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Implications of the Xylitol for Adult Caries Trial (X-ACT) for Prevention

Programs and Individuals

NIDCR U01DE018038, U01DE018047, U01DE018048, U01DE018049, U01DE018050

JP Brown1, BT Amaechi1, JD Bader2, GH Gilbert3, DA Shugars2, and WM Vollmer4

1UTHSC San Antonio TX2UNC Chapel Hill NC 3UA Birmingham AL 4Kaiser Permanente CHR Portland OR

Presenter Disclosures

The following personal financial relationships with commercial interests relevant to this presentation existed during the past 12 months:

John P Brown

No relationships to disclose

and the X-ACT trial tested xylitol itself versus sucralose, not commercial products containing these.

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Trial Registration ClinicalTrials.Gov NCT00393055

Public Web Site www.kpchr.org/xact/public/index.aspx?pageid=1

Bader JD et al Design of the xylitol for adult caries trial (X-ACT) BMC Oral Health 2010 Sept 29;10:22.

Banting DW etal Examiner training and reliability in two randomized clinical trials of adult dental caries J Pub Health Dent 2011;71:335-44.

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X-ACT Xylitol Reviews:

Hayes C, J Dent Educ, 2001 SR +Lingström P, Acta Odont Scand, 2003 SR ?Maguire A, Brit Dent J, 2003 TR +van Loveren C, Caries Res, 2004 TR ?Deshpande A, J Am Dent Assoc, 2008 SR +Antonio, A, J Pub Health Dent, 2011 SR ?Rethman M, J Am Dent Assoc, 2011 SR ?

SR = Systematic ReviewTR = Traditional Review

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Rethman, et al. Nonfluoride caries-preventive agents : Executive summary of evidence-based clinical recommendations. JADA 2011.

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Recruitment/Enrollment

Baseline Exam & Randomization

28-Day run-in period

12-Month Exam

24-Month Exam

33-Month Exam

12-Month Exam

24-Month Exam

33-Month Exam

3, 6, 9 month telephone contact and resupply

3, 6, 9 month telephone contact and resupply

3, 6 month telephone contact and resupply

X-ACT

TEST PLACEBO

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Trial Overview

X-ACT

• Randomized controlled trial• Double blind • Placebo controlled• Multi-site (UNC-CH, UA-B, UTHSC-SA)• 33 months• Caries-active adults 18-80 • Xylitol lozenges (5 per day x 1mg = 5 grams/day)

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X-ACT Caries Examinations

• D1 Non-cavitated Lesions; D2 Cavitated Lesions (ICDAS criteria with categories consolidated)

• 9 surfaces/tooth (root and crown combined)

• 4-day training and calibration

• 5% reliability sample at each exam

• Principal examiners completed >96% exams

• Inter-examiner reliability at training: 0.67, 0.74, 0.76 Kappa

• Mean inter-examiner reliability at exams: 0.58, 0.88, 0.67, 0.71 Kappa

9X-ACT Analyses

• Principal outcome: D2 crude annualized increment

• Imputed missing data

• Negative binomial regression models

• Controlled for age, oral hygiene, baseline D2FS, fluoride exposure, dental cleaning history

• Subgroup analyses by baseline D2FS, D2S, adherence, sex, race/ethnicity

10 X-ACT Began run-in

n=945

RandomizedBaseline n=691

Declined to continue n= 173

Withdrew during run-in n=81

Xylitol n=344

Placebo n=347

Final Visit n= 282 (82%)

Final Visit n=291 (84%)

In analyses n=331

In analyses n=338

Telephone contact/resupply at 3, 6, 9 months each year. Clinical exams and questionnaires at Baseline, 12, 24, and 33 months.

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Trt Cntl Total

All sites n=266 n=272 n=538

Race/Ethnicity      

Non-Hispanic white 48.9% 52.6% 50.7%

Non-Hispanic black 27.1% 25.0% 26.0%

Hispanic 19.9% 19.5% 19.7%

Other 3.8% 2.9% 3.4%

Age 47.3 (13.4)1 48.8 (13.5)1 48.1 (13.4)1

Female 60.2% 67.3% 63.8%

Brushes 2+ times/day 63.2% 70.6% 66.9%

Flosses 1+ times/day 48.9% 47.8% 48.3%

Routine (exam/clean) dental visit in past year 34.2% 28.3% 31.2%

Self-report dry mouth 5.6% 9.6% 7.6%

Extent of fluoride exposure      

Toothpaste or prof. topical fluoride 52.3% 62.9% 57.6%

Both toothpaste and prof. topical fluoride 37.6% 29.8% 33.6%

Sample Characteristics

1data expressed as mean (Standard deviation)

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X-ACT Adherence and Safety

• Adherence assessed quarterly, by self-report and resupply quantity

• All adherence measures highly correlated

• Oral and GI side effects assessed quarterly

• Severe adverse events probed for annually

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Results Principal Outcome Analysis

(3 sites, n=669)

X-ACT

Rate ratio = 0.90 95% CI 0.79-1.01 p=0.077Prevented fraction = 0.11

Xylitol Placebon 331 338

Follow-up years 2.55 (.49) 2.57 (.47)Baseline D2FS annualized 18.8 (12.8) 18.5 (12.5)

D2FS increment 2.66 2.97

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Results Principal Outcome: Subgroup Analyses

X-ACT

D2FS increment Rate ratio p value

Xylitol PlaceboBaseline D2FS0-20 2.23 2.37 0.94 0.4721+ 3.66 4.39 0.83 0.06Baseline D2S No significant difference for 0 versus 1+Adherence No significant differences for a three way split

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Discussion of Principal Outcome

X-ACT

• First large-scale, placebo-controlled, multi-site, randomized, double-blind study of xylitol

• Lozenges, not gum: possible mechanical plaque removal, chewing stimulates saliva

• Adults, not children• Fluoride exposure from CWF• Regular dental attenders

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X-ACT

Discussion of Principal Outcome – cont’d

• Surfaces saved ~ 0.30/year (crude increment), NS

• Greater but NS effect in those with higher baseline D2FS, but not in those with higher D2S at baseline

• No indication of dose-response

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Conclusion re Principal Outcome

X-ACT

Xylitol lozenges (≤ 5gm/day),

used as a supplement,

in caries active adults (av. ~ 3 D2FS/year),

with adequate fluoride exposure,

did not substantially reduce their caries experience.

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Subjects in a Secondary Analysis seeking trial efficiency through assessing non-cavitated plus cavitated lesions (D12FS) were those who completed all four examinations – baseline, 12, 24, and 33 months.

Xylitol Sucralose

Treatment Control Totaln 2° 266 272 538n 1° 331 338 669

19Regression results for treatment effect of xylitol vs placebo on increment scores of cavitated lesions (D2FS) and non-cavitated lesions (D12FS) over three cumulative time periods, increments being annualised for each period.

CPM* D2FS D12FS

xylitol placebo RR 95% CI p xylitol placebo diff 95% CI p

0-12 2.70 3.25 0.83 (0.71, 0.98) 0.024 3.56 4.78 -1.23 (-2.59, 0.14) 0.078

0-12+

12-24

2.83 3.13 0.91 (0.80, 1.03) 0.118 3.50 4.05 -0.54 (-1.41, 0.33) 0.220

0-12+

12-24+

24-33

2.80 2.99 0.94 (0.84, 1.05) 0.264 3.46 3.63 -0.17 (-0.64, 0.30) 0.475

Regression models fit using negative binomial regression (for D2FS increments) and standard linear regression (for D12FS increments) adjusting for clinical center, age, age-squared, dental cleaning history, self-fluoride use, and oral hygiene practices. The negative binomial gives rise to coefficients having the interpretation of ln (rate ratios, RR) while standard linear regression results in absolute differences in increment (diff). These differing expressions are in accordance with the differing statistical distributions of the two outcomes.

*Cumulative Periods, Months

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Regression results for treatment effect of xylitol vs placebo on increment scores of cavitated lesions (D2FS) and non-cavitated plus cavitated lesions (D12FS) over three cumulative time periods, increments being annualised for each period, for a subset of selected participants with a baseline D2FS of more than 20.

Regression models fit using negative binomial regression (for D2FS increments) and standard linear regression (for D12FS increments) adjusting for clinical center, age, age-squared, dental cleaning history, self-fluoride use, and oral hygiene practices. The negative binomial gives rise to coefficients having the interpretation of ln (rate ratios, RR) while standard linear regression results in absolute differences in increment (diff). These differing expressions are in accordance with the differing statistical distributions of the two outcomes.

*Cumulative Periods, Months

CPM* D2FS D12FS

xylitol placebo RR 95% CI p xylitol placebo diff 95% CI p

0-12 2.92 3.78 0.77 (0.62, 0.97) 0.024 3.58 6.51 -2.93 (-4.98, -0.87) 0.005

0-12+

12-24

3.39 4.09 0.83 (0.71, 0.98) 0.024 4.69 5.84 -1.15 (-2.53, 0.24) 0.104

0-12+

12-24+

24-33

3.52 4.02 0.88 (0.76, 1.01) 0.074 4.32 4.98 -0.66 (-1.34, 0.01) 0.053

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Conclusions for this Secondary Analysis, assessing non-cavitated and cavitated lesions, over 12, 24, and 33 months

1. The xylitol effect for cavitated lesion (D2FS) declined over time, was significant only at 12 months, and was not of a clinically relevant size.

2. The xylitol effect for non-cavitated plus cavitated lesions (D12FS) declined over time, was not significant and was not of a clinically relevant size.

3. These results mirrored the principal trial outcome.

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The Secondary Analysis of selected subjects with higher lifetime caries experience at baseline showed:

4. for cavitated lesions (D2FS) a somewhat greater xylitol effect, declining over time, but significant only at 12 and 24 months

5. for non-cavitated plus cavitated lesions (D12FS) a decline in xylitol effect over time, significant only at 12 and 33 months.

These effects (4 and 5) were of larger magnitude, but then more total lesions were under consideration.

If non-cavitated lesions retardation (remin or stasis) was occurring, even in periods shorter than one year, this could be expected to reveal differences over a longer time as fewer lesions progressed. This was not observed.

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The X-ACT trial failed to reveal a substantive and consistent effect of xylitol,

even with the inclusion of early caries lesions,

and even in those subjects with higher lifetime caries experience at baseline.

24Implications of the X-ACT Xylitol Trial

1. Xylitol caries preventive effect in caries active adults with adequate fluoride exposure is small and not clinically relevant.

2. Even in subjects with higher baseline lifetime caries experience and presumably of even higher caries activity, the effect was marginal.

3. Using xylitol as a caries preventive agent in caries active adult patients is not well supported. (other reviews in children have been equivocal)

4. Using xylitol in organized public programs for caries prevention is not well supported.

5. Recommending xylitol as a caries preventive agent for populations has even less grounding.