A Double-blind, Randomized, Placebo-controlled Trial of Adjunctive Suvorexant for Treatment-resistant Insomnia in Patients With Bipolar Disorder
Phase: PHASE4
Conditions: Insomnia, Bipolar Disorder
Sponsor: Stanford University

 
 
 
 
A Double-blind, Randomized, Placebo-controlled Trial of Adjunctive 
Suvorexant for Treatment-resistant Insomnia in Patients With Bipolar 
Disorder 
Study Protocol and Statistical Analysis Plan 
NCT02527564 
October 8, 2020 

      MISP Template: Protocol 
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Requirements for Submitting a Full Proposal 
 
 
Section #1 - MISP Protocol Identification 
 
Study Title: 
  
A double-blind, randomized, placebo-controlled trial of 
adjunctive suvorexant for treatment-resistant insomnia in 
patients with bipolar disorder  
Request Date: 
 
3/30/2015 
Institution Name 
 
Stanford University School of Medicine 
Investigator Contact 
Information: 
­ Full address  
­ Phone No. 
­ Fax  No. 
­ e-mail address 
 
Po Wang, MD 
Professor of Psychiatry & Behavioral Sciences 
401 Quarry Road 
Stanford, CA 94305 
P: (650) 723-2483 
wangp0@stanford.edu 
 
Trisha Suppes, MD, PhD 
Professor of Psychiatry and Behavioral Sciences  
VA Palo Alto Health Care System 
3801 Miranda Ave 
 
Palo Alto, CA 94304 
P: (650) 493-5000 
tsuppes@stanford.edu 
 
 
 
 

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Section #2- Core Protocol 
 
2.1 Objectives & 
Hypotheses  
 
 
 
 
2.1 Study Objectives 
 
Objective 1. (Hypotheses 1 and 2) To assess the acute (1-week) efficacy of 
adjunctive (added to existing treatments) suvorexant in patients with bipolar disorder 
and insomnia despite treatment with traditional hypnotic agents, anxiolytics, atypical 
antipsychotics, mood stabilizers, and/or antidepressants. 
 
Objective 2. (Hypotheses 3 and 4) To assess the subchronic (3-month) efficacy of 
open adjunctive (added to existing treatments) suvorexant in patients with bipolar 
disorder and insomnia despite treatment with traditional hypnotic agents, anxiolytics, 
atypical antipsychotics, mood stabilizers, and/or antidepressants 
 
2.1.1 Clinical Hypotheses.  
 
1. Primary acute efficacy hypothesis – Adjunctive suvorexant 20 mg at bedtime 
compared to adjunctive placebo for 1 week in patients with insomnia related to 
bipolar disorder (307.42), despite receiving treatment as usual will yield significantly 
greater increases in subjective total sleep time (sTST), as assessed by self-report. 
 
2. Secondary acute efficacy hypothesis 1 – Adjunctive suvorexant 20 mg at bedtime 
compared to adjunctive placebo for 1 week in patients with insomnia related to 
bipolar disorder (307.42), despite receiving treatment as usual will yield significantly 
greater increases in objective total sleep time (oTST), as assessed by sleep 
actigraphy. 
 
3. Secondary subchronic efficacy hypothesis 2 – Adjunctive open suvorexant 20 mg 
at bedtime for 3 months in patients with insomnia related to bipolar disorder (307.42), 
despite receiving treatment as usual will yield significant increases in subjective total 
sleep time (sTST), as assessed by self-report. 
 
4. Secondary subchronic efficacy hypothesis 3 – Adjunctive open suvorexant 20 mg 
at bedtime for 3 months in patients with insomnia related to bipolar disorder (307.42), 
despite receiving treatment as usual will yield significant increases in objective total 
sleep time (oTST), as assessed by sleep actigraphy. 
2.2 Background & 
Rationale, 
Significance of 
Selected Topic & 
Preliminary Data  
 
Insomnia is common in patients with bipolar disorder, not only when hypo/manic, but 
also when depressed, or even euthymic,1, 2 and commonly persists despite 
treatment. Sleep disturbance in remitted bipolar disorder patients may represent a 
prodrome of an impending mood episode, whereas improvement in sleep quality 
during an acute mood episode may be an early marker of recovery from the 
episode.1 Insomnia therefore represents an important target of treatment in bipolar 
disorder, regardless of current mood state.1  
 
Preliminary data from our clinic have been largely consistent with previous literature. 
Thus, among 89 bipolar disorder patients who achieved recovery from a mood 
episode and were subsequently followed longitudinally in the Stanford Bipolar 
Disorders Clinic for at least one year, worse daytime dysfunction, subjective sleep 
quality, sleep latency, and global sleep disturbance on the Pittsburgh Sleep Quality 
Index (PSQI)3 were associated with the presence of subsyndromal mood 
symptoms.4 In addition, worse PSQI daytime dysfunction significantly predicted a 
shorter time to mood episode recurrence.4 
 
Unfortunately, insomnia associated with bipolar disorder can be challenging to treat. 
Among 69 Stanford Bipolar Disorders Clinic patients who were already taking at 

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least one scheduled (i.e. non-PRN) prescription sedative-hypnotic agent at the time 
of initial assessment, 55.0% (N=38) complained of insomnia on at least one day 
within the prior week (unpublished data). Thus, treatment-resistant insomnia is both 
highly prevalent and associated with poorer longitudinal outcomes in bipolar 
disorder. More effective treatments for insomnia associated with bipolar disorder are 
urgently needed. 
 
Suvorexant is a novel hypnotic agent that promotes sleep via orexin receptor 
antagonism.5 A phase 3 randomized, double-blind, placebo-controlled study has 
demonstrated the efficacy and safety of suvorexant, in doses of 10mg to 20mg at 
bedtime, for the treatment of insomnia in healthy adults.6 We propose conducting a 
randomized, double-blind, placebo-controlled study assessing the efficacy of 
adjunctive (added to existing treatments) suvorexant in depressed or euthymic (but 
not hypo/manic) patients with bipolar disorder (Type I, Type II, or Type Not 
Otherwise Specified) and insomnia despite treatment with traditional hypnotic 
agents, anxiolytics, atypical antipsychotics, mood stabilizers, and/or antidepressants. 
 
2.3 Study Design 
 
Patients with bipolar disorder (Type I, Type II, or Type Not Otherwise Specified) who 
are currently euthymic or have current syndromal or subsyndromal depressive (but 
not hypo/manic) symptoms (i.e. have Young Mania Rating Scale [YMRS]7 total score 
< 12), and with insomnia related to bipolar disorder (307.42), with subjective total 
sleep time (sTST) < 6 hours on at least 1 night during the prior week, will be 
randomized to receive either adjunctive double-blind placebo or adjunctive double-
blind suvorexant 10 mg at bedtime for 3 nights, which as necessary and tolerated 
then may be increased to 20 mg at bedtime for 4 nights. In all patients, there will be 
an attempt to increase Suvorexant/Placebo dose from 10 to 20 mg at bedtime after 
three nights (although Suvorexant/Placebo dose may remain at 10 mg if the patient 
prefers to do so, though this is expected to be uncommon). Following the 1-week 
randomized controlled phase, all patients will receive open suvorexant 10 mg at 
bedtime for 3 nights, which as necessary and tolerated then may be increased to 20 
mg at bedtime for 3 months. All patients (i.e. those in both the active drug and 
placebo group) will revert back to the 10mg dose at the start of the open treatment 
phase in order to protect the blind.  
 
Inclusion Criteria: 
1. 
Adult outpatients (age 18 years and older) meeting Diagnostic and 
Statistical Manual of Mental Disorders, Fourth Edition, Text Revision 
(DSM-IV-TR)8 criteria for bipolar I disorder (296.70), bipolar II disorder 
(296.89), or bipolar disorder not otherwise specified (296.80), with 
concurrent insomnia related to bipolar disorder (307.42). 
2. 
Currently taking ≥ 1 prescription psychotropic medication (hypnotic 
agents, anxiolytics, atypical antipsychotics, mood stabilizers, and/or 
antidepressants) for management of bipolar disorder. 
3. 
Subjective total sleep time (sTST) < 6 hours on ≥ 1 night during the prior 
week, assessed at baseline visit using the Systematic Treatment 
Enhancement Program for Bipolar Disorder (STEP-BD) Clinical 
Monitoring Form (CMF).9 
 
Exclusion Criteria: 
1. 
Current hypo/manic symptoms, as evidenced by YMRS total score ≥ 12, 
assessed at baseline visit. 
2. 
Current (past 6 months) alcohol or substance use disorder, as 
determined by assessment with the Mini-International Neuropsychiatric 
Interview (MINI)10 at baseline visit. 
3. 
Current psychosis, as determined by assessment with the MINI at 
baseline visit. 

