Clinical trial NCT03383887
Conditions: Obstructive Sleep Apnea (OSA)
Sponsor: Brigham and Women's Hospital
Start date: 2017-12-13; Completion date: 2020-01-20
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Obstructive sleep apnea (OSA) is common and has major health implications but treatment options are limited. OSA patients show a marked reduction in upper airway (UA) dilator muscle activity at sleep onset and this phenomenon leads to increased collapsibility of UA compared to normal subjects. In this protocol the investigators will test the effect of DAW1033D administered before sleep on OSA phenotype traits and OSA severity during sleep.

Detailed description:

Arms: arm 1: Placebo capsule 30 minutes before sleep arm 2: DAW1033D capsule 30 minutes before sleep
Interventions: intervention 1: Placebo oral capsule intervention 2: DAW1033D oral capsule
Intervention descriptions: intervention 1: Placebo before sleep intervention 2: DAW1033D before sleep

Protocol documents:
Prot_SAP_000.pdf: 
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Title: Pharmacologically improving the pharyngeal muscle activity during sleep: implications for the novel 
treatment of obstructive sleep apnea. 
Principal Investigator: David Andrew Wellman, MD, PhD 
 
I. 
BACKGROUND AND SIGNIFICANCE 
Obstructive sleep apnea (OSA) is characterized by repetitive collapse or ‘obstruction’ of the pharyngeal 
airway during sleep. Over the last decade, and particularly in the last few years, research has shown that a 
number of pathogenic factors, or traits, contribute to the development of OSA (1-4).  These include: 1) an 
anatomically small, collapsible upper airway; 2) an oversensitive respiratory control system leading to 
ventilatory overshoots and undershoots, i.e., instability; 3) a loss of pharyngeal muscle tone or 
responsiveness during sleep; and 4) a low respiratory arousal threshold, i.e., premature arousal to respiratory 
stimuli. 
 
Despite our improved understanding of the pathogenesis of OSA, it has not led to improved therapy.  
Continuous positive airway pressure (CPAP) is still the only viable treatment for most patients, and it is 
usually effective because it mechanically splints the upper the airway open.  The problem, however, is that 
many patients cannot use CPAP because they find it intolerable.  This represents a significant health 
concern, as OSA is known to cause a number of adverse cardiovascular  (5-12), neurocognitive (13), and 
daytime functioning (14) consequences. 
 
One possible approach to finding alternative treatments for OSA is to continue searching for a single drug 
or agent that, like CPAP, has a large enough effect size to override the various causes of OSA.  This 
approach has proven difficult, and while we hold out hope for such a drug, in the meantime we have adopted 
another (possibly equally effective) tactic, which is to target the relevant upstream mechanisms or 
individual traits with one or more drugs in an individual patient.  The rationale for this approach is that 
non-CPAP therapies have tended to have small effect sizes and proven, by themselves, marginally effective 
at fully correcting OSA in many patients.  Another reason stems from the manner in which most major 
medical disorders are treated.  Rarely is a single drug used to treat, for example, congestive heart failure, 
hypertension, asthma, etc., unless the condition is mild.  In our view, a similar approach should be taken 
for managing OSA. 
 
Regardless of whether single or multidrug therapy is ultimately used, the search for alternative treatments 
has been lacking a very important ingredient – a drug to stimulate the pharyngeal muscles. While a host of 
oral devices and surgeries have been developed to address the anatomical predisposition to collapse, and 
our group has made significant headway in dealing with ventilatory control sensitivity (15, 16), drugs that 
activate the pharyngeal muscles are needed. Interestingly, new research in animals has improved our 
understanding of the state-dependent neurotransmitters involved in pharyngeal muscle activation during 
sleep. Importantly, the loss of noradrenergic activity is now thought to play the key role in the sleep-related 
hypotonia of pharyngeal muscles.  
 
Chan and colleagues (17) showed in rats that the noradrenergic antagonist terazosin substantially reduced 
genioglossus (a major muscle of the upper airway) activity (EMGGG) during wakefulness and produced 
REM-like atonia during NREM sleep, illustrating the importance of noradrenergic mechanisms. Other 
studies (18, 19) also support the notion that progressive withdrawal of noradrenergic tone, from 
wakefulness to NREM and REM sleep, is the major mechanism causing sleep-related pharyngeal 
hypotonia. While noradrenergic withdrawal is thought to be the main cause of pharyngeal hypotonia in 
NREM sleep, there are additional mechanisms that cause further reduction in REM sleep.  Chan and 
colleagues (17) failed to reverse REM atonia with alpha-1 receptor agonists applied to the hypoglossal 
nucleus, suggesting that another, possibly inhibitory, mechanism is at work. Horner and colleagues have 


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identified this inhibitory process as muscarinic by demonstrating restoration of EMGGG activity during 
REM sleep with the muscarinic antagonist scopolamine (20, 21).  More recently, these researchers found 
that the multiple state-dependent adrenergic, serotonergic and muscarinic systems produce suppression of 
EMGGG activity during sleep via a convergent ionic mechanism: increased potassium conductance. 
Blockade of potassium channels has been shown in mice to be capable of reactivating the pharyngeal 
musculature throughout sleep (22). 
 
 
However, due to the only recent identification of this process, there has not yet been an attempt to stimulate 
the pharyngeal muscles with noradrenergic drugs in sleeping humans. Now, more than ever, the stage has 
been set for stimulating the pharyngeal muscles across both NREM and REM sleep. 
 
II. 
SPECIFIC AIMS 
To determine the effect of noradrenergic and antimuscarinic on genioglossus activity and OSA severity. 
We hypothesize that existing drugs with these neurotransmitter profiles could (partially) restore pharyngeal 
muscle activity in humans during sleep.   
 
Specifically, we will test this hypothesis by assessing;  
1. The effect of pseudoephedrine (an α1-adrenergic agonist) combined with diphenydramine (an 
antihistaminic with sedative properties and with antimuscarinic action) on EMGGG during sleep 
(PART D). 
 
III. 
SUBJECT SELECTION 
We will recruit a group of subjects with OSA. These subjects will be recruited from the community and be 
between 21-65 years old. The purpose of studying patients with OSA is to determine what effect this drugs 
will have on improving the patient’s OSA severity.  
 
a) Obstructive Sleep Apnea Patients (n= 15): Patients with OSA will be recruited from our clinical 
sleep laboratory at Brigham and Women’s Hospital, as well as from our existing database of OSA 
patients. These individuals will be otherwise healthy (except for well-controlled hypertension; 
defined as systolic blood pressure <140 mmHg and diastolic <90 mmHg) with no active medical 
problems and on no medication that could affect respiration or muscle control. All will be 21-65 
years of age. Both men and women will have an apnea-hypopnea index (AHI) >15 events/hr during 
supine NREM sleep. These individuals will be recruited to encompass a large range of AHI’s (from 
10 to >60/hour).  
b)  Exclusion criteria: 
− 
Any active medical condition other than well controlled hypertension, hyperlipidemia, 
gastroesophageal reflux disease, depression. 
− 
Any medication known to influence breathing, sleep/arousal or muscle physiology. 
− 
Claustrophobia. 
− 
Inability to sleep supine. 
− 
Allergy to lidocaine, Oxymetazoline HCl, pseudoephedrine HCl, diphenhydramine. 
− 
Individuals with underlying cardiac disease, such as arrhythmias. 
− 
History of seizures 
− 
History of moderate or severe renal impairment 
− 
For women: Pregnancy. 
 
We will consider all applicants regardless of sex, race, color, creed, or national origin. 


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IV. 
SUBJECT ENROLLMENT 
 
Subjects will be recruited through email, telephone, newspaper, and or bulletin advertisements. Men and 
women with OSA will be recruited from a pool of patients being newly diagnosed with OSA and currently 
followed in our outpatient clinic or by advertisement in the sleep disorders clinic. Only patients who have 
stated in the initial clinical questionnaire that they are interested in hearing about research studies will be 
contacted by phone. Should the subject be interested in the study, they can call the study physician or 
coordinator to inquire about study participation. We will also recruit from our existing database of research 
participants. 
 
Subjects who respond will be given a thorough review of the risks, discomforts, potential benefits to the 
study and their expected involvement using a prepared script approved by our Institutional Review Board. 
Subjects will be given a copy of the informed consent and allowed a minimum of 24 hours to review the 
information and make a decision on study participation. During this time, the subject will have the 
opportunity to discuss the research with his/her primary care physician or clinician. The study investigators 
will be available to answer any questions should any arise. Informed consent will be obtained by the 
Principal Investigator or an experienced co-investigator prior to participation in the study. The opportunity 
to talk to a licensed MD (who is readily available at the time of consent, and available overnight at the 
hospital) will be offered in each case. Subjects will have more than 24 hours to consider participating in the 
study. Any consent issues / problems will be reported to the PHRC in real time rather than waiting to report 
at the time of Continuing Review 
 
 
Inclusion and exclusion criteria will be carefully assessed prior to enrollment. Assuming subjects meet the 
inclusion criteria, they will begin the protocol by scheduling their overnight studies in the 
clinical/physiology laboratories. Subjects will be informed that they may withdraw from the study at any 
point, with no impact on their ongoing care. We have not previously had difficulty enrolling participants 
into similar studies performed in our laboratory. 
 
If the data collected will be considered insufficient by the PI or by the co-investigators, the subject will be 
asked to repeat the whole study or a part of it without signing a new informed consent form. 
 
 
V. 
STUDY PROCEDURES 
 
Protocol:  
Two overnight sleep studies will be performed approximately 1 week apart: a placebo night and a 
pseudoephedrine-plus-diphenhydramine (120+50mg PO, DAW1033D) night, in double-blinded 
randomized control design. For each night, the subjects will arrive at the sleep laboratory at approximately 
7:00pm. A physician will complete a complete physical and medical history. The placebo or DAW1033D 
will be administered 30 minutes before lights out. At least 15 minutes of quiet wakefulness will be recorded 
to quantify the subject’s awake EMGGG activity. Subjects will then be allowed to fall asleep during which 
we will assess EMGGG activity throughout the rest of the evening (see below for details).  
 
Measurements and equipment:  
Subjects will be instrumented with standard polysomnography (PSG) recording sensors. Sleep stage and 
arousals will be measured with electrodes pasted on to the scalp, face, chin and chest (EEG, EOG, EKG, 


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chin EMG). Paste-on EMG electrodes will be placed over the anterior tibialis muscle to detect leg 
movements. Respiratory effort belts will be placed around the chest and abdomen to measure breathing 
movements. Oxygen saturation will be measured continuously with a pulse oximetry probe placed on either 
the fingertip or earlobe. Snoring will be detected with a small microphone positioned over the suprasternal 
notch. Body position will be recorded with a sensor taped to the thoracic belt. Each of these devices is 
standard for diagnostic PSG and should not be uncomfortable.  
 
One nostril and the back of the throat will be anesthetized with 4% lidocaine; only 2–3 ml (80–120 mg) of 
lidocaine is used. One small, flexible pressure-tipped catheter (Millar) will then be inserted through the 
anesthetized nostril until the tip of the catheter is located just above the epiglottis (or in the esophagus) by 
visual inspection through the mouth; the catheter is then taped to the nose to prevent movement. This 
catheter is used to assess upper airway negative pressure and to calculate airflow resistance both awake and 
during sleep.  
 
Electromyogram activity from the genioglossus (EMGGG) muscle (a major upper airway dilator muscle) 
may also be recorded using unipolar intramuscular electrodes as described in our previous studies (1, 23, 
24). Two 25 gauge needles containing 30 gauge, Teflon-coated stainless steel wires are inserted into the 
muscle after topical anaesthesia with 4% lidocaine. A maximum of 2 mls of lidocaine will be used for 
needle insertion. If the patient cannot tolerate needle insertion once the maximum dose of lidocaine has 
been applied, then the procedure will be stopped. The needle is immediately removed leaving the wire in 
place. Both electrodes are referenced to a single ground producing a bipolar recording. GG needle 
placement is as follows: The muscle is approached through the floor of the mouth with each needle being 
inserted about 3-5 mm lateral to the frenulum and about 12-15 mm into the body of the genioglossus near 
its insertion into the mandible. Once the electrodes are placed, the EMG signal is amplified, rectified, and 
integrated on a moving time average basis with a time constant of 100 msec (CWE Incorporated).  
 
The subject is then asked to lay down (supine) and a comfortable sealed mask will be placed over the nose 
and held in place with straps. The mask allows monitoring of breathing (inspiratory flow by 
pneumotachograph which can be integrated to tidal volume) and expired carbon dioxide levels (PCO2) 
using a calibrated infrared CO2 analyzer (Capnograph/Oximeter Monitor), and if available, end-tidal 
oxygen levels using a calibrated O2 analyzer.  
 
Tests performed during wakefulness. 
The patients, with the described monitoring equipment in place, will undertake two tests before going to 
sleep for the night, although some of the testing may not be performed in all subjects depending on 
availability of equipment, scheduling issues and willingness of the subject to undergo all of the testing.  
 
 
1. Upper airway muscle activity during wakefulness  
The subject will be asked to perform several maneuvers to assess the activity of the GG during wakefulness. 
The maneuvers include a maximal tongue protrusion, inspiration against a closed airway, swallow and 
maximum voluntary ventilation. Each of these maneuvers will be repeated 3 times.  
 
After these test during wakefulness, the subjects will be given Desipramine (200 mg PO) /placebo to take 
and then be connected to a positive/negative pressure source (Philips-Respironics, Murrysville, PA) to 
enable rapid switching between pressure levels and allowed to fall asleep on 4 cmH2O of CPAP. When 
stable sleep is reached, the CPAP will be modified to the level that abolishes flow limitation, as determined 
by the airflow waveform. Five minutes of stable sleep will then be recorded. Following this baseline 
recording period, the CPAP level will be reduced to varying suboptimal pressures for several minute 


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intervals to see how the genioglossus responds to airway collapse. In the case of controls, the suboptimal 
level required to collapse the airway may require negative pressures. If the subject awakens during the 
suboptimal pressure drop, the pressure will be immediately returned to the holding pressure until stable 
NREM sleep is again achieved. We have performed this technique in numerous healthy controls and OSA 
patients with no complications to date. Furthermore, it is our experience that the response to negative 
pressure drops which is often used in healthy controls is similar to the suboptimal positive pressures used 
in OSA patients.  
 
After approximately 4 hours of sleep, we will remove the CPAP and ask the subjects to sleep in the lateral 
position for the duration of the evening to minimize pharyngeal resistance similar to previous studies of 
this kind (25). As much data will be recorded from NREM and REM sleep as possible over the night. 
Following completion of the study, all equipment will be removed, and the subject will be able to sleep in 
the laboratory free from equipment for the rest of the night. Alternatively, if the subject feels alert enough 
to leave, they may do so.  
 
Data Analysis: 
Muscle activity will be quantified using standard procedures described in our previous studies (1, 23, 24). 
Briefly, the raw EMGGG signal will be rectified and smoothed with a 100 msec window.  The peak phasic, 
as well as tonic, activity of the smoothed signal will be identified for each breath. Data from quiet 
wakefulness (free of swallowing and movement artifacts) will be averaged to determine the peak phasic 
and tonic activities during this state. The same will be done for stable NREM and REM sleep (free of 
arousals and other artifacts). Both NREM and REM sleep will be analyzed, recognizing that REM is less 
frequent on these drugs. Pharyngeal muscle responsiveness will be determined by calculating the slope and 
intercept of the epiglottic pressure versus muscle EMG relationship.  
 
 
Reimbursement  
Subjects will receive $100/night for participation in each overnight study (TOTAL = $200 for each 
PART of the study). Reimbursement for parking expenses will be provided. 
If the subjects will repeat a part or the entire protocol because of insufficient data collection, they will 
be reimbursed $100 for any extra night. 
 
 
VI. 
BIOSTATISTICAL ANALYSIS 
 
Subjects will be prospectively enrolled until 10 had completed both study nights. Sample size was chosen 
to facilitate detection of a clinically-important 50±50% reduction in AHI. Calculations were based on 
previous studies conducted in our laboratory. To account for a ~30% failure rate approximately 13 patients 
will be enrolled in the study.  
In order to reduce the influence of potential outlier, data will be expressed as median [interquartile range] 
and data on placebo vs DAW1033D will be compared using Wilcoxon test. A p value < 0.05 will be 
considered as statistically significant. 
In the pilot study using the noradrenergic drug desipramine, the average difference in EMGGG activity 
(between the placebo night and the drug night, with EMGGG quantified as a percentage of wakefulness) was 
47 ± 20%.  In order to detect this difference with 80% power and a 5% level of significance, 6 subjects 
would need to be studied.  
 
 


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VII. 
RISKS AND DISCOMFORTS 
 
We believe that the risks associated with participation in this study are minimal. All study procedures have 
been conducted in our laboratory without serious incident. Anticipated risks and discomforts are listed 
below: 
 
1. The equipment used for assessing sleep (paste on electrodes) is standard and poses no risk. The 
electrodes may be mildly uncomfortable and could cause some sleep interruption. Thus subjects may 
feel somewhat tired the day following this study. 
 
2. Pharyngeal Pressure Catheter: Inserting the pressure catheter through the nostril and into the pharynx 
may be uncomfortable and could cause gagging or even vomiting. The anesthetized and fasting state 
substantially reduces the risk of discomfort or complications. As the subject will have a catheter in 
his/her pharynx and a nasal mask in place, the risk of aspiration must be considered. However, this has 
never been encountered after hundreds of similar studies. The catheter, once in place, does not gag the 
subject and the mask can easily be removed. Overall, the risk of aspiration is minimal.  
i. 
Lidocaine. If the subjects have any history of lidocaine allergy, they will be excluded from 
the study. Excessive use of lidocaine can cause seizures, but this is reported with much higher 
doses than will be utilized in this study. However, subjects will be informed that lidocaine 
has an unpleasant taste. 
 
 
3. Intramuscular EMG Determination: Needle insertion may be painful although the mucosa is topically 
anesthetized with lidocaine. We have found this pain to be similar to venipuncture and well tolerated. 
Discomfort is minimal once the needle is removed and the wire is left in place. A small amount of 
bleeding and/or a small bruise may occur. Both the needles and wires are sterilized.  However, 
intramuscular or surface infection could occur, as it is impossible to sterilize the inside of the mouth. 
We have never encountered this problem or heard of it occurring elsewhere. There may be some 
residual soreness in the tongue for several hours after the wires are removed. 
   
4. Pseudoephedrine: this drug is available at the dose of 15, 30, 60 and 120 mg as over-the-counter 
medication of nasal congestion and cold relief. Common side effects include arrhythmia, tachycardia, 
palpitations, nervousness, excitability, restlessness, dizziness, weakness, insomnia, headache, 
drowsiness. Other side effects may include anorexia, constipation, diarrhea, hypertension, dry throat, 
ischemic colitis, nausea, vomiting, xerostomia, dysuria, polyuria, urinary retention, tremor, weakness, 
blurred vision, diplopia, dry nose, dyspnea, nasal congestion, thickening of bronchial secretions, 
wheezing, tinnitus. 
5. Diphenhydramine: this drug is available at the dose of 25 and 50 mg as over-the-counter medication of 
allergy and cold relief. Common side effects include: sedation, sleepiness, dizziness, disturbed 
coordination, epigastric distress, thickening of bronchial secretions. Other side effects may include 
extrasystoles, hypotension, palpitations, tachycardia, blurred vision, diplopia, difficulty in micturition, 
urinary frequency, urinary retention, tinnitus, anorexia, constipation, diarrhea, dry mucous membranes, 
epigastric distress, nausea, vomiting, xerostomia. 
6. Combination of pseudoephedrine and diphenhydramine: the association of these drugs is already 
available (at a lower dose of 60/25 mg) as over-the-counter medication for nighttime relief of allergy, 
sinus and cold symptoms (see for example Benadryl Allergy Sinus). The most common side effects of 
the combination of the drugs are constipation, diarrhea, dizziness, drowsiness, dry mouth, nose, and 


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throat; excitability, headache, anorexia, nausea; nervousness or anxiety, insomnia, weakness. As both 
drugs are commonly administered at higher doses alone, we believe that increasing the dose of the 
combination will not determine excessive increase in the risk of serious side effects.  Furthermore, 
the drugs will be administered for only one night in a monitored setting: an experienced 
researcher will be present for the entire night checking vital signals in real time (heart rate, 
oxygen SaO2, EEG), the patient will be under audio and video-surveillance. An MD will be 
available for the duration of the study and the following morning if necessary. 
 
 
VIII. 
POTENTIAL BENEFITS 
 
Although it is unlikely that there will be any direct physical benefit to the subjects from participating in this 
study, we will make known to each subject, if requested, some of the information we have gathered from 
this physiologic testing. This study provides a unique opportunity to gain insight into the specific 
mechanisms by which these novel drugs may improve upper airway muscle function. The results may, in 
the future, lead to improved strategies for the treatment of sleep apnea. However, if previously unknown 
abnormalities of sleep and breathing are encountered, this information will be passed onto the subject. 
Results can be forwarded to the primary care physician or clinician at the request of the subject. 
 
 
IX. 
MONITORING AND QUALITY ASSURANCE 
 
We will follow the Data and Safety Monitoring Plan included as an attachment. As this study is 
a physiological investigation and not clinical trial, a formal Data and Safety Monitoring Board will 
not be implemented. The PI will be responsible for monitoring safety and quality assurance. 
Additionally, the ongoing results, problems, and limitations of the study will be presented on a 
regular basis to the investigators in the Division of Sleep Medicine. Any adverse events will be 
promptly reported to the Human Research Committee for review according to HRC guidelines.  
 
Adequacy of Protection Against Risks 
 
All of our laboratory personnel involved in the research of human subjects have completed the required 
institutional program for education in the protection of human research participants and their 
confidentiality.   The institutional educational program consists of the review of regulatory and 
informational documents pertaining to human-subject research, passing a test demonstrating knowledge of 
the ethical principles and regulations governing human-subject research and signing a statement of 
commitment to the protection of human subjects.   
 
All electronic data will be stored on secure computers under password protection with no access allowed 
to individuals outside of our research team.  All paper data will be stored under lock and key with access 
only given to the study staff.                        
 
Protection Against Risks 
 
We believe that all possible safeguards are in place to minimize the risk.  However, several steps will be 
taken to insure patient comfort and safety.  We will work with our IRB to come up with a safety 
monitoring plan to minimize risk and discomfort.  This will include: 
• 
Reporting any complications of our studies immediately to the IRB. 


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• 
Appoint a safety officer (David Andrew Wellman, MD) who will work with our physicians and 
technicians to maximize safety and comfort.  
• 
Our study coordinator will call each subject 2-3 weeks after the study to determine if any 
problems resulted from the study. 
 
The study coordinator will meet with the safety officer and PI monthly (and as needed) to go over any 
complaints or problems. The safety officer will call the patients with problems directly to verify important 
issues.  If problems are identified, the protocol will be adjusted as needed.  Based on conversations with 
the NIH and the NHLBI policy (http://www.nhlbi.nih.gov/funding/ethics.htm), we will not require a formal 
data safety monitoring board. However, we do have a thorough data safety monitoring plan whereby our 
safety officer will review all adverse events in order to classify them as serious adverse events, minor 
adverse events, and whether they are anticipated or unanticipated, and study related or unrelated as per our 
IRB rules and the NHLBI policy. The medical monitor will be an academic physician with considerable 
experience in clinical research but not involved in our research program or a co-investigator in any of our 
studies (Dr. David White).  The medical monitor will strictly adhere to the following definitions: 
 
Definitions 
Definitions are per January 2007 OHRP  Guidance on Reviewing and Reporting Unanticipated Problems 
Involving Risks to Subjects or Others and Adverse Events, OHRP Guidance,  
http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm  
Adverse Event (AE):  any untoward or unfavorable medical occurrence in a human subject, including 
any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, 
temporally associated with the subject’s participation in the research, whether or not considered related 
to the subject’s participation in the research. 
  
Serious adverse event (SAE):  any adverse event that:  
• 
Results in death  
• 
Is life threatening, or places the subject at immediate risk of death from the event as it occurred  
• 
Requires or prolongs hospitalization  
• 
Causes persistent or significant disability or incapacity  
• 
Results in congenital anomalies or birth defects  
• 
Is another condition which investigators judge to represent significant hazards 
 
Unanticipated Problem (UP): any incident, experience, or outcome that meets all of the following 
criteria:  
• 
unexpected, in terms of nature, severity, or frequency, given the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and the characteristics of the subject population being studied;  
• 
related or possibly related to participation in the research, in this guidance document, possibly 
related means there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research;  
• 
suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
 
Adverse Events (FDA) versus Unanticipated Problems (OHRP)  
• 
All adverse events are not necessarily unanticipated problems  
• 
All unanticipated problems are not necessarily adverse events  


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• 
Some events may be both 
 
 
 


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X. 
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