Adipose Dysfunction, Imaging, Physiology, and Outcomes With Sodium Glucose Cotransporter 2 Inhibitor (SGLT2i) for Sleep Apnea: The ADIPOSA Study

Sleep Apnea Clinical Trial

— ADIPOSA  

Official title:

Adipose Dysfunction, Imaging, Physiology, and Outcomes With SGLT2i's for Sleep Apnea: The ADIPOSA Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05612594
• Other study ID #: 2000033371
• Status: Recruiting
• Phase: Phase 4
• Start date: March 27, 2024
• Est. completion date: September 2027

Study information

• Verified date: April 2024
• Source: Yale University
• Contact: Henry K Yaggi, M.D.
• Phone: 203-785-4163
• Email: henry.yaggi[@]yale.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this clinical trial is to test if bexagliflozin lowers the sleep apnea severity in adults who are overweight or obese with moderate to severe obstructive sleep apnea (OSA) compared with a placebo (look-alike substance that contains no active drug).

The main question it aims to answer is:

• If SGLT2i will reduce anatomic and physiologic traits, clinical measures of OSA and sleep deficiency in participants

• If improvement in clinical measures are because of improvement in the anatomic and physiologic traits.

Participants will be placed on either drug or placebo and get routine normal care for 6 months. At the start and end of the study, participants will undergo different clinical measurements to see if the drug makes the sleep apnea better.

Description:

The primary objective of this study is to determine whether bexagliflozin 20 mg once daily compared with placebo reduces the apnea hypopnea index (AHI) in adults with overweight or obesity with moderate to severe OSA.

The secondary objectives of this study are to determine whether bexagliflozin 20 mg once daily compared with placebo (a look-alike substance that contains no active drug):

• reduces visceral and neck fat and upper airway soft tissue structure volumes and increases airway caliber

• reduces Critical closing pressure

• reduces rostral to caudal fluid shifts (measured by neck circumference)

• improves clinical measures of OSA severity and sleep deficiency

This is a 2-center clinical trial of overweight or obese adults (BMI 25-40 kg/m2) diagnosed with moderate to severe OSA, recruited from University Hospitals Cleveland Medical Center (UH) and Yale New Haven Health (YNHH). Participants will be randomized to bexagliflozin 20 mg once daily or matching placebo in addition to standard routine clinical care for both groups for 6 months. At baseline and at study end, participants will undergo measurements of anatomic traits using MRI imaging, critical closing pressure, blood-based biomarkers of dysfunctional adiposity, non-anatomic physiologic trait polysomnographic phenotyping, morning neck circumference, clinical measures of sleep apnea severity (apnea hypopnea index (AHI), oxygen desaturation index (ODI), % time with O2sat < 90% (T90)), sleep arousal index (AI)), and measures of sleep deficiency, to evaluate the effects of SGLT2i on the measured phenotypes.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 164
• Est. completion date: September 2027
• Est. primary completion date: September 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Able to provide informed consent and stated willingness to comply with all study procedures and availability for the duration of the study

• Overweight or obese (body mass index 25-40 kg/m2)

• Clinically confirmed diagnosis of obstructive sleep apnea by one of the following methods:

a. Polysomnography: AHI =15/hour sleep or b. Home sleep apnea testing: Respiratory event index (REI) =15/hour sleep

• AHI: apnea-hypopnea index (apneas + hypopneas / total sleep time in hours)

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

• Known non-OSA related conditions associated with sleep disordered breathing (e.g., central disorder of hypersomnolence, neurological, neuromuscular, or pulmonary disorder)

• Use of sleep-inducing medications (e.g. benzodiazepines, opiates, barbiturates)

• Type 1 diabetes mellitus

• History of diabetic ketoacidosis

• Known hypersensitivity reaction to bexagliflozin or any of its constituents or any contraindication to bexagliflozin use

• Severe, recurrent urinary tract or genital mycotic infections

• eGFR<30mL/min/1.73m2 at time of or within 4 weeks of enrollment in the study

• Unable to complete/tolerate magnetic resonance imaging (MRI) due to severe claustrophobia or metallic implants.

• Language barrier, mental incapacity, unwillingness or inability to understand.

• Females of childbearing potential who are pregnant, breast-feeding or intend to become pregnant.

• Currently or planning to take a SGLT2i prior to or during enrollment in the study

• Currently or planning to follow a ketogenic diet pattern ("keto diet) prior to or during enrollment in the study

• Currently or planning to follow an active weight loss program (including but not limited to use of supplements, medications, or surgery) prior to or during enrollment in the study

• Currently or planning to follow an intermittent fasting diet plan prior to or during enrollment in the study

• Currently or planning to take a GLP-1 receptor agonist prior to or during enrollment in the study .

• Existing lower limb ulcer (due to diabetes or any cause)

• Existing severe peripheral arterial disease with intermittent claudication and/or prior lower limb revascularization procedure

• Concomitant administration of UGT inducers

• Severe liver disease

Related Conditions & MeSH terms

• Apnea
• Sleep Apnea
• Sleep Apnea Syndromes

Intervention

Drug:
• Bexagliflozin 20 mg
15mg once daily
• Placebo
matching placebo once daily

Locations

Country	Name	City	State
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	Yale New Haven Health	New Haven	Connecticut

Sponsors (2)

Lead Sponsor	Collaborator
Yale University	Case Western Reserve University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Apnea hypopnea index (AHI) measured by full ambulatory polysomnography (aPSG)	All participants will undergo a full in-home aPSG with a Nox-A1 system, which collects sleep EEG required to determine the physiologic traits and measures of sleep apnea. This is an unattended sleep monitor. The AHI is the number of apneas or hypopneas recorded during the sleep study per hour of sleep. Higher AHI indicates the severity of sleep apnea.	Baseline and 6 months
Secondary	Change in Neck and body fat and lean volume by MRI	Participants will undergo standard measurements including height, weight, waist circumference, hip circumference, and neck circumference by MRI to quantify fat and lean tissue composition in the neck and body. Volumetric imaging datasets of the body will be derived by MRI using validated and readily available protocols with rapid scan time to perform precise measurements of total and regional body composition to quantify fat and lean tissue composition in the neck and body. MRI imaging using a 6-minute dual-echo Dixon Vibe protocol, providing water and fat separated volumetric data set covering neck to knees, and a single-slice multi-echo Dixon acquisition for proton density fat fraction (PDFF) assessment in the liver.	Baseline and 6 months
Secondary	Change in Airway caliber by MRI	Volumetric imaging datasets of the body derived by MRI using validated and readily available protocols with rapid scan time to perform precise measurements of total and regional body composition to quantify fat and lean tissue composition in the neck and body, including MRI imaging using a 6-minute dual-echo Dixon Vibe protocol, providing water and fat separated volumetric data set covering neck to knees, and a single-slice multi-echo Dixon acquisition for proton density fat fraction (PDFF) assessment in the liver.	Baseline and 6 months
Secondary	Change in Critical closing pressure (Pcrit)/normal ventilatory drive (Vpass) by aPSG	Mathematical modeling to determine the patient's ventilatory drive in response to changes in ventilation induced by upper airway obstruction (i.e., apnea/hypopnea). Pharyngeal collapsibility, calculated as the level of ventilation during sleep at normal or eupneic ventilatory drive (Vpassive) and is a valid proxy for critical closing pressure (Pcrit) and a reflection of the impact of the anatomic traits of sleep apnea.	Baseline and 6 months
Secondary	Change in neck circumference	Change in neck circumference measured by tape measure. Measuring the change in the evening to morning neck circumference which is a validated measure of caudal to rostral fluid shift. Higher neck circumference indicates an increase in probability of sleep apnea.	Baseline and 6 months