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4. 
Women who are currently pregnant or breastfeeding. 
5. 
Clinically significant abnormalities on baseline laboratory tests 
(comprehensive metabolic panel, fasting lipid panel, CBC with 
differential, thyroid stimulating hormone). 
6. 
Presence of any unstable and/or potentially confounding neurological 
and/or medical disorder. 
 
2.4 Study Flow 
 
 
 
Baseline 
Week 0 
Week 1 
Month 1 
Month 2 
Month 3 
ADE 
X 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
DSM-IV-
TR 307.42 
checklist 
X 
 
 
 
 
 
CMF 
X 
X 
X 
X 
X 
X 
YMRS 
X 
X 
X 
X 
X 
X 
MADRS 
X 
X 
X 
X 
X 
X 
sTST 
X 
X 
X 
X 
X 
X 
oTST 
 
X 
X 
X 
X 
X 
FISER/ 
GRSEB 
 
X 
X 
X 
X 
X 
CMP 
X 
 
 
 
 
 
FLP 
X 
 
 
 
 
 
CBC 
X 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
Upreg 
X 
 
 
 
 
 
 
ADE = Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-
BD) Affective Disorders Evaluation11; MINI = Mini-International Neuropsychiatric 
Interview10; DSM-IV-TR 307.42 checklist = Diagnostic and Statistical Manual of 
Mental Disorders, Fourth Edition, Text Revision8 criteria for insomnia related to 
bipolar disorder (307.42); CMF = STEP-BD Clinical Monitoring Form9; YMRS = 
Young Mania Rating Scale7; MADRS = Montgomery-Asberg Depression Rating 
Scale12; sTST = subjective Total Sleep Time (assessed with STEP-BD CMF at 
baseline visit, and with electronic self-report sleep diary at subsequent visits); oTST 
= objective Total Sleep Time (assessed with Actigraph device); FISER/GRSEB = 
Frequency and Intensity of Side Effects Ratings/Global Rating of Side Effects 
Burden13; CMP = comprehensive metabolic panel; FLP = fasting lipid panel; CBC = 
complete blood count with differential; TSH = thyroid stimulating hormone; Upreg = 
Urine pregnancy test (only for women of reproductive potential). 
 
 
2.5 Study 
Procedures 
Patients will have the following assessments: 
 
1. Baseline (1 week prior to randomization) 
Due to COVID-19 restrictions, all assessments will be done remotely via Zoom 
with clinician and study coordinator. Only the lab tests will be done in person. 
Medication and Actigraph will be mailed out to participant 
Diagnostic assessments  
• 
Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-
BD) Affective Disorders Evaluation (ADE)11  
• 
MINI 
• 
DSM-IV-TR insomnia related to bipolar disorder (307.42) checklist 
Clinical symptom assessments  
• 
STEP-BD CMF, including subjective Total Sleep Time (sTST)  
• 
YMRS  
• 
Montgomery-Asberg Depression Rating Scale (MADRS)12  

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Laboratory tests  
• 
Comprehensive metabolic panel  
• 
Fasting lipid panel 
• 
Complete blood count with differential 
• 
Thyroid stimulating hormone  
• 
Urine pregnancy test (only for women of reproductive potential) 
 
2. Controlled Week-0 (Randomization; prior to one week of double-blind, placebo-
controlled adjunctive suvorexant)  
Due to COVID-19 restrictions, all assessments will be done remotely via Zoom 
with clinician and study coordinator. Medication and Actigraph will be mailed 
out to participant 
 
Clinical symptom assessments  
• 
STEP-BD CMF  
• 
YMRS  
• 
MADRS  
• 
Electronic self-report sleep diary, including subjective Total Sleep Time 
(sTST) 
• 
Sleep actigraphy, including objective Total Sleep Time (oTST) assessed with 
Actigraph device 
• 
Frequency and Intensity of Side Effects Ratings/Global Rating of Side 
Effects Burden (FISER/GRSEB)13  
 
3. Controlled Week-1 (after one week of double-blind, placebo-controlled adjunctive 
suvorexant)  
Due to COVID-19 restrictions, all assessments will be done remotely via Zoom 
with clinician and study coordinator. Medication and Actigraph will be mailed 
out to participant 
 
Clinical symptom assessments  
• 
STEP-BD CMF  
• 
YMRS  
• 
MADRS  
• 
Electronic self-report sleep diary, including subjective Total Sleep Time 
(sTST) 
• 
Sleep actigraphy, including objective Total Sleep Time (oTST) assessed with 
Actigraph device 
• 
FISER/GRSEB 
 
4. Open Month-1 (after one month of open suvorexant)  
Due to COVID-19 restrictions, all assessments will be done remotely via Zoom 
with clinician and study coordinator. Medication and Actigraph will be mailed 
out to participant 
 
Clinical symptom assessments  
• 
STEP-BD CMF  
• 
YMRS  
• 
MADRS  
• 
Electronic self-report sleep diary, including subjective Total Sleep Time 
(sTST) 
• 
Sleep actigraphy, including objective Total Sleep Time (oTST) assessed with 
Actigraph device 
• 
FISER/GRSEB 
 

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5. Open Month-2 (after two months of open suvorexant)  
Due to COVID-19 restrictions, all assessments will be done remotely via Zoom 
with clinician and study coordinator. Medication and Actigraph will be mailed 
out to participant 
 
Clinical symptom assessments  
• 
STEP-BD CMF  
• 
YMRS  
• 
MADRS  
• 
Electronic self-report sleep diary, including subjective Total Sleep Time 
(sTST) 
• 
Sleep actigraphy, including objective Total Sleep Time (oTST) assessed with 
Actigraph device 
• 
FISER/GRSEB 
 
6. Open Month-3 (after three months of open suvorexant)  
Due to COVID-19 restrictions, all assessments will be done remotely via Zoom 
with clinician and study coordinator. Medication and Actigraph will be mailed 
back to study team using prepaid shipping label. 
 
Clinical symptom assessments  
• 
STEP-BD CMF  
• 
YMRS  
• 
MADRS  
• 
Electronic self-report sleep diary, including subjective Total Sleep Time 
(sTST) 
• 
Sleep actigraphy, including objective Total Sleep Time (oTST) assessed with 
Actigraph device 
• 
FISER/GRSEB 
 
2.6 Study Duration 
Estimated length of time required to recruit patients and complete the study is 6 
years, from September 1, 2015 to August 31, 2021. 
2.7 Statistical 
Analysis and 
Sample Size 
Justification  
The investigator will analyze the study data. The blind will be maintained using blinded 
medication and matching placebo provided by the sponsor. For the final analysis, the 
clinical database will not be unblinded until medical/scientific review has been 
completed, protocol violators have been identified (if appropriate), and data has been 
declared complete. Data will then be unblinded, data analysis will be completed, and 
the manuscripts will be prepared for publication. 
Variables/Time Points of Interest 
 
Primary outcome – subjective total sleep time (sTST), according to self-report, 
assessed at Controlled Week-0, Controlled Week-1, Open month-1, Open month-2, 
and Open month-3. 
Secondary outcome – objective total sleep time (oTST), according to Actigraph, 
assessed at Controlled Week-0, Controlled Week-1, Open month-1, Open month-2, 
and Open month-3. 
 
Statistical Methods 
For the randomized controlled phase, the primary outcome (change in sTST from 
Controlled Week-0 to Controlled Week-1) for adjunctive suvorexant versus 
adjunctive placebo will be assessed using a Mixed-Effect Model Repeated Measure 
(MMRM), with a significance threshold of p < 0.05.  

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For this 1-week, double-blind, placebo-controlled trial, assuming a two-tailed alpha 
of .05, a sample of 50 patients (25 patients taking double-blind adjunctive suvorexant, 
and 25 patients taking adjunctive placebo) would be required to detect an adjunctive 
suvorexant treatment effect (compared to adjunctive placebo) of 0.70, with a power of 
approximately .80, as described in greater detail below. 
 
For the open extension study, the key efficacy outcome will be change in sTST from 
Controlled Week-0 to Open Month-3, stratified by acute treatment arm (i.e., blind 
adjunctive suvorexant followed by open adjunctive suvorexant, and blind adjunctive 
placebo followed by open adjunctive suvorexant), using a paired Mixed-Effect Model 
Repeated Measure (MMRM) analysis, with a significance threshold of p < 0.05. 
 
Additional secondary analyses include evaluation of change in oTST from Controlled 
Week-0 to Controlled Week-1 for adjunctive suvorexant versus adjunctive placebo, 
using MMRM with a significance threshold of p < 0.05; and change in oTST from 
Controlled Week-0 to Open Month-3, stratified by acute treatment arm (i.e., blind 
adjunctive suvorexant followed by open adjunctive suvorexant, and blind adjunctive 
placebo followed by open adjunctive suvorexant), using a paired MMRM analysis, with 
a significance threshold of p < 0.05. 
 
There are no adjustments for dropout, as we expect no more than 5% dropout by the 
end of week 1. 
 
Multiplicity 
 
No correction for multiple comparisons will be used. 
 
Power/Sample Size: 
Based on pooled results in Table 1 of Herring, et al.,14 we expect baseline mean (SD) 
sTST in minutes of 317 (64). We expect a robust sTST benefit with suvorexant (60 
min increase) compared to placebo (15 minute increase) - admittedly this is a more 
marked suvorexant-placebo difference (60-15 = 45 minutes, which yields an effect size 
of 0.70) than in Herring et al. Supplemental Table S1,14 which had a pooled 
suvorexant-placebo difference of 33-15 = 18 minutes, which yielded a pooled effect 
size of only 0.28.  
Thus, for the primary outcome of the randomized controlled phase, based upon a 
sample size of n=25 patients per group, and a two-tailed alpha of 0.05, this study has 
80% power to detect an effect difference in change in sTST for suvorexant versus 
placebo of 0.70. 
2.8 Specific Drug 
Supply 
Requirements  
Suvorexant 10 mg tablets, 20mg tablets, and matching placebo will be supplied by 
Merck.   
 
 
Drug Supply Requirements: 
 
Drug Name: Suvorexant 10 mg tablets. 
Amount: 3 tabs for days 1-3 of 1-week, randomized, controlled treatment phase (a 
total of 150 tabs for 50 double-blind suvorexant patients), then 3 tabs for days 1-3 of 
3-month open treatment phase (a total of 300 tablets for 100 open suvorexant 
patients). 
Total 450 Suvorexant 10 mg tablets.   
 
Drug Name: Suvorexant 20 mg tablets. 
Amount: 4 tabs for days 4-7 of 1-week, randomized, controlled treatment phase (a 
total of 200 tabs for 50 double-blind suvorexant patients), then 87 tabs for days 4-90 

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of 3-month open treatment phase (a total of 8700 tablets for 100 open suvorexant 
patients). 
Total 8900 Suvorexant 20 mg tablets.   
 
Drug Name: Placebo tablets (to match suvorexant 10mg tablets). 
Amount: 3 tabs for days 1-3 of 1-week, randomized, controlled phase (a total of 150 
tablets for 50 double-blind placebo patients). 
Total 150 placebo tablets (to match suvorexant 10mg tablets). 
 
Drug Name: Placebo tablets (to match suvorexant 20mg tablets). 
Amount: 4 tabs for days 4-7 of 1-week, randomized, controlled phase (a total of 200 
tablets for 50 double-blind placebo patients). 
Total 200 placebo tablets (to match suvorexant 20mg tablets). 
 
Note: At conclusion of the study or upon drug expiration, the Merck GRS will be 
responsible for issuing a Drug Disposition Letter to the investigator for US based 
studies.   
 
The investigator will be responsible for the destruction of the supplies at the study 
center pursuant to the ICH/GCP Guidelines, local regulations and the investigator’s 
institutional policies. Clinical supplies will be received by Dr. Shefali Miller at the 
study site, handled and stored safely and properly, and kept in a secured location to 
which only the investigator and designated assistants have access. Clinical supplies 
will be dispensed in accordance with the protocol. The investigator is responsible for 
keeping accurate records of the clinical supplies, the amount dispensed to and 
returned by the patients, and the disposition at the end of the study. 
 
2.9 Adverse 
Experience 
Reporting 
Adverse experience reporting will be conducted as outlined by the Model Study 
Agreement.   
  
2.10 Itemized Study 
Budget  
A preliminary study budget is provided with the initial proposal to give guidance to the 
MISP Review Committee as to the expected study costs.   A refined itemized budget 
detailing the costs associated with the study will be provided with the final protocol or 
included in the study agreement as Exhibit B.   
2.11 References 
1. 
Plante DT, Winkelman JW. Sleep disturbance in bipolar disorder: therapeutic 
implications. Am J Psychiatry 2008;165:830-843. 
2. 
Gruber J, Harvey AG, Wang PW, et al. Sleep functioning in relation to mood, 
function, and quality of life at entry to the Systematic Treatment Enhancement 
Program for Bipolar Disorder (STEP-BD). J Affect Disord 2009;114:41-49. 
3. 
Buysse DJ, Reynolds CF, 3rd, Monk TH, et al. The Pittsburgh Sleep Quality 
Index: a new instrument for psychiatric practice and research. Psychiatry Res 
1989;28:193-213. 
4. 
Cretu JB, Culver JL, Ketter TA. Sleep disturbance/daytime dysfunction, 
subsyndromal symptoms, and time to relapse in recovered patients with bipolar 
disorder. (in preparation). 
5. 
Merck. Belsomra (suvorexant) prescribing information, updated August 
2014. http://www.merck.com/product/usa/pi_circulars/b/belsomra/belsomra_pi.pdf 
(accessed March 4, 2015). 
6. 
Michelson D, Snyder E, Paradis E, et al. Safety and efficacy of suvorexant 
during 1-year treatment of insomnia with subsequent abrupt treatment 
discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet 
Neurol 2014;13:461-471. 

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7. 
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: 
reliability, validity and sensitivity. Br J Psychiatry 1978;133:429-435. 
8. 
American Psychiatric Association. Diagnostic and Statistical Manual of 
Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Washington: 
American Psychiatric Association; 2000. 
9. 
Sachs GS, Guille C, McMurrich SL. A clinical monitoring form for mood 
disorders. Bipolar Disord 2002;4:323-327. 
10. 
Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International 
Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured 
diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 
1998;59:22-33. 
11. 
Sachs GS, Thase ME, Otto MW, et al. Rationale, design, and methods of the 
systematic treatment enhancement program for bipolar disorder (STEP-BD). Biol 
Psychiatry 2003;53:1028-1042. 
12. 
Montgomery SA, Asberg M. A new depression scale designed to be 
sensitive to change. Br J Psychiatry 1979;134:382-389. 
13. 
Wisniewski SR, Rush AJ, Balasubramani GK, et al. Self-rated global 
measure of the frequency, intensity, and burden of side effects. J Psychiatr Pract 
2006;12:71-79. 
14. 
Herring WJ, Connor KM, Ivgy-May N, et al. Suvorexant in patients with 
insomnia: results from two 3-Month randomized controlled clinical trials. Biol 
Psychiatry 2014 (epub ahead of print). 
 
2.12 Publication 
Plan 
• Publication plan – We anticipate two publications – 1. The primary paper 
(describing the  1-week double-blind placebo controlled trial; and 2. The key 
secondary paper (describing the 3-month open continuation study)   
• Projected target date for manuscript submission is November 30, 2017 for both 
papers, which will be submitted to the Journal of Affective disorders.  
• We anticipate two abstracts – as describe for the two anticipated publications 
above. 
• We anticipate presenting the two abstracts at the American Psychiatric 
Association Annual Meeting in New York, NY (May 5-10, 2018). 
 
2.13 Curriculum 
Vitae 
 
Curriculum vitae for Dr. Terence Ketter and Dr. Shefali Miller are attached. 
2.13 Protocol 
Submission for 
Investigator-
Initiated Studies  
This protocol will be submitted by the investigators directly or through the Global 
Research Specialist at www.merckiisp.com