A Double-blind, Randomized, Placebo-controlled Study to Determine the Efficacy of Suvorexant in the Treatment of Hot Flash-associated Insomnia in Midlife Women
Phase: PHASE4
Conditions: Insomnia
Sponsor: Brigham and Women's Hospital

MASS GENERAL BRIGHAM HUMAN RESEARCH COMMITTEE (FORMERLY CALLED 
PARTNERS HUMAN RESEARCH COMMITTEE (PHRC)) 
DETAILED PROTOCOL:    9/9/2021 
VERSION/DATE: Version 1.0  -   9/9/2021 
CURRENT FUNDING SOURCE: Merck Sharp & Dohme Corp. – Merck Investigator Studies 
Program 
 
I. 
BACKGROUND AND SIGNIFICANCE 
 
Insomnia is highly prevalent in women during midlife, particularly during the menopause transition, 
when epidemiologic studies show that one-quarter of women meet criteria for chronic 
insomnia.1  Nocturnal hot flashes are the primary predictor of subjective sleep disturbance2,3 and 
of a chronic insomnia syndrome in midlife women.1 Hot flashes are the most common symptom 
of the menopause transition, occurring in up to three-quarters of women during this reproductive 
transition.4  While present both during the day and night, nocturnal hot flashes (or night sweats) 
can be especially distressing when they disrupt sleep,5 leading many women to seek medical 
treatment. By repeatedly awakening women, hot flashes are responsible for a sleep maintenance 
condition, which is the most common pattern of sleep disruption reported by midlife women.6 We 
have shown that nocturnal hot flashes fragment sleep and increase the amount of time spent 
awake after sleep onset (WASO) on subjective (sleep diary) measures,7  polysomnography,7 and 
actigraphy (see Preliminary Data section). In contrast, hot flashes do not increase sleep-onset 
latency (SOL).2,3,7 Hence, a large proportion of midlife women are susceptible to developing an 
insomnia syndrome that manifests predominantly with a sleep maintenance problem when they 
experience nocturnal hot flashes. Moreover, insomnia related to hot flashes can persist for a long 
period of time as the mean duration of hot flashes is 7.4 years.8 This protracted exposure to hot 
flashes and sleep disturbance can have important implications for quality of life and work 
productivity.9 Poor sleep and hot flashes are the primary reason midlife women seek medical 
attention.  
 
Treatment options for menopause and hot flash-related insomnia have received little attention to 
date.10 Cognitive behavioral therapy for insomnia (CBTi) has recently been shown to be an 
effective treatment for insomnia in women with insomnia symptoms and hot flashes.11 For women 
with hot flashes, nonbenzodiazepine GABA-A receptor modulators have been demonstrated to 
treat insomnia.12–14 whereas estrogen therapy improves sleep quality, but its efficacy is less clear 
in women with chronic insomnia.10 However, use of these agents is limited by their side effects 
and risks, particularly breast cancer, cardiovascular, and cognitive risks that emerge with long-
term use.   
 
Given the prevalence of insomnia characterized by hot flashes and sleep maintenance problems, 
the particular efficacy of suvorexant for middle-of-the night sleep disturbance makes it an optimal 
agent for this population. Its safety profile and long-term tolerability make it an ideal strategy for 
use in midlife women.15 An additional rationale for using a dual orexin receptor antagonist in the 
treatment of hot flash-related insomnia is the specific mechanistic suppression of arousal 
pathways that are activated in insomniacs.16 Our preliminary data similarly show that, for women 
whose sleep disturbance is related to hot flashes, arousal is heightened in relation to the amount 
of WASO reported (see Preliminary Data section). Finally, orexin becomes hyperactive during the 
menopause transition, when estrogen levels fall.17 Animal data show that administration of 
suvorexant to ovariectomized hypo-estrogenic rats mimics the stabilizing effect of estrogen 
therapy on thermoregulation,18 suggesting that suvorexant may have a specific therapeutic effect 
on menopause-related sleep disturbance as well as a secondary beneficial effect on hot flashes. 
Taken together, these data potentially implicate orexin in the mechanism underlying the 

2 
 
emergence of hot flashes and related sleep disturbance and provide a specific justification for 
testing the efficacy of orexin receptor antagonists in the treatment of hot flash-related insomnia.  
 
Preliminary Data 
Preliminary data relevant for the current proposal derive from our Merck-funded hot flash-related 
insomnia study of psychological and physiological arousal in midlife women, all of whom have hot 
flashes but only some of whom meet criteria for a concurrent insomnia syndrome. Eligibility criteria 
for women meeting criteria for an insomnia syndrome included a minimum of 20 minutes of time 
for subjective WASO (sWASO) plus subjective sleep-onset latency (sSOL) together, but there 
was no requirement for a maximum total sleep time (sTST) or minimum Insomnia Severity Index 
(ISI) score. At the time when this current protocol was developed, we had enrolled 73% of our 
total accrual goal of 40 participants. Of 29 women who had consented, data were available on 23 
who had already completed study procedures. Of those who met criteria for an insomnia 
syndrome (n=17), 6 (35%) had an ISI score ≥15, consistent with eligibility criteria for the proposed 
trial.  As such, we report interim findings for this subgroup based on sleep parameter data 
obtained using a 7-day sleep diary and actigraphic assessment. This subgroup showed a mean 
ISI score of 18.8 ± 1.7 and a mean sleep efficiency of 66.8% ± 31.8% on the diary and 81.9% ± 
8.9% on actigraphy.  
 
Sleep maintenance problems characterize hot flash-related insomnia:  Those who would be 
eligible for the proposed trial report experiencing 128.7 ± 67.9 minutes of sWASO and 34.7 ± 15.4 
minutes of sSOL on their diary. sWASO time comprises 78.8% of the total wake time 
(sWASO+sSOL). All of these women would meet our proposed eligibility criterion of sWASO≥30 
minutes). This observed predominance of sleep maintenance problems is consistent with our prior 
experience7,19,20 and with extensive epidemiologic data3,21 on hot flash-related sleep disruption. 
Data using actigraphy to quantify WASO and SOL similarly indicate that aWASO time accounts 
for the vast majority (78.7%) of wakefulness (aWASO+aSOL). Consistent with extensive data 
from other insomniac populations,22 the total number of minutes of aWASO and aSOL on 
actigraphy is reduced relative to that reported on the diary. However, the actigraphic aWASO is 
consistent with our planned 30 minute average of WASO, with 100% of these women having at 
least 30 minute average of WASO over a week.  
 
