Targeted Hypoglossal Nerve Stimulation for Patients With Obstructive Sleep Apnea: A Randomized Clinical Trial.

Importance: Evidence is lacking from randomized clinical trials of hypoglossal nerve stimulation in obstructive sleep apnea (OSA). Objective: To evaluate the safety and effectiveness of targeted hypoglossal nerve stimulation (THN) of the proximal hypoglossal nerve in patients with OSA. Design, Setting, and Participants: This randomized clinical trial (THN3) was conducted at 20 centers and included 138 patients with moderate to severe OSA with an apnea-hypopnea index (AHI) of 20 to 65 events per hour and body mass index (calculated as weight in kilograms divided by height in meters squared) of 35 or less. The trial was conducted from May 2015 through June 2018. Data were analyzed from January 2022 through January 2023. Intervention: Implant with THN system; randomized 2:1 to activation at month 1 (treatment) or month 4 (control). All received 11 months of THN with follow-up at months 12 and 15, respectively. Main Outcomes and Measures: Primary effectiveness end points comprised AHI and oxygen desaturation index (ODI) responder rates (RRs). Treatment responses at months 4 and 12/15 were defined as a 50% or greater reduction in AHI to 20 or less per hour and an ODI decrease of 25% or greater. Coprimary end points comprised (1) month 4 AHI and ODI RR in the treatment greater than the control group and (2) month 12/15 AHI and ODI RR in the entire cohort exceeding 50%. Secondary end points included sleep apnea severity (AHI and ODI) and patient-reported outcomes (Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, and EQ-5D visual analog scale). Results: Among 138 participants, the mean (SD) age was 56 (9) years, and 19 (13.8%) were women. Month 4 THN RRs were substantially greater in those in the treatment vs control group (AHI, 52.3% vs 19.6%; ODI, 62.5% vs 41.3%, respectively) with treatment-control standardized mean differences of 0.725 (95% CI, 0.360-1.163) and 0.434 (95% CI, 0.070-0.843) for AHI and ODI RRs, respectively. Months 12/15 RRs were 42.5% and 60.4% for AHI and ODI, respectively. Improvements in AHI, ODI, Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, and EQ-5D visual analog scale scores were all clinically meaningful (medium to large effect size). Two serious adverse events and 100 nonserious related adverse events were observed from the implant procedure or study protocol. Conclusions and Relevance: This randomized clinical trial found that THN demonstrated improvements in sleep apnea, sleepiness, and quality of life in patients with OSAs over an extended AHI and body mass index range without prior knowledge of pharyngeal collapse pattern. Clinically meaningful improvements in AHI and patient-reported responses compared favorably with those of distal hypoglossal nerve stimulation trials, although clinically meaningful differences were not definitive for ODI. Trial Registration: ClinicalTrials.gov Identifier: NCT02263859.

NightBalance Sleep Position Treatment Device Versus Auto-Adjusting Positive Airway Pressure for Treatment of Positional Obstructive Sleep Apnea.

STUDY OBJECTIVES: Compare treatment efficacy and objective adherence between the NightBalance sleep position treatment (SPT) device and auto-adjusting positive airway pressure (APAP) in patients with exclusive positional obstructive sleep apnea (ePOSA) defined as a supine apnea-hypopnea index (sAHI) ≥ 2 times the nonsupine AHI (nsAHI) and a nsAHI < 10 events/h. METHODS: This prospective multicenter randomized crossover trial enrolled treatment naive participants with ePOSA (AHI ≥ 15 events/h and nsAHI < 10 events/h) or (AHI > 10 and < 15 events/h with daytime sleepiness and nsAH < 5 events/h). Polysomnography and objective adherence determination (device data) were performed at the end of each 6-week treatment. Patient device preference was determined at the end of the study. RESULTS: A total of 117 participants were randomized (58 SPT first, 59 APAP first). Of these, 112 started treatment with the second device (adherence cohort) and 110 completed the study (AHI cohort). The AHI on SPT was higher (mean ± standard deviation, 7.29 ± 6.8 versus 3.71 ± 5.1 events/h, P < .001). The mean AHI difference (SPT-APAP) was 3.58 events/h with a one sided 95% confidence interval upper bound of 4.96 events/h (< the prestudy noninferiority margin of 5 events/h). The average nightly adherence (all nights) was greater on SPT (345.3 ± 111.22 versus 286.98 ± 128.9 minutes, P < .0001). Participants found the SPT to be more comfortable and easier to use and 53% reported a preference for SPT assuming both devices were equally effective. CONCLUSIONS: Treatment with SPT resulted in non-inferior treatment efficacy and greater adherence compared to APAP in ePOSA suggesting that SPT is an effective treatment for this group. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: The POSAtive Study: Study for the Treatment of Positional Obstructive Sleep Apnea; Identifier: NCT03061071; URL: https://clinicaltrials.gov/ct2/show/NCT03061071.

The Use of a Fully Automated Automatic Adaptive Servoventilation Algorithm in the Acute and Long-term Treatment of Central Sleep Apnea.

BACKGROUND: Central sleep apnea (CSA), in association with obstructive disordered breathing, occurs in patients using opioids long-term and those with congestive heart failure. In these patients, treatment with CPAP frequently fails. The current adaptive servoventilation (ASV) devices are promising for the treatment of complex sleep-disordered breathing. These devices use algorithms to automatically titrate expiratory and inspiratory pressures. We hypothesized that an ASV device operating automatically would significantly reduce the frequency of breathing events in patients with mixed sleep apnea during polysomnography and with 3 months of treatment. METHODS: This was a prospective, multicenter, observational trial. Patients completed 3 nights of attended polysomnography, scored at an independent center. Twenty-seven patients with an apnea-hypopnea index (AHI) ≥ 15 and a central apnea index (CAI) ≥ 5/h underwent automated ASV titration without technician intervention. Twenty-six patients (96%) used ASV at home for 3 months. RESULTS: Patients had an AHI of 55 ± 24 (mean ± SD) and CAI of 23 ± 18 at baseline. Overnight, ASV titration improved AHI, CAI, obstructive apnea, and arousal index significantly. Patients reported better sleep quality on ASV than CPAP. Over 3 months, ASV remained effective (median AHI 11 vs four during polysomnography). Mean adherence was 4.2 h per night. Epworth Sleepiness Scale decreased from 12.8 to 7.8 (P = .001). CONCLUSIONS: The ASV device treated complex breathing disorders using automated algorithms. Compared with CPAP, patients reported improved sleep quality. Home use of ASV remained effective with acceptable adherence and improvements in daytime sleepiness. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01199042; URL: www.clinicaltrials.gov.

Evaluation of phentermine and topiramate versus phentermine/topiramate extended-release in obese adults.

OBJECTIVE: A 28-week, randomized, controlled trial compared the combination of phentermine and topiramate extended-release (PHEN/TPM ER) with its components as monotherapies and with placebo in obese adults. DESIGN AND METHODS: Subjects were randomized to placebo, phentermine 7.5 mg, phentermine 15 mg, topiramate ER 46 mg, topiramate ER 92 mg, PHEN/TPM ER 7.5/46 mg, or PHEN/TPM ER 15/92 mg. All subjects received lifestyle intervention counseling. Primary endpoints were percent weight loss (WL) and achievement of ≥5% WL. RESULTS: At week 28, PHEN/TPM ER 7.5/46 (-8.5%) and 15/92 (-9.2%) achieved greater percentage WL versus placebo (-1.7%; P < 0.0001) and their respective monotherapies (P < 0.05). The percentage of subjects achieving ≥5% WL was 15.5% for placebo, 43.3% for phentermine 7.5, 46.2% for phentermine 15, 39.2% for topiramate ER 46, 48.6% for topiramate ER 92, 62.1% for PHEN/TPM ER 7.5/46, and 66.0% for PHEN/TPM ER 15/92. PHEN/TPM ER was generally well tolerated; comprehensive assessment of cognitive functions with the Repeatable Battery for Assessment of Neuropsychological Status revealed impairment only in the attention domain. CONCLUSIONS: PHEN/TPM ER demonstrated greater WL when used in combination than when used as monotherapies, suggesting enhanced ability of the combination formulation to induce WL at doses lower than with available monotherapies.

A randomized, double-blind, placebo-controlled study of an oral, extended-release formulation of phentermine/topiramate for the treatment of obstructive sleep apnea in obese adults.

STUDY OBJECTIVES: To evaluate safety and efficacy of phentermine 15 mg plus extended-release topiramate 92 mg for treatment of moderate to severe obstructive sleep apnea (OSA) in obese adults. DESIGN: This phase 2, randomized, double-blind, placebo-controlled study included 2-week screening and 28-week treatment periods. Overnight polysomnography was performed at baseline, Week 8, and Week 28. SETTING: Single-center study conducted from August 2008 to September 2009. PARTICIPANTS: Forty-five subjects with moderate to severe OSA not receiving positive airway pressure (PAP) treatment with body mass index of 30-40 kg/m(2). INTERVENTIONS: Subjects were randomized to receive placebo (n = 23) or phentermine 15 mg plus extended-release topiramate 92 mg (n = 22). Both groups received lifestyle-modification counseling. MEASUREMENTS AND RESULTS: Primary endpoint, change in apnea-hypopnea index (AHI), significantly favored phentermine 15 mg plus extended-release topiramate 92 mg (-31.5 events/h, 95% CI: -40.0, -22.9) over placebo (-16.6 events/h, 95% CI: -25.0, -8.2) at Week 28 (P =0.0084). At Week 28, there was a 10.2% (95% CI: -12.7, -7.6; 10.8 kg, 95% CI: -13.5, -8.0) mean decrease in weight in the phentermine 15 mg plus extended-release topiramate 92 mg group compared with 4.3% (95% CI: -6.6, -2.0; 4.7 kg, 95% CI: -7.2, -2.2) in the placebo group (P = 0.0006) and a positive, significant (P = 0.0003) correlation between percent change in weight and change in AHI. Significant improvements in overnight oxygen saturation and reduction in blood pressure compared with placebo were observed. Phentermine 15 mg plus extended-release topiramate 92 mg was well tolerated with low adverse event rates. CONCLUSIONS: Phentermine 15 mg plus extended-release topiramate 92 mg induced significant weight reductions and concomitant improvements in OSA and related symptoms vs placebo. This suggests weight loss mediated by phentermine 15 mg plus extended-release topiramate 92 mg may be useful in treatment of moderate to severe OSA in obese subjects unable or unwilling to comply with PAP treatment.

A 52-week study of gabapentin enacarbil in restless legs syndrome.

OBJECTIVES: This open-label, multicenter, 52-week extension study (NCT00333359) assessed the long-term safety and efficacy of gabapentin enacarbil in subjects with moderate-to-severe primary restless legs syndrome (RLS). METHODS: Subjects had completed one of 4 randomized, double-blind parent studies (XP052/XP053/XP081/XP083). Gabapentin enacarbil 1200 mg was administered once daily at 5 pm; dose adjustments to 600 or 1800 mg were permitted based on investigator judgment. Safety assessments included adverse events (AEs), vital signs, clinical laboratory tests, and electrocardiograms. Efficacy evaluations included the International Restless Legs Scale total score and the investigator-rated Clinical Global Impression-Improvement scale, at week 52 last observation carried forward. RESULTS: The safety population comprised 573 subjects; 386 (67.4%) completed the study. Treatment-emergent AEs were reported by 80.1% of subjects and led to withdrawal in 10.3% of subjects; most (67.7%) were mild or moderate in intensity. The most common AEs were somnolence and dizziness (19.7% and 11.5% of subjects). Twenty subjects (3.5%) reported serious AEs; one subject died (fall, 25 days after stopping gabapentin enacarbil, judged not treatment related). No serious AE occurred in more than 1 subject. No clinically relevant changes were reported in vital signs, laboratory parameters, or electrocardiograms. At week 52 last observation carried forward, the mean (SD) change from parent study baseline in International Restless Legs Scale total score was -15.2 (8.85 [parent study baseline score, 23.2 (5.03)]), and 84.8% of subjects were Clinical Global Impression-Improvement responders ("much improved" or "very much improved"). CONCLUSIONS: Gabapentin enacarbil was generally safe and well tolerated and improved RLS symptoms in subjects with moderate-to-severe primary RLS for up to 64 weeks of treatment.

Interval timing accuracy and scalar timing in C57BL/6 mice.

In many species, interval timing behavior is accurate-appropriate estimated durations-and scalar-errors vary linearly with estimated durations. Whereas accuracy has been previously examined, scalar timing has not been clearly demonstrated in house mice (Mus musculus), raising concerns about mouse models of human disease. The authors estimated timing accuracy and precision in C57BL/6 mice, the most used background strain for genetic models of human disease, in a peak-interval procedure with multiple intervals. Both when timing 2 intervals (Experiment 1) or 3 intervals (Experiment 2), C57BL/6 mice demonstrated varying degrees of timing accuracy. An important finding was that, both at the individual and group levels, their precision varied linearly with the subjective estimated duration. Further evidence for scalar timing was obtained using an intraclass correlation statistic. This is the first report of consistent, reliable scalar timing in a sizable sample of house mice, thus validating the peak-interval procedure as a valuable technique, the intraclass correlation statistic as a powerful test of the scalar property, and the C57BL/6 strain as a suitable background for behavioral investigations of genetically engineered mice modeling disorders of interval timing.

New solutions for treating chronic insomnia: an introduction to behavioral sleep medicine.

Insomnia is one of the most frequent complaints brought to primary care physicians and research suggests insomnia's prevalence is on the rise. Insomnia evaluation and treatment can be a time-intensive process that puts significant demands on a busy medical practice. To date, hypnotic medications are the most frequently prescribed treatment for insomnia and have been demonstrated to be efficacious for the treatment of acute insomnia. Cognitive-behavioral treatment (CBT) has been found to be just as effective as hypnotics for the treatment of acute insomnia and more effective for the treatment of chronic insomnia. CBT is now recognized as a first-line intervention for chronic insomnia, yet is underutilized. Many patients and healthcare providers are unaware of the efficacy of CBT for insomnia and currently there are few qualified providers. To address this need, the American Academy of Sleep Medicine (AASM) has developed a new subspeciality to train providers in the provision of CBT for insomnia as well as other sleep disorders.

Ropinirole decreases periodic leg movements and improves sleep parameters in patients with restless legs syndrome.

STUDY OBJECTIVES: Polysomnographic study evaluating the efficacy of ropinirole for the treatment of patients with restless legs syndrome (RLS) suffering from periodic leg movements in sleep (PLMS). DESIGN: Double-blinded, placebo-controlled, parallel-group study. SETTING: 15 tertiary referral centers in the USA. PARTICIPANTS: 65 patients with RLS and PLMS. INTERVENTIONS: Ropinirole (0.25-4.0 mg per day) or placebo for 12 weeks. MEASUREMENTS AND RESULTS: Data from 59 patients were included in the primary endpoint analysis. PLMS per hour decreased more with ropinirole (48.5 to 11.8), compared with placebo (35.7 to 34.2; adjusted treatment difference: -27.2; 95% confidence interval [CI]: -39.1, -15.4; P < .0001). Periodic limb movements with arousal per hour decreased from 7.0 to 2.5 with ropinirole but increased from 4.2 to 6.0 with placebo (adjusted treatment difference: -4.3, 95% CI: -7.6, -1.1; P = .0096). Periodic limb movements while awake per hour decreased from 56.5 to 23.6 with ropinirole but increased from 46.6 to 56.1 with placebo (adjusted treatment difference: -39.5; 95% CI: -56.9, -22.1; P < .0001). Ropinirole treatment significantly improved patients' ability to initiate sleep (P < .05) and the amount of Stage 2 sleep compared with placebo (P < .001). There were also non-significant trends toward increases in total sleep time and sleep efficiency. Sleep adequacy (measured on the subjective Medical Outcomes Study sleep scale) was significantly improved with ropinirole treatment (adjusted treatment difference: 12.1; 95% CI: 1.1, 23.1; P = .0316). In contrast, the placebo group showed a greater increase in Stage 3/4 sleep (P < .01). No serious adverse events occurred in either group. CONCLUSIONS: Ropinirole is effective in the treatment of both the sleep and waking symptoms of RLS.