results from the xylitol for adult caries trial

8/11/2019 Results from the Xylitol for Adult Caries Trial

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10.14219/jada.archive.2013.00102013;144(1):21-30JADA

and Michael C. LeoFunkhouser, Sonia K. Makhija, Andr V. RitterJohn P. Brown, Reesa L. Laws, Kimberly A.

Shugars, Gregg H. Gilbert, Bennett T. Amaechi,James D. Bader, William M. Vollmer, Daniel A.(X-ACT)Results from the Xylitol for Adult Caries Trial

September 12, 2014):online at jada.ada.org (this information is current as ofThe following resources related to this article are available

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Many adults continue todevelop dental caries

throughout their lifespans, and caries activity

in this population is at least asextensive as it is in children andadolescents.1 However, dental cariesprevention efforts historically havefocused on children rather thanadults. Public oral health programstargeting caries prevention foradults are uncommon, and provisionof caries-preventive treatment toadult dental patients at an elevated

risk of developing caries is relativelyinfrequent.2,3 One possible reasonfor this lack of attention may bethat knowledge of the effectivenessof caries-prevention methods foradults is incomplete. The 2001National Institutes of Health (NIH)Consensus Development ConferenceStatement on the Diagnosis andManagement of Dental CariesThroughout Life expressed concernregarding the paucity of studies inadults, noting that [a]lmost all ofthe relevant studies included popu-lations of children between 6 and 15

Dr. Bader is a research professor, Department of Operative Dentistry, School of Dentistry, University of North Carolina at Chapel Hill. He also is the associateeditor for evidence-based dentistry for The Journal of the American Dental Association. Address reprint requests to Dr. Bader at School of Dentistry, Uni-versity of North Carolina at Chapel Hill, CB#7450, Chapel Hill, N.C. 27599-7450, e-mail [email protected]. Vollmer is a senior investigator, Kaiser Permanente Center for Health Research, Portland, Ore.Dr. Shugars is a professor, Department of Operative Dentistry, School of Dentistry, University of North Carolina at Chapel Hill.Dr. Gilbert is a professor and the chair, Department of Clinical and Community Sciences, School of Dentistry, University of Alabama at Birmingham.Dr. Amaechi is an associate professor and the director of cariology, Department of Comprehensive Dentistry, Dental School, University of Texas HealthScience Center at San Antonio.Dr. Brown is a professor emeritus, Department of Comprehensive Dentistry, Dental School, University of Texas Health Science Center at San Antonio.Ms. Laws is a coordinating centers manager, Kaiser Permanente Center for Health Research, Portland, Ore.Ms. Funkhouser is a data manager, Kaiser Permanente Center for Health Research, Portland, Ore.Dr. Makhija is an associate professor, Department of Clinical and Community Sciences, School of Dentistry, University of Alabama at Birmingham.Dr. Ritter is a professor and the graduate program director, School of Dentistry, University of North Carolina at Chapel Hill.Dr. Leo is an investigator, Kaiser Permanente Center for Health Research, Portland, Ore.

Results from the Xylitol for Adult CariesTrial (X-ACT)

ABSTRACTBackground.Although caries is prevalent inadults, investigators have tested few preventive

therapies in adult populations. In a randomized

controlled trial, the authors evaluated the effec-

tiveness of xylitol lozenges in preventing caries in

adults at elevated risk of developing caries.

Methods.The Xylitol for Adult Caries Trial (X-ACT) was a three-site placebo-controlled randomized trial. Participants (n = 691) aged

21 through 80 years consumed five 1.0-gram xylitol or placebo

lozenges daily for 33 months. They underwent clinical exami-

nations at baseline and at 12, 24 and 33 months.

Results.Xylitol lozenges reduced the caries increment 10 percent.This reduction, which represented less than one-third of a surfaceper year, was not statistically significant. There was no indication

of a dose-response effect.

Conclusions.Daily use of xylitol lozenges did not result in a sta-tistically or clinically significant reduction in 33-month caries incre-

ment among adults at an elevated risk of developing caries.

Clinical Implications.These results suggest that xylitol usedas a supplement in adults does not reduce their caries experience

significantly.

Key Words.Xylitol; dental caries prevention; randomized con-trolled trial; adults.

JADA 2013;144(1):21-30. ClinicalTrials.gov identifier

NCT00393055.