Total sleep time is reduced in women with hot flash-related insomnia:  Despite an absence of TST 
eligibility criteria, 100% of women in our physiologic study who would meet criteria for the 
proposed trial also meet our similar criterion to have subjective TST (sTST) <7 hours both on 
sleep diary and on actigraphy during at least 4 nights per week.   
 
Distribution of WASO time across the night in hot flash-related insomnia:  Further analyses of 
actigraphic data in this subgroup of women who would be eligible for the proposed trial show that 
36.9% of their aWASO time occurs within the terminal one-third of the night. 
    
Within-person night-to-night variability in sleep parameters: It is increasingly recognized that sleep 
patterns vary night-to-night in insomniacs, on both sleep diary23 and at-home polysomnography 
(PSG)24 measures. We explored this within-person variability across the 7 consecutive days of 
sleep diary and actigraphic monitoring in the subgroup of women who would be eligible for our 
proposed study. The coefficients of variation (CV) show that there is limited within-person night-
to-night variability in SOL or WASO as a proportion of the respective mean value for each person, 
regardless of whether they were measured using the sleep diary (sSOL, sWASO) or actigraphy 
(aSOL, aWASO). For the group as a whole, the mean CV for each sleep parameter was less than 
or close to one, indicating limited variation.  
 

3 
 
Hot flash-related insomnia and psychological indicators of hyperarousal: In our investigation 
examining the association between hyperarousal and insomnia in women with hot flashes, we 
have observed a pattern of greater psychological arousal among women with hot flashes that is 
proportionate to the amount of sleep interruption. As one indicator of psychological activation in 
the sample overall (n=23), those who had more anticipatory anxiety also had more sWASO 
(rs=0.48, p=0.02).. 
 
Summary of preliminary data: Taken together these preliminary data highlight that for women with 
hot flash-related insomnia syndromes who would be eligible for our proposed trial: 1) the extent 
of their sleep disturbance is high, 2) sleep maintenance problems dominate the time spent awake, 
and 3) WASO time persists into the final third of the night. In addition, within-person night-to-night 
variability of SOL and WASO is low on both subjective and actigraphic measures. In addition, 
psychological indicators of hyperarousal correlate with the degree of sleep disruption among 
women with hot flashes. In summary, women with a hot flash-related insomnia syndrome have 
substantial sleep continuity problems that are composed of a distinctive profile of sleep disruption 
dominated by reduced TST and large amounts of WASO, which persists throughout the night. 
These characteristics of hot flash-related insomnia make this population an ideal one in whom to 
investigate the efficacy of suvorexant. 
 
II. 
SPECIFIC AIMS 
 
PRIMARY AIM: To determine the effect of suvorexant on insomnia symptoms in peri- and 
postmenopausal women with a chronic insomnia syndrome related to nighttime hot flashes using 
a randomized placebo-controlled trial. 
 
HYPOTHESIS: Women randomized to suvorexant will show greater improvement in insomnia 
symptoms compared with women randomized to placebo. 
 
SECONDARY EXPLORATORY HYPOTHESES 
1. Relative to those assigned to placebo, women randomized to suvorexant will show: 
a. Greater reduction in wake-time after sleep-onset. 
b. Greater improvement in mood, anxiety, and quality of life. 
c. Greater reduction in hot flash frequency.  
2. Improvement in insomnia symptoms will be positively correlated with improvement in 
mood, anxiety, hot flashes, and quality of life. 
 
III. 
SUBJECT SELECTION 
 
Inclusion/Exclusion Criteria 
We plan to enroll up to 90 women who meet the following criteria in order to have 72 women 
randomized in a 1-to-1 ratio to suvorexant 10-20 mg or equivalent placebo in order to have 60 
women (30 per arm) complete the trial. 
 
Inclusion criteria: 
1. Age 40–65 years 
2. Peri- or postmenopausal women, with menopause status determined by menstrual 
marker. Women who underwent bilateral oophorectomy will be enrolled if 6+ months from 
surgery. Those who underwent hysterectomy with ovarian preservation, or who have 
amenorrhea from progesterone-secreting IUD, or endometrial ablation may be enrolled 
based on clinical assessment and judgment.  
3. DSM-5 criteria for Insomnia Disorder.  

4 
 
4. Score on the Insomnia Severity Index (ISI) measure ≥15, indicating at least a moderate 
level of insomnia symptoms 
5. Subjective sleep disruption reported retrospectively over the past month and confirmed 
prospectively on a 7-day sleep diary shows: 
a. <9 hours average for subjectively reported total sleep time (TST).  
b. 30+ minute average for subjectively reported wake after sleep onset (sWASO).  
c. Sleep parameter in inclusion criteria 5a does not decrease by more than 50% on 
a 2nd week of sleep diary monitoring obtained after the screening visit. 
d. Sleep parameter in inclusion criteria 5b does not both decrease by more than 50% 
and fall below 30 minutes on average on a 2nd week of sleep diary monitoring 
obtained after the screening visit. 
6. Average of 2 or more hot flashes per 24 hours, at least some of which occur each night, 
reported retrospectively to have occurred over the past month and confirmed prospectively 
on one 7-day hot flash diary 
7. Subjective report that at least some awakenings co-occur with night time hot flashes. 
 
Exclusion criteria: 
1. Sleep factors: 
a. Diagnosis, or strong clinical suspicion, of other primary sleep disorders: obstructive 
sleep apnea, periodic limb movement disorder, narcolepsy, or RLS 
b. Shift workers   
c. Use of hypnotic medications more than twice per week in the past month 
d. Willingness to not use other sedative-hypnotics during the study period 
2. Psychiatric factors: 
a. Current major depressive episode, by report and as indicated by the Patient Health 
Questionnaire (PHQ-9) 
b. Current suicidal ideation 
c. Lifetime history of bipolar disorder, psychosis, or other serious mental health 
problem 
d. Current alcohol/substance use disorder 
3. Medical factors: 
a. Abnormal vital signs at screening visit 
b. BMI ≥ 40 kg/m2 
c. Renal or hepatic disease judged to interfere with drug metabolism and excretion 
d. Pregnancy or breastfeeding 
e. Malignancy within past 2 years   
f. Major surgery within past 3 months   
g. 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 
h. Medical instability considered to interfere with study procedures 
i. 
Concomitant medications with drug interaction or co-administration concerns 
j. 
Contraindications or allergic responses to suvorexant 
4. Lifestyle and other factors: 
a. Travel across time zone in 2 weeks prior to enrollment or planned during study 
b. Greater than 6 cups of coffee per day  
c. Greater than 15 cigarettes per day  
d. Unwilling to limit alcohol, nicotine, and caffeine consumption during study 
5. Adherence factors:  
a. Ability to adhere to study procedures completed between screening and 
randomization visits 

