Surgical Access Combined With Systematically Administered Antibiotics in the Treatment of Peri-implantitis

Study Overview
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Brief Summary
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This randomized clinical trial evaluates the clinical and microbiological (microbial complexes and changes in the diversity of the submucosal biofilm) effects of MTZ+AMX as adjuncts to anti-infectious surgical treatment plus Er: YAG in the treatment of peri-implantitis.

Detailed Description
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Peri-implantitis is a pathological condition characterized by inflammation of peri-implant connective tissues and progressive peri-implant bone. Recently, the therapeutic protocol using non-surgical debridement associated with the combination of systemic metronidazole (MTZ) and amoxicillin (AMX) has not been shown to be effective in controlling the disease. These unfavorable results may have occurred due to the limitation in the change of the submucosal microbiological profile due to mechanical difficulties in the decontamination of the implant threads. Therefore, this randomized clinical trial (RCT) aimed to evaluate the clinical and microbiological (microbial complexes and changes in the diversity of the submucosal biofilm) effects of MTZ+AMX as adjuncts to anti-infectious surgical treatment plus Er:YAG in the treatment of peri-implantitis. Ninety-four subjects with untreated peri-implantitis are being included and will be randomly assigned to receive (i) open flap debridement plus Er:YAG irradiation alone (control), or (ii) with adjunctive systemically administered MTZ (400 mg) + AMX (500 mg) thrice a day (TID) for 14 days (test). Subjects will be monitored up to 12 months post-treatment. Submucosal biofilm samples from the deepest site of each implant with peri-implantitis will be collected in duplicate per patient: at baseline and at 3, 6 and 12 months post-therapy and analyzed by checkerboard DNA-DNA hybridization for 40 bacterial species, and at baseline, 3 and 12 months post-treatment for 16S rRNA sequencing (Ion Torrent PGM System). The primary outcome variable of this trial will be the difference between treatment groups for the change in CAL from baseline to 12 months. The significance of differences in each group (over the course of the study) will be sought using the Student's-t test; and among groups (at each time point) using either ANOVA /ANCOVA or Kruskal Wallis tests and post-hoc analyses, depending on normality of the data. Fisher's exact test will be used to compare differences in the frequency of gender. Statistical significance will be set at 5%.

Official Title
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Clinical and Microbiological Effects of Surgical Access Combined With Systematically Administered Antibiotics in the Treatment of Peri-implantitis: 1-year Randomized Double-blinded Controlled Clinical Trial

Conditions
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Peri-Implantitis

Intervention / Treatment
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* Procedure: Open flap debridement
* Other: Er: YAG irradiation
* Drug: Metronidazole
* Drug: Amoxicillin
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-70 years of age; in general good health, at least one dental implant in function for at least one year with untreated peri-implantitis defined as: presence of bleeding and/or suppuration on gentle probing, probing depths (PD) ≥ 6mm, and bone levels ≥3mm apical of the most coronal portion of the intraosseous part of the implant. Exclusion Criteria: subjects with ≥6 sites with PD ≥5mm; individuals that received periodontal treatment within three months prior to entering the study; inability to perform proper supramucosal and supragingival plaque control (e.g., due to improper restoration design or lack of skills); poorly adapted implant-supported restoration; diabetes; pregnancy; nursing; history of allergies to metronidazole and/or amoxicillin, or any other ingredient of oral care products; alcohol or drug abuse; any systemic diseases that could affect post-operative healing or that required antibiotic premedication for routine dental therapy; long-term use of mouthrinses; anti-inflammatory medications; any other drug that could interfere with the study outcomes within three months prior to entering the study; use of antibiotics within six months prior to entering the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>Open flap debridement + Er: YAG irradiation alone + systemic placebo of metronidazole and amoxicillin thrice a day (TID) for 14 days | Procedure: Open flap debridement<br>* After local anesthesia (2% lidocaine with1:100,000 epinephrine), intrasulcular incisions will be performed to create a horizontal flap extending beyond the adjacent teeth and/or implants. Buccal and lingual full-thickness flaps will be dissected, and granulation tissue will be removed to expose the implant threads and bone defect. The flap will be repositioned in its original position and stabilized with interrupted sutures, which will be removed after 10 days.<br>* Other names: OFD;Other: Er: YAG irradiation<br>* An Er:YAG laser (Lite Touch, Light Instruments, Israel) will be used, with an irradiation energy of 20 mJ, frequency of 20 Hz, output power of 0.4 W, and an energy density of 2.76 J/cm2. An 8 mm long sapphire tip will be used in the respective handpiece and not in contact with the titanium surface, with concomitant water spray irrigation, under air 6 and water spray 6, the irradiation angle will be 90 degrees, at a focal distance of 2 mm, with spot size diameter of 1.3 mm<br>Drug: Placebos<br>* Amoxicillin and metronidazole placebos thrice a day for 14 days in the healing phase (beginning after open flap debridement).<br>|
| Experimental: Test<br>Open flap debridement + Er: YAG irradiation alone + systemic metronidazole (400mg) and amoxicillin (500mg) thrice a day (TID) for 14 days | Procedure: Open flap debridement<br>* After local anesthesia (2% lidocaine with1:100,000 epinephrine), intrasulcular incisions will be performed to create a horizontal flap extending beyond the adjacent teeth and/or implants. Buccal and lingual full-thickness flaps will be dissected, and granulation tissue will be removed to expose the implant threads and bone defect. The flap will be repositioned in its original position and stabilized with interrupted sutures, which will be removed after 10 days.<br>* Other names: OFD;Other: Er: YAG irradiation<br>* An Er:YAG laser (Lite Touch, Light Instruments, Israel) will be used, with an irradiation energy of 20 mJ, frequency of 20 Hz, output power of 0.4 W, and an energy density of 2.76 J/cm2. An 8 mm long sapphire tip will be used in the respective handpiece and not in contact with the titanium surface, with concomitant water spray irrigation, under air 6 and water spray 6, the irradiation angle will be 90 degrees, at a focal distance of 2 mm, with spot size diameter of 1.3 mm<br>Drug: Metronidazole<br>* Metronidazole 400 mg thrice a day for 14 days in the active phase of the periodontal treatment (beginning after open flap debridement).<br>* Other names: MTZ;Drug: Amoxicillin<br>* Amoxicillin 500 mg thrice a day for 14 days in the active phase of the periodontal treatment (beginning after open flap debridement).<br>* Other names: AMX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference between treatment groups for the change in the clinical attachment level (CAL). |  | 12 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients (and implants) reaching the following clinical endpoint for treatment: PD< 5mm, absence of BOP and no further bone loss. |  | 12 months. | 
| Mean plaque index. |  | Baseline, 3, 6 and 12 months. | 
| Mean gingival index. |  | Baseline, 3, 6 and 12 months. | 
| Percentage of sites with bleeding on probing. |  | Baseline, 3, 6 and 12 months. | 
| Percentage of sites with suppuration. |  | Baseline, 3, 6 and 12 months. | 
| Probing depth. |  | Baseline, 3, 6 and 12 months. | 
| Occurrence of headache obtained through a questionnaire of adverse effects. |  | 14 days after taking antibiotic. | 
| Occurrence of vomiting obtained through a questionnaire of adverse effects. |  | 14 days after taking antibiotic. | 
| Occurrence of diarrhea obtained through a questionnaire of adverse effects. |  | 14 days after taking antibiotic. | 
| Occurrence of metallic taste obtained through a questionnaire of adverse effects. |  | 14 days after taking antibiotic. | 
| Occurrence of nausea obtained through a questionnaire of adverse effects. |  | 14 days after taking antibiotic. | 
| Occurrence of irritability obtained through a questionnaire of adverse effects. |  | 14 days after taking antibiotic. | 
| Proportions of periodontal pathogenic bacterial species. |  | Baseline, 3, 6 and 12 months. | 
| Counts of periodontal pathogenic bacterial species. |  | Baseline, 3, 6 and 12 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metronidazole, peri-implantitis, open flap debridement, Er:YAG irradiation, amoxicillin, microbiota