Influence of Probiotics on Clinical Parameters, the Oral Microbiome and the Immune System During an Orthodontic Treatment

• ClinicalTrials.gov Identifier: NCT04598633
• Recruitment Status: Recruiting
• First Posted: October 22, 2020
• Last Update Posted: December 22, 2020
• Sponsor: University of Erlangen-Nürnberg
• Collaborator: BioGaia AB
• Information provided by (Responsible Party): Dr. Corinna Lesley Seidel, University of Erlangen-Nürnberg

Study Description

Brief Summary:

Orthodontic treatment with fixed appliances can be necessary to correct malocclusions in adolescence or adulthood. It its known that orthodontic treatment induces aseptic pseudo-inflammatory reactions. However, studies could show that an increase of certain inflammatory cytokines during orthodontic treatment correlated with a higher risk of root resorption. Moreover, it has been shown that orthodontic treatment leads to a dysbiosis of the oral microbiome especially during the first 3 months of the orthodontic treatment. This could be a potential risk factor as the inflammation of periodontitis during an orthodontic treatment could favor root resorption and progressive destruction of the periodontal apparatus.

Probiotics are already used successfully as an adjuvant therapy in the treatment of periodontitis to improve clinical parameters and to reduce local inflammation. However, there are only a few studies that investigated the influence of probiotics during an orthodontic treatment.

Therefore, the aim of the study is to investigate if the daily intake of lozenges containing probiotics versus placebo lozenges during the first 3 months of orthodontic treatment with fixed appliances can improve clinical parameters, reduce local inflammation and prevent a dysbiosis of the oral microbiome.

Condition or disease	Intervention/treatment	Phase
Gingivitis; Orthodontic Appliance Complication	Dietary Supplement: Lactobacillus reuteri Prodentis®-lozenges (DSM 17938, ATCC PTA 5289); Dietary Supplement: Placebo-lozenges (BioGaia)	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Monocentric, randomized, double-blind, placebo-controlled, clinical study
• Masking: Double (Participant, Investigator)
• Masking Description: Study participants, meeting the inclusion criteria and not fulfilling the exclusion criteria, will be assigned to the study group or to the control group using a randomization plan. Randomization plan will be generated by the Center for Clincal Studies of the University Hospital of Erlangen. The lab manager will prepare storage boxes, in which exactly 168 lozenges will be stored. Half of the boxes will contain test-lozenges (study group), half or them will contain placebo-lozenges (control group). The storage boxes for the test and the placebo group will be identical and blinded. The storage boxes will be labelled with pseudonyms in accordance to the randomization plan generated by the Center for Clinical Studies. Therefore, study participants will not have knowledge of the group affiliation. The collection of the samples and the measuring of the clinical parameters will be performed by one orthodontist, who will be blinded to the randomization of the study participants.
• Primary Purpose: Prevention
• Official Title: Influence of Probiotics on Clinical Parameters, the Oral Microbiome and the Immune System During an Orthodontic Treatment: a Prospective, Double-blind, Randomized, Clinical Study
• Actual Study Start Date: November 24, 2020
• Estimated Primary Completion Date: November 1, 2022
• Estimated Study Completion Date: November 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Lactobacillus reuteri Prodentis®-lozenges	Dietary Supplement: Lactobacillus reuteri Prodentis®-lozenges (DSM 17938, ATCC PTA 5289); Supplementary intake of Lactobacillus reuteri Prodentis®-lozenges (DSM 17938, ATCC PTA 5289) 2 times per day for 12 weeks
Placebo Comparator: Placebo-lozenges (BioGaia)	Dietary Supplement: Placebo-lozenges (BioGaia); Placebo-lozenges (BioGaia) 2 times per day for 12 weeks

Outcome Measures

Primary Outcome Measures :

1. Gingival Index (GI) [ Time Frame: Baseline to week 4 of intake ]

   Primary endpoint is the change of the Gingival Index (GI) from baseline to week 4. The measurement of GI is described by Löe et al, which scores the gingival condition according to the defined criteria. The scores will be measured at four sites per tooth, added and divided by four to obtain the "GI for the tooth"-Index. We will use the 'GI for the tooth' described there, but only for those teeth with fixed ortodontic brackets. The 'GI for the patient' is then the mean of the GIs for the teeth.

   CRITERIA FOR THE GINGIVAL INDEX SYSTEM

   0 = Absence of inflammation.

   1. = Mild inflammation - slight cliange in color and little change in texture.
   2. = Moderate inflammation - modcrate glazing, redness,oedema, hypertrophy, bleeding on pressure.
   3. = Severe inflammation - marked redness and hypertrophy, tendency to spontaneous bleeding, ulceration.

Secondary Outcome Measures :

1. Probing pocket depth (PPD) (4-point-measurement) [ Time Frame: Baseline till 12 months after insertion of appliance ]
   The measuremtn of the probing of periodontal pockets (periodontal probing depth, PPD) is performed according to standardized protocols: insertion of a perdiotonal probe into the gingival sulcus with a force of 0.2-0.3 N; probing depth is read out at landmarks on the periodontal prove. The scores will be measured at four sites per tooth, added and divided by four to obtain the "PPDI for the tooth"-Index. We will use the 'PPD for the tooth', but only for those teeth with fixed ortodontic brackets. The 'PPD for the patient' is then the mean of the PPDs for the teeth.
2. Modified Plaque Index (MPI) [ Time Frame: Baseline till 12 months after insertion of appliance ]

   The measurement of Modified plaque index (MPI) is described by Attin et al, which scores the amount of plaque according to the defined criteria. The score will be measured at each tooth, but only for those teeth with fixed ortodontic brackets. The 'Modified plaque index for the patient' is then the mean of the MPIs per teeth: Index = (Sum of MPI per tooth×100)/ (3×number of measured teeth).

   CRITERIA FOR THE MODIFIED PLAQUE INDEX

   0 = no plaque

   1. = small plaque areas approximal
   2. = small plaque areas approximal + cervical
   3. = plaque covers 1/3 of the cervical area of the bracket
3. Local cytokine expression [ Time Frame: Baseline till 12 months after insertion of appliance ]
   Samples from different oral niches (saliva, soft and hard tissue samples, gingival crevicular fluid) will be collected to analyse local inflammation: Unstimulated saliva will be gained by the spitting method, soft tissue samples will be collected in using sterile swabs, hard tissue samples of supragingival plaque will taken by sterile curettes and samples of gingival sulcus fluid will be collected from 6 periodontal pockets of the mesio-buccal side of defined teeth (Ramfjord teeth: 16,21,24,36,41,44) using sterile paper strips. Sulcus fluid flow rate will be performed using Periotron 8000. The cytokine concentration (in pg/mL) of granulocyte-macrophage colony-stimulating-factor (GM-CSF), interferon (IFN)- gamma, interleukin (IL)-2, IL-4, IL-6, IL-8 and IL-10 as well as tumor necrosis factor (TNF) in defined oral niches will be measured using multiplex immunoassay.
4. Oral microbiome [ Time Frame: Baseline till 12 months after insertion of appliance ]
   Samples from different oral niches (saliva, soft and hard tissue samples, gingival crevicular fluid) will be collected to analyse the oral microbiome: Unstimulated saliva will be gained by the spitting method, soft tissue samples will be collected in using sterile swabs, hard tissue samples of supragingival plaque will taken by sterile curettes and samples of gingival sulcus fluid will be collected from 6 periodontal pockets of the mesio-buccal side of defined teeth (Ramfjord teeth: 16,21,24,36,41,44) using sterile paper strips. Composition of the oral microbiome will be analysed using 16 S rRNA sequencing and operational taxonomic units (OTUs) will be classified according to SILVA database.

Other Outcome Measures:

1. Adverse events [ Time Frame: Baseline till 12 months after insertion of appliance. ]
   Collection of adverse Events.

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Adolescents from age 12 to 17 with fixed appliances undergoing orthodontic treatment
• Signed declaration of consent by the patient and the parent or legal guardian for adolescent patients

Exclusion Criteria:

• Systemic or metabolic disease that are related to gingivitis or (e.g. diabetes) or could possibly influence the oral microbiome

• obesity:

  -adolescents: body mass index > + 2 standard deviations (SD) over the average value given by the World Health Organisation (weight and height will be measured)

• Eating disorder or underweight

  -adolescents: BMI > -2 SD under the average value given by the WHO (weight and height will be measured)

• Above-average consumption of milk products: > 3 portions/day = >1,2 liters of milk or 1200g yoghurt/day (daily dose recommended by the german society for nutrition = 1-3 portions of milk products)
• allergy to ingredients of the lozenges
• intake of antibiotics or dietary supplementation (probiotics, vitamin C/D) in the last 6 months or during the study
• regular use of antibacterial mouth wash
• pregnancy
• smoking
• retraction of the declaration of consent by the patient and the parent or legal guardian for adolescent patients

Contacts and Locations

Contacts

Contact: Corinna Lesley Seidel, Dr.; ++49-09131-85-45667; corinna.boeck@uk-erlangen.de

Contact: Lina Gölz, Prof.Dr.; ++ 49 (0)9131 85-33643; lina.goelz@uk-erlangen.de

Locations

Germany

UniversityHospitalErlangen-Nurenberg; Recruiting

Erlangen, Bavaria, Germany, 91054

Contact: Corinna L Seidel, Dr. 091318545667 ext 091318545667 corinna.seidel@uk-erlangen.de

Contact: Lina L Gölz, Prof. 091318533643 ext 091318545667 lina.goelz@uk-erlangen.de

Principal Investigator: Corinna L Seidel, Dr.

Sponsors and Collaborators

University of Erlangen-Nürnberg

BioGaia AB

Investigators

• Study Director: Corinna Lesley Seidel, Dr.; Department of Orthodontics and Orofacial Orthopedics
• Study Director: Lina Gölz, Prof.Dr.; Department of Orthodontics and Orofacial Orthopedics

More Information

• Responsible Party: Dr. Corinna Lesley Seidel, Orthodontist, University of Erlangen-Nürnberg
• ClinicalTrials.gov Identifier: NCT04598633
• Other Study ID Numbers: ER-Ortho-Pro-RCT-1
• First Posted: October 22, 2020
• Last Update Posted: December 22, 2020
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Dr. Corinna Lesley Seidel, University of Erlangen-Nürnberg:

Orthodontics; Inflammation; Microbiome; Probiotics

Additional relevant MeSH terms:

Gingivitis; Infections; Gingival Diseases; Periodontal Diseases; Mouth Diseases; Stomatognathic Diseases