Table 2 Common comments that are made on many initial submissions

2b

“The trial is registered in [trial registry other than ICTRP]. Please either include a supplemental table with all items from the WHO Trial Registration Data Set, or else a statement affirming whether all items can be found in the protocol. Alternatively, simply state: ‘Please refer to Item 2a and registration in the EU Clinical Trials Register https://www.clinicaltrialsregister.eu/’ (or whichever is applicable) and provide a link to your trial.”

5c

“Please note the sponsor/funder’s role in any of the design, conduct, analysis, or future writing and publication. An example of what has been written is: ‘The sponsor played no part in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication.’”

5d

“Regarding trial oversight, aside from [any already listed groups], are there any study teams (e.g., Steering Committee, Data Monitoring Committee, Data Quality Committee, Stakeholder and Public Involvement Group, etc.) involved in monitoring the progress of the trial (e.g., checking recruitment, training staff, periodic auditing of data quality, interim analyses, etc.), and if so, what is the composition of these groups and what are their roles and responsibilities? There will always be a core group running the trial day-to-day and providing organisational support for the trial. This SPIRIT item does not require names, but information such as how often they will meet is useful. If there are no such groups aside from the core group, please provide a note for why they were deemed not necessary.

6b

“Please provide more detail and rationale for your choice of comparator. Note that all randomised controlled trials have a comparator, even if it is placebo or standard care.”

8

“Please be more specific and complete in the description of the trial design framework (e.g. superiority, equivalence, non-inferiority, exploratory). For example see Dunn Trials 2018;19(1):499” [18].

11b

“Are there any reasons why participants might discontinue or modify the intervention? For instance, please state criteria for discontinuing or modifying allocated interventions for a given trial participant (e.g drug dose change in response to harms, participant request, or improving/worsening condition). The protocol may state ‘There will be no special criteria for discontinuing or modifying allocated interventions.’”

11d

“Aside from the trial interventions, are there any other treatments or therapies that participants are allowed or not permitted to use? The protocol could state that implementing X or Y will not require alteration to usual care pathways (including use of any medication) and these will continue for both trial arms.”

12

“Please fully define all your outcomes following the framework described in Zarin NEJM 2011;364:852-60 and Saldanha PlosOne 2014;9(10):e109400. Your outcome definition should include these 5 elements: the domain (name of the outcome), specific measurement, metric (i.e., will the difference at a point in time between groups be assessed, or the difference in the change in score between two groups, etc.), method of aggregation (e.g., mean, median, proportion, etc.), and time point (i.e., which of the times at which the outcome will be assessed is of interest for the comparison). For example, [missing details for at least one trial outcome that is incompletely or ambiguously described]” [19, 20]

13

“Please include a SPIRIT Figure with the protocol to present the timing of all assessments and measures in the trial. The study flow diagram currently included is helpful, but not sufficient. Please see the SPIRIT explanation and elaboration guidance (Chan, BMJ, 2013; 346: e7586) and other protocols published in Trials for examples.”

14

“The sample size estimation requires elaboration. What estimates and assumptions were used in generating this sample size? What is the minimal difference you will be able to detect and with what power and at what level of significance? Which outcome was used to inform the sample size and if it is continuous, what are the expected mean(sd) for each group being compared, with references/rationale to support the estimation?”

15

“Please insert into the protocol information on recruitment strategy to ensure adequate participant enrolment to reach sample size. The protocol must state how you will recruit and the anticipated recruitment period. Additionally, are there any extra processes or measures in place to improve recruitment and ensure an adequate enrolment is met?”

16a-c

“The randomization and allocation processes could be elaborated. What program is used to generate the random sequence and who generates it? Is the randomization simple or is there any blocking or stratification (or other adaptation) used? Is the allocation sequence concealed before randomization and how do the people performing the allocation obtain each subsequent assignment? Who performs the allocation?”

17a

“The trial is described as double-blind, which is ambiguous, and more than two parties are blinded. Consider revising the title and describe all the specific blinded parties early in the protocol.”

“For the description of blinding, please also note whether statisticians and outcome assessors will be blinded to treatment, and if not, please provide a rationale.”

