Abstract
Objectives
To evaluate effectiveness of oral rinses containing dipotassium oxalate monohydrate (KOX) in relieving dentinal hypersensitivity (DH) after 8 w use adjunctive to brushing.
Methods
Three 8-week, randomised, controlled, double-blind, parallel-group, single-centre studies were conducted in adults with DH. In each study, participants were randomised to one of two experimental rinses or a placebo in a matrix design, such that each experimental rinse was evaluated in two studies. Rinses A (pH 4.5) and B (pH 7.0) contained 1.5% KOX and were fluoride-free; Rinse C (pH 4.5) contained 2.0% KOX and 45 ppm fluoride as NaF; the placebo rinse (pH 4.5) did not contain KOX or fluoride. Participants brushed with a fluoride dentifrice for 1 min, briefly rinsed with water, then rinsed with their assigned oral rinse for 1 min twice daily for 8 w. DH was assessed at baseline and following 4 and 8 w use by response to an evaporative (air) stimulus (evaluated by Schiff sensitivity score and a 10-point visual rating scale) and a tactile stimulus (Yeaple probe).
Results
All rinses in each study were associated with statistically significant improvements from baseline in measures of DH after 4 and 8 w treatment. However, between-treatment comparisons were inconsistent across the studies, with only Study 3 demonstrating a significant difference between the experimental (Rinses B and C) and placebo rinses. A number of treatment-related adverse events (all mild) were reported.
Conclusions
Rinses containing 1.5–2.0% KOX did not consistently demonstrate a benefit over placebo in relieving DH after 8 w use.
Clinical significance
While favourable results were found in one of the investigations, this suite of studies shows that the possibility of inconsistent results exists even with the best designed and executed trials.
1
Introduction
Dentinal hypersensitivity (DH) is characterised by a short, sharp pain in response to chemical, thermal, tactile or osmotic stimuli [ ]. It arises as a consequence of the exposure of patent dentinal tubules, which may occur due to gingival recession and/or enamel loss (e.g., through erosion or abrasion) [ ]. An external stimulus, such as a temperature or osmotic differential, is hypothesised to cause movement of the fluid resident within dentinal tubules [ ]. This fluid movement may stimulate nerve processes in the pulpal area of the dentine, leading to the sensation of pain [ ].
DH may be managed using nerve depolarisation to reduce transmission of the pain stimulus, or by occlusion of the dentinal tubules to reduce fluid movement [ ]. Tubule-occluding agents – such as strontium and stannous salts, bioglasses, dental silicas and oxalate – serve to physically seal or block the exposed end of dentinal tubules, thereby reducing dentinal fluid movement and neuronal activation in response to external stimuli [ ].
Oxalate salts are particularly well studied. In vitro investigations have shown significant reductions in tubule permeability in dentine treated with solutions of 30% (di)potassium oxalate or 3% monopotassium-monohydrogen oxalate [ ]. Evidence from scanning electron microscopy utilising professional in-clinic formulations of 3% aqueous monopotassium oxalate shows extensive precipitation on the dentine surface and within tubules following a single application [ ], with multiple treatments progressively increasing the degree of surface occlusion [ ]. In a study of oral rinse formulations containing 1.5% or 2.0% w/w dipotassium oxalate, complete surface coverage with occlusion of tubules to a depth of 70 μm was achieved within 12 applications [ ]. In vitro experiments suggest enhanced deposition of oxalate crystals when the potassium oxalate is delivered from an acidic solution rather than at neutral pH and greater deposition in the presence of fluoride [ ].
While some clinical studies have demonstrated efficacy of an in-clinic aqueous 3% monopotassium oxalate formulation in reducing DH [ ], a systematic review concluded that, taken as a whole, clinical studies of such treatments are less conclusive [ ]. Recently, a 1.4% dipotassium oxalate twice-daily oral rinse was evaluated in several clinical trials [ ]. Use of the rinse as an adjunct to twice-daily brushing with a fluoride dentifrice showed greater relief of DH versus a placebo oral rinse or brushing alone, as well as comparable DH relief to twice-daily brushing with a positive-control dentifrice (5% KNO 3 ) after 4 w use [ ] and, in one study, as early as 3–5 d use [ ].
