Pharmacological Activation of Hypoglossal Motor Nucleus for Obstructive Sleep Apnea
Phase: PHASE1
Conditions: Obstructive Sleep Apnea
Sponsor: Brigham and Women's Hospital

BWH/MGH Human Subjects Research Application Form 
Filename: Detailed Protocol 
Version 4: March 2002 
 
 
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PARTNERS HUMAN RESEARCH COMMITTEE 
DETAILED PROTOCOL 
 
Title: Activating the hypoglossal motor nucleus using existing drugs for the treatment of 
obstructive sleep apnea 
 
Principal Investigator: Luigi Taranto-Montemurro, MD 
 
Version Date: December 6th, 2018  
 
I. BACKGROUND AND SIGNIFICANCE 
 
Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder associated with 
serious cardiovascular and metabolic diseases and with important consequences on the quality of 
life. It is characterized by repetitive collapse or ‘obstruction’ of the pharyngeal airway during 
sleep resulting in a complete closure (apnea) or narrowing (hypopnea) of the upper airway. The 
severity of the disease is measured as the frequency of obstructive events for each hour of sleep 
(apnea-hypopnea index, AHI). When OSA is defined as an AHI ≥5 events per hour plus 
symptoms (eg, daytime sleepiness) or AHI ≥15 events per hour with or without symptoms, the 
estimated prevalence is approximately 15 percent in males and 5 percent in females1. 
 
Over the last decade research has shown that a number of pathogenic factors, or traits, contribute 
to the development of OSA2-5. 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 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 
cardiovascular6-13, neurocognitive14, and daytime functioning15 consequences, making OSA a 
major health concern.  
 
In the presence of an anatomical predisposition to airway collapse, the sleep-related withdrawal 
of motor output from the hypoglossal motornucleus (HMN) to the upper airway dilator muscles 
can cause the collapse of pharyngeal structures, with ensuing episodes of reduced ventilation, 
intermittent hypoxia, hypercapnia, and arousals from sleep16. Loss of pharyngeal dilator muscle 
activation during sleep is central to the pathogenesis of OSA17. However, attempts to 
pharmacologically reverse pharyngeal hypotonia that occurs in sleeping humans have thus far 
been ineffective mostly because of the lack of agents that can activate receptors specific to the 
HMN motor and pre-motor areas.  
 
Our group has made significant headway in dealing with ventilatory control sensitivity.18, 19  
While a host of oral devices and surgeries have been developed to address the anatomical 
predisposition to collapse, drugs that activate the pharyngeal muscles are needed.  
 
Recent investigation based on gene expression in the HMN motor and pre-motor (pre-HMN) 
areas has shown that there is a significant unexplored potential in terms of testing FDA-approved 

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drugs that can specifically target receptors that have preferential expression on the HMN and 
pre-HMN areas. These areas are part of a neural circuit that is critical for OSA pathogenesis 
because they modulate the upper airway muscle activity during wakefulness and sleep20. There is 
now sufficient data to support a new approach to the development of a pharmacologic treatment 
for OSA, based on genome-wide analyses of the differential expression of druggable targets in 
the circuitry controlling motor output to the upper airway musculature.    
 
Our group recently discovered that the combination of atomoxetine (a norepinephrine reuptake 
inhibitor) and oxybutynin (an anticholinergic) reduced OSA severity by 63% in a group of 20 
unselected patients. The putative mechanism of action was an increase in genioglossus muscle 
responsiveness during sleep by ~3 fold. Based on animal research conducted in Richard Horner’s 
lab in Toronto, norepinephrine is the main neurochemical responsible for upper airway muscles 
hypotonia during NREM sleep while acetylcholine, through the muscarinic receptors mediate the 
REM-related atonia in the same muscles. The analysis of the effect of the drugs taken alone 
revealed that atomoxetine was able to increase the ventilation during sleep compared to placebo 
but the patients had frequent respiratory and spontaneous arousals from sleep, the sleep quality 
was compromised and the patients experienced still a high number of hypopneas. Oxybutynin 
taken alone had only a minor effect in improving ventilation during sleep, however when 
administered with atomoxetine, it had the effect of consolidating sleep by increasing sleep 
efficiency, sleep duration and sleep architecture. Based on these findings, we have reasons to 
believe that oxybutynin could be substituted (in the combination with atomoxetine) with a non-
myorelaxing hypnotic free from anticholinergic side effects such as zolpidem, trazodone or 
gabapentin.         
 
II. SPECIFIC AIMS 
 
AIM 1. To determine the effect of several FDA-approved drugs administered alone or in 
combination on OSA severity. The drugs tested in this protocol have been selected because of 
their potential to increase the upper airway muscle activity during sleep by specifically 
stimulating the HMN and/or the pre-HMN areas in the brainstem. 
 
Specifically, we will test this hypothesis by assessing:  
 
1. The effect of lorcaserin on OSA severity (LTM1201L). Lorcaserin is a weight-loss 
drug acting specifically as an agonist of 5-HT 2C, a receptor expressed in the pre-HMN area 
twice as much as the rest of the brain. Previous data collected in an animal model showed 
that the stimulation of the receptor 5-HT 2C with the agonist 2,5-dimethoxy-4-
iodoaminophentamine increased genioglossus activity during sleep 8-fold compared to 
placebo, and it also reduced the upper airway collapsibility21.  
 
2. The effect of the combination of lorcaserin and cholecalciferol on OSA severity 
(LTM1201LD). Cholecalciferol is an agonist of the vitamin D receptor, which is expressed 
on HMN neurons > 4 times than on other neurons in the brain. Therefore, the vitamin D 
receptor is highly specific to the HMN. There are no studies assessing the effect of vitamin D 
administration on OSA severity but several protocols have reported an association between 
the presence of OSA and vitamin D deficiency22. 
 
3. The effect of the combination of lorcaserin and nabilone on OSA severity 
(LTM1201LN). Nabilone is a cannabinoid 1 and cannabinoid 2 (CB1/CB2) receptor agonist 
approved for the treatment of refractory nausea and vomiting associated with cancer 

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chemotherapy. Cannabinoid 2 receptor is expressed 6.8 times more on the HMN compared to 
the rest of the brain. In an animal model, methanandamide – a CB2 agonist – increased tonic 
and phasic genioglossus activity23 during wakefulness. Furthermore, a recent clinical trial 
suggested cannabinoids might be helpful in the treatment of sleep apnea, although the 
administration of CB1/2 receptor agonist alone had only a modest effect on OSA severity24.  
 
4. The effect of the combination of lorcaserin and buspirone on OSA severity 
(LTM1201LB). Buspirone is used in the treatment of generalized anxiety disorder, and it 
increases the firing in the locus ceruleus. The locus ceruleus is an area of brain where 
norepinephrine cell bodies are found in high concentration, and it reduces the firing of 
serotonin-containing neurons. The net result of buspirone actions is that serotonergic activity 
is suppressed while noradrenergic cell firing is enhanced. The increase in norepinephrine in 
the brain is important for the HMN area, since it acts as an agonist for the alpha1-adrenergic 
receptor, which is expressed 3.7 times more on the HMN area compared to the rest of the 
brain. A previous pilot study suggested a possible modest effect of buspirone administered 
alone in the treatment of sleep apnea25. 
 
 
 
 
III. 
  SUBJECT SELECTION 
 
In this pilot study we will recruit a group of 10 OSA patients.  These individuals will be 
otherwise healthy (except for well-controlled hypertension, diabetes, or hyperlipidemia) with 
no active medical problems and on no medication that could affect respiration or muscle 
control.  Everyone will be 18-70 years of age.  Both men and women will have an apnea-
hypopnea index (AHI) >10 events/hr during supine NREM sleep. These individuals will be 
recruited to encompass a large range of AHI’s (from 10 to >60/hour).  
 
Exclusion criteria: 
• Any medical condition other than well controlled hypertension and mild diabetes.  
Patients with diabetes will be enrolled only if they are treated with one oral 
hypoglycemic drug. 
• Any medication known to influence breathing, sleep/arousal, or muscle physiology. 
• Claustrophobia. 
• Inability to sleep supine. 
• Allergy to lorcaserin, vitamin D analogues, nabilone, or buspirone. 
• History of kidney stones, hypercalcemia, primary hyperparathyroidism, sarcoidosis, 
hypervitaminosis D, which can be exacerbated by cholecalciferol. 
• Individuals with underlying cardiac disease, such as arrhythmias. 
• Individuals taking psychiatric medications, such as an MAO-I, SSRI or SNRI, or any 
of the studied medications for medical care. 
• For women: Pregnancy. 
• Pulmonary hypertension 
• Severe OSA with a mean SaO2 lower than 88% 
 
Equal number of males and females will be recruited. We will consider all applicants regardless 
of sex, race, color, creed, or national origin. 
 

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IV.   SUBJECT ENROLLMENT 
 
Men and women with OSA will be recruited in the sleep disordered clinic of BWH and BFH 
through advertisement flyers. The patients who showed interest in the research will contact us 
after talking to their physician in the clinic. 
 
Study staff may contact the patient in writing initially and allow the patient to make the first 
contact if they are interested. Study staff may ask a physician colleague or research nurse to 
initially explain the study or to re-contact the potential subject after the Investigator has 
presented the study. Study staff may offer patients the opportunity to take home the Consent 
Form and call back if they wish to participate. Study staff will recommend that the patient 
discuss participation with other health care providers. 
 
Subjects from our existing database of OSA patients who previously took part to similar research 
studies and showed interest in performing more tests will also be contacted by our study 
coordinator.  
 
Subjects also may be recruited through social media such as Facebook, and bulletin 
advertisements. Should the subject be interested in the study, they can call the study physician or 
coordinator to inquire about study participation.  
  
On the phone, subjects will be given a thorough review of the risks, discomforts, potential 
benefits (if any) 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 decide 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 from all subjects by a licensed physician 
investigator prior to commencement of any study procedures.  
 
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 laboratory. Subjects will be informed that they may withdraw from the 
study at any point, with no impact on their ongoing care.  
 
All email sent outside of the Partners firewall containing confidential information will be 
encrypted using "Send Secure" as per the Partners Policy.  Subjects may opt out of encrypted 
email communications if they have been advised of the risks associated with unencrypted email, 
and they indicate a preference to receive unencrypted email despite the risks.  Consent to receive 
unencrypted email will be documented per the Partners Policy in the subject’s record.  We will 
discourage subjects from communicating about medical issues by non-secure email. 
 
V.   STUDY PROCEDURES  
 
Protocol 
 
After a medication and screening visit, five overnight sleep studies will be performed 
approximately 1 week apart in an open-label randomized design.  This study has been designed 
to quickly generate preliminary data for future studies, targeted to the most effective 

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combinations of drugs that will be performed in a double-blinded fashion in a higher number of 
patients. 
 
Consent and medication visit 
 
The study will be explained in detail and an assessment will be made by an investigator to ensure 
the study procedures can be performed and written consent will be obtained. If the subject 
enrolled is a premenopausal woman, we will perform a urine pregnancy test at this visit. 
 
Sleep Studies 
 
For each night, the subjects will arrive at the sleep laboratory at approximately 6:30pm. A 
physician will perform a history and physical examination. The placebo or drug(s) will be 
administered 30 minutes before lights out. The patients will perform five sleep studies in random 
order:  
 
1) placebo night 
2) lorcaserin (15mg) night – LTM1201L 
3) lorcaserin (15mg) +cholecalciferol (1500 IU) night – LTM1201LD 
4) lorcaserin+nabilone (1mg) night – LTM1201LN 
5) lorcaserin (15mg) + buspirone (20mg) night – LTM1201LB 
 
 
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, 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 the fingertip. 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.  
 
To measure airflow, a standard CPAP mask will be placed over the nose and held in place with 
straps. The mask allows monitoring of breathing (inspiratory flow by pneumotachograph that can 
be integrated to yeld tidal volume) and expired carbon dioxide levels (PCO2) using a calibrated 
infrared CO2 analyzer (Capnograph/Oximeter Monitor).  
 
After all the equipment is in place, the patient will be asked to sleep in the supine position for at 
least one half of the night (4 hours). 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: 
 
Apneas, hypopneas, arousals, and sleep stages will be scored using standard American Academy 
of Sleep Medicine guidelines26 by a registered polysomnographic technologist (RPSGT) blinded 

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to the treatment allocation. Hypopneas will be defined as reduction in flow ≥30% from baseline, 
lasting at least 10 seconds and associated with an arousal from sleep or an oxyhemoglobin 
desaturation ≥ 3%. 
 
If the data collected are considered insufficient, the subject may be asked to repeat the whole 
study or a part of it. 
 
VI.   BIOSTATISTICAL ANALYSIS 
 
In this protocol, we want to collect pilot data to measure the possible effect size of this 
intervention. Variables of interest will be compared using a mixed effect model with p<0.05 
considered as statistically significant. 
 
VII. 
RISKS AND DISCOMFORTS  
 
We believe that the risks associated with participation in this study are small since the drugs are 
already FDA-approved for other purposes and we are only performing standard clinical sleep 
studies. 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. Lorcaserin side effects include: headache (15% to 17%), hypoglycemia (diabetic 
patients 29%; symptomatic 7%; severe: 2%), back pain (6% to 12%), upper respiratory tract 
infection (14%), nasopharyngitis (11% to 13%), hypertension (5%), peripheral edema (5%), 
decreased heart rate (less than 50 bpm: 4% to 5%), acquired valvular heart disease (3%), 
dizziness (7% to 9%), fatigue (7%), anxiety (4%), insomnia (4%), depression (3%), stress 
(3%), cognitive dysfunction (2%), psychiatric disturbance (2%),  exacerbation of diabetes 
mellitus (3%), nausea (8% to 9%), diarrhea (7%), constipation (6%), xerostomia (5%), 
vomiting (4%), gastroenteritis (3%), toothache (3%), decreased appetite (2%), urinary tract 
infection (7% to 9%), Decreased hemoglobin (10%), decreased neutrophils (6%), muscle 
spasm (5%), musculoskeletal pain (2%), cough (4% to 8%), oropharyngeal pain (4%), sinus 
congestion (3%) 
 
3. Cholecalciferol: no adverse reactions are listed in the manufacturer's labeling. High 
levels of Vitamin D may facilitate kidney stones formation and atherosclerosis, secondary to 
hypercalcemia. There are no known interactions between cholecalciferol and lorcaserin.  
 
4. Nabilone (Cesamet) side effects include: drowsiness (52% to 66%), dizziness (59%), 
vertigo (52% to 59%), euphoria (11% to 38%), ataxia (13% to 14%), depression (14%), lack 
of concentration (12%), sleep disorder (11%), xerostomia (22% to 36%), visual disturbance 
(13%), hypotension (8%), dysphoria (9%), headache (6% to 7%), sedation (3%), 
depersonalization (2%), disorientation (2%). There are no known interactions between 
nabilone and lorcaserin.  
 
5. Buspirone side effects include: Dizziness (3% to 12%), Chest pain (≥1%), Drowsiness 
(10%), headache (6%), nervousness (5%), confusion (2%), excitement (2%), numbness (2%), 
outbursts of anger (2%), abnormal dreams (≥1%), ataxia (1%) paresthesia (1%), Diaphoresis 

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(1%), skin rash (1%), Nausea (8%), diarrhea (2%), sore throat (≥1%) Weakness (2%), 
musculoskeletal pain (1%), tremor (1%), Blurred vision (2%), Tinnitus (≥1%), Nasal 
congestion (≥1%). There are no known interactions between buspirone and lorcaserin. Both 
these agents are serotonin modulators but the development of serotonin toxicity/serotonin 
syndrome is highly unlikely because buspirone inhibits the release of serotonin in the brain 
while lorcaserin specifically stimulates a single serotonin receptor (5HT 2C).   
 
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 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 
 
As these studies represent physiologic investigation and not clinical studies, no formal quality 
assurance programs will be implemented.  However, 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. Also, any adverse events will be promptly reported to the Human Research 
Committee for review.  See attached Data and Safety Monitoring Plan. 
 
We will also elect an independent safety monitor (ISM) to review the study and protocol on a 
quarterly basis.  The designated safety monitor is Robert Thomas, MD.  Dr. Thomas is an 
Associate Professor in Medicine at Harvard Medical School and practices out of Beth Israel 
Deaconess Hospital in Boston.  He specializes in Sleep Medicine (Circadian Rhythm Disorders, 
Complex Sleep Apnea, Insomnia, Restless Leg Syndrome, Periodic Limb Movements, and 
Narcolepsy).  He is not directly associated with our research lab.  He has no say over the design 
or implementation of these studies and will review the practices in an unbiased manner. 
 
 
 
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