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An Abbreviated Caries Clinical Trial Design Validated over 24 Months
1 Unilever Dental Research, Port Sunlight, Quarry Road East, Bebington, Wirral CH63 3JW, UK; Correspondence: * corresponding author, Richard.Chesters{at}Unilever.com
Conventional caries trials last from 24 to 36 months. This study evaluated whether the previously established difference in efficacy between 1000- and 2500-ppm-fluoride dentifrices could be detected after 12 months. Caries was assessed by clinical visual assessment (CVA-simplified version of Dundee Selectable Threshold Method - DSTM), bitewing radiography, and Fiber Optic Transillumination (FOTI). Changes in status for individual surfaces were classified by means of pre-prepared matrices as 0 (unchanged), +1 (initiation or progression), or -1 (regression) and summed for each subject to yield an event score. Mean group event scores were calculated for each product. DSTM at the D1 [enamel and dentin] threshold showed significant inter-group differences in mean event scores (p < 0.003) and D1MFS increment (< 0.007) at 12 months; these were confirmed at 24 months by traditional increment analysis (CVA & FOTI at the D3 (dentin only) threshold + radiography, p < 0.03). This study confirms the validity of an abbreviated trial protocol.
Key Words: caries clinical trials • fiber optic transillumination • clinical visual assessment • Dundee Selectable Threshold Method • digital radiography
Our understanding of the dental caries process has evolved in recent years. Caries is now considered to be a continuum, with some early lesions detected at the D1 threshold (enamel and dentin) proving to be reversible through net remineralization, and advanced lesions detected at the D3 threshold (dentin only) manifesting as cavitation (Pitts, 1985; Ismail, 1997; Featherstone, 2000; Alfano et al., 2001). However, caries clinical trials are still traditionally performed at the D3 diagnostic threshold over periods of up to 3 yrs (Stookey et al., 1993) and require large numbers of subjects (Kingman and Selwitz, 1997). Caries clinical trial design needs to be reviewed to keep pace with our evolving understanding of caries and developments in diagnostic techniques (Pitts, 1997).
This study was designed to evaluate the use of visual assessment, including non-cavitated enamel caries lesions, as well as other diagnostic methods in a 12-month clinical trial methodology for demonstrating known differences in efficacy between conventional (1000 ppm fluoride) and high-fluoride (2500 ppm F) dentifrices. Products with these fluoride levels have shown differing anticariogenic efficacies in 36-month trials (Stephen et al., 1988; Marks et al., 1994). The traditional caries 24-month increment (D3MFS index) was used as the benchmark for assessing anticaries efficacy. This paper reports data obtained by clinical visual assessment (CVA) with a simplified version of the Dundee Selectable Threshold Method (DSTM) (see Table 1
Boys and girls aged 11–14 yrs from 28 of the larger schools in Vilnius, Lithuania, were recruited. For study inclusion, subjects were required to have at least one erupted second permanent molar and a CVA D3MFS score of between 2 and 24. Low-caries subjects were excluded because previous experience had shown that they would develop few new lesions over the next 2-3 yrs. Written informed consent was obtained from each child and parent or guardian. Subjects were excluded from the trial if the parent/guardian was unwilling to disclose the child’s medical and dental history, or if the child had received an intra-oral x-ray for caries diagnosis in the previous 6 mos or had > 2 occlusal surfaces of second permanent molars that were restored and/or clinically cavitated and/or sealed. Other exclusion criteria included: inability for an oral examination to be conducted without causing unacceptable stress to the subject; medical or dental conditions likely to have a significant influence on dental caries development (e.g., long-term antibiotic therapy); a heart condition or treatment for cancer; and the presence of fixed orthodontic appliances at the baseline examination that made it impractical for all erupted teeth to be assessed. Subjects were screened against the inclusion/exclusion criteria, and suitable candidates were enrolled by a dedicated assessor (J.M.) who was not involved in the further examination of subjects. Prior to subject recruitment, approval for the study was obtained from the Lithuanian National Committee on Biomedical Ethics, the head teachers at the schools, and the Education Authority. Since the study population was at high risk for developing caries, participation in the study was considered to be to their benefit. Subjects/parents were provided with copies of all radiographs for use in treatment planning. Subjects meeting the selection criteria underwent baseline examination between January and May, 1999, and were then randomized to one of two silica-based dentifrices containing either 1000 or 2500 ppm fluoride as sodium monofluorophosphate (SMFP). Subjects were instructed to brush their teeth with their assigned dentifrice at home twice daily and to take part in a daily school brushing program during term-time; the use of fluoride-containing mouthwashes or other fluoride supplements (e.g., tablets) was discouraged. This double-blind study was designed to determine whether the significant efficacy difference expected between a conventional and a high-fluoride dentifrice could be detected at the D1 level after 12 months’ product use, and to compare the 12-month findings with 24-month data based on a traditional increment analysis.
At baseline, 12-, and 24-month examinations, caries status was assessed according to a simplified version of the DSTM for caries detection and measurement adapted for use in clinical trials (Table 1 Subjects brushed their teeth prior to assessment, and the investigator assessed all available permanent teeth visually with a mirror, with the subject in the prone position, and using good lighting on clean, dry teeth. Approximal and occlusal surfaces of posterior teeth were then examined by FOTI and scored as 0 (no evidence of caries), 1 (evidence of a caries lesion as a shadow, possibly restricted to enamel), or 2 (strong shadow probably involving dentin). For radiographic assessment, bitewing radiographs were taken by means of the DEXIS digital system and Oralix Gendex AC x-ray tube. Approximal and occlusal surfaces of posterior teeth, from the distal surface of the second permanent molar to the mesial surface of the first premolar, were scored radiographically from computer images and coded (Pitts, 1984). For determination of intra-examiner reliability, repeat DSTM and FOTI examinations were performed throughout the baseline, 12-, and 24-month examinations on 5 to 10% of subjects. For radiography, the baseline and 12- and 24-month radiographs were re-assessed for 5 to 10% of subjects. It was estimated that a sample size of 1000 subjects per group would be required to provide the study with 80% power to detect a statistically significant difference in favor of the 2500-ppm-F group at the p < 0.05 level (one-tailed test), assuming a coefficient of variation of 1.0, a true 12.5% difference at 24 mos, and a 10% annual attrition rate. Since the likely attrition rate in this population was unknown, it was agreed that up to 1500 subjects would be enrolled per treatment group.
