12 week period compared to a control sodium fluoride ⁄ silica dentifrice. The study protocol and consent form were reviewed and approved by the Institutional Ethics Committee for Global Health Research Group. After providing written informed consent, 325 healthy adult subjects between the ages of 18–65 years were screened in April 2010, with 239 subjects randomised to study treatment. The study was completed in August 2010. Subjects were enrolled into the study if they had: • Good oral health with at least 20 natural teeth (excluding third molars) and mild to moderate gingivitis at baseline (mean whole mouth Modified Gingival Index (MGI) score 1.50–2.50). Additionally they would have to demonstrate a reduction in MGI and a reduction or no change in bleeding during the pre-experimental phase. Subjects were excluded from the study if they: • Were pregnant or breast feeding. • Were smokers. • Had dental conditions requiring immediate treatment, sensitivity to oral care products, active caries, severe periodontitis or gingivitis; partial dentures, orthodontic appliances or fixed retainers or restorations in a poor state of repair. Subjects were also screened for the use of any systemic medication which would have an effect on gingival conditions (e.g. antibiotics, calcium channel blockers, ibuprofen or aspirin therapy) within 14 days of any gingivitis assessment. The study was conducted in two phases: a two week pre-experimental phase and a 12 week experimental period with a total duration of 14 weeks. Following an initial screening visit, at the start of the pre-experimental phase (Pre-Prophy Baseline visit) subjects underwent oral soft tissue (OST), gingival inflammation using the Modified Gingival Index (MGI)18, bleeding using the Bleeding Index (BI)19 and plaque using the six site Turesky Modification of the Quigley Hein Index (TPI)20 examinations (having abstained from brushing for a 12 hour period prior to the visit). To obtain optimum gingival health, subjects received a thorough professional dental prophylaxis. Afterwards, subjects received thorough professional instruction in oral hygiene which included the use of a medium bristled manual toothbrush (Aquafresh Clean Control) (Aquafresh and Clean Control are registered trademarks of GlaxoSmithKline group of companies) with a sodium fluoride ⁄ silica toothpaste (Colgate Herbal, Indian marketed product) (Colgate Herbal is a registered trademark of Colgate-Palmolive). They were instructed to use these products brushing twice daily ª 2011 FDI World Dental Federation

Maintenance of gingival health by a novel dentifrice at home for the next 14 days. Written instructions, a timer and a diary card to record brushing occasions were provided. Subjects returned to the site after seven days (two hours since their last brushing) for an additional visit at which they received an OST assessment followed by brushing their teeth under supervision followed by plaque disclosure. A qualified dental professional highlighted areas missed during brushing and reviewed the oral hygiene instructions, residual plaque was then removed by professional dental polishing. Subjects returned to site 14 days after the Pre-Prophy Baseline visit for the randomisation visit (after abstaining from brushing for 12 hours) and underwent OST, MGI, BI and TPI assessments. Only subjects who demonstrated a decrease in MGI and a decrease or no change in bleeding over the two week period since the Pre-Prophy Baseline visit were entered into the experimental phase of the study. Subjects were stratified according to their MGI score from the Pre-Prophy Baseline Visit and randomly assigned either the dentifrice containing 0.1%w ⁄ w o-cymen-5-ol and 0.6%w ⁄ w zinc chloride in a 0.204%w ⁄ w sodium fluoride ⁄ silica base or a 0.204%w ⁄ w sodium fluoride ⁄ silica base dentifrice. Subjects underwent a professional dental polishing with their assigned treatment and entered into the experimental phase. Subjects were instructed to brush twice daily (Aquafresh Clean Control flat trim toothbrush) at home for one timed minute with their assigned treatment using a strip of toothpaste that covered the head of the study toothbrush. Treatment compliance was assessed from diaries that the subjects completed each time they brushed at home throughout the study. At 6 and 12 weeks after randomisation subjects returned for appointments with overnight plaque and underwent OST, MGI, BI and TPI assessments. Randomisation and blinding procedure The randomisation schedule was generated using a computerised randomisation generator and provided to the site by the Biostatistics Department of the sponsor. Subjects were randomly assigned to one of two treatment groups according to the method of permuted blocks using a fixed block size of four. Subjects were stratified according to their Pre-Prophy Baseline MGI score into one of two strata: Low MGI (1.50–