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Background and rationale

Item 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of research question and justification for undertaking the trial, including summary of relevant studies (published and unpublished) examining benefits and harms for each intervention.

Example

Background
Introduction: For people at ages 5 to 45 years, trauma is second only to HIV/AIDS as a cause of death . . .

Mechanisms: The haemostatic system helps to maintain the integrity of the circulatory system after severe vascular injury, whether traumatic or surgical in origin.[Reference X] Major surgery and trauma trigger similar haemostatic responses . . . Antifibrinolytic agents have been shown to reduce blood loss in patients with both normal and exaggerated fibrinolytic responses to surgery, and do so without apparently increasing the risk of post-operative complications . . .

Existing knowledge: Systemic antifibrinolytic agents are widely used in major surgery to prevent fibrinolysis and thus reduce surgical blood loss. A recent systematic review [Reference X] of randomised controlled trials of antifibrinolytic agents (mainly aprotinin or tranexamic acid) in elective surgical patients identified 89 trials including 8,580 randomised patients (74 trials in cardiac, eight in orthopaedic, four in liver, and three in vascular surgery). The results showed that these treatments reduced the numbers needing transfusion by one third, reduced the volume needed per transfusion by one unit, and halved the need for further surgery to control bleeding. These differences were all highly statistically significant. There was also a statistically non-significant reduction in the risk of death (RR=0.85: 95% CI 0.63 to 1.14) in the antifibrinolytic treated group
. . .
Need for a trial: A simple and widely practicable treatment that reduces blood loss following trauma might prevent thousands of premature trauma deaths each year and secondly could reduce exposure to the risks of blood transfusion. Blood is a scarce and expensive resource and major concerns remain about the risk of transfusion-transmitted infection . . . A large randomised trial is therefore needed of the use of a simple, inexpensive, widely practicable antifibrinolytic treatment such as tranexamic acid . . . in a wide range of trauma patients who, when they reach hospital are thought to be at risk of major haemorrhage that could significantly affect their chances of survival.

Dose selection
The systematic review of randomised controlled trials of antifibrinolytic agents in surgery showed that dose regimens of tranexamic acid vary widely.[Reference X] . . .

In this emergency situation, administration of a fixed dose would be more practicable as determining the weight of a patient would be impossible. Therefore a fixed dose within the dose range which has been shown to inhibit fibrinolysis and provide haemostatic benefit is being used for this trial . . . The planned duration of administration allows for the full effect of tranexamic acid on the immediate risk of haemorrhage without extending too far into the acute phase response seen after surgery and trauma.” 65

Explanation

The value of a research question, as well as the ethical and scientific justification for a trial, depend to a large degree on the uncertainty of the comparative benefits or harms of the interventions, which depends in turn on the existing body of knowledge on the topic. The background section of a protocol should summarise the importance of the research question, justify the need for the trial in the context of available evidence, and present any available data regarding the potential effects of the interventions (efficacy and harms).66;67 This information is particularly important to the trial participants and personnel, as it provides motivation for contributing to the trial.69 It is also relevant to funders, REC/IRBs, and other stakeholders who evaluate the scientific and ethical basis for trial conduct.

To place the trial in the context of available evidence, it is strongly recommended that an up-to-date systematic review of relevant studies be summarised and cited in the protocol.70 Several funders request this information in grant applications.71;72 Failure to review the cumulated evidence can lead to unnecessary duplication of research or to trial participants being deprived of effective, or exposed to harmful, interventions.73-76 A minority of published trial reports cite a systematic review of pre-existing evidence,77;78 and in one survey only half of trial investigators were aware of a relevant existing review when they had designed their trial.79 Given that about half of trials remain unpublished,80-82 and that published trials often represent a biased subset of all trials,80;83 it is important that systematic reviews include a search of online resources such as trial registries, results databases, and regulatory agency websites.84

5d: Committees 6b: Choice of comparators
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