Domiciliary transcutaneous electrical stimulation in patients with obstructive sleep apnoea and limited adherence to continuous positive airway pressure therapy: a single-centre, open-label, randomised, controlled phase III trial

Background: Hypoglossal nerve stimulation (HNS) for obstructive sleep apnoea (OSA) is a novel way to manage the condition. We hypothesised that in patients with OSA and limited adherence to continuous positive airway pressure (CPAP) therapy, domiciliary transcutaneous electrical stimulation (TESLA) would control sleep apnoea and provide health benefits. Methods: We undertook a single-centre, open-label, randomised, controlled phase III trial in patients with OSA (apnoea-hypopnoea-index [AHI] 5-35 h-1), a BMI of 18.5-32 kg∗m-2, and a documented lack of adherence to CPAP therapy (<4 h∗night-1) at Guy's & St Thomas' NHS Foundation Trust (hospital), UK. Patients were randomly assigned (1:1) using minimisation (gender and OSA severity) to receive TESLA or usual care (CPAP) for at least 3 months; sleep study analysis was provided without knowledge of the assignment arm. The primary outcome was change in AHI at 3-months. The primary outcome and safety were analysed in the intention-to-treat population. Data are reported as median (interquartile range), unless otherwise explained. This trial is registered at ClinicalTrials.gov, NCT03160456. Findings: Between 6 June 2018 and 7 February 2023, 56 participants were enrolled and randomly assigned (29 patients in the intervention group and 27 in the usual care group). Patients were followed up for a median of 3.0 months (IQR 3.0; 10.0). The groups were similar in terms of age (55.8 (48.2; 66.0) vs 59.3 (47.8; 64.4) years), gender (male:female, 19:10 vs 18:9) and BMI (28.7 (26.4; 31.9) vs 28.4 (24.4; 31.9) kg∗m-2). The unadjusted group difference in the Δ AHI was -11.5 (95% CI -20.7; -2.3) h-1 (p = 0.016). Adjusted for the baseline value, the difference was Δ AHI -7.0 (-15.7; 1.8) h-1 (p = 0.12), in favour of the intervention. Minor adverse events were found in one of the participants who developed mild headaches related to the intervention. Interpretation: Domiciliary TESLA can be used safely and effectively in OSA patients with poor adherence to CPAP, with favourable impact on sleepiness and sleep fragmentation. Despite pandemic-related limitations of the amended protocol this trial provides the evidence that TESLA improves clinically meaningful outcomes over the observed follow up period, and the transcutaneous approach is likely to offer an affordable alternative for responders to electrical stimulation in clinical practice. Funding: British Lung Foundation, United Kingdom Clinical Research Collaboration-registered King's Clinical Trials Unit at King's Health Partners. Keywords: CPAP; Genioglossus; Hypoglossal nerve stimulation; Non-CPAP therapy

Detection of subtelomere imbalance using MLPA: validation, development of an analysis protocol, and application in a diagnostic centre

BACKGROUND: Commercial MLPA kits (MRC-Holland) are available for detecting imbalance at the subtelomere regions of chromosomes; each kit consists of one probe for each subtelomere. METHODS: For validation of the kits, 208 patients were tested, of which 128 were known to be abnormal, corresponding to 8528 genomic regions overall. Validation samples included those with trisomy 13, 18 and 21, microscopically visible terminal deletions and duplications, sex chromosome abnormalities and submicroscopic abnormalities identified by multiprobe FISH. A robust and sensitive analysis system was developed to allow accurate interpretation of single probe results, which is essential as breakpoints may occur between MLPA probes. RESULTS: The validation results showed that MLPA is a highly efficient technique for medium-throughput screening for subtelomere imbalance, with 95% confidence intervals for positive and negative predictive accuracies of 0.951-0.996 and 0.9996-1 respectively. A diagnostic testing strategy was established for subtelomere MLPA and any subsequent follow-up tests that may be required. The efficacy of this approach was demonstrated during 15 months of diagnostic testing when 455 patients were tested and 27 (5.9%) abnormal cases were detected. CONCLUSION: The development of a robust, medium-throughput analysis system for the interpretation of results from subtelomere assays will be of benefit to other Centres wishing to implement such an MLPA-based service

Domiciliary transcutaneous electrical stimulation in patients with obstructive sleep apnoea and limited adherence to continuous positive airway pressure therapy: a single-centre, open-label, randomised, controlled phase III trialResearch in context

Summary: Background: Hypoglossal nerve stimulation (HNS) for obstructive sleep apnoea (OSA) is a novel way to manage the condition. We hypothesised that in patients with OSA and limited adherence to continuous positive airway pressure (CPAP) therapy, domiciliary transcutaneous electrical stimulation (TESLA) would control sleep apnoea and provide health benefits. Methods: We undertook a single-centre, open-label, randomised, controlled phase III trial in patients with OSA (apnoea-hypopnoea-index [AHI] 5–35 h−1), a BMI of 18.5–32 kg∗m−2, and a documented lack of adherence to CPAP therapy (<4 h∗night−1) at Guy’s &amp; St Thomas’ NHS Foundation Trust (hospital), UK. Patients were randomly assigned (1:1) using minimisation (gender and OSA severity) to receive TESLA or usual care (CPAP) for at least 3 months; sleep study analysis was provided without knowledge of the assignment arm. The primary outcome was change in AHI at 3-months. The primary outcome and safety were analysed in the intention-to-treat population. Data are reported as median (interquartile range), unless otherwise explained. This trial is registered at ClinicalTrials.gov, NCT03160456. Findings: Between 6 June 2018 and 7 February 2023, 56 participants were enrolled and randomly assigned (29 patients in the intervention group and 27 in the usual care group). Patients were followed up for a median of 3.0 months (IQR 3.0; 10.0). The groups were similar in terms of age (55.8 (48.2; 66.0) vs 59.3 (47.8; 64.4) years), gender (male:female, 19:10 vs 18:9) and BMI (28.7 (26.4; 31.9) vs 28.4 (24.4; 31.9) kg∗m−2). The unadjusted group difference in the ΔAHI was −11.5 (95% CI −20.7; −2.3) h−1 (p = 0.016). Adjusted for the baseline value, the difference was ΔAHI −7.0 (−15.7; 1.8) h−1 (p = 0.12), in favour of the intervention. Minor adverse events were found in one of the participants who developed mild headaches related to the intervention. Interpretation: Domiciliary TESLA can be used safely and effectively in OSA patients with poor adherence to CPAP, with favourable impact on sleepiness and sleep fragmentation. Despite pandemic-related limitations of the amended protocol this trial provides the evidence that TESLA improves clinically meaningful outcomes over the observed follow up period, and the transcutaneous approach is likely to offer an affordable alternative for responders to electrical stimulation in clinical practice. Funding: British Lung Foundation, United Kingdom Clinical Research Collaboration-registered King's Clinical Trials Unit at King's Health Partners