Subjects (the unit of randomization) were stratified into 12 strata according to gender (M/F), D1MFS score (2-16, 17-26, > 26), and second molars with surfaces at risk (DSTM codes U, S, W, K, or H [see Table 1 Neither the subjects, the clinical examiners, nor those distributing the test products were aware of the product identities at any time during the trial. The investigators were supplied with sealed code-break envelopes that could be opened in an emergency. This was not required, and the integrity of the product code was confirmed with regular GCP monitoring and independent audit. The examiners were blind to the original dental record of the subject. The statistical manager was notified which pairs of product codes were the same product, but not which product was which.
Data obtained from DSTM, FOTI, and radiography assessments at baseline, 12, and 24 mos were used in an events analysis, which involved transition matrices based on lesion depth for recording caries initiation, progression, and regression (Pitts, 1985). An "event" was defined as a clinically observed transition in the caries status of a surface. Surface changes could be positive, negative, stable, or void (Fig. 1
Statistical assessment of the treatment effect was primarily performed by an analysis of variance procedure on the number of specific transitions (both negative and positive) for subjects seen at the relevant examinations. The mean group event score for each dentifrice group was calculated from the event score per subject. As the net sum of positive-negative events for each subject, the event score reflects the overall caries de- and re-mineralization process, and is analogous to the net caries increment per subject. Paired comparison of mean group event scores was performed with use of the z-test with the residual standard deviation of the analysis of variance and the application of two-tailed criteria. We calculated the net increment by considering the change (+ or -) in caries status for each surface alone and then combining these to give the net change per subject. Traditional increment analysis used the data from CVA and FOTI at the D3 threshold and bitewing radiography (all radiolucencies) to classify each surface as sound/ decayed/filled/missing at each examination, with the most severe score used to define the surface status at that time point. The increment was then calculated by assessment of any alterations in the status of each surface to give a net change for each subject over that time period. The traditional 12- and 24-month caries increment data were then analyzed by the above statistical methods.
The flow of subjects through the study is shown schematically in Fig. 2  . At baseline, the mean D1MFS (± SE) scores for the 12- and 24-month examination populations were slightly higher in the 1000-ppm-F group [32.89 (± 0.40) and 32.95 (± 0.42)] than in the 2500-ppm-F group [31.99 (± 0.37) and 32.01 (± 0.37)], although the differences were not statistically significant. There was no significant difference between the two product groups with regard to mean D3MFS at baseline for the 12- or 24-month population. The reproducibility of the 3 techniques used in the present study was excellent, with Kappa values > 0.8, even when the D1 threshold was used.
Results from the traditional increment analysis for the simplified DSTM at 12 and 24 mos are shown in Table 2 . As expected, there was no significant difference between the two product groups after 12 mos, but a significant product effect was seen after 24 mos. In contrast, CVA with DSTM showed a significant product effect at both 12 and 24 mos by D1 increment analysis, though not for D3.
Results from events analysis at 12 and 24 mos are also shown in Table 2  . A significant difference was demonstrated between the 2 dentifrices by DSTM at the D1 threshold after 12 mos of product use. No significant difference was seen between the two product groups at the DSTM D3 threshold at this time, although the trend was similar to that at the D1 threshold. Likewise, after 24 mos of product use, a significant difference was observed at the D1 (but not at the D3 threshold) when FOTI and radiography were not included.
Using a variety of diagnostic techniques in the current trial (CVA, FOTI, and bitewing radiography), we assessed the validity of adopting an abbreviated (12-month) protocol at a location with a background caries prevalence comparable with that reported in a caries clinical trial conducted in western Europe in the 1980s (Stephen et al., 1988). As previously reported in conventional caries clinical trials (Stookey et al., 1993), none of these 3 diagnostic techniques (CVA, FOTI, and bitewing radiography) proved capable of differentiating between the 2 dentifrices (of proven differing anticariogenic efficacies) at the D3 threshold after 12 months’ use. In contrast, CVA with the simplified DSTM alone at the D1 threshold allowed statistically significant differences between these products to be demonstrated after 12 mos. Supplementation of the DSTM data with the FOTI plus radiographic findings failed to produce significant product differentiation at the D3 threshold after 12 mos, but, as expected, resulted in statistically significant differences between the products at 24 mos, consistent with the findings of previous caries clinical trials (Stephen et al., 1988; Marks et al., 1994). In conclusion, CVA can be used as the sole diagnostic method in caries clinical trials, when non-cavitated enamel lesions are included. The results from this abbreviated 12-month trial design using the D1 threshold mirror those from more conventional increment analysis based on CVA, FOTI, and radiographic data at 24 mos.
We thank Dr. C. Deery, formerly of the University of Dundee, and all the support team in Lithuania. The study was funded by Unilever Dental Research.
A supplemental appendix to this article is published electronically only at http://www.dentalresearch.org. Received for publication October 8, 2001. Revision received June 26, 2002. Accepted for publication July 9, 2002.
Journal of Dental Research, Vol. 81, No. 9,
637-640 (2002) This article has been cited by other articles:
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