Clinical trial NCT06816277: Application of Local Melatonin in Peri-implantitis
Official title: Application of Local Melatonin for Controlling Peri-implant Diseases: a Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Periimplantitis
Keywords: melatonin
periimplant disease
marginal bone loss
inflammation
treatment
Lead sponsor: Universidad Complutense de Madrid
Sponsor class: OTHER
First posted: 2025-02-10
Enrollment: 30
Sex: ALL
Minimum age (years): 40
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two blinded groups
Primary purpose: TREATMENT

Brief summary: A randomized clinical trial was carried out in patients affected by peri-implantitis with a follow-up of 60 days. Melatonin 1.9 mg or placebo was applied locally to the peri-implant defect after nonsurgical debridement.

To determine the effectiveness anti-inflammatory, osteogenic and antimicrobial properties were evaluated. The probing depth, bleeding index, plaque index, and interleukin-1β and 6 concentrations, peri-implant bone level and the bacterial strains were analyzed.

Detailed description: This randomized clinical trial was conducted following the recommendations of the Consolidated Standards of Reporting Trials Statement (CONSORT 2010), the requirements set out in the Declaration of Helsinki (World Medical Assembly) and in accordance with the Data Protection Law (Organic Law 3/2018, of December 5, on the Protection of Personal Data and the guarantee of digital rights). The protocol was approved by the Clinical Research Ethics Committee (CEIC) of the Hospital Clínico San Carlos de Madrid, minute 7.2/19; C.P. MEL19 - C.I. 19/313-E. In Spain, the Spanish Agency for Medicines and Health Products (AEMPS), dependent on the Ministry of Health, establishes that the use of melatonin in doses higher than 1.9 mg was only possible under medical prescription for the treatment of sleep disorders and hyperactivity disorders, or autism spectrum (Royal Legislative Decree 1/2015), which is why it is only marketed in Spain in doses lower than 2 mg. Recruitment Volunteer participants diagnosed with peri-implant disease were recruited according to the criteria of the Classification of Periodontal and Peri-implant Diseases and Conditions of the 2017 Global Workshop, with an indication for peri-implant surgical treatment, with one or more fully erupted teeth.

Patients of both sexes, aged between 40 and 85 years, in good health (Category I and II of the American Society of Anesthesiologists \[ASA\]), with no history or metabolic or systemic diseases affecting the bone or the healing process, such as diabetes, without autoimmune diseases, autoimmune coagulation or healing disorders and who, meeting the inclusion criteria, agreed to sign the informed consent were included. Exclusion criteria were established as tobacco consumption \>25 cigarettes per day, the use of hormones, anti-inflammatories, corticosteroids, immunosuppressants, analgesics, antidiabetic or antiresorptive medications regularly or recently, pregnant or lactating women, and those who refused to participate in the study or did not allow follow-up and sample collection. Study design: The most severely affected implant was selected, although treatment was performed on all implants, to avoid patients with more severely affected implants having a greater statistical significance. Before treatment (T0), the peri-implant clinical and radiological study was carried out using periapical radiography with a parallelism and crevicular fluid samples were obtained from the implant in duplicate. Peri-implant surgical treatment was performed under local infiltration anesthesia with 4% articaine with 11,000,000 adrenaline. Debridement was performed using ultrasound with irrigation, supplemented with curettes.

Melatonin or placebo treatment was applied through computer block randomization. To achieve blinding, a different code was assigned to the group that applied 1.9 mg of melatonin (A) and the control group (B) that applied placebo powder (dextrinomaltose 2 mg) and the samples and records were coded. It was sutured with 4/0 monofilament on a pre-mounted 3/8 semicircular needle. In all patients, 1000 mg of paracetamol was prescribed every 8 hours in case of pain, and they were instructed not to rinse or use any topical antiseptic. At 7 days (T1), the healing process was reviewed, the sutures were removed and crevicular fluid samples were taken. At 21 days (T2), a new complete peri-implant record, new crevicular fluid samples and a radiological study were performed. At 60 days (T3), a new complete peri-implant record, crevicular fluid samples and a radiological study were performed. To detect the occurrence of complications, a record of adverse events was established for a period of two months after treatment. Variables Probing depth: The distance from the gingival margin to the bottom of the periodontal pocket was considered. The measurement was carried out at the four locations surrounding the implant, mesial, distal, lingual and vestibular. In addition, the average of the four locations was presented. Plaque index (Löe and Silness) The presence of visible bacterial plaque was considered suitable for implant rehabilitation (Grade 0: No plaque; Grade 1: No plaque visible to the naked eye.

