<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04420780</url>
  </required_header>
  <id_info>
    <org_study_id>CaPreXCh</org_study_id>
    <nct_id>NCT04420780</nct_id>
  </id_info>
  <brief_title>Effect of the Use of Xylitol Gum in the Prevention of Caries Lesions in Children Living in Ladakh</brief_title>
  <acronym>CaPreXCh</acronym>
  <official_title>Study Protocol for a Randomized Clinical Trial to Evaluate the Effect of the Use of Xylitol Gum in the Prevention of Caries Lesions in Children Living in Ladakh - the Caries Prevention Xylitol in Children (CaPreXCh) Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Bern</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Milan</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Sassari, Italy</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>WHO Collaborating Center for Epidemiology and Preventive Dentistry</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Bern</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background: Ladakh is a region administered by India, covering an area slightly larger than&#xD;
      Croatia; it is part of the larger region of Kashmir and Jammu. Till now, oral health data on&#xD;
      population living in Ladakh are not available. The aim of the present preventive project will&#xD;
      be to record the caries prevalence of schoolchildren living in Ladakh and to implement a&#xD;
      school-based xylitol program using chewing gums in order to reduce caries incidence.&#xD;
&#xD;
      Methods: The protocol of the Caries Prevention Xylitol in Children (CaPreXCh) trial is&#xD;
      designed as a triple-blind randomized, controlled, parallel-group clinical trial in children&#xD;
      aged 5-14 years. The study will be carried out from August 2021 to August 2024 in Zanskar&#xD;
      Valley (Ladakh). Participants will be randomly allocated into two groups: subjects who will&#xD;
      receive a 100% xylitol chewing gum, and those who will receive a 22% xylitol gum. The&#xD;
      subjects will be instructed to chew a total of 6 pellets for 5 min divided into 3 intakes a&#xD;
      day (2 in the morning, 2 after the midday meal and 2 in the afternoon) for one school-year.&#xD;
      Clinical examination will comprise an oral examination: caries index (ICDAS scores), bleeding&#xD;
      on probing recording and evaluation of plaque pH fluctuation after sucrose challenge and will&#xD;
      be performed at baseline (t0) and repeated 12 months at the end of the chewing-gum&#xD;
      administration period (t1) as interim examination, after 12 months (t2) and 24 months (t3)&#xD;
      after the end of the experimental period (chewing gum use). The primary outcome will be the&#xD;
      caries increment measured both at enamel and dentinal level. Data analysis will be conducted&#xD;
      through Kaplan-Meyer graphs to evaluate caries increment as primary outcome, and the methods&#xD;
      will be compared to each other with Cox regression with shared frailty. The net caries&#xD;
      increment for initial, moderate and severe caries level, using ICDAS (Δ-initial, Δ-moderate&#xD;
      and Δ-severe), will be calculated.&#xD;
&#xD;
      Discussion: This is the first clinical trial to assess the effect of chewing gum containing&#xD;
      only xylitol as sweeteners for caries prevention. Moreover, the children object of this study&#xD;
      is a population with special living conditions.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study will be carried out from August 2021 to August 2024 in Zanskar Valley (Ladakh).&#xD;
&#xD;
      Participants, interventions and outcomes Setting The study will be conducted in the Zanskar&#xD;
      Valley (Ladakh). The subjects (5 to 14 years old) will be randomly selected from a list of&#xD;
      school class in the selected schools.&#xD;
&#xD;
      Interventions&#xD;
&#xD;
      After obtaining actual caries data, schools with similar numbers of schoolchildren (at least&#xD;
      300 subjects per school) will be selected for the preventive project. The participants will&#xD;
      be randomly taking as cluster the school-class allocated into two groups (Figure 1).&#xD;
      Randomization will be performed by one author (G. Campus) using Microsoft Excel for Mac&#xD;
      (version 16.37) in permuted blocks of 2 or 4 with a random variation of the blocking number,&#xD;
      and 2 groups will be created:&#xD;
&#xD;
        1. the first group (Xyl) will receive sugar-free gums containing 100% Xylitol as sweetener;&#xD;
&#xD;
        2. the second group (Pol) will receive sugar-free gums containing a polyols mixture plus a&#xD;
           low amount of Xylitol (22%).&#xD;
&#xD;
           All chewing gums will be produced and supplied by Perfetti Van Melle SpA (Lainate,&#xD;
           Italy). The xylitol chewing gum is with xylitol (64% w/v) as the only sweetener. The&#xD;
           polyols chewing gum is a sugar-free gum with 22% of Xylitol, 30% Sorbitol, 6% Maltitol&#xD;
           syrup and 4% Mannitol. All types of chewing gums weigh 1.4 g each and will be identical&#xD;
           in colour, shape and taste. The treatment will follow the school year calendar for a&#xD;
           total of nine months of administration.&#xD;
&#xD;
           Clinical examination&#xD;
&#xD;
           Clinical examination will comprise an oral examination (caries index, bleeding on&#xD;
           probing recording) and evaluation of plaque pH fluctuation after sucrose challenge.&#xD;
           Bleeding on probing will be used as a proxy of plaque presence, since there is a causal&#xD;
           relationship between bleeding on probing and amount of plaque.&#xD;
&#xD;
           The subjects will be examined using a mouth mirror, a ball ended probe and artificial&#xD;
           light in a dental chair. Caries registration will be performed with regard to the first&#xD;
           and second primary, and first and second permanent, molars. The International Caries&#xD;
           Detection and Assessment System (ICDAS) will be use to record caries at tooth level as&#xD;
           initial or moderate or severe lesions, the number of filled teeth and the missing teeth&#xD;
           for caries. Initial caries lesion can be defined as a primary lesion, which has not&#xD;
           reached the stage of an established lesion with cavitation (ICDAS score 1 and 2).&#xD;
           Moderate caries lesions are defined as white or brown spot lesion with localized enamel&#xD;
           breakdown or an underlying dentine shadow without visible dentine exposure (ICDAS score&#xD;
           3 and 4). Severe caries lesions are defined as distinct cavity in opaque or discoloured&#xD;
           enamel with visible dentine (ICDAS score 5 and 6). The bleeding on probing score will be&#xD;
           registered in all subjects.&#xD;
&#xD;
           Plaque-pH measurements&#xD;
&#xD;
           Interproximal-plaque pH will be evaluated using pH indicator strips , which measure a pH&#xD;
           value in the range of 4.0-7.0 (Spezialindikator, pH range 4.0-7.0; Merck, Darmstadt,&#xD;
           Germany). The strips determine changes in plaque pH, discriminating differences at the&#xD;
           level of 0.2-0.5 pH units and they are easy to use. The strips are cut into 4 pieces&#xD;
           (approx. 2 mm in width) in order to get a strip that could be easily inserted into the&#xD;
           interproximal space and held in situ for 10 s, and its colour compared to the colour&#xD;
           index scheme supplied by the manufacturer.&#xD;
&#xD;
           For each subject, 3 measurements will be carried out in 2 sites, between the 2nd&#xD;
           premolar or the 2nd primary molar, if present, and the 1st molar right and left of the&#xD;
           upper jaw. Measurements will be performed before and at 2, 5, 10, 15, 20 and 30 min&#xD;
           after a mouth rinse with 10% sucrose.&#xD;
&#xD;
           Calibration of the examiners&#xD;
&#xD;
           Prior the start of the examiners that performed all the dental screenings was trained&#xD;
           and calibrated by a benchmark examiner. Baseline training consists in one-day&#xD;
           theoretical course, followed by examination on extracted teeth plus a session of&#xD;
           photographs of extracted teeth. After two days of the theoretical course a clinical&#xD;
           training will be performed. The children were re-examined after 72 h. Inter-examiner&#xD;
           reliability with the benchmark examiner will be evaluated using fixed-effects analysis&#xD;
           of variance and intra-examiner reproducibility assessed as the percentage of agreement&#xD;
           using Cohen's kappa statistic.&#xD;
&#xD;
           Treatment&#xD;
&#xD;
           The subjects will be instructed to chew a total of 6 pellets for 5 min divided into 3&#xD;
           intakes a day (2 in the morning, 2 after the midday meal and 2 in the afternoon). Thus,&#xD;
           the total daily intake of xylitol in the Xyl group is fixed in 5.4 g and 1.8 g in the&#xD;
           Pol group. Subjects will be instructed to use the chewing gum immediately after main&#xD;
           meals and snacks. To the parents/guardians will be not requested to make changes in&#xD;
           dietary and oral hygiene habits of their children. Tooth brushing will be not allowed&#xD;
           for at least 1 h after the chewing gum use. All subjects will receive a fluoridated&#xD;
           toothpaste containing 1,450 mg/g NaF and a manual toothbrush to be used during the&#xD;
           experimental period, that will be supplied during the entire experimental period (2&#xD;
           years). All children will be instructed to brush teeth twice a day (after breakfast and&#xD;
           supper) for 2 minutes using vertical movements.&#xD;
&#xD;
           In order to evaluate the success of the administration of chewing gum at school,&#xD;
           teachers will receive chewing gums necessary for a single month at a time. Children will&#xD;
           have to return the empty blister packs when receiving those for the following month.&#xD;
           This procedure will be repeated for all experimental (chewing) period (1-year school&#xD;
           calendar/9 months).&#xD;
&#xD;
           Outcomes&#xD;
&#xD;
           The primary outcome will be the caries increment measured both at enamel and dentinal&#xD;
           level. The secondary outcomes will be the differences obtained comparing caries&#xD;
           increment and the variation of plaque pH in relation to the treatment decision.&#xD;
           Furthermore, a cost- effectiveness analysis will be performed using as outcome measure&#xD;
           the quality-adjusted life years (QALY).&#xD;
&#xD;
           Participant timeline&#xD;
&#xD;
           The study will be recruiting patients from August 2021 to September 2022. Each subject&#xD;
           will be enrolled for 36 months, estimating 9 months (one school year) of treatment and&#xD;
           27 months of follow-up.&#xD;
&#xD;
           Recruitment&#xD;
&#xD;
           The recruitment will occur in Zanskar Valley (Ladakh): in Padum city.&#xD;
&#xD;
           Assignment of interventions&#xD;
&#xD;
           Allocation: sequence generation and concealment mechanism The random list will be&#xD;
           generated using a computer program (Microsoft Excel for Mac); the randomization will be&#xD;
           carried out on a school-class based by G.C. in permuted blocks of 2 or 4 with a random&#xD;
           variation of the blocking number, and 2 groups will be created.&#xD;
&#xD;
           Chewing gums will be supplied in plain white containers coded as 'green' or 'blue'&#xD;
           according to the group. The code is sealed by an independent monitor and not broken&#xD;
           until the statistical analysis will be finalized.&#xD;
&#xD;
           Implementation&#xD;
&#xD;
           All examinations of the children enrolled will be done by calibrated examiners. The&#xD;
           clinical examination of the enrolled sample will be performed at baseline (t0) and&#xD;
           repeated 12 months at the end of the chewing-gum administration period (t1) as interim&#xD;
           examination, after 12 months (t2) and 24 months (t3) after the end of the experimental&#xD;
           period (chewing gum use).&#xD;
&#xD;
           Blinding&#xD;
&#xD;
           All personnel involved into the study will be blinded to the participant assignment.&#xD;
&#xD;
           Children, parents/caregivers and teachers responsible for the treatment, examiners who&#xD;
           will evaluate the outcomes and statistician who will analyse data will be blind to the&#xD;
           allocation group of the participants.&#xD;
&#xD;
           Data collection, management, and analysis&#xD;
&#xD;
           The follow-up assessments will be performed by a pre-calibrated blind examiner. The&#xD;
           clinical data will be recorded on electronic sheets organized on PageMaker and then&#xD;
           transferred to Microsoft Excel Software. The data will be cleaned, deleting those&#xD;
           revealing the participants' identities, will be share in a public repository at the&#xD;
           moment of the submission of the manuscripts.&#xD;
&#xD;
           Data on caries will be based considering the tooth as the unit of analysis; the net&#xD;
           caries increment for initial, moderate and severe caries level, using ICDAS (Δ-initial,&#xD;
           Δ-moderate and Δ-severe), will be calculated in primary and permanent molars.&#xD;
           Differences between groups in terms of the caries increment will be evaluated using the&#xD;
           nonparametric Mann-Whitney U test. Kaplan-Meyer graphs will be constructed to evaluate&#xD;
           caries increment as primary outcome, and the methods will be compared to each other with&#xD;
           Cox regression with shared frailty. The calculation of sensitivity, specificity and&#xD;
           accuracy will consider the results obtained with the indices and the classification of&#xD;
           the presence or not of caries lesion by the proposed reference standard. The&#xD;
           cost-effectiveness ratio will also be verified, considering as effect, the prevention of&#xD;
           the primary outcome. For all tests, two-tailed analyses will be used, considering a&#xD;
           level of significance of 5%. The quality-adjusted life-year index (QALY) will be&#xD;
           calculated to assess the value of the preventive interventions.To determine QALYs, the&#xD;
           utility value associated with a given state of health by the years lived in that state&#xD;
           will be calculated. A year of life lived with no caries increment will be worth 1 QALY&#xD;
           (1 year of life × 1 Utility value].&#xD;
&#xD;
           Analyses will be performed using the statistical package Stata 16.0 (Stata Corp, College&#xD;
           Station, USA).&#xD;
&#xD;
           Monitoring&#xD;
&#xD;
           Data monitoring An independent regulation of data collection, management and analysis&#xD;
           will be assumed independently by the authors.&#xD;
&#xD;
           Harms&#xD;
&#xD;
           The procedures performed offer minimal risk to oral health of patients. Side effects of&#xD;
           the administration of both chewing gums will be assessed by means of a questionnaire&#xD;
           administered to the participants' parents after 3 months from the beginning of the&#xD;
           experimental period and a second time at the end of the administration (1 year after the&#xD;
           baseline).&#xD;
&#xD;
           Auditing&#xD;
&#xD;
           The data entered will be conducted by one of the authors of the study. The data will be&#xD;
           weekly inspected. The inconsistencies will be verified, corrected and registered.&#xD;
&#xD;
           Ethics and dissemination&#xD;
&#xD;
           Research ethics approval, Consent and Assent&#xD;
&#xD;
           No official Ethical committee is present in the area of the survey. The study proposal&#xD;
           was submitted to the authorities of the Zanskar Tibetan Hospital Health Care &amp; Sowa&#xD;
           Rigpa Research Institute and its coordinator the Lama Zopta gave the approval for the&#xD;
           study. Each school involved in the survey gave also the approval. Due to language&#xD;
           problems and the low literacy rate of the population, verbal approval will be obtained&#xD;
           for children's participation by parents or guardians.&#xD;
&#xD;
           Confidentiality&#xD;
&#xD;
           Participants will be coded with identification numbers to guarantee confidentiality&#xD;
           during data analysis. Participants files will be stored in a secure room in the&#xD;
           Department of Restorative, Preventive and Pediatric Dentistry, University of Bern.&#xD;
&#xD;
           Access to data&#xD;
&#xD;
           Clinical trial data will be granted full access via public repository after acceptance&#xD;
           of the manuscripts.&#xD;
&#xD;
           Ancillary and post-trial care&#xD;
&#xD;
           Parents/caregivers of the children participating the trial will receive information&#xD;
           about the children oral health.&#xD;
&#xD;
           Dissemination policy&#xD;
&#xD;
           A full report of the findings will be prepared and submit in full through national and&#xD;
           international journals, newsletters and via website.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">August 2021</start_date>
  <completion_date type="Anticipated">August 2024</completion_date>
  <primary_completion_date type="Anticipated">July 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>This is a triple-blind randomized, controlled, parallel-group clinical trial. Two groups will be compared: subjects who will receive a 100% xylitol chewing gum, and those who will receive a 22% xylitol gum.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change from Baseline caries status in enamel (ICDAS index)</measure>
    <time_frame>3 years</time_frame>
    <description>The primary outcome will be the caries increment measured both at surface and tooth level using ICDAS index</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from Baseline caries status in dentine (ICDAS index)</measure>
    <time_frame>3 years</time_frame>
    <description>The primary outcome will be the caries increment measured both at surface and tooth level using ICDAS index</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plaque pH measurements in relation to the treatment decision. (PlaquepH strips)</measure>
    <time_frame>3 years</time_frame>
    <description>Variation of plaque pH samples after sucrose challenge in relation to the treatment decision.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Cost- effectiveness analysis</measure>
    <time_frame>After 36 months</time_frame>
    <description>Cost- effectiveness analysis using as outcome measure the quality-adjusted life years (QALY)</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">409</enrollment>
  <condition>Caries</condition>
  <arm_group>
    <arm_group_label>Xyl Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Children will receive sugar-free gums containing 100% Xylitol as sweetener</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pol Group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Children will receive sugar-free gums containing a polyols mixture plus a low amount of Xylitol (22%).</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Administration of sugar-free gums sugar-free gums containing 100% Xylitol as sweetener</intervention_name>
    <description>The subjects will be instructed to chew a total of 6 pellets for 5 min divided into 3 intakes a day (2 in the morning, 2 after the midday meal and 2 in the afternoon)</description>
    <arm_group_label>Xyl Group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Administration of sugar-free gums sugar-free gums containing containing a polyols mixture plus a low amount of Xylitol (22%)</intervention_name>
    <description>The subjects will be instructed to chew a total of 6 pellets for 5 min divided into 3 intakes a day (2 in the morning, 2 after the midday meal and 2 in the afternoon)</description>
    <arm_group_label>Pol Group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Are aged from 5 to 14 years;&#xD;
&#xD;
          2. To be in good general health;&#xD;
&#xD;
          3. Written informed consent (by the child / parent)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Children who refuse to participate in the research; parents/guardians who refuse the&#xD;
             participation of their children to the trial;&#xD;
&#xD;
          2. Children who present systemic conditions or chronic diseases that require&#xD;
             differentiated care and follow-up.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>5 Years</minimum_age>
    <maximum_age>14 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Guglielmo Campus</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Bern</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Maria Grazia Cagetti, DDS</last_name>
    <phone>+39 02 50319008</phone>
    <email>gmaria.cagetti@unimi.it</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Fabio Cocco, ChM</last_name>
    <phone>+39 3519595035</phone>
    <email>dr.fabiococco@gmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Community Health Center, Dental Service,</name>
      <address>
        <city>Padum Chak</city>
        <country>India</country>
      </address>
    </facility>
    <contact>
      <last_name>Phunchok Zagpoo, DDS</last_name>
      <email>xangpo@gmail.com</email>
    </contact>
    <investigator>
      <last_name>Ezio Calzavara, DDS</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Davide Augello, DDS</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>India</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>May 25, 2020</study_first_submitted>
  <study_first_submitted_qc>June 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 9, 2020</study_first_posted>
  <last_update_submitted>June 3, 2020</last_update_submitted>
  <last_update_submitted_qc>June 3, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 9, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Caries prevention</keyword>
  <keyword>Xylitol gum</keyword>
  <keyword>Children</keyword>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>The study protocol Summer 2020/2024 Statistical Analysis Plan 2022 Analytic Code at the end of the study 2024</ipd_time_frame>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04420780
org study id: CaPreXCh
nct id: NCT04420780
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Background: Ladakh is a region administered by India, covering an area slightly larger than
      Croatia; it is part of the larger region of Kashmir and Jammu. Till now, oral health data on
      population living in Ladakh are not available. The aim of the present preventive project will
      be to record the caries prevalence of schoolchildren living in Ladakh and to implement a
      school-based xylitol program using chewing gums in order to reduce caries incidence.

      Methods: The protocol of the Caries Prevention Xylitol in Children (CaPreXCh) trial is
      designed as a triple-blind randomized, controlled, parallel-group clinical trial in children
      aged 5-14 years. The study will be carried out from August 2021 to August 2024 in Zanskar
      Valley (Ladakh). Participants will be randomly allocated into two groups: subjects who will
      receive a 100% xylitol chewing gum, and those who will receive a 22% xylitol gum. The
      subjects will be instructed to chew a total of 6 pellets for 5 min divided into 3 intakes a
      day (2 in the morning, 2 after the midday meal and 2 in the afternoon) for one school-year.
      Clinical examination will comprise an oral examination: caries index (ICDAS scores), bleeding
      on probing recording and evaluation of plaque pH fluctuation after sucrose challenge and will
      be performed at baseline (t0) and repeated 12 months at the end of the chewing-gum
      administration period (t1) as interim examination, after 12 months (t2) and 24 months (t3)
      after the end of the experimental period (chewing gum use). The primary outcome will be the
      caries increment measured both at enamel and dentinal level. Data analysis will be conducted
      through Kaplan-Meyer graphs to evaluate caries increment as primary outcome, and the methods
      will be compared to each other with Cox regression with shared frailty. The net caries
      increment for initial, moderate and severe caries level, using ICDAS (Δ-initial, Δ-moderate
      and Δ-severe), will be calculated.

      Discussion: This is the first clinical trial to assess the effect of chewing gum containing
      only xylitol as sweeteners for caries prevention. Moreover, the children object of this study
      is a population with special living conditions.
The study will be carried out from August 2021 to August 2024 in Zanskar Valley (Ladakh).

      Participants, interventions and outcomes Setting The study will be conducted in the Zanskar
      Valley (Ladakh). The subjects (5 to 14 years old) will be randomly selected from a list of
      school class in the selected schools.

      Interventions

      After obtaining actual caries data, schools with similar numbers of schoolchildren (at least
      300 subjects per school) will be selected for the preventive project. The participants will
      be randomly taking as cluster the school-class allocated into two groups (Figure 1).
      Randomization will be performed by one author (G. Campus) using Microsoft Excel for Mac
      (version 16.37) in permuted blocks of 2 or 4 with a random variation of the blocking number,
      and 2 groups will be created:

        1. the first group (Xyl) will receive sugar-free gums containing 100% Xylitol as sweetener;

        2. the second group (Pol) will receive sugar-free gums containing a polyols mixture plus a
           low amount of Xylitol (22%).

           All chewing gums will be produced and supplied by Perfetti Van Melle SpA (Lainate,
           Italy). The xylitol chewing gum is with xylitol (64% w/v) as the only sweetener. The
           polyols chewing gum is a sugar-free gum with 22% of Xylitol, 30% Sorbitol, 6% Maltitol
           syrup and 4% Mannitol. All types of chewing gums weigh 1.4 g each and will be identical
           in colour, shape and taste. The treatment will follow the school year calendar for a
           total of nine months of administration.

           Clinical examination

           Clinical examination will comprise an oral examination (caries index, bleeding on
           probing recording) and evaluation of plaque pH fluctuation after sucrose challenge.
           Bleeding on probing will be used as a proxy of plaque presence, since there is a causal
           relationship between bleeding on probing and amount of plaque.

           The subjects will be examined using a mouth mirror, a ball ended probe and artificial
           light in a dental chair. Caries registration will be performed with regard to the first
           and second primary, and first and second permanent, molars. The International Caries
           Detection and Assessment System (ICDAS) will be use to record caries at tooth level as
           initial or moderate or severe lesions, the number of filled teeth and the missing teeth
           for caries. Initial caries lesion can be defined as a primary lesion, which has not
           reached the stage of an established lesion with cavitation (ICDAS score 1 and 2).
           Moderate caries lesions are defined as white or brown spot lesion with localized enamel
           breakdown or an underlying dentine shadow without visible dentine exposure (ICDAS score
           3 and 4). Severe caries lesions are defined as distinct cavity in opaque or discoloured
           enamel with visible dentine (ICDAS score 5 and 6). The bleeding on probing score will be
           registered in all subjects.

           Plaque-pH measurements

           Interproximal-plaque pH will be evaluated using pH indicator strips , which measure a pH
           value in the range of 4.0-7.0 (Spezialindikator, pH range 4.0-7.0; Merck, Darmstadt,
           Germany). The strips determine changes in plaque pH, discriminating differences at the
           level of 0.2-0.5 pH units and they are easy to use. The strips are cut into 4 pieces
           (approx. 2 mm in width) in order to get a strip that could be easily inserted into the
           interproximal space and held in situ for 10 s, and its colour compared to the colour
           index scheme supplied by the manufacturer.

           For each subject, 3 measurements will be carried out in 2 sites, between the 2nd
           premolar or the 2nd primary molar, if present, and the 1st molar right and left of the
           upper jaw. Measurements will be performed before and at 2, 5, 10, 15, 20 and 30 min
           after a mouth rinse with 10% sucrose.

           Calibration of the examiners

           Prior the start of the examiners that performed all the dental screenings was trained
           and calibrated by a benchmark examiner. Baseline training consists in one-day
           theoretical course, followed by examination on extracted teeth plus a session of
           photographs of extracted teeth. After two days of the theoretical course a clinical
           training will be performed. The children were re-examined after 72 h. Inter-examiner
           reliability with the benchmark examiner will be evaluated using fixed-effects analysis
           of variance and intra-examiner reproducibility assessed as the percentage of agreement
           using Cohen's kappa statistic.

           Treatment

           The subjects will be instructed to chew a total of 6 pellets for 5 min divided into 3
           intakes a day (2 in the morning, 2 after the midday meal and 2 in the afternoon). Thus,
           the total daily intake of xylitol in the Xyl group is fixed in 5.4 g and 1.8 g in the
           Pol group. Subjects will be instructed to use the chewing gum immediately after main
           meals and snacks. To the parents/guardians will be not requested to make changes in
           dietary and oral hygiene habits of their children. Tooth brushing will be not allowed
           for at least 1 h after the chewing gum use. All subjects will receive a fluoridated
           toothpaste containing 1,450 mg/g NaF and a manual toothbrush to be used during the
           experimental period, that will be supplied during the entire experimental period (2
           years). All children will be instructed to brush teeth twice a day (after breakfast and
           supper) for 2 minutes using vertical movements.

           In order to evaluate the success of the administration of chewing gum at school,
           teachers will receive chewing gums necessary for a single month at a time. Children will
           have to return the empty blister packs when receiving those for the following month.
           This procedure will be repeated for all experimental (chewing) period (1-year school
           calendar/9 months).

           Outcomes

           The primary outcome will be the caries increment measured both at enamel and dentinal
           level. The secondary outcomes will be the differences obtained comparing caries
           increment and the variation of plaque pH in relation to the treatment decision.
           Furthermore, a cost- effectiveness analysis will be performed using as outcome measure
           the quality-adjusted life years (QALY).

           Participant timeline

           The study will be recruiting patients from August 2021 to September 2022. Each subject
           will be enrolled for 36 months, estimating 9 months (one school year) of treatment and
           27 months of follow-up.

           Recruitment

           The recruitment will occur in Zanskar Valley (Ladakh): in Padum city.

           Assignment of interventions

           Allocation: sequence generation and concealment mechanism The random list will be
           generated using a computer program (Microsoft Excel for Mac); the randomization will be
           carried out on a school-class based by G.C. in permuted blocks of 2 or 4 with a random
           variation of the blocking number, and 2 groups will be created.

           Chewing gums will be supplied in plain white containers coded as 'green' or 'blue'
           according to the group. The code is sealed by an independent monitor and not broken
           until the statistical analysis will be finalized.

           Implementation

           All examinations of the children enrolled will be done by calibrated examiners. The
           clinical examination of the enrolled sample will be performed at baseline (t0) and
           repeated 12 months at the end of the chewing-gum administration period (t1) as interim
           examination, after 12 months (t2) and 24 months (t3) after the end of the experimental
           period (chewing gum use).

           Blinding

           All personnel involved into the study will be blinded to the participant assignment.

           Children, parents/caregivers and teachers responsible for the treatment, examiners who
           will evaluate the outcomes and statistician who will analyse data will be blind to the
           allocation group of the participants.

           Data collection, management, and analysis

           The follow-up assessments will be performed by a pre-calibrated blind examiner. The
           clinical data will be recorded on electronic sheets organized on PageMaker and then
           transferred to Microsoft Excel Software. The data will be cleaned, deleting those
           revealing the participants' identities, will be share in a public repository at the
           moment of the submission of the manuscripts.

           Data on caries will be based considering the tooth as the unit of analysis; the net
           caries increment for initial, moderate and severe caries level, using ICDAS (Δ-initial,
           Δ-moderate and Δ-severe), will be calculated in primary and permanent molars.
           Differences between groups in terms of the caries increment will be evaluated using the
           nonparametric Mann-Whitney U test. Kaplan-Meyer graphs will be constructed to evaluate
           caries increment as primary outcome, and the methods will be compared to each other with
           Cox regression with shared frailty. The calculation of sensitivity, specificity and
           accuracy will consider the results obtained with the indices and the classification of
           the presence or not of caries lesion by the proposed reference standard. The
           cost-effectiveness ratio will also be verified, considering as effect, the prevention of
           the primary outcome. For all tests, two-tailed analyses will be used, considering a
           level of significance of 5%. The quality-adjusted life-year index (QALY) will be
           calculated to assess the value of the preventive interventions.To determine QALYs, the
           utility value associated with a given state of health by the years lived in that state
           will be calculated. A year of life lived with no caries increment will be worth 1 QALY
           (1 year of life × 1 Utility value].

           Analyses will be performed using the statistical package Stata 16.0 (Stata Corp, College
           Station, USA).

           Monitoring

           Data monitoring An independent regulation of data collection, management and analysis
           will be assumed independently by the authors.

           Harms

           The procedures performed offer minimal risk to oral health of patients. Side effects of
           the administration of both chewing gums will be assessed by means of a questionnaire
           administered to the participants' parents after 3 months from the beginning of the
           experimental period and a second time at the end of the administration (1 year after the
           baseline).

           Auditing

           The data entered will be conducted by one of the authors of the study. The data will be
           weekly inspected. The inconsistencies will be verified, corrected and registered.

           Ethics and dissemination

           Research ethics approval, Consent and Assent

           No official Ethical committee is present in the area of the survey. The study proposal
           was submitted to the authorities of the Zanskar Tibetan Hospital Health Care & Sowa
           Rigpa Research Institute and its coordinator the Lama Zopta gave the approval for the
           study. Each school involved in the survey gave also the approval. Due to language
           problems and the low literacy rate of the population, verbal approval will be obtained
           for children's participation by parents or guardians.

           Confidentiality

           Participants will be coded with identification numbers to guarantee confidentiality
           during data analysis. Participants files will be stored in a secure room in the
           Department of Restorative, Preventive and Pediatric Dentistry, University of Bern.

           Access to data

           Clinical trial data will be granted full access via public repository after acceptance
           of the manuscripts.

           Ancillary and post-trial care

           Parents/caregivers of the children participating the trial will receive information
           about the children oral health.

           Dissemination policy

           A full report of the findings will be prepared and submit in full through national and
           international journals, newsletters and via website.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This is a triple-blind randomized, controlled, parallel-group clinical trial. Two groups will be compared: subjects who will receive a 100% xylitol chewing gum, and those who will receive a 22% xylitol gum.
primary purpose: Prevention
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Change from Baseline caries status in enamel (ICDAS index)
time frame: 3 years
description: The primary outcome will be the caries increment measured both at surface and tooth level using ICDAS index
measure: Change from Baseline caries status in dentine (ICDAS index)
time frame: 3 years
description: The primary outcome will be the caries increment measured both at surface and tooth level using ICDAS index
measure: Plaque pH measurements in relation to the treatment decision. (PlaquepH strips)
time frame: 3 years
description: Variation of plaque pH samples after sucrose challenge in relation to the treatment decision.
measure: Cost- effectiveness analysis
time frame: After 36 months
description: Cost- effectiveness analysis using as outcome measure the quality-adjusted life years (QALY)
arm group label: Xyl Group
arm group type: Experimental
description: Children will receive sugar-free gums containing 100% Xylitol as sweetener
arm group label: Pol Group
arm group type: Active Comparator
description: Children will receive sugar-free gums containing a polyols mixture plus a low amount of Xylitol (22%).
intervention type: Dietary Supplement
intervention name: Administration of sugar-free gums sugar-free gums containing 100% Xylitol as sweetener
description: The subjects will be instructed to chew a total of 6 pellets for 5 min divided into 3 intakes a day (2 in the morning, 2 after the midday meal and 2 in the afternoon)
arm group label: Xyl Group
intervention type: Dietary Supplement
intervention name: Administration of sugar-free gums sugar-free gums containing containing a polyols mixture plus a low amount of Xylitol (22%)
description: The subjects will be instructed to chew a total of 6 pellets for 5 min divided into 3 intakes a day (2 in the morning, 2 after the midday meal and 2 in the afternoon)
arm group label: Pol Group
criteria: 
gender: All
minimum age: 5 Years
maximum age: 14 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Guglielmo Campus
role: Principal Investigator
affiliation: University of Bern
last name: Maria Grazia Cagetti, DDS
phone: +39 02 50319008
email: gmaria.cagetti@unimi.it
last name: Fabio Cocco, ChM
phone: +39 3519595035
email: dr.fabiococco@gmail.com
facility: 
contact: 
investigator: 
investigator: 
country: India
responsible party type: Sponsor
sharing ipd: Yes
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Analytic Code
ipd time frame: The study protocol Summer 2020/2024 Statistical Analysis Plan 2022 Analytic Code at the end of the study 2024