Effectiveness of Metronidazole Gel and Mobile SMS Reminders on Gingivitis in Orthodontic Patients
Condition: Gingivitis
MeSH terms: Gingivitis
Study type: Interventional
Phase: Phase 4

Summary: 
      A rapid deterioration in oral hygiene occur after bonding of orthodontic appliances.
      Zachrisson and Zachrisson have reported that even after maintaining excellent oral hygiene,
      patients usually experience mild to moderate gingivitis within 1-2 months after orthodontic
      appliance placement. Slutzkey and Levin have reported a prevalence of 72 % gingivitis in
      orthodontic patients.

      The difficulty in maintenance of oral hygiene and inefficient removal of supragingival plaque
      due to the appliances lead to development of gingivitis and hyperplasia. Tooth brush access
      to the buccal surface of the teeth becomes problematic and predisposes plaque buildup around
      the brackets.

      Investigators are now focusing on the development of localized drug delivery systems that can
      allow maximum concentration on the target site, thus minimizing the potential systemic
      effects. Metronidazole has been used by several researchers due to its selective
      antimicrobial activity against the obligate anaerobes. The topical administration in gel form
      has several advantages. Miani et al concluded that the use of metronidazole gel significantly
      reduces the total bacterial count in the gingival crevicular fluid.

      In medicine and dentistry, active mobile telephone short-message service (SMS) reminders have
      been used to improve patient compliance and positive behavior changes. A study conducted by
      Epprighta et al have reported the effectiveness of SMS reminder in orthodontic patients. They
      have reported significantly lower bleeding, gingival and plaque indices scores in SMS
      reminder group as compared to control.

      Rationale:

      The application of metronidazole gel is effective in management of gingivitis in patients
      undergoing orthodontic therapy. Additionally, the constant reminder therapy at weekly
      interval would also lead to improvement in the oral hygiene. According to pertinent
      literature survey, none of the study has been conducted to compare the effectiveness of SMS
      reminders and use of anaerobic gel to reduce gingival inflammation.

      Null Hypothesis:

      Application of 0.8% metronidazole gel and mobile telephone short-message service oral hygiene
      reminders is equally effective in reducing the gingival inflammation in orthodontic patients
      with gingivitis as compared to control group.

      Objective:

      The objectives of the study will be to assess the use of topical gel or mobile telephone
      short-message service oral hygiene reminders can reduce gingivitis in orthodontic patients as
      compared to control group.
    

Detailed description: 
      Gingivitis: It is defined as the inflammation of the gingiva in the absence of clinical
      attachment loss.

      Six standard sites on incisors, canines and premolars have been used in this study as study
      sites as described by Gettinger et al. The investigators will not include banded first molars
      because the banding itself will lead to a compromise in periodontal conditions. The study
      sites will be six proximal-buccal line angles on the following teeth: right maxillary second
      premolar, mesiobuccal line angle; right maxillary canine, distobuccal line angle; left
      maxillary central incisor, distolabial line angle; right mandibular central incisor,
      distolabial line angle; left mandibular canine, distobuccal line angle; and left mandibular
      second premolar, mesiobuccal line angle. If a study tooth was missing, the corresponding
      tooth on the contralateral side was examined. All study sites will be evaluated at baseline
      (To) and 4 weeks later at (T1).

      Bleeding Index (BI): BI will be scored as described by Saxton and van der Ouderaa upon
      probing the gingival sulci of six standard sites mentioned above.

      0. Absence of bleeding after 30 seconds

        1. Bleeding observed after 30 seconds

        2. Immediate bleeding

      Gingival index:

      0. No inflammation.

        1. Mild inflammation, slight change in color, slight edema, no bleeding on probing.

        2. Moderate inflammation, moderate glazing, redness, bleeding on probing.

        3. Severe inflammation, marked redness and hypertrophy, ulceration, tendency to spontaneous
           bleeding.

      Orthodontic Plaque Index (PI):

      According to Orthodontic Plaque Index, the investigators will assess the six standard sites
      and the condition of adjacent marginal gingiva by staining the teeth with plaque disclosing
      solution (erythrosine).

      0. No plaque deposits on the tooth surfaces surrounding the bracket base

        1. Plaque deposits on one tooth surface at the bracket base

        2. Plaque deposits on two tooth surface at the bracket base

        3. Plaque deposits on three tooth surface at the bracket base

        4. Plaque deposits on four tooth surface at the bracket base and/or gingival inflammation
           indicators (plaque deposits near the gingiva do not necessarily have to be present)
           Study Setting: Dental clinic, Aga Khan University Hospital, Karachi Duration Of Study:
           Four months after approval of synopsis by Ethical Review Committee of AKU

      Sample Size:

      Sample size is calculated in OpenEpi (version 3.01) sample size calculator. Martin et al
      reported that the mean gingival index at 4-6 weeks interval in gel group was 1.56 + 0.14;
      while in the control group, it was 1.68 + 0.12.

      Keeping the above difference at the level of significance (α) at 5% and power of study (1-β)
      at 95%, the investigators need at least 19 observations for each arm. The sample size is
      inflated by 10% to get 21 subjects per arm for any loss to follow up or noncompliance to
      metronidazole/placebo gel.

      Since, the investigators have three experimental groups, so the investigators need a total of
      63 subjects.