The objective of the three studies reported here was to further investigate the efficacy of 8 w use of three experimental oral rinses containing dipotassium oxalate monohydrate (KOX) for the relief of DH (as elicited by evaporative [air] and tactile stimuli) adjunctive to twice-daily brushing with a standard fluoride dentifrice compared with a placebo regimen.
2
Methods
Three 8-week, randomised, controlled, double-blind, stratified (by baseline Schiff sensitivity score), parallel-group, single-centre studies were carried out with healthy participants with a self-reported history of DH and at least two eligible sensitive teeth (ClinicalTrials.gov: Study 1: NCT02542943; Study 2: NCT02753075; Study 3: NCT02651467). Study 1 was conducted at Silverstone Research Group, Las Vegas, NV, USA; Studies 2 and 3 were conducted at Salus Research Inc., Fort Wayne, IN, USA. Each study was approved by an Independent Review Board (U.S. IRB, Miami, FL, USA: Study 1: U.S.IRB2015SRG/02; Study 2: U.S.IRB2015SRI/19; Study 3: U.S.IRB2015SRI/12) before initiation, and carried out in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. There were minor administrative amendments to study protocols that did not affect study flow or outcome.
2.1
Participants
Each study enrolled healthy participants aged 18–55 y (Studies 1 and 2) or 18–65 y (Study 3) with ≥20 natural teeth and a self-reported history of DH lasting more than 6 mth but not more than 10 y. At screening, eligible participants had at least two accessible, non-adjacent teeth (incisors, canines or premolars) with signs of erosion, abrasion or facial/cervical gingival recession (EAR), a Modified Gingival Index (MGI) score (adjacent to the test area) of 0, a clinical mobility score of ≤1 and signs of sensitivity, as shown by a positive response to a qualifying evaporative (air) assessment. At baseline, eligible participants had a minimum of two accessible, non-adjacent teeth with signs of sensitivity, as determined by a qualifying tactile stimulus threshold of ≤20 g and a Schiff sensitivity score of ≥2.
General exclusion criteria included: pregnancy; breastfeeding; daily use of medication/treatment that could interfere with pain perception or could cause xerostomia; current antibiotic use or use within 2 w of baseline; presence of kidney disease, hyperoxaluria or any condition that could be exacerbated by oxalic acid or oxalate salts; presence of a chronic debilitating disease that could affect study outcomes; any condition that causes xerostomia; known or suspected intolerance or hypersensitivity to the study ingredients; participation in another clinical study or receipt of an investigational drug within 30 d of the screening visit.
General oral exclusions included: dental prophylaxis within 4 w of screening; tongue or lip piercings; dental implants; desensitising treatment or tooth bleaching within 8 w of screening; gross periodontal disease; treatment of periodontal disease within 12 mth of screening; scaling or root planing within 3 mth of screening; use of an oral care product indicated for DH relief within 8 w of screening; and requirement for antibiotic prophylaxis for dental procedures.
Specific dentition exclusions for test teeth included: evidence of current or recent caries, or reported treatment of decay within 12 mth of screening; exposed dentine but with deep, defective or facial restorations; teeth used as abutments for fixed or removable partial dentures; full crowns or veneers; orthodontic bands; cracked enamel; sensitive teeth with contributing aetiologies other than EAR; and sensitive teeth not expected, in the examiner’s opinion, to respond to treatment with an over-the-counter dentifrice.
2.2
Study procedures
At the screening visit, each participant provided written informed consent to participate in the study before their demographic characteristics, medical history and use of concomitant medications were recorded and an oral soft tissue (OST) examination was conducted. Each participant’s dentition was assessed sequentially for: evidence of EAR; gingival health status using the MGI [ ]; tooth mobility using a modification of the Miller scale [ ]; and sensitivity to an evaporative air stimulus (where a ‘yes’ response from the participant indicated sensitivity). The MGI score was assessed for the facial gingiva adjacent to the test area (exposed dentine) only of teeth exhibiting facial cervical EAR. Only those teeth with an MGI score of 0 (i.e., corresponding to ‘absence of inflammation’) were clinically assessed for mobility.
