NCCL Direct Composite Restoration Performance With Self-Etch and Multimode Adhesives

2.1- DESIGN The trial design will follow the Consolidated Standards of Reporting Trials (CONSORT) statement (1, 2).

Prospective, double blind clinical trial; randomized allocation of NCCL restorations by six adhesion treatment groups (6 arms: G1 to G6) for examination of restorations performance. Study will take place in University Fernando Pessoa - Faculty of Health Sciences (UFP-FHS), Dental Medicine School Clinic. Participants recruitment estimated between November 2015 and April 2016.

The study is scheduled to last 24th months. Baseline clinical observation will be done 30 days after placement of adhesion restoration (First data), second observation at 12 months and last evaluation at 24 months (Data for Statistical analysis). Clinical trial may continue for similar assessment intervals, after 24th months evaluation. This situation requires new analysis according to clinical and economics conditions, at that time.

2.2- POPULATION AND PARTICIPANT SELECTION

All participants will be informed (Written and verbal information) about the trial conditions and purposes, but will not be aware of what tooth will received the adhesion treatment. Written informed consent, according to World Medical Association Declaration of Helsinki (3), will be obtained from all participants prior to starting the treatment. University Fernando Pessoa Ethics Committee review and approved the present protocol. This clinical trial is done according to the National Law 21/2014, of 16 April, and was analysed, approved and authorized by the National Competent Authorities:

• INFARMED, National Authority of Medicines and Health Products, IP (No.EC/011/2015; DPS/DM/450.10.053/2015/0314; Authorization at 4th August 2015)
• CEIC, National Ethics Committee for Clinical Research (No.20150305; Approved at 3th August 2015)
• CNPD, Portuguese Data Protection Authority (Authorization and registry 6430/2015 at 7 July 2015; No.2536/2015).

The decision to participate in this study is voluntary as well as the decision to refuse participation and decision of withdrawal of the same, at any time of the study course, are rights of the patient/participant. The operator (Dentist and Associate Professor of FHS-UFP) inform the patient/participant in all aspects related to the study. Refusal of patient participation, the participant's withdrawal and revocation of consent to participate in this study are rights of the patient/participant without any consequences or reprisal, and without interference in the relationship between users and teachers/ researchers / University, clinical entities.

SAMPLE:

Patients with clinical diagnosis of non-carious cervical lesion (NCCLs) located in pre-molars/molars (PM/M) teeth, with cavity dimensions defined in the study design.

Two hundred and ten restorations will be performed, randomized in order to be allocated to six interventions (G1 to G6 arms), named as adhesion intervention groups.

Within this trial, the number of teeth to be restored by participant will be between a minimum of 1 and a maximum of 6. The allocation of the study group (G1 to G6) to a particular tooth is random with the information available to the operator/principal investigator in sealed envelopes and previously prepared by the investigator-professional statistics. The allocation of the study group (G1, G2, G3, G4, G5, G6) to each tooth for a patient is performed randomly, but ensuring that the distribution of the groups is not repeated in the same patient. For this purpose, 210 envelopes with 35 sequences of 6 study groups will be organized by the statistical investigator (wherein each order of 6 groups is randomized).

2.3- STUDY ADHESION ARMS Six groups (G1 to G6) of NCCL restorations will be randomized allocated according to adhesion strategy intervention.

2.4- OPERATOR / EXAMINERS CALIBRATION Operator will do one restoration of each group in order to identify all steps involved in the application technique. This procedure will be done three times, with one week, interval. All restorations done by the same calibrated operator. Three experienced and calibrated dentists, not involved with the restoring procedures and therefore blinded to the group assignment, will perform the clinical evaluation. For training purposes, the examiners observed 10 photographs that were representative of each score for each criterion, in 10 cervical restorations (not included in this trial), each one, on two consecutive days. An intra-examiner and inter-examiner agreement will be calculated.

Medical Devices Composition (According to Manufactures, Voco and Ivoclar Vivadent Safety data sheets for Adhesives and products):

1. Futurabond® DC (Voco, Cuxhaven, Germany) Batch No.1532592: Liquid 1. Acidic adhesive monomer; BIS-GMA (5-10%), 2-HEMA (5-10%); pH-value 1.5 Liquid 2. Ethanol (50-100%); Initiator (2.5-5%) Mixture. organic acids, BIS-GMA, 2-HEMA, TMPTMA, campherchinon, amines (DABE), BHT, catalysts, fluorides and ethanol.
2. Futurabond® U (Voco, Cuxhaven, Germany) Batch No.1543141: Liquid 1. 2-hidroxyethyl methacrylate (2-HEMA) (25-50%); BIS-GMA (25-50%); HEDMA (10-25%); Acidic adhesive monomer (5-10%); Urethanedimethacrylate (UDMA) (5-10%); catalysts (≤ 2.5%); pH-value 2.3 Liquid 2. Ethanol (50-100%); Initiator (2.5-5%); catalysts (≤ 2.5%)
3. Ivoclar Vivadent's Adhese® Universal (Ivoclar Vivadent AG, Liechtenstein) Batch No.U35131: Composition/information on ingredients; mixture of substances Liquid: 2-hydroxyethyl methacrylate (20-<25%); bisphenol A diglycidyl ether dimethacrylate (20-<25%); ethanol (10-<25%); decamethylene dimethacrylate (3-<10%); Methacrylated phosphoric acid ester (3-<10%); campherquinone (1-<2.5%); 2-dimethylaminoethyl methacrylate (1-<2.5%); 2,6-di-tert-butyl-p-cresol (0.1-<0.3%). (MDP-Methacryloyloxydecyl dihydrogen phosphate; MCAP- Methecrylated carboxylic acid polymer; HEMA-Hydroxyethil methacrylate; Bis-GMA_ Bisphenol A glycidyl methacrylate; D3MA- Decandiol dimethacrylate); pH-value 2.5-3.0.
4. Vococid® (Voco, Cuxhaven, Germany) Batch No.152135: 35% orthophosphoric acid; 2.5- DATA REGISTRY/PROTECTION AND RESTORATIONS PROCEDURES Only in the registration database (with access to the principal investigator and other team members, with the exception of the statistical investigator for the purposes of observational clinical records) there should be registration/membership of this key with the code-process of patients. The database in question will be lodged in own servers with restricted access levels and well identified. The servers that lodge the photos/ records and the database belong to Dental School Clinic of Faculty of Health Sciences - UFP and are located in data centre with fully controlled access. This mechanism ensures the concealment of identity of the user in records file, having access to them only the investigator and research team (except investigator of statistics). This mechanism fulfilled the recommendation and Authorisation of CNPD, Portuguese Data Protection Authority (Authorization and registry 6430/2015 at 7 July 2015; Case 2536/2015).

Appointment and restorative procedures, in accordance with the following steps:

One week, before the Restorative procedure (1st appointment): Inform the patient (Written/Verbal); Patient signature of informed consent; Fulfilment of the project clinical file (patient identification, general clinical summary, oral clinic examination, oral hygiene state); Dental prophylaxis with fluoride toothpaste and water with a nylon brush. Vitality tests (cold and hot) executed with spray Endo cool (ethyl chloride) and warm instrument; Pre-operative sensitivity evaluation by applying air for 10 seconds from a dental syringe placed 2 cm from the tooth surface (4); NCCLs cavities will be evaluated according to the degree (1, 2, 3, 4) of sclerotic dentin (5), cavity dimensions (H-height, W-width, and D-depth) in millimetres (mm) and geometry (evaluated by profile photograph, as Angles Acute (A), Severe (S), Obtuse (O) (4); 1st Appointment-Intervention: Initial intra-oral/cavity surface and tooth digital photography; Teeth anaesthesia with 3% mepivacaine (Scandinibsa, Sintra Business Park, Portugal); Operatory field isolation with cotton rolls and retraction floss (Ultradent). All cavities cleaned with pumice and water in a rubber cup, followed by rinsing and drying. Selection composite colour by shade guide; Adhesive interventions according to G1 to G6 arms assignment. Adhesive systems will be used as SingleDose mode. Composite restorations (AdmiraFusion Universal nano-hybrid composite) with incremental filling technique (two increments maximum), light-cured (LED Unit) with an intensity of 1000mW/cm2, during 40 seconds. Restorations will be finished immediately with diamond disks (OptiDisc® medium 40μm; Kerr) and burns. Polishing performed with diamond-impregnated silicone polishers (Dimanto, Voco, CuxHaven) during 10 seconds. Intra-oral digital photography of the restoration.