5 
 
Off-Study Criteria: 
 
Subjects will be dropped from the study if any of the following:  
1. Meeting criteria for a current episode of major depression on the Patient Health 
Questionnaire 9 (PHQ-9) or depressive symptoms that are deemed by the psychiatrist 
investigator to be too severe to continue with study procedures  
2. Emergence of suicidal ideation; homicidal ideation, or psychotic symptoms  
3. Initiation of stimulants, medications for sleep, hormonal medications, or other 
contraindicated medications 
4. Evidence of abuse or misuse of study medications 
5. Development of any significant medical problem 
6. Pregnancy 
7. Enrollment in another clinical trial involving study procedures or medications that might 
put subject at risk for drug interactions or interfere with study procedures. 
8. Significant deviation from study protocol or protocol violation 
9. Serious side effect from study medication 
10. Inability to tolerate a minimum dose of 10-mg/day of suvorexant  
Participants who are dropped from the study will be asked to complete final questionnaires  
remotely. In this case, vitals will not be collected, and adverse event monitoring will be completed 
over the phone. 
 
Source of Subjects & Recruitment Methods 
Co-investigators and staff will be responsible for recruiting study participants. Subjects will be 
recruited from the general population, from BWH and affiliated outpatient and community clinics 
around Boston, using posted signs, Craigslist, the Partners All-User and RSVP for Health 
(Research Study Volunteer Program), as well as paid advertising (e.g., Metro, PostcardMania, 
Facebook). ResearchMatch.org will be utilized as a recruitment tool for this protocol. 
ResearchMatch.org is a national electronic, web-based recruitment tool that was created through 
the Clinical & Translational Science Awards Consortium in 2009 and is maintained at Vanderbilt 
University as an IRB-approved data repository. Insomniacs will also be recruited through the BWH 
sleep clinics (pulmonary and neurology) in Boston and Chestnut Hill. We will post IRB-approved 
flyers in these clinics, as well as provide them to other sleep clinicians, and these sleep physicians 
can decide to distribute to their own patients as they see fit. Subjects answering posted or printed 
ads will be directed to a pre-screen survey on REDCap. If initial eligibility requirements are met, 
the research coordinator will assess further eligibility using an IRB-approved telephone screen 
and diaries completed at home. 
  
IV. 
SUBJECT ENROLLMENT 
 
Methods of Enrollment & Consenting Procedures 
 
Pre-Screening 
In response to local recruitment efforts and after passing initial eligibility on the REDCap pre-
screen survey, women will speak with a study coordinator. During the phone screen the 
preliminary eligibility criteria and study protocol will be discussed with each woman. 
 
Consent to complete the telephone screen will be obtained orally at the start of the phone call.  
Before the research coordinator asks any of the screening questions, she will inform the potential 
participant that the purpose of the call is to begin the process of pre-screening for eligibility and 
that all responses are confidential and completely voluntary. Continuation of the phone call and 
responding to questions implies consent to the phone call screening.  Women who prefer not to 

6 
 
answer questions will be thanked for their time and the phone call will end.  Women may ask to 
stop the screening phone call at any time. The pre-screen questionnaires will be administered to 
assess insomnia status. The full written ISI will be administered at Visit 3 and Visit 4. The ISI may 
be administered again over the phone before Visit 1 or Visit 2, if one of these visits has been 
delayed, and insomnia status must be reassessed. Preliminary screening determination will 
include questions modified from the Berlin Questionnaire to exclude women at high risk for 
obstructive sleep apnea. We will also ask some questions drawn from the PHQ-9 which will be 
completed at the first visit. The PHQ-2 asks specifically about frequency of anhedonia and 
depression in the past two weeks. We will exclude participants who do not qualify initially on the 
phone screen. Anyone identified as being at risk for depression will be instructed to assess their 
symptoms with their physician and be offered resources for where they can seek additional help. 
The full PHQ-9 will be administered at Visit 1, Visit 3, and Visit 4. 
 
Following the screening phone call, women who are interested and preliminarily eligible to 
complete the screening process will be mailed or emailed the pre-screening materials, a copy of 
the informed consent and a cover letter describing the pre-screening procedures. The pre-
screening materials include hot flash and sleep diaries to be completed at home for 1 week. BWH 
study staff will call potential participants to determine whether they received these materials and 
review how to complete them. Women who are currently taking medications to help them sleep 
will be asked if they are willing to refrain from taking sleep medications for the duration of the 
study (approx. 6 weeks) beginning with the tracking period. Women who agree to complete the 
pre-screening diaries will be contacted by phone after ample time has elapsed. During this call, 
the BWH study staff member will review the diary entries to determine eligibility for the screening 
visit. The pre-screening diaries are used to reduce subject burden by only scheduling subjects 
eligible for the screening visit. 
 
Women whose pre-screening diaries indicate that they are eligible to proceed with the study will 
be scheduled for an initial visit at Brigham and Women’s Hospital. If the participant does not have 
a medical record number, she will be asked to call patient registration and register as a patient 
before her initial visit can be scheduled. A reminder will be sent one day before the visit is to 
occur. 
 
Obtaining Informed Consent 
No subject will undergo any study procedures until it is clear that she understands the risks and 
benefits and consents to participate. At the screening visit, the PI or one of her co-investigator 
designates will carefully review the consent form in its entirety with prospective subjects. The 
consent form will include information about the risks and benefits of study participation. Women 
enrolling must be capable of understanding the nature of the study as well as the discomforts and 
potential benefits. Any questions or areas of concern regarding the protocol will be addressed by 
the PI or a co-investigator designate. If a woman feels comfortable with the study procedures, she 
will sign the consent form along with the PI or a co-investigator designate. During the screening 
visit, study staff will explain the purpose of the study, the procedures used, the requirements of 
participation, risks and benefits, and the right to withdraw at any time, and answer any questions. 
Signed consent forms will be placed in the participant’s administrative research file and a copy 
will be given to the participant.  
 
