Study in progress!
Authors: Dr Jane Nikles, A/Prof. John O’Sullivan, Prof. Geoff Mitchell, Dr Alex Ritchie, A/Prof. Simon Smith, Dr Hugh Senior, A/Prof James McGree, and Dr Nadeeka Dissanayaka.
Background
This study will close a current gap in knowledge and improve quality of life for the 40% of Parkinson’s Disease (PD) sufferers currently experiencing insomnia. This has impact on health and quality of life for both patients and their family members, especially if the latter include carers. Sleep disorders often cause major discomfort and morbidity in PD, but there is limited research into treatment for sleep disturbance in PD and little evidence that current treatments are effective. A small number of studies have investigated different drugs, cognitive behaviour therapy, and even caffeine, but the results have not been sufficiently convincing to recommend any of these treatments for the long-term treatment of sleep-related problems in people with PD. There is emerging evidence that PD has many features exhibiting daily fluctuations, suggestive of circadian rhythm disturbances, which result in sleep disorders.
Melatonin is a hormone released by the pineal gland which regulates the sleep-wake cycle, temperature regulation, reproductive rhythm, and immune function. Melatonin regulates the circadian rhythm by promoting the desire to sleep at night. Studies in other populations indicate that melatonin can increase sleep efficiency, decrease night-time activity, and shorten sleep latency, and may be particularly effective to help promote sleep onset. Little research exists on the use of melatonin in PD. Melatonin has been investigated in a couple of small trials with equivocal results. There is some evidence it might help insomnia in PD. The response rate to melatonin in people with PD and insomnia is not known. It is important to identify those people who do respond to melatonin. N-of-1 trials provide a means to do this.
N-of-1 trials are clinical trials that involve a single patient, with the patient serving as their own control. This means the subject’s individual response to a treatment is compared to their response to placebo, over a number of cycles. They are the most powerful means of proving whether a treatment works in an individual or not. They are a very patient-oriented and clinically-relevant method, which facilitates rapid translation of personalised evidence into practice.
Study Aims
To use N-of-1 trials to improve the precision of clinical decision-making in prescribing melatonin for individual adults with PD and insomnia, by identifying individual responders and non-responders to melatonin.
To aggregate group data from a series of N-of-1 trials to arrive at population estimates of the effectiveness (measured by improvements in PD Sleep Scale-2) and safety (measured by adverse events) of melatonin in improving sleep quality in PD.
To assess feasibility of offering N-of-1 trials for insomnia to all suitable people with PD.
Expected outcomes
The project has a high potential to provide an additional therapeutic option for the treatment of insomnia in PD. Using N-of-1 trials to identify those people with PD who respond to melatonin is a novel approach. The study will provide direct and immediate feedback to individual participants about the effectiveness of melatonin for them. It will also determine whether it is feasible to use N-of-1 trials in this group of patients.
Benefits
The use of N-of-1 methodology makes the findings more personally relevant for participants and increases the likelihood of translation of evidence into practice within a viable timeframe. N-of-1 trials can also be aggregated to produce an estimate of treatment effect for the whole population, requiring less than half the number of participants of a comparable randomised controlled trial. This means strong evidence of effect is possible to obtain even where it may be difficult to recruit the number of patients required for a standard RCT, which is particularly relevant in low prevalence diseases such as PD.
Significance
There has been little research into melatonin for insomnia in PD. As melatonin is a potentially useful and relatively safe therapy, there have been calls for further research in this area. As not all older adults respond to melatonin, using N-of-1 trials to identify PD patients who respond would be useful. The N-of-1 design provides a method to determine response and benefit for every individual patient. This approach could help patients move more quickly through a treatment pathway – e.g. if a patient is a non-responder, then an alternative could be trialled earlier, and the patient would not be subjected to a medicine that does not work for them. After each individual trial, patients will discuss their results with their doctor based on an individual report provided by research staff. Thus, the trial will provide direct and immediate feedback to individual patients and their doctors about the effectiveness of melatonin for them.
Aggregated N-of-1 trials can reduce the sample size required, compared to an RCT, to produce a group estimate of effect, because of their greater power (3 crossovers). This has implications in low prevalence diseases such as PD (0.3% of the general population). Although cognitive behaviour therapy for insomnia is current ‘first line’ treatment (recommended by peak bodies including the National Institutes of Health, National Heart, Lung, and Blood Institute and the American Sleep Association), melatonin may become a useful additional/alternative therapy for insomnia in PD. Also, if N-of-1 trials are feasible to introduce in standard practice, the ongoing identification of responders to melatonin would be of benefit. We anticipate that this study may ultimately broaden the therapeutic options available to clinicians, PD sufferers and their families.
The study is currently recruiting. For more information, please see the study website.
Blog contributed by Shahiq Rizvi & Chloe McKillop
- Shahiq is currently a third-year medical student at the University of Queensland. His research interests revolve around optimising perception practices and service delivery.
- Chloe is a second-year medical student at the University of Queensland. Her interest in clinical research stems from a desire to help improve current treatment options and enhance patient care.
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