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JADA 144(1) http://jada.ada.org January 2013 21

S T O R YC O V E R

James D. Bader, DDS, MPH; William M. Vollmer, PhD; Daniel A. Shugars, DDS, PhD, MPH;Gregg H. Gilbert, DDS, MBA; Bennett T. Amaechi, BDS, MS, PhD; John P. Brown, BDS, MS,PhD; Reesa L. Laws, BS; Kimberly A. Funkhouser, BS; Sonia K. Makhija, DDS, MPH;

Andr V. Ritter, DDS, MS; Michael C. Leo, PhD; for the X-ACT Collaborative Research Group

Copyright 2013 American Dental Association. All rights reserved.

on September 12, 2014jada.ada.orgDownloaded from
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22 JADA 144(1) http://jada.ada.org January 2013

years of age.4 The authors of both this state-ment and another published by the Centers forDisease Control and Prevention, Atlanta, thatsame year recommended evaluation of severalpreventive interventions in adult populations,particularly adults at an elevated risk of devel-oping caries.4,5

One potentially effective preventive interven-tion identified in the systematic review pre-pared for the NIH Consensus Development Con-ference was xylitol.6 Xylitol acts to reduce levelsof mutans streptococci in the plaque and saliva.The effectiveness of xylitol-based interventionshas been controversial, primarily because of dif-ferences in opinion regarding the quality of thepublished trials.7-9 Several reviews of portions ofthe evidence for the effectiveness of xylitol haveappeared during the past decade.10-17 The conclu-sions of these reviews differ, principally owing

to their assessments of the quality of thestudies. Some conclude that there is evidencefor a caries-preventive effect of xylitol, andothers indicate that the evidence is inconclusive.However, all of the review investigators indi-cated that the existing evidence should be sup-plemented by well-designed randomized con-trolled trials. The need for evidence is themotivation for the Xylitol for Adult Caries Trial(X-ACT). In X-ACT, we tested the hypothesisthat daily use of xylitol lozenges reduces dentalcaries incidence in adults at an elevated risk of

experiencing caries.

METHODS

Because a detailed description of study methodsappeared previously,18 we merely summarizethem here, together with describing one impor-tant change in the analysis plan.

Study design.X-ACT was a 33-month,multicenter, placebo-controlled, double-masked,phase 3 randomized controlled clinical trial totest the effectiveness of daily xylitol lozenge use(up to 5 grams per day) versus placebo lozengeuse to prevent caries in adults at elevated riskof experiencing caries. The primary outcomewas the increment of cavitated lesions. In thetrial, we randomly assigned 691 participants, 92percent of the goal of 750, with assignmentsstratified according to site and age and allocatedrandomly in blocks of varying size within strata.

We conducted the trial at three clinical cen-ters in the dental schools of the University ofNorth Carolina at Chapel Hill (UNC), the Uni-versity of Alabama-Birmingham (UAB) and theUniversity of Texas Health Science Center atSan Antonio (UTHSCSA). The Kaiser Perma-

nente Center for Health Research in Portland,

Ore., served as the data coordinating center.The institutional review board at each siteapproved the study, and all participants pro-vided written informed consent. The majority ofparticipants were recruited from amongpatients receiving treatment in the dentalschools clinics. Participants also were recruited

in regional dental clinics and throughadvertisements.

Study procedures.Figure 1 summarizesthe trial events from a participants perspective.The study required a participant to visit thedental school a minimum of five times. Initialtelephone or in-person screening preceded anenrollment visit to confirm eligibility and obtainconsent, which was followed by a four-week run-in period (involving the use of placebo lozenges)to allow both potential participants and studycoordinators to evaluate willingness to adhere

to the study regimen.19 We randomly assignedadherent, eligible participants to a study groupat a baseline visit and scheduled them to returnat 12 months, 24 months and 36 months forcaries examinations. Before the 24-month visitsbegan, we shifted the final examinationschedule to 33 months to adjust for slower-than-expected completion of enrollment. Quarterlytelephone contacts by research coordinators ateach site occurred between the annual follow-upvisits to arrange for resupply of lozenges,inquire about adherence, assess adverse effects

and screen for possible serious adverse events(SAEs).Inclusion and exclusion criteria.Inclu-

sion criteria were age of 21 through 80 years;the presence of at least one coronal or root-surface cavitated caries lesion (present atscreening or documented in the patient recordor by self-report as having been restored in theprevious year); the presence of at least 12 teeth;the ability to read and understand English; and

S T O R YC O V E R

ABBREVIATION KEY. C: Presence of crowns. D1: Non-

cavitated enamel lesion. D2: Cavitated lesion pene-trating the enamel or shadowing. D2FS: Cumulativedecayed or filled surface increment. D2S: Decayedsurface. D3: Cavitated lesion penetrating into thedentin. DSMB: Data safety and monitoring board.F: Presence of restorations. GI: Gastrointestinal.ICDAS II: International Caries Detection andAssessment System II. M: Missing teeth. NIH:National Institutes of Health. OTC: Over the counter.S: Sound. SAE: Serious adverse event. UAB: Univer-sity of Alabama at Birmingham. UNC: University ofNorth Carolina at Chapel Hill. UTHSCSA: Univer-sity of Texas Health Science Center at San Antonio.X-ACT:Xylitol for Adult Caries Trial. Y: Surfaces

unable to be scored.




