[ps2id id=’title’ target=”/]1. TITLE

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

Example

“A Multi-center, Investigator-blinded, Randomized, 12-month, Parallel-group, Non-inferiority Study to Compare the Efficacy of 1.6 to 2.4 g Asacol®  Therapy QD [once daily] Versus Divided Dose (BID) in the Maintenance of Remission of Ulcerative Colitis.” ¹⁹

Explanation

The title provides an important means of trial identification. A succinct description that conveys the topic (study population, interventions), acronym (if any), and basic study design – including the method of intervention allocation (e.g., parallel-group randomised trial; single-group trial) – will facilitate retrieval from literature or Internet searches and rapid judgment of relevance.²⁰ It can also be helpful to include the trial framework (e.g., superiority, non-inferiority), study objective or primary outcome, and if relevant, the study phase (e.g., phase II).

[ps2id id=’trial-registration’ target=”/]2. TRIAL REGISTRATION

2a. Trial registration

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

Example

“EudraCT: 2010-019180-10

ClinicalTrials.gov: NCT01066572

ISRCTN: 54540667.” ²¹

Explanation

There are compelling ethical and scientific reasons for trial registration.^22-24 Documentation of a trial’s existence on a publicly accessible registry can help to increase transparency,^24;25 decrease unnecessary duplication of research effort, facilitate identification of ongoing trials for prospective participants, and identify selective reporting of study results.^26-28 As mandated by the International Committee of Medical Journal Editors (ICMJE) and jurisdictional legislation,^29-31 registration of clinical trials should occur before recruitment of the first trial participant.

We recommend that registry names and trial identifiers assigned by the registries be prominently placed in the protocol, such as on the cover page. If the trial is not yet registered, the intended registry should be indicated and the protocol updated upon registration. When registration in multiple registries is required (e.g., to meet local regulation), each identifier should be clearly listed in the protocol and each registry. [ps2id id=’data-set’ target=”/]

2b. Data set

All items from the World Health Organization Trial Registration Data Set.

Example 

[table nl=”~~” div style=”float:left” class=”table table-bordered” tablesorter=”0″ table delimiter=”|”]
Data category[attr width=”175″]|Information³²
Primary registry and trial identifying number|ClinicalTrials.gov~~NCT01143272
Date of registration in primary registry|11 June, 2010
Secondary identifying numbers|BNI-2009-01, 2009-017374-20, ISRCTN01005546, DRKS00000084
Source(s) of monetary or material support|Bernhard Nocht Institute for Tropical Medicine
Primary sponsor|Bernhard Nocht Institute for Tropical Medicine
Secondary sponsor(s)|German Federal Ministry of Education and Research
Contact for public queries|SE, MD, MPH [phone number] [email address]
Contact for scientific queries|SE, MD, MPH~~Bernhard Nocht Institute for Tropical Medicine Hamburg, Germany
Public title|Probiotic Saccharomyces boulardii for the prevention of antibiotic associated diarrhoea (SacBo)
Scientific title|Saccharomyces boulardii for the prevention of antibiotic associated diarrhoea—randomised, double blind, placebo controlled trial
Countries of recruitment|Germany
Health condition(s) or problem(s) studied|Antibiotic treatment, Clostridium difficile, diarrhoea
Intervention(s)|Active comparator: S boulardii (500 mg S boulardii per day)~~Placebo comparator: microcristallin cellulose (matching capsules containing no active ingredients)
Key inclusion and exclusion criteria|Ages eligible for study: ≥18 years~~Sexes eligible for study: both~~Accepts healthy volunteers: no~~Inclusion criteria: adult patient (≥ 18 years), patient hospitalised . . .~~Exclusion criteria: allergy against yeast and/or Perenterol forte and/or placebos containing S cerevisiae HANSEN CBS 5926, lactose monohydrate, magnesium stearate, gelatine, sodium dodecyl sulfate, titan dioxide, microcrystalline cellulose . . .
Study type|Interventional~~Allocation: randomized~~Intervention model: parallel assignment~~Masking: double blind (subject, caregiver, investigator, outcomes assessor)~~Primary purpose: prevention~~Phase III
Date of first enrolment|June 2010
Target sample size|1520
Recruitment status|Recruiting
Primary outcome(s)|Cumulative incidence of any antibiotic associated diarrhoea (time frame: 2 years; not designated as safety issue)
Key secondary outcomes|Cumulative incidence of C difficile associated diarrhoea (time frame: 2 years; not designated as safety issue) . . .[/table]

Explanation

3. PROTOCOL VERSION

Date and version identifier.

Example

“Issue Date: 25 Jul 2005
Protocol Amendment Number: 05
Author(s): M.D.; J.H.

Revision Chronology:

Explanation

Sequentially labelling and dating each protocol version helps to mitigate potential confusion over which document is the most recent. Explicitly listing the changes made relative to the previous protocol version is also important (see Item 25). Transparent tracking of versions and amendments facilitates trial conduct, review, and oversight.[ps2id id=’funding’ target=”/]

[ps2id id=’funding’ target=”/]4. FUNDING

Sources and types of financial, material, and other support.

Example

“Tranexamic acid will be manufactured by Pharmacia (Pfizer, Sandwich, UK [United Kingdom]) and placebo by South Devon Healthcare NHS Trust, UK. The treatment packs will be prepared by an independent clinical trial supply company (Brecon Pharmaceuticals Limited, Hereford, UK)  . . .