All subjects will be given contact information for the investigator, research assistant and IRB 
office, in the event that they have any questions or concerns, before any study procedures are 
completed. If subjects have reservations about study participation at the first visit, they have the 
option to take the consent form home to review the decision to participate in the study with their 
family and health-care providers, and then return at a later date to discuss the study again with 

7 
 
research physicians before signing the consent form and initiating study procedures. Subjects will 
be informed that they may choose to decline to participate or withdraw from the study. She will be 
informed that the decision whether or not to participate will not affect her care at Brigham and 
Women’s Hospital and she is free to withdraw at any time. 
 
After the informed consent process is complete, study staff will continue with screening 
procedures. 
 
Final eligibility determination 
Final eligibility criteria will be assessed after the informed consent process is complete, including 
a clinical interview conducted by a study clinician to diagnose a chronic insomnia disorder and to 
ensure that women with contraindicated sleep, medical, and psychiatric problems and 
medications are excluded. Vital signs will be obtained, and blood will be drawn (15mL) for 
screening safety labs, a toxicology screen, and female reproductive hormones. All women who 
sign the consent form will be assigned a study identification number regardless of eligibility 
status.  Eligible participants will be sent home with a 7-day sleep and hot flash diary to complete 
during the screening run-in period. They will also be given the Actiwatch actigraphic monitor and 
Biolog skin conductance hot flash monitor, which will be worn continuously for one week 
(Actiwatch) or one 24-hr period (Biolog) to quantify sleep patterns (Actiwatch) and the number of 
objectively measured nighttime and daytime hot flashes (Biolog). No medication will be provided. 
They will be asked to bring their diaries, Actiwatch, and Biolog monitors back for review at the 
Randomization Visit, at which point final review of the sleep diary, and laboratory results for 
definitive eligibility will be conducted before the participant is randomized to treatment. 
 
Treatment Assignment and Randomization 
Women who are deemed eligible after screening procedures have been completed will then 
complete a Randomization Visit, at which eligible women will be randomized to 4 weeks of 
suvorexant or placebo. Suvorexant and identical placebo will be obtained from Merck and stored 
in the Brigham and Women’s Hospital Research Pharmacy. The Research Pharmacist will 
generate a confidential randomization schema using a block size of 4 to balance the one-to-one 
treatment assignment between the two study arms. Study participants and all study personnel, 
including those entering data, will be blinded to the assignment. Only the Research Pharmacist 
will be unblinded to treatment assignment.   
 
At the Randomization Visit, a one-week supply of suvorexant 10-mg pills or identical placebo will 
be given to each participant. Participants will be instructed to start taking 10-mg nightly for the 
first 7 days. At the Interim Treatment Visit conducted after one-week on treatment, the dose will 
be increased up to 20-mg nightly unless there are dose-limiting side effects. After the Interim 
Treatment Visit, women unable to tolerate a 20-mg dose will be given the option to reduce to a 
10-mg dose. Consistent with FDA-approved directions, suvorexant will be started at 10-mg to first 
establish tolerability and then expected treatment efficacy will be optimized by increasing to the 
target 20-mg dose 7 days later. Women who are unable to tolerate the 10-mg dose will be dropped 
from the study.  Any unused medication will be returned at the Final Treatment Visit, and unused 
pills will be counted as an indicator of adherence. Participants will not be informed of their 
treatment assignment at the Final Treatment Visit to maintain the blinding for study personnel. 
Participants who choose to stop participating in the study will be asked to complete remaining 
study  questionnaires remotely. In this case, participants will return unused medication by mail. 
 
V. 
STUDY PROCEDURES 
 
Study Procedures and Outcome Measures 

8 
 
This study is a parallel-arm randomized trial involving 4 in-person study assessments conducted 
over approximately 6 weeks, during which participants will be randomized to receive double-
blinded suvorexant 10–20 mg/day or placebo for the final 4 weeks of the study. See attached 
Table of Procedures for all study procedures. Details describing individual study procedures and 
surveys are provided below: 
 
Screening period:  There are 3 phases to our screening procedures: 1) an initial screening 
conducted via REDCap and over the phone, 2) prospective sleep and hot flash diary screening 
process completed over 14 days, and 3) final screening conducted at and after the in-person 
Screening Visit. We have found this phased screening approach to be highly efficient and readily 
approved by our Institutional Review Board. Consent to screen will be obtained orally on the 
phone for the initial screening procedures and diaries, and written informed consent will be 
obtained at the Screening Visit for the remaining screening procedures and all treatment-related 
procedures. Risks and benefits associated with use of suvorexant will be described.  
 
Women interested in participating in this trial will be screened by phone to assess preliminary 
eligibility after oral consent for screening is obtained. Some questions from the Berlin 
Questionnaire will be administered to screen for sleep apnea, and the ISI will help assess 
eligibility. Those who are interested and appear eligible will be sent a 7-day sleep and hot flash 
diary. Subjects who are taking any medications to help them sleep will be asked if they are willing 
to suspend taking those medications for the duration of the study, beginning with the tracking 
period, in order to attain an accurate assessment of their current sleep difficulties. Upon receiving 
these completed diaries, those who meet further eligibility criteria determined by the diaries (see 
Inclusion and Exclusion Criteria above) will be scheduled for an in-person Screening Visit.  
 
At the Screening Visit, written informed consent will be obtained and final eligibility criteria will be 
assessed, including a clinical interview conducted by a study clinician to diagnosis a chronic 
insomnia disorder and to ensure that women with contraindicated sleep, medical, and psychiatric 
problems and medications are excluded. Vital signs will be obtained and blood will be drawn 
(15mL) for screening safety labs, a toxicology screen, and female reproductive hormones. The 
PHQ-9 will be administered in person. All women who sign the consent form will be assigned a 
study identification number regardless of eligibility status.  Eligible participants will be sent home 
with a 7-day sleep and hot flash diary to complete during the screening run-in period. They will 
also be given the Actiwatch actigraphic monitor and Biolog skin conductance hot flash monitor, 
which will be worn continuously for one week (Actiwatch) or one 24-hour period (Biolog) to 
quantify sleep patterns (Actiwatch) and the number of objectively measured nighttime and 
daytime hot flashes (Biolog). No medication will be provided. They will be asked to bring their 
diaries, Actiwatch, and Biolog monitors back for review at the Randomization Visit, at which point 
final review of the sleep diary and laboratory results for definitive eligibility will be conducted before 
the participant is randomized to treatment. 
 
