Systemic Probiotics in the Periodontal Treatment

NCT ID: NCT03733379

Last Updated: 2020-01-13

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 176 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-11-05
• Study Completion Date: 2021-12-30

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%.

Conditions

Periodontitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: PLACEBO_COMPARATOR

Scaling and root planing

Intervention Type: PROCEDURE

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.

Metronidazole and Amoxicillin placebos

Intervention Type: DRUG

Amoxicillin and metronidazole placebos thrice a day for 14 days (beginning with the first SRP session).

Probiotic placebo

Intervention Type: DIETARY_SUPPLEMENT

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.

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.

Group Type: EXPERIMENTAL

Scaling and root planing

Intervention Type: PROCEDURE

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.

Metronidazole and Amoxicillin placebos

Intervention Type: DRUG

Amoxicillin and metronidazole placebos thrice a day for 14 days (beginning with the first SRP session).

Probiotic

Intervention Type: DIETARY_SUPPLEMENT

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.

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.

Group Type: EXPERIMENTAL

Scaling and root planing

Intervention Type: PROCEDURE

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.

Metronidazole

Intervention Type: DRUG

Metronidazole 400 mg thrice a day for 14 days (beginning with the first SRP session).

Amoxicillin

Intervention Type: DRUG

Amoxicillin 500 mg thrice a day for 14 days (beginning with the first SRP session).

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.

Group Type: EXPERIMENTAL

Scaling and root planing

Intervention Type: PROCEDURE

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.

Metronidazole

Intervention Type: DRUG

Metronidazole 400 mg thrice a day for 14 days (beginning with the first SRP session).

Amoxicillin

Intervention Type: DRUG

Amoxicillin 500 mg thrice a day for 14 days (beginning with the first SRP session).

Probiotic placebo

Intervention Type: DIETARY_SUPPLEMENT

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.

Interventions

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.

Intervention Type: PROCEDURE

Metronidazole and Amoxicillin placebos

Amoxicillin and metronidazole placebos thrice a day for 14 days (beginning with the first SRP session).

Intervention Type: DRUG

Metronidazole

Metronidazole 400 mg thrice a day for 14 days (beginning with the first SRP session).

Intervention Type: DRUG

Amoxicillin

Amoxicillin 500 mg thrice a day for 14 days (beginning with the first SRP session).

Intervention Type: DRUG

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.

Intervention Type: 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.

Intervention Type: DIETARY_SUPPLEMENT

Other Intervention Names

SRP

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.

• Minimum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Belén Retamal-Valdes

OTHER

Sponsor Role: lead

Responsible Party

Belén Retamal-Valdes

Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Magda Feres, Professor

Role: PRINCIPAL_INVESTIGATOR

University of Guarulhos

Locations

Federal University of Paraná

Curitiba, Paraná, Brazil

Site Status: RECRUITING

University of Guarulhos

Guarulhos, São Paulo, Brazil

Site Status: NOT_YET_RECRUITING

Countries

Brazil

Central Contacts

Belén Retamal-Valdes, Professor

Role: CONTACT

belenretamalvaldes@gmail.com

+55 (11) 942801064

Magda Feres, Professor

Role: CONTACT

mferes@ung.br

Facility Contacts

Geisla Soares, Professor

Role: primary

geisla.soares@ufpr.br

+55 (41) 33604134

Natalie Temporão, Master student

Role: backup

natalie.temporao@gmail.com

+55 (41) 99960339

Belén Retamal-Valdes, Professor

Role: primary

belenretamalvaldes@gmail.com

+55 (11) 942801064

Magda Feres, Professor

Role: backup

mferes@ung.br

References

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.

Reference Type: BACKGROUND

PMID: 25494600 (View on PubMed)

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.

Reference Type: RESULT

PMID: 23016867 (View on PubMed)

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.

Reference Type: RESULT

PMID: 28303587 (View on PubMed)

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.

Reference Type: RESULT

PMID: 26427036 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33858486 (View on PubMed)

Other Identifiers

CAAE: 74049717.7.1001.5506

Identifier Type: -

Identifier Source: org_study_id