Clinical trial NCT04706091
Conditions: Restless Legs Syndrome Insomnia Sleep Disorder
Keywords: Suvorexant
Sponsor: Massachusetts General Hospital
Start date: 2021-08-12; Completion date: 2023-10-20
Enrollment: 46 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The investigators aim to determine the effect of suvorexant on actigraphically-derived total sleep time in patients with effectively treated restless legs syndrome with persistent insomnia in a two-arm, double-blind, randomized placebo-controlled crossover 2.5-month trial.

Detailed description:
Restless Legs Syndrome (RLS) is a sensory-motor neurological disorder characterized by an irresistible urge to move the legs. Persistent difficulties with all phases of sleep are common in patients whose RLS symptoms are resolved with treatment. Multiple potential causes for treatment-refractory sleep disturbance exist, including activating effects of dopamine agonists (which are first-line RLS treatments), conditioned insomnia and poor sleep habits as a result of chronic RLS-related sleep disturbance, and comorbid medical and psychiatric illness. Suvorexant provides an important therapeutic option to treat insomnia in the context of RLS. It has demonstrated long-term efficacy, particularly in shortening the duration of nocturnal awakenings and increasing total sleep time. Similarly, it has a comparatively benign side effect profile compared to many other agents typically prescribed to treat insomnia. The investigators aim to determine the effect of suvorexant on actigraphically-derived total sleep time, as well as actigraphically-derived wake after sleep onset, Insomnia Severity Index score, subjective sleep endpoints, and RLS symptom severity.

Arms: arm 1: This group will receive suvorexant during the first 4-week phase, and placebo during the second 4-week phase. arm 2: This group will receive placebo during the first 4-week phase, and suvorexant during the second 4-week phase.
Interventions: intervention 1: Suvorexant intervention 2: Placebo
Intervention descriptions: intervention 1: 10-mg or 20-mg suvorexant capsules intervention 2: Matching placebo capsules

Protocol documents:
Prot_SAP_000.pdf: 
Version Date: 7/5/2022 
Winkelman, John W., M.D., Ph.D. 
 
PARTNERS HUMAN RESEARCH COMMITTEE DETAILED PROTOCOL 
Efficacy of Suvorexant in Patients with Effectively Treated Restless Legs Syndrome and 
Persistent Chronic Insomnia: A Randomized Placebo-Controlled Crossover Trial 
 
I. BACKGROUND AND SIGNIFICANCE 
Restless Legs Syndrome (RLS) is a sensory-motor neurological disorder characterized by an 
irresistible urge to move the legs that is often paired with leg discomfort. Symptoms are provoked 
by rest, relieved with movement, and worst in the evening or at night.1 Clinically significant RLS 
that occurs at least two times per week, and is associated with moderate to severe distress, is 
present in roughly 3% of the general population.2 Such sufferers describe these leg sensations on 
a spectrum from annoying to unbearable and the physical distress and lack of sleep associated with 
RLS contribute to high levels of morbidity and poor quality of life.3-5 
Sleep disturbance is present in over 75% of individuals with RLS, producing most of the morbidity 
of moderate to severe RLS,6 and is the primary complaint which drives individuals with RLS to 
seek medical attention.2  RLS is associated with difficulty falling asleep, repeated awakenings, and 
total sleep times averaging less than 5.5 hours.7  Both the sensory discomfort as well as the periodic 
limb movements of sleep (PLMS) are thought to contribute to RLS sleep disturbance. 
Dopamine agonists (DAs) have been the mainstay of medical treatment for 20 years and remain 
first-line therapy for many patients. Most patients with RLS initially experience prompt 
suppression of the sensory symptoms upon treatment with a DA.8 Alpha-2-delta agents such as 
gabapentin and pregabalin are also used in RLS treatment with substantial benefit for the sensory 
symptoms.9 
Unfortunately, persistent difficulties with all phases of sleep are common in patients whose RLS 
symptoms are resolved with treatment. Meta-analyses of DA clinical trials in RLS demonstrate 
that the absolute effect size (as change from baseline) is only .4 when compared to placebo.10 
These small to moderate effects of DAs leave the average treated RLS patient with sleep durations 
of just over 6 hours.11,12 Alpha-2-deltas also leave effectively treated RLS patients with persistent 
insomnia,13,14 with average sleep latencies over 30 minutes, WASO of 60-90 minutes, and sleep 
efficiencies of 75-85%. Similarly, iron treatments, which often produce substantial benefits for 
RLS symptoms, do not produce any improvement for sleep in clinical trials.13  In community 
surveys of treated RLS patients, 53% report sleep disruption four or more nights per week.15  
Multiple potential causes for treatment-refractory sleep disturbance exist, including activating 
effects of DAs, conditioned insomnia and poor sleep habits as a result of chronic RLS-related sleep 
disturbance, and comorbid medical and psychiatric illness.  Another potential explanation is the 
suggestion from emerging data that RLS and insomnia share genetic underpinnings and thus may 
be comorbid independent of any prior sensory symptoms.16 


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Winkelman, John W., M.D., Ph.D. 
 
In the absence of any clinical trials addressing the issue, the persistent insomnia in patients with 
effectively treated RLS is currently addressed empirically with FDA-approved (benzodiazepine 
receptor agonists) and non-approved (trazodone) agents, with varying success. Use of the former 
category risks the emergence of complex sleep-related behaviors, which occur at higher rates in 
RLS,17,18 whereas the latter risks worsening the underlying RLS.19 Gabapentin is sometimes 
attempted as a hypnotic in such patients though its side-effect profile may worsen underlying gait 
instability in older patients. Cognitive-behavioral treatment of insomnia (CBT-I) is generally 
efficacious for chronic insomnia and is first-line treatment for this disorder.  However, as the sleep 
deprivation initially produced by CBT-I is known to exacerbate RLS severity,20 this approach is 
generally not used in RLS. 
Suvorexant provides an important therapeutic option to treat insomnia in the context of RLS. It 
has demonstrated long-term efficacy, particularly in shortening the duration of nocturnal 
awakenings and increasing total sleep time.21 Similarly, it has a comparatively benign side effect 
profile compared to many of the agents described above. 
Orexin is thought to play a key role in the central regulation of arousal which accounts for its 
benefits in insomnia. RLS, like insomnia, has been associated with hyperarousal.  Whether orexin 
plays a specific role in RLS-related sleep disturbance is unclear. Two previous studies have 
examined orexin levels in RLS patients, with conflicting results.22,23  
To summarize, the proposed study is not to treat RLS but rather to address the substantial 
proportion of RLS patients whose core RLS symptoms are effectively managed by medications 
but are left with persistent insomnia.  Clinically significant RLS is present in 3% of adults, roughly 
one-half of whom have control of core RLS symptoms with treatment.  Over half of these patients 
report persistent insomnia, even with substantial control of their RLS symptoms, due to the 
limitations of current RLS medications.  Thus, roughly 0.5-1% of adults have persistent insomnia 
with effectively treated RLS.  Existing insomnia treatments can either worsen underlying RLS or 
lead to complex sleep-related behaviors or other side effects in this primarily older population.  
Suvorexant provides a potentially important option due to its efficacy and tolerability profile.   
 
II. SPECIFIC AIMS 
Primary Aim:  
• To determine whether suvorexant will have significantly greater effect than placebo in 
increasing actigraphically-derived total sleep time (TST) in patients with effectively treated 
restless legs syndrome (RLS) with persistent insomnia. 
Secondary Aims: 


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Winkelman, John W., M.D., Ph.D. 
 
• To determine whether suvorexant will have significantly greater effect than placebo in 
reducing actigraphically-derived wake after sleep onset (WASO) in patients with 
effectively treated RLS with persistent insomnia. 
• To determine whether suvorexant will have significantly greater effect than placebo in 
decreasing Insomnia Severity Index (ISI) scores in patients with effectively treated RLS 
with persistent insomnia. 
Exploratory Aims: 
• To determine whether suvorexant will have significantly greater effect than placebo for 
self-reported sleep metrics (e.g., quality, disturbance, sleep latency and duration) in 
patients with effectively treated RLS with persistent insomnia.  
• To determine whether suvorexant will have an effect on RLS severity in patients with 
effectively treated RLS with persistent insomnia.  
III. SUBJECT SELECTION 
The following lists the inclusion/exclusion criteria for prospective participants. 
Inclusion Criteria: 
1. Men or women of any ethnic origin 
2. Written informed consent is obtained  
3. Speaks and writes in English 
4. A willingness and ability to comply with study procedures. 
5. Age 18 years or older 
6. Diagnosis of RLS via Cambridge-Hopkins RLS questionnaire24 
7. International Restless Legs Syndrome Study Group scale score (IRLS)<1525 
8. RLS treatment with a dopaminergic agonist, an alpha-2-delta agent, iron, cannabinoids, or an 
opioid* 
9. No changes in RLS medication in the previous month  
10. DSM-5 criteria for Insomnia Disorder 
11. Report a total sleep time ≤ 7 hours and wake after sleep onset > 45 minutes on 7 or more of 
the 14 nightly sleep logs during both the initial 2-week screening period and the two-week 
screening run-in period. WASO does not decrease by more than 50% on the 2-week sleep diary 
obtained between the screening visit and the randomization visit.  
 
*If patient is using an opioid to treat their RLS, the following additional exclusion criteria will 
apply: 
1. Individuals taking opioids at an MME > 40 MME daily (e.g., oxycodone > 26 mg, 
methadone > 10 mg) 
2. Individuals taking opioids who have comorbid conditions accompanied by significant 
hypoxia, hypercapnia, or decreased respiratory reserve such as: severe asthma, chronic 
obstructive pulmonary disease, or severe obesity 


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Winkelman, John W., M.D., Ph.D. 
 
3. Individuals taking opioids at any dose with concurrent gabapentin, pregabalin or 
gabapentin enacarbil 
4. Individuals who have changed their opioid dose within the past 6 weeks 
 
Exclusion Criteria: 
1. Sleep and medical factors:  
a. Diagnosis of moderate/severe obstructive sleep apnea (AHI>30) not using CPAP (can be 
included if CPAP adherent), or other untreated primary sleep disorders (e.g. narcolepsy)  
b. Shift workers   
c. Unwillingness to not use sedative-hypnotics (other than suvorexant) during the study period  
d. Unwillingness to maintain stable RLS medication during the study unless medically 
indicated 
e. Current use of an opiate medication. 
f. Unwillingness to not take stimulants (e.g. caffeine) after 4:00 pm during the study. 
 
2. Psychiatric factors:  
a. Current major depressive episode, by report and as indicated by the Patient Health 
Questionnaire (PHQ-9)26 
b. Lifetime history of bipolar disorder, psychosis, or other serious psychiatric illness  
c. Current alcohol/substance use disorder  
 
3. Medical factors:  
a. BMI ≥ 40 kg/m2  
b. Renal or hepatic disease judged to interfere with drug metabolism and excretion  
c. Pregnancy or breastfeeding  
d. Malignancy within past 2 years  
e. Surgery within past 3 months  
f. Neurological disorder or cardiovascular disease raising safety concerns about use of 
suvorexant and/or judged to interfere with ability to assess efficacy of the treatment  
g. Medical instability considered to interfere with study procedures  
h. Concomitant medications with drug interaction or co-administration concerns  
i. Contraindications or allergic responses to suvorexant 
j. History of being treated with suvorexant  
 
4. Lifestyle and other factors:  
a. Travel across two time-zones during the week prior to enrollment  
b. Greater than 6 cups of coffee per day  
 
Exclusionary Medications 
The following medications are considered exclusionary: 


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Winkelman, John W., M.D., Ph.D. 
 
• Strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole, 
clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, 
telaprevir, telithromycin, conivaptan) 
• *Maximum dose of 10 mg will be considered for subjects taking: moderate CYP3A 
inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, 
erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil) 
o In certain cases, subjects on moderate CYP3A inhibitors may be administered 20 
mg of suvorexant if the study doctor determines that side effects at 10 mg do not 
preclude an increase in dose.  In these events, an additional safety phone call will 
be performed after 1 week at the higher dose (20 mg) in both treatment periods, in 
which it will be determined whether the subject should stay at 20 mg or decrease 
back to 10 mg. 
 
IV. SUBJECT RECRUITMENT AND ENROLLMENT 
Methods of recruitment and procedures for informed consent: 
The target enrollment for the study is N=90 individuals with treated RLS and insomnia. Potential 
subjects will be informed of the study in one of five ways: 1) through advertisements on the 
Partners Clinical Trials webpage, 2) through advertisements on Facebook, Google, and Reddit, 3) 
through referral by a providing clinician, 4) through the RSVP for Health, or 5) through 
letters/announcements via Patient Gateway. Patients will be identified using RPDR and Epic. We 
will only send targeted letters and announcements to patients with a diagnosis of RLS. 
The enrollment goal for effectively treated RLS with persistent insomnia will be addressed by 
specifically targeting sleep clinics at Massachusetts General and Brigham and Women's Hospital, 
as well as the HMS-affiliated Beth Israel Deaconess Hospital, for all of which the PI teaches and 
supervises Fellows in sleep clinics. The PI has close ties to many clinicians in these clinics, and 
they have conveyed their interest in recruiting for this study given the high prevalence of insomnia 
in this population.  
Interested patients may contact the study staff using the contact information provided in the 
advertisements or by the research coordinator/clinician (in the form of a small handout). During 
initial phone contact with MGH staff, interest in the study will be re-confirmed and verbal 
informed consent will be obtained, after which a phone screen will be conducted by a member of 
the study staff.  
The potential risk of coercion for study subjects will be managed by ensuring that their treating 
physician provides only a study handout to potential study participants. Potentially eligible patients 
may separately contact a research coordinator to further inquire about participation. Once the 
subject has agreed to participate, the MGH study physician will participate in the consenting 


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Winkelman, John W., M.D., Ph.D. 
 
procedures to ensure that any questions regarding the study are answered accurately and to the 
fullest extent possible.  
Interested subjects will provide verbal consent at the time of the initial phone call, at which time 
they will be informed that their data will be used to study the effect of suvorexant on sleep 
disturbance in people with treated RLS. Verbally consented subjects will be assigned a unique 
identifier that will be used to link screening questionnaire data to the subject’s record.  
Verbally consented subjects will be re-consented during the Screening Visit. Written consent will 
be obtained by the study physician using a written Informed Consent Form including a summary 
of HIPAA policies; the signatures on the Informed Consent Form will be obtained electronically 
(via the REDCap e-consent framework). A signed copy will be given to the subject. Once consent 
is obtained, patients will be assigned a new unique identifier, which will be used to link all 
questionnaire data with the patient’s record throughout the study. The questionnaire data linked 
with each unique identifier will be collected and stored on REDCap (Research Electronic Data 
Capture), which is a secure, HIPAA compliant web-based application and database hosted by 
Partners HealthCare. A separate database at the Sleep Disorders Clinical Research Program at 
Massachusetts General Hospital will contain personal identification data. 
If subjects have questions concerning their rights as a research subject, they may call the Human 
Subjects Committee office at MGH, or speak with study clinicians. All study documents will be 
stored electronically in REDCap as well as encrypted laboratory computers, and access to this 
information will only be given to the research personnel. 
 
Study Design and projected enrollment: 
This is a two-arm, double-blind, randomized placebo-controlled crossover 2.5-month trial, 
investigating the effects of suvorexant 10–20 mg on actigraphically-derived total sleep time in 
patients with persistent insomnia and effectively treated RLS. 
All study procedures will be conducted at Massachusetts General Hospital. Based on experience 
from our research group in patients with insomnia and RLS, we expect to consent and evaluate 
for eligibility up to 90 patients in order to achieve our projected randomized sample size of 44 
patients with effectively treated RLS, who will be randomized in a 1:1 ratio to suvorexant 10–20 
mg or equivalent placebo for four weeks followed by crossover (after a 2 week washout) to the 
alternate treatment.  Our goal is to have 34 patients with effectively treated RLS complete the 
trial with evaluable data at 2.5 months, after allowing for post-randomization drop-outs.  
 
We expect that many of the participants in this study will have numerous other health conditions 
which are thought to place them at higher risk of COVID-19-related complications. Thus, 
considering the safety and mental wellbeing of our subjects, all study visits will occur remotely. 
 


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For the remote visits, research staff will follow the MGB requirements for using the appropriate 
virtual tools. The study physician will remain on call during all points of remote visits in case 
there any emergent medical or psychiatric issues. 
 
 
V. OVERVIEW OF STUDY PROCEDURES 
Visit 1: TELEPHONE SCREEN (WEEK -4) 
An initial screen will be conducted over the phone, consisting of a brief clinical and sleep history 
for inclusion and exclusion criteria.  If preliminary eligibility appears adequate and the individual 
expresses interest, they will be sent links to complete the following questionnaires on REDCap: 
1) the Insomnia Severity Index to assess insomnia severity27 
2) the PHQ-9 to screen for depression 
3) the IRLS to assess RLS severity 
4) the STOP-BANG questionnaire to screen for sleep apnea28 
5) an electronic 14-day sleep diary 
 
Upon our review of these completed surveys and diaries, those who meet further eligibility criteria, 
as determined by the diaries (see Inclusion and Exclusion Criteria above), will be scheduled for a 
Screening Visit. 
 
Visit 2: SCREENING VISIT (WEEK -2) 
Written informed consent will be obtained by the study doctor at the Screening Visit for the 
remaining screening procedures and all treatment-related procedures (via the IRB-approved 
Informed Consent Form via the REDCap e-consent framework). Risks and benefits associated 
with use of suvorexant will be described. At that time, further eligibility will be assessed with a 
clinical interview conducted by a sleep medicine-trained psychiatrist to diagnose chronic insomnia 
disorder and to ensure that contraindicated sleep, medical and psychiatric problems and 
medications are excluded. Urine screens for pregnancy will be performed at an affiliated site; the 
study physician will order these tests. 
Phillips Actiwatch Spectrum Plus actiwatches will be mailed to participants, and returned by mail 
to investigators, at the outset and the end, respectively, of the screening run-in. Actigraphy baseline 
data will be collected during the 14 days of the screening run-in period.  Actiwatches will be worn 
on the non-dominant wrist both day and night at all times except when showering.  Standardized 
operating procedures developed by the Actigraphy Core of the Division of Sleep Medicine at MGH 
will be followed.  Event marker button press will establish “lights out” and “lights on” and will be 
compared with the daily diary times and adjusted if necessary, using written protocols. Sleep onset 


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and offset times will be computed using the vendor provided software by a trained technician 
supervised by the consultant (Dr. Klerman, the Core Chief). The following key standard actigraphy 
metrics will be generated on each day’s data: Sleep onset, sleep offset, time in bed (TIB), total 
sleep time (TST), sleep latency, wake after sleep onset (WASO), sleep efficiency and naps. 
Screening Run-In: They will receive daily email links to an online sleep diary to complete on 14 
consecutive days during the screening run-in period.  
 
Visit 3: BEGIN FIRST TREATMENT (WEEK 0) 
At this Randomization Visit, the 2-week sleep diary will be reviewed for definitive eligibility 
before the participant is randomized to treatment. Baseline questionnaires will be determined at 
this visit. Baseline subjective and actigraphic sleep measures will be determined from the last 7 
days of this 2-week period. Baseline pre-treatment symptom measures will be determined from 
the Randomization Visit. If the subject did not wear the actiwatch over 80% of the time during the 
two weeks before randomization, or if their data is missing (e.g. due to device malfunction), the 
actigraph will be sent back to the subject and he or she will be asked to repeat the baseline data 
collection period.  
Eligible participants will be randomized in a 1:1 ratio for the first 4-week period of placebo or 
suvorexant. Subjects will be mailed 14 days of the 10 mg dose of study medication following this 
visit.  
Subjects will also be mailed 42 additional pills of the 10 mg dose for use in weeks 1 to 3. Subjects 
will also be mailed actiwatches, and will be instructed to wear these during the two weeks leading 
up to Visit 5. 
 
Visit 4: INTERIM PHONE CONTACT 1 (WEEK 1) 
The study physician will call the participant to inquire about efficacy and adverse events. If the 10 
mg dose is well tolerated but not effective, the dose can be increased to 20 mg. The study physician 
will instruct the participant to take either one pill (10 mg) or two pills (20 mg) nightly over the 
next three weeks. 
 
Visit 5: END FIRST TREATMENT (WEEK 4) 
At this virtual visit, participants will meet with a study physician and the study coordinator. The 
physician will assess the participant on the Clinical Global Impression-Improvement (CGI-I) scale 
and will also inquire about any adverse events experienced. Questionnaires will also be determined 
at this visit. Subjects will be asked to mail actiwatches back to the study team. 


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At this point, subjects will begin the 2-week washout phase. 
 
Visit 6: BEGIN SECOND TREATMENT (WEEK 6) 
After the 2-week washout phase all participants will be crossed over to the other treatment for the 
second 4-week treatment phase. Subjects will be mailed 14 days of the 10 mg dose of either 
suvorexant or placebo following this visit.  
Subjects will also be mailed 42 additional pills of the 10 mg dose for use in weeks 7 to 9. Subjects 
will also be mailed actiwatches, and will be instructed to wear these during the two weeks leading 
up to Visit 8. 
 
Visit 7: INTERIM PHONE CONTACT 2 (WEEK 7) 
The study physician will call the participant to inquire about efficacy and adverse events. If the 10 
mg dose is well tolerated but not effective, the dose can be increased to 20 mg. The study physician 
will instruct the participant to take either one pill (10 mg) or two pills (20 mg) nightly over the 
next three weeks. 
 
Visit 8: END SECOND TREATMENT (WEEK 10) 
During this final virtual study visit, participants will meet with a study physician. The physician 
will assess the participant on the Clinical Global Impression-Improvement (CGI-I) scale and will 
also inquire about any adverse events experienced. Questionnaires will also be administered at this 
visit. Subjects will be asked to mail actiwatches back to the study team after the visit. 
 
Compensation: 
Subjects will be compensated $50 for study visit 2 and for virtual visits 3-8 ($25/visit). Subjects 
will receive a completion bonus when they have completed the study in its entirety ($50). The total 
possible compensation is $250. 
 
See below for the Table of Procedures and Study Flowchart. 
Table of Procedures: 


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hCG = Human chorionic gonadotropin, ISI = Insomnia Severity Index, PHQ-9 = Patient Health Questionnaire, CH-RLSq = Cambridge-Hopkins 
RLS questionnaire, BDI = Beck Depression Inventory, IRLS = International Restless Legs Scale, CGI-I = Clinician Global Impression of 
Improvement, PGI-I = Patient Global Impression of Improvement, DBAS = Dysfunctional Beliefs and Attitudes about Sleep29, PSQI = Pittsburgh 
Sleep Quality Index.30       
Study Flowchart: 
 
Initial 
Call
Study 
Visit
(2 weeks)
Screening 
Period 1
(Sleep 
diaries)
Randomization
Screening 
Period 2
(Diaries + 
actigraphy)
(2 weeks)
(4 weeks, with sleep diaries and 
actigraphy during last 2 weeks)
(2 weeks)
Washout
Period
(4 weeks, with sleep diaries and 
actigraphy during last 2 weeks)
Belsomra
Belsomra
Placebo
Placebo
Week
-4
Week
-2
Week
0
Week
4
Week
6
Week
10
Zoom
PC
Zoom
PC
Zoom
Zoom
PC – Phone Contact
Week
1
Week
7
Zoom
PC


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VI. STUDY MEDICATION AND SUPPLIES 
Study Treatments: 
The study medication will consist of 10 mg suvorexant tablets, or matching placebo, prepared in 
identically appearing capsules by Merck and distributed by the MGH Clinical Trials Pharmacy. 
The medication will be titrated and distributed according to the following schedule: 
 
Dispensing Schedule: 
Double-Blind Suvorexant / Placebo Dosing 
Week 
Group: 
Treatment à 
Placebo 
Placebo à 
Treatment 
0 
One 10 mg suvorexant tablet 
One 10 mg placebo tablet 
1-3 
One or two 10 mg suvorexant 
tablets 
One or two 10 mg placebo tablets 
6 
One 10 mg placebo tablet 
One 10 mg suvorexant tablet 
7-9 
One or two 10 mg placebo tablets 
One or two 10 mg suvorexant tablets 
 
Subjects will be instructed to take the study medication within 30 minutes of going to bed and will 
be informed during the consent process that they may be receiving drug or placebo at different 
points during the study. Participants will be instructed to take 10 mg nightly for the first 7 days. If 
the 10-mg dose is well tolerated but not effective after one week of treatment, as determined by 
the one-week phone visit, the dose can be increased to 20 mg (i.e. two 10 mg pills). This will be 
repeated at the 7-week phone call. 
 
Study Medication Packaging: 
Medication will be prepared and packaged by the MGH Clinical Trials Pharmacy. The medication 
will be dispensed in bottles containing enough for 14 days of medication after the Randomization 
visit, as well as enough for weeks 1-3. After the 6-week visit, a 14-day supply will again be 
dispensed, as well as a supply sufficient for weeks 7-9. Bottles will be labeled with the patient 


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name and ID and the dosing information. Bottles will be clearly labeled as containing 10 mg 
matching placebo or suvorexant tablets. 
Subjects will be dispensed the appropriate number of tablets needed until the next medication 
dispensing date. Study medication should be stored at room temperature 15-30°C (59-86°F), be 
protected from moisture, and be maintained in a secure area. 
 
Study Medication Accountability and Compliance: 
Starting at the Randomization Visit, study medication will be dispensed to each subject with 
instructions to save all unused study medication in order to assess compliance. Participants will be 
required to show the study team over video how much medication is remaining. Additional bottles 
will be dispensed to each subject as needed. 
All study medication dispensed by the investigator or designee will be accounted for throughout 
the study. Information about subject dosing and compliance will be recorded in the subject’s study 
records. Subjects who are noncompliant with medications (according to pill counts and diaries) 
may be removed from the study at the discretion of the investigators.  
The investigator agrees not to allow access to the study medication to any person except those 
named as sub-investigator(s) or clinical care staff and dispense only to qualified subjects 
participating in the study. 
 
Randomization: 
Randomization will be used to avoid bias in the assignment of subjects to treatment, to increase 
the likelihood that known and unknown subject attributes (e.g., demographics and baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups. Blinded treatment will be used to reduce potential 
bias during data collection and evaluation of clinical endpoints.  
At the Screening Visit, subjects will be assigned a 3-digit subject number, in ascending sequential 
order beginning with 001. The subject number will be retained by the subject for the duration of 
the study. The MGH Clinical Trials Pharmacy will provide and maintain randomization and 
blinding. Subjects will be randomized to the two crossover groups in a 1:1 ratio. Subject and 
investigator will be blinded to treatment assignment. Subjects will be randomized sequentially as 
they qualify for the study. 
 
Blinding: 


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The randomization code will be maintained by the MGH Clinical Trials Pharmacy and will not be 
revealed to study subjects, investigators or blinded clinical staff until all subjects have completed 
and the database has been finalized. 
Under normal circumstances, the blind should not be broken. The blind should be broken only if 
specific treatment would be dictated by knowing the treatment status of the subject. Individual 
code breaks by the investigator will normally result in withdrawal of the subject from the trial. The 
date, time and reason for the unblinding must be documented in the study files.  
 
VII. RISKS AND DISCOMFORTS 
Medication Side Effects and Adverse Events: 
The package insert for suvorexant includes warnings and precautions related to the following side 
effects or adverse events: sleepiness during the day, not thinking clearly; acting strangely, 
confused, or upset; “sleep-walking” or doing other activities during sleep, such as eating, talking, 
having sex, or driving a car;  temporary weakness in your legs or inability to move or talk, 
cataplexy; and diarrhea, dry mouth, upper respiratory tract infection, headache, next-day 
drowsiness, dizziness, abnormal dreams, and cough. 
Subjects will be informed of the risks associated with consuming alcohol while taking suvorexant, 
both at the time of consent and throughout the study.  Subjects will be advised not to consume 
alcohol in combination with suvorexant due to additive psychomotor effects. 
Subjects will be assessed for depression and suicidal ideation at each study visit, using the Beck 
Depression Inventory (BDI).31  
All adverse events that occur between the first study-related procedure and within 30 days of the 
last dose of study medication will be reported. Adverse events will be reported to the Partners IRB 
according to guidelines. 
Subjects should report any adverse events voluntarily or in response to general, non-directed 
questioning (e.g., “How has your health been since the last visit?). For each adverse event reported 
by the subject, the investigator should obtain all the information required to complete 
documentation in the subject’s research file. 
All adverse events, regardless of seriousness, severity, or presumed relationship to study therapy, 
must be recorded using medical terminology in the subject’s study documents. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (e.g., cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as “upper respiratory 
infection”). The investigator must document his/her opinion concerning the relationship of the 
adverse event to the study medication. All measures required for adverse event management must 
be recorded in the source document. 


Version Date: 7/5/2022 
Winkelman, John W., M.D., Ph.D. 
 
 
VIII. POTENTIAL BENEFITS 
Subjects will receive suvorexant, which may help their condition. They may benefit from the 
sleep diaries, actigraphy, review of symptoms, and regular discussions with the study doctor. 
Their participation in this study may help other people with RLS and insomnia by adding to the 
knowledge about this drug, and whether it is a beneficial treatment.   
 
 
IX. BIOSTATISTICAL ANALYSIS 
Analysis of all study data will be conducted by Dr. Winkelman. All study personnel and 
participants will remain blinded to treatment assignment, including staff entering study data. Only 
the hospital Research Pharmacist who generates the randomization code will be unblinded to 
treatment assignment. The final database will not be unblinded until a medical and scientific 
review, protocol violators have been identified, and all study data are complete.  
 
Overview of analytic plan:  
The primary hypothesis for this trial is that suvorexant is superior to placebo in reducing 
actigraphically-derived total sleep time in patients with persistent insomnia in the context of 
effectively treated restless legs syndrome. The primary endpoint is the change in actigraphically-
derived total sleep time from baseline to the end of each 4-week treatment period. Key secondary 
endpoints include actigraphically-derived wake after sleep onset and self-reported ISI, and 
exploratory endpoints include subjective total sleep time and wake after sleep onset, and RLS 
severity. 
 
Study endpoints: 
The primary outcome (actigraphically-derived total sleep time) and all secondary and exploratory 
measures are continuous variables. Primary analyses will focus on the difference from the baseline 
total sleep time (in minutes) to the total sleep time evaluated in each of the two treatment periods, 
within subjects. The key secondary variables are the difference from baseline to the end of each 
treatment period are actigraphically-derived wake after sleep onset and self-reported ISI.  
Exploratory analyses will similarly focus on the differences from the baseline value to the final 
observed value at the end of each treatment period. As these are exploratory analyses, no p-values 
will be determined other than as described below in the hierarchical testing.  These endpoints 
include:  
a) Diary-derived wake after sleep onset 


Version Date: 7/5/2022 
Winkelman, John W., M.D., Ph.D. 
 
b) Diary-derived total sleep time 
c) Diary-derived SOL, sleep efficiency and sleep quality  
d) RLS severity via IRLS 
 
STATISTICAL METHODS 
Efficacy variables will be analyzed using an analysis of variance model with treatment, sequence, 
and period as fixed effects and subject within sequence as a random effect. Least squares (LS) 
mean treatment difference will be calculated from the model. Diagnostic methods will be used for 
all variables to assess their distributional assumptions and to examine potential outlying or 
influential data points. This analytical method will similarly be used to assess secondary outcomes. 
Within-treatment changes from baseline will also be evaluated using a paired t-test for the primary 
and secondary efficacy variables of change from baseline in total sleep time, wake after sleep 
onset, and ISI. 
The primary outcome analysis will use the intention-to-treat principle and include all participants 
who received at least one dose of study medication and completed at least one week of sleep diaries 
following randomization.  
Per-protocol analyses will be repeated on the subgroup of subjects that achieve 85% medication 
adherence based on the number of pills returned at the end of study. Variables related to subjective 
total sleep time will be determined by Pearson correlation and simple regression analysis using 
weighted least squares. A two-sided P value <0.05 will be considered significant. 
 
Power/Sample Size: 
Statistical power for the primary endpoint, actigraphically-assessed total sleep time, was estimated 
from pooled analyses of data from placebo-controlled clinical trials of suvorexant for the treatment 
of insomnia using polysomnographically-measured total sleep time.21 The difference between 
15/20 mg suvorexant and placebo at 1 month in least squares mean change from baseline was 34.7 
minutes (95% CI: 27.8, 41.5), corresponding to an effect size of 0.58. Although actigraphy is not 
identical to polysomnography, multiple studies (including one by our group and two using the 
Phillips Spectrum actiwatch) with insomnia patients demonstrate high correlations between these 
two objective recording methods for total sleep time, wake after sleep onset, and sleep efficiency,  
particularly when event markers are employed.32-34  
With an effect size of .58, 34 randomized subjects are required to achieve 90% power to detect a 
statistical significance level of 0.05. In total, we expect to randomize 44 participants to treatment 
to have 34 completed subjects with evaluable data.  


Version Date: 7/5/2022 
Winkelman, John W., M.D., Ph.D. 
 
XI. REFERENCES 
1. 
Allen RP, Picchietti DL, Garcia-Borreguero D, et al. Restless legs syndrome/Willis-Ekbom 
disease diagnostic criteria: updated International Restless Legs Syndrome Study Group 
(IRLSSG) consensus criteria--history, rationale, description, and significance. Sleep 
medicine. 2014;15(8):860-873. 
2. 
Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact: 
REST general population study. Archives of internal medicine. 2005;165(11):1286-1292. 
3. 
Hening W, Walters AS, Allen RP, Montplaisir J, Myers A, Ferini-Strambi L. Impact, 
diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the 
REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep medicine. 
2004;5(3):237-246. 
4. 
Winkelman JW, Shahar E, Sharief I, Gottlieb DJ. Association of restless legs syndrome 
and cardiovascular disease in the Sleep Heart Health Study. Neurology. 2008;70(1):35-42. 
5. 
Winkelman JW. Is restless legs syndrome a sleep disorder? Neurology. 2013;80(22):2006-
2007. 
6. 
Kushida CA, Allen RP, Atkinson MJ. Modeling the causal relationships between 
symptoms associated with restless legs syndrome and the patient-reported impact of RLS. 
Sleep medicine. 2004;5(5):485-488. 
7. 
Allen RP, Stillman P, Myers AJ. Physician-diagnosed restless legs syndrome in a large 
sample of primary medical care patients in western Europe: Prevalence and characteristics. 
Sleep medicine. 2010;11(1):31-37. 
8. 
Winkelman JW, Sethi KD, Kushida CA, et al. Efficacy and safety of pramipexole in 
restless legs syndrome. Neurology. 2006;67(6):1034-1039. 
9. 
Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of pregabalin with pramipexole 
for restless legs syndrome. The New England journal of medicine. 2014;370(7):621-631. 
10. 
Scholz H, Trenkwalder C, Kohnen R, Riemann D, Kriston L, Hornyak M. Dopamine 
agonists for restless legs syndrome. The Cochrane database of systematic reviews. 
2011(3):Cd006009. 
11. 
Bogan RK, Fry JM, Schmidt MH, Carson SW, Ritchie SY. Ropinirole in the treatment of 
patients with restless legs syndrome: a US-based randomized, double-blind, placebo-
controlled clinical trial. Mayo Clinic proceedings. 2006;81(1):17-27. 
12. 
Ferini-Strambi L, Aarskog D, Partinen M, et al. Effect of pramipexole on RLS symptoms 
and sleep: a randomized, double-blind, placebo-controlled trial. Sleep medicine. 
2008;9(8):874-881. 
13. 
Hornyak M, Scholz H, Kohnen R, Bengel J, Kassubek J, Trenkwalder C. What treatment 
works best for restless legs syndrome? Meta-analyses of dopaminergic and non-
dopaminergic medications. Sleep medicine reviews. 2014;18(2):153-164. 
14. 
Garcia-Borreguero D, Patrick J, DuBrava S, et al. Pregabalin versus pramipexole: effects 
on sleep disturbance in restless legs syndrome. Sleep. 2014;37(4):635-643. 
15. 
Ondo W. Restless Legs Syndrome "Patient Odyssey" survey of disease burden on patient 
and spouses/partners. Sleep medicine. 2018;47:51-53. 
16. 
Hammerschlag AR, Stringer S, de Leeuw CA, et al. Genome-wide association analysis of 
insomnia complaints identifies risk genes and genetic overlap with psychiatric and 
metabolic traits. Nature genetics. 2017;49(11):1584-1592. 
17. 
Inoue Y. Sleep-related eating disorder and its associated conditions. Psychiatry and clinical 
neurosciences. 2015;69(6):309-320. 


Version Date: 7/5/2022 
Winkelman, John W., M.D., Ph.D. 
 
18. 
Morgenthaler TI, Silber MH. Amnestic sleep-related eating disorder associated with 
zolpidem. Sleep medicine. 2002;3(4):323-327. 
19. 
Kolla BP, Mansukhani MP, Bostwick JM. The influence of antidepressants on restless legs 
syndrome and periodic limb movements: A systematic review. Sleep medicine reviews. 
2018;38:131-140. 
20. 
Hening WA, Walters AS, Wagner M, et al. Circadian rhythm of motor restlessness and 
sensory symptoms in the idiopathic restless legs syndrome. Sleep. 1999;22(7):901-912. 
21. 
Herring WJ, Connor KM, Snyder E, et al. Suvorexant in Patients with Insomnia: Pooled 
Analyses of Three-Month Data from Phase-3 Randomized Controlled Clinical Trials. 
Journal of clinical sleep medicine : JCSM : official publication of the American Academy 
of Sleep Medicine. 2016;12(9):1215-1225. 
22. 
Allen RP, Mignot E, Ripley B, Nishino S, Earley CJ. Increased CSF hypocretin-1 (orexin-
A) in restless legs syndrome. Neurology. 2002;59(4):639-641. 
23. 
Stiasny-Kolster K, Mignot E, Ling L, Möller JC, Cassel W, Oertel WH. CSF hypocretin-1 
levels in restless legs syndrome. Neurology. 2003;61(10):1426-1429. 
24. 
Allen RP, Burchell BJ, MacDonald B, Hening WA, Earley CJ. Validation of the self-
completed Cambridge-Hopkins questionnaire (CH-RLSq) for ascertainment of restless 
legs syndrome (RLS) in a population survey. Sleep medicine. 2009;10(10):1097-1100. 
25. 
Walters AS, LeBrocq C, Dhar A, et al. Validation of the International Restless Legs 
Syndrome Study Group rating scale for restless legs syndrome. Sleep medicine. 
2003;4(2):121-132. 
26. 
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity 
measure. Journal of general internal medicine. 2001;16(9):606-613. 
27. 
Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: psychometric 
indicators to detect insomnia cases and evaluate treatment response. Sleep. 
2011;34(5):601-608. 
28. 
Chung F, Abdullah HR, Liao P. STOP-Bang Questionnaire: A Practical Approach to 
Screen for Obstructive Sleep Apnea. Chest. 2016;149(3):631-638. 
29. 
Morin CM, Vallières A, Ivers H. Dysfunctional beliefs and attitudes about sleep (DBAS): 
validation of a brief version (DBAS-16). Sleep. 2007;30(11):1547-1554. 
30. 
Buysse DJ, Reynolds CF, 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep 
Quality Index: a new instrument for psychiatric practice and research. Psychiatry research. 
1989;28(2):193-213. 
31. 
Wang YP, Gorenstein C. Psychometric properties of the Beck Depression Inventory-II: a 
comprehensive review. Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999). 
2013;35(4):416-431. 
32. 
McCall C, McCall WV. Comparison of actigraphy with polysomnography and sleep logs 
in depressed insomniacs. Journal of sleep research. 2012;21(1):122-127. 
33. 
Marino M, Li Y, Rueschman MN, et al. Measuring sleep: accuracy, sensitivity, and 
specificity of wrist actigraphy compared to polysomnography. Sleep. 2013;36(11):1747-
1755. 
34. 
Withrow D, Roth T, Koshorek G, Roehrs T. Relation between ambulatory actigraphy and 
laboratory polysomnography in insomnia practice and research. Journal of sleep research. 
2019;28(4):e12854. 
 

ICF_001.pdf: 
 
 
 
Research Consent Form 
General Consent Form Template 
Version Date:  February 2021 
 
 
 
 
Page 1 of 17 
 
 
Subject Identification 
Protocol Title: Efficacy of Suvorexant in Patients with Effectively Treated 
Restless Legs Syndrome and Persistent Chronic Insomnia: A Randomized 
Placebo-Controlled Crossover Trial 
 
Principal Investigator: John W Winkelman MD PhD  
 
Site Principal Investigator:       
 
Description of Subject Population: Patients with Effectively Treated Restless Legs 
Syndrome and Persistent Chronic Insomnia 
 
About this consent form 
 
Please read this form carefully.  It tells you important information about a research study.  A 
member of our research team will also talk to you about taking part in this research study.  
People who agree to take part in research studies are called “subjects.”  This term will be used 
throughout this consent form. 
 
If you decide to take part in this research study, you must sign this form to show that you want to 
take part.  We will give you a signed copy of this form to keep. 
 
 
Key Information 
 
Taking part in this research study is up to you.  You can decide not to take part.  If you decide to 
take part now, you can change your mind and drop out later.  Your decision won’t change the 
medical care you get within Mass General Brigham now or in the future.   
 
The following key information is to help you decide whether or not to take part in this research 
study.  We have included more details about the research in the Detailed Information section that 
follows the key information. 
 
Why is this research study being done? 
 


 
 
 
Research Consent Form 
General Consent Form Template 
Version Date:  February 2021 
 
 
 
 
Page 2 of 17 
 
 
Subject Identification 
The purpose of the study is to learn about the safety and effectiveness of oral (taken by mouth) 
suvorexant (BelsomraÒ) in improving sleep quality and sleep quantity in patients who have 
treated restless legs syndrome (RLS). 
 
How long will you take part in this research study? 
 
It will take you about 12 weeks (about 3 months) to complete the study; during this time, you 
will be asked to make 5 study visits. All study visits will occur remotely over Zoom. In addition, 
a member of the study staff will call you 2 times in addition to the initial phone call that you 
already had with the study team. 
 
What will happen if you take part in this research study? 
 
If you decide to join this research study, you will be asked to complete: sleep diaries, home 
actigraphy, questionnaires, 2 phone calls, and 5 visits. During those visits, you will speak with 
the study team and complete questionnaires. 
 
Why might you choose to take part in this study? 
 
We cannot promise any benefits to you from taking part in this research study. Others with 
treated RLS and insomnia may benefit in the future from what we learn in this study. 
Additionally, you will be compensated up to $250 for your participation in this study.  
 
Why might you choose NOT to take part in this study? 
 
Taking part in this research study has some risks and requirements that you should consider 
carefully.  
 
Important risks and possible discomforts to know about include side effects of the study 
medication, suvorexant. Side effects include: sleepiness or drowsiness during the day, not 
thinking clearly, acting strangely, sleep-walking, temporary weakness, diarrhea, dry mouth, 
upper respiratory tract infection, headache, dizziness, abnormal dreams, and cough. 
 
A detailed description of side effects, risks, and possible discomforts can be found later in this 
consent form in the section called “What are the risks and possible discomforts from being in this 
research study?” 
 
Another thing to consider is the time commitment for completing daily sleep diaries, which will 
be sent to your email address each morning and submitted back to us online.  


 
 
 
Research Consent Form 
General Consent Form Template 
Version Date:  February 2021 
 
 
 
 
Page 3 of 17 
 
 
Subject Identification 
 
 
What other treatments or procedures are available for your condition? 
 
You do not have to take part in this research study to receive treatment for your disease. There 
are other currently-approved treatments for insomnia, and the study doctor can tell you what 
other options are available to you. There are more details on approved treatments for insomnia 
later in this form.  
 
If you have questions or concerns about this research study, whom can 
you call? 
 
You can call us with your questions or concerns.  Our telephone numbers are listed below.  Ask 
questions as often as you want.   
 
John Winkelman, MD PhD is the person in charge of this research study.  You can call him at 
617-643-9101 from 9 am to 5 pm on weekdays. He is available 24 hours a day, 7 days a week, 
by paging him at Massachusetts General Hospital, 617-726-2000. 
 
If you have questions about the scheduling of appointments or study visits, call Jordana Zackon 
at 617-643-6026 or email jzackon@mgh.harvard.edu.
 
If you want to speak with someone not directly involved in this research study, please contact 
the Mass General Brigham IRB office.  You can call them at 857-282-1900. 
 
You can talk to them about: 
§ Your rights as a research subject 
§ Your concerns about the research 
§ A complaint about the research 
§ Any pressure to take part in, or to continue in the research study 
 
 
 
 


 
 
 
Research Consent Form 
General Consent Form Template 
Version Date:  February 2021 
 
 
 
 
Page 4 of 17 
 
 
Subject Identification 
Detailed Information 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
 
Why is this research study being done? 
 
The purpose of the study is to learn about the safety and effectiveness of oral (taken by mouth) 
suvorexant (BelsomraÒ) in improving sleep quality and sleep quantity in patients who have treated 
RLS. We are asking you to take part in this research study because you have RLS and significant 
sleep disruption. There is evidence that sleep disturbances are common in patients with treated 
RLS. 
 
In this study we are comparing suvorexant to placebo. A placebo is a pill that looks exactly like 
the study drug, but it does not have any active drug in it. You will receive both suvorexant and 
placebo during the study. You will receive one medication during the first four-week treatment 
period, and the other during the second four-week treatment period. You will not be informed as 
to which medication you are taking at various points throughout the study. We use placebos in 
research studies to learn if the effects seen in research subjects are truly from the study drug or 
from other reasons. Throughout this form, the phrase “study drug” applies to both treatments that 
you could get: suvorexant and placebo. 
 
Suvorexant (BelsomraÒ) is approved by the U.S. Food and Drug Administration (FDA) for the 
treatment of insomnia in patients 18 years of age and older. This study is investigating the use of 
suvorexant specifically in a population of patients with treated RLS.  
 
Suvorexant (Belsomra®) is manufactured by Merck & Co., Inc. 
 
We hope to enroll 90 subjects between the ages of 25 and 85. 
 
 
 
Who will take part in this research? 
 
This is a pilot study. A pilot study is done on a small group of subjects to learn if the study drug 
will be effective and safe, before the study drug is given to a larger group of subjects.  
 


 
 
 
Research Consent Form 
General Consent Form Template 
Version Date:  February 2021 
 
 
 
 
Page 5 of 17 
 
 
Subject Identification 
In this study, we hope to enroll 90 subjects between the ages of 25 and 85, with treated RLS and 
insomnia. 
 
This study is being funded by Merck & Co., Inc. 
 
 
What will happen in this research study? 
 
The study has the following phases: 
 
 Screening Phase 
 
• 
Screening Period (two weeks): You have already completed the Telephone Screen and 
the two-week period that proceeds the virtual Screening Visit (including the completion 
of two weeks of sleep diaries, which will be reviewed at the Screening Visit). At the 
Screening Visit, you will be informed of all the study procedures and evaluated for 
eligibility.  
• 
At the Screening Visit, if you wish to participate in the study, we will ask you to stop 
taking any medications that are considered exclusionary. These include: 
o Strong inhibitors of CYP3A 
§ Ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, 
ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, 
telithromycin, conivaptan 
o *Subjects may continue, but a maximum dose of 10 mg will typically be given for 
subjects taking moderate CYP3A inhibitors  
§ Amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, 
erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, 
verapamil 
o In certain cases, subjects on moderate CYP3A inhibitors may be administered 20 
mg of suvorexant if the study doctor determines that side effects at 10 mg do not 
preclude an increase in dose.  In these cases, an additional safety phone call will 
be performed after 1 week at the higher dose (20 mg) in both treatment periods. 
 
• 
At the Screening Visit, you will meet with the study doctor (approximately 30 minutes). 
The doctor will ask you questions about your medical history, sleep history, psychiatric 
history, RLS, sleep quality, and medications.  
• 
If you are a woman who is able to become pregnant, a urine pregnancy test will be done. 
If you are pregnant, you will not be allowed to take part in the study. You will need to 
have this test performed at an affiliated site or a satellite clinic. We will pay for this test. 


 
 
 
Research Consent Form 
General Consent Form Template 
Version Date:  February 2021 
 
 
 
 
Page 6 of 17 
 
 
Subject Identification 
• 
After the Screening Visit, the study doctor will continue to evaluate whether you are 
eligible for this study over another two-week period. You will be asked to complete 
another two weeks of sleep diaries. We will also mail you a Phillips Actiwatch Spectrum 
Plus. We will ask you to wear this device on your non-dominant wrist both day and night 
at all times except when showering. After two weeks of use, we will ask you to mail the 
actiwatch back to us. We will pay for the postage fees.  
 
 
Study Drug 
We will assign you by chance to one of two study groups. One out of every two people will 
receive suvorexant up to 20 mg/night, and the rest of participants will receive placebo 
(contains no active drug). You, the study doctor, and the study staff will not know which 
group you are in, but we can find out this information if we need it.  
 
Throughout this form the phrase “study drug” applies to suvorexant and placebo. The study 
drug will be provided in a single capsule of suvorexant or placebo. It is important that you 
follow your study doctor’s or the study staff’s instructions on when and how to take the study 
drug. The study drug will be provided in child-resistant bottles. 
 
 
Start of Treatment 1 (Week 0) 
 
• 
At this virtual visit, the study doctor will determine whether you are still eligible to 
participate in the study.  
• 
You will meet with the study doctor to discuss medications, sleep quality, health 
conditions, and the details of your participation in the study. The study doctor will 
discuss all possible side effects from the study drug, and you will be able to ask any 
questions.  
• 
You will be asked to complete questionnaires (approximately 20 minutes). This 
information is kept confidential and will only be used for study purposes. 
• 
You will be mailed a 14-day supply of study drug at this visit to be taken at night 
before bed, and you will be provided with instructions on how to store, how/when to take, 
and any risks associated with, the study drug. The study drug may be suvorexant or 
placebo, you will be assigned randomly to either group, and neither the study staff nor 
you will know which one you are taking. 
• 
You will also be mailed an additional 3-week supply of study drug. During Interim 
Phone Call 1, you will be provided with instructions on how/when to take this additional 
medication. 
• 
You will also be mailed an actiwatch with the medication. 
   


 
 
 
Research Consent Form 
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Version Date:  February 2021 
 
 
 
 
Page 7 of 17 
 
 
Subject Identification 
Interim Phone Call 1 (Week 1) 
 
• 
During week 1, you will be contacted via phone by the study doctor. The study doctor 
will discuss with you the effectiveness of the study drug and ask about any side effects 
you may have experienced. If you did not experience any side effects during the first 
week, and the 10-mg dose was ineffective, your dose will be increased to 20 mg (i.e. the 
doctor will instruct you to take two 10-mg pills nightly).  
 
End of Treatment 1 (Week 4) 
• Prior to this virtual visit, you will be asked to complete 2 weeks of sleep diaries and 
actigraphy.  
• You will meet with the study doctor to discuss your medications, sleep quality, health 
conditions, and mood, and you will be able to ask any questions. The study doctor will 
discuss with you the effectiveness of the study drug and inquire about any side effects 
you may have experienced. 
• You will be asked to complete questionnaires (approximately 20 minutes). This 
information is kept confidential and will only be used for study purposes. 
• You will be asked to show the study doctor all remaining medication over Zoom. 
• You will be asked to mail the actiwatch back to the study team following this visit.  
• At this point, you will begin a two-week washout phase, meaning that you will not be 
taking any medication until after the next visit.  
 
 
Start of Treatment 2 (Week 6) 
 
• 
You will meet with the study doctor to discuss medications, sleep quality, health 
conditions, and the details of your participation in the study. The study doctor will 
discuss all possible side effects from the study drug, and you will be able to ask any 
questions.  
• 
You will be mailed a 14-day supply of study drug at this visit to be taken at night 
before bed, and you will be provided with instructions on how to store, how/when to take, 
and any risks associated with, the study drug. The study drug may be suvorexant or 
placebo, you will be assigned randomly to either group, and neither the study staff nor 
you will know which one you are taking. 
• 
You will also be mailed an additional 3-week supply of study drug. During Interim 
Phone Call 2, you will be provided with instructions on how/when to take this additional 
medication. 
• 
You will also be mailed an actiwatch with the medication.  
 


 
 
 
Research Consent Form 
General Consent Form Template 
Version Date:  February 2021 
 
 
 
 
Page 8 of 17 
 
 
Subject Identification 
Interim Phone Call 2 (Week 7) 
 
• 
During week 7, you will be contacted via phone by the study doctor. The study doctor 
will discuss with you the effectiveness of the study drug and ask about any side effects 
you may have experienced. If you did not experience any side effects during the first 
week, and the 10-mg dose was ineffective, your dose will be increased to 20 mg (i.e. the 
doctor will instruct you to take two 10-mg pills nightly).  
 
 
End of Treatment 2 (Week 10) 
 
• Prior to this virtual visit, you will be asked to complete 2 weeks of sleep diaries and 
actigraphy.  
• You will meet with the study doctor to discuss your medications, sleep quality, health 
conditions, and mood, and you will be able to ask any questions. The study doctor will 
discuss with you the effectiveness of the study drug and inquire about any side effects 
you may have experienced. 
• You will be asked to complete questionnaires (approximately 20 minutes). This 
information is kept confidential and will only be used for study purposes. 
• You will be asked to show the study doctor all remaining medication over Zoom. 
• You will be asked to mail the actiwatch back to the study team following this visit.  
 
Remote Visits 
 
During this study we may need to make changes to study visits and procedures to comply with 
public health efforts to address COVID-19 (coronavirus). We may need to adjust the study visit 
schedule and/or research procedures as a result of study site restrictions. We will contact you 
about any such changes that may arise. 
 
Remote visits will be conducted either over the phone or by Zoom. During these visits, someone 
from the study staff will contact you. 
 
Video Conferencing 
 
Study staff will provide you information on how to access the video conferencing platform. We 
will launch the video conferencing in a private and secure area. To protect your privacy we ask 
that you do not take screenshots, photographs, or recordings of any kind with any electronic 
equipment.  
 


 
 
 
Research Consent Form 
General Consent Form Template 
Version Date:  February 2021 
 
 
 
 
Page 9 of 17 
 
 
Subject Identification 
We would like to remind you that a video meeting is similar to us visiting you at home. We may 
learn more about your home and the people living with you than we would during a visit at the 
hospital. For example, we may learn information from you that must be reported to public health 
or public safety authorities. We are required by law to report known or suspected child or elder 
abuse. If we make such report, the public health and safety authorities can use the information as 
they see fit and may end up sharing it with other government agencies. Please ask the research 
staff if you have any questions about this prior to your video visit. 
 
Early Withdrawal 
You may withdraw from this study at any time. If you wish to stop taking part in the study for 
any reason, please contact the study staff. We will give you instructions to gradually stop taking 
the study drug, if necessary. Depending on the point at which you withdraw from the study, we 
may ask you to participate in a final visit.  
 
The study doctor may decide to end your participation in the study. This might happen if you 
have changes in your health, if you do not follow instructions, or if you do not attend the study 
visits. 
 
General Information 
All of the information collected in this study will only be used for research and will not be placed 
in your medical records. To protect your privacy, we will use a unique identification number on 
your study forms instead of your name or address. The study staff will keep a list that matches 
your unique identification number to your name, but we will not share this list with anyone. 
 
 
How may we use and share your samples and health information for other 
research?
 
The information we collect in this study may help advance other research.  If you join this study, 
we may remove all information that identifies you (for example, your name, medical record 
number, and date of birth) and use these de-identified samples and data in other research.  It 
won’t be possible to link the information or samples back to you.  Information and/or samples 
may be shared with investigators at our hospitals, at other academic institutions or at for-profit, 
commercial entities.  You will not be asked to provide additional informed consent for these 
uses. 
 
 
 
 


 
 
 
Research Consent Form 
General Consent Form Template 
Version Date:  February 2021 
 
 
 
 
Page 10 of 17 
 
 
Subject Identification 
Will you get the results of this research study? 
 
No.  The research study we are doing is only a stepping stone in understanding [condition].  
Therefore, no information about the results of this research study or the results of your individual 
participation in the research study will be given to you or your doctor.  Tests done for the 
research using your samples will not be useful in directing your medical treatment.  The results 
of the tests will not be placed in your medical record.    
 
 
What are the risks and possible discomforts from being in this research 
study? 
 
RISKS ASSOCIATED WITH THE STUDY DRUG 
All drugs may cause side effects. The most commonly reported side effects associated with 
suvorexant in research studies include:  
• 
sleepiness or drowsiness during the day  
• 
headache 
• 
dizziness 
 
Less-common side effects include: 
• 
diarrhea 
• 
dry mouth 
• 
upper respiratory tract infection 
• 
abnormal dreams 
• 
cough 
 
Rare, but serious side effects include: 
• 
temporary weakness in your legs or inability to move or talk, otherwise known as cataplexy  
• 
not thinking clearly 
• 
acting strangely, confused, or upset  
• 
“sleep-walking” or doing other activities during sleep, such as eating, talking, having sex, 
or driving a car   
 
Suvorexant may cause a change (increase or decrease) in the effect of some other drugs. If you 
are taking other drugs while you are participating in this study, the study doctor will explain 
whether suvorexant may have an effect on those drugs. If necessary, the study doctor may adjust 
your drug dose. 
 


 
 
 
Research Consent Form 
General Consent Form Template 
Version Date:  February 2021 
 
 
 
 
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Subject Identification 
There may be other risks and side effects to suvorexant that are not known at this time. You will 
be notified of any new significant findings that might affect your willingness to continue to 
participate in this study.   
 
Due to the possibility of dizziness or drowsiness, you must be cautious when operating a vehicle 
or heavy equipment while in this study. You should wait to operate a vehicle or heavy equipment 
until you have experience using suvorexant. 
 
Your condition may remain the same or worsen while you are taking part in this study. 
 
If you experience any side effects, you should contact John Winkelman, MD, PhD (the study 
doctor) immediately at one of the contact numbers listed in the study contacts section near the 
beginning of this form. 
 
 
RISKS ASSOCIATED WITH CONSUMING ALCOHOL The use of suvorexant and alcohol are 
contraindicated due to potential serious side effects, including drowsiness, dizziness, and 
diminished judgement and coordination. If you consume alcohol while taking the study drug and 
experience any side effects, contact John Winkelman, MD, PhD (the study doctor) immediately.  
 
REPRODUCTIVE RISKS 
You cannot take part in this study if you are pregnant or nursing an infant. If you are a woman 
who is able to become pregnant, you must use birth control throughout the study. Acceptable 
methods of birth control include:  
▪  hormonal contraceptives (birth control pills, patches, implants, or injections)  
▪  spermicide and barrier (barriers include condoms and diaphragms)  
▪  intrauterine device (IUD)  
▪  spousal/partner sterility (unable to father or mother a child) 
▪  abstinence (If you are practicing abstinence, you must agree to continue abstinence or 
to use an acceptable method of contraception, as noted above, if sexual activity begins.) 
 
It is possible that some hormonal contraceptives (birth control pills, hormonal implants or 
hormonal injections) may be made less effective because of the use of suvorexant. If necessary, 
your study doctor will discuss alternatives or additional non-hormonal methods of birth control 
that you should use while you are taking part in the study. If you are taking birth control pills, 
you should report to your study doctor any change in your bleeding patterns.   
 
If you are a female who is able to become pregnant, you will have periodic pregnancy tests 
throughout the research study. If these tests show that you are pregnant, you will not be able to 
enter and stay in the study. You must accept the risk that pregnancy could still result even though 


 
 
 
Research Consent Form 
General Consent Form Template 
Version Date:  February 2021 
 
 
 
 
Page 12 of 17 
 
 
Subject Identification 
you are using a reliable method of birth control. If you become pregnant during the study, you 
must inform the study doctor immediately.  
 
If you become pregnant during this study, you will be discontinued from the study and the study 
drug will be stopped immediately. Your study doctor will explain the potential hazards that may 
affect the fetus and possible alternatives, which may include ending the pregnancy. 
 
 
RISKS ASSOCIATED WITH TAPERING OFF OF MEDICATIONS 
A number of risks associated with tapering off prescribed medications can occur, including a 
return of symptoms for which the medication is prescribed, and medication specific withdrawal 
effects. The study doctor will discuss any of these risks with you. 
 
What are the possible benefits from being in this research study? 
 
You may not benefit from taking part in this study. You will receive suvorexant at a point during 
the study, which may help your condition. You may benefit from the sleep diaries, actigraphy, 
urine tests, review of your symptoms, and regular discussions with the study doctor. Your taking 
part in this study may help other people with insomnia and RLS by adding to the knowledge 
about this drug, and whether it is a beneficial treatment.   
 
What other treatments or procedures are available for your condition? 
 
You do not have to take part in this research study to receive treatment for your disease. There 
are other currently approved treatments for insomnia, and the study doctor can tell you what 
other options are available to you.  
 
The study drug is available by prescription without participating in this study. Other medications 
approved for the treatment of insomnia include: Zolpidem (Ambien), Zaleplon (Sonata), 
Ramelteon (Rozerem), Eszopiclone (Lunesta), Doxepine (Silenor), some benzodiazepines, and 
some antidepressants.  
 
Can you still get medical care within Mass General Brigham if you don’t 
take part in this research study, or if you stop taking part?  
 
Yes.  Your decision won’t change the medical care you get within Mass General Brigham now 
or in the future.  There will be no penalty, and you won’t lose any benefits you receive now or 
have a right to receive.  
 


 
 
 
Research Consent Form 
General Consent Form Template 
Version Date:  February 2021 
 
 
 
 
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Subject Identification 
We will tell you if we learn new information that could make you change your mind about taking 
part in this research study. 
 
 
What should you do if you want to stop taking part in the study? 
 
If you take part in this research study, and want to drop out, you should tell us.  We will make 
sure that you stop the study safely.  We will also talk to you about follow-up care, if needed. 
 
Also, it is possible that we will have to ask you to drop out of the study before you finish it.  If 
this happens, we will tell you why.  We will also help arrange other care for you, if needed.  
 
 
Will you be paid to take part in this research study? 
 
You will be paid for each study visit ($50 for the Screening Visit and $25 for each subsequent 
visit) and for the 1-week and 7-week phone calls ($25 each). You will receive a completion 
bonus when you have completed the study in its entirety ($50 at the End of Treatment 2 Visit).  
We may be using an approved, outside vendor (Forte Research) to make these payments to you 
via a reloadable credit card-based system, called Forte Payments. This secure system is similar to 
a gift card or credit card. If you are paid by this system, you will be given a Forte Payments Visa 
card when you enroll in the study. Once the card is activated, the study team will add a payment 
after each paid visit you complete. You may use the card anywhere Visa cards are accepted, such 
as at a grocery store.   
We may use your samples and information to develop a new product or medical test to be sold.  
The Sponsor, hospital, and researchers may benefit if this happens. There are no plans to pay you 
if your samples or information are used for this purpose. 
 
 
What will you have to pay for if you take part in this research study? 
 
You will not have to pay anything to take part in this study. The study drug, medical care, and all 
tests and procedures that are done as part of the research will be paid for by study funds. If you 
have any questions about costs to you that may result from taking part in the research, please 
speak with the study doctors and study staff.  If necessary, we will arrange for you to speak with 
someone in Patient Financial Services about these costs. 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template 
Version Date:  December 2008 
 
 
 
Page 14 of 17 
 
 
Subject Identification 
 
What happens if you are injured as a result of taking part in this 
research study?
 
We will offer you the care needed to treat any injury that directly results from taking part in this 
research study.  We reserve the right to bill your insurance company or other third parties, if 
appropriate, for the care you get for the injury.  We will try to have these costs paid for, but you 
may be responsible for some of them.  For example, if the care is billed to your insurer, you will 
be responsible for payment of any deductibles and co-payments required by your insurer. 
 
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
you or give you other compensation for an injury, should one occur.  However, you are not 
giving up any of your legal rights by signing this form. 
 
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of this study as soon as possible.  The 
researcher's name and phone number are listed in the beginning of this consent form.
 
 
If you take part in this research study, how will we protect your privacy? 
 
Federal law requires Mass General Brigham to protect the privacy of health information and 
related information that identifies you.  We refer to this information as “identifiable 
information.” 
 
In this study, we may collect identifiable information about you from: 
• Past, present, and future medical records 
• Research procedures, including research office visits, tests, interviews, and 
questionnaires 
 
Who may see, use, and share your identifiable information and why they may need 
to do so: 
• Mass General Brigham researchers and staff involved in this study 
• The sponsor(s) of the study, and people or groups it hires to help perform this research or 
to audit the research 
• Other researchers and medical centers that are part of this study 
• The Mass General Brigham ethics board or an ethics board outside Mass General 
Brigham that oversees the research 


 
 
 
Research Consent Form 
General Consent Form Template 
Version Date:  February 2021 
 
 
 
 
Page 15 of 17 
 
 
Subject Identification 
• A group that oversees the data (study information) and safety of this study 
• Non-research staff within Mass General Brigham who need identifiable information to do 
their jobs, such as for treatment, payment (billing), or hospital operations (such as 
assessing the quality of care or research) 
• People or groups that we hire to do certain work for us, such as data storage companies, 
accreditors, insurers, and lawyers 
• Federal agencies (such as the U.S. Department of Health and Human Services (DHHS) 
and agencies within DHHS like the Food and Drug Administration, the National 
Institutes of Health, and the Office for Human Research Protections), state agencies, and 
foreign government bodies that oversee, evaluate, and audit research, which may include 
inspection of your records 
• Public health and safety authorities, if we learn information that could mean harm to you 
or others (such as to make required reports about communicable diseases or about child 
or elder abuse) 
• Other:        
 
Some people or groups who get your identifiable information might not have to follow the same 
privacy rules that we follow and might use or share your identifiable information without your 
permission in ways that are not described in this form.  For example, we understand that the 
sponsor of this study may use your identifiable information to perform additional research on 
various products or conditions, to obtain regulatory approval of its products, to propose new 
products, and to oversee and improve its products’ performance.  We share your identifiable 
information only when we must, and we ask anyone who receives it from us to take measures to 
protect your privacy.  The sponsor has agreed that it will not contact you without your 
permission and will not use or share your identifiable information for any mailing or marketing 
list.  However, once your identifiable information is shared outside Mass General Brigham, we 
cannot control all the ways that others use or share it and cannot promise that it will remain 
private. 
 
Because research is an ongoing process, we cannot give you an exact date when we will either 
destroy or stop using or sharing your identifiable information.  Your permission to use and share 
your identifiable information does not expire. 
 
The results of this research study may be published in a medical book or journal, or used to teach 
others.  However, your name or other identifiable information will not be used for these 
purposes without your specific permission. 
 
Your Privacy Rights 


 
 
 
Research Consent Form 
General Consent Form Template 
Version Date:  February 2021 
 
 
 
 
Page 16 of 17 
 
 
Subject Identification 
 
You have the right not to sign this form that allows us to use and share your identifiable 
information for research; however, if you don’t sign it, you can’t take part in this research study. 
 
You have the right to withdraw your permission for us to use or share your identifiable 
information for this research study.  If you want to withdraw your permission, you must notify 
the person in charge of this research study in writing.  Once permission is withdrawn, you cannot 
continue to take part in the study. 
 
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others, and such information may continue to be used for certain 
purposes, such as to comply with the law or maintain the reliability of the study. 
 
You have the right to see and get a copy of your identifiable information that is used or shared 
for treatment or for payment.  To ask for this information, please contact the person in charge of 
this research study.  You may only get such information after the research is finished.  
 
 
Informed Consent and Authorization 
 
Statement of Person Giving Informed Consent and Authorization 
 
§ I have read this consent form. 
§ This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the study. 
§ I have had the opportunity to ask questions. 
§ I understand the information given to me. 
 
 
 
 
 


 
 
 
Research Consent Form 
General Consent Form Template 
Version Date:  February 2021 
 
 
 
 
Page 17 of 17 
 
 
Subject Identification 
Signature of Subject: 
 
I give my consent to take part in this research study and agree to allow my health information to 
be used and shared as described above. 
 
 
 
 
 
 
 
 
Subject 
Date 
Time (optional) 
 
Signature of Study Doctor or Person Obtaining Consent: 
 
Statement of Study Doctor or Person Obtaining Consent 
 
§ I have explained the research to the study subject. 
§ I have answered all questions about this research study to the best of my ability. 
 
 
 
 
 
 
 
 
Study Doctor or Person Obtaining Consent 
Date 
Time (optional) 
 
 
 
Consent Form Version:  2 
 
 
Consent Form Created on: 2/18/2021