Secondary	Change in Oxygen desaturation index (ODI) measured by aPSG	Percent of time with O2 saturation < 90% (T90) recorded during the aPSG	Baseline and 6 months
Secondary	Change in Sleep arousal index (ArI) measured by aPSG	Total arousal index (ArI) was defined as the total number of arousals recorded during the aPSG per hour of sleep.	Baseline and 6 months
Secondary	Change in Insomnia Severity Index (ISI)	The Insomnia Severity Index has seven questions. The seven answers are added up to get a total score. Total scores scale: 0-7 = No clinically significant insomnia 8-14 = Subthreshold insomnia 15-21 = Clinical insomnia (moderate severity) 22-28 = Clinical insomnia (severe)	Baseline, 3 months and 6 months
Secondary	Change in Sleep Quality measured by Pittsburgh Sleep Quality Index Form	This questionnaire contains 19 self-rated questions that are combined to form seven "component" scores, each of which has a range of 0-3 points. In all cases, a score of 0 indicates no difficulty in that area, while a score of 3 indicates severe difficulty. The seven component scores are then added to yield one global score, with a range of 0-21 points, with 0 indicating no difficulty and 21 indicating severe difficulties in all areas.; The seven component domains are: 1. Subjective sleep quality, 2. Sleep latency, 3. Sleep duration, 4. Habitual sleep efficiency, 5. Step disturbances, 6. Use of sleeping medication, and 7. Daytime dysfunction.	Baseline, 3 months and 6 months
Secondary	Change in Reduced Morningness Eveningness Questionnaire (MEQ)	The 5 questions reduced MEQ is a self-assessment questionnaire. Responses to the questions are combined to form a composite score that indicates the degree to which the respondent favors morning versus evening. In Total Score (0-25) higher scores indicate morningness, lower scores indicate eveningness.	Baseline, 3 months and 6 months
Secondary	Change in Regulatory Satisfaction Alertness Timing Efficiency Duration (RU-SATED)	Regulatory Satisfaction Alertness Timing Efficiency Duration (RU-SATED) questionnaire. This is a multidimensional metric for sleep health with 6 questions. RU-SATED stands for: regularity of sleep, satisfaction with sleep, alertness during the day, timing of sleep, efficiency of sleep, and duration of sleep. Each question is scored 0, 1, or 2 based on rarely/never, sometimes, usually always responses. The scores are summed, and a higher score indicates better sleep health.	Baseline, 3 months and 6 months
Secondary	Change in Sleep Deprivation Questionnaire (SDQ)	The questionnaire is divided into two sections. The first section assesses sleep duration in hours as a weighted average of work night hours and weekend night hours. Sleep deprivation is determined from the reported hours of sleep as follows: =7 hours = no sleep deprivation; <7 but =5 hours = mild to moderate sleep deprivation; <5 hours = severe sleep deprivation. The second section assesses the circadian timing of sleep by asking questions related to circadian-sleep mismatch; a higher score indicates worse circadian sleep timing.	Baseline, 3 months and 6 months
Secondary	Change in STOP - Bang questionnaire	The snoring, tiredness, observed apnea, high BP, BMI, age, neck circumference, and gender (STOP-Bang) questionnaire. The Total Sore 0-8 with higher scores indicating higher risks for obstructive sleep apnea. Affirmative answers get a "1" and the sum of the eight question scores is stratified into low risk for OSA (0-2), moderate risk (3-4), and high risk (5-8).	Baseline, 3 months and 6 months
Secondary	Change inThe Sleep Apnea Quality of Life Index (SAQLI).	This is a disease specific quality of life index for OSA in adults. Categories and domains include daily functioning, social interactions, emotional functioning, and symptoms. The scaling of items ranges from "not at all" to "all the time," a seven point scale.	Baseline, 3 months and 6 months
Secondary	Change in The Epworth Sleepiness Scale (ESS)	This is a validated scale to assess perceived hypersomnia. Patients are asked to score on a scale of 0 to 3 the likelihood that they would "doze-off" in different scenarios ranging from passes activities to active situations. The low score is zero in the high score is 24. The score of greater than 10 is considered clinically significant hypersomnia.	Baseline, 3 months and 6 months
Secondary	Change in height.	Height measured in cm.	Baseline and 6 months
Secondary	Change in weight.	Weight will be recorded to the nearest 0.1 kg using calibrated scales. Weight will be measured in a fasting state with an empty bladder, without shoes and only wearing light clothing.	Baseline and 6 months
Secondary	Change in body mass index (BMI)	Body mass index (BMI) is a value derived from the mass (weight) and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms and height in metres.	Baseline and 6 months
Secondary	Change in Waist circumference	Waist circumference measured in cm.	Baseline and 6 months
Secondary	Change in hip circumference	Hip circumference measured in cm.	Baseline and 6 months
Secondary	Change in sleep walking periods measured using Wrist-wearable actigraphy	The amount of time spent sleep walking in naturalistic settings will be measured using the ActiGraph which will be worn on the non-dominant wrist for 24-hours each day for seven consecutive days.	Baseline, 3 months and 6 months
Secondary	Change in 24 hour ambulatory average systolic blood pressure	24-hour ambulatory blood pressure monitoring using a blood pressure monitoring device to measure average systolic blood pressure	Baseline, 3 months and 6 months
Secondary	Change in 24 hour ambulatory average diastolic blood pressure	24-hour ambulatory blood pressure monitoring using a blood pressure monitoring device to measure average diastolic blood pressure	Baseline, 3 months and 6 months
Secondary	Change in 24 hour ambulatory blood pressure variability	24-hour ambulatory blood pressure monitoring using a blood pressure monitoring device measure blood pressure variability over 24 hour monitoring session.	Baseline, 3 months and 6 months
Secondary	Change in 24 hour ambulatory nighttime blood pressure dipping	Comparing average BP during wakefulness to average BP during major sleep episode in 24 hours monitoring session	Baseline, 3 months and 6 months
Secondary	Change in Vdrive/Loop gain by aPSG	Mathematical modeling to determine the patient's ventilatory drive (or desired ventilation, Vdrive) in response to changes in ventilation induced by upper airway obstruction (i.e., apnea/hypopnea). The Vdrive signal is fit to the ventilation (VE) signals when the airway is expected to be patent (VE = Vdrive). Recorded during the sleep study. Measures of Vdrive allow determinations of Loop gain (LG), measured by the increase in ventilatory drive that occurs following a unit reduction in ventilation due to apneas/hypopneas.	Baseline and 6 months
Secondary	Vdrive/Arousal threshold (ArTH) by aPSG	Mathematical modeling to determine the patient's ventilatory drive (or desired ventilation, Vdrive) in response to changes in ventilation induced by upper airway obstruction (i.e., apnea/hypopnea). The Vdrive signal is fit to the ventilation (VE) signals when the airway is expected to be patent (VE = Vdrive). Recorded during the sleep study. Measures of Vdrive allow determinations of Arousal threshold (ArTH), quantified as the level of "ventilatory drive" just before arousal from sleep.	Baseline and 6 months
Secondary	Vdrive/Pharyngeal muscle compensation (Mresp) by aPSG	Mathematical modeling to determine the patient's ventilatory drive (or desired ventilation, Vdrive) in response to changes in ventilation induced by upper airway obstruction (i.e., apnea/hypopnea). The Vdrive signal is fit to the ventilation (VE) signals when the airway is expected to be patent (VE = Vdrive). Recorded during the sleep study. Measures of Vdrive allow determinations of Pharyngeal muscle compensation (Mresp), assessed by the increase in ventilation achieved during sleep per unit increase in the ventilatory drive. The analysis is automated using custom MATLAB software.	Baseline and 6 months