Ca-hydroxyapatite, Fluoroapatite, and Mg-Zn-hydroxyapatite for Dentin Hypersensitivity Management
Condition: Dentin Hypersensitivity
MeSH terms: Dentin Sensitivity; Calcium Metabolism Disorders; Hypersensitivity
Study type: Interventional
Phase: Phase 4

Summary: 
      This will be a double-blind, randomized, three-arm parallel groups study of the effect of
      toothpastes containing Ca-hydroxyapatite (HAP), Mg-Zn-hydroxyapatite (Zn-Mg-HAP), or
      fluoroapatite (FAP).

      The aim of the study is to compare the effect of toothpastes containing Ca-hydroxyapatite
      (HAP), fluoroapatite (FAP), and Mg-Zn-hydroxyapatite (Mg-Zn-HAP) on dentin hypersensitivity
      associated with dental abrasion.

      Materials and methods. Thirty consent patients aged 35-45 with dentin hypersensitivity
      associated with abrasion will be recruited for the study. The study will have 2 phases:
      preparatory phase (recruitment of the patients, standardization of their oral hygiene
      protocols, wash-out period, calibration of the researchers and training) and the main part
      (double-blind, randomized, parallel groups study of toothpastes effect). Patients will be
      randomly divided into 3 groups (group 1 - toothpastes with Ca-HAP, group 2 - toothpastes with
      Zn-Mg-HAP, group 3 - toothpastes with FAP). Clinical examination will be performed at the
      baseline, after 2 and 4 weeks, and will include patient's interview, oral hygiene level
      assessment (OHI-S), and dentin sensitivity testing (Shiff's index).

      The null hypothesis is that there will be no statistically significant differences in dentin
      sensitivity level between the study groups.
    

Detailed description: 
      Background: Dentin hypersensitivity (DH) represents a sharp, short pain arising from exposed
      dentin in response to various stimuli which cannot be ascribed to any other form of dental
      defect or pathology. The use of toothpastes containing various HAP-formulations has become
      one of the most common methods for dentin hypersensitivity management. However, there is a
      paucity of literature concerning the comparison of the effect of different HAP-formulations.

      This will be a double-blind, randomized, three-arm parallel groups study of the effect of
      toothpastes containing Ca-hydroxyapatite (HAP), Mg-Zn-hydroxyapatite (Zn-Mg-HAP), or
      fluoroapatite (FAP). The groups will include adults with DH diagnosed clinically.

      The aim of the study is to compare the effect of toothpastes containing Ca-hydroxyapatite,
      fluoroapatite, and Mg-Zn-hydroxyapatite on dentin hypersensitivity in patients with dental
      abrasion. The sample size was determined according to the trial by Vano et al. (2017), where
      similar design was used. The power was set at 80%, alfa-level was set as 0.05, the means in
      the study groups were 2.65±0.68 and 1.72. The allocation ratio was equal to 1. The resultant
      target sample size comprised 10 participants in each group (7 participants according to
      sample size calculations plus 30% to account for possible drop-out), 30 patients total.

      Subjects who meet all inclusion and exclusion criteria will be randomized on
      Baseline/Screening Visit in a 1:1:1 ratio to the Group 1, 2, or 3 in accordance with a
      computer-generated schedule prepared by a third-party person, who will not participate in the
      study.

      The study is estimated to complete enrollment within 1 week from study initiation; however,
      enrollment will remain open until the study goal is met. The duration of this study for each
      subject will be a maximum of eight (8) weeks: 4 weeks - preparatory period and 4 weeks -
      intervention period.

      Baseline/Screening Visit

        -  Review the study with the subject and obtain written informed consent

        -  Assign the subject a unique screening/enrollment number

        -  Review and record medical history, and medication history to determine eligibility based
           on inclusion/exclusion criteria

        -  Record demographics (age, race, ethnicity, gender)

        -  Document vitals

        -  Document all current medications, including medications over-the-counter and herbal
           medications

        -  Perform physical examination

             -  Administer OHI-S and Shiff test.

             -  The allocation concealment will be performed by the use of containers numbered by a
                "third party" (person, who will not participate in the study). The toothpastes in
                white bottles without any titles will be placed in the containers. The weight of
                the pastes and bottles in different groups will be the same. The patient on
                enrolment will receive a sealed container with a toothpaste. Neither patients nor
                researchers will be aware of the type of a toothpaste received by each patient
                (double blinding).

      Second visit (2 weeks from the baseline visit) - all groups

        -  Simplified Oral Hygiene index (OHI-S),

        -  Schiff test for the assessment of enamel sensitivity,

        -  Assess for adverse events

      Third visit (2 weeks from the second visit) = Final Study Visit - all groups

        -  Simplified Oral Hygiene index (OHI-S),

        -  Schiff test for the assessment of enamel sensitivity

        -  Assess for adverse events

      Early Termination visit

        -  Assess for adverse events

        -  Assess for complications following treatments

        -  Document all current medications, including medications over-the-counter and herbal
           medications

      Preparatory phase of the study "Wash-out" period and patient training Most recruited patients
      with DH are using desensitizing products, and a "wash-out" period will be included before
      subjects enter the main phase of the study. During this time, the potential study population
      should not use desensitizing, and their home-care regimen and products will be standardized
      (provision of identical toothpastes and identical soft toothbrushes). Oral hygiene
      instructions will be given and the compliance with the recommendations will be controlled
      with weekly visits to the dental office. The participants will be familiarized with the
      assessment techniques and trial procedures. Initial sensitivity measurements will be made so
      that erratic and inconsistent responders can be identified and eliminated.

      Qualification and calibration of the observers The clinical examinations will be performed by
      two dentists who are the members of Therapeutic Dentistry Department, Sechenov University,
      Moscow, Russia. The examiners will be trained and calibrated to obtain an intra- and
      inter-examiner agreement of 90%, using Kappa statistics.

      The main phase of the study

      Thirty people aged 35-45 will be examined and randomly assigned to one of the study groups:

      Group 1 will use toothpaste containing HAP. Group 2 will use toothpaste containing Mg-Zn-HAP.
      Group 3 will use toothpaste containing FAP. The allocation concealment will be performed by
      the use of containers numbered by a "third party" (person, who will not participate in the
      study). The toothpastes in white bottles without any titles will be placed in the containers.
      The weight of the pastes and bottles in different groups will be the same. The patient on
      enrolment will receive a sealed container with a toothpaste. Neither patients nor researchers
      will be aware of the type of a toothpaste used.

      Treatment protocol The assigned toothpastes and uniform toothbrushes should be used twice
      daily according to the technique which was used during the preparatory phase of the study.

      The patients will use the prescribed toothpastes for a month. Control examinations will be
      carried out in the following periods: 2 weeks and 4 weeks.

      The examination will include:

      Simplified Oral Hygiene index (OHI-S), Schiff test for the assessment of enamel sensitivity.

      Schiff test is performed to assess enamel sensitivity in all groups as follows: air from
      air/water syringe is applied perpendicular to the cervical areas of all teeth from a distance
      of 1 cm for a second. Enamel sensitivity is estimated in accordance with the following
      criteria:

      0 - no reaction,

        1. - discomfort but the patient does not insist on stopping the test,

        2. - discomfort, accompanied by a request to discontinue the test,

        3. - severe pain reaction with pronounced motor reactions aimed at the immediate
           termination of the test.

      Data collection and reporting. Data will be collected at the following points: at baseline,
      and after 2 and 4 weeks of the assigned toothpastes use.

      Data from the study will be maintained for two (2) years after the date the investigation is
      completed, terminated or until the records are no longer required to support the protocol,
      whichever date is later. Patient records and data are eligible for inspection and/or copying
      by applicable regulatory authorities.

      Data handling and record keeping Data entry will be completed in the RedCap database (which
      will cover all the created CRFs). The data will be exported into CSV file format, which will
      then be used for data analysis. Only de-identified data will be used for data analysis. All
      hard copy documents will be shredded within five years after completion of the study upon
      Sponsor approval. Collected de-identified data will be sent to a biostatistician for
      statistical analysis.

      Expected outcomes. It is the expectation that all of the tested toothpastes (HAP, Mg Zn HAP,
      FAP) will show comparable outcomes. Improvements in tooth hypersensitivity are expected in
      all groups. Data interpretation and the statistical significance of the results will be
      described later in this protocol.

      Adverse reactions. There is no expectation of any adverse outcomes or reactions due to a
      patient using the assigned toothpastes. However, hypersensitivity reactions to some of the
      toothpastes' components are still possible. All participants will be given access to contact
      info of the investigators. Any adverse reactions should be reported immediately to the
      investigators.

      Reasons for Withdrawal or Termination

      The following is a list of possible reasons for study treatment discontinuation:

        -  Screening Failure

        -  Subject withdrawal of consent

        -  Subject is not compliant with study procedures

        -  Adverse Event that in the opinion of the Investigator would be in the best interest of
           the subject to discontinue study participation

        -  Protocol violation requiring discontinuation

        -  Lost to follow-up All subjects are free to withdraw from participation at any time, for
           any reason, specified or unspecified, and without prejudice.

      Statistical analysis plan All analyses will be performed using per-protocol population: the
      researchers will analyse all subjects who did not substantially deviate from the protocol as
      to be determined on a per-subject basis by the study principal investigator immediately
      before database lock.

      The normality and sphericity of distribution will be assessed with Shapiro-Wilk and Leven's
      tests, respectively. The data will be presented as means, standard deviations and 95%
      confidence intervals for each group at each timepoint of the study. Three-way repeated
      measures mixed ANOVA model will be performed followed by post-hoc Nemeniy test with
      adjustment for multiple comparisons. All summary tables will be structured with a column for
      each timepoint and rows for each toothpaste used in the order (HAP, Zn-Mg-HAP, FAP) and will
      be annotated with the total population size relevant to that table/treatment, including any
      missing observations.
    

Intervention name(s): Hygienic procedure (toothbrushing using HAP-containing toothpaste); Hygienic procedure (toothbrushing using Zn Mg HAP-containing); Hygienic procedure (toothbrushing using FAP-containing toothpaste)
Intervention type(s): Combination Product; Combination Product; Combination Product
Intervention description(s): Toothbrushing using standardised technique and pear-sized amount of HAP-containing toothpaste twice daily for 1 month.; Toothbrushing using standardised technique and pear-sized amount of Zn Mg HAP-containing toothpaste twice daily for 1 month.; Toothbrushing using standardised technique and pear-sized amount of FAP-containing toothpaste twice daily for 1 month.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: dentin sensitivity; tooth abrasion; Ca-hydroxyapatite; fluoroapatite; Mg-Zn-hydroxyapatite