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. 2023 Jun 1;149(6):512-520.
doi: 10.1001/jamaoto.2023.0161.

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

Alan R Schwartz  1   2 , Ofer Jacobowitz  3 , David W Eisele  4 , Samuel A Mickelson  5 , Mitchell B Miller  6 , Arie Oliven  7   8 , Victor Certal  9   10 , Martin L Hopp  11 , David H Winslow  12 , Tod C Huntley  13 , Nathan E Nachlas  14 , Luu V Pham  15 , M Boyd Gillespie  16 , Brian H Weeks  17 , Eric G Lovett  18 , John Shen  19 , Atul Malhotra  20 , Joachim T Maurer  21
Affiliations

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

Alan R Schwartz et al. JAMA Otolaryngol Head Neck Surg. .

Erratum in

  • Errors in Table 2.
    [No authors listed] [No authors listed] JAMA Otolaryngol Head Neck Surg. 2024 Jun 1;150(6):530. doi: 10.1001/jamaoto.2024.0412. JAMA Otolaryngol Head Neck Surg. 2024. PMID: 38512282 Free PMC article. No abstract available.

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Schwartz reported grants from ImThera during the conduct of the study as well as personal fees from LivaNova, AE Mann Foundation, Deerfield Catalyst, Invicta Medical, Nyxoah, and Respicardia/Zoll, Apnimed, Itamar/Zoll, Periodic Breathing, Respimetrix, and Sunrise as a scientific advisor outside the submitted work. Dr Jacobowitz reported personal fees and grants from LivaNova during the conduct of the study. Dr Gillespie reported grants from the University of Tennessee Health Science Center/LivaNova during the conduct of the study. Dr Lovett reported being employed by and a shareholder of LivaNova during the conduct of the study and outside the submitted work as well as a patent for LivaNova. Dr Malhotra reported personal fees from LivaNova, Jazz, Eli Lilly, and Zoll and research support from Resmed during the conduct of the study. Dr Maurer reported grants and personal fees from LivaNova during the conduct of the study as well as personal fees from Inspire, Nyxoah, MedEl, and Neuwirth Medical Products outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Design
All eligible patients who provided consent underwent implant. One month following implant, patients were randomized 2:1 to receive targeted hypoglossal nerve therapy beginning at month 1 (treatment) or month 4 (control). Short-term end points were measured between the treatment and control groups at month 4, and long-term end points were measured following 11 months of therapy, months 12 and 15, respectively, for the treatment and control groups pooled.
Figure 2.
Figure 2.. Primary Effectiveness Outcomes at Baseline, at the Conclusion of the Trial (Month 4), and After 11 Months of Therapy (Months 12/15) for Patients With Complete Data at All Points
At baseline, apnea-hypopnea index (AHI) (A) differed but oxygen desaturation index (ODI) (B) did not differ between the treatment and control groups. At month 4, the treatment group exhibited significantly greater, clinically meaningful reductions in AHI and ODI than the control group (vs baseline), and AHI and ODI were meaningfully and significantly lower in the treatment vs control group. After 11 months of therapy, targeted hypoglossal nerve stimulation in the control group generated similar reductions in AHI and ODI as in the treatment group. These parameters were significantly lower than the baseline. Standard errors of the median and P values were computed with bootstrapping methods.
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