How to use the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) in orthodontic research

ABSTRACT Introduction: Clinical trial protocols are essential documents that serve as a basis for research planning. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement aimed to increase the transparency and integrity of clinical trial protocols. Objectives: This paper described the main aspects of the SPIRIT, highlighting the importance of using this guideline in Orthodontics. Results: The SPIRIT is composed of 33 items and the diagram, which were presented and explained. Conclusion: The use of the SPIRIT checklist must become essential to increase the transparency and integrity of more reliable and less biased clinical trials in orthodontic research, improving the quality of future publications in this field.


INTRODUCTION
Clinical trial protocols are essential documents that describe the rationale, aims, methods, ethical issues and dissemination plans of clinical trials, and serve as a basis for research planning. 1,2 All clinical trials, including those performed in the area of Orthodontics, should be based on a complete and transparent protocol. High-quality protocols facilitate assessing adherence to scientific, ethical and safety issues before the beginning of the research; analyzing the conduct and monitoring; as well as checking the results after the completion of the study. [3][4][5] In addition, a good protocol allows evaluation of the consistency between the final report and the original intention. 6 As a consequence, the importance of protocols has been emphasized by journal editors, reviewers and researchers in diverse areas. 4,7 In 2007, a first meeting was held in which a group launched the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT). 5,8 However, the first article describing this checklist was only published in 2013. 3 The SPIRIT 2013 Statement was rigorously developed from two systematic reviews and a Delphi consensus process, and involved 115 experts from different areas. 1,6,9 SPIRIT 7 The SPIRIT consisted of a list of 33 items and a diagram (Fig 1) and aimed to increase the transparency and integrity of clinical trial protocols, providing evidence-based guidance and facilitating the development of high-quality protocols. 7,8 SPIRIT was not dedicated to prescribe how a study should be designed or conducted, but to help the researcher, including in the area of Orthodontics, to describe clearly and completely what is planned and to understand the main elements of a protocol. 3 Another positive point is that several items from SPIRIT corresponded to items from the Consolidated Standards of Reporting Trials (CONSORT). 10,11 It is important to emphasize that SPIRIT and CONSORT were constructed in a different and complementary way in the development of clinical trials.
SPIRIT was developed to assist in the construction, planning and appraisal of protocols for interventional studies, acting as a guide to decrease errors in the design of the study and to avoid possible biases. On the other hand, CONSORT can be used for reporting the results of (already conducted) clinical trials. In addition, it was designed to assist in quality assessment of randomized controlled trials (RCTs) throughout their structure. 11 Since SPIRIT mirrored applicable items     where, when and how recruitment was carried out.

16-17):
The protocol should describe the method used to generate the allocation sequence and the list for stratification factors. It should provide planned restrictions (to reduce the predictability of a randomized sequence) in a separate document, unavailable to those responsible for participant registration. It needs to specify the allocation concealment mechanism used until the assignment of interventions is carried out. Also, the responsible for generating the allocation sequence, registering participants, and assigning participants to the interventions needs to be described. On blinding, the protocol should identify who will be blinded after assignment to interventions and how this will be done. If blind, it is needed to describe the circumstances under which unblinding is permissible, and the procedure for revealing the participant's intervention during the trial. For example, a trial comparing two drugs for pain control after fixed orthodontic appliance placement should clearly describe how randomization was conducted: using opaque, labeled, and sealed envelopes or trough a website/software. In addition, it should be informed whether a single (patient), double (patient and clinician) or triple (patient, clinician and statistician) blinding was achieved.

» Data collection, management and analysis (items 18-20):
The protocol should describe evaluation plans for evaluation and outcome collection, baseline, and other trial data, description of study instruments (including reliability and validity), and reference to where data collection forms can be found. The plans for promoting participant retention and complete follow-up, including a list of outcome data of those who discontinue the protocols, should be described. Its should inform plans for data entry, encoding, security, and storage. Reference to the location of information on data management procedures should be included.  11 and audit procedures for conducting the trial. Following the example given above about the use of two drugs for pain relief after initial orthodontic treatment, researchers need to clarify how monitoring of side, harmful, undesirable effects would occur and how reporting would be conducted and the protocol for trial interruption.

ETHICS AND DISCLOSURE (ITEMS 24-31)
The protocol should describe plans for obtaining approval from the Research Ethics Committee/Institutional Review Committee or, if the research is already approved, inform its protocol number. The plans for communicating important protocol changes to relevant parties should be described.
It should inform who will obtain consent/assent from prospective trial participants or authorized surrogates, and how it will be conducted. If necessary, it should inform consent for collection and use of data and biological samples from participants. An important point is to describe how personal information of participants will be collected, shared and maintained.

APPENDICES (ITEMS 32-33)
The protocol should present the consent form and other documentation related to the participants and authorized surrogates. Plans for collection, laboratory evaluation, and storage of biological samples for genetic or molecular analysis in the current study and for future use should be presented.
For example, in a trial that needs to collect saliva, crevicular fluid or blood for biochemical analyses in patients undergoing fixed orthodontic appliance treatment, a document with detailed information about use and storage of these biological samples should be presented.
SPIRIT also has two extensions, which provide specific guidance for protocols related to patient-reported outcomes (PROs) 2 and for Traditional Chinese Medicine. 12 The SPIRIT-PRO extension was developed according to the methodological structure of EQUATOR, and provided international guidance based on consensus about specific PRO information that should be included in clinical trial protocols, such as health-related