Methods

Trial design: parallel (2 arms)

Location: clinical centres of university dental schools, USA

Number of centres: 3

Recruitment period: April 2007 to September 2008

Participants

Inclusion criteria: aged 21 to 80 years; minimum of one coronal or root surface cavitated caries lesion; minimum of 12 teeth with exposed coronal or root surfaces; ability to read and understand study materials in English (the caries criteria were meant to ensure the inclusion of participants with an elevated risk of experiencing caries)

Exclusion criteria: more than 10 teeth with caries lesions; type IV periodontitis (pocket depths or attachment loss greater than 6 mm); long‐term antibiotic use; requiring antibiotic treatment before dental treatment; history of head and neck radiotherapy; history of adverse reaction to either the active or placebo ingredients; serious illness that would interfere with participation; plans to leave the area within the following 3 years; no telephone; co‐inhabiting with someone already enrolled in the study

Baseline caries: (D₂FS) Gp A: mean 18.8 (SD 12.8); Gp B: mean 18.5 (SD 12.5)

Age at baseline (years): Gp A: mean 46.3 (SD 13.5); Gp B: mean 47.7 (SD 13.7)
Gender: Gp A: 62.2% female; Gp B: 67% female

Any other details of important prognostic factors: fluoride exposure (toothpaste and professionally applied topical fluoride) was similar in both groups; all 3 study areas had fluoridated water

Number randomised: 691 (Gp A: 344; Gp B: 347)

Number evaluated: 669 (Gp A: 331; Gp B: 338) ‐ numbers including data from all 3 centres (see comment in risk of bias table below under 'Other bias')

Interventions

Comparison: xylitol lozenges versus placebo lozenges

Gp A (n = 344): one peppermint flavoured lozenge (1 g xylitol) dissolved in the mouth five times per day (total dose = 5 g xylitol per day)

Gp B (n = 347): as above but containing sucralose (considered to be inert, i.e. neither causes nor prevents caries) instead of xylitol

Duration of treatment: 33 months

Outcomes

• Caries: cumulative decayed or filled surfaces (D₂FS) increment (root and coronal surfaces combined) from baseline through the three follow‐up examinations (expressed as annualised increment). Assessed at 12, 24 and 33 months

• Adverse effects

Notes

Sample size calculation: "80% power to detect a 20% reduction in the D₂FS increment assuming a two‐tailed test with a type I error rate of 5%. The target sample size of 750 allowed a 10% attrition rate per year"
Adverse effects: "all adverse effects...similar for the two study groups." Data not reported in a usable format
Funding source: grants from the National Institute of Dental and Craniofacial Research (NIDCR)
Declarations/conflicts of interest: none of the authors reported any disclosures

The information and quotes used in this table and the risk of bias table below are from both the papers listed under Bader 2013 in the reference section (one paper is dedicated to design/methods)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was carried out using a web‐based randomization application process. Allocation assignments were stratified by site and age group (≥ 50, < 50 yrs.) in permuted blocks of varying sizes within each stratum"

Comment: this is an appropriate method of random sequence generation

Allocation concealment (selection bias)

Low risk

Quote: "permuted blocks of varying sizes within each stratum"

Comment: the use of varying sizes of random permuted blocks implies that a reasonable attempt was made to prevent those admitting participants from knowing upcoming assignments. We feel that this was probably done properly in this study

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The placebo lozenge was identical in size and color to the active lozenge...Both the active and placebo lozenges were peppermint flavored" and "Staff and participants were blinded to treatment assignment"

Comment: participants and personnel would not know to which group a participant was assigned

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The placebo lozenge was identical in size and color to the active lozenge...Both the active and placebo lozenges were peppermint flavored" and "Staff and participants were blinded to treatment assignment"

Comment: participants and personnel would not know to which group a participant was assigned

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only 3% of randomised participants were not included in the final analysis (Gp A: 4%; Gp B: 3%)

Comment: we do not believe that any of the above could pose a risk of bias significant enough to have led to a distortion of the true intervention effect

Selective reporting (reporting bias)

Low risk

All raw data is publicly available on the study website (www.xactstudy.org). The authors also provided us with the mean and SD for the 33 month increment

Other bias

Low risk

• The study authors report that there was a problem with adherence data at one of the three centres arising due to protocol violation (despite the exclusion criterion, 10 participants who were co‐inhabiting with another participant had been randomly assigned). However, this was transparently reported and the authors reported results both including and excluding the problematic centre's data. The results including this centre were analysed per protocol (therefore five participants from each group were excluded from the analyses for the same reason) and were virtually identical to those excluding the centre. There does not appear to be any risk of bias

• "To the extent possible, the same examiner who conducted the baseline examination performed all follow‐up examinations" and "Primary and back‐up examiners and recorders from all three clinical centers participated in a four‐day training and calibration session with a reference‐standard examiner, as well as refresher sessions before the 12‐, 24‐ and 33‐month examinations." We consider that the risk of differential diagnostic activity was low

Methods

Trial design: cluster (3 arms)

Location: interventions given in schools in Tartu, Estonia; clinical examinations took place in standard dental units of the Department of Stomatology, University of Tartu

Number of centres: 10 schools/4 dental units

Recruitment period: January to February 2008

Participants

Inclusion criteria: first and second grade primary school children

Exclusion criteria: children who were not at school on the day of the baseline clinical examination

Baseline caries: (d₄‐₆mfs + D₄‐₆MFS) Gp A: mean 11.22 (SE 0.74); Gp B: mean 12.71 (SE 0.8)

Age at baseline (years): Gp A: mean 8.2 (SD 0.5); Gp B: mean 8.1 (SD 0.6)
Gender: Gp A: 45.5% female; Gp B: 48.2% female

Any other details of important prognostic factors: "fluoride content in drinking water is low"

Number randomised: 320 (Gp A: 156; Gp B: 164) (numbers only including the two relevant arms)

Number evaluated: 252 (Gp A: 126; Gp B: 126)

Interventions

Comparison: the 3 arms were as follows:

1) erythritol candy (excluded: erythritol is considered, like xylitol, to be caries‐preventive so cannot be used as a control group)

2) xylitol candy

3) sorbitol candy

Gp A (n = 156): four candies (90% xylitol) three times per day (total dose = 7.5 g xylitol per day)

Gp B (n = 164): as above but with sorbitol instead of xylitol

Duration of treatment: 3 years

* Sorbitol is considered to be inert (i.e. neither causes nor prevents caries) and therefore is commonly used as a control in xylitol studies

Outcomes

• Caries: number of decayed missing filled surfaces (d₄‐₆mfs + D₄‐₆MFS) (dentin). Assessed at 12, 24 and 36 months

• Adverse effects

Notes

Sample size calculation: based on previous study and target was achieved
Adverse effects: none observed
Funding source: Cargill R&D Center Europe (Vilvoorde, Belgium). "The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript"
Declarations/conflicts of interest: the authors stated that they had no conflict of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "At enrolment...school classes were randomly divided into three groups...The list of all classes from all participating schools...was used as a sample frame. The statistician...allocated the classrooms according to computer‐generated random numbers"

Comment: this is an appropriate method of random sequence generation

Allocation concealment (selection bias)

Low risk

Quote: "Concealment of allocation was maintained by the Cargill company up to the main statistical analyses and fixing of the data"

Comment: it appears that allocation was carried out remotely (third‐party allocation). We feel that this was probably done properly in this study

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double‐blind" and "Each child consumed four candies three times per school day, not knowing which group they belonged to"

Comment: participants and personnel would not know to which group a participant was assigned

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "double‐blind clinical examinations of the children in all groups were completed four times"

Comment: outcome assessment appears to have been adequately blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

21% of randomised participants were not included in the final analysis (Gp A: 19%; Gp B: 23%). If the missing participants had higher mean caries increments in one group than the other, as the attrition rate increased, so would over/understatement of the mean difference

Selective reporting (reporting bias)

High risk

Inappropriate combining of deciduous and permanent teeth in the results (dmfs and DMFS)

Other bias

Low risk

Quote: "clinical examinations of the children in all groups were completed...by four trained and calibrated investigators" and "Consistency of the ICDAS codes by each of the examiners and between the examiners was very high (K > 0.9)"

Comment: we consider that the risk of differential diagnostic activity was low

Methods

Trial design: cluster (5 arms)

Location: interventions given in schools in Kotka, Finland; clinical examinations took place in local dental clinics

Number of centres: 21 schools

Recruitment period: not stated

Participants

Inclusion criteria: not stated but all children were in grade 4 (10 years old)

Exclusion criteria: not stated but from the study flow diagram (figure 1) systemic disease appears to be an exclusion criterion

Baseline caries: (D₃MFS) Gp A: mean 0.35 (SD 0.8); Gp B: mean 0.27 (SD 0.7)

Age at baseline (months): Gp A: mean 123.4 (SD 4.2); Gp B: mean 122.6 (SD 3.6)
Gender: Gp A: 45.5% male; Gp B: 47.5% male

Any other details of important prognostic factors: "all subjects would have accessed water with a fluoride content not exceeding 1.5 mg/mL"; the study was conducted in a low‐caries prevalence population (i.e. average DMFT of 12‐year‐olds approximately 0.8 for this area, compared to the Finnish average of 1.2)

Number randomised: 228 (Gp A: 110; Gp B: 118) (numbers only including the two relevant arms)

Number evaluated: 200 (Gp A: 99; Gp B: 101)

Interventions

Comparison: the 5 arms were as follows:

1) xylitol/maltitol* lozenges for 1 year (excluded: we felt it was more appropriate to use the arm with longer‐term use)

2) xylitol/maltitol lozenges for 2 years (included)

3) erythritol/maltitol lozenges for 1 year (excluded: erythritol is considered, like xylitol, to be caries‐preventive so cannot be used as a control group)

4) erythritol/maltitol lozenges for 2 years (excluded: see arm 3)

5) control (included: no lozenges and no additional prevention)

Gp A (n = 110): eight xylitol/maltitol lozenges per day (two in the morning, three after lunch, and three before the child went home) (total dose = 4.7 g xylitol plus 4.6 g maltitol per day)

Gp B (n = 118): children received the same comprehensive routine caries prevention as those in the xylitol group, but no lozenges

Duration of treatment: children in Gp A received the lozenges for 2 years

* Maltitol is considered to be inert (i.e. neither causes nor prevents caries) so we did not consider its inclusion in the lozenges to be a problem

Outcomes

• Caries: decayed missing filled surfaces (D₃MFS) increment (dentin). Assessed at 4 years

• Caries: proportion of children with and without caries increment. Assessed at 4 years

• Adverse effects

Notes

Sample size calculation: "It was estimated that a 20% difference between the control and each study group...would be clinically relevant...To avoid the risk of a false‐negative result (the type II error) and for the test to have a 90% power to detect a statistically significant difference, even when taking attrition of 10% or less per year into account, one hundred subjects per group were required"

Adverse effects: mentioned but no usable data

Funding source: CSM Leaf (Turku, Finland) provided the lozenges
Declarations/conflicts of interest: the authors stated that they had no conflict of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The 21 participating schools were assigned as clusters by means of restricted randomization and blocking into five different groups of approximately the same size" and "After the determination of the groups, they were randomly given a role as one of the four groups receiving colour‐coded lozenges...or a nonlozenge control group, by
drawing lots"

Comment: this is an appropriate method of random sequence generation

Allocation concealment (selection bias)

Low risk

Quote: "The generation of the random allocation sequence, enrolling the participants, ascertaining treatment assignment and administering the intervention was performed by the Chief Dental Officer of Kotka who did not take part in the clinical examinations. The allocation sequence was concealed until all analyses completed"

Comment: it seems that the allocation was performed by someone not involved in the study. We feel that this was probably done properly in this study

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Although the study is described as double‐blinded, we are only interested in the 2‐year xylitol arm and the control group who received no lozenges. Therefore we cannot discount that this would have an effect on the behaviour/motivation (in terms of oral care) of the participants which may affect the results (for example, control group participants may overcompensate by taking extra care of their oral health, or conversely, the xylitol group may feel they do not need to take as much care of their oral health as they usually would due to an expected effect of the xylitol)

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "the examining dentist...the dentists interpreting the radiographs...were all completely blinded and not aware of the group the child belonged to until all the data analyses had been carried out"

Comment: outcome assessment appears to have been adequately blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

12% of randomised participants were not included in the final analysis (Gp A: 10%; Gp B: 14%). This amount of attrition may be considered low for a 4‐year study. Also, one school of 20 participants in Gp A discontinued the intervention during the first year, but they were included in the analyses on an intention‐to‐treat basis

Comment: we do not believe that any of the above could pose a risk of bias significant enough to have led to a distortion of the true intervention effect

Selective reporting (reporting bias)

Unclear risk

There were no usable data reported for adverse events. This should be considered an important outcome in xylitol trials

Other bias

High risk

• Confounding: due to the lack of a placebo, we cannot exclude the possibility that some of the effects would be due to salivary stimulation as a result of sucking a lozenge

• Clinical examinations and radiographs were done by a single dentist as far as was possible. The radiographs were read by the same two dentists (blinded to clinical score and group allocation) and inter‐rater reliability was assessed as 92.9%. We consider that the risk of differential diagnostic activity was low

Methods

Trial design: parallel (3 arms)

Location: communities in the Republic of the Marshall Islands (in the northern Pacific Ocean)

Number of centres: unclear

Recruitment period: April to August 2006

Participants

Inclusion criteria: children aged 9 to 15 months

Exclusion criteria: in the lower 10th percentile of US standard weight and height; history of oesophageal or digestive disease; congenital craniofacial malformation; history of adenoidectomy, tympanostomy tubes, or tympanic membrane perforations (due to secondary outcome of reduction of acute otitis media)

Baseline caries: not stated

Age at baseline (months): Gp A: mean 15.9 (SD 2.6); Gp B: mean 13.7 (SD 2.4); Gp C: mean 15.6 (SD 2.7)

Gender: Gp A: 57.6% female; Gp B: 56.3% female; Gp C: 48.3% female

Any other details of important prognostic factors: high rate of early childhood caries on the islands; drinking water contains no appreciable fluoride; generally poor diets

Number randomised: 100 (Gp A: 35; Gp B: 33; Gp C: 32)

Number evaluated: 94 (Gp A: 33; Gp B: 32; Gp C: 29)

Interventions

Comparison: xylitol topical oral syrup (A) versus xylitol topical oral syrup (B) versus xylitol topical oral syrup (C)

Gp A (n = 35): three doses of syrup per day: two doses contained 4 g xylitol each, plus one dose with 2 g sorbitol (total dose = 8 g xylitol plus 2 g sorbitol per day)

Gp B (n = 33): three doses of syrup per day: each dose contained 2.67 g xylitol (total dose = 8 g xylitol per day)

Gp C (n = 32): three doses of syrup per day: one dose contained 2.67 g xylitol, plus two doses contained 2 g sorbitol each (total dose = 2.67 g xylitol plus 4 g sorbitol per day)

Duration of treatment: 1 year

• Sorbitol is considered to be inert (i.e. neither causes nor prevents caries) so we did not consider its inclusion in the syrups to be a problem

• The study authors state that the internal review committee required that the control group syrup contain a small amount of xylitol, but that evidence does not suggest that a dose of 2.67 g per day would have any effect. The study authors therefore considered this to be a control group

• Due to the fact that the xylitol dose was the same in Gp A and Gp B, and also because sorbitol is not expected to have any effect, we combined these two groups in the analysis

Outcomes

• Caries: number of decayed primary teeth. Assessed at 1 year

• Acute otitis media (not an outcome of interest in this review)

• Adverse effects

Notes

Sample size calculation: "We estimated that the rate of decayed cavitated lesions for children at 24 months of age was 60% in the control group and 30% in the xylitol‐treated groups. Based on 80% power to detect a significant difference (2‐sided P=.05) between the xylitol‐treated and control groups, 32 children were required for each study group"

Adverse effects: percentage experiencing loose stools or diarrhoea is reported per group. Appears to be at participant level (i.e. not counting multiple events experienced by the same child) but the percentages stated do not equate to whole persons (e.g. 11.7% of 33 participants is 3.861 persons)

Funding source: grants from: a) the Health Resources and Services Administration Maternal and Child Health Bureau; and b) the National Institute of Dental and Craniofacial Research. Danisco USA donated the raw materials for making the syrups
Declarations/conflicts of interest: none of the authors reported any disclosures

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "subjects were given identification numbers that had been randomly assigned to study groups by a statistician using block randomization and the sample function of commercially available statistical software...Block sizes of 30 and 15 were used for the Laura district, and block sizes of 36 and 18 were used for the Delap district. Except for the statistician, all study team members were blinded until study completion"

Comment: this is an appropriate method of random sequence generation

Allocation concealment (selection bias)

Low risk

Quote: "subjects were given identification numbers that had been randomly assigned to study groups by a statistician using block randomization and the sample function of commercially available statistical software...Block sizes of 30 and 15 were used for the Laura district, and block sizes of 36 and 18 were used for the Delap district. Except for the statistician, all study team members were blinded until study completion"

Comment: use of different block sizes administered by a statistician implies that a reasonable attempt was made to prevent those admitting participants from knowing upcoming assignments. We feel that this was probably done properly in this study

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double‐blind" and "The syrups were matched for color, taste, and viscosity"

Comment: participants and personnel would not know to which group a participant was assigned

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The examiner was always blinded to study group assignment"

Comment: outcome assessment appears to have been adequately blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only 6% of randomised participants were not included in the final analysis (Gp A: 6%; Gp B: 3%; Gp C: 9%). Attrition was actually 16% but most of these had at least an interim examination and were included in the intention‐to‐treat analysis. The reasons for drop‐out in each group were the same and in similar proportions (either moved off island or parent stopped giving syrup and withdrew)

Comment: we do not believe that any of the above could pose a risk of bias significant enough to have led to a distortion of the true intervention effect

Selective reporting (reporting bias)

Unclear risk

There were no usable data reported for adverse events. This should be considered an important outcome in xylitol trials

Other bias

Low risk

Quote: "A single dental examiner" and "Compared with another examiner (P.M.), the study examiner demonstrated excellent reliability for caries diagnosis (interrater correlation coefficient, 1.00 at the prestudy dental examination and 0.96 at the midstudy examination)"

Comment: we consider that the risk of differential diagnostic activity was low

Methods

Trial design: parallel (2 arms)

Location: public dental clinic in Lycksele, Sweden

Number of centres: 1

Recruitment period: not stated

Participants

Inclusion criteria: all healthy 2‐year‐old children, born in 2000 and the first quarter of 2001, attending the public dental clinic in Lyycksele

Exclusion criteria: children with severe disabilities; children that did not co‐operate for an oral inspection

Baseline caries: not stated

Age at baseline: all children were 2 years old

Gender: Gp A: 49% female; Gp B: 46% female

Any other details of important prognostic factors: not stated

Number randomised: 132 (Gp A: 66; Gp B: 66)

Number evaluated: 118 (Gp A: 55; Gp B: 63)

Interventions

Comparison: xylitol sucking tablets versus control (no tablets and no additional prevention)

Gp A (n = 66): one tablet (0.48 g xylitol) slowly dissolved in the mouth per day, at bedtime after toothbrushing, for the first 6 months, then two tablets (one in the morning and one in the evening) for another year (total dose = 1 g xylitol per day)

Gp B (n = 66): children received the same routine prevention and restorative care and advice as those in the xylitol group, but no tablets

Duration of treatment: children in Gp A received the tablets for 1.5 years

Outcomes

• Caries: dmfs increment. Assessed at 2 years

• Caries: incidence measured using dichotomous presence of a dmfs increment or not. Assessed at 2 years

• Microbial counts (not an outcome of interest in this review)

Notes

Sample size calculation: only a post‐investigation sample size analysis was performed

Adverse effects: not reported

Funding source: grants from: a) the County of Västerbotten; b) the Patent Revenue Fund for Dental Prophylaxis; and c) the Swedish Dental Society
Declarations/conflicts of interest: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "the children were randomly assigned"

Comment: insufficient information on the method of sequence generation

Allocation concealment (selection bias)

Unclear risk

Quote: "the children were randomly assigned"

Comment: allocation concealment not mentioned

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

It was not possible to blind participants and personnel because the control group had no tablets. Therefore we cannot discount that this would have an effect on the behaviour/motivation (in terms of oral care) of the participants/carers which may affect the results (for example, control group participants/carers may overcompensate by taking extra care of their oral health, or conversely, the xylitol group may feel they do not need to take as much care of their oral health as they usually would due to an expected effect of the xylitol)

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "single‐blind" and "Caries was registered by tactile and visual examination in a dental chair by two blinded calibrated examiners"

Comment: outcome assessment appears to have been adequately blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

11% of randomised participants were not included in the final analysis, but this was unbalanced with appreciably higher attrition in the xylitol group (Gp A: 17%; Gp B: 5%). If the higher rate of attrition was related to the intervention, then this could be considered a risk of bias

Selective reporting (reporting bias)

Unclear risk

Adverse events should be considered an important outcome in xylitol trials, but were not considered in this study

Other bias

High risk

• Confounding: due to the lack of a placebo, we cannot exclude the possibility that some of the effects would be due to salivary stimulation as a result of sucking a tablet

• Caries was assessed by two blinded calibrated examiners. We consider that the risk of differential diagnostic activity was low

Methods

Trial design: parallel (4 arms)

Location: public dental clinic in Hyltebruk, Sweden

Number of centres: 1

Recruitment period: not stated

Participants

Inclusion criteria: healthy 12‐ to 13‐year‐olds

Exclusion criteria: not stated

Baseline caries: not clearly stated (presented graphically) but there was a statistically significant difference between Gp A and Gp B

Age at baseline: all children were 12 to 13 years old

Gender: not stated

Any other details of important prognostic factors: the study site was chosen due to a relatively high caries frequency and stable population; the water supply had a fluoride concentration of about 0.1 ppm

Number randomised: 322 (Gp A: 78; Gp B: 83; Gp C: 78; Gp D: 83)

Number evaluated: 284 (Gp A: 67; Gp B: 74; Gp C: 68; Gp D: 75)

Interventions

Comparison: the 4 arms were as follows:

1) xylitol toothpaste with sorbitol and normal level of fluoride

2) xylitol toothpaste with sorbitol and low level of fluoride

3) toothpaste with sorbitol and normal level of fluoride

4) toothpaste with sorbitol and low level of fluoride

Gp A (n = 78): twice daily brushing with toothpaste containing 0.8% sodium monofluorophosphate, 3% xylitol, 6% sorbitol

Gp B (n = 83): twice daily brushing with toothpaste containing 0.03% sodium fluoride, 3% xylitol, 6% sorbitol

Gp C (n = 78): twice daily brushing with toothpaste containing 0.8% sodium monofluorophosphate, 9% sorbitol

Gp D (n = 83): twice daily brushing with toothpaste containing 0.03% sodium fluoride, 9% sorbitol

Duration of treatment: 3 years

• Sorbitol is considered to be inert (i.e. neither causes nor prevents caries) so we did not consider its inclusion in the syrups to be a problem

• We would have compared Gp A versus Gp C and Gp B versus Gp D in the analyses, if there had been any usable data

Outcomes

• Caries: number of DFS. Assessed at 1, 2, and 3 years

• Microbial counts (not an outcome of interest in this review)

Notes

Sample size calculation: 65 to 75 participants per group to allow 95% power to detect a true difference between group means of approximately 4 DFS (theoretical calculations made via a pilot study)

Adverse effects: not reported

Funding source: Kema Nobel Consumer Goods Division (Stockholm, Sweden) provided toothpastes (also states they provided "economical support" but this may just be the toothpastes)
Declarations/conflicts of interest: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "All children taking part were randomly distributed into four experimental groups"

Comment: insufficient information on the method of sequence generation

Allocation concealment (selection bias)

Unclear risk

Quote: "All children taking part were randomly distributed into four experimental groups"

Comment: allocation concealment not mentioned

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "They were produced and delivered in 100‐gram tubes, marked with the name 'Toothpaste' in different colours...corresponding to groups 1‐4 respectively" and "The study was carried out double‐blind for subjects as well as for examiners"

Comment: participants and personnel would not know which group a participant was assigned to

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The study was carried out double‐blind for subjects as well as for examiners"

Comment: outcome assessment appears to have been adequately blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

12% of randomised participants were not included in the final analysis (Gp A: 14%; Gp B: 11%; Gp C: 13%; Gp D: 10%). This amount of attrition may be considered as low for a 3‐year study and the reasons were mainly due to them moving away from the area

Comment: we do not believe that any of the above could pose a risk of bias significant enough to have led to a distortion of the true intervention effect

Selective reporting (reporting bias)

High risk

The caries data have not been reported adequately (on a small graph) or in a way that would allow them to be included in a meta‐analysis (i.e. there is no measure of variance (SD, SE or 95% CIs) reported for the mean DFS scores). Adverse events should be considered an important outcome in xylitol trials, but were not considered in this study

Other bias

Low risk

Quote: "The children were clinically examined...by one of the authors" and "A pilot study...was performed to train the examiner and to standardize the clinical and radiographic registrations"

Comment: we consider that the risk of differential diagnostic activity was low

Methods

Trial design: parallel (2 arms)

Location: schools in the metropolitan area of San José, Costa Rica

Number of centres: 17 schools

Recruitment period: not stated

Participants

Inclusion criteria: 8‐ to 10‐year‐olds (however, children younger than 8 years yet at the scholastic third grade level, or older than 10 years yet still at the scholastic fifth grade level, were accepted if they met the following criterion); minimum of one DFS

Exclusion criteria: not stated

Baseline caries: (DFS) Gp A: mean 5.6 (SD 2.9); Gp B: mean 5.5 (SD 3.0)

Age at baseline: unclear due to first inclusion criterion above but stratified by age

Gender: not stated but stratified by gender

Any other details of important prognostic factors: the water supply had a fluoride concentration of less than 0.1 ppm; fluoridated table salt was introduced in Costa Rica around the time the study began, but availability was equal for all participants

Number randomised: 2630 (not reported by group)

Number evaluated: 1677 (Gp A: 840; Gp B: 837)

Interventions

Comparison: xylitol plus fluoride toothpaste versus fluoride toothpaste

Gp A (n = 840 evaluated): twice daily brushing for 1 minute with toothpaste containing 10% xylitol plus 0.243% sodium fluoride (1100 ppm fluoride); participants were instructed to spit out the slurry after brushing and rinse thoroughly with water; eating/drinking was discouraged for at least 30 minutes following brushing; application of toothpaste to toothbrush was supervised

Gp B (n = 837 evaluated): as above but without xylitol

Duration of treatment: 3 years

Outcomes

• Caries: DFS increment. Assessed at 2 and 3 years

• Adverse effects

Notes

Sample size calculation: the authors state that the study met the sample size requirements of the American Dental Association (ADA) guidelines for clinical trials of anticaries toothpaste efficacy (minimum 80% power to detect 10% difference)

Adverse effects: none observed

Funding source: several authors employed by Colgate‐Palmolive
Declarations/conflicts of interest: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Each child was randomly assigned to use either..."

Comment: insufficient information on the method of sequence generation

Allocation concealment (selection bias)

Unclear risk

Quote: "Each child was randomly assigned to use either..."

Comment: allocation concealment not mentioned

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Product was provided in plain white tubes (identified only by a solid colour‐coded label) in order to maintain the double‐blindness"

Comment: participants and personnel would not know to which group a participant was assigned

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Product was provided in plain white tubes (identified only by a solid colour‐coded label) in order to maintain the double‐blindness"

Comment: outcome assessment appears to have been adequately blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

36% of randomised participants were not included in the final analysis (not reported by group). If the missing participants had higher mean caries increments in one group than the other, as the attrition rate increased, so would over/understatement of the mean difference

Selective reporting (reporting bias)

Low risk

Appropriate outcome measures were considered and reported in full, as described in the methods section

Other bias

Low risk

Caries evaluations were carried out by a single dentist who was calibrated before and during the study. We consider that the risk of differential diagnostic activity was low

Methods

Trial design: parallel (2 arms)

Location: schools in the central plateau of Costa Rica (including San José, Cartago, Alajuela, and Heredia)

Number of centres: 28 schools

Recruitment period: not stated

Participants

Inclusion criteria: 7‐ to 12‐year‐olds; minimum of one decayed/filled surface (DFS)

Exclusion criteria: not stated

Baseline caries: (DFS) Gp A: mean 3.69 (SD 2.2); Gp B: mean 3.7 (SD 2.19)

Age at baseline: all children were 7 to 12 years old; stratified by age

Gender: not stated but stratified by gender

Any other details of important prognostic factors: the water supply had a fluoride concentration of less than 0.1 ppm

Number randomised: 3394 (not reported by group)

Number evaluated: 2539 (Gp A: 1280; Gp B: 1259)

Interventions

Comparison: xylitol plus fluoride toothpaste versus fluoride toothpaste

Gp A (n = 1280 evaluated): twice daily brushing for 1 minute with toothpaste containing 10% xylitol plus 0.836% sodium monofluorophosphate (1100 ppm fluoride); participants were instructed to spit out the slurry after brushing and rinse thoroughly with water; eating/drinking was discouraged for at least 30 minutes following brushing; application of toothpaste to toothbrush was supervised

Gp B (n = 1259 evaluated): as above but without xylitol

Duration of treatment: 30 months

Outcomes

• Caries: DFS increment. Assessed at 12 and 30 months

• Adverse effects

Notes

Sample size calculation: not stated

Adverse effects: none observed

Funding source: several authors employed (or formerly employed) by Colgate‐Palmolive
Declarations/conflicts of interest: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Children accepted for participation were stratified into two balanced groups within the participating schools on the basis of age and sex"

Comment: although the word 'random' is not used, and we were unable to obtain a response from the corresponding author, we are confident that participants would have been randomised on the basis that: a) the Sintes 1995 study with three of the same authors was randomised; and b) we have information from another Cochrane review that toothpaste trials by Colgate‐Palmolive are normally randomised. However, there is insufficient information on the method of sequence generation

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not mentioned

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Each subject was provided the assigned study dentifrice in tubes with colour‐coded labels, to ensure that the use of the assigned dentifrice was maintained throughout the study"

Comment: the use of colour‐coded labels implies that blinding was carried out. We feel that this was probably done properly in this study

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "double blind"

Comment: we assumed that this refers to blinding of participants and outcome assessors

Incomplete outcome data (attrition bias)
All outcomes

High risk

25% of randomised participants were not included in the final analysis (not reported by group). If the missing participants had higher mean caries increments in one group than the other, as the attrition rate increased, so would over/understatement of the mean difference

Selective reporting (reporting bias)

Low risk

Appropriate outcome measures were considered and reported in full, as described in the methods section

Other bias

Low risk

Caries evaluations were carried out by a single dentist who was calibrated before and during the study. We consider that the risk of differential diagnostic activity was low

Methods

Trial design: parallel (3 arms)

Location: healthcare centres in Muurame and Korpilahti, Finland

Number of centres: not stated

Recruitment period: September 2004 to February 2007

Participants

Inclusion criteria: healthy child; parents willing to use the novel slow‐release pacifier and the tablet; child started receiving tablet before age of 2 months (if they did not, but the parents were motivated to remain in the study, they were offered the possibility of administering the crushed up tablet on a spoon)

Exclusion criteria: not stated

Baseline caries: children were aged 2 months so had no teeth and no caries

Age at baseline: 1 to 2 months

Gender: Gp A: 57% male; Gp B: 46% male

Any other details of important prognostic factors: not stated

Number randomised: 108 (Gp A: 54; Gp B: 54)

Number evaluated: 62 (Gp A: 33; Gp B: 29)

Interventions

Comparison: the 3 arms were as follows:

1) probiotic bacteria (BB‐12) plus xylitol tablet via a slow‐release pacifier or a spoon (excluded)

2) xylitol tablet via a slow‐release pacifier or a spoon

3) sorbitol tablet via a slow‐release pacifier or a spoon

Gp A (n = 54): one tablet (100 mg or 300 mg xylitol ‐ depending on size of pacifier) twice per day via a novel slow‐release pacifier or crushed on a spoon (total dose = 200 mg to 600 mg xylitol per day)

Gp B (n = 54): as above but with sorbitol instead of xylitol

Duration of treatment: tablets were given from the age of 1 to 2 months until the child was 2 years of age

* Sorbitol is considered to be inert (i.e. neither causes nor prevents caries) and therefore is commonly used as a control in xylitol studies

Outcomes

• Caries: incidence measured both using categorical International Caries Detection and Assessment System (ICDAS) and dichotomous presence of a dmfs increment or not. Assessed at 4 years

• Microbial counts (not an outcome of interest in this review)

Notes

Sample size calculation: based on microbial colonisation percentages rather than on caries

Adverse effects: not reported

Funding source: personal grants from: a) the Emil Aaltonen and Sohlberg Foundations; b) the Finnish Dental Society Apollonia and the Finnish Dental Association. All study materials were donated by industry but they did not provide any financial support
Declarations/conflicts of interest: none reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The infants were assigned to 1 of 3 study groups by one of the authors...according to a randomization list which had been previously computer‐generated in blocks of 3"

Comment: this is an appropriate method of random sequence generation

Allocation concealment (selection bias)

Low risk

Quote: "The infants were assigned to 1 of 3 study groups by one of the authors...according to a randomization list which had been previously computer‐generated in blocks of 3. The block randomization was prepared by a statistician with no clinical involvement in the trial. All the study personnel and participants were blinded to treatment assignment"

Comment: blocks of three would mean that it was difficult to conceal the random sequence if not done properly. However, it sounds as if the statistician carried this out remotely so that there could be no foreknowledge of intervention assignment by the study personnel

