Amoxicillin and Metronidazole During Periodontal Treatment

Study Overview
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Brief Summary
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The aim of this multicenter randomized clinical trial is to compare the clinical, microbiological and immunological effects of the adjunctive use of systemic metronidazole plus amoxicillin administered in different phases of the treatment of generalized chronic periodontitis.

Detailed Description
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The combination of systemic metronidazole (MTZ) and amoxicillin (AMX) to scaling and root planing (SRP) has shown to be a promising periodontal treatment. However, some essential issues associated with the use of these antibiotics remain to be established. Although these agents are often prescribed after the healing phase of the SRP procedure, there is biological plausibility to support its use in conjunction with the mechanical treatment. However, to date, no placebo controlled randomized clinical trial (RCT) has directly compared these two protocols. Therefore, the aim of this multicentric RCT is to compare the clinical, microbiological and immunological effects of adjunctive systemic MTZ+AMX administered in different phases of the treatment of generalized chronic periodontitis (GChP). 180 subjects with GChP will be randomly assigned into three groups (n=60/group) that will receive SRP-only (control group) or in combination with 400 mg MTZ+500 mg AMX beginning at the first SRP session (group test 1) or after 3 months of its completion (group test 2). All volunteers will receive clinical and microbiological evaluation at baseline, 3, 6 and 12 months, and immunological assessment (levels of 20 chemokines) at baseline and 12 months post-therapy. Nine subgingival biofilm samples will be collected by subject and analyzed for counts and proportions of 40 bacterial species by checkerboard DNA-DNA hybridization. Differences in clinical, microbiological and immunological parameters among groups and over time will be evaluated using the ANOVA, ANCOVA, Chi-square and Tukey tests. Microbiological analyzes will be performed using adjustments for multiple comparisons. Statistical significance will be set at 5%.

Official Title
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Influence of Moment of Systemic Metronidazole and Amoxicillin Administration in the Treatment of Chronic Periodontitis: a Randomized Clinical Trial.

Conditions
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Chronic Periodontitis

Intervention / Treatment
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* Procedure: Scaling and root planing
* Drug: Metronidazole active phase
* Drug: Metronidazole healing phase
* Drug: Amoxicillin active phase
* Drug: Amoxicillin healing phase
* Drug: Placebos active phase
* Drug: Placebos healing phase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥35 years of age; at least 15 teeth (excluding third molars and teeth with advanced decay indicated for extraction); a minimum of 6 teeth with at least one site each with probing depth (PD) and clinical attachment level (CAL) ≥5 mm; at least 30% of the sites with PD and CAL ≥4 mm and bleeding on probing (BOP). Exclusion Criteria: pregnancy; breastfeeding; current smoking and former smoking within the past 5 years; systemic diseases that could affect the progression of periodontitis (e.g. diabetes, immunological disorders, osteoporosis); scaling and root planing an in the previous 6 months; antibiotic therapy in the previous 6 months; long-term intake of anti-inflammatory medications; need for antibiotic pre-medication for routine dental therapy; use of orthodontic appliances; extensive dental prosthetic rehabilitation; allergy to metronidazole and/or amoxicillin.

Ages Eligible for Study
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Minimum Age: 35 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>Scaling and root planing + Placebos active phase thrice a day (TID) for 14 days and Placebos healing phase TID for 14 days. | Procedure: Scaling and root planing<br>* SRP will be performed in four to six appointments lasting approximately 1 h each, using manual curettes (Hu-Friedy, Chicago, IL, USA) and ultrasonic device (Cavitron Select SPC, Dentsply professional, York, PA, USA) under local anesthesia. The deep sites will be scaled throughout the first week and treatment of the entire oral cavity will be completed in 14 days.<br>* Other names: SRP;Drug: Placebos active phase<br>* Amoxicillin and metronidazole placebos thrice a day for 14 days in the active phase (beginning with the first SRP session).<br>* Other names: P 1;Drug: Placebos healing phase<br>* Amoxicillin and metronidazole placebos thrice a day for 14 days in the healing phase (3 months after active phase).<br>* Other names: P 2;|
| Active Comparator: Active phase<br>Scaling and root planing + Metronidazole active phase (400 mg/thrice a day,TID) + Amoxicillin active phase (500 mg/ TID) for 14 days and Placebos healing phase TID for 14 days. | Procedure: Scaling and root planing<br>* SRP will be performed in four to six appointments lasting approximately 1 h each, using manual curettes (Hu-Friedy, Chicago, IL, USA) and ultrasonic device (Cavitron Select SPC, Dentsply professional, York, PA, USA) under local anesthesia. The deep sites will be scaled throughout the first week and treatment of the entire oral cavity will be completed in 14 days.<br>* Other names: SRP;Drug: Metronidazole active phase<br>* Metronidazole 400 mg thrice a day for 14 days in the active phase of the periodontal treatment (beginning with the first SRP session).<br>* Other names: MTZ 1;Drug: Amoxicillin active phase<br>* Amoxicillin 500 mg thrice a day for 14 days in the active phase of the periodontal treatment (beginning with the first SRP session).<br>* Other names: AMX 1;Drug: Placebos healing phase<br>* Amoxicillin and metronidazole placebos thrice a day for 14 days in the healing phase (3 months after active phase).<br>* Other names: P 2;|
| Active Comparator: Healing phase<br>Scaling and root planing + Placebos active phase thrice a day (TID) for 14 days and Metronidazole healing phase (400 mg/TID) + Amoxicillin healing phase (500 mg/TID) for 14 days. | Procedure: Scaling and root planing<br>* SRP will be performed in four to six appointments lasting approximately 1 h each, using manual curettes (Hu-Friedy, Chicago, IL, USA) and ultrasonic device (Cavitron Select SPC, Dentsply professional, York, PA, USA) under local anesthesia. The deep sites will be scaled throughout the first week and treatment of the entire oral cavity will be completed in 14 days.<br>* Other names: SRP;Drug: Metronidazole healing phase<br>* Metronidazole 400 mg thrice a day for 14 days in the healing phase of the periodontal treatment (3 months after active phase).<br>* Other names: MTZ 2;Drug: Amoxicillin healing phase<br>* Amoxicillin 500 mg thrice a day for 14 days in the healing phase of the periodontal treatment (3 months after active phase).<br>* Other names: AMX 2;Drug: Placebos active phase<br>* Amoxicillin and metronidazole placebos thrice a day for 14 days in the active phase (beginning with the first SRP session).<br>* Other names: P 1;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects reaching ≤ 4 periodontal sites with probing depth (PD) ≥ 5 mm at 12 months |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of sites with PD ≥ 5 mm. |  | Baseline, 3, 6 and 12 months. | 
| Number of sites with PD ≥ 6 mm. |  | Baseline, 3, 6 and 12 months. | 
| Number of sites with PD ≥ 7 mm. |  | Baseline, 3, 6 and 12 months. | 
| Reduction in the number of sites with PD ≥ 5 mm. |  | Baseline, 3, 6 and 12 months. | 
| Reduction in the number of sites with PD ≥ 6 mm. |  | Baseline, 3, 6 and 12 months. | 
| Reduction in the number of sites with PD ≥ 7 mm. |  | Baseline, 3, 6 and 12 months. | 
| Mean PD changes in sites with initial PD between 4-6 mm |  | Baseline - 12 months. | 
| Mean PD changes in sites with initial PD ≥ 7 mm. |  | Baseline - 12 months. | 
| Mean CAL changes in sites with initial CAL between 4-6 mm |  | Baseline - 12 months. | 
| Mean CAL changes in sites with initial CAL ≥ 7 mm. |  | Baseline - 12 months. | 
| Full-mouth PD. |  | Baseline, 3, 6 and 12 months. | 
| Full-mouth clinical attachment level. |  | Baseline, 3, 6 and 12 months. | 
| Percentage of sites with bleeding on probing. |  | Baseline, 3, 6 and 12 months. | 
| Percentage of sites with plaque accumulation |  | Baseline, 3, 6 and 12 months. | 
| Percentage of sites with marginal bleeding. |  | 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. | 
| Counts of chemokines in the crevicular gingival fluid. |  | Baseline and 12 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Periodontal disease, Metronidazole, Amoxicillin, Scaling and root planing, Healing phase