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the ability to provide informed consent. Exclu-

sion criteria were the presence of extensivecaries (more than 10 teeth with lesions); perio-dontal disease requiring aggressive treatment;residing in the same household with anotherparticipant; or anticipated move within threeyears.

Study treatments.The intervention con-sisted of one lozenge dissolved in the mouth fivetimes during the day. Each active lozenge con-tained 1.0 g of xylitol as a sweetening agent.The placebo lozenge was identical in size andcolor to the active lozenge but was sweetenedwith sucralose, which lacks any plausible bio-logical cariostatic or cariogenic properties otherthan sugar substitution. Both the active andplacebo lozenges were peppermint flavored. Asecond placebo with different flavoring was usedfor the run-in period. At baseline, we providedparticipants with a sufficient number oflozenges for three months (seven containers of75 lozenges each), and we used the quarterlytelephone contacts to determine the number ofadditional containers needed for the next threemonths.

Caries examinations.Trained and cali-

brated examiners identified caries lesions visu-

ally by using a standard dental operating light

and chair, a nonmagnifying plane mirror and aCommunity Periodontal Index of TreatmentNeed-Epidemiologic (CPITN-E) probe. Exam-iners used loupes at their discretion, but consis-tently within each examiner. They dried toothsurfaces for five seconds with an air-watersyringe. They used a modification of the Inter-national Caries Detection and AssessmentSystem II (ICDAS II) criteria,20 in which fourdisease levels were possible for each coronalsurface: sound (S), noncavitated enamel lesion(D1) (ICDAS codes 1 and 2), cavitated lesionpenetrating the enamel or shadowing (D2)(ICDAS codes 3 and 4) or cavitated lesion pene-trating into the dentin (D3) (ICDAS codes 5 and6). Examiners scored tooth surfaces as sound(S), having a lesion with an estimated depth ofless than 0.5 mm (D1), and having a lesion withan estimated depth of 0.5 mm or greater (D 2).Other surface conditions noted were the pres-ence of pit-and-fissure sealants (P), the presenceof restorations (F), the presence of crowns (C),missing teeth (M) and surfaces unable to bescored (Y). Examiners made one classificationper tooth surface, with each tooth deemed to

have five coronal surfaces (including the incisal

S T O R YC O V E R

Recruitment/Enrollment

28-day run-in period Midperiod check-in call

Random assignment and baseline examination

Xylitol arm

Three-, six- and nine-month check-inand resupply calls

Placebo arm

Twelve-month examination Twelve-month examination

Twenty-fourmonth examination Twenty-fourmonth examination

Thirty-threemonth examination Thirty-threemonth examination



Figure 1.Sequence of trial events.




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surface) and four root surfaces.A primary examiner at each clinical center

completed almost all examinations (100 percentat UAB, 98 percent at UNC and 96 percent atUTHSCSA), although backup examiners wereavailable as needed. To the extent possible, thesame examiner who conducted the baseline

examination performed all follow-up exami-nations. A recorder was present for all cariesexaminations. Primary and back-up examinersand recorders from all three clinical centers par-ticipated in a four-day training and calibrationsession with a reference-standard examiner,21 aswell as refresher sessions before the 12-, 24- and33-month examinations. All primary examinerscompleted second examinations of approxi-mately 5 percent of participants annually todetermine intraexaminer reliability. Secondaryexaminers also completed examinations of these

participants.Study outcomes and statistical power.

The primary study outcome was the cumulativedecayed or filled surface (D2FS) increment (rootand coronal surfaces combined; D2and D3lesions combined for coronal surfaces) frombaseline through the three follow-up exami-nations, which we expressed in terms of anannualized increment. In the event of missedvisits, we based the increment on the observabletransitions, so that only participants with nofollow-up visits (5 percent of all randomly

assigned participants) had missing incrementscores. We computed the D2FS increment as theweighted sum of changes in surface status asso-ciated with 64 predefined transitions in tooth-surface status.18 We considered illogical rever-sals to be invalid transitions and gave them ascore of 0effectively excluding them from theanalyses. We also scored null transitions (suchas from F to F), transitions from D2to treatedstatus (F or C) or to or from an unscorablestatus (that is, Y or M) as 0. We scored transi-tions from S to C as 0 to minimize the influenceof noncaries-related treatment on incrementcounts. We designed the study to provide 80 per-cent power to detect a 20 percent reduction inthe D2FS increment assuming a two-tailed testwith a type I error rate of 5 percent. The targetsample size of 750 allowed a 10 percent attritionrate per year.

