Abstract
Objectives
To explore relative efficacy of six negative-control dentifrices utilised as controls in clinical studies compared with two dentine hypersensitivity (DH)-relief dentifrices used 2×/day for 8 weeks.
Methods
Six control dentifrices differing in terms of fluoride source (sodium fluoride/sodium monofluorophosphate), abrasive base (silica/dicalcium phosphate), relative dentine abrasivity (RDA) (∼17 to ∼180) and colour (white/blue/multicoloured stripes) were compared with a depolarising dentifrice (5% KNO 3 ; RDA ∼70–97; ‘Test 1’) and an occlusion-technology dentifrice (0.454% SnF 2 ; RDA ∼160–180; ‘Test 2’). DH was assessed using tactile and evaporative (air) (measured by Schiff Sensitivity Scale and a visual rating scale [VRS]) stimuli.
Results
In total 249 subjects were randomized. All dentifrices yielded statistically significant improvements from baseline on all endpoints. The two DH-relief dentifrices ranked highest in terms of improvement in scores over the control dentifrices. While there was a clear differentiation between Test 1 and control dentifrices on both measures at 4/8 weeks, for Test 2, statistically significant improvements in Schiff scores were observed over all controls at Week 4 but only over three at Week 8. At Week 4 none of the controls separated from Test 2 on tactile threshold; all separated by Week 8. VRS scores did not separate test and control dentifrices. Dentifrices were generally well-tolerated.
Conclusions
The six negative-control dentifrices can be used to assess dentifrices considered to be effective in reducing DH. Although response ranges for commercially available negative controls varied, these results may begin to set acceptable performance ranges for control dentifrices in DH trials.
1
Introduction
The pain of dentinal hypersensitivity (DH) is postulated to occur when a stimulus applied to exposed dentine causes fluid movement within dentine tubules, which in turn stimulates nerve processes and produces impulse transmission perceived as pain . Based on this hypothesis, two treatment approaches are commonly used in dentifrices for DH management: i) nerve-depolarising agents, such as potassium ions, postulated to interfere with neural transduction of pain stimuli , and ii) tubule-occluding agents, such as strontium salts , bioglasses , arginine and stannous fluoride (SnF 2 ) , which work toward sealing or physically blocking the exposed ends of the dentinal tubules, thereby reducing fluid movement within tubules and lessening the effect of external stimuli .
The clinical efficacy of a range of dentifrice products for DH relief has been examined in numerous clinical studies with a variety of designs, largely based on standard ‘guidelines’ since 1997 . These have included investigations into the efficacy of both depolarising and occlusion formulations compared with a range of controls. A systematic review and meta-analysis of desensitising dentifrice performance versus placebo has been published by Bae and colleagues .
To date there is no accepted ‘standard’ negative-control dentifrice recommended for inclusion in DH studies. Published studies have used a range of available dentifrices, making it difficult to compare findings across studies. For example, while Parkinson and colleagues used a dentifrice containing 0.15% fluoride as sodium monofluorophosphate (SMFP) in their studies , Zaidel and colleagues used one containing 0.24% fluoride as sodium fluoride (NaF) , both of which are marketed dentifrices. Furthermore, such studies have been conducted in different countries, with diverse populations, at a variety of clinical sites, and by different dental examiners, thus introducing further sources of variability.
In oral health research, true placebo dentifrice formulations (fully blinded and matched to all physical and organoleptic parameters such as taste, viscosity, abrasivity, colour, etc.) can be difficult and complex to manufacture. Hence, the efficacy of a dentifrice with a novel potential anti-sensitivity activity is often evaluated against that of a commercially available negative-control dentifrice. This is usually a fluoride-containing dentifrice with no known (published) anti-sensitivity efficacy and containing no recognised anti-sensitivity agents or known occluding agents such as certain dental abrasive silica grades. While it is both convenient and scientifically appropriate to compare the potential new dentifrice against commercially available fluoride dentifrices to document efficacy of a new formulation, the lack of true blinding can raise doubts regarding potential bias. Furthermore, while many DH studies have shown clear benefits for test dentifrices containing an anti-sensitivity agent versus controls, despite using the same or similar test dentifrices and study design, results from other studies have been inconclusive or inconsistent . These results may be due to simple statistical probability or irreproducible efficacy of the test formulation; however, the more ‘routine’ and random failure of clinical studies expected to reproducibly differentiate between dentifrices merits further examination and clinical investigation.
