Caries, Dental
Conditions
Brief summary
Adult tooth decay is an infectious disease that afflicts the majority of Americans aged 55 and older and is the most common chronic disease at midlife with an ever growing economic toll. Despite the fact that specific bacteria cause tooth decay, no FDA-approved anti-microbial treatment for decay is available to the American dental professional. The Prevention of Adult Caries Study (PACS) is a study designed to evaluate the efficacy of a topical, temporary, 10% w/v chlorhexidine dental coating in reducing new decay in adult dental patients at risk for decay.
Detailed description
The Prevention of Adult Caries Study (PACS) is a randomized, double-blind, placebo-controlled Phase III clinical trial conducted under F.D.A. Investigational New Drug license #45,466, with a target enrollment of 1000 at four clinical centers with vastly different populations. The centers participating in this proposed research are: Kaiser Permanente's Dental Plan in Portland, Oregon; Tufts University Dental Clinic in central Boston, Massachusetts; Delta Dental Massachusetts' Dental Clinic in Southborough, Massachusetts; and the dental clinic of the Tuba City Regional Health Care Corporation in Tuba City, Arizona. Kaiser Permanente's Center for Health Research in Portland, Oregon will act as the data-coordinating center, and Tufts University will act as the Administrative Center. This study is designed to evaluate the efficacy of a topical, temporary, 10% w/v chlorhexidine dental coating in reducing caries increment in at-risk adult dental patients. This study will treat participants in months 1(4 weekly applications) and 7(1 application) with final outcome measured at 13 months after randomization. Examiners were trained and certified before data collection started and were recalibrated annually. The primary outcome analysis in the intent -to- treat sample compares active to placebo group on the rank-normalized caries increment score, adjusting for examiner, age and age squared. Multiple imputation (data augmentation using MCMC) will be used to replace missing outcome. Planned secondary analysis examine the secondary caries increment outcomes using the same model, as well as parallel analyses in the per-protocol group. Safety of the coating will be evaluated by comparing development of resistant S. mutans or C. albicans as well as incidence of MedDRA-coded adverse events between the two arms.
Interventions
DRUG10% w/v chlorhexidine acetate coating FDA IND #45466
Dental coating topically applied by dental professional supragingivally to the full dentition
OTHERPlacebo
Sponsors
National Institute of Dental and Craniofacial Research (NIDCR)
Tufts University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 18 years of age and older * at least 20 intact natural teeth, excluding third molars * 2 or more lesions, of which at least one must be a cavitated D2 or D3 * willing and able to provide informed consent
Exclusion criteria
* pregnant or planning to become pregnant or planning to become pregnant during the study (breastfeeding is permitted) * use of fixed orthodontic appliances * allergic to any of the ingredients of the study medication * long-term antibiotic therapy * a history of, or currently active, radiation therapy for cancers of the head or neck * Sjögren's syndrome * advanced periodontitis * consumption of the equivalent of more than five servings of acidic or sugared drinks per day * having 10 or more lesions requiring restorative care at the time of the screening visit * remineralization therapy within one month of randomization * investigator discretion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Net D12FS Caries Increment (Total of Non-cavitated Lesions (D1), Cavitated Lesions (D2) and Sound Surfaces (S)) | (V1) to the 13 month follow-up visit | Study duration was too short to have progression from D2 (cavitated lesions) to D3 (cavitated lesions that involved dentin). D2 and D3 were treated equivalently for analysis. This measure is computed as the sum of weighted counts of transitions in tooth surface status (root and coronal surfaces combined) from randomization to the 13-month follow-up visit. Disease progression had a positive weight (e.g., S-to-D1 (sound to non-cavitated lesion) or D1-to-D2 (non-cavitated to cavitated lesion) = 1, S-to-D2 (sound to cavitated lesion)= 2). Reversal had a negative weight (e.g., D1-to-S = -1). No change, transitions to or from missing or unscorable, and impossible transitions had 0 weight. Incident fillings and crowns were treated the same as incident D2 lesions for purposes of scoring. More details of the transition weights may be found at Vollmer WM et al. (2010). Design of the Prevention of Adult Caries Study (PACS): a randomized clinical trial assessing the effect of a |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Net D12FS Caries Increment | Visit 1, 7-month follow-up, 13-month follow-up | This measure was computed similar to the total net D12FS increment, but separately scored and combined transitions from the baseline to 7-month visits and from the 7- to 13-month visits, rather than simply looking at the baseline to 13-month visits. |
| Total Crude D12FS Caries Increment | V1-13-month follow-up | Computed analogous to the total net D12FS caries increment, but ignoring reversals (essentially assigned them zero weight). Computed only using baseline to 13-month visit data. |
| Cumulative Crude D12FS Caries Increment | Visit 1, 7-month follow-up, 13-month follow-up | This is computed analogous to the cumulative net D12FS increment, but ignoring reversals by assigning them weights of zero. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Dental Coating Dental coating with all ingredients except Chlorhexidine topically applied by dental professional supragingivally to the full dentition | 493 |