      Sampling Technique: Random Permuted block sampling 6 and 8

      Ethical considerations:

      The study will be started after obtaining approval from ethical review committee. Only those
      participants will be recruited who will sign the consent form. The study will be conducted
      according to the World Medical Association's Declaration of Helsinki and the principles of
      GCP (Good Clinical Practice). Any subsequent protocol amendments will be submitted to ERC and
      regulatory authorities for approval. The trial will be conducted in compliance with
      regulations, particularly specifying pharmaco-vigilance reporting and a copy of final study
      report will be submitted to ERC.

      Possible Risks or Benefits:

      There may be no risk involved in this study as the study is based on treatment options which
      is routinely used in dental clinics to treat gingivitis. The metallic taste in the
      metronidazole gel might lead to nausea.

      Benefits include the evaluation of the best modality to manage gingivitis in orthodontic
      patients. Additionally, there would not be any direct benefit to the participants but
      significant results from the study would lead to improvement in the standard protocol for
      future patients.

      Adverse Events:

      There is no adverse event reported in the literature related to topical gel to be used in the
      study. The trial related events would be covered by the department of surgery. The product
      related adverse events would be managed, reported and recorded to ERC within a specified
      period of time while the serious adverse events will be reported immediately to ERC.

      Right Of Refusal To Participate And Withdrawal:

      Participants will be given choice to either participate or refuse to participate in the study
      All participants non-compliant with gel therapy will be excluded from the study

      Incentive:

      After T1 all patients will be given free of cost scaling and polishing treatment. If the
      indices are still high, and clinical examination shows higher score of gingivitis, additional
      systemic antibiotics will be prescribed.

      Patient confidentiality, access and storage:

      The information provided by the participant will remain confidential. Nobody except
      investigators will have access to it. Participants' name and identity will not be disclosed
      at any time. However, the data may be seen by ethical review committee, DSMB or any local
      regulatory body. As per GCP and other guidelines, data will be retained for 15 years.

      Randomization, blinding and treatment allocation:

      Subjects will be assigned to one of the three study groups using a computer generated
      randomization list. The randomization will be performed by clinical trials unit (CTU) using a
      random permuted block sampling of 6 and 8. The study investigators will be blinded and only
      CTU pharmacist will be unblinded in this study.

      The recruitment of the patients will be performed by one investigator who will explain the
      objective and three arms of the study and participant could be in any arm that is selected by
      computer. All the measurements at the baseline (To) and follow ups (T1) will be recorded by
      the second investigator on separate To and T1 sheets. Patient and the investigator who is
      taking the measurement will be blinded about the intervention groups. The reminder SMS
      messages will be sent by another clinician who will not be the part of the study.

      Investigational product management:

      The metronidazole gel 0.8% contains metronidazole tablets and carboxy methyl cellulose 2% as
      a base solution. The placebo gel contains similar ingredients except metronidazole tablet.
      The metronidazole and placebo gel will be prepared by Pharmacy Department, Aga Khan
      University Hospital. The participants will be instructed to apply 1.5 gm approximately
      metronidazole/placebo gel (Aga Khan University Hospital) twice daily for four weeks. The
      participants will be given tubes of metronidazole/placebo gel each stored at room
      temperature. The packing, labelling, storage and dispatch of the gel will be performed by
      clinical trials unit.

      Data collection procedure:

      Ethical approval will be taken from the institutional ethical review committee before
      commencement of the study. All those patients who fulfilled the inclusion criteria will
      receive detailed information regarding the study and only those patients will be included who
      signed an informed consent.

      Training of the examiner:

      Participating investigator will be trained and calibrated on the development of the trial,
      case selection, measurement techniques, sample collection, data compilation sheets and their
      precise role in the study. For assessment of intra-examiner reliability, measurements will be
      repeated by same investigator for 5 subjects at 1 week interval.

      Data analysis:

      Data will be analyzed using SPSS version 20.0. Descriptive statistics for all the base line
      clinical parameters such as bleeding index, orthodontic plaque index and gingival index
      scores will be calculated. It will be an intention to treat analysis. Gingival index,
      bleeding index and orthodontic plaque index will be compared across group A, B and C. The
      level of significance will be kept at < 0.05.

      Finance:

      Department of Surgery

      Publication policy/plan:

      The data will be used for the publication nationally and internationally and could be
      presented in either local or international forum.
    

Intervention name(s): Metronidazole gel; SMS text reminder; Placebo gel
Intervention type(s): Drug; Other; Other
Intervention description(s): The application of metronidazole gel is effective in the management of gingivitis in patients undergoing orthodontic therapy. Additionally, the constant reminder therapy at weekly interval would also lead to improvement in the oral hygiene.16 According to pertinent literature survey, none of the study has been conducted to compare the effectiveness of SMS reminders and use of anaerobic gel to reduce gingival inflammation.; Subjects will be provided biweekly reminder via 'SMS text reminder' in the form of text message reinforcing oral hygiene. Additionally, patients will be given standard oral hygiene instructions on the visit with a placebo gel topically instructed to apply on the marginal gingiva for the next 4 weeks, twice a day for 30 minutes, after morning and evening tooth brushing.; Group C will be subjects will be given standard oral hygiene instructions on the visit with a placebo gel topically instructed to apply on the marginal gingiva for the next 4 weeks, twice a day for 30 minutes, after morning and evening tooth brushing.
Other intervention name(s): Anaerobic gel; Reminder
Intervention MeSH terms: Metronidazole
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment