X-ACT

Report
1
Implications of the Xylitol for Adult
Caries Trial (X-ACT) for Prevention
Programs and Individuals
JP Brown1, BT Amaechi1, JD Bader2, GH Gilbert3, DA
Shugars2, and WM Vollmer4
1UTHSC
San Antonio TX
2UNC Chapel Hill NC
3UA Birmingham AL
4Kaiser Permanente CHR Portland OR
NIDCR U01DE018038, U01DE018047, U01DE018048, U01DE018049, U01DE018050
2
Presenter Disclosures
John P Brown
The following personal financial relationships with
commercial interests relevant to this presentation
existed during the past 12 months:
No relationships to disclose
and the X-ACT trial tested xylitol itself versus sucralose,
not commercial products containing these.
3
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.
4
X-ACT
Xylitol Reviews:
Hayes C, J Dent Educ, 2001
Lingström P, Acta Odont Scand, 2003
Maguire A, Brit Dent J, 2003
van Loveren C, Caries Res, 2004
Deshpande A, J Am Dent Assoc, 2008
Antonio, A, J Pub Health Dent, 2011
Rethman M, J Am Dent Assoc, 2011
SR = Systematic Review
TR = Traditional Review
SR
SR
TR
TR
SR
SR
SR
+
?
+
?
+
?
?
5
Rethman, et al. Nonfluoride caries-preventive agents : Executive summary of evidence-based clinical
recommendations. JADA 2011.
6
X-ACT
Recruitment/Enrollment
28-Day run-in period
Baseline Exam & Randomization
TEST
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
PLACEBO
12-Month Exam
24-Month Exam
33-Month Exam
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X-ACT
Trial Overview
•
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)
X-ACT
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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
X-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
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10
X-ACT
Withdrew during run-in
n=81
Began run-in
n=945
Declined to continue
n= 173
Randomized
Baseline n=691
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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Sample Characteristics
Trt
Cntl
Total
n=266
n=272
n=538
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%
Toothpaste or prof. topical fluoride
52.3%
62.9%
57.6%
Both toothpaste and prof. topical fluoride
37.6%
29.8%
33.6%
All sites
Race/Ethnicity
Extent of fluoride exposure
1data
expressed as mean (Standard deviation)
12
X-ACT
Adherence and Safety
• Adherence assessed quarterly, by selfreport 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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X-ACT
Results
Principal Outcome Analysis
(3 sites, n=669)
n
Xylitol
331
Placebo
338
Follow-up years
Baseline D2FS annualized
D2FS increment
2.55 (.49)
18.8 (12.8)
2.66
2.57 (.47)
18.5 (12.5)
2.97
Rate ratio = 0.90 95% CI 0.79-1.01 p=0.077
Prevented fraction = 0.11
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X-ACT
Results
Principal Outcome: Subgroup Analyses
D2FS increment Rate ratio
p value
Xylitol
Placebo
0-20
2.23
2.37
0.94
0.47
21+
3.66
4.39
0.83
0.06
Baseline D2FS
Baseline D2S
No significant difference for 0 versus 1+
Adherence
No significant differences for a three way split
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X-ACT
Discussion of Principal Outcome
• First large-scale, placebo-controlled, multisite, 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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X-ACT
Conclusion re Principal Outcome
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
Total
n 2°
266
272
538
n 1°
331
338
669
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Regression 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
*Cumulative Periods, Months
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.
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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.
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
*Cumulative Periods, Months
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.
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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.
Implications 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.
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