Flapless Application of Enamel Matrix Derivative in Class II Mandibular Furcation Defects

Study Overview
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Brief Summary
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Patients diagnosed with stage III or IV periodontitis that exhibit mandibular first or second molars with increased periodontal probing depth (PPD > 4 mm) and class II buccal mandibular furcation defects (horizontal probing depth of >= 3 mm ) will be recruited. This study will be a non-inferiority, prospective, randomized, double-blind controlled clinical trial with a parallel design. Patient will be recruited from the clinics of the School of Dentistry at the Aristotle University of Thessaloniki and private dental practices in Thessaloniki, Greece. Initially, non-surgical periodontal treatment will be performed through scaling and root planning in combination with oral hygiene instructions and motivation. The re-evaluation will be performed 4-6 weeks following the treatment and the patients who meet the inclusion criteria will be included in the study. Patients will be randomly allocated at a 1:1 ratio to either subgingival debridement and flapless application of EMD (test group) into the affected furcation defect or to periodontal surgery in combination with EMD application (control group). Periodontal and radiographic parameters, patient reported outcomes, oral cavity measurements and gingival crevicular fluid will be collected before as well as up to 9 months following the treatment.

Detailed Description
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The first step in periodontal therapy aims to successfully remove supragingival dental biofilm, improve oral hygiene and control potential risk factors. During the second step of treatment, the cause-related therapy, non-surgical periodontal treatment consisting of subgingival debridement aiming to reduce plaque accumulation, calculus deposits, gingival inflammation, pocket depths is performed,which is effective for gaining attachment level. However, non-surgical periodontal treatment per se rarely translates into periodontal regeneration. In patients with severe periodontal disease residual periodontal pockets may remain after an initial therapy. Furcation defects often do not respond favourably to non-surgical periodontal therapy and are associated with elevated risk of progression. The elimination of these residual periodontal pockets can be achieved at the thirdstep of the treatment by resective or regenerative procedures based on the morphology of the defect or alternatively repeated subgingival instrumentation with or without adjunctive therapies can be carried out. Regeneration of the periodontal tissues includes cementum, periodontal ligament (PDL) and alveolar bone. Currently, several flap designs and biomaterials have been utilized and tested in the literature aiming at periodontal regeneration including bone grafts, bone substitute materials, growth factors, enamel matrix derivative proteins (EMD), guided tissue regeneration or even a combination of these materials. Although the application of EMD in conjunction with non-surgical periodontal treatment has shown a positive effect with evidence of regeneration, its effectiveness remains inconclusive. Further studies in various disease conditions (intrabony defects, furcation defects, suprabony defects) are needed to confirm the potential benefit of adjunctive EMD application in combination with subgingival debridement (non surgical periodontal therapy). No study to our knowledge has tested the efficacy of flapless application of EMD in the healing of molars with furcation involvement. Study design: Non-inferiority, double-blind, randomized, controlled clinical trial with parallel design. Null Hypothesis: The adjunctive flapless use of enamel matrix derivative (EMD) during subgingival debridement in patients diagnosed with Stage III or IV periodontitis that exhibit class II buccal mandibular furcation involvement leads to inferior outcomes in clinical and radiographic as well as in biomarkers in comparison with surgical periodontal treatment with EMD. Hypothesis: The adjunctive flapless use of enamel matrix derivative (EMD) during subgingival debridement in patients diagnosed with Stage III or IV periodontitis that exhibit class II buccal mandibular furcation involvement results in noninferior/equivalent outcome in clinical and radiographic variables as well as in biomarkers in comparison with surgical periodontal treatment with EMD. Aim: The aim of this study is to investigate the non-inferiority of the flapless application of enamel matrix derivate (EMD) in addition to subgingival debridement in class II buccal mandibular furcationsin regards to the clinical and radiographic outcome as well as the level of biomarkers related to periodontal disease activity, inflammation and regeneration compared with periodontal surgery with EMD. Methods: Patients diagnosed with stage III or IV periodontitis that exhibit mandibular first or second molars with increased periodontal probing depth (PPD > 4 mm) and class II buccal mandibular furcation defects (horizontal probing depth of >= 3 mm)will be recruited. This study will be a non-inferiority, prospective, randomized, double-blind controlled clinical trial with a parallel design. Patient will be recruited from the clinics of the School of Dentistry at the Aristotle University of Thessaloniki and private dental practices in Thessaloniki, Greece. Pre-treatment: Non-surgical periodontal treatment will be performed through scaling and root planning in combination with oral hygiene instructions and motivation. The reevaluation will be performed 4-6 weeks following the treatment and the patients who meet the inclusion criteria will be included in the study. Patients will be randomly allocated at a 1:1 ratio to either subgingival debridement and flapless application of EMD (test group) into the affected furcation defect or to periodontal surgery in combination with EMD application (control group). Periodontal and radiographic parameters, patient reported outcomes, oral cavity measurements and gingival crevicular fluid will be collected before as well as up to 9 months following the treatment. Sample size calculation An estimate of the expected PPD reduction from OFD+EDTA+EMD was drawn from Casarin et al. 2010. The mean PPD reduction following OFD+EDTA+EMD was 1.9 +/- 1.6 mm and 1.0 +/-1.3 mm when OFD+EDTA was only performed. The differential effect of using EMD in a surgical periodontal treatment amounts about 1 mm. The sample size calculation was performed using α=0.05 and 90% power to detect a difference of 1 mm between treatment groups (MINST+Flapless EMD vs MIST+EMD) which is clinically significant and detectable. The estimated standard deviation was 1 mm. The required sample size was calculated to be 18 individuals in each group (total 36). Considering that some patients might be lost during the follow-up, a total of 44 participants will be enrolled (dropout rate of 20%). When the power was set to 80%, the required sample size is 13 patients per group (total 26). Considering a dropout rate of 20%, a total of 32 patients will be enrolled. Statistical methods Descriptive statistics will be used to present the results of the sample's characteristics (mean and standard deviation for age, number of teeth, clinical periodontal and radiographic parameters; counts and percentages for categorical variables such as gender, medical and smoking history etc). The distribution of the sample will be measured with the Shapiro-Wilk test. In case of normal distribution: paired and unpaired t-tests will be utilized. In case a non-parametric test is used, Wilcoxon signed-rank and Mann Whitney U tests will be utilized. Chi-square test will be also used to compare categorical variables. GCF and periodontal measurements can be correlated with Spearman or Pearson rank correlation test. A statistical significant result will be set to a threshold level of <=0.05.

