Authors: Joanne Bradbury and Sandra Grace
In many ways, N-of-1 trials are well-suited to complementary and alternative medicine (CAM) research. CAM practitioners use patient-centred approaches to treatment that are readily extended to individually-tailored research processes (1). CAM practice is underpinned by the principles of treating the whole person (tolle totum) and treating the cause (tolle causam) of disease, rather than the symptoms (2). CAM practitioners are trained to take all aspects of a person into account when performing assessments and prescribing interventions. Such an approach facilitates identifying the underlying causes of conditions, which typically takes time to identify and, in many cases, considerable time to address. However, a number of challenges arise when implementing N-of-1 trials in CAM research, including slow onset of therapeutic effect and long washout periods.
N-of-1 trials are best indicated to test the efficacy of short-acting interventions in chronic, symptomatic diseases (3). Such circumstances lend themselves well to the requirements of an N-of-1 trial to have multiple exposures to intervention and control conditions in a randomised order to compare outcomes on the active intervention and placebo, typically under double blinded conditions (4). However, many CAM interventions take time to act physiologically. For example, probiotics take time to be incorporated into the gut microbiota and fish oil takes time to be incorporated into cell membranes.
The implications of a slow onset therapeutic effect are that: (i) the phases of the trial design need to be long enough to capture any change, and (ii) they require a long washout of the substance after cessation of application. Figure 1 is an example of an N-of-1 trial which required a 2 week washout period between each exposure. N-of-1 trials are best suited to test interventions that are rapidly withdrawn. Interventions that are likely to have a sustained effect over time risk contamination in the subsequent exposure conditions (e.g. fat soluble nutritients such as fish oil) (5). This can be addressed by adding ‘washout’ periods between exposures (e.g. A period – washout period – B period), or by deleting the data that may be contaminated if the time it takes to be washed out is known. However, these washout periods can be 3 – 4 weeks, which adds considerable time to the duration of the N-of-1 trial. Long trials may increase participant burden and the likelihood of attrition and other extraneous factors such as seasonal variation impacting on the trial outcomes.
Figure 1: Hypothetical N-of-1 trial design in complementary medicine
One approach that can be used to overcome some of the challenges described above of using N-of-1 trials in CAM, is to use a Multiple Baseline Design (MBD). N-of-1 trials and MBD are both part of a family of research designs called ‘single-case designs’. MBD trials may be more suited to CAM trials (6). They require only one cycle (A B) (but can have more), reduce the need for multiple washout periods and shorten the duration of the trial, but still accommodate individualised and slower acting interventions (5). Participants are randomised to start taking the active intervention at different times. MBD trials usually need a minimum of three patients (see Figure 2). In trials with only one patient, a baseline ABAB follow-up design is more rigorous. Alternatively, a baseline AB follow-up design can be used if two cycles are not practical.
Figure 2: Hypothetical MBD design in complementary medicine
Arguably, single-case designs are better suited to CAM research than group-based clinical trials because they accommodate the patient-centred focus. A key aspect of holistic CAM treatment is the focus on the therapeutic relationship, in which the patient’s preferences are integrated with practitioner expertise and best available evidence in the determination of the treatment plan. Recognising patient perspectives on their health empowers patients (7) and may increase compliance with treatment plans over time. The same rationale can be applied to single-case designs in practice.
If patient-reported outcome measures (PROMS) (8) are used as the primary outcome, then the design of the trial is centred around the patient’s perceived improvements. For example, patient-specific functions scales (PSFS) (9) are simple visual analogue scales based on an aspect of functional ability that the patient has nominated. The patient may nominate several physical functions they would like to see improved by an intervention. In our recent N-of-1 trial on probiotics in osteoarthritis (10), these included walking, walking upstairs, and sweeping. If the intervention helps these functions by a minimal clinically important difference compared to a placebo or baseline, then the intervention is considered effective. This patient-centred approach to research is strongly aligned with the principles of holism practised by many CAM practitioners.
While the implementation of single-case designs in CAM can be associated with practical challenges, adopting different types of single-case designs can help to ensure high quality and patient-centred outcomes in CAM research and practice.
About the Authors
Dr Joanne Bradbury is a clinical and health services researcher with interests in nutrition and mental health. She has a Ph.D. in nutritional pharmacology, and her current research interests include nutrition and complementary medicine, stress and positive mental health, and research methods and biostatistics. She is currently appointed as a Senior Lecturer, Evidence-Based Healthcare at Southern Cross University.
is a professor of Osteopathy and Integrative Medicine. Her research interests include models of primary care, program evaluation and interprofessional education and practice. She established the Osteopathic Research Alliance in 2017 and co-founded the Southern Cross University N-of-1 Clinical Trials Group.
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