[1-5] Administrative information

1. Title

Item 1:

Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym

2. Trial registration

Item 2a:

Trial identifier and registry name. If not yet registered, name of intended registry

Item 2b:

All items from the World Health Organization Trial Registration Data Set

3. Protocol version

Item 3:

Date and version identifier

4. Funding

Item 4:

Date and version identifier

5. Roles and responsibilities

Item 5a:

Names, affiliations, and roles of protocol contributors

Item 5b:

Name and contact information for the trial sponsor

Item 5c:

Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities

Item 5d:

Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable (see Item 21a for data monitoring committee)



[6-8] Introduction

6. Background and rationale

Item 6a:

Description of research question and justification for undertaking the trial, including summary of relevant studies (published and unpublished) examining benefits and harms for each intervention

Item 6b:

Explanation for choice of comparators

7. Objectives

Item 7:

Specific objectives or hypotheses

8. Trial design

Item 8:

Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)



[9-15] Methods: Participants, interventions, and outcomes

9. Study setting

Item 9:

Description of study settings (e.g., community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained

10. Eligibility criteria

Item 10:

Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists)

11. Interventions

Item 11a:

Interventions for each group with sufficient detail to allow replication, including how and when they will be administered

Item 11b:

Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in response to harms, participant request, or improving/worsening disease)

Item 11c:

Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet return, laboratory tests)

Item 11d:

Relevant concomitant care and interventions that are permitted or prohibited during the trial

12. Outcomes

Item 12:

Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended

13. Participant timeline

Item 13:

Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended

14. Sample size

Item 14:

Estimated number of participants needed to achieve study objectives and how it was determined, including clinical and statistical assumptions supporting any sample size calculations

15. Recruitment

Item 15:

Strategies for achieving adequate participant enrolment to reach target sample size



[16-17] Methods: Assignment of interventions (for controlled trials)

16. Allocation

Item 16a: Sequence generation

Method of generating the allocation sequence (eg, computergenerated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions

Item 16b: Allocation concealment mechanism

Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned

Item 16c: Implementation

Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions

17. Blinding (masking)

Item 17a:

Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how

Item 17b:

If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s allocated intervention during the trial



[18-20] Methods: Data collection, management, and analysis

18. Data collection methods

Item 18a:

Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol

Item 18b:

Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols

19. Data management

Item 19:

Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol

20. Statistical methods

Item 20a:

Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol

Item 20b:

Methods for any additional analyses (eg, subgroup and adjusted analyses)

Item 20c:

Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation)



[21-23] Methods: Monitoring

21. Data monitoring

Item 21a:

Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed

Item 21b:

Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial

22. Harms

Item 22:

Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct

23. Auditing

Item 23:

Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor



[24-31] Ethics and dissemination

24. Research ethics approval

Item 24:

Plans for seeking research ethics committee/institutional review board (REC/IRB) approval

25. Protocol amendments

Item 25:

Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes, analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, regulators)

26. Consent or assent

Item 26a:

Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and how (see Item 32)

Item 26b:

Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if applicable

27. Confidentiality

Item 27:

How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial

28. Declaration of interests

Item 28:

Financial and other competing interests for principal investigators for the overall trial and each study site

29. Access to data

Item 29:

Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that limit such access for investigators

30. Ancillary and post-trial care

Item 30:

Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial participation

31. Dissemination policy

Item 31a:

Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing arrangements), including any publication restrictions

Item 31b:

Authorship eligibility guidelines and any intended use of professional writers

Item 31c:

Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code



[32-33] Appendices

32. Informed consent materials

Item 32:

Plans, if any, for granting public access to the full protocol, participant level dataset, and statistical code

33. Biological specimens

Item 33:

Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in the current trial and for future use in ancillary studies, if applicable




Citation

When referring to the SPIRIT-AI guidelines, please cite one of the following articles:

Nature Medicine

The Lancet Digital Health

BMJ