Biomarkers of Orthodontic Tooth Movement With Fixed Appliances and Vibration Appliance Therapy
Condition: Tooth Movement
Study type: Interventional

Summary: 
      Currently, orthodontic treatment typically lasts approximately 2 years. There are a number of
      advantages for reducing the duration of treatment, including reducing the potential risk of
      caries, root resorption and for minimizing patient "burn out" from prolonged treatment.

      While some evidence does exist that vibration may accelerate the speed of tooth movement, the
      biological mechanism is still unknown. Identification of specific factors involved in tooth
      movement that are further stimulated by vibration would help to understand the mechanisms
      involved as well as discover possible biologic targets which could be utilized or modified to
      maximize the benefits of vibration treatment.

      The purpose of this study is to identify novel biological factors that are expressed in
      patients undergoing orthodontic tooth movement in conjunction with vibration appliance
      therapy.
    

Detailed description: 
      Specific Aims

        1. To determine if combined vibration-fixed appliance treatment alters the expression of
           specific bone remodeling factors in saliva compared to fixed orthodontic treatment
           alone.

        2. To further elucidate the role of vibration treatment on the degree of tooth mobility
           during fixed appliance treatment compared to control.

        3. To determine if combined vibration-fixed appliance treatment increases the speed of
           orthodontic tooth movement during the alignment phase of treatment.

        4. To evaluate the role of vibration treatment in the control of pain in patients
           undergoing orthodontic treatment.

      Screening & Recruitment Procedures Approximately 600 patients begin treatment every year in
      the University of Connecticut Orthodontic Clinic. The pilot project aim is to recruit a total
      of 40 patients, with 20 male and 20 female subjects, equally divided between control and
      vibration groups. Based on the projected starts, we anticipate meeting the recruitment goals
      during the first 12 months of the study.

      Prospective subjects will be screened for this study after completing all the usual initial
      screening procedures for patients in the University of Connecticut Orthodontic Clinic with
      their appointed primary orthodontic provider. The primary orthodontic provider will determine
      if the patient is likely to qualify (pre-screen) for the study based on the
      inclusion/exclusion criteria. The initial clinical indicators of eligibility evaluated during
      the pre-screen are a healthy patient undergoing non-extraction treatment with good oral
      hygiene. Male and female subjects of all ethnicities will be included if between the ages of
      15-35 years of age.

      If the prospective patient meets the initial criteria, the orthodontic provider will notify
      the study coordinator and PI to screen the patient's existing dental records, including
      screening forms, models and/or radiographs for confirmation of likely eligibility for
      participation in the study.

      Study Procedures I. Standardized Orthodontic Treatment Protocol The orthodontic clinic
      treatment protocol will be standardized to minimize variability in the sequence of treatment.
      All subjects will be bonded with 0.022"X0.028" brackets passive self-ligating brackets with
      maximal band tension (MBT) prescription from 2nd premolar to 2nd premolar in both arches and
      bonded tubes on the 1st molars at the baseline (T0) visit. Each subject will have a 0.014"
      copper nickel titanium (NiTi) archwire placed at the initial visit. At T2, the next archwire
      in the sequence (0.014"X0.025" copper NiTi) will be placed.

      Subjects will be seen at normally appointed visits every 4-6 weeks. The primary orthodontic
      provider will direct the alignment and leveling phase of treatment and proceed through the
      wire sequence as indicated. No specific procedure/timeframe will be assigned to placement of
      each archwire. Providers are expected to proceed to the next archwire when it can be placed
      comfortably based on the degree of alignment achieved.

      In the event of bracket breakages, the subject is to be seen within 7 days to have the
      bracket rebonded, in standard care as well as the study. The primary orthodontic provider
      will reposition the bracket in the ideal position and continue with alignment using the study
      archwires. If the subject does not present with 7 days of the breakage, he/she will be
      disqualified from the study.

      II. Randomization Procedures Once recruited to the study and after baseline measures are
      taken at T0 by the study coordinator, the randomization will be performed. Since study groups
      will be subdivided by gender, separate randomization will be performed for males and females.
      Block randomization will be used. Based on gender, 20 opaque envelopes will be generated
      containing the group allocation (10 for the vibration study group, 10 for the non-vibration
      control group). At the time of randomization, the subject will choose an envelope and
      disclose the group assignment. For subjects allocated to the vibration group, the study
      coordinator will provide detailed instructions as to how to operate the appliance and will
      instruct those subjects to use it for 20 minutes per day.

      III. Data Collection Procedures On the day of bonding (T0), prior to the placement of any
      appliances, baseline unstimulated whole saliva will be collected and Periotest will performed
      on selected teeth in the mandibular arch. In addition, alginate model impressions will be
      taken. These procedures will be described in more detail in the next sections. Once baseline
      measures have been taken, the PI will perform the randomization and notify the study
      coordinator as to which group the subject is assigned to ("vibration treatment" or "no
      vibration"). The patients allocated to the vibration treatment group will be provided with
      the vibration appliance (Acceledent) appliance and instructed to use the 20 minutes per day
      according to the manufacturer's instructions.

      After fixed appliances are placed and tooth movement begins, subjects will proceed with
      standard orthodontic treatment with or without vibration treatment based on allocation.
      Collection of saliva samples, Periotest and alginate impressions will be taken at T1 (5-6
      weeks post-T0), T2 (10-12 weeks post-T0) and T3 (15-17 weeks post-T0). Subjects will be seen
      between noon and 5pm to help minimize possible confounding of salivary markers by circadian
      rhythms.

      Salivary Biomarkers Collection of unstimulated whole saliva will be performed using the same
      methods described by Navazesh and Kumar. Unstimulated whole saliva will be collected by
      passive drooling into sterile centrifuge tubes on ice for 15 minutes or once 2-10 milliliters
      (mL) of saliva is collected at baseline and each visit, whichever occurs first. Once saliva
      is collected, samples will be kept on ice and supplemented with proteinase inhibitor. Samples
      will then be centrifuged for 10 minutes at 3000 rpm to remove cellular debris and
      supernatants will be collected and stored at -80°C until they are ready to be analyzed for
      biomarkers.

      Biomarkers will be evaluated by ELISA assay by a direct sandwich method using a standard
      protocol.

      Periotest Measurement Procedures This measurement is obtained at baseline and each visit. The
      degree of tooth mobility will be used using a Periotest device (Siemens, Bensheim, Germany)
      on the central incisors, canines and 2nd premolars in both mandibular quadrants as previously
      described by Liou et al. The archwire will be removed and the Periotest measurements will be
      taken in triplicate, with means recorded.

      Dental Model Analysis

      Two blinded clinical evaluators will assess the rate of alignment of the lower incisors for
      both groups. Analyses of dental casts will be done on the mandibular cast using a method
      based on Little's irregularity index. Little's irregularity index was developed to assess
      amount of anterior tooth displacement from canine to canine. Contact displacement will be
      measured in millimeters around the arch from canine to canine. Irregularity will be measured
      on models from each of the four time points and be evaluated based on percentage change over
      the 6-month evaluation period.

      Orthodontic Pain Assessment

      Subjects will be given a pain diary on the baseline (T0), visits T1 & T2 to record the level
      of orthodontic pain each evening for the first 7 days after each study visit. The degree of
      pain will be assessed using a Visual Analog Scale (VAS) ranging from 1 (least pain) to 10
      (highest pain). In addition, patients will report if the pain is constant or only present on
      biting/chewing. The subjects will return the completed diary to the next visit to be
      collected by the study coordinator and kept in the study record.

      Oral Health Quality of Life (OHQoL)

      To assess the impact of the vibration appliance on the overall oral health quality of life of
      the subject, subjects will be given an Oral Health Impact Profile (OHIP-14) questionnaire.
      The OHIP-14 consists of 14 questions divided into specific dimensions including functional
      limitation, physical pain, psychological discomfort, physical disability, psychological and
      social disability and overall life handicap from orthodontic treatment with or without the
      vibration appliance. The OHIP-14 will be administered at each study visit and the profile
      changes will be compared across time points in data analyses.

      Individual scores are multiplied by the weights to give a subscale score for each category.

      IV. Sample size and justification Few studies exist evaluating salivary biomarkers during
      orthodontic tooth movement. Our primary outcome is changes in the expression of specific
      biomarkers of cellular activation and bone remodeling. No randomized clinical trials (RCTs)
      are currently available to predict treatment effects on biomarker expression. This study will
      serve as a pilot project with 40 patients total in 4 groups divided by gender and
      vibration/no-vibration treatment arms.

      We estimate 600 patients in the target age range beginning orthodontic treatment at the
      University of Connecticut Orthodontic Clinic each year. We anticipate meeting our recruitment
      goal for this study.

      V. Subject Participation The timing of visit activity is planned to coincide with normally
      scheduled clinic provider/patient visits. Typically, treatment for non-extraction cases last
      from 12-30 months in the Orthodontic clinic using fixed appliances. However, the subjects
      will only be evaluated during the first 6 months of their clinical appliance treatment for
      the study purpose and data. Providers will follow patients every 5-6 weeks and the study
      coordinator will ensure/confirm the patients for study appointments. After completion of the
      observation and data collection phase ( up to 17 weeks), the patients will continue to
      proceed with treatment as directed by the their primary orthodontic provider. Data collection
      will occur at normally scheduled visits with no additional appointments specific to the
      study.

      In the event that the PI determines that a subject is not suited to continue in the study
      (eg. the subject shows consistent failure to keep appointed visits, consistent breakage of
      appliances, patient safety considerations, etc.) he/she will be withdrawn by the PI from the
      study and no further data will be collected. Specifically, poor compliance with attending
      appointments during the allotted time frame for each study visit will result in subjects
      being disqualified from the study. For example, the follow-up time frame for T1 is 5-6 weeks
      after T0 (baseline). Therefore if the patient misses an appointment and cannot or does not
      reschedule to attend his/her appoint during the allotted time from (by 6 weeks after T0),
      then he/she will be disqualified from the study. Also, in the event of bracket breakages (as
      stated earlier), the subject is to be seen within 7 days to have the bracket rebounded. The
      primary orthodontic provider will reposition the bracket in the ideal position and continue
      with alignment using the study archwires. If the subject does not present with 7 days of the
      breakage, he/she will be disqualified from the study.

      The data collected to that point will be utilized in analyses. The patient's treatment will
      continue with the primary orthodontic provider consistent with the standard of care.

      VI. Statistical/Data Analysis Intra and inter-rater reliability of the irregularity
      measurements will be assessed using the T0 and T3 models evaluated by the two blinded
      evaluators one week apart for all patients. A Cronbach alpha analysis will be used to assess
      reliability of the measurements. A single calibrated evaluator (the study coordinator) will
      collect all tooth mobility measurements with the Periotest and means will be evaluated using
      non-parametric statistical analyses.

      A Wilcoxon Rank Sum test for independent samples will be used to assess differences between
      groups for all the continuous variables with an α=0.05 for irregularity index
      changes-Periotest measurements, VAS &OHIP-14 measures.

      Salivary biomarker expression will be analyzed by ANOVA to assess differences between the
      four study groups at each time point. The study coordinator and principal investigator will
      perform statistical analyses.
    

Intervention name(s): Vibration Device
Intervention type(s): Device
Intervention description(s): Subjects receiving the OrthoAccel Aura device will be instructed to use the device for 20 minutes/day per the manufacturer's instructions during the study period.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment