Daily Low Oxygen Exposure and Weight Status

Study Overview
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Brief Summary
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The objective of this single-blind, parallel-arm, randomized clinical trial is to evaluate changes in body weight and composition, assess determinants of energy balance, and measure modulators of energy intake and expenditure, following 8 wk of calorie restriction (CR, -500 kcal/d) in combination with either overnight exposure (8 h/night) to normobaric hypoxia (NH; 15% oxygen,  8500 ft elevation) or normoxia (NN; 21% oxygen, sea level), using a commercially available, in-home tent system, in adults who are overweight or obese.

Detailed Description
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The current research study will evaluate changes in body weight and composition, assess determinants of energy balance, and measure modulators of energy intake and expenditure, following 8 wk of calorie restriction (CR, -500 kcal/d) in combination with either overnight exposure to normobaric hypoxia (NH) or normoxia (NN). Participants will be instructed to follow their normal diet but with a 500 kcal/day deficit as advised by a Registered Dietitian. Participants will spend 8 hours/night in a tent, set-up around their bed, in their home, for 8 weeks. Participants sleeping in the hypoxic tent (Hypoxico Inc., New York, NY, commercially available tents: https://hypoxico.com/) will breath  15% oxygen (achieved with nitrogen dilution, equivalent to  8500 ft elevation), whereas those in the control tent (Hypoxico Inc.) will breath  21% oxygen (achieved with nitrogen dilution, equivalent to sea level elevation). Trained research staff will set-up the hypoxic or control tent system in each participant's home on day 0 and will visit the participant's home on days 1, 2, and 3 to check and/or adjust the tent settings. After day 3, research staff will visit the participant's home weekly to check and/or adjust the tent settings. participants will be weighed each morning following an overnight fast and morning void. Participants will come to the laboratory on two separate days for baseline testing (days -1 and 0) and again on two separate days at the end of the study (days 55 and 56) for endpoint testing.

Official Title
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Effects of Daily Low Oxygen Exposure on Weight Status, Body Composition, and Metabolic Health

Conditions
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Overweight and Obesity

Intervention / Treatment
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* Other: Normobaric hypoxia
* Other: Normobaric normoxia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged 20 - 50 years Overweight or obese (BMI between 27.5-34.9 kg/m2) Born at altitudes less than 2,100 meters ( 7,000 feet) Currently residing in Tallahassee, Florida, or the surrounding area Not taking any medication(s) that interfere with metabolism or oxygen delivery/transport for 4 weeks prior to and throughout the entire study (e.g., includes sedatives, sleeping aids, tranquilizers, and/or any medication that depresses ventilation, diuretics, alpha, and beta-blockers). Willing to refrain from smoking, vaping, chewing tobacco, and dietary supplement use throughout the entire study Willing to have a hypoxic tent set-up in their home and spend 8 consecutive hours per night in the tent for 8 weeks Lives with a family member, partner/spouse, or roommate who can hear and respond in the unlikely event that the blood oxygen, air oxygen, or air carbon dioxide monitoring alarm would sound. Exclusion Criteria: Living in areas that are more than 1,200 m ( 4,000 feet), or have traveled to areas that are more than 1,200 m for five days or more within the last 2 months Metabolic or cardiovascular abnormalities, gastrointestinal disorders, and any condition that interferes with metabolism or oxygen delivery/transport (e.g., kidney disease, diabetes, cardiovascular disease, etc.) Evidence of apnea or other sleeping disorders Evidence of prior high-altitude pulmonary edema (HAPE) or high-altitude cerebral edema (HACE) diagnosis Diagnosis or family history of sickle cell anemia/trait Hematocrit <42% for males, <36% for females Hemoglobin <13 g/dL for males, <12 g/dL for females Blood donation within 8 weeks of beginning the study Present condition of alcoholism, anabolic steroids, or other substance abuse issues Allergies or intolerance to foods included in the standardized and ad libitum meal tests (e.g., lactose intolerance/milk allergy) Women who are pregnant, lactating, planning to become pregnant, or who have had an irregular menstrual cycle in the past 6 mo. Weight gain or loss > 10% of body weight during the past 6 months Adults unable to consent Individuals who are not yet adults (infants, children, teenagers) Prisoners

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Normobaric hypoxia (NH)<br>8 weeks of overnight exposure (8 hrs/night) to NH conditions ( 15% oxygen; achieved with nitrogen dilution, equivalent to  8500 feet elevation) using a commercially available tent and generator system (Hypoxico, Inc., New York, NY). | Other: Normobaric hypoxia<br>* Low oxygen exposure to mimic  8500 feet elevation (experimental).<br>|
| Sham Comparator: Normobaric normoxia (NN)<br>8 weeks of overnight exposure (8 hrs/night) to NN conditions ( 21% oxygen; sea level) using a commercially available tent and generator system (Hypoxico, Inc., New York, NY). | Other: Normobaric normoxia<br>* Normal oxygen exposure to mimic sea level conditions (sham comparator).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change in body weight | Body weight will be measured during baseline (days -7 to 0) and each morning during the study (days 1 to 56) following an overnight fast and morning void, using a calibrated digital scale provided to participants to use at home (A&D Medical wireless weight scale UC-352BLE, San Jose, CA). Percent change in body weight will be calculated as: [Body weight - baseline body weight (average of days -7 to 0)]/ baseline body weight * 100 | 8 weeks (56 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change in body weight | Body weight also will be measured 4 weeks after the study intervention ends to assess whether weight loss is sustained. | 4 weeks after intervention ends | 
| 4-compartment body composition using DEXA and deuterium dilution | Body composition will be determined following a 12 hour fast and morning void on day -1 and 55 using dual energy x-ray absorptiometry (DEXA, Discovery W, Hologic Inc., Bedford, MA or equivalent). The volunteer will remove all metal-containing objects from their body, lay face-up on the DEXA densitometer table in light clothing (t-shirt, shorts, socks), and be asked to remain motionless for the 8-10 min scan. A scanner emitting low energy x-rays and a detector will pass over the participant. These data will be used to calculate total body mass, fat-free mass, fat mass, and bone mass. Total body water will be measured following a 12 hour fast and 1 hour without water intake using the deuterium dilution method on days -1 and 55. | Days -1 and 55 | 
| Resting metabolic rate | Resting metabolic rate will be measured with open circuit, indirect calorimetry (ParvoMedics TrueOne 2400 metabolic cart, Sandy, UT) in the morning, upon arrival to the lab on days 0 and 56. | Days 0 and 56 | 
| Resting substrate oxidation | Resting substrate oxidation will be measured with open circuit, indirect calorimetry (ParvoMedics TrueOne 2400 metabolic cart, Sandy, UT) in the morning, upon arrival to the lab on days 0 and 56. | Days 0 and 56 | 
| Total daily energy intake | Participants will complete 3 dietary records (2 week days, 1 weekend day) prior to the in-person baseline visit and during weeks 1, 2, 4, 6, and 8 of the study using the Automated Self-Administered 24-Hour (ASA24®) Dietary Assessment Tool. This web-based tool was developed by the National Cancer Institute: https://epi.grants.cancer.gov/asa24/. | Weeks -1, 1, 2, 4, 6, and 8 | 
| Total daily macronutrient intake | Participants will complete 3 dietary records (2 week days, 1 weekend day) prior to the in-person baseline visit and during weeks 1, 2, 4, 6, and 8 of the study using the Automated Self-Administered 24-Hour (ASA24®) Dietary Assessment Tool. This web-based tool was developed by the National Cancer Institute: https://epi.grants.cancer.gov/asa24/. | Weeks -1, 1, 2, 4, 6, and 8 | 
| Ad libitum energy intake | Ad libitum energy intake will be assessed by measuring total energy intake during an ad libitum buffet-style meal provided to participants on days 0 and 56. | Days 0 and 56 | 
| Food preferences | Food preferences will be assessed by measuring macronutrient intake during an ad libitum buffet-style meal provided to participants on days 0 and 56. | Days 0 and 56 | 
| Heart rate variability | A 3-lead electrocardiogram will be conducted on days 0 and 56 to assess heart rate variability. Participants will have electrode patches placed on their chest to measure the electrical activity of the heart. | Days 0 and 56 | 
| Urinary epinephrine | On days -1, 13, and 55 urine will be collected during the overnight time period. Participants will void their bladder before entering the tent in the evening (they will not collect this portion). Participants will collect any urine produced throughout the night and will collect one final time in the morning after exiting the tent. Epinephrine concentrations in the urine samples will be measured. | Days -1, 13, and 55 | 
| Urinary norepinephrine | On days -1, 13, and 55 urine will be collected during the overnight time period. Participants will void their bladder before entering the tent in the evening (they will not collect this portion). Participants will collect any urine produced throughout the night and will collect one final time in the morning after exiting the tent. Norepinephrine concentrations in the urine samples will be measured. | Days -1, 13, and 55 | 
| Urinary dopamine | On days -1, 13, and 55 urine will be collected during the overnight time period. Participants will void their bladder before entering the tent in the evening (they will not collect this portion). Participants will collect any urine produced throughout the night and will collect one final time in the morning after exiting the tent. Dopamine concentrations in the urine samples will be measured. | Days -1, 13, and 55 | 
