5.3 SPIRIT 2025: Standard Protocol Items for Interventional Trials

SPIRIT 2025: Standard Protocol Items for Interventional Trials

Why Protocol Reporting Matters

A protocol is the prospective record of why a trial is being done and how it will be designed, conducted, analyzed, overseen, and disseminated. Complete reporting helps investigators implement the same plan across sites, enables ethics committees and regulators to review the study, supports monitoring, and lets readers distinguish prespecified decisions from later changes.

SPIRIT does not guarantee good design. It tells authors what information a protocol should report. Ethics approval, regulatory authorization, prospective registration, contracts, manuals, the statistical analysis plan (SAP), data-management plan, and standard operating procedures remain separate controls.

Administrative Information

The protocol should be identifiable and traceable. Include a descriptive title, trial registration information, protocol version and date, funding, and the names and roles of sponsors and other responsible parties. Describe the sponsor's role in design, data collection, analysis, interpretation, report writing, and the decision to submit results.

Roles and responsibilities matter because “sponsor” may refer to legal responsibility while day-to-day tasks are delegated to a coordinating center, contract research organization, data monitoring committee, or investigators. Delegation does not erase accountability. State who owns or controls the data and who has access.

Background, Rationale, and Objectives

Explain the clinical question and the evidence supporting the trial. Describe the intervention and comparator sufficiently to justify the study. State specific objectives or hypotheses and identify the trial framework, such as superiority, noninferiority, or equivalence.

The rationale should address benefits and risks without promotional framing. If patients, caregivers, or public partners contributed to the research question or protocol, report their involvement as required by the current checklist and applicable policies.

Trial Design

Describe:

• the type of trial;
• allocation ratio;
• framework;
• number and structure of groups;
• important design features, such as parallel, crossover, cluster, factorial, or adaptive elements;
• the study setting and participating-site context;
• start and planned end points where relevant.

A visual schedule or SPIRIT figure organizes enrollment, interventions, and assessments across time. It should agree with the narrative and the schedule used operationally.

Participants and Recruitment

State inclusion and exclusion criteria for participants and, where relevant, for centers or individuals delivering an intervention. Describe recruitment strategies and the consent process. Eligibility criteria should be scientifically justified and reviewed for avoidable exclusion or inequity.

For vulnerable populations or those with limited decision-making capacity, describe the protections and applicable consent or assent procedures. If biological specimens or ancillary studies are planned, explain the consent and governance relevant to those uses.

Interventions and Concomitant Care

Describe each intervention with enough detail for consistent delivery. Include criteria for modifying or discontinuing assigned interventions, adherence strategies, and permitted or prohibited concomitant care. Explain relevant post-trial access or care arrangements.

A protocol should not use vague phrases such as “standard care” when standard care varies by site or country. Define the comparator or explain how local practice will be documented.

Outcomes and Assessment Schedule

For each primary and secondary outcome, define:

• the specific measurement variable;
• analysis metric;
• method of aggregation;
• assessment time point;
• who or what performs the measurement when relevant.

Align outcomes across the protocol, registry, SAP, case-report forms, and later publications. If an outcome changes, preserve the audit trail and explain the amendment. Do not overwrite the earlier plan as though it never existed.

The schedule figure should show major enrollment, intervention, and assessment events. Inconsistency between a table, diagram, and narrative is a practical implementation risk and a future publication problem.

Sample Size and Analysis

Explain the sample-size calculation, including the outcome, expected effect or margin, variability or event assumptions, power, significance level, loss-to-follow-up allowance, and any design effect relevant to clusters or repeated measurements.

Prespecify the principal analysis, analysis population, covariate adjustment, handling of missing data, subgroup analyses, and additional methods as appropriate. The protocol can refer to a separate SAP, but the documents must be version-controlled and consistent. Plans for interim analysis and stopping should identify decision rules and who may see comparative results.

Randomization and Masking

For randomized trials, report:

1. how the allocation sequence will be generated;
2. how assignment will be concealed until enrollment;
3. who will generate the sequence, enroll participants, and assign interventions;
4. who will be masked and how;
5. when and how unmasking is permitted.

These details reduce the chance that implementation choices will be improvised after enrollment begins.

Data Management, Confidentiality, and Oversight

Describe how data will be collected, entered, coded, secured, checked, and retained. Address confidentiality and access. Explain monitoring, auditing, harms collection, and the composition and independence of any data monitoring committee, or explain why one is not needed.

Specify processes for adverse-event reporting and trial stopping. Oversight structures should fit trial risk; the guideline does not require every trial to use the same committee architecture.

Ethics, Consent, and Dissemination

State plans for research-ethics approval and informed consent, including authorized waivers or alternative processes where legally and ethically appropriate. Describe how important protocol amendments will be approved and communicated to investigators, participants, registries, journals, regulators, or other parties as applicable.

Include plans for communicating results to participants and the public, publication policy, authorship or contributor principles, and access to protocol, data, code, and other materials where applicable. A dissemination plan should include unfavorable and inconclusive findings, not only positive results.

Amendment Control

A material amendment should create a traceable record:

identified need → scientific/operational review → revised version and date
→ required ethics/regulatory approval → registry/document updates
→ communication and implementation

Record what changed, why, when, and who approved it. Synchronize the protocol, SAP, registry, consent materials, manuals, and publication plan. The final publication should disclose important changes from the planned methods or outcomes.

SPIRIT and CONSORT Compared

The guidelines are complementary. A well-reported protocol makes later CONSORT reporting easier, but the results report must still explain actual conduct and deviations.

Publication Professional Workflow

Before a protocol manuscript is submitted:

1. download the current SPIRIT 2025 checklist and identify extensions;
2. confirm version number and date;
3. reconcile protocol, registry, SAP, consent materials, and schedule;
4. verify roles, funding, sponsor involvement, and data access;
5. check all outcomes and time points;
6. map checklist items to page numbers;
7. obtain required approvals and author confirmation;
8. follow the journal's instructions.