Generally, studies in which anti-sensitivity dentifrices do not separate from controls can be characterised as reporting unexpectedly large control group responses resulting in little differentiation from the test dentifrice. Some investigators have speculated that the unexpectedly large control group responses could be due to the inclusion of a negative control with anti-sensitivity properties derived from an unrecognised agent. Some silicas, for example, may have occluding, and therefore anti-sensitivity, properties . Other physical and organoleptic parameters, such as taste, viscosity, abrasivity, and colour, have the potential to influence results. Another feature of dentifrices that may impact DH is their degree of abrasivity. The abrasiveness of a dentifrice formulation on dentine is generally defined by the quantitative in vitro measure relative dentine abrasivity (RDA) . There is evidence to suggest that dentifrices with a higher RDA are associated with increased dentine loss and hence may contribute to DH . Thus, evaluation of dentifrices that are not abrasivity-matched may also confound clinical trial results. In view of these factors, detailed consideration should be given to the most appropriate choice of comparator dentifrice in DH efficacy studies.
Finally, the ‘clinical trial effect’ itself (i.e., a positive response arising simply from the act of intervention rather than from the action of an active ingredient) may also contribute to unexpected outcomes in DH dentifrice clinical trials. Given the subjective nature of pain, studies investigating its management are often difficult to conduct and interpret; clinical studies of DH are no exception. In particular, a considerable placebo effect has been reported in clinical studies of DH, with an estimated 20–60% of the improvement in symptoms being attributed to such an effect . Attempts to address the placebo effect include incorporation of an ‘acclimatisation’ period into the clinical study design, such that subjects are requested to use a standard dentifrice before use of study products to minimise the bias associated with participating in a clinical trial (e.g., studies by Schiff et al. , West et al. and Yates et al. ).
The aim of this 8-week study was to rank order the performance of a range of negative-control dentifrices containing fluoride as either NaF (at concentrations of 1100 or 1150 ppm fluoride) or SMFP (at 1150 ppm fluoride), and differing by base (silica or dicalcium phosphate), RDA (from ∼17 to ∼120) and/or colour (white, blue or white/blue/green stripes). Where possible, the negative-control dentifrices were chosen to match those reported to have been used in DH clinical trials over the last 10 years (e.g. studies by Parkinson et al. , Zaidel et al. , He et al. , Schiff et al. , Li et al. ). These negative-control dentifrices were compared with a clinically proven depolarising dentifrice containing 5% potassium nitrate and a clinically proven occlusion-technology dentifrice containing 1150 ppm SnF 2 . The actions of these dentifrices on DH were assessed using a tactile stimulus (assessed via tactile threshold) and an evaporative (air) stimulus (assessed using the Schiff Sensitivity Scale [3] and a visual rating scale [VRS]). To limit variability, the study was conducted by one dental examiner at a single clinical site.
2
Methods
This was an 8-week single-centre, randomised, single-examiner, single-blind (blinded to the examiner), eight-treatment, parallel-group, stratified (by maximum baseline Schiff sensitivity score of the test teeth) study in healthy subjects with self-reported and clinically diagnosed DH and at least two sensitive teeth. It was conducted in the USA by Silverstone Research Group in accordance with the Declaration of Helsinki and was approved by an independent research ethics committee before initiation (US Investigational Review Board Inc.; IRB number: U.S.IRB2014SRG/06). There was one minor protocol amendment that did not affect study flow or outcome.
2.1
Subjects
The study enrolled healthy subjects aged 18–55 years with no clinically significant or relevant abnormalities on oral examination. Subjects were required to have a self-reported history of DH lasting more than 6 months but not more than 10 years, and ≥20 natural teeth. At screening, eligible subjects had at least four accessible teeth (incisors, canines or premolars) with signs of erosion, abrasion and/or facial/cervical gingival recession (EAR), a Gingival Index score ≤1, a clinical mobility score ≤1 and a positive response to a qualifying evaporative (air) assessment. At baseline (Day 0), eligible subjects had a minimum of two accessible, non-adjacent teeth with signs of sensitivity, determined by a qualifying tactile stimulus threshold of ≤20 g and a Schiff sensitivity score ≥2.
General exclusion criteria included pregnancy; breastfeeding; any known/suspected allergy/intolerance to study materials/ingredients; participation in another clinical study or receipt of an investigational drug within 30 days of screening or participation in a tooth-desensitising treatment study within 8 weeks of screening; presence of any chronic debilitating disease that could affect study outcome; any condition/current medication causing clinically relevant xerostomia; daily use of medication that could affect pain perception; current use of antibiotics or use within 2 weeks of baseline visit.
General oral exclusions included dental prophylaxis within 4 weeks of screening; tongue/lip piercings; presence of dental implants; desensitising treatment or tooth bleaching within 8 weeks of screening; gross periodontal disease; treatment of periodontal disease within 12 months of screening; scaling or root planing within 3 months of screening; exposed dentine with deep, defective or facial restorations; teeth used as abutments for fixed/removable partial dentures; full crowns or veneers; orthodontic bands; cracked enamel; sensitive teeth with contributing aetiologies other than EAR. Specific dentition exclusions for test teeth included: evidence of current/recent caries, or reported treatment of decay within 12 months of screening; sensitive teeth not expected, in the investigator’s opinion, to respond to treatment with an over-the-counter dentifrice.
2.2
Procedures
At the screening visit, each subject 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 subject’s dentition was assessed sequentially for: evidence of EAR; gingival health status using the Gingival Index ; tooth mobility using a modification of the Miller scale ; and sensitivity to an evaporative (air) stimulus (where a ‘yes’ response from the subject indicated sensitivity).
Eligible subjects were supplied with a standard fluoride dentifrice (Colgate ® Triple Action, containing 1100 ppm fluoride as NaF; Colgate-Palmolive, Piscataway, NJ, USA) (‘Control 2’) and a toothbrush (Aquafresh ® Clean Control, GSK Consumer Healthcare, Weybridge, UK [GSKCH]) to use twice daily for 4–6 weeks between screening and baseline visits (acclimatisation period). The subjects’ first use of the dentifrice was carried out under supervision at the study site.
At the baseline visit (Day 0), 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 subject-completed diary cards. Following an OST examination, sensitivity of the clinically eligible teeth identified at screening was evaluated by the subject’s response to a tactile stimulus administered by a constant-pressure Yeaple probe . Teeth with a tactile threshold ≤20 g were evaluated for sensitivity to an evaporative (air) stimulus, assessed using the Schiff Sensitivity Scale and a 10-point VRS completed by the subject. The examiner selected two non-adjacent teeth to be evaluated for the remainder of the study from those that met the qualifying sensitivity assessments.
Before their study visits subjects were asked to refrain from all oral hygiene procedures and chewing gum 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 within 4 h before the visits but not within 1 h. During the study, subjects were not permitted to use any dental 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 the removal of impacted food. Subjects were requested to delay having any non-emergency dental treatment (including prophylaxis) until after study completion.
Eligible subjects were randomised to one of eight dentifrices, detailed in Table 1 , according to a randomisation schedule provided by the Biostatistics Department of GSKCH. Randomisation was stratified by maximum baseline Schiff sensitivity score (either 2 or 3) of the two selected test teeth. Randomisation numbers were assigned in ascending numerical order as each subject was determined to be eligible. The dental examiner, study statistician, data management staff and other employees of the sponsor who could have influenced study outcomes were blinded to the dentifrice allocation.
| Dentifrice | Active ingredients (base) | Colour | RDA | Product |
|---|---|---|---|---|
| Test 1 | 5% KNO 3 , 1150 ppm F as NaF (silica) | Pale green | ∼70–97 * | US Sensodyne ® Freshmint Maximum Strength a |
| Test 2 | 1150 ppm F as SnF 2 (silica) | Pale blue | ∼160–180 * | US Crest ® Pro-Health™ Healthy Fresh b |
| Control 1 | 1150 ppm F as SMFP (dicalcium phosphate) | White | ∼70 * | US Colgate ® Cavity Protection c |
| Control 2 | 1100 ppm F as NaF (silica) | White/blue/green stripes | ∼120 * | US Colgate ® Triple Action c |
| Control 3 | 1100 ppm F as NaF (silica) | Pale blue | ∼108 * | US Crest ® Cavity Protection b |
| Control 4 | 1150 ppm F as NaF (silica) | White | ∼17 ** | Non-marketed formulation |
| Control 5 | 1100 ppm F as SMFP (silica; 5% abrasive silica) | White | ∼99 ** | Non-marketed formulation |
| Control 6 | 1100 ppm F as SMFP (silica; 0% abrasive silica) | White | ∼19 ** | Non-marketed formulation |
* RDA is according to manufacturer.
** RDA tested during production.
a GSKCH, Weybridge, Surrey, UK; US marketed dentifrice.
b Procter & Gamble, Cincinnati, OH, USA; US marketed dentifrice.
c Colgate-Palmolive, Colgate-Palmolive, Piscataway, NJ, USA; US marketed dentifrice.
All study product tubes were overwrapped with white vinyl to assist in keeping the subject blinded to the product’s identity. Subjects brushed with a full ribbon of dentifrice for 1 timed minute, twice a day (morning and evening) for 8 weeks. First use of the study dentifrice was carried out under supervision at the study site and a further supervised brushing was conducted at the end of the Week 4 visit procedures. Compliance with use of the study dentifrice was assessed by review of the subject-completed diary cards.
Clinical assessments of tooth sensitivity in response to tactile (Yeaple probe) and evaporative (air) stimuli were made after 4 and 8 weeks of dentifrice use. At each visit, subjects underwent an OST examination before any clinical assessment of sensitivity.
2.3
Assessments
In accordance with consensus guidelines , two independent stimulus-based clinical measures were used to assess DH. Firstly, a tactile stimulus was administered using a constant-pressure (Yeaple) probe , which permitted application of a known force to the tooth surface. The greater the tactile threshold, the less sensitive the tooth. Testing began at a pressure 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 subject at the same pressure setting (which was recorded as the tactile threshold in grams) or the maximum force was reached. At baseline, the maximum force was set at 20 g; at subsequent visits it was 80 g.
Secondly, after a minimum 5-min recovery period following the evaluation of tactile threshold, evaporative (air) sensitivity was assessed by directing an application of air from a triple air dental syringe onto the exposed dentine surface from a distance of approximately 1 cm, with the test tooth surface isolated to prevent adjacent teeth or surrounding soft tissue being exposed to the stimulus . The examiner’s assessment of the subject’s response to the air stimulus was recorded on the Schiff Sensitivity Scale (0 = subject does not respond to air stimulus; 1 = subject responds to air stimulus but does not request discontinuation; 2 = subject responds to air stimulus and requests discontinuation or moves from stimulus; 3 = subject responds to air stimulus, considers stimulus to be painful and requests discontinuation of the stimulus) . Subjects rated the intensity of their response to the evaporative (air) stimulus using a 10-point VRS on which 1 = ‘no pain’ and 10 = ‘intense pain’. A single examiner performed all assessments for the duration of the study.
2.4
Safety
Spontaneously reported AEs and any abnormalities in the OST examination were recorded from the start of use with the acclimatisation dentifrice at the screening visit until 5 days after the last use of study dentifrice. The investigator graded the AEs as mild, moderate or severe and assessed whether they were treatment-related or not. Treatment-emergent AEs (TEAEs) were reported for the safety population, which included all randomised subjects who received the study dentifrice.
2.5
Data analysis
2.5.1
Sample size determination
As this study was exploratory in nature, it was not statistically powered to detect between-treatment differences. Based on outcomes from previous sensitivity studies , it was estimated that a sample of 30 subjects per group would have an 80% power to detect a difference between the dentifrices with known anti-sensitivity efficacy and the control dentifrices of 0.39–0.44 units in Schiff sensitivity score (assuming a standard deviation [SD] of 0.6) and 9.7–11.0 g in tactile threshold (assuming an SD of 15 g) at a 10% significance level. To achieve approximately 30 subjects completing treatment in each group, approximately 250 subjects were to be randomised to treatment and hence 270 subjects were required to enter the acclimatisation phase of the study.
2.5.2
Efficacy analyses
Efficacy analyses were performed on the intent-to-treat (ITT) population, defined as all randomised subjects who provided at least one post-baseline assessment of efficacy. The per-protocol population was defined as all subjects in the ITT population who had at least one efficacy assessment unaffected by protocol violations.
The efficacy variables were: subject-level change from baseline (mean of the two selected test teeth) at Weeks 4 and 8 in evaporative (air) sensitivity (Schiff Sensitivity Scale and VRS) and in tactile sensitivity (tactile threshold). Change from baseline was evaluated by analysis of covariance, with terms for treatment and the corresponding baseline score as a covariate. For tactile threshold and VRS, the maximum baseline Schiff sensitivity score of the two selected test teeth was included as a factor. For all treatment groups, adjusted means and 95% confidence intervals (CIs) were presented for mean changes from baseline to 4 and 8 weeks; these were used to assess the relative performance of each of the study products.
To rank the relative performance of the study treatments, the treatment differences, 95% CIs and p -values between each of the test dentifrices and the controls are presented. To control for the number of treatment comparisons, the Benjamini–Hochberg step-up procedure was used to control the overall false discovery rate (FDR) at 10% (adjusted p -values of <0.1 were considered statistically significant). The FDR is defined as the expected proportion of false discoveries, i.e., the proportion of rejected null hypotheses that are incorrect rejections. As the primary aim of this study was to rank the relative performance of the dentifrices rather than to detect significant differences between dentifrices, an FDR approach was planned to be used rather than the more conservative method of controlling the family-wise error rate (the probability of at least one false discovery, i.e., at least one incorrect rejection of null hypotheses that are true). In this manuscript, the adjusted means of treatments for changes from baseline at each post-baseline time point (obtained from ANCOVA models described above) were used to rank the treatments. The assumptions of normality were investigated and no violations were observed.
2
Methods
This was an 8-week single-centre, randomised, single-examiner, single-blind (blinded to the examiner), eight-treatment, parallel-group, stratified (by maximum baseline Schiff sensitivity score of the test teeth) study in healthy subjects with self-reported and clinically diagnosed DH and at least two sensitive teeth. It was conducted in the USA by Silverstone Research Group in accordance with the Declaration of Helsinki and was approved by an independent research ethics committee before initiation (US Investigational Review Board Inc.; IRB number: U.S.IRB2014SRG/06). There was one minor protocol amendment that did not affect study flow or outcome.
2.1
Subjects
The study enrolled healthy subjects aged 18–55 years with no clinically significant or relevant abnormalities on oral examination. Subjects were required to have a self-reported history of DH lasting more than 6 months but not more than 10 years, and ≥20 natural teeth. At screening, eligible subjects had at least four accessible teeth (incisors, canines or premolars) with signs of erosion, abrasion and/or facial/cervical gingival recession (EAR), a Gingival Index score ≤1, a clinical mobility score ≤1 and a positive response to a qualifying evaporative (air) assessment. At baseline (Day 0), eligible subjects had a minimum of two accessible, non-adjacent teeth with signs of sensitivity, determined by a qualifying tactile stimulus threshold of ≤20 g and a Schiff sensitivity score ≥2.
General exclusion criteria included pregnancy; breastfeeding; any known/suspected allergy/intolerance to study materials/ingredients; participation in another clinical study or receipt of an investigational drug within 30 days of screening or participation in a tooth-desensitising treatment study within 8 weeks of screening; presence of any chronic debilitating disease that could affect study outcome; any condition/current medication causing clinically relevant xerostomia; daily use of medication that could affect pain perception; current use of antibiotics or use within 2 weeks of baseline visit.
General oral exclusions included dental prophylaxis within 4 weeks of screening; tongue/lip piercings; presence of dental implants; desensitising treatment or tooth bleaching within 8 weeks of screening; gross periodontal disease; treatment of periodontal disease within 12 months of screening; scaling or root planing within 3 months of screening; exposed dentine with deep, defective or facial restorations; teeth used as abutments for fixed/removable partial dentures; full crowns or veneers; orthodontic bands; cracked enamel; sensitive teeth with contributing aetiologies other than EAR. Specific dentition exclusions for test teeth included: evidence of current/recent caries, or reported treatment of decay within 12 months of screening; sensitive teeth not expected, in the investigator’s opinion, to respond to treatment with an over-the-counter dentifrice.
2.2
Procedures
At the screening visit, each subject 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 subject’s dentition was assessed sequentially for: evidence of EAR; gingival health status using the Gingival Index ; tooth mobility using a modification of the Miller scale ; and sensitivity to an evaporative (air) stimulus (where a ‘yes’ response from the subject indicated sensitivity).
Eligible subjects were supplied with a standard fluoride dentifrice (Colgate ® Triple Action, containing 1100 ppm fluoride as NaF; Colgate-Palmolive, Piscataway, NJ, USA) (‘Control 2’) and a toothbrush (Aquafresh ® Clean Control, GSK Consumer Healthcare, Weybridge, UK [GSKCH]) to use twice daily for 4–6 weeks between screening and baseline visits (acclimatisation period). The subjects’ first use of the dentifrice was carried out under supervision at the study site.
At the baseline visit (Day 0), 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 subject-completed diary cards. Following an OST examination, sensitivity of the clinically eligible teeth identified at screening was evaluated by the subject’s response to a tactile stimulus administered by a constant-pressure Yeaple probe . Teeth with a tactile threshold ≤20 g were evaluated for sensitivity to an evaporative (air) stimulus, assessed using the Schiff Sensitivity Scale and a 10-point VRS completed by the subject. The examiner selected two non-adjacent teeth to be evaluated for the remainder of the study from those that met the qualifying sensitivity assessments.
Before their study visits subjects were asked to refrain from all oral hygiene procedures and chewing gum 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 within 4 h before the visits but not within 1 h. During the study, subjects were not permitted to use any dental 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 the removal of impacted food. Subjects were requested to delay having any non-emergency dental treatment (including prophylaxis) until after study completion.
Eligible subjects were randomised to one of eight dentifrices, detailed in Table 1 , according to a randomisation schedule provided by the Biostatistics Department of GSKCH. Randomisation was stratified by maximum baseline Schiff sensitivity score (either 2 or 3) of the two selected test teeth. Randomisation numbers were assigned in ascending numerical order as each subject was determined to be eligible. The dental examiner, study statistician, data management staff and other employees of the sponsor who could have influenced study outcomes were blinded to the dentifrice allocation.
