A randomized controlled trial evaluating the efficacy of a 67% sodium bicarbonate toothpaste on gingivitis

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1 ORIGINAL ARTICLE A Lomax S Patel N Wang K Kakar A Kakar ML Bosma A randomized controlled trial evaluating the efficacy of a 67% sodium bicarbonate toothpaste on gingivitis Authors affiliations: A Lomax, S Patel, N Wang, ML Bosma, GSK Consumer Healthcare, Weybridge, UK K Kakar, A Kakar, Global Health Research Group, New Delhi, India Correspondence to: Shiva Patel GSK Consumer Healthcare St Georges Avenue Weybridge Surrey KT13 0DE, UK Tel.: Fax: +44 (0) Shiva.8.patel@gsk.com This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Abstract: Introduction: In previous studies, toothpastes with high levels of sodium bicarbonate (>50%) have reduced gingival inflammation and oral malodour. This study compared the effects of brushing for 6 weeks with 67% (test group) or 0% (control group) sodium bicarbonate toothpaste on gingival health. Methods: This was a single-centre, single examiner-blind, randomized, controlled, twotreatment, parallel-group study. Eligible subjects ( 18 years) had 20 gradable teeth, mild-to-moderate gingivitis, a positive response to bleeding on brushing and 20 bleeding sites. The primary objective was to compare the number of bleeding sites following twice-daily use of 67% sodium bicarbonate toothpaste or 0% sodium bicarbonate toothpaste after 6 weeks. Secondary endpoints included Modified Gingival Index (MGI), Bleeding Index (BI) and volatile sulphur compounds (VSC), assessed after 6 weeks. Safety was assessed by treatment-emergent oral soft tissue abnormalities and adverse events. Results: Of 148 patients randomized (74 to each treatment), 66 (89.2%) completed the study in the test group, compared with 69 (93.2%) in the control group. Compared with the control group, the test group had a significant reduction in the number of bleeding sites at Week 6 (absolute difference 11.0 [ 14.0, 8.0], P < ; relative difference 25.4%), together with significant reductions in MGI and BI (both P < ). Although the median reductions from baseline for VSC were numerically greater in the test group, the difference did not reach statistical significance (P = ). Conclusions: This 67% sodium bicarbonate toothpaste provided statistically significant improvements in gingival health and bleeding after 6 weeks of use. Dates: Accepted 19 April 2016 To cite this article: Int J Dent Hygiene. 15, 2017; e35 e41 DOI: /idh Lomax A, Patel S, Wang N, Kakar K, Kakar A, Bosma ML. A randomized controlled trial evaluating the efficacy of a 67% sodium bicarbonate toothpaste on gingivitis The Authors. International Journal of Dental Hygiene Published by John Wiley & Sons Ltd. Key words: dentifrice; gingivitis; sodium bicarbonate; toothpaste; volatile sulphur compounds Introduction The main cause of gingival bleeding is plaque build-up, especially at the gingival margin (1), which can in turn lead to gingivitis. Untreated gingivitis is a risk factor for periodontitis; this is a major cause of abnormal tooth mobility (2). Although flossing has traditionally been advocated for preventing gingivitis and plaque build-up, the evidence to support this is mixed, with studies showing limited benefit from interdental brushing or regular flossing (at least at a population level) (3, 4). In contrast, a recent systematic review and meta-analysis have shown that antiplaque chemical Int J Dent Hygiene 15, 2017; e35--e41 e35

2 formulations can provide significant improvements in gingival, bleeding and plaque indices (5). Furthermore, a number of other studies have demonstrated the beneficial effect of mouthrinses in reducing oral malodour (6, 7), although a systematic review suggested that due to limited evidence, the potential effect of a specifically formulated dentifrice, a mouthwash or a tongue scraper for treating oral malodour is, in general, unclear (8). In particular, previous studies have demonstrated the efficacy of sodium bicarbonate toothpastes on the removal of plaque, with a suggestion that a higher concentration of sodium bicarbonate is associated with greater efficacy (in terms of mean plaque removal) (9). Furthermore, toothpastes with high levels of sodium bicarbonate (>50%) have been shown to reduce gingival inflammation (10) and oral malodour (11). These previous studies have typically been of 3-6 months duration, with a maximum strength of sodium bicarbonate of 65%. However, a review described data supporting the use of sodium bicarbonate in the management of oral malodour as being few and inconclusive (12). The aim of this study was to determine the effects of brushing for 6 weeks with 67% sodium bicarbonate toothpaste on gingival health, compared to a 0% sodium bicarbonate toothpaste. As there is a suggestion from previous studies of a correlation between oral malodour (measured as volatile sulphur compounds [VSCs]) and gingivitis (13, 14), the study also aimed to evaluate the effect of 67% sodium bicarbonate toothpaste on VSC levels. Study population and methodology Trial design This was a single-centre, single examiner-blind, randomized, controlled, two-treatment, parallel-group study, with a 6-week intervention period conducted at a specialized research centre. At the screening visit (Visit 1), after providing informed consent, eligible subjects underwent a limited, intra-oral, visual oral soft tissue (OST) examination followed by a gingival health examination. Eligible subjects were then required to brush as they normally would (using a supplied manual, medium toothbrush) for one timed minute and expectorate into a white cup. Evidence of either blood in the expectorant or bleeding when brushing was the initial screening criterion. A washout period of at least 7 10 days occurred between Visits 1 and 2, during which all subjects used a commercially available non-sodium bicarbonate toothpaste (Aquafresh; GlaxoSmithKline Asia Pvt. Ltd, Punjab, India). At Visit 2, subjects went through baseline full OST and Modified Gingival Index (MGI) examinations, followed by a Bleeding Index (BI) assessment (note that MGI examinations always preceded BI assessments throughout the study). Subjects were then stratified according to their number of bleeding sites and smoking status. The first baseline VSC samples were collected and frozen at 20 C. At Visit 3, which took place between 0 and 7 days after Visit 2, a dental professional performed a dental prophylaxis which included scaling and use of a conventional dental prophylaxis paste followed by flossing. Immediately post-dental prophylaxis, subjects were randomized equally into one of two treatment groups before undergoing timed, supervised brushing with their assigned toothpaste. A VSC sample was then collected and frozen at 20 C. After 6 weeks of twice-daily brushing with the assigned toothpaste at home, subjects underwent full OST and MGI examinations, followed by a BI assessment (Visit 4). The final VSC sample was collected and again frozen at 20 C. For 24 h prior to any study visit, and until all evaluations had been performed, consistent with other similar studies (15, 16), subjects were instructed not to consume heavily spiced food, garlic or onions, and not to use medicated oral products, mouthwash or mouth sprays, chew gum, or use oral deodorant products. Furthermore, from 11 p.m. on the evening prior to each visit, subjects were instructed not to consume anything by mouth (except water, which was allowed up to 1 h prior to visits), or to smoke or consume tobacco, and were instructed not to consume alcohol for 48 h prior to visits. Throughout the study, subjects were asked to refrain from any other forms of oral hygiene. The study was conducted in accordance with the provisions of the Declaration of Helsinki (2008) and Good Clinical Practice guidelines and was approved by an Independent Ethics Committee prior to initiation (Society for the Promotion of Ethical Clinical Trials (SPECT), Pitampura, New Delhi, India). All subjects provided written informed consent before any study procedure was performed. There was one non-substantial amendment, in which the procedure for stratification of subjects into the study was clarified, and typographical errors of visit numbers were corrected. Participants Subjects were at least 18 years of age and had a total score of at least 7 on a Subject s level of understanding questionnaire (a 12-question form that tested whether the subject understood the instructions for participating in the study, such as how many times they were to attend the site, how long they had to brush their teeth for and when they were to complete their diary cards; see the online supplement). In addition, eligible subjects were in good general and mental health, with no clinically significant or relevant abnormalities. They had at least 20 gradable teeth, with mild-to-moderate gingivitis, a positive response to bleeding on brushing (at screening) and at least 20 bleeding sites (at baseline). Otherwise, subjects were in good oral health (in the opinion of the investigator). Key exclusion criteria were intolerance or hypersensitivity to the study materials or stated ingredients, currently active dental caries, more than three pockets with 5 mm or over, excessive calculus, other severe oral/gingival conditions, medical conditions which may influence gingival bleeding, restorations in a poor state of repair or orthodontic appliances. Detailed inclusion and exclusion criteria are listed in the online supplement. Subjects who prematurely withdrew from the study were not replaced. e36 Int J Dent Hygiene 15, 2017; e35--e41

3 Interventions Subjects were randomized 1:1 to receive either Parodontax â Daily Toothpaste (GlaxoSmithKline Asia Pvt. Ltd, Punjab, India), supplied in commercial packaging with a study label affixed to the tube (described hereafter as test group ), or an experimental non-sodium bicarbonate, silica sodium fluoride toothpaste, not commercially available (control group). Both toothpastes contained 923 ppm fluoride (as sodium fluoride). Randomization was achieved using randomization numbers assigned in ascending numerical order according to a schedule provided by the study sponsor. The study statistician, data management staff and other employees of the sponsor were blinded to treatment, as was the examiner. Objectives and evaluation criteria The primary objective was to evaluate and compare gingival health (as assessed at Saxton and Van der Ouderaa sites (17)) following twice-daily use of test or control toothpaste after 6 weeks. This was assessed by determining the number of (Saxton and Van der Ouderaa) bleeding sites with a BI score of 1 or 2 across all evaluable tooth sites. This evaluation was performed by a single examiner (to eliminate the possibility of interexaminer variability) using a Williams periodontal probe (17). The secondary objectives were to compare the effects of tooth brushing with the test toothpaste to the effects of brushing with the control toothpaste at 6 weeks in terms of the levels of MGI, BI and VSC. The MGI is a non-invasive evaluation of early visual changes in severity and extent of gingivitis, in which multiple areas were graded to give an average score per subject (18). The whole-mouth average MGI and BI scores were calculated for each subject at baseline and after 6 weeks by summing the respective scores at each gradable site and dividing by the number of gradable sites. For the VSC collection, three replicate 20 ml-mouth air samples were to be drawn from each subject s mouth into a syringe and frozen at 20 C. Samples were analysed for hydrogen sulphide (HS) and methyl mercaptan (MM) concentrations by gas chromatography with flame photometric detection (FPD). Total VSC is the sum of the concentrations of HS and MM. As an exploratory objective, this study included an evaluation of the correlation between the levels of HS and MM and the levels of gingivitis (as assessed by the MGI) after 6 weeks. The assessment of safety and tolerability was based on the safety profiles of the test treatments with respect to treatmentemergent oral soft tissue abnormalities and adverse events reported by subjects following use of the study treatments. Treatment compliance (in terms of the number of missing brushings) was assessed using diary card data. Sample size and statistical methods It was planned to randomize 150 subjects (75 subjects per treatment) with the intent that 130 subjects (65 per treatment) completed the study. This would provide 90% power to detect a treatment difference of eight in the number of bleeding sites. The standard deviation used in the sample determination was 13.8 as observed in a previous study (19). The primary efficacy variable, the number of bleeding sites at Week 6, was analysed using an analysis of covariance (ANCO- VA) model with treatment and smoking status as factors and baseline number of bleeding sites as a covariate. From this model, the adjusted mean of each treatment and its 95% confidence interval (CI), together with the treatment difference and its 95% CI and P-value, were provided. MGI and wholemouth mean BI were analysed using an ANCOVA model with treatment, bleeding site stratification and smoking status as factors, and baseline values of both MGI and BI as covariates. From this model, the adjusted mean of each treatment and its 95% CI together with the treatment difference and associated 95% CI and P-value were presented. Log-transformed values (log10) of HS and MM at immediate post-baseline treatment and at 6 weeks post-baseline were planned to be analysed using an ANCOVA model. However, 73% of the VSC values (297/405) were below the level of quantification (BLOQ), and as a result, normality of residuals was not satisfied. The BLOQ was therefore replaced by half of the LOQ; the nonparametric Wilcoxon rank sum test was then applied to change from baseline for the treatment comparisons. The exploratory analyses of the correlations between VSC and BI and between VSC and MGI were assessed using Pearson s correlation coefficient. Correlation was assessed with baseline data (before supervised brushing), Week 6 data, and pooled data from baseline and Week 6. All assessments of safety were based on the safety population, defined as all subjects randomized and received study medication at least once. The main population used for the efficacy assessments was the intent-to-treat (ITT) population, defined as all subjects randomized, receiving study product at least once, and provided at least one post-baseline (i.e. at Week 6) assessment of efficacy. Results Participants The first subject was enrolled into the study in November 2013, with the final subject completing in January Of 198 subjects screened, 148 were randomized (74 to each group); the majority of subjects in each group completed the study (Figure 1). Most of the subjects combined the baseline and dental prophylaxis visits. The baseline demographics (Table 1) and disease characteristics (Table 2) of the randomized subjects were well balanced between the two groups, and compliance to treatment was high, with the mean number of brushings missed being 0.7 (SD 1.48) in the test group and 0.5 (1.16) in the control group. Compliance to protocol was high, with a total of seven brushings missed in the test group and five in the control group. Int J Dent Hygiene 15, 2017; e35--e41 e37

4 Fig. 1. Subject flow through the study. Table 1. Subject baseline demographics (safety population) Outcomes Primary endpoint The number of bleeding sites at Week 6 was statistically lower (P < ) in the test group compared with the control group, with an absolute difference of 11.0 and a relative difference of 25.4% (Table 2). Secondary endpoints Test group (N = 74) Control group (N = 74) Male gender, n (%) 27 (36.5) 37 (50.0) Race, n (%) Asian 74 (100) 74 (100) Age, years, mean (SD) 27.7 (7.69) 28.6 (10.34) Number of bleeding sites, n (%) < (1.4) (100) 73 (98.6) Smoking status, n (%) Non-smoker 71 (95.9) 72 (97.3) Smoker 3 (4.1) 2 (2.7) Consistent with the primary endpoint, both the MGI score and the whole-mouth BI score were significantly lower in the test group compared with the control group, with relative differences of 28.8% and 27.4%, respectively (Table 2). As described in the methods section, VSC and the components, HS and MM were not analysed as planned, given the large number of values that were below the level of quantification. Although the median reductions from baseline for all parameters were greater in the test group, the differences did not reach statistical significance (Table 3). Exploratory endpoint Pearson s correlation coefficients between MGI and VSC components (VSC, HS, MM) and between BI and VSC components varied between 0.08 and 0.26; the large number of values below the LOQ makes these data difficult to interpret. Safety results A total of four subjects, two from each treatment group, reported four treatment-emergent adverse events. One of the four AEs was an oral AE (pharyngitis, in the test group); the other three AEs were non-oral (headache, one in the test group and two in the control group). None of the four treatment-emergent AEs were treatment related. Discussion This study provided evidence of the efficacy of a high-concentration sodium bicarbonate toothpaste in reducing a number of markers of poor dental health, with statistically significant reductions at Week 6 compared with the non-sodium bicarbonate toothpaste in the number of bleeding sites (25.4% reduction), the MGI (28.8% improvement) and the wholemouth BI (27.4% reduction). e38 Int J Dent Hygiene 15, 2017; e35--e41

5 Table 2. Baseline and Week 6 data for number of bleeding sites, Modified Gingival Index (MGI) and Bleeding Index (BI) (ITT population) Test group (N = 66) Control group (N = 69) Mean (SD)*, adjusted mean Change from baseline, mean (SD) Mean (SD)*, adjusted mean Change from baseline, mean (SD) Adjusted mean difference (95% CI) No. of Baseline 76.0 (13.06) 73.5 (12.25) bleeding sites Week (12.21), (10.15) 42.5 (12.85), 43.3 MGI Baseline 1.26 (0.28) 1.26 (0.23) Week (0.24), 0.61 (0.14) 0.91 (0.27), BI Baseline 1.00 (0.27) 0.94 (0.22) Week (0.16), (0.18) 0.47 (0.16), (8.71) 11.0 ( 14.0, 8.0), P < (0.16) 0.26 ( 0.31, 0.21), P < (0.13) 0.13 ( 0.16, 0.10), P < *Mean (SD): raw data summary statistics. Adjusted mean (for Week 6 only): obtained from ANCOVA analysis: No. of bleeding sites: ANCOVA with treatment and smoking status as factors and baseline value as a covariate (residual SD=8.78). MGI: ANCOVA with treatment, bleeding site stratification and smoking status as factors and baseline value as a covariate (residual SD=0.14). BI: ANCOVA with treatment, bleeding site stratification and smoking status as factors and baseline value as a covariate (residual SD=0.10). Table 3. Baseline and Week 6 data for volatile sulphur compounds (VSC), hydrogen sulphide (HS) and methyl mercaptan (MM) (ITT population) Test group (N = 66) Control group (N = 69) Mean (SD), median Change from baseline, mean (SD), median Mean (SD), median Change from baseline, mean (SD), median P-value for treatment contrast for median change from baseline* VSC Baseline (538.98), Week (424.89), HS Baseline (392.05), Week (308.76), MM Baseline (167.86), Week (127.17), (604.72), (441.72), (181.39), (537.05), (325.86), (424.68), (250.35), (133.09), (90.26), (524.52), (402.98), (139.78), *P-value from Wilcoxon rank sum test on change from baseline. Previous studies investigating the effect of sodium bicarbonate toothpastes have generally been of 3 or 6 months duration (10, 20). Zambon and colleagues report the results of a study in which 27 participants used a 65% sodium bicarbonate toothpaste and 74 used a toothpaste containing 52% sodium bicarbonate and 3% sodium percarbonate (10). The participants used these toothpastes for 6 months and were then followedup for a further 3 months. Both toothpastes resulted in significant reductions in plaque and gingival inflammation, with the 65% toothpaste being associated with a 74.5% reduction from baseline in MGI. It is notable, therefore, that the improvements in this current study were observed as early as 6 weeks. Furthermore, although the current study only included one concentration of sodium bicarbonate toothpaste, previous studies demonstrated a dose relationship, with higher concentrations associated with greater efficacy than lower concentrations (10, 11). In particular, in a single-brushing study, a 65% sodium bicarbonate toothpaste resulted in 13% mean greater plaque removal than a 20% sodium bicarbonate toothpaste (P = ) (9). In a similar single-brushing study, both a 67% sodium bicarbonate toothpaste and a 62% sodium bicarbonate toothpaste resulted in statistically significantly greater plaque removal than a 0% sodium bicarbonate toothpaste (21). The current study used a concentration of 67%, so this would be anticipated to be at least as effective as the highest concentrations tested previously. The current study was designed to examine the impact of the 67% sodium bicarbonate toothpaste on gingival disease, and as a consequence recruited subjects with some evidence of gingival disease at baseline. Previous studies have suggested that there is a correlation between gingivitis and VSC levels (13, 14), although it is not clear whether the sulphur Int J Dent Hygiene 15, 2017; e35--e41 e39

6 compounds are a marker of gingival disease, or [as some researchers have suggested (22)] the compounds contribute to the process. However, even at low concentrations, these compounds have been shown to be highly toxic to tissues (23, 24). The researchers therefore collected VSCs in the current study and sought to evaluate the correlation with gingival disease as an exploratory outcome. However, there was no requirement for subjects to have measurable levels of VSCs at baseline and 73% of VSC values were below the LOQ. When the available data were analysed, there was some suggestion of a greater reduction from baseline in VSC levels with the 67% sodium bicarbonate toothpaste compared with the 0% toothpaste, but limited conclusions can be drawn from this. To fully evaluate the question on the effect of a sodium bicarbonate toothpaste on VSC, a specifically designed study would be required, considering aspects such as inclusion criteria with respect to baseline VSC levels. Another potential direction for future research includes a study with both a negative control (as here) and a positive control (for example, a toothpaste containing a different concentration of sodium bicarbonate). The current study was single centre, with a study population that was 100% Asian, predominantly non-smoking, and with a high number of bleeding sites. Although this limits the generalizability of the data, the results of this study are consistent with a number of previous studies (20, 25, 26). In the first, after 6 and 12 weeks, a toothpaste containing 67% sodium bicarbonate resulted in statistically significant reductions in both the number of bleeding sites and the bleeding index compared with a 0% sodium bicarbonate toothpaste (20). In the second, after 2 months, the then marketed Parodontax toothpaste was associated with statistically significant reductions in gingivitis and bleeding on probing compared with both a placebo toothpaste and a commercially available non-sodium bicarbonate toothpaste (25). In the third study, after 6 months of use, the same marketed sodium bicarbonate toothpaste was associated with a statistically significant reduction in bleeding and plaque levels compared with a placebo toothpaste, together with a statistically significant reduction from baseline in gingivitis (26). Conclusion In conclusion, this study demonstrated that a 67% sodium bicarbonate toothpaste provides statistically significant improvements in gingival health and bleeding after just 6 weeks of use. Further studies are required to confirm the reproducibility of this result and the potential utility of a 67% sodium bicarbonate toothpaste in the short-term management of gingival health. Clinical relevance Scientific rationale for study Previous studies have demonstrated the efficacy of sodium bicarbonate toothpastes on plaque removal, with a suggestion that a higher concentration of sodium bicarbonate is associated with greater efficacy. The aim of this study was to determine the effects of brushing for 6 weeks with 67% sodium bicarbonate on gingival health and oral malodour, compared to a 0% sodium bicarbonate toothpaste. Principal findings This 67% sodium bicarbonate toothpaste provided statistically significant improvements in gingival health and bleeding after 6 weeks of use. Practical implications Further studies are required to confirm the reproducibility of this result and the potential utility of a 67% sodium bicarbonate toothpaste in the short-term management of gingival health. Acknowledgements The authors would like to thank the trial team, in particular Marc Renard, Clinical Operations Manager at GSK. Funding This study was funded by GSK Consumer Healthcare. Writing support was provided by David Young of Young Medical Communications and Consulting Ltd. This support was funded by GSK Consumer Healthcare. Contributors AL, SP, NW and MLB were responsible for the design of the study; KK and AK conducted the study and were responsible for the generation of the data. All authors were responsible for the development of the publication, the selection of the journal and approved the final version submitted to the journal. Conflict of interest AL and MLB were employees of GSK Consumer Healthcare at the time the study was conducted. SP and NW are employees of GSK Consumer Healthcare. AK and KK have received grants from GSK Consumer Healthcare. References 1 Ledingham J, Warrell D, eds. Concise Oxford Textbook of Medicine. Oxford, Oxford University Press, Scottish Dental Clinical Effectiveness Programme. Prevention and Treatment of Periodontal Diseases in Primary Care. Dundee: Scottish Dental Clinical Effectiveness Programme; Poklepovic T, Worthington HV, Johnson TM et al. Interdental brushing for the prevention and control of periodontal diseases and dental caries in adults. Cochrane Database Syst Rev 2013; 12: CD e40 Int J Dent Hygiene 15, 2017; e35--e41

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