Systemic Probiotics in the Periodontal Treatment

Sponsor

Belén Retamal-Valdes (Other)

Overall Status

Unknown status

CT.gov ID

NCT03733379

Collaborator

(none)

176

Enrollment

Locations

Arms

37.8

Anticipated Duration (Months)

Patients Per Site

2.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of this multicenter randomized clinical trial is to evaluate the clinical, microbiological and immunological effects of probiotics as an adjunct to Scaling and Root Planing alone or in combination with Metronidazole and Amoxicillin in the treatment of periodontitis.

Condition or Disease	Intervention/Treatment	Phase
Periodontitis	Procedure: Scaling and root planing Drug: Metronidazole and Amoxicillin placebos Drug: Metronidazole Drug: Amoxicillin Dietary Supplement: Probiotic Dietary Supplement: Probiotic placebo	Phase 3

Detailed Description

The association of scaling and root planing (SRP) with systemic metronidazole (MTZ) and amoxicillin (AMX) has been advocated as one of the most promising therapeutic protocol for the treatment of advanced periodontitis, since the early 2000's. More recently, probiotics has also been suggested as a promising adjunctive treatment for periodontitis due to their antimicrobial and anti-inflammatory properties. Therefore, the aim of this study is to evaluate the clinical, microbiological and immunological effects of probiotics as an adjunct to SRP alone or in combination with MTZ and AMX in the treatment of periodontitis. In this randomized, double-blind, placebo-controlled trial, subjects with periodontitis will be randomly assigned to receive (i) SRP alone, or combined with: (ii) two probiotics lozenges a day for 90 days (Prob), (iii) 400 of MTZ, plus AMX (500 mg) thrice a day (TID) for 14 days (MTZ+AMX), or (iv) Prob and MTZ+AMX. Subjects will be monitored up to 1 year post-therapy. Nine subgingival plaque samples will be collected at baseline and at 3, 6 and 12 months post-therapy; three samples in each of the following pockets categories: shallow (probing depth [PD]≤3 mm), moderate (PD=4-6 mm) and deep (PD≥7 mm). The microbiological samples will be analyzed by checkerboard DNA-DNA hybridization for 40 bacterial species. Two non-contiguous diseased sites (i.e PD and CAL ≥ 5mm, bleeding and probing [BOP] and no furcation involvement) and two non-contiguous healthy sites (i.e. PD and clinical attachment level [CAL] ≤ 4 mm without BoP and/or marginal bleeding) will be randomly chosen per patient for gingival crevicular fluid (GCF) sampling, from the same sites selected for the microbiological monitoring. Peripheral blood samples will also be collected one week after clinical examination. The GCF and blood samples will be analyzed using a multi-analyte method by means of a 17-multiplex fluorescent bead-based immunoassay for 17 cyto/chemokines. The significance of differences over the course of the study will be sought using repeated measures ANOVA and Tukey multiple comparison tests, and at each time point (among groups) using either ANOVA and Tukey multiple comparison tests or ANCOVA with adjustments for the baseline values. The Chi-square test will be used to compare the differences in the frequency of gender, and to compare the differences in the frequency of subjects achieving the clinical endpoint at 1 year and of self-perceived adverse effects. A stepwise forward logistic regression analysis will be performed in order to investigate the impact of predictor variables on the clinical endpoint for treatment, i.e., "presence of ≤4 sites with PD≥5 mm at 12 months post-therapy (yes/no)". The Number Needed to Treat (NNT) with adjunctive antibiotic in order to obtain treatment success (≤4 sites with PD ≥5 mm) will be calculated. The level of significance will be set at 5%.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

176 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Clinical, Microbiological and Immunological Evaluation of the Effects of Systemic Probiotics in the Periodontal Treatment

Actual Study Start Date :

Nov 5, 2018

Anticipated Primary Completion Date :

Dec 30, 2020

Anticipated Study Completion Date :

Dec 30, 2021

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Control Scaling and root planing + Placebos of Metronidazole and Amoxicillin three times a day (TID) for 14 days + placebo lozenges of probiotics two times a day for 90 days.	Procedure: Scaling and root planing 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. Other Names: SRP Drug: Metronidazole and Amoxicillin placebos Amoxicillin and metronidazole placebos thrice a day for 14 days (beginning with the first SRP session). Dietary Supplement: Probiotic placebo The placebo is identical to the active but without L. reuteri. The two Study Products are identical in taste, texture and shape. It will be used 2 times per day by 90 days.
Experimental: Probiotic Scaling and root planing + Placebos of Metronidazole and Amoxicillin three times a day (TID) for 14 days + lozenges of probiotics two times a day for 90 days.	Procedure: Scaling and root planing 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. Other Names: SRP Drug: Metronidazole and Amoxicillin placebos Amoxicillin and metronidazole placebos thrice a day for 14 days (beginning with the first SRP session). Dietary Supplement: Probiotic The probiotic contains 2 different strains of Lactobacillus reuteri: L.reuteri DSM 17938 and L. reuteri ATCC PTA 5289 each at a concentration of 1 x 108 CFU per tablet. It will be used 2 times per day by 90 days.
Experimental: Antibiotic Scaling and root planing + Metronidazole (400 mg/thrice a day,TID) and Amoxicillin (500 mg/ TID) for 14 days + placebo lozenges of probiotics two times a day for 90 days.	Procedure: Scaling and root planing 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. Other Names: SRP Drug: Metronidazole Metronidazole 400 mg thrice a day for 14 days (beginning with the first SRP session). Drug: Amoxicillin Amoxicillin 500 mg thrice a day for 14 days (beginning with the first SRP session).
Experimental: Antibiotic + probiotic Scaling and root planing + Metronidazole (400 mg/thrice a day,TID) and Amoxicillin (500 mg/ TID) for 14 days + lozenges of probiotics two times a day for 90 days.	Procedure: Scaling and root planing 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. Other Names: SRP Drug: Metronidazole Metronidazole 400 mg thrice a day for 14 days (beginning with the first SRP session). Drug: Amoxicillin Amoxicillin 500 mg thrice a day for 14 days (beginning with the first SRP session). Dietary Supplement: Probiotic placebo The placebo is identical to the active but without L. reuteri. The two Study Products are identical in taste, texture and shape. It will be used 2 times per day by 90 days.

Outcome Measures

Primary Outcome Measures

Percentage of subjects reaching ≤ 4 periodontal sites with probing depth (PD) ≥ 5 mm at 12 months [12 months]

Secondary Outcome Measures

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]
Change in the number of sites with PD ≥ 5 mm. [Baseline, 3, 6 and 12 months]
Change in the number of sites with PD ≥ 6 mm [Baseline, 3, 6 and 12 months]
Change 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 Probing Depth (mm). [Baseline, 3, 6 and 12 months]
Full-mouth Clinical Attachment Level (mm) [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 headache obtained through a questionnaire of adverse effects [90 days after taking probiotic]
Occurrence of vomiting obtained through a questionnaire of adverse effects [14 days after taking antibiotic]
Occurrence of vomiting obtained through a questionnaire of adverse effects [90 days after taking probiotic]
Occurrence of diarrhea obtained through a questionnaire of adverse effects. [14 days after taking antibiotic]
Occurrence of diarrhea obtained through a questionnaire of adverse effects. [90 days after taking probiotic]
Occurrence of nausea obtained through a questionnaire of adverse effects. [14 days after taking antibiotic]
Occurrence of nausea obtained through a questionnaire of adverse effects. [90 days after taking probiotic]
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]
Counts of chemokines in the peripheral blood samples [Baseline and 12 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

30 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

≥30 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 probing depth (PD) and clinical attachment level (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 12 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.