Treatment period: At the Randomization Visit, eligible women will be randomized to 4 weeks of 
suvorexant or placebo. Pre-treatment symptom measures will be assessed at the Randomization 
Visit and interim and final on-treatment symptom measures will be assessed at the Interim 
Treatment Visit and Final Treatment Visit, respectively. The primary endpoint measures will be 
obtained at the Final Treatment Visit, conducted after 4 weeks on treatment. Participants will 
complete sleep and hot flash diaries for the 4 weeks they are on treatment and will be sent an 
Actiwatch and Biolog monitor to wear for one week (Actiwatch) and for one 24-hr period (Biolog) 
before returning them at the Final Treatment Visit. Participants will also be asked to provide saliva 
samples for two consecutive days in between Visits 1 and 2 and Visits 3 and 4.  These samples 
will be used to measure cortisol.  We have implemented these procedures in prior clinical trials 

9 
 
with efficiency and high levels of adherence.  Adverse events will be assessed at each study visit 
using spontaneous-reporting adverse event procedures employed in our other clinical trials.   
 
Intervention design: Suvorexant and identical placebo will be obtained from Merck and stored in 
the Brigham and Women’s Hospital Research Pharmacy. The Research Pharmacist will generate 
a confidential randomization schema using a block size of 4 to balance the one-to-one treatment 
assignment between the two study arms. Study participants and all study personnel, including 
those entering data, will be blinded to the assignment. Only the Research Pharmacist will be 
unblinded to treatment assignment.   
 
At the Randomization Visit, a one-week supply of suvorexant 10-mg pills or identical placebo will 
be given to each participant. Participants will be instructed to start taking 10-mg nightly for the 
first 7 days. At the Interim Treatment Visit conducted after one-week on treatment, participants 
who do not have treatment-limiting side effects will be instructed to increase the dose to 20-mg 
nightly. After the Interim Treatment Visit, women unable to tolerate a 20-mg dose will be given 
the option to reduce to a 10-mg dose. Consistent with FDA-approved directions, suvorexant will 
be started at 10-mg to first establish tolerability and then expected treatment efficacy will be 
optimized by increasing to the target 20-mg dose 7 days later. Any unused medication will be 
returned at the Final Treatment Visit, and unused pills will be counted as an indicator of 
adherence. If participants are unable to attend the Final Treatment Visit in person, subjects will 
complete remaining study procedures remotely, and will mail back any unused medication for a 
measure of adherence. Participants will also return the Actiwatch, Biolog monitor, and saliva 
samples by mail if a remote Final Treatment Visit is performed. In addition to answering 
questionnaires remotely, a study clinician will call the participant for safety monitoring. Study staff 
will review responses to the PHQ9 before ending study visits, and a study clinician will query 
participants directly about suicidal ideation and other adverse events at study visits while 
participants are on medication. Participants will not be informed of their treatment assignment at 
the Final Treatment Visit to maintain the blinding for study personnel.  
 
Protocol Schema 
 
 
 
 
 

10 
 
Table of Procedures 
 
 

11 
 
Study assessments and procedures include the following: 
1. Insomnia and sleep quality symptoms will be measured using: 
1. DSM 5 diagnostic interview for chronic insomnia. A clinical diagnosis of chronic 
insomnia will be made using the DSM-V diagnostic interview, allowing for 
associated hot flashes (see Inclusion Criteria). 
2. Sleep diary. Consistent with research consensus guidelines of insomnia,25 a 
standard daily sleep diary will be completed to quantify perceived total sleep time, 
sleep latency, wake time after sleep onset, number of awakenings, sleep 
efficiency, and sleep quality.  
3. The Actiwatch actigraphic watch (Philips Respironics, Murrysville, Pennsylvania) 
will be worn on the non-dominant wrist to quantify sleep patterns based on 
acceleration and movement and the data output will be analyzed using standard 
actigraphic analysis algorithms.   
4. The Insomnia Severity Index (ISI), a 7-item self-rated questionnaire (range 0–28) 
used to assess the severity of insomnia symptoms over the past 2 weeks.26 
5. The Pittsburgh Sleep Quality Index (PSQI), a 19-item self-rated measure of global 
sleep quality (range 0–21) occurring during the past one-month.27 
6. Pre-Sleep Arousal Scale (PSAS), a 16-item self-rated scale that generally 
assesses physiological and cognitive arousal prior to sleep.28 
7. Dysfunctional Beliefs and Attitudes about Sleep (DBAS), a 30-item self-rated scale 
about cognitions related to sleep (e.g., expectations, consequences).29 
8. Sleep Locus of Control Scale, an 8-item self-rated scale that measures perception 
of control of sleep as being internal or by chance.30 
9. Hyperarousal Scale, a 26-item self-rated scale of alertness during wake that is 
widely used to measure trait arousal.31  
2. Sleep apnea will be screened out using a combination of self-reported prior diagnosis 
and the following study procedure to exclude women likely to have apnea: 
1. The Berlin Questionnaire, a validated 10-item questionnaire to assess risk of 
obstructive sleep apnea.32,33 
3. Mood, anxiety, and quality of life symptoms will be measured using the: 
1. Patient Health Questionnaire 9-item (PHQ-9), an 9-item self rated measure of 
depression based on DSM criteria that assesses the core psychological and 
neuro-vegetative symptoms of depression occurring over the past 2 weeks.34  
2. Center for Epidemiological Studies Depression Scale (CES-D), a 20-item self-
rated scale (range 0–60) that measures the severity of predominantly 
psychological symptoms of depression experienced over the past week.35 
3. Anxiety Sensitivity Index (ASI-3), an 18-item self report questionnaire (range 0–
72) assessing sensitivity to the experience of anxiety as an indicator of anxiety 
and psychological hyperarousal.36 
4. Generalized Anxiety Disorder Questionnaire (GAD-7): The GAD-7 is a 7-item self-
report measure frequently used in clinical and research settings to identify four of 
the most common anxiety disorders in primary care: generalized anxiety, panic, 
social anxiety, and posttraumatic stress disorder.37   
5. Menopause-Specific Quality-of-Life Questionnaire (MENQOL), a widely used 33-
item self-rated questionnaire about quality-of-life specifically in menopausal 
women.38   
6. The Clinical Global Impression (CGI) and Patient Global Impression (PGI), which 
are widely used 2-item clinician-rated and patient-rated measures, respectively, 
which are used to assess global severity of illness and change in a patient over 
time. They are widely used in clinical trials for depression, fatigue, and other 
neuropsychological endpoints. 