LSHTM [London School of Hygiene & Tropical Medicine] is funding the run-in costs for the WOMAN trial and up to 2,000 patients’ recruitment. The main phase is funded by the UK Department of Health and the Wellcome Trust. Funding for this trial covers meetings and central organisational costs only. Pfizer, the manufacturer of tranexamic acid, have provided the funding for the trial drug and placebo used for this trial. An educational grant, equipment and consumables for ROTEM [thromboelastometry procedure] analysis has been provided by Tem Innovations GmbH, M.-Kollar-Str. 13-15, 81829 Munich, Germany for use in the WOMAN-ETAC study. An application for funding to support local organisational costs has been made to University of Ibadan Senate Research Grant. The design, management, analysis and reporting of the study are entirely independent of the manufacturers of tranexamic acid and Tem Innovations GmbH.” ³⁴

Explanation

A description of the sources of financial and non-financial support provides relevant information to assess study feasibility and potential competing interests (Item 28). Although both industry funded and non-industry funded trials are susceptible to bias,^4;35 the former are more likely to report trial results and conclusions that favour their own interventions.^27;36-39 This tendency could be due to industry trials being more likely to select effective interventions for evaluation (Item 6a), to use less effective control interventions (Item 6b), or to selectively report outcomes (Item 12), analyses (Item 20) or full studies (Item 31).^38;40-43 Non-financial support (e.g., provision of drugs) from industry has not been shown to be associated with biased results, although few studies have examined this issue.^44;45

At a minimum, the protocol should identify the sources of financial and non-financial support; the specific type (e.g., funds, equipment, drugs, services) and time period of support; and any vested interest that the funder may have in the trial. If a trial is not yet funded when the protocol is first written, the proposed sources of support should be listed and updated as funders are confirmed.

No clear consensus exists regarding the level of additional funding details that should be provided in the trial protocol as opposed to trial contracts, although full disclosure of funding information in the protocol can help to better identify financial competing interests. Some jurisdictional guidelines require more detailed disclosure, including monetary amounts granted from each funder, the mechanism of providing financial support (e.g., paid in fixed sum or per recruited participant), and the specific fund recipient (e.g., trial investigator, department/institute).⁴⁶ Detailed disclosure allows research ethics committees/institutional review boards (REC/IRBs) to assess whether the reimbursement amount is reasonable in relation to the time and expenses incurred for trial conduct.

[ps2id id=’contributorship’ target=”/]

5. ROLES AND RESPONSIBILITIES

5a. Contributorship

Names, affiliations, and roles of protocol contributors.

Example

“R.T.L.^*x, E.J.M. ^x, A.K.^x . . .

Authors’ contributions

RTL conceived of the study. AK, EN, SB, PR, WJ, JH, and MC initiated the study design and JK and LG helped with implementation. RTL, JK, LG, and FP are grant holders. LT and EM provided statistical expertise in clinical trial design and RN is conducting the primary statistical analysis. All authors contributed to refinement of the study protocol and approved the final manuscript.” ⁴⁷

Explanation

Individuals who contribute substantively to protocol development and drafting should have their contributions reported. As with authorship of journal articles⁴⁸ listing the protocol contributors, their affiliations, and their roles in the protocol development process provides due recognition, accountability, and transparency. Naming of contributors can also help to identify competing interests and reduce ghost authorship (Items 28 and 31b).^9;10 If professional medical writers are employed to draft the protocol, then this should be acknowledged as well.

Naming of authors and statements of contributorship are standard for protocols published in journals such as Trials⁴⁹ but are uncommon for unpublished protocols. Only five of 44 industry-initiated protocols approved in 1994-95 by a Danish research ethics committee explicitly identified the protocol authors[ps2id id=’sponsor-contact-information’ target=”/].⁹

5b. Sponsor contact information

Name and contact information for the trial sponsor.

Example

“Trial Sponsor: University of Nottingham
Sponsor’s Reference: RIS 8024 . . .
Contact name: Mr PC
Address: King’s Meadow Campus . . .
Telephone: . . .
Email: . . .” ⁵⁰

Explanation

The sponsor can be defined as the individual, company, institution, or organisation assuming overall responsibility for the initiation and management of the trial, and is not necessarily the main funder.^51;52 In general, the company is the sponsor in industry-initiated trials, while the funding agency or institution of the principal investigator is often the sponsor for investigator-initiated trials. For some investigator initiated trials, the principal investigator can be considered to be a ‘sponsor-investigator’ who assumes both sponsor and investigator roles.^51;53

Identification of the trial sponsor provides transparency and accountability. The protocol should identify the name, contact information, and if applicable, the regulatory agency identifying number of the sponsor.[ps2id id=’sponsor-and-funder’ target=”/]

5c. Sponsor and funder

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.

Example

“This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results.” ⁵⁴

Explanation

There is potential for bias when the trial sponsor or funder (sometimes the same entity) has competing interests (Item 28) and substantial influence on the planning, conduct, or reporting of a trial. Empirical research indicates that specific forms of bias tend to be more prevalent in trials funded by industry compared to those funded by non-commercial sources.^{36-38;45;55-60}

The design, analysis, interpretation, and reporting of most industry-initiated trials are controlled by the sponsor; this authority is often enforced by contractual agreements signed between the sponsor and trial investigators (Item 29).^10;61

The protocol should explicitly outline the roles and responsibilities of the sponsor and any funders in study design, conduct, data analysis and interpretation, manuscript writing, and dissemination of results. It is also important to state whether the sponsor or funder controls the final decision regarding any of these aspects of the trial.

Despite the importance of declaring the roles of the trial sponsor and funders, few protocols explicitly do so. Among 44 protocols for industry-initiated trials receiving ethics approval in Denmark from 1994-95, none stated explicitly who had contributed to the design of the trial[ps2id id=’committees’ target=”/].⁹

5d. Committees