Plaque is present when probing in the peri-implant area; Grade 2: Visible bacterial plaque is present; Grade 3: Visible bacterial plaque is present surrounding the implant, including the interdental spaces. Stones may be present. Adequate plaque control is considered when the index results in a value ≤1. Bleeding index (Löe and Silness) It was considered during the 30 seconds after probing adapted to the implant model (Grade 0: No bleeding; Grade 1: A spot of blood does not appear until a few seconds after probing; Grade 2: Bleeding immediately after probing; Grade 3: Bleeding at the slightest contact with the mucosa, extension of bleeding along the sulcus). marginal bone loss Assessment of the peri-implant crestal bone level was performed using ImageJ® software (NIH, Bethesda, MD, USA). From the pixel measurement of the known implant length, the vertical bone level measurement was determined from the implant platform and perpendicular to it, to the area of the turbinate bone in contact with the implant surface both mesial and distal. It was considered as a single measurement of the mesial and distal mean of each implant taking into account the clinical importance.

IL-1β and IL-6 concentration Crevicular fluid samples obtained using Perio-paper strips were analyzed with the enzyme-linked immunosorbent assay (ELISA) technique. The samples were stored in sterile 13x75mm x 2 mL BD Vacutainer® tubes and were processed using the ELH-IL1B-1 Human IL-1 beta ELISA Kits 1 x 96-Wel BIONOVA CIENTIFICA S.L and HEA079HU-48T High Sensitive ELISA Kit for Interleukin 6 (IL-6) 48T BIONOVA CIENTIFICA SL for analysis of interleukin-1β and 6 at 60-90 minutes after obtaining it. The determinations were read using the ELISA reader (Ivymen System 2100-C). The standard curve of the kits was made in duplicate for IL-1β and IL-6 both in the test and in the total analysis of the samples.

Microbiological count: A Colon Forming Unit (CFU) count was performed on the crevicular fluid samples obtained using sterile paper points. They were transferred into a vial of reduced transport liquid with 1.0 mL of RTF transport medium to preserve the anaerobiosis of the samples for 24 hours and quantify the sample volume. The samples were immediately cultured on blood agar medium and the peri-implantopathogenic, periodontopathogenic and candida species were identified.

Sample size calculation: The calculation of the sample size was carried out taking as reference previous similar studies. 30 patients (15/15) were considered to detect differences with a large effect size (d=1) and with a statistical power of 80%. Considering a possible drop out of patients, a minimum recruitment of 33 patients was estimated.

Statistical analysis: A descriptive analysis of the most relevant statistics was carried out for all the variables collected in the research: absolute and relative frequencies (for the categorical ones) and mean, standard deviation, range, median and 25th and 75th percentiles (for the continuous ones).

The Shapiro-Wilk test was applied to evaluate the adjustment to a normal distribution of the variables in both groups. To carry out the inferential analysis, the non-parametric Brunner-Langer Model for longitudinal data was used. To study the evolution of the different variables (clinical, inflammatory, microbiological) throughout all measurements of the period depended on the type of treatment.

A level of statistical significance p≤0.05 was established.

Eligibility criteria: Inclusion criteria:

* Peri-implant disease was recruited according to the criteria of the 2017 World Workshop Classification of Periodontal and Peri-implant Diseases and Conditions.
* Indication for peri-implant surgical treatment.
* One or more fully erupted teeth.
* American Society of Anesthesiologists \[ASA\] Category I and II.
* No history or metabolic or systemic diseases affecting the bone or healing process.
* Agreed to sign informed consent.

Exclusion criteria:

* Tobacco use \>25 cigarettes per day.
* Use of hormonal, anti-inflammatory, corticosteroid, immunosuppressant, analgesic, antidiabetic or antiresorptive medications on a regular or recent basis.
* Pregnant or lactating women.
* Those who refused to participate in the study or did not allow follow-up and sample collection.

Primary outcomes:
measure: Probing depth
timeFrame: 60 days
Secondary outcomes:
measure: Plaque Index (Löe y Silness)
timeFrame: 60 days
measure: Bleeding Index (Löe y Silness)
timeFrame: 60 days
measure: Marginal bone loss
timeFrame: 60 days
measure: IL-1β concentration
timeFrame: 60 days
measure: IL-6 concentration
timeFrame: 60 days
measure: Microbiological count
timeFrame: 60 days
Other outcomes:
Locations:
city: Madrid
country: Spain
facility: Department of Clinical Specialities. Faculty of Dentistry. Complutense University of Madrid.
Study officials:
References: