4.2: The ‘SPIRIT’ checklist for standard protocol items for clinical trials

Nearly all intervention trials will need to have a protocol developed, which serves as the basis for trial planning, conduct, and reporting. Before a trial starts, it is recommended or, in many cases, required that the protocol is deposited in a trial register (see Chapter 7, Section 5). Until recently, there has not been specific guidance as to exactly what items should be included in such a protocol. However, such guidance has recently been published (Chan et al., 2013a; Chan et al., 2013b) as a component of the EQUATOR project (Enhancing the QUAlity and Transparency Of health Research) (<http://www.equator-network.org/>). The publications include a 33-item checklist, the so-called SPIRIT (Standard Protocol Items: Recommendations for Intervention Trials) 2013 checklist, which is reproduced in Table 4.1. This gives a useful outline of how a trial protocol might be organized, bearing in mind the issues we have discussed in this chapter. Readers should refer to the SPIRIT website (<http://www.spirit-statement.org/>) for the most recent version.

Table 4.1 The SPIRIT 2013 checklist: recommended items to address in a clinical trial protocol and related documents*

Section/item	Item no.	Description
ADMINISTRATIVE INFORMATION
Title	1	Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym
Trial registration	2a	Trial identifier and registry name. If not yet registered, name of intended registry
	2b	All items from the World Health Organization Trial Registration Data Set
Protocol version	3	Date and version identifier
Funding	4	Sources and types of financial, material, and other support
Roles and responsibilities	5a	Names, affiliations, and roles of protocol contributors
	5b	Name and contact information for the trial sponsor
	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
	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)
INTRODUCTION
Background and rationale	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
	6b	Explanation for choice of comparators
Objectives	7	Specific objectives or hypotheses
Trial design	8	Description of trial design, including type of trial (for example, parallel group, crossover, factorial, single group), allocation ratio, and framework (for example, superiority, equivalence, non-inferiority, exploratory)
METHODS: PARTICIPANTS, INTERVENTIONS, AND OUTCOMES
Study setting	9	Description of study settings (for example, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained
Eligibility criteria	10	Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (for example, surgeons, psychotherapists)
Interventions	11a	Interventions for each group with sufficient detail to allow replication, including how and when they will be administered
	11b	Criteria for discontinuing or modifying allocated interventions for a given trial participant (for example, drug dose change in response to harms, participant request, or improving/worsening disease)
	11c	Strategies to improve adherence to intervention protocols and any procedures for monitoring adherence (for example, drug tablet return, laboratory tests)
	11d	Relevant concomitant care and interventions that are permitted or prohibited during the trial
Outcomes	12	Primary, secondary, and other outcomes, including the specific measurement variable (for example, systolic blood pressure), analysis metric (for example, change from baseline, final value, time to event), method of aggregation (for example, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended
Participant timeline	13	Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see figure at <http://annals.org/article.aspx?articleid=1556168>)
Sample size	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
Recruitment	15	Strategies for achieving adequate participant enrolment to reach target sample size
METHODS: ASSIGNMENT OF INTERVENTIONS (FOR CONTROLLED TRIALS)
Allocation:
Sequence generation	16a	Method of generating the allocation sequence (for example, computer-generated random numbers) and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (for example, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions
Allocation concealment mechanism	16b	Mechanism of implementing the allocation sequence (for example, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence, until interventions are assigned
Implementation	16c	Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions
Blinding (masking)	17a	Who will be blinded after assignment to interventions (for example, trial participants, care providers, outcome assessors, data analysts), and how
	17b	If blinded, circumstances under which unblinding is permissible and procedure for revealing a participant’s allocated intervention during the trial
METHODS: DATA COLLECTION, MANAGEMENT, AND ANALYSIS
Data collection methods	18a	Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (for example, duplicate measurements, training of assessors) and a description of study instruments (for example, 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
	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
Data management	19	Plans for data entry, coding, security, and storage, including any related processes to promote data quality (for example, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol
Statistical methods	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
	20b	Methods for any additional analyses (for example, subgroup and adjusted analyses)
	20c	Definition of analysis population relating to protocol non-adherence (for example, as randomized analysis) and any statistical methods to handle missing data (for example, multiple imputation)
METHODS: MONITORING
Data monitoring	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
	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
Harms	22	Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported AEs and other unintended effects of trial interventions or trial conduct
Auditing	23	Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor
ETHICS AND DISSEMINATION
Research ethics approval	24	Plans for seeking research ethics committee/institutional review board (REC/IRB) approval
Protocol amendments	25	Plans for communicating important protocol modifications (for example, changes to eligibility criteria, outcomes, analyses) to relevant parties (for example, investigators, REC/IRBs, trial participants, trial registries, journals, regulators)
Consent or assent	26a	Who will obtain informed consent or assent from potential trial participants or authorized surrogates, and how (see item 32)
	26b	Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if applicable
Confidentiality	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
Declaration of interests	28	Financial and other competing interests for principal investigators for the overall trial and each study site
Access to data	29	Statement of who will have access to the final trial dataset and disclosure of contractual agreements that limit such access for investigators
Ancillary and post-trial care	30	Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial participation
Dissemination policy	31a	Plans for investigators and sponsor to communicate trial results to participants, health care professionals, the public, and other relevant groups (for example, via publication, reporting in results databases, or other data sharing arrangements), including any publication restrictions
	31b	Authorship eligibility guidelines and any intended use of professional writers
	31c	Plans, if any, for granting public access to the full protocol, participant level dataset, and statistical code
APPENDICES
Informed consent materials	32	Model consent form and other related documentation given to participants and authorized surrogates
Biological specimens	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

*Reproduced with permission of the SPIRIT group. It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Statement (Chan et al., 2013a), in order to fully understand the scope and context of the checklist. It is important to note that this is a minimum list of items, and certain trial protocols may warrant the inclusion of additional items. This table is distributed under the terms of the Creative Commons Attribution Non Commercial 4.0 International licence (CC-BY-NC), a copy of which is available at http://creativecommons.org/licenses/by-nc/4.0/.