2.6- CLINICAL FOLLOW-UP Baseline (30 days after restoration), 12th (NCCLs observation) and 24th months (for statistical analysis) Appointments

1 - Intra-oral digital photography of the NCCL restoration; 2- Post-operative sensitivity evaluation by applying air for 10 seconds from a dental syringe placed 2 cm from the tooth surface (4); 3 - Direct evaluation by 3 calibrated examiners according to FDI (6, 7) and USPHS (8); 4- Data register Study variable definition - Clinical/direct observation and performance evaluation acceptance by means of FDI and USPHS criteria.

2.7- DATA BASE AND STATISTICAL ANALISYS Data statistical analysis and description according to aims of this trial; Specific program for statistical data analysis (IBM(c) SPSS(c) Statistics vs. 23 or later) will be used. Differences will be considered to be significant at p<0.05.

2.8- OBSERVATIONS REGARDING SAMPLE CALCULATION Was assumed that the minimum number of bonded restorations to be held in each of the six arms (G1 to G6) is 35 (210 restorations). The researchers did not have detailed information that allows the estimation of the sample size based on power analysis (the effect of the expected difference to the end of the time considered for the study). Thus, using rules of thumb usually considered in research situations where there is no prior information concerning the performance evaluation of these class IIa medical devices available on the market. In this case, considering that it intends to make a prospective longitudinal study, to determine factors associated with failure rate and reduced clinical performance (effect) criteria of the restorations, and to detect effects depends the number of events (failure, for example, or other event that is to be considered in the defined evaluation criteria) and not the number of participants, the thumb rules stipulate a minimum of 10 cases by group. Moreover, when considering an "simple" analysis comparison using a McNemar test (repeated measures) in six groups would be necessary in total, including at least 80 cases (to restore teeth) in the sample. When considering at least 35 restorations by group, researchers are greatly increasing the minimum number stipulated in any of the aforementioned techniques. In addition, clinical studies previously performed on this issue (between 2004 and 2012) relative to the post-market clinical evaluation performance of class IIa medical devices, in the context of restorative dentistry field, has enabled to measure a minimum of 30 restorations as viable for determining events in a short/medium-term as the clinical performance evaluation of a similar nature of medical devices.

2.9- GOOD CLINICAL PRACTICE FOR CLINICAL RESEARCH Reporting mechanism of possible adverse incident during the investigation will be held according to Medical Devices (MD) commercially available in the market, so it interprets and assumes the issue as applicable to assumptions in the Portuguese National Law (Article 22) 21/2014, of 16 April, calling up a mechanism for reporting any incidents inherent to medical devices or resulting from the use of medical devices. In this way, and considering the type of intervention to carry out in this research (restoration of very small extension of NCCL with dental adhesives), the medical devices (Adhesive systems) are not described in the literature and not known records for the occurrence of undesirable incidents, with interpretative effects as Serious or Unexpected "adverse incidents". However, and according to good clinical practice for clinical research, the reporting mechanism of Serious or Unexpected incidents (protocol version FHS-UFP-FFP-2014 April-19.07.2015) for this research are approved by CEIC (National Ethics Committee for Clinical Research (No.20150305; Approved at 3th August 2015).

Sponsor reports annually to CEIC and INFARMED a list of all suspected serious adverse events, during this period as well as a report on the safety of participants, if applicable. Under the study protocol (Version FCS-UFP-FFP-2014 April-19.07.2015), all the possible non-serious adverse events such as, clinical signs or symptoms associated with loss of aesthetic, functional and biological performance of restorations and situations described in the instructions, labelling and safety data sheets of medical devices or even, without incident and security maintenance data of the participants the sponsor notifies the CEIC and INFARMED, only by the final evaluation of this study (two years of clinical performance), as set forth in article 24th of Law 21/2014 of 16 April, which will include a report of suspicious occurrences and safety records and, if applicable, in the clinical trial in the period Evaluation of two years.