Eligible participants were supplied with a standard fluoride dentifrice (1000 ppm fluoride as sodium monofluorophosphate; Colgate ® Cavity Protection, Colgate-Palmolive Company, New York, NY, USA) and a toothbrush (Aquafresh ® Clean Control [Everyday Clean], GSK Consumer Healthcare, Weybridge, UK) to use twice daily for 4–6 w between the screening and baseline visits.
At the baseline visit, ongoing eligibility was assessed, any adverse events (AEs), incidents and changes to concomitant medications were recorded and compliance with use of the acclimatisation dentifrice was evaluated based on a participant-completed diary. Following an OST examination, the sensitivity of all clinically eligible teeth identified at screening was evaluated by the participant’s response to a tactile stimulus administered by a constant-pressure Yeaple probe [ ]. Those teeth meeting the required tactile threshold (≤20 g) were then evaluated for sensitivity to an evaporative (air) stimulus, assessed using the Schiff Sensitivity Scale [ ] and a 10-point visual rating scale (VRS). Within each of the studies, a single examiner performed all of the tactile threshold and evaporative (air) sensitivity assessments. The same examiner carried out all assessments for Studies 2 and 3, which took place at the same study centre. The assessments of evaporative sensitivity were conducted at least 5 min after the tactile assessment. The investigator who conducted the evaporative (air) sensitivity assessment selected two non-adjacent teeth, preferably in different quadrants, from those that met the qualifying sensitivity assessments (i.e., both the tactile threshold and Schiff sensitivity score criteria) to be evaluated for the remainder of the study.
Eligible participants were stratified according to the mean baseline Schiff sensitivity score of their two selected teeth, giving rise to three strata with mean baseline scores of 2, 2.5 and 3 (see Results section for details of stratum assignment). Within each stratum, participants were randomised (1:1:1) to an oral rinse study product (one of two experimental oral rinses or the placebo oral rinse) according to randomisation schedules generated by the Biostatistics Department of GSK Consumer Healthcare before the start of each study. Details of which rinses were used in each study are shown in Table 1 and Table 2 gives formulation details of the study rinses. Within each study, randomisation numbers were assigned by the study-site personnel in ascending numerical order as each participant was determined to be eligible. The clinical dental examiners, study statisticians, data management staff and other employees of the sponsor and study sites who could have influenced study outcomes were blinded to product allocation.
| Study 1 | Study 2 | Study 3 | |
|---|---|---|---|
| Rinse A | X | X | |
| Rinse B | X | X | |
| Rinse C | X | X | |
| Placebo | X | X | X |
| Study centre | Silverstone | Salus | Salus |
| Study dates | Sep–Dec 2015 | Sep–Dec 2015 | Jan–Apr 2016 |
| Rinse A | Rinse B | Rinse C | Placebo | |
|---|---|---|---|---|
| Dipotassium oxalate monohydrate | 1.5% | 1.5% | 2.0% | 0% |
| Sodium fluoride | 0 ppm | 0 ppm | 45 ppm | 0 ppm |
| pH | 4.5 | 7.0 | 4.5 | 4.5 |
| Sodium benzoate | X | – | X | X |
| Phosphoric acid | X | – | X | – |
| Methyl parahydroxybenzoate | – | X | – | – |
| Propyl hydroxybenzoate | – | X | – | – |
| Disodium phosphate, anhydrous | – | X | – | – |
a All rinses including the placebo contained identical amounts of water, glycerol, Cremophor RH60, cocamidopropyl betaine and sodium saccharin.
Participants were also supplied with a standard fluoride dentifrice (1000 ppm fluoride as sodium monofluorophosphate; Colgate ® Cavity Protection, Colgate-Palmolive Company, New York, NY, USA), wrapped in opaque white vinyl to conceal the product identity, to use in conjunction with the oral rinse products.
First use of the allocated study treatment was conducted under supervision at the study site. Participants first applied a full brush head of dentifrice and brushed for 1 min before expectorating. They then rinsed with 20 mL of water for 10 s, before rinsing with 10 mL of their assigned oral rinse for 1 min. Participants expectorated after each rinse; no further rinsing was allowed and they were not permitted to eat or drink for 30 min after rinsing. Participants continued to use their assigned regimen as directed twice daily for 8 w, recording each brushing/rinsing occasion in a diary. Further supervised brushing and rinsing was conducted at the Week 4 visit.
At each visit, participants underwent an OST examination before any clinical assessment of sensitivity. Compliance with use of the study products was assessed by review of the participant-completed diaries. Before their study visits, participants were asked to refrain from all oral hygiene procedures for at least 8 h, from eating and drinking for at least 4 h, and from excessive alcohol consumption for 24 h. Small sips of water were permitted for taking medication or to relieve thirst within the 4 h before the visits but not within 1 h. Throughout the study, participants were not permitted to use any oral care products other than those provided to them, nor any products (including home remedies) intended for treating sensitive teeth. Use of dental floss was permitted only for removal of impacted food and participants were not permitted to chew gum. Participants were requested to delay having any non-emergency dental treatment (including prophylaxis) until after study completion.
2.3
Assessments
Tooth sensitivity in response to tactile and evaporative (air) stimuli was reassessed at baseline and after 4 and 8 w of oral rinse use. Two independent stimulus-based efficacy measures were used to assess DH in accordance with published recommendations [ ]. Firstly, the tactile stimulus was administered using a constant-force (Yeaple) probe, which allowed application of a known force to the dentine surface. The greater the tactile threshold (i.e., the greater the force the participant could tolerate), the less sensitive the tooth. Testing began at a force of 10 g and was increased by 10 g with each successive challenge until either two consecutive ‘yes’ responses (with ‘yes’ indicating the stimulus caused pain or discomfort) were elicited from the participant at the same force setting (which was recorded as the tactile threshold in grams) or the maximum force was reached. At baseline, the maximum applied force was set at 20 g; at subsequent visits it was 80 g. If no pain response was found, the threshold was recorded as >80 g. The examiners were fully trained and experienced in using the Yeaple probe and recording tactile threshold data. The Yeaple probe was calibrated prior to use on each day participants were assessed, following a defined procedure that spanned the range of pressure used in the study.
Secondly, after a recovery period of at least 5 min following the evaluation of tactile threshold, evaporative (air) sensitivity was assessed by directing an air jet from a triple air dental syringe onto the exposed dentine surface of the isolated test tooth [ ]. The examiner’s assessment of the participant’s response to the air stimulus was recorded on the four-point Schiff Sensitivity Scale (where: 0 = participant does not respond to air stimulus; 1 = participant responds to air stimulus but does not request discontinuation; 2 = participant responds to air stimulus and requests discontinuation or moves from stimulus; 3 = participant responds to stimulus, considers stimulus to be painful and requests discontinuation of the stimulus) [ ]. Participants rated the intensity of their response to the evaporative (air) stimulus using a 10‐point VRS to mark their pain on a scale of 1 (‘no pain’) to 10 (‘intense pain’). The examiners were fully trained and experienced in administering and recording the evaporative (air) assessment.
Participants were also assessed with regard to DH-related impact on quality of life using the short-form Dentine Hypersensitivity Experience Questionnaire (DHEQ-15) [ ]; these results are not presented in the current paper.
2.4
Safety
Spontaneously reported AEs and any abnormalities in the OST examination were recorded from the time of supervised brushing with the acclimatisation dentifrice at the screening visit until 5 d after the last use of study product. The investigator assessed the relationship between the assigned regimen and the occurrence of each AE using clinical judgement, and graded the AE as mild, moderate or severe. Treatment-emergent AEs (TEAEs) were reported for the safety population, which included all randomised participants who received study product.
2.5
Data analysis
2.5.1
Sample size determination
In each study, sufficient participants were to be screened so that a minimum of 240 would be randomised to ensure that approximately 216 participants (72 per treatment group) completed the study. With 72 participants per group, the studies were estimated to have 80% power to detect a mean treatment difference of 0.36 in the primary efficacy variable of change from baseline in Schiff sensitivity score, using a two-sided t test at a significance level of 0.05 under Dunnett’s adjustment for two experimental products versus a placebo. The standard deviation used in the sample size calculation was 0.70, as derived from earlier studies (data on file).
2.5.2
Efficacy analyses
All efficacy analyses were performed on the intent-to-treat populations, defined as all participants who were randomised, who used a study oral rinse at least once, and who provided at least one post-baseline assessment of efficacy. Each study was analysed separately. All statistical analyses were conducted using SAS (version 9.2; SAS Institute Inc., Cary, NC, USA).
For each study, participant-level mean change from baseline (mean of the two selected test teeth) in Schiff sensitivity score at Week 4 and Week 8 (primary efficacy variable) was analysed using an analysis of covariance (ANCOVA) model with treatment as a factor and mean baseline Schiff sensitivity score as a covariate. Comparisons of each experimental oral rinse versus the placebo oral rinse or versus the other experimental oral rinse were adjusted for multiple comparisons using Dunnett’s procedure. Treatment differences were also calculated by Schiff stratification. Change from baseline in VRS score at Weeks 4 and 8 was analysed using an ANCOVA model with treatment and baseline Schiff stratification as factors and baseline VRS score as a covariate.
In Studies 1 and 2, non-parametric methods were used for analysis of change from baseline in tactile threshold at Weeks 4 and 8 as the assumptions of normality were not met for the ANCOVA model with treatment and baseline stratification as factors and baseline as a covariate. In Study 1, the change from baseline in tactile threshold at Weeks 4 and 8 was analysed using a non-parametric van Elteren test (with the baseline Schiff stratification as controlling factor) and two-sided Hodges–Lehmann estimates to calculate p-values and 95% confidence intervals (CIs), respectively. In Study 2, tactile threshold was analysed using a Wilcoxon rank-sum test and non-parametric Hodges-Lehmann estimates to calculate p-values and 95% CIs, respectively. In Study 3, the change from baseline in tactile threshold was analysed using the ANCOVA model with treatment and baseline stratification as factors and baseline tactile threshold as a covariate.
2
Methods
Three 8-week, randomised, controlled, double-blind, stratified (by baseline Schiff sensitivity score), parallel-group, single-centre studies were carried out with healthy participants with a self-reported history of DH and at least two eligible sensitive teeth (ClinicalTrials.gov: Study 1: NCT02542943; Study 2: NCT02753075; Study 3: NCT02651467). Study 1 was conducted at Silverstone Research Group, Las Vegas, NV, USA; Studies 2 and 3 were conducted at Salus Research Inc., Fort Wayne, IN, USA. Each study was approved by an Independent Review Board (U.S. IRB, Miami, FL, USA: Study 1: U.S.IRB2015SRG/02; Study 2: U.S.IRB2015SRI/19; Study 3: U.S.IRB2015SRI/12) before initiation, and carried out in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. There were minor administrative amendments to study protocols that did not affect study flow or outcome.
2.1
Participants
Each study enrolled healthy participants aged 18–55 y (Studies 1 and 2) or 18–65 y (Study 3) with ≥20 natural teeth and a self-reported history of DH lasting more than 6 mth but not more than 10 y. At screening, eligible participants had at least two accessible, non-adjacent teeth (incisors, canines or premolars) with signs of erosion, abrasion or facial/cervical gingival recession (EAR), a Modified Gingival Index (MGI) score (adjacent to the test area) of 0, a clinical mobility score of ≤1 and signs of sensitivity, as shown by a positive response to a qualifying evaporative (air) assessment. At baseline, eligible participants had a minimum of two accessible, non-adjacent teeth with signs of sensitivity, as determined by a qualifying tactile stimulus threshold of ≤20 g and a Schiff sensitivity score of ≥2.
