Reboxetine for Sleep Apnoea After ENT Surgery (RENTOSA)

• ClinicalTrials.gov Identifier: NCT05978505
• Recruitment Status: Not yet recruiting
• First Posted: August 7, 2023
• Last Update Posted: August 7, 2023
• Sponsor: Flinders University
• Collaborator: Flinders Medical Centre
• Information provided by (Responsible Party): Professor Danny Eckert, Flinders University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Sleep Apnea, Obstructive	Drug: Reboxetine 4 MG Oral Tablet; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Double-blind, randomized, placebo-controlled, cross-over study
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Identical capsule for placebo and study drug prepared by study pharmacist
• Primary Purpose: Other
• Official Title: Reboxetine for Obstructive Sleep Apnoea After Upper Airway Surgery: a Randomised, Double-blind, Placebo-controlled Study
• Estimated Study Start Date: August 15, 2023
• Estimated Primary Completion Date: December 2024
• Estimated Study Completion Date: December 2024

Arms and Interventions

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 Name: 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 Name: Sugar pill

Outcome Measures

Primary Outcome Measures :

1. Treatment protocol adherence [ Time Frame: 7 days ]
   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.
2. Data capture efficiency [ Time Frame: 14 days ]
   The percentage of successful data collection nights versus missed nights of at-home oximetry for this feasibility study.

Secondary Outcome Measures :

1. Oxygen desaturation index (ODI) [ Time Frame: 14 days ]
   Number of times per hour that a participant has a drop in blood oxygen levels during sleep
2. nadir SpO2 [ Time Frame: 14 days ]
   The lowest oxygen saturation value the patient drops to in a night.
3. Time spent below 90% SpO2 [ Time Frame: 14 days ]
   The total amount of time per night for which oxygen saturation falls below 90%.
4. mean SpO2 [ Time Frame: 14 days ]
   Average nightly oxygen level
5. Sleep duration [ Time Frame: 14 days ]
   Total amount of time spent asleep per night, sleep tracking performed using an under mattress sensor device.
6. Sleep efficiency (%) [ Time Frame: 14 days ]
   The estimated percentage of time in bed spent asleep performed using an under mattress sensor device.
7. Daytime sleepiness [ Time Frame: 14 days ]
   Measured via Karolinska Sleepiness Scale Questionnaire (9 point scale where 1 = extremely alert and 9 = extremely sleepy - fighting sleep)
8. Perceived sleep quality measured via the Leeds Sleep Evaluation Questionnaire [ Time Frame: 14 days ]
   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.
9. Insomnia Severity Score [ Time Frame: 14 days ]
   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.
10. Apnoea-hypopnea hndex (AHI) [ Time Frame: 14 days ]
    Change in OSA severity (AHI estimated via the Withings under mattress sensor number of events/hour) between placebo and reboxetine
11. Study enrolment rate [ Time Frame: 12 months ]
    The number of referred patients successfully enrolled into this feasibility study

Other Outcome Measures:

1. Reboxetine-related side effects [ Time Frame: 14 days ]
   Documented via adverse-event forms.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Emma J Thomas; +61 8 8201 2912; ethomas@flinders.edu.au

Contact: Carolin Tran; +61 8 7421 9873; carolin.tran@flinders.edu.au

Sponsors and Collaborators

Flinders University

Flinders Medical Centre

Investigators

• Principal Investigator: Danny J Eckert, PhD; Flinders University

More Information

Publications:

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.

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.

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.

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, 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.

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.

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.

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.

• Responsible Party: Professor Danny Eckert, Director, Adelaide Institute for Sleep Health, Flinders University
• ClinicalTrials.gov Identifier: NCT05978505
• Other Study ID Numbers: 2023/HRE00060
• First Posted: August 7, 2023
• Last Update Posted: August 7, 2023
• Last Verified: July 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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
• Supporting Materials: Study Protocol; Informed Consent Form (ICF)
• Time Frame: At conclusion of the study and any related publications
• Access Criteria: IPD may be shared for research purposes on application to the chief investigator and subject to applicable ethical review.

• 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

Keywords provided by Professor Danny Eckert, Flinders University:

sleep apnea, obstructive; upper airway surgery; ENT surgery; reboxetine; noradrenaline reuptake inhibitor; randomised; feasibility; placebo; double-blind

Additional relevant MeSH terms:

Apnea; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Reboxetine; Antidepressive Agents; Psychotropic Drugs; Adrenergic Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Adrenergic Agents; Neurotransmitter Agents; Physiological Effects of Drugs