| Plasma glucose concentrations | A 75-g oral glucose tolerance test (OGTT) will be conducted on days 0 and 56. A venous catheter will be placed and blood samples obtained at -5, 30, 60, 90, and 120 min during the OGTT for measurements of plasma glucose and insulin concentration. Insulin sensitivity will be determined by using the whole-body insulin sensitivity index (WBISI), also known as the Matsuda Index. | Days 0 and 56 | 
| Plasma insulin concentrations | A 75-g oral glucose tolerance test (OGTT) will be conducted on days 0 and 56. A venous catheter will be placed and blood samples obtained at -5, 30, 60, 90, and 120 min during the OGTT for measurements of plasma glucose and insulin concentration. Insulin sensitivity will be determined by using the whole-body insulin sensitivity index (WBISI), also known as the Matsuda Index. | Days 0 and 56 | 
| Whole-body insulin sensitivity index | A 75-g oral glucose tolerance test (OGTT) will be conducted on days 0 and 56. A venous catheter will be placed and blood samples obtained at -5, 30, 60, 90, and 120 min during the OGTT for measurements of plasma glucose and insulin concentration. Insulin sensitivity will be determined by using the whole-body insulin sensitivity index (WBISI), also known as the Matsuda Index. | Days 0 and 56 | 
| Thermic effect of glucose | The thermic effect of glucose will be measured on study days 0 and 56 with open circuit, indirect calorimetry (2400 TrueOne, Parvo Medics) using established protocols. Resting metabolic rate measurements will be taken prior to glucose administration in a thermo-neutral room while the participant is in the supine position (as described above). During the oral glucose tolerance test the thermic effect of glucose will be measured in 15 min increments for 2 hours (15-30, 45-60, 75-90, and 105-120 minutes). | Days 0 and 56 | 
| Subjective appetite measures | Subjective appetite will be measured on study days 0 and 56. Subjectively rated appetite will be assessed immediately before the oral glucose tolerance test (OGTT) and at 15, 30, 45, 60, 90, and 120 minutes after beginning the OGTT using 100 mm visual analog scales to rate fullness, hunger, desire to eat, and prospective food consumption. Composite satiety score will be calculated from the individual appetite scores using the equation: CSS = (fullness + (100 - Desire to eat) + (100 - Hunger) + (100 - Prospective food consumption) / 4. | Days 0 and 56 | 
| Prevalence of acute mountain sickness | The prevalence and severity of acute mountain sickness (AMS) will be determined from information gathered using the shortened version of the Environmental Symptoms Questionnaire (ESQ) (5 min; 26 questions total). The minimum score is 0 and the maximum score is 5. A lower score indicates fewer AMS symptoms. At completion, oxygen saturation will be determined using finger pulse oximetry (PalmSAT® 2500A, Nonin Medical, Inc., Plymouth, MN). AMS and oxygen saturation measurements will be taken in the morning on days 0-7, 14, 21, 28, 35, 42, and 56. | Days 0-7, 14, 21, 28, 35, 42, and 56 | 
| Continuous overnight oxygen saturation | Oxygen saturation will be measured continuously overnight (8 h/night) using a finger pulse oximeter (PalmSAT® 2500, Nonin Medical, Inc., Plymouth, MN) during 8 weeks of overnight exposure to NH or NN. | 8 weeks (56 days) | 
| Sleep quality | The Pittsburgh Sleep Quality Index (PSQI; 5 minutes, 18 questions) will be used to examine volunteer sleep quality on days 0-7, 14, 28, 35, 42, and 56. The minimum score is 0 and the maximum score is 21. Lower scores indicate better sleep quality. | Days 0-7, 14, 28, 35, 42, and 56 | 
| 24-hour continuous glucose concentrations | A continuous glucose monitor (Freestyle Libre Pro) will be inserted into the subcutaneous adipose tissue behind the arm and will be used to collect and assess 24-hour glucose concentrations during baseline (day -7 to day 0), days 1-14, and days 42-56. | Days -7 to 0, 1 to 14, and 42 to 56 | 
| 24-hour glucose variability | A continuous glucose monitor (Freestyle Libre Pro) will be inserted into the subcutaneous adipose tissue behind the arm and will be used to collect and assess 24-hour glucose concentrations during baseline (day -7 to day 0), days 1-14, and days 42-56. | Days -7 to 0, 1 to 14, and 42 to 56 | 
| Blood volume | Blood volume will be determined using the optimized carbon monoxide rebreathing method on days -1 and 55. In this method, a capillary blood sample is taken, and basal carboxyhemoglobin concentrations will be determined using a blood gas analyzer. Carbon monoxide is then inhaled via a spirometer (SpiCo, Blood Tec.) for 2 minutes. Seven minutes after inhaling the carbon monoxide bolus, a second capillary blood sample is taken to determine the increase in carboxyhemoglobin concentration. The change in percentage of carboxyhemoglobin between the basal and second measurements can be used to calculate hemoglobin mass and blood volume. | Days -1 and 55 | 
| Fasting measures of iron status | Serum iron, total iron binding capacity, soluble transferrin receptor, hepcidin, hemoglobin, hematocrit, ferritin, erythroferrone, and erythropoietin will be measured in fasting blood samples collected on days 0 and 56. | Days 0 and 56 | 
| Psychosocial Factors | The Positive and Negative Affect Schedule, Cohen Perceived Stress Scale, Big Five Inventory-2, Delay Discounting questionnaire, Palatable Eating Motives Scale, and the Generalized Self-Efficacy scale will be administered on days -1, 14, and 55. | Days -1, 14, and 55 | 
| Fasting blood pressure | Fasting blood pressure will be measured on days 0 and 56 using an automated blood pressure cuff. All blood pressure readings will be taken on the right arm, and participants will be in a seated position, after resting for at least 5 minutes. Blood pressure will be measured in triplicate. | Days 0 and 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Normobaric hypoxia, Overwieght and obesity, Negative energy balance, Energy expenditure, Energy intake, Body weight