General exclusion criteria included: pregnancy; breastfeeding; daily use of medication/treatment that could interfere with pain perception or could cause xerostomia; current antibiotic use or use within 2 w of baseline; presence of kidney disease, hyperoxaluria or any condition that could be exacerbated by oxalic acid or oxalate salts; presence of a chronic debilitating disease that could affect study outcomes; any condition that causes xerostomia; known or suspected intolerance or hypersensitivity to the study ingredients; participation in another clinical study or receipt of an investigational drug within 30 d of the screening visit.
General oral exclusions included: dental prophylaxis within 4 w of screening; tongue or lip piercings; dental implants; desensitising treatment or tooth bleaching within 8 w of screening; gross periodontal disease; treatment of periodontal disease within 12 mth of screening; scaling or root planing within 3 mth of screening; use of an oral care product indicated for DH relief within 8 w of screening; and requirement for antibiotic prophylaxis for dental procedures.
Specific dentition exclusions for test teeth included: evidence of current or recent caries, or reported treatment of decay within 12 mth of screening; exposed dentine but with deep, defective or facial restorations; teeth used as abutments for fixed or removable partial dentures; full crowns or veneers; orthodontic bands; cracked enamel; sensitive teeth with contributing aetiologies other than EAR; and sensitive teeth not expected, in the examiner’s opinion, to respond to treatment with an over-the-counter dentifrice.
2.2
Study procedures
At the screening visit, each participant provided written informed consent to participate in the study before their demographic characteristics, medical history and use of concomitant medications were recorded and an oral soft tissue (OST) examination was conducted. Each participant’s dentition was assessed sequentially for: evidence of EAR; gingival health status using the MGI [ ]; tooth mobility using a modification of the Miller scale [ ]; and sensitivity to an evaporative air stimulus (where a ‘yes’ response from the participant indicated sensitivity). The MGI score was assessed for the facial gingiva adjacent to the test area (exposed dentine) only of teeth exhibiting facial cervical EAR. Only those teeth with an MGI score of 0 (i.e., corresponding to ‘absence of inflammation’) were clinically assessed for mobility.
Eligible participants were supplied with a standard fluoride dentifrice (1000 ppm fluoride as sodium monofluorophosphate; Colgate ® Cavity Protection, Colgate-Palmolive Company, New York, NY, USA) and a toothbrush (Aquafresh ® Clean Control [Everyday Clean], GSK Consumer Healthcare, Weybridge, UK) to use twice daily for 4–6 w between the screening and baseline visits.
At the baseline visit, ongoing eligibility was assessed, any adverse events (AEs), incidents and changes to concomitant medications were recorded and compliance with use of the acclimatisation dentifrice was evaluated based on a participant-completed diary. Following an OST examination, the sensitivity of all clinically eligible teeth identified at screening was evaluated by the participant’s response to a tactile stimulus administered by a constant-pressure Yeaple probe [ ]. Those teeth meeting the required tactile threshold (≤20 g) were then evaluated for sensitivity to an evaporative (air) stimulus, assessed using the Schiff Sensitivity Scale [ ] and a 10-point visual rating scale (VRS). Within each of the studies, a single examiner performed all of the tactile threshold and evaporative (air) sensitivity assessments. The same examiner carried out all assessments for Studies 2 and 3, which took place at the same study centre. The assessments of evaporative sensitivity were conducted at least 5 min after the tactile assessment. The investigator who conducted the evaporative (air) sensitivity assessment selected two non-adjacent teeth, preferably in different quadrants, from those that met the qualifying sensitivity assessments (i.e., both the tactile threshold and Schiff sensitivity score criteria) to be evaluated for the remainder of the study.