Covariates.We created several measures tocharacterize participants baseline oral healthand oral health care practices. These included abinary indicator of a routine dental visit (forprophylaxis or examination) in the past year, athree-level indicator of over-the-counter (OTC)

fluoride use (toothpaste, mouthrinse or both), a

five-level indicator of oral hygiene practices(from infrequent to frequent brushing andflossing) and the baseline D2FS count. We alsoassessed participants adherence by comparingthe number of containers of resupplied lozengeswith the number that would be used under idealadherence. (Authors note:Forms used for all

data collection are available on the studyspublic Web site, www.xactstudy.org.)

Safety monitoring.We asked participantsabout hospital admissions, gastrointestinal (GI)symptoms and mouth symptoms at three-monthintervals throughout the study. We also askedparticipants to characterize symptoms as severeor not severe.

Statistical methods.We performed mul-tiple imputations of missing data by using dataaugmentation with Markov Chain Monte Carlosampling (SAS 9.1 PROC MI, SAS Institute,

Cary, N.C.). We used an inclusive approach toimputation, as described by Collins and col-leagues,22 that included a wide range of base-line and interim variables to minimize bias.We carried out all analyses identically on alleight copies of the imputed data and combinedthem according to the Rubin23 rules to adjuststatistical test results for the uncertaintyinherent in the imputation process.

We conducted the primary outcome analysison the intent-to-treat sample using negativebinomial regression to model the ln(annual

incidence) as a function of the xylitol armwhile adjusting for clinical center, age atrandom assignment, age squared, dentalcleaning history, use of OTC fluoride, oralhygiene practices and severity of caries atbaseline (D2FS) and study site. The regressioncoefficients from this model have the interpre-tation of ln(rate ratios), but we have re-expressed them as rate ratios (RRs) for thetables, which can be interpreted as relativerisks. We included the natural log of person-years at risk as an offset to adjust for thevarying length of time from random assign-ment to final oral examination acrossparticipants.

During the final study year, the data coordi-nating center uncovered irregularities in par-ticipant data at the UTHSCSA site. After sub-sequent investigation, the studys data safetyand monitoring board (DSMB) deemed that,although the caries examination data appearedsound, the adherence data were unreliable. Inaddition, 10 participants who were householdmembers of existing participants had beenrandomly assigned in violation of the protocol.

The DSMB also could not discount the possi-

S T O R YC O V E R




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bility that some participants had receivedincorrect lozenges. The DSMB therefore recom-mended that the primary analysis be based ondata from only the unaffected sites, UNC andUAB, although secondary analyses couldinclude the caries examination data from allthree sites. They also agreed that, per protocol,we should exclude from all analyses the 10participants who had been randomly assignedin error. Because the UTHSCSA sites adher-ence data were unusable, we did not imputemissing data from that site. Thus, secondaryanalyses that include the UTHSCSA data donot include 12 UTHSCSA participants forwhom there were no follow-up data, 10 partici-pants who had been randomly assigned inerror and an additional five participants forwhom covariate data were missing.

Additional secondary analyses we reporthere were to assess the effect of xylitol in sub-

groups defined according to baseline D2FS

S T O R YC O V E R

score, baseline D2S (decayed surface) score,adherence to the study protocol (that is,lozenge use), sex, and race or ethnicity. For theD2FS score we used a binary split (0-20 versus21 or higher, roughly a median split), whereasfor D2S we defined groups as none versus any,and for adherence we defined three levels (0-40percent, 41-80 percent and 81-100 percent, cor-responding to roughly 20 percent, 40 percentand 40 percent of the sample) on the basis ofthe quantity of lozenges supplied as a per-centage of the quantity that the participantwould have used with perfect adherence. Forthe primary examiners, we report intraexam-iner reliability scores on the basis of a roughly5 percent convenience sample of participantswho returned for repeat examinations duringthe study. We report simple pairwise statis-tics for each year for the combined examinersreliability in distinguishing D2D3lesions from

all other surface conditions.

Enrollment visit(n = 945)

Ineligible (n = 4)Refused (n = 250)

Randomly assigned(n = 691)

Xylitol

Overall (n = 344)

UNC/UAB (n = 218)

UTHSCSA (n = 126)

Placebo

Overall (n = 347)

UNC/UAB (n = 219)

UTHSCSA (n = 128)

No follow-up visits (n = 20; 12 UNC/UAB, 8 UTHSCSA)

One follow-up visit (n = 13; 11 UNC/UAB, 2 UTHSCSA)

Two follow-up visits (n = 39; 15 UNC/UAB, 24 UTHSCSA)Three follow-up visits (n = 272; 180 UNC/UAB, 92 UTHSCSA)

Any follow-up visit (n = 324; 206 UNC/UAB, 118 UTHSCSA)

