Prolonged Hypoxic Breathing in Healthy Volunteers: a Safety Study
Prolonged Hypoxic Breathing in Healthy Volunteers: a Safety Study
The purpose of this study is to define the safety and the biochemical-physiological response
 of prolonged exposure to a normobaric low-oxygen environment in healthy volunteers.
The primary endpoint of this research study is to prove safety in healthy subjects breathing
 humidified hypoxic inspiratory gas mixture for 5 days.

 The secondary endpoint of our study is to describe the physiological and biochemical changes
 during the 5-day hypoxic period and the 2 days after return to normoxia.

 The specific aims are as follows:

 AIM 1: To provide a safe, controlled setting for prolonged exposure of monitored healthy
 adults to a normobaric, low-oxygen environment for five days.

 AIM 2: To carry out a seven-days long pilot safety-study in twelve healthy young subjects by
 inducing hypoxia with a humidified normobaric gas mixture containing oxygen (O2) content as
 low as 11% to reach a peripheral oxygen saturation (SpO2) between 80%-85%.

 Screening will consist of a physical examination, 12-lead electrocardiogram, cardiac
 echocardiography, sickle cell screening test, and current (within 12 weeks of clearance exam
 with no intervening medical treatment) routine blood and urine analyses.

 Women using oral, subdermal or injectable contraceptives, and those using other means of
 birth control may participate. A urine pregnancy test will be conducted as part of the
 screening process for study participation no more than 7 days before starting the study and
 it will be repeated on the day of enrollment. The test result will be read by a female staff
 member who will keep the result confidential. If a woman declines to have a pregnancy test,
 she will not be able to participate.

 Recruitment will be done in three ways:

 1. Broadcast MGH: Research Studies In Need of Volunteers

 2. Enrollment in the Research Study Volunteer Program (RSVP) for Health of Massachusetts
 General Hospital (MGH) and Brigham Women Hospital (BWH)

 3. Advertising at the Partners clinical trials Potential study subjects will be able to
 contact study investigators by phone or email to verify eligibility according to the
 inclusion/exclusion criteria and to set up the first visit, at which point the study
 will be explained in detail and they will be asked to provide informed consent. Subjects
 may contact the study investigators at any time to withdraw from the study.
 Confidentiality will be preserved to the fullest extent.

 The study will be explained to each volunteer in detail. Signing of an Informed Consent Form
 will be requested for participation in the study. Volunteers will sign the informed consent
 at the beginning of the study. The Principal Investigator (PI) and/or Co-PIs of the study
 will be available to answer any questions the volunteer may have. Consent can be withdrawn at
 any time. The investigators will access personal Medical Information (PMI) for study
 purposes. There is no randomization in this interventional physiological study. All patients
 will receive the same procedures in the same order.

 Biostatistical analysis:

 A de-identified code will be assigned to the patient and registered on a dedicated enrollment
 log. The baseline study volunteer data (vital signs and biochemical measurements) will be
 collected from the MGH electronic medical chart (EPIC). Prospective collection of patient
 data will include specific data sheet. Data will be expressed as means ± standard deviation
 (SD) or median/interquartile range (IQR) as appropriate.

 Sample size: this research-project is aimed to study 12 healthy subjects for the entire 7-day
 study period. To account for possible dropouts and missing data, up to 18 healthy volunteers
 will be enrolled.

 Sample size calculation: This is an intra-hospital safety trial with the purpose of testing
 methods to re-create a safe hypoxic environment for possible future studies in patients with
 mitochondrial dysfunction. While 2 or 3 subjects would likely be sufficient to test our
 methods to reliably delivery humidified nitrogen (N2) and (O2) in predetermined
 concentrations, this method will be tested in 12 healthy subjects to reproduce our methods
 and obtain feedback from the volunteers. To account for possible dropouts, up to 18 healthy
 volunteers will be enrolled.

 Risk and discomforts

 1. Complications of surgical and non-surgical procedures, etc. Participants in the study
 will undergo 3 procedures during the study: hypoxic gas administration, phlebotomy, and
 echocardiography.

 -  Facemask.

 1. Claustrophobia is one of the exclusion criteria. If a subject develops
 claustrophobia, he/she may leave the trial at any point.

 2. The most common side effects of facemask are pressure related, such as
 redness, irritation over the mask's borders. To decrease possible skin
 irritation and abrasions, subjects will be using a tent during the night and
 high flow nasal cannula during the day for breakfast, lunch and dinner.
 Additionally they will be able to choose whether to use high-flow nasal
 cannula or the facemask during the day at any time as an alternative to the
 facemask.

 -  Tent. Risks associated with use of tents include unintended hypoxia, hypercarbia,
 and claustrophobia. These tents are made at the MGH shop and routinely used on the
 burn unit to maintain elevated temperature (80-90 °F) and humidification in
 critically ill patients. Our subjects will be continuously monitored for hypoxia
 and clinical condition to limit risk of unintended hypoxia or hypercarbia.
 Claustrophobia will be handled as described previously.

 -  Nasal cannula and non-invasive high flow humidified gas. All participants will wear
 non-invasive high flow humidified gas for part of study period. Unlike masks, high
 flow nasal cannula is well tolerated in hospitalized patients and warm humidified
 air alleviates discomfort of the high flow. In order to avoid abrasions, we will
 inspect subjects' nasal mucosa in the morning and evening.

 -  Intravenous (IV) punctures and phlebotomy. Risks related to phlebotomy include
 bruising, hematoma formation, cellulitis, superficial thrombosis, bleeding and
 phlebitis. An IV nurse or an anesthesiologist will perform phlebotomy to minimize
 subject discomfort.

 -  Trans-thoracic echocardiography. Echocardiography will be performed on daily basis:
 Echocardiographic assessment of pulmonary artery pressure and cardiac output is a
 noninvasive and painless maneuver. It is commonly used in clinical practice, has
 been used in the field under hypoxic conditions, and is safe for the study
 subjects. If the echocardiographic study reveals any unexpected cardiac disease the
 subjects will be informed and also their primary care physician (PCP) will be
 informed. If the subject does not have a PCP, we will provide information about
 choosing a PCP.

 In presence of an abnormal physical exam and/or additional abnormal laboratory results
 (including a positive pregnancy test), subjects will be informed.

 2. Drug side effects and toxicities

 A gas mixture enriched with nitrogen will be tested. It is expected that subjects may
 suffer to a certain degree of acute mountain sickness. Symptoms may include: headache,
 dizziness, poor sleep, poor appetite and fatigue that are related to hypoxia. These
 symptoms are well described in mountain climbers and will not require interruption of
 the study, unless the subject requests exiting the study. Furthermore, in this proposed
 model of normobaric hypoxia, the risk of acute mountain sickness symptoms has been
 reported to be lower than hypobaric hypoxia (simulated altitude). The following risks
 might also occur:

 -  Risks Associated with Hypoxia: Severe hypoxemia (SpO2 ≤ 70%), especially with
 decreased respiratory rate can ensue. Since the fraction of inspired of oxygen can
 be quickly increased, there is no risk of developing prolonged hypoxia events. If
 SpO2 ≤ 70% decreases for more than one continuous minute, nitrogen administration
 will be stopped and the fraction of inspired of oxygen will be increased to 50%.
 The study will be stopped. Symptoms of hypoxia (light headedness, dizziness)
 typically resolve immediately upon return to a normal range of SpO2. If hypoxia
 symptoms are present, subjects will exit the study only after all symptoms of
 light-headedness or dizziness are resolved, and headache or nausea is absent.

 -  Acute mountain sickness can very rarely progress to high altitude pulmonary edema
 (HAPE) or high altitude cerebral edema (HACE) and would be case reportable were
 either to occur in normobaria at the limited hypoxic challenge we will be
 employing. Though HAPE is very unlikely to occur, we will provide daily monitoring
 by echocardiography, clinical exam (auscultation for rales and unusual dyspnea at
 rest solicited), and pulse oximetry. If HAPE does occur, the study will stop and
 the subject treated with oxygen until resolution of symptoms.

 -  HACE is also a very unlikely potential risk in this study. If a subject develops
 any evidence of ataxia or altered mental status, they will be immediately withdrawn
 from the study. FiO2 will be increased to 50%, dexamethasone 8 mg IV will be
 administered, and head computed tomography (CT) will be performed to rule out other
 much more common sources (e.g. spontaneous subarachnoid hemorrhage) of these
 complaints. If no CT abnormalities are noted, a brain magnetic resonance imaging
 (MRI) will be obtained to assess for cerebral edema and characteristic T2 weighted
 signal change in the corpus callosum consistent with HAPE..

 Any study subject who experiences side effects sufficient to prompt premature
 termination of the study will not be allowed to continue in the protocol. He or she will
 be monitored until vital signs normalize and transthoracic echocardiography (TTE) shows
 normal right heart function.

 3. Device complications/malfunctions Nitrogen generator: If the nitrogen generator is
 malfunctioning, air will be enriched with nitrogen from nitrogen-tanks. The manufacturer
 will be contacted (Higher Peak LLC, Winchester, Massachusetts (MA) 01890) in order to
 deliver a new nitrogen generator.

 4. Psychosocial (non-medical) risks Psychosocial risks include prolonged indoor exposure
 and perceived isolation from a subject's daily routine, family and friends. Subjects
 will have ready access to their personal communication devices (e.g. smart phone for
 voice/ social media use) during times when they are not actively participating in
 testing procedures. Subjects may be visited in person on the study floor. We do not
 anticipate any other psychosocial risks to the study subjects from participation in this
 protocol. Strict confidentiality will be maintained by the research team at all times,
 including keeping all data in a secure, locked cabinet with limited access. All
 specimens will be coded after they are obtained and the code key kept in a locked
 cabinet. All electronic data will be stored in a Partners encrypted laptop. Samples
 given to parties outside of MGH for analysis will be coded to maintain confidentiality.

 Monitoring and Quality Insurance:

 Due to the small size of the study, no independent monitoring is deemed necessary. The PI
 himself will be responsible for the monitoring of the study.

 The PI and co-Is will be responsible for the monitoring of the study. Dr. Lorenzo Berra is
 the Principal Investigator and he is an Anesthesiologist and Intensivist at MGH and Assistant
 Professor at Harvard Medical School.

 Stopping rules

 The principal investigator and co-investigators will perform the review and decision
 regarding altering or stopping the protocol. Mild or moderate adverse events will be
 presented in progress reports at continuing reviews. Protocol exit criteria will be:

 -  Desaturation: SpO2<70% for more than 1 minute not immediately responsive to oxygen
 therapy.

 -  Chest pain with evidence of ischemia on electrocardiography (EKG) (e.g., T-wave
 inversions, ST segment changes).

 -  Signs and symptoms of acute pulmonary edema:

 -  Rapidly progressive, severe shortness of breath at rest..

 -  Severe dyspnea, or a feeling of suffocating or drowning despite return to normoxia.

 -  Wheezing or gasping accompanied with anxiety, restlessness or a sense of
 apprehension.

 -  A cough that produces frothy sputum that may be tinged with blood

 -  Signs and symptoms of acute cerebral edema:

 -  acute ataxia or altered mental status

 -  any focal neurologic deficit.

 -  Increase in systolic pulmonary artery pressure of 15 mmHg from baseline (first
 trans-echocardiography in ambient air)

 -  Syncope.

 -  Febrile illness (> 100.4 on two contiguous assays 1 hour apart)

 -  Subject may voluntarily withdraw from the study at any time.
Inclusion criteria

 -  Have a photo identification (ID)

 -  Male or female individuals age between 18 and 40 years old

 -  BMI between 19 and 24.9 kg/m2

 -  Having capacity to consent to the study Exclusion criteria

 -  Evidence of any physical, mental, and/or medical conditions that would make the
 proposed studies relatively more hazardous

 -  Prior high altitude pulmonary edema (HAPE) or high-altitude cerebral edema (HACE)
 diagnosis

 -  Born at altitudes greater than 2,100 m (~7,000 ft)

 -  Systemic disease with or without any functional limitation; including

 -  controlled hypertension

 -  controlled diabetes without systemic effects

 -  Pregnancy determined by urine pregnancy test, detecting presence of human chorionic
 gonadotropin (hCG), or less than six weeks postpartum

 -  Women who are not willing to receive urine pregnancy tests

 -  Active smoking. Volunteers may be enrolled if they quit smoking for more than 1 year.

 -  Excess alcohol use: more than ½ L/day of wine consumption or equivalent

 -  Any current medication use except oral contraceptives.

 -  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 more than four days within the last 2 months

 -  Tobacco chewers

 -  Abnormal hemoglobin or hematocrit levels or presence of hemoglobin S

 -  Evidence of apnea or other sleeping disorders

 -  Evidence of asthma

 -  Lower respiratory infection within the last 30 days

 -  If applicable, unwilling to refrain from using energy drinks or other caffeinated
 beverages for 7 days prior to and during the study

 -  If applicable, unwilling to refrain from use of all over-the-counter oral medications,
 herbal remedies, and nutritional supplements for 7 days prior to and during the study

 -  Not willing to have blood drawn from an arm vein each test day of the study

 -  Claustrophobia (inability to wear a facemask) or other active psychiatric conditions
 or not willingness to cooperate with the investigators and the other medical team

 -  Currently enrolled in another research study

 -  Facial abnormalities that would preclude proper use of a face mask

 Pregnancy Prevention/Testing: Women using oral, subdermal or injectable contraceptives, and
 those using other means of birth control may participate. A urine pregnancy test will be
 conducted as part of the screening process for study participation no more than 7 days
 before starting the study. The test result will be read by a female staff member who will
 keep the result confidential. If a woman declines to have a pregnancy test, she will not be
 able to participate.