17b

“If the trial includes any blinding, N/A is not acceptable: please describe any circumstances under which involved parties (e.g., clinicians, coordinator, etc.) may be unblinded. Alternatively, the protocol could state ‘We do not anticipate any requirement for unblinding but if required, the Trial Manager, Data Coordinator, Clinicians will have access to group allocations and any unblinding will be reported.’ or, if the trial is not blinded: ‘The design is open label so unblinding will not occur.’”

18a

“The data collection and management processes could be elaborated. How will data be collected and are the forms pre-existing or created by the investigators? Are there any processes in place during data collection/entry to ensure data are complete and accurate?”

18b

“Given the anticipated drop-out as described in the sample size section, are there any plans or measures in place to improve participant retention and minimise loss to follow up?”

19

“Please give details for data entry, coding, security, and storage, including any related processes to promote data quality (e.g. double data entry, range checks for data values). Reference to where data management procedures can be found, if not in the protocol. For instance, will paper based and electronic data entry be used? Who will collect data? And who will enter the data into the database for screening and randomisation purposes? If paper forms are used, will you ensure that the paper-based Case Report Form (CRF) data are delivered securely to the Trial Office for data entry?”

20b

“If there are any secondary/subgroup/interim analyses planned for the trial, please include a description of these including rationale and the methods of analysis. If none are planned, please include a statement to that effect.”

“For the analysis section, please define who is included in all trial analysis populations (e.g., ITT, modified-ITT, full analysis set, per protocol, safety) in the context of the trial (i.e., how will you analyse those that are randomised to the intervention but do not adhere to the intervention?). Additionally, please include a statement about how missing data will be handled in the trial.”

21b

“The description of interim analyses requires more detail. Please include stopping guidelines in relation to your interim analysis, as well as who will conduct the analysis and how the results will influence decisions to continue or terminate the trial.”

22

“Regarding harms, are there any harms that may be potentially expected given previous experiences with the study intervention(s)? If so, please list them.”

“Will unexpected harms also be collected and how will all harms be assessed: systematically (i.e., using a standardised approach for all participants) or non-systematically (i.e., spontaneous reporting from participants or asking about non-specific events)?”

“Will harms be coded (i.e., standardised according to structured language such as Medical Dictionary for Regulatory Activities (MedDRA) or Common Terminology Criteria for Adverse Events (CTCAE))?”

“Additionally, what are the plans for reporting harms in trial publications (i.e., will you report all harms or only those which meet specific criteria)?”

25

“If there are any amendments required to the protocol over the course of the trial, how and to whom will these be communicated? For example, notifying the sponsor and funder first then the PI notifying the centres with a copy of the revised protocol sent to the PI to add to the Investigator Site File. You may also want to state that any deviations from the Protocol will be fully documented using a breach report form. You can also include that you will update the protocol in the clinical trial registry.”

26a

“Please give information on who was actually recruiting the participant and gaining informed consent. When and how is this done?”

26b

“If this item is Not Applicable because biological specimens will not be collected, it is important to state that ‘This trial does not involve collecting biological specimens for storage.’ Please also include a note about whether there are any plans for additional studies using the general participant data collected in this trial and whether consent will need to be sought to use that data.”

Item 27

“Please expand the description of how confidentiality will be ensured. Verify that data collected during the course of the research will be kept strictly confidential and only accessed by members of the trial team (or individuals from the Sponsor organisation or centre sites where relevant to the trial). Will participants be allocated an individual trial identification number and will participant’s details be stored on a secure database? Who will access rights to the data set? Will anonymised trial data be shared with other researchers to enable international prospective meta-analyses?”

Item 29

Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that limit such access for investigators. Consider stating “Any data required to support the protocol can be supplied on request.”

30

“What are the provisions for post-trial care and compensation for any participants who suffer harm? The protocol could potentially state: ‘There is no anticipated harm and compensation for trial participation.’”

31b

“Please include a note about how authorship will be determined for future trial publications and any intended use of professional writers. Additionally, please ensure that the protocol states that ‘all authors read and approved the final manuscript.’”

31c

“Please include a statement about whether there are any plans to give public access to the data generated for this trial. If data will be made available (either at participant or summary level), please include a description of how the data can be obtained or requested. For example, ‘The datasets analysed during the current study are available from the corresponding author on reasonable request.’”

32

“Please include a copy of the informed consent documents provided to participants.”

33

For this SPIRIT item, please add information on plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in the current trials and for future use in ancillary studies. OR state there will be no biological samples collected.