Eligible participants were stratified according to the mean baseline Schiff sensitivity score of their two selected teeth, giving rise to three strata with mean baseline scores of 2, 2.5 and 3 (see Results section for details of stratum assignment). Within each stratum, participants were randomised (1:1:1) to an oral rinse study product (one of two experimental oral rinses or the placebo oral rinse) according to randomisation schedules generated by the Biostatistics Department of GSK Consumer Healthcare before the start of each study. Details of which rinses were used in each study are shown in Table 1 and Table 2 gives formulation details of the study rinses. Within each study, randomisation numbers were assigned by the study-site personnel in ascending numerical order as each participant was determined to be eligible. The clinical dental examiners, study statisticians, data management staff and other employees of the sponsor and study sites who could have influenced study outcomes were blinded to product allocation.
| Study 1 | Study 2 | Study 3 | |
|---|---|---|---|
| Rinse A | X | X | |
| Rinse B | X | X | |
| Rinse C | X | X | |
| Placebo | X | X | X |
| Study centre | Silverstone | Salus | Salus |
| Study dates | Sep–Dec 2015 | Sep–Dec 2015 | Jan–Apr 2016 |
| Rinse A | Rinse B | Rinse C | Placebo | |
|---|---|---|---|---|
| Dipotassium oxalate monohydrate | 1.5% | 1.5% | 2.0% | 0% |
| Sodium fluoride | 0 ppm | 0 ppm | 45 ppm | 0 ppm |
| pH | 4.5 | 7.0 | 4.5 | 4.5 |
| Sodium benzoate | X | – | X | X |
| Phosphoric acid | X | – | X | – |
| Methyl parahydroxybenzoate | – | X | – | – |
| Propyl hydroxybenzoate | – | X | – | – |
| Disodium phosphate, anhydrous | – | X | – | – |
a All rinses including the placebo contained identical amounts of water, glycerol, Cremophor RH60, cocamidopropyl betaine and sodium saccharin.
Participants were also supplied with a standard fluoride dentifrice (1000 ppm fluoride as sodium monofluorophosphate; Colgate ® Cavity Protection, Colgate-Palmolive Company, New York, NY, USA), wrapped in opaque white vinyl to conceal the product identity, to use in conjunction with the oral rinse products.
First use of the allocated study treatment was conducted under supervision at the study site. Participants first applied a full brush head of dentifrice and brushed for 1 min before expectorating. They then rinsed with 20 mL of water for 10 s, before rinsing with 10 mL of their assigned oral rinse for 1 min. Participants expectorated after each rinse; no further rinsing was allowed and they were not permitted to eat or drink for 30 min after rinsing. Participants continued to use their assigned regimen as directed twice daily for 8 w, recording each brushing/rinsing occasion in a diary. Further supervised brushing and rinsing was conducted at the Week 4 visit.
At each visit, participants underwent an OST examination before any clinical assessment of sensitivity. Compliance with use of the study products was assessed by review of the participant-completed diaries. Before their study visits, participants were asked to refrain from all oral hygiene procedures for at least 8 h, from eating and drinking for at least 4 h, and from excessive alcohol consumption for 24 h. Small sips of water were permitted for taking medication or to relieve thirst within the 4 h before the visits but not within 1 h. Throughout the study, participants were not permitted to use any oral care products other than those provided to them, nor any products (including home remedies) intended for treating sensitive teeth. Use of dental floss was permitted only for removal of impacted food and participants were not permitted to chew gum. Participants were requested to delay having any non-emergency dental treatment (including prophylaxis) until after study completion.
2.3
Assessments
Tooth sensitivity in response to tactile and evaporative (air) stimuli was reassessed at baseline and after 4 and 8 w of oral rinse use. Two independent stimulus-based efficacy measures were used to assess DH in accordance with published recommendations [ ]. Firstly, the tactile stimulus was administered using a constant-force (Yeaple) probe, which allowed application of a known force to the dentine surface. The greater the tactile threshold (i.e., the greater the force the participant could tolerate), the less sensitive the tooth. Testing began at a force of 10 g and was increased by 10 g with each successive challenge until either two consecutive ‘yes’ responses (with ‘yes’ indicating the stimulus caused pain or discomfort) were elicited from the participant at the same force setting (which was recorded as the tactile threshold in grams) or the maximum force was reached. At baseline, the maximum applied force was set at 20 g; at subsequent visits it was 80 g. If no pain response was found, the threshold was recorded as >80 g. The examiners were fully trained and experienced in using the Yeaple probe and recording tactile threshold data. The Yeaple probe was calibrated prior to use on each day participants were assessed, following a defined procedure that spanned the range of pressure used in the study.