12 
 
4. Hot flashes will be measured using: 
1. Hot flash diaries will be completed twice daily (morning and night) to capture the 
number of hot flashes, their severity, and how bothersome they are.39 
2. The Biolog skin conductance hot flash monitor (UFI, Morro Bay, CA) is a widely 
used and validated ambulatory monitor that will be worn to quantify the number 
of objectively measured hot flash events by detecting changes in skin 
conductance on the sternum. This approach measures physiologic hot flashes 
independent of recall for the events, thereby eliminating potential recall bias for 
nighttime events.  
3. The Hot Flash Related Daily Interference Scale (HFRDIS) is a 10-item self-rated 
scale (range 0–100) that measures the degree to which hot flashes interfere with 
daily activities and quality-of-life during the prior week.40 
 
Drugs to be used 
This study will compare the effect of suvorexant 10–20 mg to placebo on insomnia symptoms in 
peri- and postmenopausal women who have an insomnia syndrome related to nighttime hot 
flashes. Up to seventy-two women will be randomized in a 1-to-1 ratio to suvorexant 10–20 mg 
or equivalent placebo (see Schema) in order to have 60 women (30 per arm) complete the trial, 
after allowing for post-randomization drop-outs.  
 
Eligible women will be randomized to 4 weeks of suvorexant or placebo after a 1-week screening 
period and a one-week screening run-in period. Participants will complete 4 in-person study visits 
(consent / screening visit, randomization visit, one-week on-treatment visit, and a final week-4 on-
treatment visit) and one telephone-based initial screening assessment. Suvorexant will be started 
at 10-mg nightly for the first 7 days. After one-week of treatment, the dose will be increased to 20-
mg nightly unless there are dose-limiting side effects. Women unable to tolerate a 20-mg dose 
will be given the option to reduce to a 10-mg dose.  
 
Known toxicities of suvorexant include daytime somnolence, nighttime “sleep driving”, worsening 
of depression or suicidal thinking, compromised respiratory function, sleep paralysis, 
hypnagogic/hypnopompic hallucinations, and cataplexy-like symptoms. 
 
Devices to be used 
Actiwatch actigraphic Watch: This is an actigraphic watch (Philips Respironics, Murrysville, 
Pennsylvania) that will be worn on the non-dominant wrist to quantify sleep patterns based on 
acceleration and movement data.  The data output will be analyzed using standard actigraphic 
analysis algorithms. 
 
Biolog skin conductance hot flash monitor: This is a widely used and validated ambulatory skin 
conductance monitor (UFI, Morro Bay, CA) that will be worn to quantify the number of objectively 
measured hot flash events by detecting changes in skin conductance on the sternum. This 
approach measures physiologic hot flashes independent of recall for the events, thereby 
eliminating potential recall bias for nighttime events. 
 
Surgical Interventions 
No surgical interventions will be used in this study. 
 
VI. 
BIOSTATISTICAL ANALYSIS 
 
Overview of analytic plan: The primary hypothesis for this trial is that suvorexant is superior to 
placebo in treating insomnia symptoms. The primary endpoint is the change in the ISI score from 

13 
 
baseline to 4-week follow-up.  Exploratory analyses will examine the effect of suvorexant relative 
to placebo on secondary endpoints of sleep continuity parameters and diary-reported hot flashes, 
and exploratory endpoints including mood, anxiety, hot flashes (skin-conductance monitor), 
physiological stress (salivary cortisol), and quality of life.    
 
Study endpoints:  
 
Primary endpoint: 
1. The primary endpoint is the change in the ISI score from baseline to 4-week follow-up. 
 
Secondary endpoints: 
1. Diary-reported WASO, SOL, TST, and sleep efficiency 
2. Number of hot flashes reported on the diary separately during the day and night 
 
Exploratory endpoints: 
1. Actigraphy-measured WASO, SOL, TST, and sleep efficiency 
2. Depressive symptoms  
3. Anxiety symptoms  
4. Quality of life  
5. Number of hot flashes measured on the skin-conductance monitor 
6. Physiological Stress (measured by salivary cortisol) 
 
Primary analysis: The primary analysis will compare the within-person change in outcomes at 
Week 4 relative to baseline using general linear models, adjusting for baseline values and relevant 
covariates showing group differences at baseline. Diagnostic methods will be used for all models 
to assess their distributional assumptions, model adequacy, and to examine potential outlying or 
influential data points.  An additional exploratory ISI responder analysis will be conducted using 
logistic regression to determine whether there is a group difference in the proportion of women 
that had a 8-point reduction in the ISI score from baseline.41 
 
Missing data: Every effort will be made to avoid missing data and to include all randomized 
subjects in the analysis. The effects of missing information on statistical power have been 
addressed to the degree feasible in the sample size calculations. Missing data will be imputed as 
last observation carry forward.    
 
Power and sample size: In total, up to 90 women will be enrolled in this study. Treatment will be 
randomly assigned in a 1:1 ratio. Allowing for 10% to be lost to follow up after consent (n=8) and 
15% to be lost after randomization (n=12), we expect to randomize up to 72 participants to 
treatment and complete 60 subjects (30 per treatment group). This sample size provides enough 
subjects to have 80% power for the primary hypothesis, assuming that there is a between-group 
difference in the change from baseline to study-end in the ISI score of 4 points with a standard 
deviation of 4.86 (two-sided alpha = 0.05). Previous clinical trials have found between-group 
differences in ISI change scores of 5.2 points11 when women with hot flash-related insomnia were 
randomized to CBTi vs. behavioral control and between-group differences in ISI change scores 
of 2–3 points43 when women with hot flashes and sleep disturbance were randomized to the SSRI 
citalopram vs. placebo. The standard deviation in the change in ISI for these interventions and 
controls arms was selected because it is in the midpoint of standard deviations from previous 
studies, which ranged from 4 to 6.11,43 Data from the Phase 3 suvorexant trials were not used to 
support our sample size calculations because of differences in the sleep profile between our hot 
flash-related insomnia population  (see Preliminary Data) and the general insomnia population 

14 
 
enrolled in suvorexant trials for which there was no minimum ISI score required for eligibility (mean 
ISI ~14).44 
 
VII. RISKS AND DISCOMFORTS 
 
Potential risks of study procedures:  
Potential risk to study subjects is minimized by the frequent visits and tests required by the study 
design.  Careful screening procedures, including medical history and evaluation, laboratory tests, 
and psychological interviews, will facilitate the identification of any medical problems and potential 
adverse events so that subjects can be treated appropriately. At each visit, spontaneously 
reported adverse events will be noted by research staff. Any serious or non-serious adverse event 
will be recorded in the participant’s study binder at each examination.  Serious and non-serious 
adverse events will be reported to the Partners Human Research Committee in accordance with 
Human Research Committee reporting guidelines, following the timeframes specified by the 
Partners Investigator’s Guidelines.  In case of a serious adverse event, study medication will be 
unblinded and discontinued, and appropriate diagnostic and therapeutic measures will be taken, 
as determined by the investigator. All adverse event reports will be reviewed by the study 
physician.   
 