Final follow-up visit (n = 282; 189 UNC/UAB, 93 UTHSCSA)

No follow-up visits (n = 14; 10 UNC/UAB, 4 UTHSCSA)

One follow-up visit (n = 13; 9 UNC/UAB, 4 UTHSCSA)

Two follow-up visits (n = 41; 10 UNC/UAB, 31 UTHSCSA)Three follow-up visits (n = 279; 190 UNC/UAB, 89 UTHSCSA)

Any follow-up visit (n = 333; 209 UNC/UAB, 124 UTHSCSA)

Final follow-up visit (n = 291; 196 UNC/UAB, 95 UTHSCSA)

Analyzed for primary outcome

Overall (n = 329; 218 UNC/UAB; 111 UTHSCSA)

Not in analysis (n = 15)

Dual household participants at UTHSCSA site (n = 5)

UTHSCSA participants with no follow-up data (n = 8)

UTHSCSA participants with missing covariate data (n = 2)

Analyzed for primary outcome

Overall (n = 335; 219 UNC/UAB; 116 UTHSCSA)

Not in analysis (n = 12)

Dual household participants at UTHSCSA site (n = 5)

UTHSCSA participants with no follow-up data (n = 4)

UTHSCSA participants with missing covariate data (n = 3)

Figure 2. Participant flowchart. UAB: University of Alabama at Birmingham. UNC: University of North Carolina at Chapel Hill.UTHSCSA: University of Texas Health Science Center at San Antonio.




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among the primary analysissample (the 437 randomlyassigned participants from UNCand UAB). (Authors note:Tables for each site are availableat www.xactstudy.org).

Examiner reliability.The

target intraexaminer reliabilityvalue (unweighted value; D2D3versus all else) for primary exam-iners during examiner trainingwas 0.70. The mean valueachieved for the three primaryexaminers was 0.72.18 The meanvalues achieved during the par-ticipant examinations were 0.58,0.88, 0.67 and 0.71 for the base-line and 12-, 24- and 33-monthexaminations, respectively. The

baseline value was lower prima-rily owing to small numbers ofobserved lesions at one site.

Primary outcome analysis.Among participants from theUNC and UAB sites, the crudeannualized D2FS increment inthe xylitol group was 2.69 com-pared with 2.98 in the placebogroup, a 10 percent lower incre-ment. This difference did notachieve statistical significance

(RR, 0.90; 95 percent confidenceinterval [CI], 0.78-1.03). Results with the fullregression model (not shown) indicated thatannualized caries increments increased signifi-cantly with increasing baseline D2FS score butdid not differ according to site, age, routinedental visit history, use of OTC fluoride or fre-quency of oral hygiene. (Authors note:Fullregression model tables for all analyses are avail-able at www.xactstudy.org.) We saw similarresults when we included the UTHSCSA data(Table 2).

Subgroup analyses.Because baseline D2FSscore was such a highly statistically significantcovariate in the primary analysis, we conducteda secondary analysis to assess treatment effectsseparately for those with baseline D2FS scores of20 or lower and those with scores of 21 or higher.We observed no evidence of a treatment effect inthe former group (RR = 1.00) but saw a signifi-cant effect in the higher D2FS group (RR = 0.80;P = .03) (Table 3, page 28). However, when weincluded the UTHSCSA data, the treatmenteffect was reduced in the high D2FS group and nolonger was statistically significant (RR = 0.83;

P= .05) (Table 3). In both analyses, the interac-


RESULTS

Figure 2 delineates the flow of participantsthrough the study. We screened informally inclinics and did not record these contacts. Of 945participants who attended the enrollment visit,we ultimately randomly assigned 691, 73 per-cent (344 in the xylitol arm and 347 in theplacebo arm). Of the 254 we did not randomlyassign, 81 withdrew during the run-in period,and 173 elected not to continue after completingthe run-in period. The mean duration of follow-up was 2.56 years for UNC and UAB partici-pants, and loss to follow-up was balancedbetween study arms.

Table 1 shows participant characteristics.The mean age was 47 years (range, 21-80years), and 65 percent were female. Themajority brushed at least twice per day andwere exposed to fluoride through office visits,home use of toothpaste or both (all three siteshad fluoridated water). A small minorityreported having dry mouth. We noted nomarked differences between the xylitol andplacebo groups in these observations. We

observed similar participant characteristics

S T O R YC O V E R

TABLE 1

Baseline characteristics of study participantsfrom all study sites.

CHARACTERISTIC PERCENTAGE* OF PARTICIPANTS,ACCORDING TO STUDY GROUP

Xylitol(n = 339)

Placebo(n = 342)

TOTAL(n = 681)

Race or Ethnicity

Non-Hispanic white 46.6 50.3 48.5

Non-Hispanic black 27.1 25.4 26.3

Hispanic 23.0 21.4 22.2

Other 3.0 2.9 2.9

Age in Years (Mean [StandardDeviation])

46.3 (13.5) 47.7 ( 13.7) 47.0 (13.6)

Female 62.2 67.0 64.6

Brushes Two or More Times perDay

63.1 69.3 66.2

Flosses One or More Times perDay 47.5 46.8 47.1

Routine Dental Visit(Examination or Prophylaxis) inPast Year

32.2 30.1 31.6

Self-report of Dry Mouth 4.7 9.1 6.9

Extent of Fluoride Exposure

Toothpaste or professionallyapplied topical fluoride

52.8 60.3 56.5

Both toothpaste and professionallyapplied topical fluoride

37.5 31.0 34.2

* Except where noted in column 1.




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tion Pvalue exceeded .12.To investigate whether this

apparent subgroup effect might bemore closely related to lesions atbaseline, we conducted a similaranalysis for the D2S score (Table3). Here, neither the group with

no D2surfaces at baseline nor thegroup with one or more D2sur-faces at baseline displayed a sig-nificant treatment effect. Wefound similar results when wereran the analyses including theUTHSCSA data.

We evaluated treatment effectsin subgroups according to adher-ence to the daily protocol of onelozenge five times per day(Table 3). We found a nonsignifi-

cant RR associated with lozengeuse in all three adherence groupsand no evidence of any treatment-by-dose interaction. We alsoobserved no effect of adherence onD2FS increment in analysesrestricted to placebo-group par-ticipants. We observed similarresults when we includedUTHSCSA data. Finally, when weexamined treatment effectsaccording to sex and race or eth-

nicity, we found no differencebetween men and women ineither the two-site or three-site samples; how-ever, we did find that the treatment effect wassignificant for non-Hispanic whites, but not forHispanics or those in the other category(mostly unkown) in the two-site sample but notin the three-site sample. (Authors note:Theseanalyses are available on the public Web site.)

Safety outcomes.Randomly assigned par-ticipants (including those from UTHSCSA)reported 46 SAEs (22 in the xylitol arm and 24in the placebo arm). Of these, we considered one(diagnosis of longstanding gastroparesis) pos-sibly study related, whereas we could not deter-mine whether an additional three were studyrelated because participants declined to providethe necessary information. In addition, partici-pants reported severe oral adverse effects atrates of less than 0.5 percent for all reportingperiods, whereas participants reported severeGI adverse effects at a rate of 1 percent or lessduring the study. Reports of any oral or GIadverse effects ranged from 3.2 to 8.4 percentfor the mouth and from 3.3 to 11.4 percent for

the GI tract across the duration of the study.

Most oral adverse effects were sores, whereasGI adverse effects were distributed acrossreports of cramps, bloating, constipation, flatu-lence, and loose stool or diarrhea. For alladverse effects, these patterns were similar forthe two study groups.

DISCUSSION

The results of this clinical trial did not demon-strate a statistically significant reduction in 33-month caries incidence either in the primaryanalysis or in the secondary analysis thatincluded all three sites. This finding is at oddswith those in some reviews of xylitol studies inwhich investigators concluded definitively thatxylitol is effective in reducing cariesincrements,10,12,14,15,17 but it supports findings inother reviews in which researchers determinedthat the evidence is inconclusive, or that xylitolhas little or no effect on caries increments.11,13,16

It is important to realize that this, to our knowl-edge, is the first large-scale, placebo-controlled,multisite, randomized, double-masked study of

xylitol as a caries-preventive agent. All previous

S T O R YC O V E R

TABLE 2

Summary of principal outcome analysisfor D2FS* increment.

OUTCOME STUDY GROUP RATE RATIO(95% CI)

P

VALUE

Xylitol Place bo

UTHSCSA DataExcluded

n = 218 n = 219

0. 90 (0.78-1.03) .14

Follow-up (years) 2.54 (0.55) 2.58 (0.50)

Baseline D2FS

score21.3 (13.6) 21.4 (13.3)

Annualized D2FSincrement#

2.69 2.98

UTHSCSA DataIncluded

n = 331 n = 338

0.89 (0.80-1.01) .06

Follow-up (years) 2.55 (0.49) 2.57 (0.47)

Baseline D2FS score 18.8 (12.8) 18.5 (12.5)

Annualized D2FSincrement#**

2.64 2.96

* D2FS: Cumulative decayed or filled surface increment. Based on negative binomial model adjusting for age at random assignment, age

squared, dental prophylaxis or examination in the preceding 12 months, use of over-the-counter fluoride, usually brush and floss, severity of caries at baseline and studysite. CI: Confidence interval.

UTHSCSA: University of Texas Health Science Center at San Antonio. Data are expressed as mean (standard deviation). Time from baseline to last observed follow-up visit.# Includes imputed data (from baseline to first annual visit) for 22 participants from

the University of Alabama at Birmingham or University of North Carolina at ChapelHill for whom there were no follow-up data.

** Based on analysis excluding an additional five participants for whom covariate datawere missing.




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studies lacked one or more of these essentialfeatures intended to minimize the likelihood ofbias.24 The study also differs from most previousstudies in that it involved evaluation of lozenges(mints), rather than chewing gum, thereby ren-dering inoperative one possible method ofaction: mechanical plaque removal.25 Mints maybe less effective than gum for this reason. Also,and perhaps most importantly, in this study weevaluated xylitol in adults, rather than in chil-dren and adolescents, who have been the focusof virtually every preceding xylitol study.Finally, most of the participants lived in areaswith fluoridated water, used fluoridated tooth-paste and, owing to our recruitment strategies,could be characterized as recently havingreceived dental care.18

The results of this study help explain theexisting controversy regarding xylitols effective-ness. At best, xylitols effect appears to be

modest in this study group. We observed a

reduction in the risk of dentalcaries on the order of 10 percent,which was not statistically sig-nificant. Such a small effectwould be easy to miss in sometrials, and in other trials per-haps would be open to exaggera-

tion through the unintentionalincorporation of bias. We sawessentially the same magnitudeof risk reduction at each of thethree study sites, which gives usconfidence that our methodsespecially our caries measure-mentswere well standardized.

Among this group of adults atelevated risk of experiencingcaries, this reduction amounts to0.29 surfaces saved per year.

However, our observed crudeincrements, on the order of threedecayed and/or filled surfacesper year, are higher than whatwould be expected from the liter-ature we reviewed to estimatethe power of our study,18 becausewe chose not to adjust the incre-ments for reversalsthat is, il-logical calls.18 Thus, the estimateof surfaces saved would be lowerif we had adjusted for reversals.

Although not negligible, themagnitude of surfaces saved isnot encouraging for the wide-spread adoption of xylitol aseither a public health measure or

a dentist-recommended supplemental preven-tive intervention for adults who are at an ele-vated risk of developing caries and who alreadyuse fluoride toothpaste.

We found a significant reduction in the inci-dence of caries when we analyzed the treatmenteffect in subgroups stratified according to base-line D2FS. Those with D2FS scores higher than20 experienced a reduction of 20 percent,whereas those with D2FS scores of 20 or lowershowed essentially no reduction. However, thisreduction was not statistically significant whenwe included the UTHSCSA participants in theanalysis. When we explored this relationshipfurther by stratifying participants according totheir baseline D2counts, we observed no similartrend toward increased effectiveness in thosewith any cavitated lesions at baseline versusthose with none. Thus, at two sites, participantswho had more filled surfaces seemingly had a

greater reduction in caries incidence with the

S T O R YC O V E R

TABLE 3

Summary of analyses for selected subgroups.

SUBGROUP STUDY GROUP RATE RATIO(95% CI)*

PVALUE*

Xyli tol Plac ebo

UTHSCSA Data Excluded

Baseline D2FS

0 to 20 D2FS n = 109 n = 119

Annualized D2FS increment 2.23 2.24 1.00 (0.81-1.22) .96

21 or more D2FS n = 109 n = 100


Baseline D2S

0 D2S n = 94 n = 94

Annualized D2S increment 2.34 2.75 0.85 (0.68-1.07) .16

One or more D2S n = 124 n = 125

Annualized D2S increment 3.07 3.23 0.95 (0.75-1.15) .62

Lozenge use adherence

0 to 40 percent n = 42 n = 46


41 to 80 percent n = 72 n = 96


81 to 100 percent n = 104 n = 77Annualized D2FS increment 2.85 3.09 0.92 (0.73-1.12) .43

UTHSCSA Data Included

Baseline D2FS

0 to 20 D2FS n = 194 n = 211


21 or More D2FS n = 135 n = 124


Baseline D2S

0 D2S n = 114 n = 117


One or more D2S n = 215 n = 218


* Based on negative binomial model adjusting for age at random assignment, dental prophylaxis

or examination in the preceding 12 months, use of over-the-counter fluoride, usually brush andfloss, severity of caries at baseline and study site. CI: Confidence interval.

UTHSCSA: University of Texas Health Science Center at San Antonio. D2FS: Cumulative decayed or filled surface increment. D2S: Decayed surface.




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use of xylitol, but those who had active diseasedid not enjoy any increased effect. We speculatethat we observed this contradictory effectbecause, in this group of participants who hadreceived recent dental care, D2FS may havebeen a better reflection of recent caries activitythan was the presence of cavitated lesions.

We observed no apparent xylitol dose-response effect nor any effect associated withadherence in the placebo group. In the placebogroup, the extra salivary stimulation resultingfrom consumption of more lozenges apparentlywas insufficient to affect caries incidence. Simi-larly, exposure to increasing amounts of xylitolalso had no additive effect on caries incidence.The trial protocol may have specified a dailydose that is below an as-yet-undeterminedthreshold of daily consumption for effectiveness.

At the time we designed the study, the typical

daily dose in reported studies was between 3and 5 g per day; the range was 0.7 to 7.0 g perday.13 We chose the high side of the typical doseto ensure that the trial would provide an effec-tive dose. Furthermore, we recommended fiveone-lozenge doses to minimize underdosing if aparticipant missed one dose. In 2009, investiga-tors suggested a threshold dose of 5 to 6 gdaily.26 However, because the most adherentparticipants in our study were consuming xyl-itol near or at this threshold, some effect mightbe expected. Another explanation might be that

frequency of exposure is more important than isthe total dose. Because even moderatelyadherent participants likely would experiencethe three daily exposures suggested in 2009,26

exposure response would be difficult to detect.In any event, dosage protocols requiring morethan 5 g daily, near-perfect adherence or bothmay well mean that benefits experienced inpractice will not approach the optimum benefitpossible.

Future trials of caries-prevention interven-tions in adults can benefit from the experiencesin this trial. We included only adults at an ele-vated risk of developing caries, defined for thisstudy as having or recently having had a cavi-tated lesion. However, the presence of one lesionmay not necessarily indicate a person truly athigh risk. Thus, trial investigators seeking toassess effectiveness in high-risk populationsmay need to establish a longitudinal assessmentof caries activity. In addition, recruitment ofparticipants from dental clinic populations maymask subtle treatment effects owing to exten-sive restorative activity that may not be cariesrelated. Our trial had excellent participant

retention, possibly because of our use both of a

run-in period and of frequent contacts fromstudy coordinators, who deliberately sought toestablish continuing relationships with partici-pants. We observed adherence that was higherthan what we had expected given the length ofthe trial and the need for daily action. Again, weattribute this to preselecting adherent partici-

pants and establishing close personal relation-ships with them.

The results of this trial may not apply toyounger populations, in which almost all of theprevious research on xylitol as a caries-preventive agent has been conducted. Neverthe-less, the lack of a statistically significant effectin this adult population at an elevated risk ofexperiencing caries should serve to temperoveroptimistic expectations that xylitol lozengesused as a supplement in patients or the publicat large with access to fluoride will substan-

tially reduce their caries experience.

CONCLUSION

Daily use of xylitol lozenges did not result in astatistically or clinically significant reduction in33-month caries increment among adults at anelevated risk of developing caries.

Disclosure.None of the authors reported any disclosures.

The research described in this article was supported by the fol-lowing grants from the National Institute of Dental and CraniofacialResearch: U01DE018038 (Xylitol Adult Caries Trial [X-ACT] StudyChair), U01DE018047 (Xylitol Adult Caries Trial [X-ACT] Data Coor-

dinating Center), U01DE018048 (Xylitol Adult Caries Trial [X-ACT]UNC Clinical Center), U01DE018049 (Xylitol Adult Caries Trial [X-ACT] UAB Clinical Center) and U01DE018050 (Xylitol Adult CariesTrial [X-ACT] UTHSC San Antonio Clinical Center). The authorsreceiving grants were Drs. Bader, Vollmer, Shugars, Gilbert andAmaechi.

The authors thank the Xylitol Adult Caries Trial (X-ACT) DataSafety and Monitoring Board. They extend special thanks to theX-ACT participants and to Dr. Christina Gullion.

In addition to the authors of this article, the Xylitol Adult CariesTrial collaborative research group consists of the following people:Jan Carlton Holland, RDH, MS, and Debbie S. Robinson, CDA, MS,from the University of North Carolina, Chapel Hill; Mona Z.Anabtawi, DDS, MS, from the University of Alabama, Birmingham;Anna Theresa Vega, RDA, Bithiah Radcliffe and Belinda Vitolas,

RDA, from the University of Texas Health Science Center at SanAntonio; Donna J. Eubanks, BSCS, Kelly Kirk, Chuhe Chen, PhD,Deborah Reck, Jeanette Bardsley, BA, Arthur R. Dixon, MSTM, andElizabeth J. Esterberg, MS, from the Coordinating Center, KaiserPermanente Center for Health Research, Portland, Ore.; and Jane C.Atkinson, DDS, from the Project Office, National Institute for Dentaland Craniofacial Research, National Institutes of Health,Bethesda, Md.

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