Secondly, after a recovery period of at least 5 min following the evaluation of tactile threshold, evaporative (air) sensitivity was assessed by directing an air jet from a triple air dental syringe onto the exposed dentine surface of the isolated test tooth [ ]. The examiner’s assessment of the participant’s response to the air stimulus was recorded on the four-point Schiff Sensitivity Scale (where: 0 = participant does not respond to air stimulus; 1 = participant responds to air stimulus but does not request discontinuation; 2 = participant responds to air stimulus and requests discontinuation or moves from stimulus; 3 = participant responds to stimulus, considers stimulus to be painful and requests discontinuation of the stimulus) [ ]. Participants rated the intensity of their response to the evaporative (air) stimulus using a 10‐point VRS to mark their pain on a scale of 1 (‘no pain’) to 10 (‘intense pain’). The examiners were fully trained and experienced in administering and recording the evaporative (air) assessment.
Participants were also assessed with regard to DH-related impact on quality of life using the short-form Dentine Hypersensitivity Experience Questionnaire (DHEQ-15) [ ]; these results are not presented in the current paper.
2.4
Safety
Spontaneously reported AEs and any abnormalities in the OST examination were recorded from the time of supervised brushing with the acclimatisation dentifrice at the screening visit until 5 d after the last use of study product. The investigator assessed the relationship between the assigned regimen and the occurrence of each AE using clinical judgement, and graded the AE as mild, moderate or severe. Treatment-emergent AEs (TEAEs) were reported for the safety population, which included all randomised participants who received study product.
2.5
Data analysis
2.5.1
Sample size determination
In each study, sufficient participants were to be screened so that a minimum of 240 would be randomised to ensure that approximately 216 participants (72 per treatment group) completed the study. With 72 participants per group, the studies were estimated to have 80% power to detect a mean treatment difference of 0.36 in the primary efficacy variable of change from baseline in Schiff sensitivity score, using a two-sided t test at a significance level of 0.05 under Dunnett’s adjustment for two experimental products versus a placebo. The standard deviation used in the sample size calculation was 0.70, as derived from earlier studies (data on file).
2.5.2
Efficacy analyses
All efficacy analyses were performed on the intent-to-treat populations, defined as all participants who were randomised, who used a study oral rinse at least once, and who provided at least one post-baseline assessment of efficacy. Each study was analysed separately. All statistical analyses were conducted using SAS (version 9.2; SAS Institute Inc., Cary, NC, USA).
For each study, participant-level mean change from baseline (mean of the two selected test teeth) in Schiff sensitivity score at Week 4 and Week 8 (primary efficacy variable) was analysed using an analysis of covariance (ANCOVA) model with treatment as a factor and mean baseline Schiff sensitivity score as a covariate. Comparisons of each experimental oral rinse versus the placebo oral rinse or versus the other experimental oral rinse were adjusted for multiple comparisons using Dunnett’s procedure. Treatment differences were also calculated by Schiff stratification. Change from baseline in VRS score at Weeks 4 and 8 was analysed using an ANCOVA model with treatment and baseline Schiff stratification as factors and baseline VRS score as a covariate.
In Studies 1 and 2, non-parametric methods were used for analysis of change from baseline in tactile threshold at Weeks 4 and 8 as the assumptions of normality were not met for the ANCOVA model with treatment and baseline stratification as factors and baseline as a covariate. In Study 1, the change from baseline in tactile threshold at Weeks 4 and 8 was analysed using a non-parametric van Elteren test (with the baseline Schiff stratification as controlling factor) and two-sided Hodges–Lehmann estimates to calculate p-values and 95% confidence intervals (CIs), respectively. In Study 2, tactile threshold was analysed using a Wilcoxon rank-sum test and non-parametric Hodges-Lehmann estimates to calculate p-values and 95% CIs, respectively. In Study 3, the change from baseline in tactile threshold was analysed using the ANCOVA model with treatment and baseline stratification as factors and baseline tactile threshold as a covariate.
Stay updated, free dental videos. Join our Telegram channel
VIDEdental - Online dental courses
