BMJ 2014;348:g2674 doi: 10.1136/bmj.g2674 (Published 10 April 2014)
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Endgames
ENDGAMES STATISTICAL QUESTION
What is an “n-of-1” trial? Philip Sedgwick reader in medical statistics and medical education Centre for Medical and Healthcare Education, St George’s, University of London, London, UK
Researchers assessed the effectiveness of “n-of-1” trials for the short term choice of drugs for osteoarthritis. The efficacy of sustained release paracetamol was compared with celecoxib in the management of symptoms associated with osteoarthritis. A series of double blind randomised n-of-1 controlled trials using a double dummy design was performed. The intervention was sustained release paracetamol (two 665 mg tablets, three times a day), or celecoxib (200 mg daily, or 200 mg twice a day for those who were already using this dose). Each treatment regimen was taken for two weeks, administered for three treatment cycles. The primary outcome measures included pain, stiffness, and functional limitation scores; preferred treatment; and adverse effects.1 Participants were eligible if they had osteoarthritis in multiple sites, with pain for at least one month. In addition, their pain was severe enough to warrant consideration of the long term use of celecoxib, but the efficacy of this drug was in doubt. In total, 59 patients were recruited, with 41 completing an n-of-1 trial. It was reported that 33 of the 41 patients could not identify a difference between sustained release paracetamol and celecoxib in terms of overall symptom relief. Of the eight patients who were able to identify differences, seven reported better relief with celecoxib and one with sustained release paracetamol. It was concluded that n-of-1 trials may provide a rational and effective method to help choose the most effective drug for patients with osteoarthritis. Which of the following statements, if any, are true? a) Patients received both paracetamol and celecoxib b) All patients received a placebo c) Each patient acted as his or her own control d) The patient was the unit of randomisation
Answers
Statements a, b, and c are true, whereas d is false.
Advisory guidelines based on results from clinical trials recommend paracetamol as the agent of first choice in managing the symptoms associated with osteoarthritis. Nonetheless, some patients, particularly those with moderate to severe pain or those whose pain is unresponsive to paracetamol, prefer non-steroidal
anti-inflammatory drugs (NSAIDs). One of the aims of the above study was to compare the short term efficacy on an individual basis of sustained release paracetamol with celecoxib, a subtype 2 specific NSAID. A series of double blind randomised “n-of-1” controlled trials was performed. The n-of-1 trial, sometimes referred to as a single patient trial, receives its name by virtue of its sample size: n is equal to one. The n-of-1 trial is a randomised controlled crossover trial in a single patient. The n-of-1 trial provides a pragmatic approach to individual patient care. The patient receives each treatment, with the treatment order decided at random. Each trial is analysed separately, with the outcomes compared within the patient to establish the optimal treatment for that patient. In the above study, each patient received both sustained release paracetamol and celecoxib in their n-of-1 trial (a is true). The treatments were taken separately, one after the other, with each drug given for two weeks. The pair of treatments—two weeks of sustained release paracetamol and two weeks of celecoxib, was referred to as the treatment cycle. The treatment order in a cycle was decided at random. Each patient received three treatment cycles. It is generally recommended that an n-of-1 trial includes a minimum of three cycles of treatment to enable the correct decisions about patient care to be made. To minimise assessor and response biases, it was essential that the recruiting clinicians, patients, and outcome assessors were blinded to treatment allocation in the above trial.2 Double blinding was possible only by using the double dummy study design, as described in a previous question,3 for each n-of-1 trial. This involved the manufacture of two placebos, with each patient taking both placebos in each treatment cycle (b is true). The intervention was paracetamol (two 665 mg tablets, three times a day) or celecoxib (200 mg daily, or 200 mg twice a day for those who were already using this dose). Because it was not possible to manufacture paracetamol and celecoxib in a form that was indistinguishable from one another, a placebo was needed for each drug—that is, paracetamol (665 mg) placebo and celecoxib (200 mg) placebo. Therefore, when patients were taking celecoxib, they also received a paracetamol placebo (two tablets, three times a day). When taking paracetamol, each
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BMJ 2014;348:g2674 doi: 10.1136/bmj.g2674 (Published 10 April 2014)
Page 2 of 2
ENDGAMES
patient also received a celecoxib placebo—either once or twice daily, depending on the dose they were taking when recruited.
The n-of-1 trial has a within subject design, with outcomes for treatments compared within patients so that the optimal treatment for the patient can be established. Therefore, each patient acted as his or her own control (c is true). The n-of-1 trial is similar in design to the traditional randomised crossover trial, described in a previous question.4 In a randomised crossover trial, patients are randomised to one of two interventions and then they receive the other intervention after a washout period. Although both study designs compare outcomes within subjects, there are noticeable differences between them. In an n-of-1 trial, the unit of randomisation is the treatment order within a treatment cycle for a patient (d is false). This is in contrast to the randomised crossover trial, where the patient is the unit of randomisation. In a randomised crossover trial, participants typically receive only one cycle of treatment, whereas in an n-of-1 trial they receive at least two cycles. In particular, the n-of-1 trial establishes which treatment is best for a patient. In comparison, the traditional crossover trial design estimates which treatment is best for the population. Despite the dissimilarities between the two study designs, they are both suitable only for studying chronic stable conditions that are not resolved by treatment. The traditional randomised controlled superiority trial has become the standard for assessing the efficacy of treatments in
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clinical medicine.5 The assumption that the observed treatment effects can be generalised to all patients in the population underlies the inferences made from such trials. However, this assumption is unlikely to be true. Patients in the population will differ in their response to a treatment and may even benefit from the treatment shown to be inferior in a trial. Therefore, the uniqueness of patients may need to be accounted for in clinical practice. The n-of-1 trial provides data on individual responses to treatment options. The study design provides rigorous information on the efficacy of treatment, permitting the optimal treatment to be identified for the individual patient. Nonetheless, the n-of-1 trial is not always a rational and effective study design for all conditions, and its usefulness in identifying the optimal treatment for individual patients might warrant investigation. Competing interests: None declared. 1 2 3 4 5
Yealland MJ, Nikles CJ, McNairn N, Del Mar CB, Schluter PJ, Brown RM. Celecoxib compared with sustained-release paracetamol for osteoarthritis: a series of n-of-1 trials. Rheumatology 2007;46:135-40. Sedgwick P. Bias in clinical trials. BMJ 2011;342:d4176. Sedgwick P. Double dummy trials. BMJ 2011;343:d7294. Sedgwick P. Crossover trials. BMJ 2012;344:e3710. Sedgwick P. What is a superiority trial? BMJ 2013;347:f5420.
Cite this as: BMJ 2014;348:g2674 © BMJ Publishing Group Ltd 2014
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