Reboxetine for Sleep Apnoea After ENT Surgery (RENTOSA)

Reboxetine for Obstructive Sleep Apnoea After Upper Airway Surgery: a Randomised, Double-blind, Placebo-controlled Study

This pilot study will establish the feasibility of a larger trial to investigate whether reboxetine, a medication used to treat depression, can reduce the severity of obstructive sleep apnea (OSA) including increased blood oxygenation in post-surgical OSA patients where positive airway pressure (CPAP) therapy is either frequently poorly tolerated or not an option immediately post surgery. In this randomized, placebo-controlled, double-blind study, participants will use at-home sleep monitoring equipment before and after surgery plus measures of oxygenation. They will be prescribed either reboxetine or a placebo for seven days after surgery and complete questionnaires at the beginning and end of the study.

Study Overview

• Status: Recruiting
• Conditions: Sleep Apnea, Obstructive
• Intervention / Treatment: Drug: Reboxetine 4 MG Oral Tablet; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Emma Thomas; Phone Number: +61882012912; Email: ethomas@flinders.edu.au
• Study Contact Backup: Name: Carolin Tran; Phone Number: +61874219873; Email: carolin.tran@flinders.edu.au

Study Locations

• Australia
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Recruiting
      • Flinders, Private and Public Hospitals and Flinders University
      • Contact: Carolin Tran; Phone Number: +61 8 7421 9873; Email: carolin.tran@flinders.edu.au
      • Contact: Emma Thomas; Phone Number: +61 8 8201 2912; Email: ethomas@flinders.edu.au
      • Contact: Danny J. Eckert, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age >18 years
• Undergoing elective upper airway surgery
• History of obstructive sleep apnoea (OSA)

Exclusion Criteria:

• Clinically significant cardiac disease (e.g., arrhythmia, coronary artery disease, or cardiac failure)
• History of clinically significant urinary retention, bladder outlet obstruction, or benign prostatic hyperplasia
• Poorly controlled hypertension
• Epilepsy
• History of schizophrenia, schizoaffective disorder or bipolar disorder according to Diagnostic and Statistical Manual of Mental Disorders-V or International Classification of Disease 10th edition criteria
• History of attempted suicide or suicidal ideation within 1 year prior to screening, or current suicidal ideation
• Narrow angle glaucoma

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Reboxetine; 7-day course of 4mg reboxetine, taken nightly before bed time. Reboxetine will be taken for 7-nights post-surgery.	Drug: Reboxetine 4 MG Oral Tablet; 7 nightly doses (4mg) to commence after surgery.; Other Names: Edronax
Placebo Comparator: Placebo; Placebo sugar pill in the form of one capsule, taken before bedtime. Dosage is taken for 7 nights post-surgery.	Drug: Placebo; 7 nightly doses to commence after surgery.; Other Names: Sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment protocol adherence	The percentage of total doses of the study drug (reboxetine or placebo) that were taken versus prescribed (assessed via pill counts) for this feasibility study.	7 days
Data capture efficiency	The percentage of successful data collection nights versus missed nights of at-home oximetry for this feasibility study.	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxygen desaturation index (ODI)	Number of times per hour that a participant has a drop in blood oxygen levels during sleep	14 days
nadir SpO2	The lowest oxygen saturation value the patient drops to in a night.	14 days
Time spent below 90% SpO2	The total amount of time per night for which oxygen saturation falls below 90%.	14 days
mean SpO2	Average nightly oxygen level	14 days
Sleep duration	Total amount of time spent asleep per night, sleep tracking performed using an under mattress sensor device.	14 days
Sleep efficiency (%)	The estimated percentage of time in bed spent asleep performed using an under mattress sensor device.	14 days
Daytime sleepiness	Measured via Karolinska Sleepiness Scale Questionnaire (9 point scale where 1 = extremely alert and 9 = extremely sleepy - fighting sleep)	14 days
Perceived sleep quality measured via the Leeds Sleep Evaluation Questionnaire	This questionnaire asks participants to rate their perceived sleep across 4 domains on a visual analog scale as follows: 1) getting to sleep, 2) quality of sleep, 3) Awake following sleep, 4) Behavior following wakening. Higher scores indicate better perceived sleep.	14 days
Insomnia Severity Score	A patient-reported measure of insomnia symptoms using the Insomnia Severity Index- A 28 point scale where 0 indicates no clinically significant insomnia and 28 indicates maximally severe clinical insomnia.	14 days
Apnoea-hypopnea hndex (AHI)	Change in OSA severity (AHI estimated via the Withings under mattress sensor number of events/hour) between placebo and reboxetine	14 days
Study enrolment rate	The number of referred patients successfully enrolled into this feasibility study	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reboxetine-related side effects	Documented via adverse-event forms.	14 days

Collaborators and Investigators

• Sponsor: Flinders University
• Collaborators: Flinders Medical Centre
• Investigators: Principal Investigator: Danny J. Eckert, PhD, Flinders University

Publications and helpful links

General Publications

• Khanna AK, Bergese SD, Jungquist CR, Morimatsu H, Uezono S, Lee S, Ti LK, Urman RD, McIntyre R Jr, Tornero C, Dahan A, Saager L, Weingarten TN, Wittmann M, Auckley D, Brazzi L, Le Guen M, Soto R, Schramm F, Ayad S, Kaw R, Di Stefano P, Sessler DI, Uribe A, Moll V, Dempsey SJ, Buhre W, Overdyk FJ; PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) Group Collaborators. Prediction of Opioid-Induced Respiratory Depression on Inpatient Wards Using Continuous Capnography and Oximetry: An International Prospective, Observational Trial. Anesth Analg. 2020 Oct;131(4):1012-1024. doi: 10.1213/ANE.0000000000004788.
• Opperer M, Cozowicz C, Bugada D, Mokhlesi B, Kaw R, Auckley D, Chung F, Memtsoudis SG. Does Obstructive Sleep Apnea Influence Perioperative Outcome? A Qualitative Systematic Review for the Society of Anesthesia and Sleep Medicine Task Force on Preoperative Preparation of Patients with Sleep-Disordered Breathing. Anesth Analg. 2016 May;122(5):1321-34. doi: 10.1213/ANE.0000000000001178.
• Chung F, Liao P, Yegneswaran B, Shapiro CM, Kang W. Postoperative changes in sleep-disordered breathing and sleep architecture in patients with obstructive sleep apnea. Anesthesiology. 2014 Feb;120(2):287-98. doi: 10.1097/ALN.0000000000000040.
• Chan MTV, Wang CY, Seet E, Tam S, Lai HY, Chew EFF, Wu WKK, Cheng BCP, Lam CKM, Short TG, Hui DSC, Chung F; Postoperative Vascular Complications in Unrecognized Obstructive Sleep Apnea (POSA) Study Investigators. Association of Unrecognized Obstructive Sleep Apnea With Postoperative Cardiovascular Events in Patients Undergoing Major Noncardiac Surgery. JAMA. 2019 May 14;321(18):1788-1798. doi: 10.1001/jama.2019.4783.
• Altree TJ, Eckert DJ. Obstructive sleep apnea endotypes and their postoperative relevance. Int Anesthesiol Clin. 2022 Apr 1;60(2):1-7. doi: 10.1097/AIA.0000000000000357. No abstract available.
• Chung F, Memtsoudis SG, Ramachandran SK, Nagappa M, Opperer M, Cozowicz C, Patrawala S, Lam D, Kumar A, Joshi GP, Fleetham J, Ayas N, Collop N, Doufas AG, Eikermann M, Englesakis M, Gali B, Gay P, Hernandez AV, Kaw R, Kezirian EJ, Malhotra A, Mokhlesi B, Parthasarathy S, Stierer T, Wappler F, Hillman DR, Auckley D. Society of Anesthesia and Sleep Medicine Guidelines on Preoperative Screening and Assessment of Adult Patients With Obstructive Sleep Apnea. Anesth Analg. 2016 Aug;123(2):452-73. doi: 10.1213/ANE.0000000000001416.
• Altree TJ, Chung F, Chan MTV, Eckert DJ. Vulnerability to Postoperative Complications in Obstructive Sleep Apnea: Importance of Phenotypes. Anesth Analg. 2021 May 1;132(5):1328-1337. doi: 10.1213/ANE.0000000000005390.
• Reilly EK, Boon MS, Vimawala S, Chitguppi C, Patel J, Murphy K, Doghramji K, Nyquist GG, Rosen MR, Rabinowitz MR, Huntley CT. Tolerance of Continuous Positive Airway Pressure After Sinonasal Surgery. Laryngoscope. 2021 Mar;131(3):E1013-E1018. doi: 10.1002/lary.28968. Epub 2020 Sep 16.
• Perger E, Taranto Montemurro L, Rosa D, Vicini S, Marconi M, Zanotti L, Meriggi P, Azarbarzin A, Sands SA, Wellman A, Lombardi C, Parati G. Reboxetine Plus Oxybutynin for OSA Treatment: A 1-Week, Randomized, Placebo-Controlled, Double-Blind Crossover Trial. Chest. 2022 Jan;161(1):237-247. doi: 10.1016/j.chest.2021.08.080. Epub 2021 Sep 20.
• Taranto-Montemurro L, Messineo L, Sands SA, Azarbarzin A, Marques M, Edwards BA, Eckert DJ, White DP, Wellman A. The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover Trial. Am J Respir Crit Care Med. 2019 May 15;199(10):1267-1276. doi: 10.1164/rccm.201808-1493OC.
• Lim R, Messineo L, Grunstein RR, Carberry JC, Eckert DJ. The noradrenergic agent reboxetine plus the antimuscarinic hyoscine butylbromide reduces sleep apnoea severity: a double-blind, placebo-controlled, randomised crossover trial. J Physiol. 2021 Sep;599(17):4183-4195. doi: 10.1113/JP281912. Epub 2021 Jul 14.
• Liao P, Luo Q, Elsaid H, Kang W, Shapiro CM, Chung F. Perioperative auto-titrated continuous positive airway pressure treatment in surgical patients with obstructive sleep apnea: a randomized controlled trial. Anesthesiology. 2013 Oct;119(4):837-47. doi: 10.1097/ALN.0b013e318297d89a. Erratum In: Anesthesiology. 2014 May;120(5):1302. Anesthesiology. 2014 May;120(5):1302. doi: 10.1097/ALN.0000446879.21458.99.

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2023
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: June 2, 2023
• First Submitted That Met QC Criteria: July 28, 2023
• First Posted (Actual): August 7, 2023

Study Record Updates

• Last Update Posted (Actual): October 3, 2024
• Last Update Submitted That Met QC Criteria: October 2, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: placebo; feasibility; double-blind; randomised; sleep apnea, obstructive; reboxetine; ENT surgery; upper airway surgery; noradrenaline reuptake inhibitor
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Apnea; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Adrenergic Uptake Inhibitors; Reboxetine
• Other Study ID Numbers: 2023/HRE00060

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Participants will be informed in plain language through the consent form that their deidentified data may be made available to other researchers. Deidentified participant data will only be shared with other researchers upon request to the chief investigator after study publication and subject to ethical approval
• IPD Sharing Time Frame: At conclusion of the study and any related publications
• IPD Sharing Access Criteria: IPD may be shared for research purposes on application to the chief investigator and subject to applicable ethical review.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No