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double‐blind" and "Test tablets of a similar size and colour were administered" and "All the study personnel and participants were blinded to treatment assignment as well as the colour code of the tablet bottles for the duration of the study"

Comment: participants and personnel would not know to which group a participant was assigned

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "double‐blind" and "All the study personnel and participants were blinded to treatment assignment as well as the colour code of the tablet bottles for the duration of the study. Only one of the authors...had the code...However, she did not participate in producing or analysing the data at any stage of the trial and had no contact with the study participants"

Comment: outcome assessment appears to have been adequately blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

43% of randomised participants were not included in the final analysis (Gp A: 38%; Gp B: 46%). If the missing participants had a higher risk of caries in one group than the other, as the attrition rate increased, so would over/understatement of the risk ratio

Selective reporting (reporting bias)

Unclear risk

Adverse events should be considered an important outcome in xylitol trials, but were not considered in this study

Other bias

Low risk

Quote: "All children were examined by a dentist...trained specifically for the study examination" and "The intraexaminer agreement percentage at the surface level was 97.3%"

Comment: we consider that the risk of differential diagnostic activity was low

Methods

Trial design: parallel (2 arms)

Location: paediatric dental clinic in San Francisco, USA

Number of centres: 1

Recruitment period: January 2007 to January 2008

Participants

Inclusion criteria: healthy children aged 6 to 35 months; mothers using the wipes were primary caregivers (> 8 hours per day); minimum of one active caries lesion within a year

Exclusion criteria: oral or systemic diseases; mother or child had taken antibiotics (or other medication which may potentially affect oral flora) in the previous 3 months

Baseline caries: (dmfs > 0) Gp A: 2; Gp B: 1

Age at baseline (months): Gp A: mean 16.7 (SD 8.6); Gp B: mean 17.9 (SD 8.6)

Gender: Gp A: 64% male; Gp B: 59% male

Any other details of important prognostic factors: 80% of the population attending this clinic were of low socioeconomic status

Number randomised: 44 (Gp A: 22; Gp B: 22)

Number evaluated: 44 (Gp A: 22; Gp B: 22) (there were 2 drop‐outs in Gp A and 5 in Gp B but all participants were analysed on an intention‐to‐treat basis, and imputation procedure is clearly stated)

Interventions

Comparison: xylitol wipes versus placebo wipes

Gp A (n = 22): mothers used two wipes to clean the teeth and gums three times per day (in addition to their normal toothbrushing) (total dose = 4.2 g xylitol per day)

Gp B (n = 22): as above but without xylitol

Duration of treatment: 1 year

Outcomes

• Caries: incidence measured using dichotomous presence of a dmfs increment or not. Assessed at 1 year

• Microbial counts (not an outcome of interest in this review)

• Adverse effects

Notes

Sample size calculation: based on previous study and on maternal microbial transmission rather than on caries

Adverse effects: none observed

Funding source: "This research project was supported by the California Society of Pediatric Dentistry Foundation, a Graduate Scientific Research Award from American Academy of Pediatric Dentistry, and NIH/NIDCR grant U54 DE019285. Xylitol and placebo wipes were provided free of charge from DR Products Inc"
Declarations/conflicts of interest: the authors stated that they had no conflict of interest

The study authors report a statistically significant difference in favour of the xylitol group. However, using the raw data from the study report, we did not find a statistically significant difference

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The participants were then randomized...using a pre‐set computer‐generated random number table"

Comment: this is an appropriate method of random sequence generation

Allocation concealment (selection bias)

Low risk

Quote: "The groups were blinded as Groups A and B" and "Only one investigator...who was not involved in any patient contact, dental examinations, and microbiological assays, knew the group assignment"

Comment: it appears that allocation was carried out remotely by an investigator who did not know into which group they were allocating participants

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "double‐blinded" and "The placebo wipes were custom synthesized...for the study and were identical in appearance and composition"

Comment: participants and personnel would not know to which group a participant was assigned

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "double‐blinded" and "Only one investigator...who was not involved in any patient contact, dental examinations, and microbiological assays, knew the group assignment. All the other investigators involved in participant contact, microbiological assays, and statistical analysis were blinded"

Comment: outcome assessment appears to have been adequately blinded

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

16% dropped out between baseline and final examination (Gp A: 9%; Gp B: 23%). Although all participants were included in the analysis on an intention‐to‐treat basis and imputation rules were clearly stated, we cannot be certain that the study is free of attrition bias

Selective reporting (reporting bias)

Low risk

Appropriate outcome measures were considered and reported in full, as described in the methods section

Other bias

Low risk

Quote: "The two dental examiners were trained by one investigator (LZ) to score caries lesions in a standard pediatric dental setting. Cross calibration on inter‐examiner reliability was performed on seven children (15% of the study population). The two examiners showed 100% agreement on caries scoring, with Kappa = 1 (P < 0.01)"

Comment: we consider that the risk of differential diagnostic activity was low