Randomised and Controlled Trials The Unofficial Guide by Goadsby&Gould

Why do a randomised controlled trial? “Randomised controlled trials are the most rigorous way of determining whether a cause-effect relation exists between treatment and outcome and for assessing the cost effectiveness of a treatment.” “Other study designs, including non-randomised controlled trials, can detect associations between an intervention and an outcome. But they cannot rule out the possibility that the association was caused by a third factor linked to both intervention and outcome” Understanding controlled trials: Why are randomised controlled trials important? BMJ 1998;316:201

Identify and Eliminate Spurious Correlation Per capita consumption of mozzarella cheese (US) Per capita consumption of mozzarella cheese (US) correlates with Civil engineering doctorates awarded (US) Civil engineering doctorates awarded (US) Spurious: not what it purports to be; false or fake

How does a RCT work?

Conduct of the trial Eligible patient presents Consents Randomised ControlNew Treatment Assessment

Define clinical trial Any form of planned experiment which involves patients and is designed to elucidate the most appropriate method of treatment of future patients with a given medical condition

Define randomisation Random allocation of participants into study groups wherein each participant has an equal chance of being put into each group, analogous to flipping a coin

What are the advantages of random allocation? [4] Gives equal chance of receiving each treatment In long run leads to groups that are likely to be similar in characteristics by chance Reduces selection bias if patients enter trial before randomisation Is used in other experimental settings

What is the placebo effect? The psychological benefit gained from being treated, even if the treatment has no physiological effects “the illness itself, may be improved by a feeling that something is being done about it”

What is a placebo? Why is it used? An inert substance which is identical (in terms of appearance, taste and packaging) to the treatment being investigated Blinding: Aims to remove differential placebo effect that could bias comparison between treatments – Double blind vs. Single Blind

In what situation would a placebo not be used? When there is an existing standard treatment

Clinical equipoise - is there reasonable uncertainty about what is the best treatment? Scientifically robust - is the sample size big enough to gain a clinically important effect? Is the question being asked relevant? Informed consent - has it been taken? Written or verbal? Name and explain TWO ethical issues that you will consider when advising the patient about the RCT [2+2]

How can informed consent issues be overcome? [3] Explain what the different treatment groups are Explain allocation is random Explain the patient may withdraw at any time (verbally and written)

Nick has started a trial looking at the comfort of Slazenger vs. Donnay black socks. He initially has 160 medical students equally split into the Slazenger and Donnay group. At the end of the trial 30 people have dropped out from the Slazenger group and 23 from the Donnay group. Nick only analyses those who complete the study. What kind of analysis is this? What kind of analysis is most clinically relevant? As treated analysis Intention-to-treat

As-Treated analysis = had the new treatment + had the standard treatment/placebo. Not those who dropped out! Lose effects of randomisation – non-compliers may be systematically different to compliers Intention-to-treat = effect as measured on all initial participants. Includes those who discontinued! Better reflection of likely effect in clinical practice.

“Although randomised controlled trials are powerful tools, their use is limited by ethical and practical concerns”