Official Title
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Flapless Application of Enamel Matrix Derivative in Class II Mandibular Furcation Defects: a Randomized Clinical Trial

Conditions
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Periodontal Diseases, Periodontal Disease, AVDC Stage 3, Periodontal Disease, AVDC Stage 4, Furcation Defects

Intervention / Treatment
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* Other: Emdogain® FL (flapless Emdogain®) - Enamel Matrix Derivative
* Other: Emdogain® - Enamel Matrix Derivative


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals of at least 18 years of age with a diagnosis of stage III or IV periodontitis. Have at least one class II furcation defect with PPD >4 mm and horizontal probing depth of >= 3 mm in a mandibular first or second molar. Teeth have to be vital or properly treated endodontically. Gingival recession ≤ 2mm on furcation site Proper oral hygiene: full-mouth plaque score (FMPS) ≤20%. Systemically healthy (absence of systemic conditions such as diabetes mellitus that can affect the treatment outcome of periodontal therapy) Ability to understand the study procedures and comply with them through the length of the study. Given written informed consent form for participation in the study. Exclusion Criteria: Pregnant or lactating female (self-reported). Current acute infection. Non-surgical periodontal treatment within the last 6 months or/and surgical periodontal treatment the last 12 months before the initial pre-treatment. Need for antibiotic premedication. Antibiotic treatment in the previous 3 months. Allergy to any materials or medications that could be used during or after the procedure. Teeth having an improper endodontic therapy with clinical signs of infection or subgingival restorations. Tooth mobility of 2nd and 3rd degree. History of radiation therapy in the head and neck region. Chronic use of medications that may alter the response of periodontal tissues. Smoke ≥ 10 cigarettes/day.

