Giving weight to incretin-based pharmacotherapy for obesity-related sleep apnea: a revolution or a pipe dream?

Obesity is a chronic disease affecting over 670 million adults globally, with multiple complications including obstructive sleep apnea (OSA). Substantial weight loss in patients with obesity-related OSA can reduce or even eliminate OSA as well as reduce sleepiness and improve cardio-metabolic health. Evidence suggests that these improvements exceed those that occur with device-based OSA therapies like continuous positive airway pressure which continue to be the first-line of therapy. Resistance to weight management as a first-line strategy to combat OSA could arise from the complexities in delivering and maintaining adequate weight management, particularly in sleep clinic settings. Recently, incretin-based pharmacotherapies including glucagon-like peptide 1 (GLP-1) receptor agonists alone or combined with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been developed to target glycemic control in type 2 diabetes. These medications also slow gastric emptying and reduce energy intake. In randomized, placebo-controlled trials of these medications in diabetic and non-diabetic populations with obesity, participants on active medication lost up to 20% of their body weight, with corresponding improvements in blood pressure, lipid levels, physical functioning, and fat mass loss. Their adverse effects are predominantly gastrointestinal-related, mild, and transient. There are trials currently underway within individuals with obesity-related OSA, with a focus on reduction in weight, OSA severity, and cardio-metabolic outcomes. These medications have the potential to substantially disrupt the management of OSA. Pending coming data, we will need to consider pharmacological weight loss as a first-line therapy and how that influences training and management guidelines.

Safety of higher doses of melatonin in adults: A systematic review and meta-analysis.

Melatonin is commonly used for sleep and jetlag at low doses. However, there is less documentation on the safety of higher doses, which are being increasingly used for a wide variety of conditions, including more recently COVID-19 prevention and treatment. The aim of this review was to investigate the safety of higher doses of melatonin in adults. Medline, Scopus, Embase and PsycINFO databases from inception until December 2019 with convenience searches until October 2020. Randomised controlled trials investigating high-dose melatonin (≥10 mg) in human adults over 30 years of age were included. Two investigators independently abstracted articles using PRISMA guidelines. Risk of bias was assessed by a committee of three investigators. 79 studies were identified with a total of 3861 participants. Studies included a large range of medical conditions. The meta-analysis was pooled data using a random effects model. The outcomes examined were the number of adverse events (AEs), serious adverse events (SAEs) and withdrawals due to AEs. A total of 29 studies (37%) made no mention of the presence or absence of AEs. Overall, only four studies met the pre-specified low risk of bias criteria for meta-analysis. In that small subset, melatonin did not cause a detectable increase in SAEs (Rate Ratio = 0.88 [0.52, 1.50], p = .64) or withdrawals due to AEs (0.93 [0.24, 3.56], p = .92), but did appear to increase the risk of AEs such as drowsiness, headache and dizziness (1.40 [1.15, 1.69], p < .001). Overall, there has been limited AE reporting from high-dose melatonin studies. Based on this limited evidence, melatonin appears to have a good safety profile. Better safety reporting in future long-term trials is needed to confirm this as our confidence limits were very wide due to the paucity of suitable data.

Development and validation of a model for diagnosis of obstructive sleep apnoea in primary care.

BACKGROUND AND OBJECTIVE: Use of in-laboratory polysomnography (PSG) to diagnose obstructive sleep apnoea (OSA) is cost and resource intensive. Questionnaires, physical measurements and home monitors have been studied as potential simpler alternatives. This study aimed to develop a diagnostic model for OSA for use in primary care. METHODS: Primary care practitioners were trained to recognize symptoms of sleep apnoea and recruited patients based on the clinical need to investigate OSA. Assessment was by symptom questionnaires, anthropomorphic measurements, digital facial photography, and a single-channel nasal flow monitor (Flow Wizard©, DiagnoseIT, Sydney, Australia) worn at home for 3 nights. The in-laboratory PSG was the reference test, with OSA defined as apnoea-hypopnoea index (AHI) ≥10 events/h. RESULTS: In the model development phase, 25 primary care practitioners studied 315 patients in whom they suspected OSA, of which 57% had AHI≥10 and 22% had AHI≥30. Published OSA questionnaires provided low to moderate prediction of OSA (area under the curve [AUC] 0.53-0.73). The nasal flow monitor alone yielded high accuracy for predicting OSA with AUC of 0.87. Sensitivity was 0.87 and specificity 0.77 at a threshold respiratory event index (REI) of 18 events/h. A model adding age, gender, symptoms and BMI to the nasal flow monitor REI only modestly improved OSA prediction (AUC 0.89), with similar AUC (0.88) confirmed in the validation population of 114 patients. CONCLUSION: Sleep apnoea can be diagnosed in the primary care setting with a combination of clinical judgement and portable monitor test outcomes.

Feasibility of 3-month melatonin supplementation for brain oxidative stress and sleep in mild cognitive impairment: protocol for a randomised, placebo-controlled study.

INTRODUCTION: Melatonin has multiple proposed therapeutic benefits including antioxidant properties, synchronisation of the circadian system and lowering of blood pressure. In this protocol, we outline a randomised controlled trial to assess the feasibility, acceptability and tolerability of higher dose (25 mg) melatonin to target brain oxidative stress and sleep disturbance in older adults with mild cognitive impairment (MCI). METHODS AND ANALYSIS: The study design is a randomised double-blind, placebo-controlled, parallel group trial. Forty individuals with MCI will be recruited from the Healthy Brain Ageing Clinic, University of Sydney and from the community, and randomised to receive either 25 mg oral melatonin or placebo nightly for 12 weeks. The primary outcomes are feasibility of recruitment, acceptability of intervention and adherence to trial medication at 12 weeks. Secondary outcomes will include the effect of melatonin on brain oxidative stress as measured by magnetic resonance spectroscopy, blood pressure, blood biomarkers, mood, cognition and sleep. Outcomes will be collected at 6 and 12 weeks. The results of this feasibility trial will inform a future conclusive randomised controlled trial to specifically test the efficacy of melatonin on modifiable risk factors of dementia, as well as cognition and brain function. This will be the first trial to investigate the effect of melatonin in the population with MCI in this way, with the future aim of using this approach to reduce progression to dementia. ETHICS AND DISSEMINATION: This protocol has been approved by the Sydney Local Health District Ethics Committee (X18-0077). This randomised controlled trial will be conducted in compliance with the protocol published in the registry, the International Conference for Harmonisation on Good Clinical Practice and all other applicable regulatory requirements. The findings of the trial will be disseminated via conferences, publications and media, as applicable. Participants will be informed of results of the study at the conclusion of the trial. Eligible authors will include investigators who are involved in the conception and design of the study, the conduct of the trial, the analysis of the results, and reporting and presentation of study findings. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ANZCTRN 12619000876190). PROTOCOL VERSION: V.8 15 October 2020.

The association of insomnia disorder characterised by objective short sleep duration with hypertension, diabetes and body mass index: A systematic review and meta-analysis.

Insomnia disorder with objective short sleep duration (less than 6 h of objective sleep or sleep efficiency less than 85%) has been considered as a biologically severe subtype of insomnia associated with a higher risk of cardiometabolic disease morbidity. This systematic review and meta-analysis firstly compared insomnia disorder with objective short and normal sleep duration, and subsequently, objective short sleep duration with and without insomnia disorder, and their associations with hypertension, type 2 diabetes and body mass index. A systematic search of five databases yielded 2345 non-duplicated articles, of which 11 individual studies were used for the qualitative review and 10 individual studies for the meta-analysis. The sample size varied from 30 to 4994 participants. A higher risk of hypertension (RR 1.54, 95% CI: [1.30; 1.82] p < 0.0001) and type 2 diabetes (RR 1.63 [1.37; 1.94], p < 0.0001) was associated with insomnia disorder with objective short sleep compared to normal sleep duration, but not for body mass index. Comparisons between insomnia disorder with objective short sleep and objective short sleep without insomnia disorder showed no significant differences. However, the majority of these studies were cross-sectional, and there is a need for more cohort study data.

Does craniofacial morphology relate to sleep apnea severity reduction following weight loss intervention? A patient-level meta-analysis.

STUDY OBJECTIVES: Obesity is a common and reversible risk factor for obstructive sleep apnea (OSA). However, there is substantial unexplained variability in the amount of OSA improvement for any given amount of weight loss. Facial photography is a simple, inexpensive, and radiation-free method for craniofacial assessment. Our aims were (1) to determine whether facial measurements can explain OSA changes, beyond weight loss magnitude and (2) whether facial morphology relates to how effective weight loss will be for OSA improvement. METHODS: We combined data from three weight loss intervention trials in which participants had standardized pre-intervention facial photography (N = 91; 70.3% male, mean ± SD weight loss 10.4 ± 9.6% with 20.5 ± 51.2% apnea-hypopnea index [AHI] reduction). Three skeletal-type craniofacial measurements (mandibular length, lower face height, and maxilla-mandible relationship angle) were assessed for relationship to AHI change following weight loss intervention. RESULTS: Weight and AHI changes were moderately correlated (rho = 0.3, p = 0.002). In linear regression, an increased maxilla-mandible relationship angle related to AHI improvement (ß [95% CI] -1.7 [-2.9, -0.5], p = 0.004). Maxilla-mandible relationship angle explained 10% in the variance in AHI over the amount predicted by weight loss amount (20%). The relationship between weight change and AHI was unaffected by the maxilla-mandible relationship angle (interaction term p > 0.05). CONCLUSIONS: Regardless of facial morphology, weight loss is similarly moderately predictive of OSA improvement. Increased maxilla-mandible relationship angle, suggestive of retrognathia, was weakly predictive of OSA response to weight loss. Although this is unlikely to be clinically useful, exploration in other ethnic groups may be warranted.

Objective measurement of sleep in mild cognitive impairment: A systematic review and meta-analysis.

Older adults with mild cognitive impairment (MCI) are at-risk of developing dementia, particularly Alzheimer's disease. While some research suggests that alterations in sleep architecture may mediate cognitive decline, the nature and magnitude of changes to sleep macro- (sleep stages) and micro-architecture (electroencephalography (EEG) oscillations) in MCI is not yet clear. This study aimed to systematically review and meta-analyse case-control studies objectively measuring sleep in MCI. A systematic search was conducted using PubMed, Scopus, Web of Science, Embase and Psycinfo databases and after review, a total of 10 studies met inclusion criteria. Of these, all reported sleep macro-architecture and four reported micro-architecture outcomes. A combined total of 430 participants (209 with and 221 without MCI) underwent objective sleep assessments in the included full text articles. Findings show that compared to healthy controls, those with MCI have pronounced changes in sleep macro-architecture with greater wake after sleep onset, reduced total sleep time, lower sleep efficiency, longer sleep onset latency, longer rapid eye movement sleep (REM) latency, reduced REM sleep, greater N1 sleep, and worse severity of hypoxemia. Pooling of sleep micro-architecture EEG measures was not possible due to limited studies, however reduced spindles in non-REM sleep and greater EEG slowing in REM sleep were reported.

Magnesium supplementation for the treatment of restless legs syndrome and periodic limb movement disorder: A systematic review.

Magnesium supplementation is often suggested for restless legs syndrome (RLS) or period limb movement disorder (PLMD) based on anecdotal evidence that it relieves symptoms and because it is also commonly recommended for leg cramps. We aimed to review all articles reporting the effects of magnesium supplementation on changes in RLS and/or PLMD. We conducted a systematic search looking for all relevant articles and then two reviewers read all article titles and abstracts to identify relevant studies. Eligible studies were scored for their quality as interventional trials. We found 855 abstracts and 16 of these could not be definitively excluded for not addressing all aspects of our research question. Seven full-text articles were unlocatable and one was ineligible which left eight studies with relevant data. One was a randomised placebo-controlled trial, three were case series and four were case studies. The RCT did not find a significant treatment effect of magnesium but may have been underpowered. After quality appraisal and synthesis of the evidence we were unable to make a conclusion as to the effectiveness of magnesium for RLS/PLMD. It is not clear whether magnesium helps relieve RLS or PLMD or in which patient groups any benefit might be seen.

A review of psychosocial factors and personality in the treatment of obstructive sleep apnoea.

Effective treatment of obstructive sleep apnoea (OSA) is primarily determined by adherence to the selected intervention. The most common treatment pathways are mechanical devices such as continuous positive airway pressure (CPAP) or a mandibular advancement device, often combined with weight loss therapy. Weight reduction is usually an adjunct therapy but may be used as a secondary treatment in mild-to-moderate OSA when mechanical treatments cannot be tolerated. To enhance the uptake and adherence to treatment, clinicians may assess patient's personality profiles and psychological readiness. There is a paucity of evidence related to these aspects of patient care and this article outlines the current research in relation to patient presentation, treatment uptake and barriers, and methods to enhance treatment adherence.This article disseminates personality traits observed in patients with OSA and identifies vulnerable groups who may require additional support to increase treatment adherence. It summarises the current evidence for treatment barriers in patients with OSA. Low self-efficacy in relation to CPAP and weight loss adherence will be explored as well as the potential to predict treatment responders and enhance therapeutic uptake and adherence. Extending personality traits into research and clinical practice could potentially result in more successful CPAP therapy and weight loss treatment outcomes.

Parsing the craniofacial phenotype: effect of weight change in an obstructive sleep apnoea population.

PURPOSE: Craniofacial structure is an important risk factor in the development of obstructive sleep apnoea. Most craniofacial imaging methods are not feasible for large-scale studies or the clinic. Craniofacial photography is a high-throughput technique for facial phenotyping; however, derived measurements are a composite of skeletal and soft tissue craniofacial information. Weight change is a paradigm to help determine which facial measurements most relate to regional soft tissue (i.e. change with weight) versus skeletal structure (i.e. stable with weight changes). We aimed to assess the association between weight change and changes in key facial measurements from facial photography. METHODS: Calibrated frontal and profile photographs were taken of participants in weight loss studies (N = 106). Univariate linear regression was used to assess whether weight change explained changes in facial dimensions. RESULTS: Patients lost 11.7 ± 10.8 kg body weight and 2.0 ± 2.0 cm of neck circumference. Weight changes influenced face width (r = 0.3, p < 0.001), mandibular width (r = 0.4, p < 0.001) and cervicomental angle (r = 0.3, p = 0.001). Facial angles, facial heights and mandibular length were not influenced by weight change. CONCLUSIONS: A weight loss paradigm suggests that face and mandibular width and cervicomental angle most strongly reflect regional adiposity. Facial angles and heights are insensitive to weight change and could be more representative of craniofacial skeletal structure. This study informs the interpretation of facial phenotype assessed by this craniofacial photographic method which can be applied to future studies of craniofacial phenotype in OSA.

Intra-individual stability of NREM sleep quantitative EEG measures in obstructive sleep apnea.

Electroencephalography is collected routinely during clinical polysomnography, but is often utilised to simply determine sleep time to calculate apnea-hypopnea indices. Quantitative analysis of these data (quantitative electroencephalogram) may provide trait-like information to predict patient vulnerability to sleepiness. Measurements of trait-like characteristics need to have high test-retest reliability. We aimed to investigate the intra-individual stability of slow-wave (delta power) and spindle frequency (sigma power) activity during non-rapid eye movement sleep in patients with obstructive sleep apnea. We recorded sleep electroencephalograms during two overnight polysomnographic recordings in 61 patients with obstructive sleep apnea (median days between studies 47, inter-quartile range 53). Electroencephalograms recorded at C3-M2 derivation were quantitatively analysed using power spectral analysis following artefact removal. Relative delta (0.5-4.5 Hz) and sigma (12-15 Hz) power during non-rapid eye movement sleep were calculated. Intra-class correlation coefficients and Bland-Altman plots were used to assess agreement between nights. Intra-class correlation coefficients demonstrated good-to-excellent agreement in the delta and sigma frequencies between nights (intra-class correlation coefficients: 0.84, 0.89, respectively). Bland-Altman analysis of delta power showed a mean difference close to zero (-0.4, 95% limits of agreement -9.4, 8.7) and no heteroscedasticity with increasing power. Sigma power demonstrated heteroscedasticity, with reduced stability as sigma power increased. The mean difference of sigma power between nights was close to zero (0.1, 95% limits -1.6, 1.8). We have demonstrated the stability of slow-wave and spindle frequency electroencephalograms during non-rapid eye movement sleep within patients with obstructive sleep apnea. The electroencephalogram profile during non-rapid eye movement sleep may be a useful biomarker for predicting vulnerability to daytime impairment in obstructive sleep apnea and responsiveness to treatment.

Is Metabolic Rate Increased in Insomnia Disorder? A Systematic Review.

Background: Insomnia disorder is a highly prevalent health condition, affecting ~10-15% of the adult population worldwide. A central feature of insomnia is hyperarousal characterized as persistent and increased somatic, cognitive and cortical stimulation. Hyperarousal leads to a state of conditioned arousal that disrupts both sleep and daytime function. Research studies have shown increases in body temperature, heart rate, electroencephalographic activity, catecholamines, and oxygen consumption as a measure of metabolic rate. These findings provide evidence of increased physiological activation in insomnia however results are not consistent. The aim of the systematic review was to determine if metabolic rate in patients with insomnia is increased in keeping with the hyperarousal hypothesis. Methods: We searched Pubmed, Web of Science, CINAHL, PsycINFO, EMBASE, and Scopus databases for observational and interventional studies that have measured metabolic rate in insomnia. Study characteristics were extracted and summarized and a risk of bias was performed for each of the studies. Results: Two reviewers screened 963 abstracts with 35 articles of interest for full-text review. Four articles evaluating 75 participants were included in this systematic review. Two studies showed increased oxygen consumption across 24 h in insomnia patients compared with good-sleeping controls. One study which measured oxygen consumption at only a single timepoint showed no difference between insomnia patients and good-sleeping controls. A further study evaluating the effect of lorazepam on oxygen consumption in patients with chronic insomnia showed that lorazepam reduced metabolic rate during the night time only. Conclusions: These findings show that metabolic rate appears to be increased across 24 h in line with the hyperarousal model of insomnia. However, these increases in metabolic rate in insomnia were minor compared to good-sleeping controls and the clinical significance is unclear. Larger, methodologically robust studies are required to confirm these findings and the effect of any increase in metabolic rate on sleep-wake disturbances or pathophysiology.

Does Armodafinil Improve Driving Task Performance and Weight Loss in Sleep Apnea? A Randomized Trial.

RATIONALE: Patients with obstructive sleep apnea (OSA) unable to tolerate standard treatments have few alternatives. They may benefit from weight loss, but the major symptom of daytime performance impairment may remain during weight loss programs. OBJECTIVES: We hypothesized that wakefulness-promoter armodafinil would improve driving task performance over placebo in patients undergoing weight loss. METHODS: This was a placebo-controlled, double-blind, randomized trial of armodafinil versus placebo daily for 6 months in patients who were also randomized to one of two diets for 6 months with follow-up at 1 year in overweight, adult, patients with OSA who had rejected standard treatment and suffered daytime sleepiness. MEASUREMENTS AND MAIN RESULTS: Primary outcome was change in steering deviation in the final 30 minutes of a 90-minute afternoon driving task (AusED) at 6 months. Secondary outcomes were Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, and fat mass measured by dual-emission X-ray absorptiometry. Armodafinil improved driving task performance over placebo at 3 months (12.9 cm; 95% confidence interval, 4.1-21.7; P = 0.004), but not the primary time point of 6 months (5.5 cm; 95% confidence interval, -3.3 to 14.3; P = 0.223). Patients on armodafinil lost 2.4 kg more fat than those on placebo at 6 months (95% confidence interval, 0.9-4.0; P = 0.002). Other secondary outcomes were not significantly improved. CONCLUSIONS: Armodafinil did not improve driving task performance at the primary endpoint of 6 months. Armodafinil might be a useful adjunctive to weight loss in patients with OSA rejecting conventional treatments but this needs to be directly tested in a specifically designed, properly powered clinical trial. Clinical trial registered with Australian and New Zealand Clinical Trials Registry (ACTRN 12611000847910).

Agreement between electronic and paper Epworth Sleepiness Scale responses in obstructive sleep apnoea: secondary analysis of a randomised controlled trial undertaken in a specialised tertiary care clinic.

OBJECTIVES: Originally developed as a paper questionnaire, the electronic Epworth Sleepiness Scale (ESS) is widely used in sleep clinics and sleep population research. Despite potential differences between computer-based and conventional questionnaire delivery, studies have not evaluated the agreement between electronic and paper versions of the ESS. Given the widespread use of the ESS, a bias between results would present considerable data concerns. Thus, the aim of this study was to examine agreement between electronic and paper ESS responses in obstructive sleep apnoea (OSA). DESIGN: We undertook a secondary analysis of baseline data from a randomised controlled trial (ANZCTR: ACTRN12611000847910). SETTING: Data were collected in a tertiary sleep research laboratory located in Sydney, Australia. PARTICIPANTS: Data were analysed from 112 adult patients with OSA. MEASUREMENTS: Patients were given the English version of the ESS as part of a battery of sleep laboratory questionnaires. They completed electronic and subsequently paper ESS questionnaires on the same day. RESULTS: We found no significant difference between electronic and paper ESS questionnaires (mean=0.1, SD=2.1, 95% CI -0.3 to 0.5, P=0.57) or heteroscedasticity. There was no evidence of bias along the range of the measure. 95% limits of agreement at 4.3 and -4.1 were comparable with previous data. CONCLUSIONS: We found no evidence of bias between electronic and paper ESS questionnaires in this sample of patients with OSA, as the two formats displayed sufficient agreement to be clinically comparable. Regardless of severity, patients reported the same level of daytime sleepiness with the same level of accuracy across both measures. TRIAL REGISTRATION NUMBER: ACTRN12611000847910; Pre-results.

Residual Daytime Sleepiness in Obstructive Sleep Apnea After Continuous Positive Airway Pressure Optimization: Causes and Management.

Excessive daytime sleepiness (EDS) is common in obstructive sleep apnea (OSA), but it is also common in the general population. When sleepiness remains after continuous positive airway pressure (CPAP) treatment of OSA, comorbid conditions or permanent brain injury before CPAP therapy may be the cause of the residual sleepiness. There is currently no broad approach to treating residual EDS in patients with OSA. Individual assessment must be made of comorbid conditions and medications, and of lifestyle factors that may be contributing to the sleepiness. Modafinil and armodafinil are the only pharmacologic agents indicated for residual sleepiness in these patients.

Modafinil/armodafinil in obstructive sleep apnoea: a systematic review and meta-analysis.

Modafinil is used internationally to treat residual sleepiness despite continuous positive airway pressure in obstructive sleep apnoea (res-OSA). In 2011, the European Medicines Agency removed the indication based on an unfavourable risk-benefit profile in two trials for efficacy and all accumulated safety data. We performed a meta-analysis of all randomised controlled trials of modafinil (or armodafinil) in res-OSA to quantify efficacy and safety.We systematically searched and assessed studies from major databases, conferences and trials registries to find randomised, placebo-controlled trials of modafinil/armodafinil for ≥2 weeks in adult res-OSA treating sleepiness.We analysed 10 of the 232 articles identified that met inclusion criteria (1466 patients). Modafinil/armodafinil improved the Epworth Sleepiness Scale score (2.2 points, 95% CI 1.5-2.9) and the Maintenance of Wakefulness Test over placebo (3 min, 95% CI 2.1-3.8 min). Modafinil/armodafinil tripled adverse events and doubled adverse events leading to withdrawal but did not increase serious adverse events (hospitalisations or death).Modafinil and armodafinil improve subjective and objective daytime sleepiness in res-OSA. We believe our analysis is a fairer analysis of the risk-benefit profile of this indication. Clinicians may want to use this data to balance the risks and benefits on a case-by-case basis with their patients.

Modafinil improves daytime sleepiness in patients with mild to moderate obstructive sleep apnoea not using standard treatments: a randomised placebo-controlled crossover trial.

INTRODUCTION: Patients with mild to moderate obstructive sleep apnoea (OSA) commonly suffer excessive daytime sleepiness. Continuous positive airway pressure (CPAP) has limited effectiveness in reducing sleepiness in milder OSA. Modafinil is a wake-promoting drug licensed to treat residual sleepiness in CPAP-treated OSA. We hypothesised that modafinil may effectively treat sleepiness in untreated mild to moderate OSA. METHODS: Untreated sleepy men with mild to moderate OSA (age 18-70, apnoea-hypopnoea index (AHI) 5-30/h, Epworth Sleepiness Scale (ESS) ≥10) were randomised to receive 200 mg modafinil or matching placebo daily for 2 weeks before crossing over to the alternative treatment after a minimum 2-week washout. Mixed model analysis of variance was used to compare the changes on modafinil to placebo while classifying all randomised patients as random factors. RESULTS: 32 patients were randomised (mean (SD) AHI 13 (6.4)/h, age 47 (10.7) years, ESS 13.6 (3.3), body mass index 28.2 (3.6) kg/m(2)), 29 of whom (91%) completed the trial. The primary outcome (ESS) improved more on modafinil than placebo (3.6 points, 95% CI 1.3 to 5.8, p=0.003) and the secondary outcome (40-min driving simulator performance) also improved more on modafinil than placebo (steering deviation 4.7 cm, 95% CI 0.8 to 8.5, p=0.018). Psychomotor Vigilance Task reciprocal reaction time improved significantly over placebo (0.15 (1/ms), 95% CI 0.03 to 0.27, p=0.016). Improvements on the Functional Outcomes of Sleep Questionnaire were not significant (5.3 points over placebo, 95% CI -1 to 11.6, p=0.093). CONCLUSIONS: Modafinil significantly improved subjective sleepiness in patients with untreated mild to moderate OSA. The size of this effect is clinically relevant at 3-4 ESS points of improvement compared with only 1-2 points in CPAP clinical trials. Driving simulator performance and reaction time also improved on modafinil. CLINICAL TRIAL REGISTRATION: ACTRN#12608000128392.