Study setting {9}
The study will be conducted in the private offices of two of the co-investigators involved in the study (GMA and VHMC), located in the cities of Itabuna (Bahia) and Goiânia (Goiás), Brazil, respectively. All investigators and examiners are specialists in Endodontics with more than 10 years of clinical experience. They will participate in this randomized clinical trial after receiving adequate training to obtain a comprehensive view of the principles and strategy of the 3 clinical approaches that will be used. A total of 150 adult patients, ages 18 and 60 years old, who voluntarily seek endodontic treatment in the Brazilian Unified Health System in the cities of Itabuna, in the State of Bahia, in Goiânia, in the State of Goiás, Brazil. After an assessment of eligibility and informed consent, patients will be randomly assigned to one of 3 clinical study groups. Patients who agree to participate in this study will sign an informed consent form.
Eligibility criteria {10}
Inclusion criteria
To enroll in the study, subjects must: (1) be diagnosed with apical periodontitis in lower molar teeth (first or second molars), the periradicular lesion with a diameter between 1 and 5mm analyzed through the real tomographic scale of 1:1, (2) be asymptomatic, (3) spontaneously agree and sign the informed consent form, (4) be in good health, and (5) be not taking antibiotics and anti-inflammatory drugs.
Exclusion criteria
Patients may not participate in the study if they are as follows: (1) Teeth with extensive coronary destruction that makes direct restoration with composite resin unfeasible; (2) Calcified teeth; (3) Teeth with incomplete root formation; (4) Teeth with persistent exudation; (5) Teeth with anatomical complexities that prevent endodontic treatment in a single visit; (6) Teeth recommended for endodontic retreatment; (7) Teeth with advanced periodontal pocket; and (8) Teeth in which foraminal patency is not obtained.
Who will take informed consent? {26a}
All participants will be given an information sheet including, the names and affiliations of the investigators, a description of the study and its duration. Theiy will have the right to withdraw at any time without giving reasons, ethics committee approvals, and the personal data privacy guarantee. Patients will have unlimited time to read the consent and ask questions. After the period of reflection, during the enrolment visit, the written informed consent will be signed.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
N/A. Neither collection nor use of participant data and biological specimens.
Interventions
Explanation for the choice of comparators {6b}
Traditionally, root canal treatment in teeth with apical periodontitis is performed in multiple-visits, with the use of intracanal dressing between visits, aiming to reduce miroorganisms and their by-products from the root canal system prior to filling. However, this type of conventional endodontic treatment has as a disadvantage the inconvenience of requiring patient return (in multiple sessions) for medication changes, until the root canal filling is possible. In the comparison group, the root canal treatment will be performed in a single session, which represents a more objective form of treatment, with the convenience of only one appointment for the patient and a lower operating cost for the professional.
Intervention description {11a}
In order to treat apical periodontitis, in the first visit, the same endodontic instrumentation protocol will be performed for all teeth randomly divided into the 3 study groups. What will vary will be complementary and additional maneuvers such as the use of ultrasonic activation and intracanal dressing between visits of endodontic instrumentation. All endodontic therapy procedures will be performed under a dental microscope, except for anesthesia and rubber dam placement steps.
First Clinical Appointment
The first visit will include the following clinical protocol depending on the study group. For the 3 groups (G1, G2 and G3): (1) Anesthesia and caries removal. After local anesthesia with articaine hydrochloride and epinephrine tartrate injection (with 1:200,000 adrenaline [Produits Dentaires Pierre Rolland, Merignac, France]), all decayed tissue from the tooth is removed; (2) Isolation and access preparation. The tooth is isolated with a rubber dam and disinfected, and the pulp chamber will be completely unroofed; (3) Initial irrigation with 5 ml of 5.25% NaOCl; (4) Root canal preparation: The #10 C-Pilot file will be used to perform the glide path along the length of the tooth on the radiograph, irrigated with 2 ml of 5.25% NaOCl, followed by rotary instrumentation with #15/.03, #25/.04 and #30/.05 NiTi files, initially in the cervical and middle thirds, after which the working length with foraminal locator will be performed. Finally, the instrumentation of the apical third will be performed with the same sequence of NiTi rotary files used previously; and (5) The canal will be copiously irrigated in three stages using 10ml of 5.25% NaOCl for each of thirds: cervical, middle and apical, totaling 30ml, followed by a final rinse with 10ml of 5.25% NaOCl stirred with the ultrasonic inserts and 10 ml of 17% EDTA stirred also with ultrasonic inserts. The final rinse will be carried out with 10ml of saline solution.
Group 1- Root canal treatment in single visit (RCT-SV):
(1) The root canals will be filled in the first visit. In this group, a #30/.05 gutta-percha cone and epoxy resin-based sealer with the continuous heat wave technique and a final restoration with Z250 composite resin (3M ESPE, St. Paul, USA) will be used.
Group 2- Root canal treatment in two visits with intracanal dressing (RCT-TVWD):
(1) The root canals will receive intracanal dressing with Ca(OH)2 (Supplied by Farmácia Fórmula & Ação, São Paulo, Brazil), CPMC (Supplied by Farmácia Fórmula & Ação, São Paulo, Brazil) and glycerin (Supplied by Farmácia Fórmula & Ação, São Paulo, Brazil) paste for a period of 7 days. To restrict bacterial regrowth and supply continued disinfection, the root canal will be filled homogeneously to the working length with Ca(OH)2/CPMC/glycerin paste. The tooth will be shielded with glass ionomer cement (GIC) (Vidrion R, SSWhite, Rio de Janeiro, Brazil) as a temporary restoration.
Group 3- Root canal treatment in two visits without intracanal dressing (RCT-TVWOD):
(1) The root canals will be without intracanal dressing for a period of 2 days, taking into account that the tooth will be shielded with GIC (Vidrion R, SSWhite, Rio de Janeiro, Brazil) as a temporary restoration.
Second Clinical Appointment
The second visit will include the following clinical protocol depending on the study group. For the 2 remaining groups (Group 2 and Group 3): (1) Anesthesia and restorative material removal. After local anesthesia with articaine hydrochloride and epinephrine tartrate injection (with 1:200,000 adrenaline [Produits Dentaires Pierre Rolland, Merignac, France]), all temporary restorative material from the tooth is removed; and (2) Isolation and Access. The tooth is isolated with a rubber dam and the root canal will be accessed one more time.
Group 2:
(1) After 7 days, the intracanal dressing will be removed and the root canal will receive a new chemomechanical preparation, identical to the one performed in the first visit, and then it will be filled and permanently restored similarly to group 1.
Group 3:
(1) After 2 days, the root canal will receive a new chemomechanical preparation, identical to the one performed in the first visit, and then it will be filled and permanently restored similarly to group 1.
Criteria for discontinuing or modifying allocated interventions {11b}
(1) Presence of serious adverse events that doctors believe should lead to termination of trial participation, such as severe internal or external root resorption and tooth fracture; (2) Poor clinical compliance; and (3) Withdrawal of consent for study participation by the patient.
Patients who present a profile that fits to that described in the inclusion and exclusion criteria will then be referred for evaluation by other examiners (experts in Endodontics), for confirmation of diagnosis and treatment planning, if necessary. Patients who do not fit the required profile will be forwarded to the health unit of origin. All the steps of interviews and clinical examination necessary to complete the diagnosis will be carried out by the examiners who will perform the treatment.
Strategies to improve adherence to interventions {11c}
During the study patients will receive text messages and phone calls to remind them of their appointments for treatment, follow-up visits and to answer the questionnaires.
Relevant concomitant care permitted or prohibited during the trial {11d}
Patients with systemic diseases (diabetes, transplants, heart disease, liver failure and kidney failure) and Immunodepressed patients. are prohibited during the trial as these conditions can affect the oral functions.
Provisions for post-trial care {30}
At the end of the study, patients will be proposed to continue their long-term oral follow-up at the Brazilian Unified Health System in the cities of Itabuna, in the State of Bahia, in Goiânia, in the State of Goiás, Brazil.
Outcomes {12}
All the steps of clinical examination will be carried out by the two examiners responsible for the study. Imaging evaluation will be done by other 2 (two) specialists in Endodontics and 1 (one) radiologist. All with at least 15 years of experience.
Assessments will also be carried out at 6, 12 and 24 months for analysis of the tissue repair process, through periapical radiographs and CBCT. The therapeutic effect evaluation criteria are the following: (1) Success: After RCT, the tooth should be asymptomatic, without fistula, without pain on percussion and palpation tests, without edema and in normal chewing function. Radiographically in the process of periapical lesion regression from the first assessment at 06 months and fully repaired after 2 years with confirmation through CBCT; and (2) Failure: After RCT, the tooth is symptomatic, with symptoms of apical infection such as pain and fistula. The radiographic examination demonstrates absence of decreased apical lesion or an enlarged apical lesion.
Primary outcome measures
Healing of periradicular lesions by radiographic findings according to periapical Index (PAI)
The periapical index (PAI) is a structured scoring system for categorization of radiographic features of apical periodontitis. It is based on a visual scale of periapical periodontitis severity and was built upon a classical study of histological-radiological correlations. It is a five-point ordinal scale as listed below: (1) Normal periapical structures; (2) Small changes in bone structure with no demineralization; (3) Changes in bone structure with some diffuse demineralization; (4) Apical periodontitis with well-defined radiolucent area; (5) Severe apical periodontitis, with exacerbating features [22,23].
Secondary outcome measures
Patient's postoperative pain using questionnaire
Patients will answer a questionnaire for the analysis of postoperative pain, through the analogue pain scale, in an interval of 24h, 48h, 72h and 7 days: (0) No pain; (1) Mild; (2) Moderate; (3) Severe; and (4) Intense (Figure 2).
Patient's preference regarding the number of clinical visit using questionnaire
Data on the patient's preference regarding the number of clinical visit to be planned for the conduction of endodontic treatment, patients will answer their preferences according to hypothetical conditions described in a previously delivered questionnaire: (1) Single-visit; (2) Two- (or multiple-) visits; and (3) No preference (Figure 3).
Patient's post-treatment satisfaction using questionnaire
A post-treatment satisfaction questionnaire will be applied to patients undergoing clinical interventions in a single visit and multiple visits, using the following criteria: (5) Fully satisfied; (4) Satisfied; (3) Neither dissatisfied nor satisfied; (2) Dissatisfied; and (1) Totally dissatisfied (Figure 4).
Participant timeline {13}
The study timeline is summarized in Table 1.
Sample Size {14}
The determination of the sample size will be performed sequentially, with a minimum of 210 statistical units (teeth) to be recruited in the first stage, and the second stage of recruitment will be performed if the selection is insufficient to clinically and radiographically identify valid cases. This sampling will also allow the adjustment of the sample size for the intra-subject correlation of statistical units (teeth). In the first stage, 150 adults aged 18 to 60 years, with at least one tooth diagnosed with asymptomatic apical periodontitis and periradicular lesion with a diameter between 1 and 5 mm, will be recruited.
Sample size and statistical methods
Sample size details
The required sample size was calculated based on the preliminary outcome parameter of success, in a sequential approach, with each clinical case (tooth) serving as the statistical unit. Clinical studies that allow us to estimate, by means of CBCT, the repair index (complete absence of periapical radiolucency), therefore the success, after endodontic treatment of teeth with apical periodontitis and periradicular lesion, state that it is necessary a follow-up of at least 2 years to determine the success or failure of the treatment. After the first year of follow-up, post-endodontic treatment it is still possible to observe the presence of periapical radiolucency in 52% to 84% of cases [1,21,22]. The sample will consist of 210 mandibular molars (first or second molars), based on statistical sample calculation, considering a power of 80%, alpha value of 0.05 and effect size of 20%. All patient characteristics at the beginning of treatment, such as age, gender, lesion size, among others, will be considered in the statistical analysis, in order to confirm the randomization of groups and the possible confounding effect of these characteristics.
Recruitment {15}
For achieving adequate participant enrolment to reach the target sample size, all new patients meeting eligibility criteria will be given the opportunity to participate in the study. A close coordination is made between the private offices of both co-investigators involved in the study (GMA and VHMC) to identify and refer adequately potential participants.
Assignment of interventions: allocation
Sequence generation {16a}
Assignments will be prepared by the statistician author of this study (TLA) prior to the trial start. A total of 150 patients (210 teeth) will be recruited and divided into 3 groups at a ratio of 1:1:1, namely, the RCT in single-visit, RCT in two-visits with intracanal dressing, and RCT in two-visits without intracanal dressing.
Randomization and allocation will be performed before all the clinical procedures.
First, a list of number from 1 to 210 will be created, each of the number represents one participant, then the list of numbers was assigned randomly following simple randomization procedures, by using Excel 2019 (Microsoft, Redmond, WA, USA) into three groups of 50 participants (70 teeth) each. Eventually, two columns in the spreadsheet are used, the first column contains the number of the participant (teeth) and the second contains the group to which the participant (teeth) is allocated, determined solely by the software.
Concealment mechanism {16b}
Each number and the group to which a number is allocated will be concealed in sequentially numbered, opaque, sealed and stapled envelopes. Only investigators can open the envelope, at the moment of intervention, to check the group to which the number is allocated, and perform the interventions according to the instructions of this study.
Implementation {16c}
The randomization list is implemented in the software by the study statistician (TLA). Access to the randomization list is limited to the study investigators.
Assignment of interventions: Blinding
Who will be blinded {17a}
As a double-blinded trial, the patients and outcome evaluators will be blinded to the group assignment until the completion of the study. As dentists cannot be blinded to treatment allocation due to the notable differences in the treatment methods, they will not be allowed to discuss the type of intervention with either patients or outcome evaluators.
Procedure for unblinding if needed {17b}
N/A. Not applicable.
Data Collection and Management
Plans for assessment and collection of outcomes {18a}
Data associated with this study will be collected in the standardized case report forms (CRF) for the outcome analysis, and a specific supervisor will be responsible for reviewing the integrity, accuracy, and consistency of the data. To ensure the accuracy of data entry, three investigators (two endodontists and 1 radiologist) will be responsible for entering the data independently and data query forms (DQF) will be resolved by tracing the source data.
A questionnaire to score the patient postoperative pain levels will be administered by two investigators in periods of 24, 48, 72 hours and 7 days after the completion of a root canal treatment. Questionnaires of patient satisfaction rate with regard to the treatment, and the patient preference in relation to the frequency of clinical visits will also be performed. The secondary outcomes will be obtained from self-administered questionnaires completed immediately after the completion of a root canal. All the data will be registered in document clouds (in a specific Microsoft 365 OneDrive institutional account files), and only authorized personnel will have access. Data monitoring will be independent from the investigators and competing interests.
Plans to promote participant retention and complete follow-up {18b}
A patient will be considered as lost-to-follow-up if no contact can be made during 24 months, after an active search from the two investigators. Participants will receive no financial compensation but they will be given the root canal and the restorative treatments of the teeth.
Data management {19}
Data are entered anonymously. Data collection will be monitored by a clinical research assistant. When requested, the two investigators will clarify data. Data management is under the responsibility of the University of Brasilia.
The Data Management Coordinating Center will oversee the intra-study data sharing process, with the involvement of the Data Management Subcommittee. Only the principal investigator will be given access to all the data with a special password. Other project investigators will have direct access to their own site's data sets, and other sites’ data by request. To ensure confidentiality, data dispersed to project team members will be blinded to any identifying participant information.
Confidentiality {27}
The final trial dataset will be available to the clinical research assistants, data managers, and statistician, subject to professional secrecy. Data are anonymous.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
N/A. No collection.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
The data will be analyzed using SPSS 25.0 software (IBM Co., Armonk, NY, USA).
(1) Baseline analysis
The three groups will be similar in terms of disease type, and periapical lesion size.
(2) Main outcome analysis
The inter-group comparison of success rates will be analyzed using the Kruskal-Wallis test at 5% of level of significance. For the missing data, the last observation carried forward (LOCF) method will be adopted to fill the validity analysis.
(3) Secondary outcome analysis
Intra-group and inter-group comparisons for analysis of postoperative pain and post-treatment satisfaction will be performed by Friedman and Kruskal-Wallis test, respectively. Inter-group comparisons for preferences regrading to the number of clinical visits will be performed by Chi-square test. All tests will be performed at 5% of level of significance.
Interim analyses {21b}
N/A. No interim analyses are planned.
Methods for additional analyses (e.g. subgroup analyses) {20b}
N/A. No additional analyses are planned.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Protocol violations after randomization will be listed in the Clinical Study Report, tabulated by subject and recruitment site. We will perform intention-to-treat analyses with a “missing=failure” strategy to the management of missing data.
Sensitivity analyses will be performed for the missing data management: multiple imputation, available data, and maximum bias.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
The full protocol, participant-level data, and statistical code are available upon request and after a contract has been put in place to ensure, among other things, that the recipient complies with the GDPR.
Oversight and monitoring
Composition of the coordinating center and trial steering committee {5d}
The steering committee is made up of the following people: Dr Gustavo M. ALMEIDA (chairman, principal investigator), Dr Vitor Hugo M. CARVALHO (clinical investigator), Dr André F. LEITE (radiologist and responsible for the center of Brasilia), Dr Erica L. QUEIROZ, Dr Ana Paula D. RIBEIRO, and Dr Jacy R. CARVALHO-JUNIOR (methodologists), and Dr Tien Li AN (statistician). This committee checks ethics. With the Center for Methodology and Data Management, this committee checks also the status of the research, possible problems, and available results. It decides on any relevant modification of the protocol necessary for the continuation of the research. It may propose to extend or interrupt the research.
Composition of the data monitoring committee, its role and reporting structure {21a}
The establishment of a data monitoring committee is not necessary for this study, which does not entail any particular risk a priori for the participants.
Adverse event reporting and harms {22}
Adverse events that may occur will be monitored by the investigators and a research assistant. All information regarding adverse events during the study will be recorded in detail, including symptoms, signs, onset time, and severity. Some possible adverse events that may be attributed to RCT include reinfection of the root canal, flare up, root and coronary fracture, and discomfort to chewing.
Frequency and plans for auditing trial conduct {23}
In the context of the data monitoring plan, a clinical research assistant mandated by the responsible for the center of Brasilia will visit each investigating center on a regular basis, during the implementation of the research, one or more times during the research according to the rhythm of the inclusions and at the end of the research. An audit can be conducted any time at the request of the responsible for the center of Brasilia and independent from the investigators, but also at the request of the competent health authority.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
The protocol has been approved by the Medical Ethics Committee of University of Brasilia CAAE protocol: 87963117.3.0000.0030 and registered at ClinicalTrials.gov. NCT05256667.
Any important protocol amendment must obtain, prior to its implementation, a favorable opinion from a Medical Ethics Committee of University of Brasilia (Comitê de Ética em pesquisa da Universidade de Brasília [CEPE]). All modifications to the protocol should be brought to the attention of all investigators participating in the research. Any modification that modifies the coverage of participants or the benefits, risks, and constraints of the research is the subject of a new information sheet and a new consent form. Any amendments to the protocol will be reviewed and approved. Written informed consent will be obtained from all patients.
Dissemination plans {31a}
Results of the trial will be communicated to the participants through a brochure that will be sent at the. patient’s home. They will be also submitted to national and international journals for publication.
Results of the trial will be communicated to the participants upon request to the investigators.