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Patients will be randomly allocated at a 1:1 ratio to either subgingival debridement and flapless application of EMD (test group) into the affected furcation defect or to periodontal surgery in combination with EMD application (control group). The selected sites will be randomly assigned to test and control groups using an online software for randomization. The therapist will be kept unaware of treatment allocation until the treatment.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Subgingival debridement + Flapless Enamel Matrix Derivative<br>Subgingival debridement following a minimally-invasive non-surgical treatment (MINST) approach with flapless application of EMD Root instrumentation under local anesthesia using mini hand instruments (mini curettes) and ultrasonic instruments with fine tips in the furcation area of mandibular first or second molars with class II buccal furcation defects. EDTA gel will be applied for 2 minutes on the affected root surfaces, followed by rinsing with saline and drying prior to the application of Emdogain® FL. Emdogain® FL has been shown to enhance the early healing of periodontal soft tissue wounds resulting from the instrumentation of periodontal pockets. | Other: Emdogain® FL (flapless Emdogain®) - Enamel Matrix Derivative<br>* Emdogain® FL has been shown to enhance the early healing of periodontal soft tissue wounds resulting from the instrumentation of periodontal pockets.<br>|
| Active Comparator: Periodontal surgery + Enamel Matrix Derivative<br>Periodontal surgery following a minimally-invasive surgical treatment (MIST) protocol with application of EMD Following local anesthesia, minimal flap elevation on the buccal aspect of first or second molars associated with a grade II furcation defect will be performed.Removal of granulation tissues and root instrumentation with mini hand instruments (mini curettes) and ultrasonic instruments with fine tips in the furcation area will then be carried out. EDTA gel will be applied for 2 minutes on the affected root surfaces, followed by rinsing with saline and drying prior to the application of Emdogain®. Then, the surgical flaps will be positioned and sutured in order to completely cover the defects. | Other: Emdogain® - Enamel Matrix Derivative<br>* Enamel matrix derivative (EMD) has been widely used in the surgical treatment of periodontal disease and in furcation defects.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Periodontal probing pocket depth (PPD) change | Changes in pocket probing depth will be measured using a periodontal probe. The depth of the sulcus will be assessed by gently inserting a graduated periodontal probe until resistance is encountered at the base of the sulcus. The depth from the free gingival margin to the base of the sulcus is measured in millimeters and represents PPD. | 9 months after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Horizontal and vertical furcation involvement change. | Changes in horizontal and vertical furcation involvement will be measured using a periodontal probe. | 9 months after treatment | 
| Periodontal clinical attachment level (CAL) change. | Changes in clinical attachment level will be measured using a periodontal probe. | 9 months after treatment | 
| Bleeding on Probing (BOP) change | Bleeding on Probing will be tested using a periodontal probe that is carefully introduced to the bottom of the pocket gently. | 9 months after treatment | 
| Gingival recession (REC) change | Changes in gingival recession will be measured using a periodontal probe. | 9 months after treatment | 
| Furcation involvement grade change | Proportion of sites demonstrating change in furcation grade level as measured with Nabers probe | 9 months after treatment | 
| Radiographic defect depth, height, root trunk and width. | Assessment of the defect depth, height, root trunk and width using Cone-beam computed tomography systems (CBCT) and periapical radiographs and subtraction radiography | 9 months after treatment | 
| Levels of markers related to periodontal disease activity, inflammation as well as regeneration in the GCF. | The levels of markers will be assessed using gingival crevicular fluid (GCF) and analyzed with multiplex assays (in pg or ng based on the assays) | 9 months after treatment | 
| Patient-reported outcome measures | Patient-reported outcome measures using Visual Analogue Scales (VAS) Visual analogue Scale: range from 0 mm no, to 100 mm, the worst possible | 9 months after treatment | 
| Oral health-related quality of life | Oral health-related quality of life measures using OHIP-14 (Greek version) The OHIP-14 captures seven domains of OHRQoL with two items per domain: functional limitation, physical pain, psychological discomfort, physical disability, psychological disability, social disability, and handicap. The responses are rated on a 5-point Likert scale: 0 = never; 1 = hardly ever; 2 = occasionally; 3 = fairly often; 4 = very often/every day. The OHIP-14 scores can range from 0 to 56 and are calculated by summing the ordinal values for the 14 items. | 9 months after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EMD, Periodontal disease, Enamel Matrix Derivative, Flapless, MINST, Periodontal treatment, Furcation defect