Item 9a: Scientific background and rationale, including summary of relevant studies (published and unpublished) examining benefits and harms for each intervention.

Example

“1.  Background

[Introduction]: Over 300 million people undergo major surgical procedures annually.[reference] A significant proportion of patients experiences perioperative neurocognitive disorders (NCDs) after surgery including delirium and postoperative neurocognitive disorder (P-NCD) (mild and major P-NCD)…

[Existing knowledge]: In recent years, dexmedetomidine (DEX) has gained attention for its potential perioperative therapeutic effects. DEX is a potent and selective α2 receptor (α2R) agonist approved for procedural sedation by anaesthesiologists or as a sedative in the intensive care unit (ICU). Recent studies indicate that DEX reduces postoperative delirium after cardiac and non-cardiac surgery.[references to systematic review and individual randomised trials]

[Mechanisms]: In murine models, DEX reduces anaesthetic/surgery-induced learning and memory deficits from propofol, etomidate, benzodiazepines and halogenated inhalational anaesthetics.[references] These salutary effects on learning and memory have also been demonstrated when DEX is administered in murine models of sepsis without any surgical insult or anaesthetic exposure.[references] The mechanisms of DEX neuroprotection are proposed to be both direct and indirect. Directly, it has opioid/GABA-ergic drug-sparing effects.[reference] Indirectly, it has anti-inflammatory effects in the CNS and is protective of neuro-apoptosis.[reference] The synergistic anaesthetic sparing and anti-inflammatory effects of DEX in the CNS [central nervous system] could reduce the incidence of major P-NCD after open cardiac surgery, the surgical population with the highest observed risk…

[Need for a trial]: The evidence for DEX reducing major P-NCD, while biologically plausible, is limited by suboptimal outcome measurement in terms of both neurocognitive assessments and the dose of DEX highlighting the need for a large, well-designed trial.

With approximately 300 000 open cardiac procedures occurring yearly in North America, the burden of P-NCD is enormous. Currently, there are no interventions to prevent persistent cognitive impairment after surgery. Thus, effective mitigation strategies for major P-NCD are urgently needed” [138].

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“[Introduction]: Traumatic brain injury (TBI) is a significant public health concern and represents the leading cause of mortality and long-term disability in young adults [reference]…

[Mechanism]: the cerebral autoregulation that normally compensates for variations in oxygen delivery is impaired,[reference] rendering their brain vulnerable to ischaemia and secondary injuries. In the absence of high-quality evidence, several experts have suggested maintaining higher haemoglobin (Hb) levels (>100 g/L) on the assumption that it reduces metabolic distress and improves brain tissue oxygenation [references]…

[Existing evidence]: The evidence to support transfusion strategies in patients with TBI remains scarce. In a systematic review of studies in neurocritical care patients, we found insufficient evidence to support the use of a specific transfusion threshold to improve morbidity and mortality.[reference] A recent randomized controlled trial showed no effect of red blood cell (RBC) transfusion on neurological outcomes in patients with moderate or severe TBI, although the expected effect size was large and most patients included were not anaemic [reference]…

[Need for a trial]: To date, clinical practice guidelines are based on limited evidence and do not provide clear recommendations regarding RBC transfusion in TBI.[references] As a result, transfusion practices vary greatly within and between centres [references]; many clinicians extrapolate the evidence supporting the non-inferiority of a restrictive strategy in critically ill patients without TBI [references] while others advocate for a liberal transfusion strategy pending stronger evidence to support this practice [reference]..." [139].

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Explanation

The ethical and scientific justification for a trial depends on the uncertainty of the benefit or harm of the intervention to be tested. This uncertainty depends in turn on what is known on the topic before the trial commences. The background section of a protocol should summarise the relevance of the research question, justify the need for the trial in the context of available evidence, and present any available preliminary data regarding the potential effects of the interventions (benefits and harms), thus reporting a rationale for the trial.

This information is particularly important to the trial participants, as it provides motivation for contributing to the trial [140]. It is also relevant to funders, research ethics committees/institutional review boards, and other groups who evaluate the scientific and ethical basis for trial approval. The background should also present a plausible explanation for how the intervention might work. Understanding the rationale or theory underpinning an intervention helps readers to understand which aspects or components are likely to be essential to its efficacy or harm, and which are likely to be incidental [24]. 

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Reviews of two samples of 108 and 292 trial protocols from 2016 found that 44% and 26% justified the research question, respectively [9,10].

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The World Medical Association’s Declaration of Helsinki states that biomedical research involving people should be based on a thorough knowledge of the scientific literature, as it is unethical to expose humans unnecessarily to the risks of research [2]. To place the trial in the context of available evidence, it is strongly recommended that an up-to-date, systematic review of relevant trials be summarised and cited in the protocol, or in the absence of a published review, that the protocol authors systematically identify and summarise previous trials [141, 142].  This evidence can also help researchers to optimise the usefulness of the new trial by informing design aspects such as outcome definition and sample size [143-145].

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Several funders request this background information in grant applications [146, 147]. Failure to review the cumulative evidence can lead to unnecessary and wasteful duplication of research [148] or to trial participants being deprived of effective interventions, or exposed to harmful interventions [144, 149-151]. Prior reviews of trial protocols have found that many do not cite the systematic reviews or trials that exist on the same topic [152-154]. 

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Summary of key elements to address

• Importance of the research question

• Why a new trial is needed in the context of available evidence

  • Explanation of how the intervention might work

  • Pretrial evidence of the benefits and harms of the interventions

  • Reference to systematic review(s) of relevant trials; if none is available, a summary of relevant trials based on a systematic search

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