The risks of the study are mainly from drug side effects, phlebotomy, and psychosocial risks. 
 
Common side effects of suvorexant: 
The most common side effects that were reported in previous studies with suvorexant included: 
 
• 
Headache (7 out of 100 people reported this side effect) 
• 
Next-day drowsiness (7 out of 100 people reported this side effect) 
• 
Dizziness (3 out of 100 people reported this side effect) 
• 
Abnormal dreams (2 out of 100 people reported this side effect) 
• 
Cough (2 out of 100 people reported this side effect) 
• 
Diarrhea (2 out of 100 people reported this side effect) 
• 
Dry mouth (2 out of 100 people reported this side effect) 
• 
Upper respiratory tract infection (2 out of 100 people reported this side effect) 
 
Suvorexant may cause serious side effects that participants may not know are happening. These 
side effects include: 
• 
Sleepiness during the day 
• 
Not thinking clearly 
• 
Acting strangely, confused or upset 
• 
“Sleep-walking” or doing other activities when you are asleep like eating, 
talking, having sex, or driving a car. 
 
Suvorexant can cause next-day mental impairment, and this risk is increased with higher doses 
if instructions are not carefully followed.  Subjects in their second, third, or fourth week of study 
drug dosing should avoid driving and other activities requiring full mental alertness in the morning.  
Subjects in their first week of study drug dosing should also be careful about driving in the 
morning, because there is individual variation in people's sensitivity to suvorexant. Before taking 
the study drug subjects will be advised to read the FDA-approved Medication Guide. 
 

15 
 
The participant will be informed that the study medication suvorexant must only be taken by the 
subject alone, the person for whom it was intended. In addition, the study medication must be 
kept out of the reach of children or persons with limited ability to read and understand.  
 
Reproductive Risks 
There are no adequate and well-controlled studies of either suvorexant in pregnant women. The 
study drug should be used during pregnancy only if the potential benefit justifies the potential risk 
to the fetus.  The effect of the study drug on infants or unborn children is not known, and, as with 
any new drug, there is the potential for very serious harmful effects. In order to prevent any 
possible damage to an unborn child, subjects must not become pregnant while participating in 
this research study and for 30 days after finishing the study. Contraceptive methods must be used 
during and immediately after this study by women who are sexually active and have reproductive 
potential.   Women using hormones will be excluded from study participation. Study participants 
will be required to use barrier methods of contraception if they are of reproductive potential. The 
following is a list of acceptable birth control methods: female sterilization, intrauterine device 
(IUD), diaphragm with spermicide, male condom, female condom, cervical cap, etc.   
 
Women who are pregnant or breastfeeding will be excluded from the study. A pregnancy test will 
be conducted at screening for all subjects. If a subject thinks she might be pregnant at any time 
during this study, she will be advised to contact the study physician or research assistant 
immediately. In addition, participants will be informed that they cannot use hormonal 
contraception as a primary form of birth control until after medication discontinuation.  At each 
visit these precautions will be discussed thoroughly with the subject.   
  
Psychological Risks 
Answering questions on the research instruments and questionnaires used to evaluate 
psychological symptoms can be upsetting to some subjects.  
 
Blood Sampling  
The risks associated with phlebotomy are minimal and include hematoma, pain, infection, and 
fainting spells. The amount of blood drawn for this study is approximately 15 mL (3 teaspoons) 
and is not enough to cause harm to the subjects. All blood draws will be performed by trained 
personnel who use standard sterile techniques.   
 
Objective hot flash monitor   
There are no significant risks associated with skin-conductance methodologies. The Biolog 
ambulatory recorder is an 8-ounce, 9V battery-powered device measuring 1.3 x 2.8 x 5 inches 
that is worn in a pouch and suspended by a shoulder strap, similar to a Holter monitor. It is a 
portable and ambulatory device. There is a minor risk of skin irritation and reddening from the 
adhesive gel required to attach the electrodes to the sternum. This irritation is typically mild and 
resolves within a few days.  
 
Actigraphy watch  
There are no significant risks associated with the actigraphy watch. The actigraphic watch is a 
light-weight sports watch that can be worn continuously and can get wet.  
 
Procedures to Minimize Risks 
All study procedures will be approved by the Partners (renamed Mass General Brigham) IRB 
before being initiated. To avoid serious adverse effects from medications, the following 
precautions will be taken:   
 

16 
 
A urine HCG test will be performed on all subjects at the screening visit to confirm that subjects 
are not pregnant. This procedure for confirming the absence of pregnancy will be followed 
regardless of whether or not the subject informs us that she is sexually active and regardless of 
the specific type of contraception that is being used. All subjects who are of reproductive potential 
will be advised to use a barrier method of contraception for the duration of the study and after 
study completion until menses resume.  Adverse events will be monitored at each study visit.   
 
The dose of study medication will be reduced to 10-mg/day if a participant is unable to tolerate 
the target dose of 20-mg/day. 
 
Participants with conditions which are contraindications to suvorexant use will be excluded.   
 
In order to minimize risks to participants, all research records will be kept with maximum possible 
confidentiality. Results will be de-identified and subject binders will be maintained in a locked 
closet. No names will be used in the presentation of any data. Source documents will be reviewed 
only by study personnel. All HIPAA regulations will be followed.  
 
Participants will be informed that they are free to withdraw from the study at any time and that 
withdrawing will not have any adverse effects on their medical care within Partners/Mass General 
Brigham. 
 
Adverse events requiring medical attention are expected to be rare in this proposal. The 
investigators have substantial experience conducting the proposed study procedures and 
managing adverse events that may result from the implementation of these procedures. 
Emergency facilities for managing any serious adverse event that requires urgent evaluation and 
treatment are available to the investigators. 
 
In order to minimize potential psychological risks, those who self report on the phone screen and 
in the screening questionnaires and are judged by the PI to meet criteria for a current depressive 
episode will be encouraged to follow up with their primary care physician and provided referrals 
to mental health services. They will not be eligible for enrollment. Treatment decisions (including 
type of and when to initiate) will not be influenced by study participation. Additionally, as answering 
questions on the research instruments and questionnaires used to evaluate psychological 
symptoms can be upsetting to some, subjects will be told that they can skip questions that make 
them feel uncomfortable.  The informed consent process will include an explicit discussion that 
the study is not guaranteed to provide treatment for symptoms. 
 
As stated above, the amount of blood drawn for this study is approximately 15 mL (3 teaspoons) 
and is not enough to cause harm to the subjects. All blood draws will be performed by trained 
personnel that use standard sterile techniques.  These procedures will be included in the patient 
informed consent document. 
 
VIII. POTENTIAL BENEFITS 
 
A potential benefit of participating in this study is to improve the subject’s overall quality of life and 
decrease insomnia symptoms. Participants may benefit from the close monitoring of their 
vasomotor symptoms (VMS), sleep patterns, and psychological symptoms. If a significant 
abnormality is detected on any of the study measures, including hormone assays, participants 
will be informed and encouraged to follow up with their health care providers. 
 

17 
 
Information from this study will benefit others because the medical community will gain more 
knowledge on the efficacy of suvorexant for hot flash associated insomnia.   
 
As a way of thanking participants for their time, subjects will be compensated up to $275.  
 
 
IX. 
MONITORING AND QUALITY ASSURANCE 
 
Independent Monitoring of Source Data 
Confidentiality will be maintained by storing data with a subject identification number only. Only 
the PI, co-investigators, and study staff will have access to the database and the study binders. 
Data will be entered into a secure, HIPAA-compliant Research Electronic Data Capture (REDCap) 
database hosted by Partners HealthCare and analyzed using STATA 14.0 (College Station, 
Texas). All exported data will be de-identified using only the subject’s identification number. 
Analysis of all study data will be conducted by Dr. Joffe, other co-Investigators on the study, and 
a master’s level statistician in her lab in consultation with Sybil Crawford, PhD, the statistical 
consultant on this project. All study personnel and participants will remain blinded to treatment 
assignment, including staff entering study data. Only the BWH Research Pharmacist who 
generates the randomization code will be unblinded to treatment assignment. 
 
Medical Monitoring Plan 
Margo Nathan, MD, a clinical psychiatrist and co-Investigator on this protocol, has been appointed 
the Medical Monitor for this protocol by the Principal Investigator. An SOP for the medical monitor 
has been developed and includes the following: 
- 
Reviews all safety data from all study visits within 2 business days. Serious adverse events 
will be reviewed and reported to the IRB within 24 hours, per PHRC guidance. Additional 
procedures regarding assessment of suicidal ideation are described below. 
- 
Meets with the Research Coordinator weekly to review status of all active participants 
- 
If a safety concern is identified, confers with consenting MD, PI, and/or Independent Safety 
Monitor to create an action plan. 
A Medical Monitoring Checklist has been developed to be included with each participant’s binder, 
which triggers the Medical Monitor to double-check lab results, vital signs, concomitant 
medications, adverse events, and the scores on the Patient Health Questionnaire-9 (PHQ-9) at 
all visits. 
 
Additional measures for assessing suicidal ideation 
Several measures are in place to assess for suicidal ideation in participants throughout the study. 
1. The Informed Consent form includes a statement informing participants to let study 
staff know if at any time they experience thoughts of self-harm or suicidal ideation 
during the study. The consenting clinician verbally confirms this statement prior to the 
participant signing the form. 
2. Participants are screened by a study clinician for current Major Depressive Disorder 
and/or suicidal ideation at the Screening Visit after consent. Both are exclusion criteria 
for continued participation in the study. If excluded for depression or suicidal ideation, 
participants would be assessed by a study clinician for need for urgent care and 
referred to mental health services for treatment. 
3. Participants complete the PHQ-9 at study visits while on medication. The PHQ-9 is 
completed on an iPAD during the study visit. If a participant indicates thoughts of self-
harm or suicidal ideation on the PHQ9, an alert is set to immediately send an email to 
the Principal Investigator, the Medical Monitor, the Sr. Project Manager, and the 
Research Coordinator. 

18 
 
4. Study staff review the responses to the PHQ9 before ending the study visit. 
5. A study clinician will query participants directly about suicidal ideation and will inquire 
about adverse events at study visits while participants is on medication. 
6. Any participant indicating emergence of suicidal ideation as determined by a study 
clinician will be taken off-study and referred to mental health services for further 
treatment. 
 
Independent Safety Monitor 
Jacob Taylor, MD MPH, will serve as the Independent Safety Monitor (ISM) for the remainder of 
this trial. The plan for Independent Safety Monitoring is as follows: 
- 
In the case of a Serious Adverse Event (SAE), the study team will notify the ISM within 24 
hours of becoming aware of the SAE. The ISM will review the case and, if appropriate, will 
examine the participant. The ISM will produce a short report on the SAE. 
- 
Every month, the ISM will review all Adverse Events. This review and any recommended 
actions will be documented in the Regulatory Binder. 
- 
Upon completion of data collection, the final database will not be unblinded until the ISM 
has completed all reviews, protocol violators have been identified, and all study data are 
complete. 
 
Adverse Event Reporting 
Subjects will be closely monitored for adverse events at every visit. Research staff will record 
adverse events using standard spontaneous IRB-approved reporting procedures. Participants will 
be told during the consent process that they should report any changes in mood or thoughts of 
self harm immediately to the study team, using the contact information provided on the form. 
Participants will be informed that they can contact the investigator between visits if they have 
concerns about potential side effects.  Routine adverse events and serious adverse events will 
be reported consistent with local IRB requirements and per Merck guidelines for reporting to the 
sponsor. In addition, the Medical Monitor and Independent Safety Monitor will review all adverse 
events and investigate those considered serious and unexpected consistent with standard ISM 
procedures. 
 
X. 
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