| Active Dental Coating Dental coating with all ingredients including Chlorhexidine topically applied by dental professional supragingivally to the full dentition | 490 |
| Total | 983 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative withdrawal | 1 | 1 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Lost to Follow-up | 20 | 23 |
| Overall Study | Other | 0 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Active Dental Coating | Placebo Dental Coating | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 31 Participants | 30 Participants | 61 Participants |
| Age, Categorical Between 18 and 65 years | 459 Participants | 463 Participants | 922 Participants |
| Age, Continuous | 42.9 years STANDARD_DEVIATION 14.3 | 42.8 years STANDARD_DEVIATION 14.3 | 42.8 years STANDARD_DEVIATION 14.3 |
| Region of Enrollment United States | 490 participants | 493 participants | 983 participants |
| Sex: Female, Male Female | 250 Participants | 242 Participants | 492 Participants |
| Sex: Female, Male Male | 240 Participants | 251 Participants | 491 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 87 / 493 | 84 / 490 |
| serious Total, serious adverse events | 31 / 493 | 28 / 490 |
Outcome results
Primary
Total Net D12FS Caries Increment (Total of Non-cavitated Lesions (D1), Cavitated Lesions (D2) and Sound Surfaces (S))
Study duration was too short to have progression from D2 (cavitated lesions) to D3 (cavitated lesions that involved dentin). D2 and D3 were treated equivalently for analysis. This measure is computed as the sum of weighted counts of transitions in tooth surface status (root and coronal surfaces combined) from randomization to the 13-month follow-up visit. Disease progression had a positive weight (e.g., S-to-D1 (sound to non-cavitated lesion) or D1-to-D2 (non-cavitated to cavitated lesion) = 1, S-to-D2 (sound to cavitated lesion)= 2). Reversal had a negative weight (e.g., D1-to-S = -1). No change, transitions to or from missing or unscorable, and impossible transitions had 0 weight. Incident fillings and crowns were treated the same as incident D2 lesions for purposes of scoring. More details of the transition weights may be found at Vollmer WM et al. (2010). Design of the Prevention of Adult Caries Study (PACS): a randomized clinical trial assessing the effect of a
Time frame: (V1) to the 13 month follow-up visit
Population: Intention to treat (ITT) sample. Multiple imputation with 8 datasets imputed via Markov Chain Monte Carlo sampling was used to handle missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Net D12FS Caries Increment (Total of Non-cavitated Lesions (D1), Cavitated Lesions (D2) and Sound Surfaces (S)) | 2.43 weighted increment units/13 months | Standard Error 0.32 |
| Active | Total Net D12FS Caries Increment (Total of Non-cavitated Lesions (D1), Cavitated Lesions (D2) and Sound Surfaces (S)) | 2.68 weighted increment units/13 months | Standard Error 0.32 |
Comparison: We hypothesized a lower increment score for the active treatment group but carried out two-tailed hypothesis testing. Sample size was estimated with simulated data with rank normalized scores. We calculated that 832 participants would yield a power of 90% to detect a 20% reduction in caries incidence (from a hypothesized mean increment of 1.5), and adopted a target of 1000 randomized participants to allow for attrition.p-value: 0.5695% CI: [-0.6, 1.11]Regression, Linear
Secondary
Cumulative Crude D12FS Caries Increment
This is computed analogous to the cumulative net D12FS increment, but ignoring reversals by assigning them weights of zero.
Time frame: Visit 1, 7-month follow-up, 13-month follow-up
Population: Intention-to-Treat sample
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cumulative Crude D12FS Caries Increment | 11.39 caries increment units/13 months | Standard Error 0.42 |
| Active | Cumulative Crude D12FS Caries Increment | 10.72 caries increment units/13 months | Standard Error 0.43 |
Comparison: Hypothesized a lower increment for active treatment arm, although hypothesis testing was two-sided.p-value: 0.2495% CI: [-1.8, 0.45]Regression, Linear
Secondary
Cumulative Net D12FS Caries Increment
This measure was computed similar to the total net D12FS increment, but separately scored and combined transitions from the baseline to 7-month visits and from the 7- to 13-month visits, rather than simply looking at the baseline to 13-month visits.
Time frame: Visit 1, 7-month follow-up, 13-month follow-up
Population: Intention-to-Treat sample
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cumulative Net D12FS Caries Increment | 5.53 caries increment units/13 months | Standard Error 0.42 |
| Active | Cumulative Net D12FS Caries Increment | 5.88 caries increment units/13 months | Standard Error 0.43 |
Comparison: hypothesized a reduced caries increment in active arm, though conducted two-tailed hypothesis test.p-value: 0.5495% CI: [-0.77, 1.46]Regression, Linear
Secondary
Total Crude D12FS Caries Increment
Computed analogous to the total net D12FS caries increment, but ignoring reversals (essentially assigned them zero weight). Computed only using baseline to 13-month visit data.
Time frame: V1-13-month follow-up
Population: Intention-to-Treat sample
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Crude D12FS Caries Increment | 6.47 caries increment units/13 months | Standard Error 0.27 |
| Active | Total Crude D12FS Caries Increment | 5.96 caries increment units/13 months | Standard Error 0.28 |
Comparison: Hypothesized lower increment in active arm, though hypothesis testing was two-sided.p-value: 0.1895% CI: [-1.25, 0.23]Regression, Linear