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

Study Overview
=================
Brief Summary
-----------------
The goal of this clinical trial is to test if ertugliflozin 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.

Detailed Description
-----------------
The primary objective of this study is to determine whether ertugliflozin 15 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 ertugliflozin 15 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 ertugliflozin 15 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.

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

Conditions
-----------------
Sleep Apnea

Intervention / Treatment
-----------------
* Drug: Ertugliflozin 15 mg
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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: 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 ertugliflozin or any of its constituents or any contraindication to ertugliflozin use Severe, recurrent urinary tract or genital mycotic infections Plan to initiate glucagon-like peptide 1 (GLP-1) receptor agonist therapy for weight loss or glycemic control in the next 6 months 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ertugliflozin<br>Ertugliflozin once daily for 6 months | Drug: Ertugliflozin 15 mg<br>* 15mg once daily<br>|
| Placebo Comparator: Placebo<br>Placebo once daily for 6 months | Drug: Placebo<br>* matching placebo once daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Change in height. | Height measured in cm. | Baseline and 6 months | 
| 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 | 
| 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 | 
| Change in Waist circumference | Waist circumference measured in cm. | Baseline and 6 months | 
| Change in hip circumference | Hip circumference measured in cm. | Baseline and 6 months | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 |