"Surgical Vs. Non-surgical Peri-implant Therapy"

1. Objectives 1.1 Primary objective

• To evaluate the radiographic bone fill of non-surgical mechanical debridement combined with systemic antibiotic therapy, compared to the adjunctive regenerative surgical therapy in the treatment of infraosseous peri-implant defects. 1.2 Secondary objectives
• To evaluate the following clinical parameters: modified plaque index (mPI), modified - Bleeding Index (mBI), BOP, SOP, implant PPD, mucosal recession (MR).
• To evaluate the following radiographic outcomes: bone level (BL), intrabony defect (ID)
• To evaluate the following Patient reported outcome measures (PROMs): Oral health impact profile (OHIP-14sp), VAS Score, pain medication.

1. Hypothesis

• The non-surgical mechanical and antibiotic therapy of peri-implantitis in the treatment of infraosseous defects around implants will achieve similar radiographic bone fill and similar clinical results, when compared to the same protocol and the adjunction of a regenerative surgical therapy by means of xenograft plus a collagen membrane.

1. Material y methods:

3.1 Study design: This is a prospective, single-blinded, randomized, controlled clinical trial with 1-year follow-up.

3.2 Setting of the study Patients referred to Department of Periodontology (CUO) for treatment of periodontal and/or peri-implant diseases and who meet the inclusion criteria will be included in the study. Patients will be recruited consecutively. Furthermore, all study subjects will provide written informed consent before participating in the study. The present investigation will be performed following the principles outlined in the Declaration of Helsinki.

3.3 Study population To take part in this study, patients must present at least one implant diagnosed with peri-implantitis [i.e., peri-implant bone level ≥ 3mm apical to the most coronal portion of the intraosseous part of the implant, peri-implant pocket depth (PPD) ≥ 6 mm, and presence of bleeding and/or suppuration on gentle probing (BOP/SOP).

3.4 Randomization, allocation concealment and blindness The original participant identifiers (number of clinical history) will be replaced by new generated identifiers (code numbers) assigned according to patients' entrance in the study.

The randomization sequence will be carried out using a computer-generated list with a 1:1 allocation ratio according to a block randomization procedure (block size of four). Allocation concealment will be kept by means of opaque-sealed envelopes that will be opened immediately after the reevaluation of phase I therapy.

3.5 Sample size Using the radiographic bone fill as the primary outcome variable, the sample size has been calculated. Thirty-six patients (18 patients in each group) are necessary to detect a difference ≥ 0.5 mm in bone fill, assuming a common standard deviation of 0.41. This calculation assumes an alpha error of 0.05, a beta error of 0.1, and a statistical power of 90%. In addition, an estimation that 20% of subjects will be lost to follow-up has been taken into account.

3.6 Study visits 3.6.1 Screening examination Two calibrated investigators (C.V. and R.P.) will evaluate and enroll the patients. The clinicians will review with the patient the Information and Medication History Forms and record the information.

3.6.2 Treatment visits Baseline All subjects will receive a session of full-mouth professional prophylaxis, including scaling and tooth polishing. Supragingival debridement by means of an ultrasonic device using a plastic tip will be performed. Finally, the prosthetic components will be polished using a rubber cup.

Individualized instructions in proper oral hygiene measures will be given to all patients enrolled in the study.

Non-surgical therapy All the patients included in the study (both test and control groups) will received a peri-implant non-surgical therapy that will be standardized as follows: after local anesthesia (articaine 4% and adrenaline 1:100,000), the implant surfaces will be treated with ultrasonic devices with the H3 dental ultrasonic scaler. Curettage (SyG 7/89) of the bone defect will be performed and glycine air powder will be applied subgingivally (Air-flow®) with an air-flow piezon device.

After mechanical treatment, the antibiotic regimen consisting on metronidazole 500 mg every 8 hours for 7 days will be prescribed for all patients. Anti-inflammatory therapy was prescribed (ibuprofen 600 mg maximum thrice daily) for the first three days after the treatments. In addition, the use of additional pain killers (paracetamol every 4 hours) was recorded.

Six weeks after the non-surgical therapy, a clinical and radiographic evaluation will be performed. Immediately, an opaque-sealed envelope will be opened, and the patient will be assigned to test or control group.

Surgical therapy Patients assigned to the control group will undergo surgical peri-implant treatment that will be performed in the following way: after rinsing with 0.12% CHX for 1 minute and the appliance of local anesthesia, intrasulcular incisions will be designed and mucoperiosteal flaps will be raised. Granulation tissue will be removed using curettes and an ultrasonic device with the H3 dental ultrasonic. An implantoplasty procedure will be used to eliminate the supracrestal exposed moderate rough titanium surface of the implant using a diamond bur and surface will be polished with an Arkansas stone.

The infrabony component of the implant surface will be further decontaminated using ultrasonic scalers and with further chemical rinsing with 3% H2O2.

The intrabony component of the defect will be filled with a xenograft moistened in sterile saline for 5 minutes. Defects will be then covered with a collagen membrane over the entire defect. The flaps will be then repositioned with polypropylene 5/0 interrupted sutures allowing for a non-submerged healing.

Post-surgically, anti-inflammatory therapy will be prescribed for the first three days after the treatments and, according to the patients' individual needs, up to the first week. In addition, the use of additional pain killers will be recorded.

All patients will be recommended to use a 0.12% CHX mouth rinse, twice daily for 2 weeks. Finally, sutures will be removed after 15 days and patients will be reinstructed to re-install mechanical toothbrushing first with an ultra-soft brush for one week and then regular toothbrushing as explained during the initial therapy.

3.7.3 Follow-up visits Patients will be seen after 6 weeks from the non-surgical therapy, for the revaluation of the therapy and the first radiographic follow-up.

Patients of the control group will be seen after 6 weeks from the surgical therapy, for the revaluation of the therapy and the radiographic follow-up.

All patients (both test and control group) will be included in a peri-implant maintenance therapy (PIMT) program ever 3 months until the end of the study. At each PIMT visit, a clinical examination with the assessment of full mouth plaque index (FMPI) and full mouth bleeding index (FMBI), a reinforcement of oral hygiene instructions, supragingival and, if needed, subgingival debridement [BOP and/or peri-implant pocket depth (PPD) ≥ 5mm] as well as tooth polishing will be performed. Two of these visits will correspond to the radiographic examination and PROMs evaluation, at 6 and 12 months after the treatment.

3.8 Clinical and radiological examination 3.8.1 Demographic data An initial questionnaire will be conducted to obtain information regarding age, race, gender (female/male), medical history, medication, and health behavior (smoking habits). Smoking behavior will be specified as 3 categories: never smoker, former smoker, or current smoker (light smokers: < 10 cigarettes/day). Patients will be asked about their tobacco smoke exposure in terms of consumption (i.e. the number of cigarettes consumed per day); duration (i.e. the number of years of smoking); and lifetime exposure (i.e. the accumulated exposure as formed by the product of consumption and duration: cigarette-years). In case of former smokers, patients will be asked about the smoke-free time following cessation. Furthermore, implant position (maxilla/mandible and incisors, canines, premolars, and molars) and implant system will be further recorded as well as the type of prosthesis (cemented/screw-retained).

3.8.2 Clinical measurements

The following clinical parameters will be assessed for each implant by a single calibrated examiner (R.P.) at baseline and at 6 weeks, 6 and 12 months after the therapy using a periodontal probe:

1. Full mouth plaque index (FMPI) assessed dichotomously at four sites per tooth.
2. Full mouth bleeding index (FMBI) assessed dichotomously as presence or absence of bleeding after 30 seconds of gently probing.
3. Full mouth PD measured at six aspects around all teeth.
4. Modified plaque index (mPI) will be measured at six aspects around implants.
5. Modified bleeding index (mBI) will be assessed 30 seconds after 0.15 N force probing. This variable will be dichotomized in presence/absence of bleeding (BOP).
6. SOP evaluated after assessing dichotomously the presence of suppuration within 30 seconds after gentle probing.
7. Implant PPD, measured from the mucosal margin to the bottom of the probable pocket, determined at six aspects per implant: with a resin splint.
8. Mucosal recession (MR) at the implant will be recorded at six aspects per implant with a resin splint.

5.8.3 Radiographic examination A periapical radiograph will be obtained using the long-cone parallel technique and a film at baseline and six weeks, 6 and 12-month follow-up visit. All radiographs will be standardized in their exposure (7 mA-60 kV/20 ms).

The following measurements will be recorded by an independent previously calibrated examiner (M.C.S) at the mesial and distal aspects of the treated implants:

• Bone level (BL): distance (mm) between the implant shoulder and the base of the defect,
• Intrabony defect (ID), distance (mm) between the bottom of the defect and the line connecting the distal and mesial interproximal bone crest.

Radiographic bone fill (BF) will be calculated as it follows:

BF = (BLbaseline - BL6/12 months) / (IDbaseline) x 100 The measurements will be determined using an image-processing program (ImageJ)

5.8.4 Patient reported outcome measures (PROMs) Patients of test and control group will be subjected to the 14-items oral health-related quality of life (OHIP-14sp) questionnaire in the Spanish version at the baseline and after 6 weeks as well as 6 and 12 months of follow-up.

3.9 Intra-examiner reproducibility Reproducibility of radiographic and clinical examinations will be conducted by the repeated examination of radiographic bone level and PPD record of 5 implants in 5 patients, 1 week apart, before the beginning of the study.

3.10 Withdrawal of consent The Patient Information Sheet will clearly state that the patient can withdraw from the study at any time without prejudice or explanation. Such withdrawal will be documented in the medical record file. Losses to follow-up are taken into account in the sample size calculations (20%).

1. Statistical Analysis: The patient will be considered the unit of analysis. In order to describe the qualitative variables, absolute frequencies and percentages will be used. The description of quantitative variables will be performed using the mean, standard deviation (SD), median and quartiles. The Kolmogorov-Smirnov test will be used to assess the normality of distributions The results will be described with odds ratios (OR) with a 95% confidence interval (CI) and p-values. Level of significance will be set at 0.05. The SP