Clinical trial NCT03733379: Systemic Probiotics in the Periodontal Treatment
Official title: Clinical, Microbiological and Immunological Evaluation of the Effects of Systemic Probiotics in the Periodontal Treatment
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Periodontitis
Keywords: Periodontitis
Probiotic
Metronidazole
Amoxicillin
Scaling and root planing
Periodontal treatment
Lead sponsor: University of Guarulhos
Sponsor class: OTHER
First posted: 2018-11-07
Enrollment: 176
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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%.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of subjects reaching ≤ 4 periodontal sites with probing depth (PD) ≥ 5 mm at 12 months
timeFrame: 12 months
Secondary outcomes:
measure: Number of sites with PD ≥ 5 mm.
timeFrame: Baseline, 3, 6 and 12 months
measure: Number of sites with PD ≥ 6 mm.
timeFrame: Baseline, 3, 6 and 12 months
measure: Number of sites with PD ≥ 7 mm.
timeFrame: Baseline, 3, 6 and 12 months
measure: Change in the number of sites with PD ≥ 5 mm.
timeFrame: Baseline, 3, 6 and 12 months
measure: Change in the number of sites with PD ≥ 6 mm
timeFrame: Baseline, 3, 6 and 12 months
measure: Change in the number of sites with PD ≥ 7 mm
timeFrame: Baseline, 3, 6 and 12 months
measure: Mean PD changes in sites with initial PD between 4-6 mm
timeFrame: Baseline - 12 months
measure: Mean PD changes in sites with initial PD ≥ 7 mm.
timeFrame: Baseline - 12 months
measure: Mean CAL changes in sites with initial CAL between 4-6 mm
timeFrame: Baseline - 12 months
measure: Mean CAL changes in sites with initial CAL ≥ 7 mm.
timeFrame: Baseline - 12 months
measure: Full-mouth Probing Depth (mm).
timeFrame: Baseline, 3, 6 and 12 months
measure: Full-mouth Clinical Attachment Level (mm)
timeFrame: Baseline, 3, 6 and 12 months
measure: Percentage of sites with bleeding on probing
timeFrame: Baseline, 3, 6 and 12 months
measure: Percentage of sites with plaque accumulation
timeFrame: Baseline, 3, 6 and 12 months
measure: Percentage of sites with marginal bleeding
timeFrame: Baseline, 3, 6 and 12 months
measure: Occurrence of headache obtained through a questionnaire of adverse effects
timeFrame: 14 days after taking antibiotic
measure: Occurrence of headache obtained through a questionnaire of adverse effects
timeFrame: 90 days after taking probiotic
measure: Occurrence of vomiting obtained through a questionnaire of adverse effects
timeFrame: 14 days after taking antibiotic
measure: Occurrence of vomiting obtained through a questionnaire of adverse effects
timeFrame: 90 days after taking probiotic
measure: Occurrence of diarrhea obtained through a questionnaire of adverse effects.
timeFrame: 14 days after taking antibiotic
measure: Occurrence of diarrhea obtained through a questionnaire of adverse effects.
timeFrame: 90 days after taking probiotic
measure: Occurrence of nausea obtained through a questionnaire of adverse effects.
timeFrame: 14 days after taking antibiotic
measure: Occurrence of nausea obtained through a questionnaire of adverse effects.
timeFrame: 90 days after taking probiotic
measure: Proportions of periodontal pathogenic bacterial species.
timeFrame: Baseline, 3, 6 and 12 months
measure: Counts of periodontal pathogenic bacterial species.
timeFrame: Baseline, 3, 6 and 12 months
measure: Counts of chemokines in the crevicular gingival fluid.
timeFrame: Baseline and 12 months
measure: Counts of chemokines in the peripheral blood samples
timeFrame: Baseline and 12 months
Other outcomes:
Locations:
city: Curitiba
country: Brazil
facility: Federal University of Paraná
state: Paraná
city: Guarulhos
country: Brazil
facility: University of Guarulhos
state: São Paulo
Study officials:
affiliation: University of Guarulhos
name: Magda Feres, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Feres M, Figueiredo LC, Soares GM, Faveri M. Systemic antibiotics in the treatment of periodontitis. Periodontol 2000. 2015 Feb;67(1):131-86. doi: 10.1111/prd.12075.
citation: Feres M, Soares GM, Mendes JA, Silva MP, Faveri M, Teles R, Socransky SS, Figueiredo LC. Metronidazole alone or with amoxicillin as adjuncts to non-surgical treatment of chronic periodontitis: a 1-year double-blinded, placebo-controlled, randomized clinical trial. J Clin Periodontol. 2012 Dec;39(12):1149-58. doi: 10.1111/jcpe.12004. Epub 2012 Sep 27.
citation: Borges I, Faveri M, Figueiredo LC, Duarte PM, Retamal-Valdes B, Montenegro SCL, Feres M. Different antibiotic protocols in the treatment of severe chronic periodontitis: A 1-year randomized trial. J Clin Periodontol. 2017 Aug;44(8):822-832. doi: 10.1111/jcpe.12721. Epub 2017 Jul 26.
citation: Laleman I, Yilmaz E, Ozcelik O, Haytac C, Pauwels M, Herrero ER, Slomka V, Quirynen M, Alkaya B, Teughels W. The effect of a streptococci containing probiotic in periodontal therapy: a randomized controlled trial. J Clin Periodontol. 2015 Nov;42(11):1032-41. doi: 10.1111/jcpe.12464. Epub 2015 Nov 29.
citation: Retamal-Valdes B, Teughels W, Oliveira LM, da Silva RN, Fritoli A, Gomes P, Soares GMS, Temporao N, Furquim CP, Duarte PM, Doyle H, Faveri M, Figueiredo LC, Feres M. Clinical, microbiological, and immunological effects of systemic probiotics in periodontal treatment: study protocol for a randomized controlled trial. Trials. 2021 Apr 15;22(1):283. doi: 10.1186/s13063-021-05246-0.