Clinical trial NCT03331042
Conditions: Transient Insomnia
Keywords: Insomnia Transient Insomnia Sleep initiation and maintenance disorder
Sponsor: Sequential Medicine Ltd
Start date: 2017-10-09; Completion date: 2018-03-22
Enrollment: 85 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to investigate the effectiveness, safety and tolerability of a combination drug product (SM-1) containing diphenhydramine, zolpidem and lorazepam, in adult participants who sometimes have difficulty in falling asleep or staying asleep, but who do not have chronic insomnia. Participants will receive SM-1, or a combination of diphenhydramine and zolpidem, or a combination of diphenhydramine and lorazepam, or placebo during 4 one-night stays at a sleep center.

Detailed description:

Arms: arm 1: SM-1 (Treatment Period 1), D+Z (Treatment Period 2), D+L (Treatment Period 3), Placebo (Treatment Period 4). arm 2: D+Z (Treatment Period 1), D+L (Treatment Period 2), Placebo (Treatment Period 3), SM-1 (Treatment Period 4). arm 3: D+L (Treatment Period 1), Placebo (Treatment Period 2), SM-1 (Treatment Period 3), D+Z (Treatment Period 4). arm 4: Placebo (Treatment Period 1), SM-1 (Treatment Period 2), D+Z (Treatment Period 3), D+L (Treatment Period 4).
Interventions: intervention 1: SM-1 intervention 2: D+Z intervention 3: D+L intervention 4: Placebo
Intervention descriptions: intervention 1: 3-drug combination product containing 50-mg diphenhydramine, 5-mg delayed-release zolpidem and 0.5-mg delayed-release lorazepam. intervention 2: 2-drug combination comparator product containing 50-mg diphenhydramine and 5-mg delayed-release zolpidem. intervention 3: 2-drug combination comparator product containing 50-mg diphenhydramine and 0.5-mg delayed-release lorazepam. intervention 4: Identical in appearance to SM-1, D+Z and D+L and has the same excipients, but no diphenhydramine, zolpidem, lorazepam or delayed-release coating materials.

Protocol documents:
Prot_001.pdf: 
Sequential Medicine, Ltd 
SM-1 
Protocol no. SM-A-05, Version 1.0, Amendment 1 
12 December 2017 
 
CLINICAL STUDY PROTOCOL 
 
A Randomized, Double-Blind, Single-Dose, 4-Way Crossover Study to 
Assess the Efficacy and Safety of SM-1 (50-mg Diphenhydramine, 5-mg 
Delayed-Release Zolpidem, and 0.5-mg Delayed-Release Lorazepam) 
versus 2 Comparators (50-mg Diphenhydramine and 5-mg Delayed-
Release Zolpidem; 50-mg Diphenhydramine and 0.5-mg Delayed-Release 
Lorazepam) and Placebo in a 5-Hour Phase Advance Model of Transient 
Insomnia 
SM-A-05 
Sponsor: 
Sequential Medicine, Ltd 
6F, No.135 Sec 3 
Minsheng East Road 
Taipei, 10546 
Taiwan, Republic of China 
Sponsor Contact: 
Thomas Dahl, PhD 
Sponsor Representative 
Telephone: 1-617-818-2735 
Project Manager: 
Monica Tansil 
Senior Project Manager 
PPD 
7551 Metro Center Drive 
Suite 300 
Austin, TX 78744 USA 
Telephone: 1-910-558-4833 
Medical Monitor: 
PPD Pharmacovigilance 
Safety Hotline: 1-888-483-7729 
Safety Fax Line: 1-888-529-3580 
Version of Protocol:  
Protocol 1.0, Amendment 1 
Date of Protocol:  
12 December 2017 
CONFIDENTIAL  
All financial and nonfinancial support for this study will be provided by Sequential Medicine Ltd. The concepts 
and information contained in this document or generated during the study are considered proprietary and may 
not be disclosed in whole or in part without the expressed, written consent of Sequential Medicine Ltd. 
The study will be conducted according to the International Council for Harmonisation harmonised tripartite 
guideline E6(R2): Good Clinical Practice.  






Sequential Medicine, Ltd 
SM-1 
Protocol no. SM-A-05, Version 1.0, Amendment 1 
12 December 2017 
 
Protocol Approval – Lead Statistician 
Study Title 
A Randomized, Double-Blind, Single-Dose, 4-Way Crossover Study to 
Assess the Efficacy and Safety of SM-1 (50-mg Diphenhydramine, 
5-mg Delayed-Release Zolpidem, and 0.5-mg Delayed-Release 
Lorazepam) versus 2 Comparators (50-mg Diphenhydramine and 5-mg 
Delayed-Release Zolpidem; 50-mg Diphenhydramine and 0.5-mg 
Delayed-Release Lorazepam) and Placebo in a 5-Hour Phase Advance 
Model of Transient Insomnia 
Protocol Number SM-A-05 
Protocol Date 
12 December 2017 
 
Protocol accepted and approved by: 
Lead Statistician 
Raymond Claus, MS 
Associate Director, Biostatistics 
PPD 
3900 N Paramount Parkway 
Morrisville, NC 27560 USA 
 
 
 
Signature 
 
Date 
 
Raymond Claus
Digitally signed by Raymond Claus 
DN: dc=LOCAL, dc=PPDI, dc=americas, ou=Sites, 
ou=RTP, ou=Users, cn=Raymond Claus, 
email=Raymond.Claus@ppdi.com 
Date: 2018.03.28 13:36:17 -04'00'


Sequential Medicine, Ltd 
SM-1 
Protocol no. SM-A-05, Version 1.0, Amendment 1 
12 December 2017 
 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Randomized, 
Double-Blind, Single-Dose, 4-Way Crossover Study to Assess the Efficacy and Safety of 
SM-1 (50-mg Diphenhydramine, 5-mg Delayed-Release Zolpidem, and 0.5-mg 
Delayed-Release Lorazepam) versus 2 Comparators (50-mg Diphenhydramine and 5-mg 
Delayed-Release Zolpidem; 50-mg Diphenhydramine and 0.5-mg Delayed-Release 
Lorazepam) and Placebo in a 5-Hour Phase Advance Model of Transient Insomnia” and the 
current Investigator’s Brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 1.0, Amendment 1, dated 12 December 2017, the 
International Council for Harmonisation harmonised tripartite guideline E6(R2): Good 
Clinical Practice and all applicable government regulations. I will not make changes to the 
protocol before consulting with Sequential Medicine Ltd or implement protocol changes 
without independent ethics committee approval except to eliminate an immediate risk to 
subjects. I agree to administer study treatment only to subjects under my personal supervision 
or the supervision of a subinvestigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Subject identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Sequential Medicine Ltd. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 


Sequential Medicine, Ltd 
SM-1 
Protocol no. SM-A-05, Version 1.0, Amendment 1 
12 December 2017 
 
Page 6 
Table of Contents 
Table of Contents ....................................................................................................................... 6 
List of Tables .............................................................................................................................. 9 
Protocol Synopsis..................................................................................................................... 10 
List of Abbreviations................................................................................................................ 16 
1 
Introduction ...................................................................................................................... 18 
2 
Study Objectives............................................................................................................... 20 
2.1 
Primary Objectives.................................................................................................. 20 
2.2 
Secondary Objectives.............................................................................................. 20 
2.3 
Safety Objective ...................................................................................................... 20 
2.4 
Other Objectives ..................................................................................................... 20 
3 
Investigational Plan .......................................................................................................... 21 
3.1 
Study Design ........................................................................................................... 21 
3.1.1 
Rationale of Study Design ....................................................................... 23 
4 
Subject Selection and Withdrawal Criteria ...................................................................... 24 
4.1 
Selection of Study Population ................................................................................. 24 
4.1.1 
Inclusion Criteria ..................................................................................... 24 
4.1.2 
Exclusion Criteria .................................................................................... 26 
4.2 
Withdrawal of Subjects From the Study ................................................................. 27 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................ 27 
4.2.2 
Handling of Withdrawals ......................................................................... 28 
4.2.3 
Replacements ........................................................................................... 29 
5 
Study Treatments .............................................................................................................. 30 
5.1 
Method of Assigning Subjects to Treatment Groups .............................................. 30 
5.2 
Treatments Administered ........................................................................................ 30 
5.3 
Identity of Investigational Product.......................................................................... 30 
5.4 
Management of Clinical Supplies ........................................................................... 31 
5.4.1 
Study Drug Packaging and Storage ......................................................... 31 
5.4.2 
Study Drug Accountability ...................................................................... 31 
5.4.3 
Other Supplies ......................................................................................... 31 


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SM-1 
Protocol no. SM-A-05, Version 1.0, Amendment 1 
12 December 2017 
 
Page 7 
5.5 
Blinding .................................................................................................................. 32 
5.5.1 
Breaking the Blind ................................................................................... 32 
5.6 
Treatment Compliance ............................................................................................ 32 
5.7 
Prior and Concomitant Therapy .............................................................................. 32 
5.7.1 
Prohibited Medications and Therapies .................................................... 33 
5.7.2 
Restrictions .............................................................................................. 34 
6 
Study Assessments and Procedures .................................................................................. 35 
6.1 
Study Visits ............................................................................................................. 35 
6.2 
Screening Assessments ........................................................................................... 40 
6.2.1 
Medical History and Other Information .................................................. 40 
6.2.2 
Sleep History ........................................................................................... 40 
6.2.3 
Vital Sign Measurements ......................................................................... 40 
6.2.4 
Physical Examination .............................................................................. 41 
6.2.5 
Epworth Sleepiness Scale ........................................................................ 41 
6.2.6 
Drug and Alcohol Screen ......................................................................... 41 
6.2.7 
Laboratory Assessments .......................................................................... 41 
6.2.8 
Urine Pregnancy Test ............................................................................... 42 
6.2.9 
Pretreatment Sleep Diary ......................................................................... 42 
6.3 
Efficacy Assessments .............................................................................................. 42 
6.3.1 
Polysomnography .................................................................................... 42 
6.3.2 
Post-Sleep Questionnaire ......................................................................... 43 
6.3.3 
Washout Interval Sleep Diary .................................................................. 43 
6.4 
Safety Assessments ................................................................................................. 43 
6.4.1 
Adverse Events ........................................................................................ 44 
6.4.1.1 
Definitions of Adverse Events ................................................................. 44 
6.4.1.2 
Eliciting and Documenting Adverse Events ............................................ 44 
6.4.1.3 
Reporting Adverse Events ....................................................................... 45 
6.4.1.4 
Assessment of Severity ............................................................................ 46 
6.4.1.5 
Assessment of Causality .......................................................................... 46 
6.4.1.6 
Follow-Up of Subjects Reporting Adverse Events .................................. 47 
6.4.2 
Alcohol Screen ......................................................................................... 47 
6.4.3 
Urine Pregnancy Test ............................................................................... 48 
6.4.4 
Karolinska Sleepiness Scale .................................................................... 48 
6.4.5 
Digit Symbol Substitution Test ................................................................ 48 


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SM-1 
Protocol no. SM-A-05, Version 1.0, Amendment 1 
12 December 2017 
 
Page 8 
6.4.6 
Vital Sign Measurements ......................................................................... 48 
6.4.7 
Predischarge Evaluation .......................................................................... 49 
6.5 
Pregnancy ................................................................................................................ 49 
6.6 
Laboratory Analyses ............................................................................................... 49 
6.7 
Sample Collections ................................................................................................. 49 
7 
Statistical and Analytical Plan .......................................................................................... 50 
7.1 
Primary Efficacy Endpoints .................................................................................... 50 
7.2 
Secondary Efficacy Endpoints ................................................................................ 50 
7.3 
Safety and Other Endpoints .................................................................................... 50 
7.4 
Sample Size Calculations ........................................................................................ 50 
7.5 
Analysis Sets ........................................................................................................... 51 
7.6 
Description of Subgroups to be Analyzed .............................................................. 52 
7.7 
Statistical Analysis Methodology ........................................................................... 52 
7.7.1 
Analysis of Primary Efficacy Endpoint ................................................... 52 
7.7.2 
Analysis of Secondary Efficacy Endpoint ............................................... 52 
7.7.3 
Safety Analyses ........................................................................................ 53 
7.7.4 
Other Analyses ......................................................................................... 53 
7.7.5 
Interim Analyses ...................................................................................... 53 
7.8 
Data Quality Assurance........................................................................................... 54 
7.8.1 
Data Management .................................................................................... 54 
8 
Ethics ................................................................................................................................ 56 
8.1 
Independent Ethics Committee or Institutional Review Board .............................. 56 
8.2 
Ethical Conduct of the Study .................................................................................. 56 
8.3 
Subject Information and Consent ........................................................................... 56 
9 
Investigator’s Obligations ................................................................................................ 58 
9.1 
Confidentiality ........................................................................................................ 58 
9.2 
Financial Disclosure and Obligations ..................................................................... 58 
9.3 
Investigator Documentation .................................................................................... 59 
9.4 
Study Conduct ......................................................................................................... 59 
9.5 
Adherence to Protocol ............................................................................................ 59 
9.6 
Adverse Events and Study Report Requirements ................................................... 60 


Sequential Medicine, Ltd 
SM-1 
Protocol no. SM-A-05, Version 1.0, Amendment 1 
12 December 2017 
 
Page 9 
9.7 
Investigator’s Final Report ..................................................................................... 60 
9.8 
Records Retention ................................................................................................... 60 
9.9 
Publications ............................................................................................................. 60 
10 Study Management ........................................................................................................... 61 
10.1 Monitoring .............................................................................................................. 61 
10.1.1 
Monitoring of the Study ........................................................................... 61 
10.1.2 
Inspection of Records .............................................................................. 61 
10.2 Management of Protocol Amendments and Deviations.......................................... 61 
10.2.1 
Modification of the Protocol .................................................................... 61 
10.2.2 
Protocol Deviations ................................................................................. 62 
10.3 Study Termination ................................................................................................... 62 
10.4 Final Report ............................................................................................................ 62 
11 Reference List................................................................................................................... 64 
12 Appendices ....................................................................................................................... 65 
12.1 Appendix 1: STOP-Bang Questionnaire ................................................................. 65 
12.2 Appendix 2: Epworth Sleepiness Scale .................................................................. 66 
12.3 Appendix 3: Post-Sleep Questionnaire ................................................................... 67 
12.4 Appendix 4: Karolinska Sleepiness Scale .............................................................. 68 
12.5 Appendix 5: Digit Symbol Substitution Test .......................................................... 69 
 
 
List of Tables 
Table 3-1 
Randomized Treatment Sequences ................................................................. 22 
Table 6-1 
Schedule of Events .......................................................................................... 36 
Table 6-2 
Sleep Study Events by Day for Treatment Periods 1, 2, 3, and 4 ................... 39 
 


Sequential Medicine, Ltd 
SM-1 
Protocol no. SM-A-05, Version 1.0, Amendment 1 
12 December 2017 
 
Page 10 
Protocol Synopsis 
Protocol Number: 
SM-A-05 
Title: 
A Randomized, Double-Blind, Single-Dose, 4-Way Crossover 
Study to Assess the Efficacy and Safety of SM-1 (50-mg 
Diphenhydramine, 5-mg Delayed-Release Zolpidem, and 0.5-mg 
Delayed-Release Lorazepam) versus 2 Comparators (50-mg 
Diphenhydramine and 5-mg Delayed-Release Zolpidem; 50-mg 
Diphenhydramine and 0.5-mg Delayed-Release Lorazepam) and 
Placebo in a 5-Hour Phase Advance Model of Transient Insomnia 
Sponsor: 
Sequential Medicine, Ltd 
6F, No.135 Sec 3 
Minsheng East Road 
Taipei, 10546 
Taiwan, Republic of China 
Study Phase: 
3 
Study Sites: 
2 study centers in the US 
Indication: 
Transient insomnia 
Rationale: 
The current study will serve to confirm the efficacy, safety, and 
tolerability of SM-1 in subjects with a history of transient 
insomnia. In addition, the inclusion of the additional drug 
combination arms will serve to generate data to assess the 
contribution of zolpidem and lorazepam to the overall efficacy of 
the investigational product. 
Objectives: 
The primary objective of the study is to assess efficacy of SM-1 
versus placebo and 2 additional combination products comprised 
of 2 of the 3 components of SM-1 (diphenhydramine plus 
zolpidem and diphenhydramine plus lorazepam) as measured by 
polysomnography (PSG)-defined total sleep time (TST). 
The secondary objectives of this study are: 
• To assess activity of SM-1 versus placebo and the two 
2-drug combination products on additional PSG measures 
of sleep induction  
• To assess subject reported efficacy measures from the 
Post-Sleep Questionnaire (PSQ) 
• To assess the activity of the two 2-drug combination 
products versus placebo on PSG-defined TST and 
additional PSG measures of sleep induction 
The safety objective of this study is to assess safety of SM-1 in 
terms of adverse events (AEs) and morning measures of alertness 


Sequential Medicine, Ltd 
SM-1 
Protocol no. SM-A-05, Version 1.0, Amendment 1 
12 December 2017 
 
Page 11 
(Karolinska Sleepiness Scale [KSS] and Digit Symbol 
Substitution Test [DSST]). 
Other objectives include the assessment of the effect of SM-1 and 
the two 2-drug combination products on sleep stage distribution. 
Subject Population: 
The study will enroll male and female subjects 18 years of age or 
older in good general health who routinely spend between 6.5 and 
9 hours in bed per night and report at least 1 prior episode of 
transient insomnia defined by all of the following criteria:  
• Difficulty falling asleep or staying asleep  
• Next day impairment or distress associated with the 
disturbed sleep  
• Frequency of 1 to 7 nights per week 
• Duration of less than 1 month or more than 1 month of 
intermittent episodes 
Subjects should have no clinically significant medical, 
psychiatric, or sleep disorders.  
Study Design: 
Potential subjects will be evaluated during a screening period 
(Visit 1). Subjects who satisfy all eligibility criteria will be issued 
a paper sleep diary and instructed to record the time they go to 
bed with the intention of sleeping and the time they get up for a 
minimum of 7 days during the screening period, with at least 
5 entries completed over the 7 days (≥70% compliance). 
Information recorded in the diary will be communicated to study 
personnel no later than 24 hours prior to check-in for the first day 
of the first treatment period (Visit 2) to allow the calculation of 
each subject’s median habitual bedtime. 
At Visit 2, subjects will check-in at the study center 
approximately 7 hours earlier than their median habitual bedtime, 
as calculated from their diary data. Once eligibility has been 
reconfirmed, subjects will be randomly assigned to 1 of 
4 treatment sequences as shown in the following table: 
 
Randomized Treatment Sequences 
 
Treatment 
Period 1 
Visit 2 
Treatment 
Period 2 
Visit 3 
Treatment 
Period 3 
Visit 4 
Treatment 
Period 4 
Visit 5 
Sequence 1 
SM-1 
D+Z 
D+L 
Placebo 
Sequence 2 
D+Z 
D+L 
Placebo 
SM-1 
Sequence 3 
D+L 
Placebo 
SM-1 
D+Z 
Sequence 4 
Placebo 
SM-1 
D+Z 
D+L 


Sequential Medicine, Ltd 
SM-1 
Protocol no. SM-A-05, Version 1.0, Amendment 1 
12 December 2017 
 
Page 12 
SM-1 = 50-mg diphenhydramine, 5-mg delayed-release zolpidem, and 0.5-mg 
delayed-release lorazepam; D+Z = 50-mg diphenhydramine and 5-mg 
delayed-release zolpidem; D+L = 50-mg diphenhydramine and 0.5-mg 
delayed-release lorazepam; placebo = identical in appearance to SM-1, D+Z, 
and D+L and has the same excipients, but no diphenhydramine, zolpidem, 
lorazepam, or delated-release coating materials. 
Subjects will go to bed (“lights out”) 5 hours ± 30 minutes before 
their median habitual bedtime. Prior to lights out, subjects will 
undergo a baseline DSST assessment, eat a light snack, have PSG 
electrodes applied, and the machine will be calibrated. Subjects 
will be administered their assigned treatment by study personnel 
30 minutes prior to lights out. At the assigned lights out time the 
subject will go to bed, PSG biocalibration will be performed, and 
PSG recording will begin. The recording will continue for 
8 hours. At the completion of the 8-hour PSG recording period, 
subjects will complete morning assessments (PSQ, KSS, and 
DSST) and will undergo a predischarge evaluation, consisting of 
tandem gait, the Romberg test, and an assessment of vital signs 
and AEs. Upon discharge, subjects will undergo an interdose 
washout interval of no less than 5 days and will be asked to 
complete a daily washout interval diary during this time. The 
schedule of procedures for Visits 3, 4, and 5 will be the same as 
for Visit 2 except that subjects will be given the next treatment in 
their randomization sequence and lights out will occur at the time 
established at Visit 2, ± 15 minutes. 
Within 7 days after completion of Treatment Period 4 (Visit 5), 
but at least 72 hours after administration of the final dose, study 
personnel will contact the subject for a follow-up safety phone 
call. Outcomes of any AEs will be discussed and recorded. If 
indicated, a visit to the study center for safety assessments will be 
scheduled. 


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SM-1 
Protocol no. SM-A-05, Version 1.0, Amendment 1 
12 December 2017 
 
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Estimated Study 
Duration: 
Subjects will be evaluated during a screening period lasting at 
least 8 and no more than 21 days, followed by 4 inpatient PSG 
and treatment periods lasting approximately 11 to 12 hours from 
check-in to discharge. Between each treatment period, subjects 
will undergo an interdose washout interval of no less than 5 days. 
Subjects will then be contacted by telephone for a safety follow-
up within 7 days but at least 72 hours after their last dose of study 
drug. From screening to the safety follow-up phone call, 
assuming a 7-day washout interval between each treatment 
period, subjects will participate in the study for approximately 
8 weeks. 
Efficacy Assessments: 
Polysomnography data will be the primary source for efficacy 
endpoints, including TST, WASO, LPS, NAW, and TST by 
quarters of the night. Each night of PSG for each treatment period 
(Visits 2, 3, 4, and 5) will consist of an 8-hour (960 30-second 
epochs) assessment during which electroencephalographic, 
electrooculographic, electrocardiographic, and submental 
electromyographic activity will be recorded according to methods 
consistent with the standards of the American Academy of Sleep 
Medicine. Subject-reported efficacy measures will be assessed 
from data collected from the PSQ, which includes subject self-
reporting of time to sleep onset, NAW, wake time during the 
night, TST, and sleep quality. The PSQ data will be used to 
determine subjective TST (sTST) and subjective sleep onset 
latency (sSOL). Subjects will also be required to complete a daily 
diary during each interdose washout interval. 
Safety Assessments: 
Safety and tolerability will be assessed in terms of the incidence, 
severity and relationship to treatment of AEs, and by morning 
measures of alertness (KSS and DSST). In addition, safety 
assessments will include alcohol screening, urine pregnancy 
testing for women of childbearing potential, vital sign 
measurements, and predischarge evaluations. 
Study Drug, Dosage, 
and Route of 
Administration: 
The SM-1 study drug contains 50-mg diphenhydramine, 5-mg 
delayed-release zolpidem, and 0.5-mg delayed-release lorazepam 
as active ingredients. 
The 2-drug combination D+Z study drug contains 50-mg 
diphenhydramine and 5-mg delayed-release zolpidem as active 
ingredients. 
The 2-drug combination D+L study drug contains 50-mg 
diphenhydramine and 0.5-mg delayed-release lorazepam as active 
ingredients. 


Sequential Medicine, Ltd 
SM-1 
Protocol no. SM-A-05, Version 1.0, Amendment 1 
12 December 2017 
 
Page 14 
The SM-1, D+Z, and D+L capsules are all Size 0 white capsules 
and contain the inactive excipients PROSOLV® SMCC HD 90, 
starch 1500, and magnesium stearate. Delayed-release coating 
materials include Eudragit L100-55, Eudragit L100, and Eudragit 
S100. 
The placebo is identical in appearance to SM-1, D+Z, and D+L, 
and has the same excipients, but no diphenhydramine, zolpidem, 
lorazepam, or delayed-release coating materials. 
For each treatment period (Visits 2, 3, 4, and 5), 30 minutes prior 
to each subject’s lights out time (5 hours ± 30 minutes prior to the 
subject’s median habitual bedtime), a single dose of study drug 
will be administered according to the subject’s treatment 
sequence randomization. All doses of study drug will be 
administered orally by study personnel with 250 mL of water. An 
oral cavity check will be performed to assure compliance with 
treatment. 
Sample Size: 
A minimum of 68 blinded subjects will be able to ensure 80% 
power to detect treatment difference in TST between SM-1 and 
all 3 controls (D+Z, D+L, and placebo) at a 2-sided 0.05 
significance level. Approximately 84 subjects will be randomly 
assigned to receive study drug. A blinded interim analysis will be 
performed after approximately 50% of blinded subjects have 
completed the study to allow for an option to increase the sample 
size to preserve power if the observed SD of the primary efficacy 
endpoint is different than was estimated for the a priori sample 
size calculation. 
Statistical Methods: 
Statistical analysis will be performed using SAS software Version 
9.2 or later. Continuous variables will be summarized using the 
mean, SD, median, minimum value, and maximum value. 
Categorical variables will be summarized using frequency counts 
and percentages. Data will be provided in by-subject data listings. 
All statistical tests will be 2-sided and performed using a 5% 
significance level, leading to 95% 2-sided CIs. The overall study 
wide type I error rate (alpha) will be 0.05. 
The analysis of the primary efficacy endpoint will be conducted 
using an analysis of variance (ANOVA) method with the TST as 
the response variable and treatment, sequence, center, and period 
as the fixed effects. The primary comparison will be SM-1 with 
placebo, followed by SM-1 with D+Z, and SM-1 with D+L. 
Analyses will be performed to evaluate effect of sex and age on 
TST using the same ANOVA model with addition of sex and age 


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Protocol no. SM-A-05, Version 1.0, Amendment 1 
12 December 2017 
 
Page 15 
(greater than median vs less than median) as fixed factors. 
The data collected from PSG recordings and PSQ responses will 
be used to analyze the secondary efficacy endpoints for the 
comparisons of SM-1 versus placebo on WASO, LPS, NAW, 
sTST sSOL, and TST by quarters of the night; SM-1 versus both 
D+Z and D+L on WASO, LPS, NAW, sTST, sSOL, and TST by 
quarters of the night; and both D+Z and D+L versus placebo on 
TST, WASO, LPS, NAW, sTST, sSOL, and TST by quarters of 
the night. These analyses will be performed using the same 
ANOVA model as for the primary efficacy endpoint. Endpoints 
that are not normally distributed will be log-transformed first. 
Adverse events will be summarized by using count summaries. 
Adverse events will be listed for each subject and summarized by 
system organ class and preferred term assigned to the event by 
the Medical Dictionary for Regulatory Activities. 
The KSS and DSST data will be analyzed using the same 
statistical methods as the primary efficacy endpoint analysis. 
Vital sign measurements will be summarized and listed. Physical 
examination findings, alcohol breath test results, and urine 
pregnancy test results will be provided in by-subject data listings. 
Sleep stage will be summarized by the duration (in minutes) and 
percentage of each sleep stage. The latency to rapid eye 
movement (REM) will be summarized. The duration and 
percentage of each sleep stage (N1, N2, N3) and the latency to 
REM will be analyzed using the same statistical methods as for 
the primary endpoint analysis.  
Disposition, demographics, medical history, sleep history, and 
concomitant medications will be summarized and listed. 
Date of Protocol: 
12 December 2017 
 


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Protocol no. SM-A-05, Version 1.0, Amendment 1 
12 December 2017 
 
Page 16 
List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ANOVA 
analysis of variance 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
D+L 
50-mg diphenhydramine plus 0.5-mg delayed-release lorazepam 
D+Z 
50-mg diphenhydramine and 5-mg delayed-release zolpidem 
DSST 
Digit Symbol Substitution Test 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ESS 
Epworth Sleepiness Scale 
FAS 
full analysis set 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IRB 
institutional review board 
KSS 
Karolinska Sleepiness Scale 
LPS 
latency to persistent sleep 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
modified full analysis set 
NAW 
number of awakenings 
OSA 
obstructive sleep apnea 
OTC 
over the counter 
PPD 
Pharmaceutical Product Development, LLC 
PPS 
per-protocol set 
PSG 
polysomnography, polysomnographic 
PSQ 
Post-Sleep Questionnaire 
REM 
rapid eye movement 
SAE 
serious adverse event 
SM-1 
50-mg diphenhydramine, 5-mg delayed-release zolpidem, and 0.5-mg 
delayed-release lorazepam 


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Abbreviation 
Definition 
sSOL 
subjective sleep onset latency 
sTST 
subjective total sleep time 
TST 
total sleep time 
WASO 
wakefulness after sleep onset 
 


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1 Introduction 
Sequential Medicine Ltd (sponsor) is currently developing a product intended for the 
short-term treatment of individuals with transient insomnia. The product candidate, 
code-named SM-1, is a controlled-release combination of established medications intended 
to both induce and maintain sleep while avoiding impairment of next-day functioning. The 
dose of each drug in the SM-1 formulation is the lowest dose that has been shown to have 
sleep-promoting properties. 
The formulation provides 50-mg immediate-release diphenhydramine, a histamine (H1) 
receptor antagonist working on the wake side of the sleep/wake system, a 5-mg 
delayed-release dose of zolpidem, a drug which works on the sleep side of the sleep/wake 
system, and a low dose (0.5 mg) of delayed-release lorazepam with the intent of inducing and 
maintaining sleep without residual effects. This combination and staging is a unique 
approach to addressing the problem of transient insomnia, where most current treatments for 
difficulty sleeping tend to provide sleep onset relief, but inadequate benefit of duration or 
maintenance of sleep in the absence of morning impairment. If successful, SM-1 will be a 
unique and important therapeutic option for the treatment of transient insomnia. 
The investigational product SM-1 was studied in a pharmacokinetic/pharmacodynamic study 
in normal healthy volunteers in a daytime sedation study. By both objective and subjective 
criteria, SM-1 displayed the desired activity profile with onset of sedative effects 0.5 to 
1 hour following dose administration and offset generally 8 hours following dose 
administration, for a duration of action of 7 to 7.5 hours. The product was well-tolerated with 
minimal side effects. 
A Phase 2 clinical study of SM-1 was conducted in the target patient population, 39 subjects 
who had a history of transient insomnia. During the clinical study, sleep disturbance was 
induced using a 5-hour phase advance model with 8 hours of polysomnographic (PSG) 
recording for the primary efficacy endpoint of total sleep time (TST). The efficacy of SM-1 
was compared both with placebo and to a drug combination product comprised of 2 of the 
3 components of SM-1 (5-mg delayed-release zolpidem plus 0.5-mg delayed-release 
lorazepam) in a double-blind, single-dose, 3-way crossover study. 
The study’s primary endpoint was the comparison of TST between SM-1 and placebo. 
Administration of SM-1 resulted in a significantly greater TST than placebo (P<0.001) as 


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well as the 2-drug combination (P=0.014). Administration of SM-1 reduced wakefulness 
after sleep onset (WASO) significantly compared with placebo (P<0.001). On waking, there 
were no residual drug effects as indicated by Karolinska Sleepiness Scale (KSS), Digit 
Symbol Substitution Test (DSST), or predischarge neurological examination results. The 
single doses of SM-1 were safe and well-tolerated in the study population that included male 
and female subjects who had reported occasional difficulty falling asleep of staying asleep 
but who were not experiencing such difficulties at the time of the study. 
The current study will serve to confirm the efficacy, safety, and tolerability of SM-1 in 
subjects with a history of transient insomnia. In addition, the inclusion of additional drug 
combination arms will serve to generate data to assess the contribution of zolpidem and 
lorazepam to the overall efficacy of the investigational product. 


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2 Study Objectives 
2.1 Primary Objectives 
The primary objectives of this study are: 
• To assess efficacy of SM-1 versus placebo as measured by PSG-defined TST 
• To assess efficacy of SM-1 versus 2 additional combination products comprised of 
2 of the 3 components of SM-1 (diphenhydramine plus zolpidem and 
diphenhydramine plus lorazepam) as measured by PSG-defined TST 
2.2 Secondary Objectives 
The secondary objectives of this study are: 
• To assess activity of SM-1 versus placebo and the two 2-drug combination products 
on additional PSG measures of sleep induction and maintenance 
• To assess subject-reported efficacy measures from the Post-Sleep Questionnaire 
(PSQ) 
• To assess the activity of the two 2-drug combination products versus placebo on 
PSG-defined TST, and additional PSG measures of sleep induction and maintenance 
2.3 Safety Objective 
The safety objective of this study is to assess safety of SM-1 in terms of adverse events 
(AEs) and morning measures of alertness (KSS and DSST). 
2.4 Other Objectives 
Other objectives include the assessment of the effect of SM-1 and the two 2-drug 
combination products on sleep stage distribution. 


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3 Investigational Plan 
3.1 Study Design 
This is a randomized, double-blind, single dose, 4-way crossover study to assess the efficacy 
and safety of SM-1 compared with placebo and two 2-drug combination products in subjects 
who report previous transient insomnia. Sleep disturbance will be induced using a 5-hour 
phase advance model with 8 hours (960 30-second epochs) of PSG recording as the primary 
efficacy assay. The study consists of the following periods: screening, treatment and PSG 
periods, and a follow-up safety phone call. 
Screening Period 
Potential subjects will be evaluated during a screening period lasting at least 8 and no more 
than 21 days before the first day of the first treatment period. After signed written informed 
consent is obtained, screening visit (Visit 1) procedures will be performed as specified in the 
schedule of events (Table 6-1). Subjects who satisfy all eligibility criteria will be issued a 
pretreatment paper diary and instructed to record the time they go to bed with the intention of 
sleeping and the time they get up for a minimum of 7 nights, with at least 5 entries completed 
over the 7 nights. Information recorded in the diary will be communicated to study personnel 
no later than 24 hours before check-in for the first day of the first treatment period (Visit 2) to 
allow the calculation of each subject’s median habitual bedtime. Before Visit 2, subjects will 
be contacted by study personnel and told the time and date to present for their first overnight 
visit. Subjects will be advised to eat lunch before check-in due to the long fasting intervals 
required by the study schedule. 
Treatment and Polysomnography Periods 
At Visit 2, subjects will check-in at the study center approximately 7 hours earlier than their 
median habitual bedtime, as calculated from their diary data and will return their paper diary 
to study personnel for review. Visit 2 procedures will be performed as specified in the 
schedule of events (Table 6-1) and according to the timing of sleep study events relative to 
each subject’s habitual bedtime (Table 6-2). Each treatment and PSG period visit will last 
approximately 11 to 12 hours. Once eligibility has been reconfirmed, subjects will be 
randomly assigned to 1 of 4 treatment sequences as shown in Table 3-1. 


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Table 3-1 
Randomized Treatment Sequences 
 
Treatment Period 1 
Visit 2 
Treatment Period 2 
Visit 3 
Treatment Period 3 
Visit 4 
Treatment Period 4 
Visit 5 
Sequence 1 
SM-1 
D+Z 
D+L 
Placebo 
Sequence 2 
D+Z 
D+L 
Placebo 
SM-1 
Sequence 3 
D+L 
Placebo 
SM-1 
D+Z 
Sequence 4 
Placebo 
SM-1 
D+Z 
D+L 
SM-1 = 50-mg diphenhydramine, 5-mg delayed-release zolpidem, and 0.5-mg delayed-release lorazepam; 
D+Z = 50-mg diphenhydramine and 5-mg delayed-release zolpidem; D+L = 50-mg diphenhydramine and 
0.5-mg delayed-release lorazepam; placebo = identical in appearance to SM-1, D+Z, and D+L and has the same 
excipients, but no diphenhydramine, zolpidem, lorazepam, or delated-release coating materials 
Subjects will go to bed (“lights out”) 5 hours ± 30 minutes before their median habitual 
bedtime. Approximately 90 minutes before lights out, baseline DSST measurements will be 
obtained and subjects will be provided a light, low-fat snack (e.g., fruit and crackers). 
Approximately 60 minutes before lights out, PSG electrodes will be applied to the subject 
and the machine will be calibrated. Subjects will be administered their assigned treatment by 
study personnel 30 minutes before lights out and an oral cavity check will be performed to 
assure compliance with treatment. At the assigned lights out time subject will go to bed, PSG 
biocalibration will be performed, and PSG recording will begin. The recording will continue 
for 8 hours. 
At the completion of the 8-hour PSG recording period, subjects will be awakened and 
allowed a bathroom visit. Approximately 30 minutes after the end of PSG recording, subjects 
will complete the PSQ, KSS, and DSST and will be served a standard breakfast. Before 
leaving the study center, subjects will undergo a brief discharge evaluation consisting of 
tandem gait, the Romberg test, and an assessment of vital signs and AEs. Subjects will 
remain at the study center until they are able to pass the evaluation. Upon discharge, subjects 
will be told the time and date to return for the next overnight visit, dispensed a daily washout 
interval diary and instructed to maintain their normal sleep patterns. 
Following a washout interval of no less than 5 days, subjects will return to the study center at 
the assigned time and date and will return their paper diary to study personnel for review. The 
schedule of procedures for Visits 3, 4, and 5 will be the same as for Visit 2 except that 
subjects will be given the next treatment in their randomization sequence (Table 3-1) and 


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lights out will occur at the time established at Visit 2, ± 15 minutes. Subjects will be 
dispensed a new daily washout interval diary at Visits 3, and 4. 
Follow-Up Safety Phone Call 
Within 7 days after completion of Treatment Period 4 (Visit 5), but at least 72 hours after 
administration of the final dose, study personnel will contact the subject for a follow-up 
safety phone call. Outcomes of any AEs will be discussed and recorded. If indicated, a visit 
to the study center for safety assessments will be scheduled. 
From screening to the follow-up safety phone call, assuming a 7-day washout interval 
between each treatment period, subjects will participate in the study for approximately 
8 weeks. 
3.1.1 Rationale of Study Design 
A Phase 2 clinical study of SM-1 was previously conducted using a 5-hour phase advance 
model in subjects who had a history of transient insomnia. The efficacy of SM-1 was 
compared with both placebo and a drug combination product comprised of 2 of the 
3 components of SM-1 (5-mg delayed-release zolpidem plus 0.5-mg delayed-release 
lorazepam) in a 3-way crossover design, with 8 hours of PSG recording for the primary 
efficacy endpoint of TST. The current study will serve to confirm the efficacy, safety, and 
tolerability of SM-1 and will generate data for the additional drug combination arms of 
50-mg diphenhydramine plus 5-mg delayed-release zolpidem and 50-mg diphenhydramine 
plus 0.5-mg delayed-release lorazepam. These additional drug combination arms will serve to 
generate data to assess the contribution of zolpidem and lorazepam to the overall efficacy of 
the investigational product. 
The crossover design enables subjects to serve as their respective controls, thereby increasing 
the efficiency of the study design with respect to the number of subjects that need to be 
treated in order to demonstrate efficacy. The phase advance model is an established approach 
to the assessment of the efficacy of agents being developed to improve sleep. 
Polysomnography offers objective assessment of sleep wake function, enabling a thorough 
understanding of the effect of SM-1 and its components on several aspects of sleep. The 
assessment of next-day effects on morning performance serves to establish the safety of 
SM-1 and to understand possible impacts on ability to conduct normal daily activities. 


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4 Subject Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
Approximately 128 subjects will be screened, and 84 subjects will be randomly assigned to 
receive study drug at 2 study centers in the United States. Subjects will be assigned to study 
drug only if they meet all of the inclusion criteria and none of the exclusion criteria.  
Deviations from the inclusion and exclusion criteria are not allowed. 
4.1.1 Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Is capable of understanding the written informed consent, provides signed and 
witnessed written informed consent, and agrees to comply with protocol requirements. 
2. Is 18 years of age or older at screening. 
3. Reports at least 1 prior episode of transient insomnia meeting all of the following 
criteria: 
• Difficulty falling asleep or staying asleep 
• Next day impairment or distress associated with the disturbed sleep 
• Frequency of 1 to 7 nights per week 
• Duration of less than 1 month or more than 1 month of intermittent episodes 
4. Routinely spends between 6.5 and 9 hours in bed each night with bed time varying no 
more than 2 hours over a week, as confirmed by data from a paper diary completed for 
a minimum of 7 days during the screening period, with at least 5 entries completed 
over the 7 days (≥70% compliance). 
5. Has a body mass index (BMI) between 19 and 32 kg/m2, inclusive at screening. 
6. In the opinion of the investigator, is in good general health as determined by a 
thorough medical, sleep, and psychiatric history review, brief physical examination 
including vital sign measurements, and an assessment of screening laboratory test 
results. 


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7. Female subjects of childbearing potential must be using an acceptable method of 
contraception during the study and for the 30 days following the last dose of study 
drug and must have a negative urine pregnancy test at every study visit. Acceptable 
methods of contraception include oral, intrauterine, transdermal, and injectable 
contraceptives or double barrier methods (e.g., condom plus spermicidal gel or foam). 
Subjects who have been using oral contraceptives for less than 30 days before 
screening must agree to use an additional method of contraception from screening 
until they have been taking oral contraceptives for 30 days. Female subjects of 
non-childbearing potential are not required to use contraception if they have been 
surgically sterilized (tubal ligation, hysterectomy, or bilateral oophorectomy) or are 
postmenopausal as defined by the cessation of menses for a period of at least 2 years 
before screening. 
8. Male subjects must use an acceptable method of contraception during the study and for 
the 30 days following the last dose of study drug. Acceptable methods of contraception 
include: 
a. 
Vasectomy with evidence of a sperm-negative ejaculate 3 months after 
vasectomy 
b. Condom and a female partner who meets one of the following conditions: 
i. Uses oral, intrauterine, transdermal, and injectable contraceptives 
ii. Uses a spermicidal foam/gel/film/cream/suppository 
iii. Uses a diaphragm or cervical/vault cap 
c. 
A female partner who is surgically sterile or postmenopausal 
9. Is willing and able to be confined to the study center for 1 night in each of 4 treatment 
periods as required by the protocol. 
10. Refrains from the use of alcohol within 24 hours of check-in on Visits 2, 3, 4, and 5. 
11. Refrains from napping, defined as any sleep episode occurring outside of the subject’s 
main sleep episode of on days of check-in for Visits 2, 3, 4, and 5. 
12. Has an Epworth Sleepiness Scale (ESS) score ≤8 at screening. 


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4.1.2 Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Females who are pregnant, breast-feeding, or planning a pregnancy during the study 
period. 
2. Clinically significant medical disorder or currently unstable medical condition that, in 
the opinion of the investigator, would confound the results of the study. 
3. An abnormal laboratory value at screening that is judged to be clinically significant as 
determined by the investigator. 
4. History or current evidence of severe hepatic impairment. 
5. Clinically significant psychiatric illness, or the history or presence of a major 
psychiatric illness in the past year. 
6. Any clinically significant abnormal finding on physical examination, as determined by 
the investigator. 
7. Lifetime history of seizure disorder (other than childhood febrile seizures) or serious 
head injury. 
8. History of chronic insomnia or other sleep disorders, such as sleep apnea, narcolepsy, 
parasomnia, restless leg syndrome, or circadian rhythm disorder. 
9. Air travel across more than 2 time zones, an expected change in sleep schedule, or 
involvement in night work or shift work within 1 month before screening or during the 
study period. 
10. Reports a recent history of napping of more than once per week. 
11. History of alcohol or substance use disorder within the year before screening, or 
current evidence of alcohol or substance use disorder as defined by the Diagnostic and 
Statistical Manual of the American Psychiatric Association, 5th Edition. 
12. Self-report of a usual consumption of more than 14 units of alcohol per week. One unit 
of alcohol is equivalent to 12 ounces of beer, 4 ounces of wine, or 1 ounce of liquor. 
13. Regular consumption of greater than 500 mg of caffeine per day. 
14. History of routinely smoking during sleep period. 


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15. Discontinuation of smoking or participation in a smoking cessation program within 
30 days of screening or plans to discontinue smoking during the study. 
16. A positive urine drug screen at screening. 
17. Positive alcohol breathalyzer test at any visit. 
18. History of allergy or known sensitivity, hypersensitivity, or adverse reaction to 
diphenhydramine, zolpidem, or lorazepam or other drugs of the same pharmaceutical 
classes. 
19. Use of any medication which affects sleep-wake function within 5 half-lives or 
2 weeks, whichever is longer, before screening until study completion. This includes 
prescription, over-the-counter (OTC), and herbal (e.g., valerian root, melatonin) 
medications. 
20. Use of any investigational drug within 30 days or 5 half-lives, whichever is longer, 
before screening. 
21. Planned surgery (inpatient or outpatient) during the study period. 
22. Is an employee or family member of the investigator or study center personnel. 
4.2 Withdrawal of Subjects From the Study 
The duration of the study is defined for each subject as the date signed written informed 
consent is provided through the follow-up safety phone call within 7 days after the last dose 
of study drug. 
4.2.1 Reasons for Withdrawal/Discontinuation 
Subjects may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the investigator or at the study center. Every effort should be 
made to keep subjects in the study. The reasons for subjects not completing the study will be 
recorded. A subject may be withdrawn from the study for any of the following reasons: 
1. Failure to continue to meet the protocol inclusion or exclusion criteria. 
2. Noncompliance with the protocol or uncooperativeness. 
3. In the investigator’s opinion, continuation in the study would be detrimental to the 
subject’s well-being. 


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4. Symptoms or an intercurrent illness not consistent with the protocol requirements or 
that justifies withdrawal. 
5. Subject is lost to follow-up. 
6. Other (e.g., pregnancy, development of contraindications of use of study drug). 
7. The subject withdraws consent or the investigator or sponsor decides to discontinue 
the subject’s participation in the study. 
The investigator will also withdraw a subject if Sequential Medicine, Ltd terminates the 
study. Upon occurrence of a serious or intolerable AE, the investigator will confer with the 
medical monitor. If a subject is discontinued because of an AE, the event will be followed 
until it is resolved. Any subject may withdraw his or her consent at any time. 
4.2.2 Handling of Withdrawals 
Subjects are free to withdraw from the study or from receiving study drug at any time upon 
request. Subject participation in the study may be stopped at any time at the discretion of the 
investigator or at the request of the sponsor. 
Subjects who discontinue study drug or active participation in the study will no longer 
receive study drug. When a subject withdraws from the study, the reason(s) for withdrawal 
shall be recorded by the investigator on the relevant page of the electronic case report form 
(eCRF). 
Whenever possible, all subjects who discontinue study drug or withdraw from the study 
prematurely will be contacted within 24 hours of the final dose of study drug for a follow-up 
safety phone call (Visit 6). The outcomes of any AEs will be discussed and recorded. If 
indicated, a visit to the study center for safety assessments will be scheduled. Nonserious 
AEs that are ongoing at the subject’s last study visit or follow-up safety phone call must be 
followed until resolution or for 30 days after the subject’s last study drug dose, whichever 
comes first. 
Subjects who are unable to be reached for the follow-up safety phone call will continue to be 
contacted by the study center in an attempt to have them comply with the protocol 
(2 documented telephone calls followed by 1 registered letter). 


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It is vital to obtain follow-up data on any subject withdrawn because of an AE or serious AE 
(SAE). In every case, efforts must be made to undertake protocol-specified, safety follow-up 
procedures. All data collected from all subjects, including early withdrawals and early 
discontinuations of treatment, will be used in the reporting and analysis of the study. 
4.2.3 Replacements 
Subject who discontinue study drug or withdraw from the study prematurely will not be 
replaced. 


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5 Study Treatments 
5.1 Method of Assigning Subjects to Treatment Groups 
Subjects will be randomly assigned equally to 1 of 4 treatment sequences, as presented in 
Table 3-1. 
The Pharmaceutical Product Development, LLC (PPD) biostatistics department will generate 
the randomization schedules and randomization will be performed manually. Subjects will be 
assigned kit numbers in sequential order within each site. Within each assigned kit, 4 bottles 
will be labeled with the study visit (Visit 2, 3, 4, and 5) at which the study drug inside the 
bottle is to be administered per the subject’s randomization sequence. The randomization 
schedule will also use an appropriate block size, which will not be revealed. No stratification 
will be used in this study. 
5.2 Treatments Administered 
For each treatment period (Visits 2, 3, 4, and 5), 30 minutes before each subject’s lights out 
time (5 hours ± 30 minutes before the subject’s median habitual bedtime), a single dose of 
study drug will be administered according to the subject’s treatment sequence randomization. 
All doses of study drug will be administered orally by study personnel with 250 mL of water. 
An oral cavity check will be performed to assure compliance with treatment.  
5.3 Identity of Investigational Product 
The SM-1 study drug contains 50-mg diphenhydramine, 5-mg delayed-release zolpidem, and 
0.5-mg delayed-release lorazepam as active ingredients. 
The 2-drug combination D+Z study drug contains 50-mg diphenhydramine and 5-mg 
delayed-release zolpidem as active ingredients. 
The 2-drug combination D+L study drug contains 50-mg diphenhydramine and 0.5-mg 
delayed-release lorazepam as active ingredients. 
The SM-1, D+Z, and D+L capsules are all Size 0 white capsules and contain the inactive 
excipients PROSOLV® SMCC HD 90, starch 1500, and magnesium stearate. Delayed-release 
coating materials include Eudragit L100-55, Eudragit L100, and Eudragit S100. 


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The placebo is identical in appearance to SM-1, D+Z, and D+L, and has the same excipients, 
but no diphenhydramine, zolpidem, lorazepam, or delayed-release coating materials. 
5.4 Management of Clinical Supplies 
5.4.1 Study Drug Packaging and Storage 
Study drug for each individual subject will be supplied in a single kit of 4 bottles. Each bottle 
contains a single dose of SM-1, D+Z, D+L, or placebo. Bottles will be labeled for the visit at 
which the dose of study drug should be administered (e.g., Visit 2, 3, 4, or 5) according to the 
subject’s randomization sequence. All packaging and labeling operations will be performed 
according to Good Manufacturing Practice for Medicinal Products and the relevant 
regulatory requirements. 
At the study center, study drug must be stored in a secure area (e.g., a double-locked cabinet), 
protected from moisture, and kept at a controlled room temperature 15°C to 25°C (59°F to 
77°F). 
Further details on study drug packaging, labelling, storage, and administration instructions 
are provided in the Pharmacy Manual. 
5.4.2 Study Drug Accountability 
The investigator will maintain accurate records of receipt of all test articles, including dates 
of receipt. In addition, accurate records will be kept regarding when and how much test 
article is dispensed and used by each subject in the study. Reasons for departure from the 
expected dispensing regimen must also be recorded. At the completion of the study, to satisfy 
regulatory requirements regarding drug accountability, all study drug will be reconciled and 
retained or destroyed according to applicable regulations. 
5.4.3 Other Supplies 
Urine dipsticks for urine pregnancy testing and on-site drug screening, an alcohol 
breathalyzer, and a tape measure to complete part of the STOP-Bang questionnaire will be 
provided to study centers. 


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5.5 Blinding 
The study will be performed in a double-blind manner, with the subjects, investigator, and 
study center staff being blinded to the identity of study drug. All study drug will be supplied 
in identical packaging and will be identical in color, smell, taste, and appearance to enable 
double-blind conditions. 
5.5.1 Breaking the Blind 
A subject’s treatment assignment will not be broken until the end of the study unless medical 
treatment of the subject depends on knowing the study drug the subject received. In the event 
that the blind needs to be broken because of a medical emergency, the 
investigator/subinvestigator may instruct the unblinded study personnel to reveal an 
individual subject’s treatment allocation. A sealed copy of each subject’s randomization 
scheme will be retained at the study center and treatment assignment will be unblinded by an 
individual delegated the responsibility for unblinding treatment assignment. Before 
unblinding a subject’s treatment assignment, the investigator/subinvestigator should make 
every effort to contact the medical monitor to discuss the medical emergency and the reason 
for revealing the actual treatment received by that subject. If a subject’s treatment is 
unblinded, the sponsor must be notified immediately. Reasons for treatment unblinding must 
be clearly explained and justified in the subject’s eCRF. The date on which the blind was 
broken together with the identity of the person responsible for breaking the blind must also 
be documented. Please refer to the supplemental instructions in the Unblinded Process 
Document. 
5.6 Treatment Compliance 
Doses of study drug will be administered by study personnel and an oral cavity check will be 
performed to assure compliance with treatment. 
5.7 Prior and Concomitant Therapy 
The use of concomitant medications during this study is discouraged, unless required to treat 
AEs. The use of other concomitant medications should be approved by the investigator and 
sponsor (or designee) before subjects enroll in the study. 


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Any prior therapy within the 30 days before screening or concomitant therapy taken by a 
subject during the course of the study will be documented, along with the reason for its use. 
Use of all concomitant medications will be recorded in the subject’s eCRF. Concomitant 
medications will include all prescription drugs, OTC medications, herbal products, vitamins, 
minerals, and nutritional supplements. The minimum requirement is that medication name 
and the dates of administration are to be recorded. Any changes in concomitant medications 
will also be recorded in the subject’s eCRF. 
Any concomitant medication deemed necessary for the welfare of the subject during the 
study may be given at the discretion of the investigator. However, it is the responsibility of 
the investigator to ensure that details regarding the medication are recorded in full in the 
eCRF. 
5.7.1 Prohibited Medications and Therapies 
For the duration of the study, starting with signature of the informed consent, consumption or 
use of the following medications and therapies is prohibited: 
• Any medication which affects sleep-wake function. This includes prescription, OTC, 
and herbal (e.g., valerian root, melatonin) medications. 
• Illicit drugs or drugs prescribed for any individual except the subject 
• Marijuana, marijuana oil, or extracts of marijuana containing cannabinoids 
• Any investigational drug 
In general, subjects are prohibited from using any prescription or OTC medications or 
alternative medicinal products (e.g., homeopathic preparations and herbal or dietary 
supplements) that may affect the outcome of the study. Use of vitamins, acetaminophen, or 
hormonal contraceptives during the study is permitted. 


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5.7.2 Restrictions 
A subject’s consumption of alcohol during the study is not to exceed 14 units of alcohol per 
week: 1 unit of alcohol is equivalent to 12 ounces of beer, 4 ounces of wine or 1 ounce of 
liquor. Subjects are not to consume greater the 500 mg of caffeine per day. Subjects are not to 
smoke during their sleep period. Furthermore, subjects should not discontinue smoking or 
participate in a smoking cessation program within 30 days of screening, or plan to 
discontinue smoking during the study.  
On check-in days for PSG recording (Day 1 of each treatment and PSG period), subjects will 
be instructed to maintain their normal daily activities and not do anything unusual or engage 
in excessively strenuous activity. Subjects will be advised to eat lunch before check-in due to 
the long fasting intervals required by the study schedule. Subjects are to refrain from the use 
of alcohol and from napping, defined as any sleep episode occurring outside of the subject’s 
main sleep episode of the day. To the extent possible, subjects are to avoid consuming any 
caffeinated beverage or caffeinated food (e.g., chocolate) for 5 hours before administration of 
study drug. Study drug will be administered with 250 mL of water and no additional water 
will be allowed until completion of all post-PSG activities. 


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6 Study Assessments and Procedures 
Before performing any study procedures, each potential subject will sign an informed 
consent form (ICF). Subjects will have the opportunity to have any questions answered 
before signing the ICF. The investigator must address all questions raised by the subject. The 
investigator will also sign the ICF. 
6.1 Study Visits 
The schedule of events by study visit for this study is presented in Table 6-1. The timing of 
study procedures upon check-in to the study center during Treatment Periods 1, 2, 3, and 4 is 
presented in Table 6-2. Detailed instructions for the conduct of study assessments and 
procedures will be described in the study manual. 


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Table 6-1 
Schedule of Events 
 
Screeninga 
Treatment and Polysomnography Periodsb 
Follow-Up Safety 
Phone Callb 
 
Period 1 
Period 2 
Period 3 
Period 4 
Study Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Study Day 
Day –21 to Day–8  
Day 1 
Day 8 
Day 15 
Day 22 
3-7 days postdose 
Assessments 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical/psychiatric/medication history 
X 
 
 
 
 
 
Sleep historyc 
X 
 
 
 
 
 
Epworth Sleepiness Scale 
X 
 
 
 
 
 
Brief physical examinationd 
X 
 
 
 
 
 
Vital sign measurementse 
X 
X 
X 
X 
X 
 
Urine pregnancy test (females of 
childbearing potential) 
X 
X 
X 
X 
X 
 
Urine drug screen 
X 
 
 
 
 
 
Alcohol breath test 
X 
X 
X 
X 
X 
 
Clinical laboratory assessmentsf 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Paper sleep diary issuedg 
X 
X 
X 
X 
 
 
Diary return and review 
 
X 
X 
X 
X 
 
Study center check-in for overnight visith 
 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
Xi 
Concomitant medications 
X 
X 
X 
X 
X 
 
Randomizationj 
 
X 
 
 
 
 
Treatment administration 
 
X 
X 
X 
X 
 


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Screeninga 
Treatment and Polysomnography Periodsb 
Follow-Up Safety 
Phone Callb 
 
Period 1 
Period 2 
Period 3 
Period 4 
Study Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Study Day 
Day –21 to Day–8  
Day 1 
Day 8 
Day 15 
Day 22 
3-7 days postdose 
Assessments 
 
 
 
 
 
 
Polysomnography 
 
X 
X 
X 
X 
 
Post-Sleep Questionnaire 
 
X 
X 
X 
X 
 
Karolinska Sleepiness Scale 
 
X 
X 
X 
X 
 
Digit Symbol Substitution Test training 
X 
 
 
 
 
 
Digit Symbol Substitution Test 
 
X 
X 
X 
X 
 
Predischarge evaluationk 
 
X 
X 
X 
X 
 
a 
Potential subjects will be evaluated during a screening period lasting at least 8 and no more than 21 days before the first day of the first treatment period. 
b 
Example study days are shown for a 1-week washout interval. Washout intervals must be no less than 5 days. Actual study days for Treatment Periods 2, 3, 
and 4 and the follow-up safety phone call will depend on the length of interdose washout intervals. 
c 
Sleep history will be assessed using the STOP-Bang questionnaire, which includes 4 subjective items (STOP: snoring, tiredness, observed apnea, and high 
blood pressure) and 4 demographics items (Bang: body mass index, age, neck circumference, and gender). 
d 
A brief physical examination will include evaluation of height (meters); body weight (kg); appearance; skin; head and neck; eyes, ears, nose, and throat; 
chest and lungs; heart; abdomen; and extremities. Each subject’s height and weight measured at screening will be used to calculate their body mass index. 
e 
Vital sign measurements will include pulse, blood pressure, and respiration rate. All vital signs will be measured after the subject has been supine for 
5 minutes. On polysomnography recording days, vital signs will be measured at check-in approximately 7 hours earlier than each subject’s median habitual 
bedtime and again before discharge from the study center. 
f 
Clinical laboratory assessments will include hematology, chemistry, electrolytes, liver function tests, and renal function parameters. 
g 
Subjects are to record the time they go to bed with the intention of sleeping and the time they get up in a pretreatment paper diary for a minimum of 7 days 
during the screening period, with at least 5 entries completed over the 7 days (≥70% compliance). Information recorded in the diary will be communicated to 
study personnel no later than 24 hours before check-in at Visit 2 to allow the calculation of each subject’s median habitual bedtime. Subjects will return their 
paper diary to study personnel at each visit during the treatment and PSG period. Upon discharge from the study center at Visits 2, 3, and 4, subjects will be 
dispensed a new daily washout interval diary to record the time they went bed with the intention of sleeping and the time they got up. Subjects will be 
instructed to maintain their normal sleep patterns. 


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h 
Before Visit 2, subjects will be contacted by study personnel and told the time and date to present for their first overnight visit. Table 6-2 describes the timing 
of study procedures upon check in to the study center. Upon discharge from the study center at Visits 2, 3, and 4, subjects will be told the time and date to 
return for the next overnight visit. 
i 
Subjects will be contacted by phone for a safety follow-up within the 7 days after completion of Treatment Period 4 (Visit 5) but at least 72 hours after 
administration of the final dose of study drug. Subjects who discontinue study drug or withdraw from the study prematurely will be contacted within 
24 hours of the final dose of study drug. Outcomes of any adverse events will be discussed and recorded. If indicated, a visit to the study center for safety 
assessments will be scheduled.  
j 
Once eligibility has been reconfirmed at Visit 2, subjects will be randomly assigned to 1 of 4 treatment sequences. Subjects will be crossed-over to their next 
treatment at each visit based on their treatment sequence randomization. 
k 
Before leaving the study center at Visits 2, 3, 4, and 5, subjects will undergo a brief discharge evaluation consisting of tandem gait and the Romberg test. 
 


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Table 6-2 
Sleep Study Events by Day for Treatment Periods 1, 2, 3, and 4 
Treatment 
Period Day 
Time Relative to 
Habitual Bedtime 
Time Relative to 
Lights Out/Waking 
Procedurea 
Day 1 
Approximately 7 hours 
before 
Approximately 
120 minutes before 
lights out 
• 
Subjects report to the study center 
• 
Alcohol breathalyzer administered 
• 
Urine pregnancy testing performed for females 
of childbearing potential 
• 
Return and review diary 
• 
Pretreatment assessment of adverse events 
• 
Update concomitant medications and therapies 
•
Vital signs measured 
Approximately 6.5 hours 
before 
Approximately 
90 minutes before 
lights out 
• 
Baseline Digit Symbol Substitution Test 
measurement obtained 
• 
Subjects provided a light, low-fat snack (e.g., 
fruit and crackers) 
Approximately 6 hours 
before 
Approximately 
60 minutes before 
lights out
• 
PSG electrodes applied to the subject and 
machine calibrated 
5.5 hours before 
30 minutes before 
lights out 
• 
Subjects administered dose of study drug 
• 
Oral cavity check performed administered 
Period 1: 5 hours 
± 30 minutes before 
Period 2, 3, and 4: Same as 
Period 1 ± 15 minutes before 
Lights out 
• 
Subjects go to bed 
• 
PSG biocalibration 
• 
Begin PSG recording 
Day 2 
— 
Waking  
(8 hours after lights 
out) 
• 
End PSG recording 
• 
Subjects awakened and allowed a bathroom 
visit 
— 
30 minutes after 
waking  
(8.5 hours after lights 
out) 
• 
Subjects complete the morning assessments in 
the following order: 
1. 
Post-Sleep Questionnaire 
2. 
Karolinska Sleepiness Scale 
3. 
Digit Symbol Substitution Test 
• 
Subjects served a standard breakfast 
• 
Before leaving the study center, subjects 
undergo a predischarge evaluation consisting of 
tandem gait and the Romberg test, as well as an 
assessment of vital signs and adverse events to 
determine whether they may be safely 
discharged from the study center. 
• 
Subjects who pass this evaluation will be 
discharged from the study center. Failure will 
be considered an adverse event, and subjects 
will remain at the study center until able to pass.
Abbreviation: PSG, polysomnography  
a 
Procedures must be conducted in the order they appear in the bulleted list. 


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6.2 Screening Assessments 
Screening assessments will include medical history and other information, sleep history, vital 
sign measurements, physical examination, ESS, drug and alcohol screen, laboratory 
assessments and urine pregnancy test for females of childbearing potential. 
6.2.1 Medical History and Other Information 
Medical history information will be collected at screening and should include (but not be 
limited to) demographic information, current and past medical conditions, current and past 
medications, and current and past psychiatric conditions. This information must be 
documented in the subject’s study chart before random assignment of study drug and also 
recorded in on the appropriate eCRF pages. In addition to conventional medical and 
psychiatric history, information pertaining the subject’s average alcohol and caffeine 
consumption and average tobacco usage should be recorded in the eCRF. 
6.2.2 Sleep History 
Subject sleep history will be assessed by the investigator at screening to confirm subject 
eligibility for the study. In addition, the STOP-Bang questionnaire will be completed for each 
subject (STOP-Bang, 2012). The questionnaire, a simple, self-reportable paper screening 
tool, consists of 8 dichotomous (yes/no) items related to the clinical features of obstructive 
sleep apnea (OSA). It includes 4 subjective items (STOP: snoring, tiredness, observed apnea, 
and high blood pressure) and 4 demographics items (Bang: BMI, age, neck circumference, 
and gender). The total score ranges from 0 to 8 and subjects can be classified for OSA risk 
based on their respective scores. Subjects with a STOP-Bang score of 0 to 2 can be classified 
as low risk for moderate to severe OSA whereas those with a score of 5 to 8 can be classified 
as high risk for moderate to severe OSA. In subjects whose STOP-Bang scores are in the 
midrange (3 or 4), further criteria are required for classification. An example of the 
STOP-Bang questionnaire is presented in Appendix 12.1. 
6.2.3 Vital Sign Measurements 
Vital sign measurements will include pulse, blood pressure, and respiration rate. All vital 
signs will be measured after the subject has been supine for 5 minutes. 


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6.2.4 Physical Examination 
A brief physical examination will be performed at screening and should include evaluation of 
height (meters); body weight (kg); appearance; skin; head and neck; eyes, ears, nose, and 
throat; chest and lungs; heart; abdomen; and extremities. All physical examination findings 
must be documented in the subject’s study chart and also recorded in the eCRF. 
The subject’s height and weight measured at screening will be used to calculate BMI used for 
the STOP-Bang questionnaire and to ensure that the subject meets the BMI entry criterion. 
6.2.5 Epworth Sleepiness Scale 
The ESS, completed by each subject at the screening visit, is a self-administered paper 
questionnaire consisting of 8 questions (Johns, 1990; Johns, 1991; Johns, 1992; Johns, 2000). 
It provides a measure of a person’s general level of daytime sleepiness, or their average sleep 
propensity in daily life. Subjects rate, on a 4-point scale (0 – 3), their usual chances of dozing 
off or falling asleep in 8 different situations or activities that most people engage in as part of 
their daily lives. The total ESS score is the sum of 8 item scores and can range between 0 and 
24. The higher the score, the higher the person’s level of daytime sleepiness. Eligible subjects 
must have an ESS score ≤8 at screening. An example of the ESS is presented in 
Appendix 12.2. 
6.2.6 Drug and Alcohol Screen 
Each subject’s urine will be screened on-site by dipstick. In addition, the subject will undergo 
an alcohol breath test. Any subject who tests positive for any drug or alcohol at screening 
will be excluded from participating in the study. 
6.2.7 Laboratory Assessments 
Clinical laboratory assessments performed on samples of blood collected at screening will 
include hematology, chemistry, electrolytes, liver function tests, and renal function 
parameters. 
 
 


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6.2.8 Urine Pregnancy Test 
A urine pregnancy test will be performed at screening for female subjects who are of 
childbearing potential. If the urine pregnancy test at screening is positive, the subject will not 
be eligible to participate in the study. 
6.2.9 Pretreatment Sleep Diary 
At the screening visit, subjects who satisfy all eligibility criteria will be issued a pretreatment 
paper diary and instructed to record the time they went bed with the intention of sleeping and 
the time they got up for a minimum of 7 days during the screening period, with at least 
5 entries completed over the 7 days (≥70% compliance). Information recorded in the diary 
will be communicated to study personnel no later than 24 hours before check-in for Visit 2 to 
allow the calculation of each subject’s median habitual bedtime. 
6.3 Efficacy Assessments 
Polysomnography data will be the primary source for efficacy endpoints, including TST, 
WASO, latency to persistent sleep (LPS), number of awakenings (NAW), and TST by quarter 
of the night. Subject-reported efficacy measures will be assessed from data collected from the 
PSQ, which includes subject self-reporting of time to sleep onset, NAW, wake time during 
the night, TST, and sleep quality. The PSQ data will be used to determine subjective TST 
(sTST) and subjective sleep onset latency (sSOL). Subjects will also be required to complete 
a daily diary during each interdose washout interval. 
6.3.1 Polysomnography 
Each night of PSG for each treatment period (Visits 2, 3, 4, and 5) will consist of an 8-hour 
(960 30-second epochs) assessment during which electroencephalographic, 
electrooculographic, electrocardiographic, and submental electromyographic activity will be 
recorded according to methods consistent with the standards of the American Academy of 
Sleep Medicine. 
Polysomnography recordings will begin at bed time (lights out) 5 hours ± 30 minutes before 
the subject’s median habitual bedtime calculated from each subject’s diary data at screening. 
Approximately 60 minutes before lights out, PSG electrodes will be applied to the subject 
and the machine will be calibrated. At the assigned lights out time, PSG biocalibration will 


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be performed. Once the PSG recordings begin, they will continue for 8 hours. Subjects will 
be required to remain in bed for the duration of the PSG recording period, except for 
interruptions to use the bathroom. 
All PSG recordings will be scored blind by a central site: 
Clinilabs, Inc 
423 W. 55th Street 
New York, NY 10019 USA 
Polysomnography recordings will provide all the data for the efficacy measures previously 
listed as well as the percentage and number of minutes of sleep stages NI, N2, N3, rapid eye 
movement (REM), and latency to REM sleep onset that will be used to assess sleep stage 
distribution for other analyses. 
6.3.2 Post-Sleep Questionnaire 
The PSQ includes subject self-reporting of time to sleep onset, NAW, wake time during the 
night, TST, and sleep quality. An example of the questions included in the PSQ is presented 
in Appendix 12.3. 
6.3.3 Washout Interval Sleep Diary 
Subjects will return their paper diary to study personnel at each visit during the treatment and 
PSG period. Upon discharge from the study center at Visits 2, 3, and 4, subjects will be 
dispensed a new daily washout interval diary to record the time they went bed with the 
intention of sleeping and the time they got up. Subjects will be instructed to maintain their 
normal sleep patterns. Washout intervals must be no less than 5 days.  
6.4 Safety Assessments 
Safety and tolerability will be assessed in terms of the incidence, severity and relationship to 
treatment of AEs, and by morning measures of alertness (KSS and DSST). In addition, safety 
assessments will include alcohol screening, urine pregnancy testing for women of 
childbearing potential, vital sign measurements, and predischarge evaluations. 


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6.4.1 Adverse Events 
6.4.1.1 Definitions of Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or their clinical significance. 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study 
regardless of its causal relationship to study drug. 
A treatment-emergent AE is defined as any event not present before exposure to study drug 
or any event already present that worsens in either intensity or frequency after exposure to 
study drug. 
An SAE is defined as any event that results in death, is immediately life threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability/incapacity, or is a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life threatening, or require hospitalization may be 
considered SAEs when, based upon appropriate medical judgment, they may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that 
do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
6.4.1.2 Eliciting and Documenting Adverse Events 
Adverse events will be assessed starting from the time the subject provides signed written 
informed consent and must be followed until resolution or for 30 days after the subject’s last 
study drug dose, whichever comes first. 
At every study visit, subjects will be asked a nonleading question to elicit any medically 
related changes in their well-being. They will also be asked if they have been hospitalized, 
had any accidents, used any new medications, or changed concomitant medication regimens 
(e.g., prescription and OTC medications, nutritional supplements, herbal remedies). 


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6.4.1.3 Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF. 
Information to be collected includes drug treatment, dose, event term, time of onset, 
investigator-specified assessment of severity and relationship to study drug, time of 
resolution of the event, seriousness, any required treatment or evaluations, and outcome. 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states must also be reported. 
All AEs will be followed to adequate resolution. The Medical Dictionary for Regulatory 
Activities (MedDRA) will be used to code all AEs. 
Any medical condition that is present at the time that the subject is screened but does not 
change should not be reported as an AE; however, if it changes in severity, frequency, or 
intensity at any time during the study, it should be recorded as an AE. 
Any AE that meets SAE criteria (Section 6.4.1.1) must be entered into the electronic data 
capture (EDC) system immediately (i.e., within 1 business day) after the study center 
personnel first learn about the event. Once the qualifying SAE data are entered, PPD 
Pharmacovigilance will be notified by an email alert, which will contain high-level safety 
information. Additional safety information will be obtained from the EDC system via 
applicable eCRF pages. If the EDC system is not available, the study center should send a 
completed manual paper SAE report form to PPD Pharmacovigilance by fax: 
• Safety Fax Line: 1-888-488-9697 
When the EDC system is again available, the study center must enter all applicable 
information into the EDC system. All supporting source information concerning the SAE 
(e.g., hospital records) should be provided by fax or email. 
If there is a question concerning an SAE, the study center needs guidance regarding reporting 
of an SAE, the study center is returning a call from a PPD safety specialist, or the study 
center urgently needs to report an SAE or make PPD Pharmacovigilance aware of an SAE, 
the Safety Hotline should be used: 
• Safety Hotline: 1-888-483-7729 


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If a study center makes an initial report of an SAE via the Safety Hotline, the study center 
must subsequently enter all applicable information into the EDC system immediately 
thereafter. 
All SAEs must be reported starting from the time that signed written informed consent for 
study participation is provided. If the investigator becomes aware of an SAE within 30 days 
after the subject’s last dose of study drug, the SAE must be reported. Serious AEs must be 
followed until the event resolves, the event or sequelae stabilize, or it is unlikely that 
additional information can be obtained after demonstration of due diligence with follow-up 
efforts (i.e., the subject or health care practitioner is unable to provide additional information, 
or the subject is lost to follow up). Serious AEs that occur more than 30 days after the last 
dose of study drug need not be reported unless the investigator considers them related to 
study drug. 
6.4.1.4 Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the subject’s 
daily activities. The intensity of the AE will be rated as mild, moderate, or severe using the 
following criteria: 
Mild: 
These events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
Moderate: 
These events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
normal functioning. 
Severe: 
These events interrupt a subject’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating.  
 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events characterized 
as intermittent do not require documentation of onset and duration of each episode. 
6.4.1.5 Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 


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study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 
The relationship or association of the study drug in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
Unrelated: 
This relationship suggests that there is no association between the study drug 
and the reported event. 
Possible: 
This relationship suggests that treatment with the study drug caused or 
contributed to the AE, i.e., the event follows a reasonable temporal sequence 
from the time of drug administration or follows a known response pattern to the 
study drug, but could also have been produced by other factors. 
Probable: 
This relationship suggests that a reasonable temporal sequence of the event 
with drug administration exists and, based upon the known pharmacological 
action of the drug, known or previously reported adverse reactions to the drug 
or class of drugs, or judgment based on the investigator’s clinical experience, 
the association of the event with the study drug seems likely. The event 
disappears or decreases on cessation or reduction of the dose of study drug. 
Definite: 
This relationship suggests that a definite causal relationship exists between drug 
administration and the AE, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do 
not appear to explain the event. The event reappears or worsens if the study 
drug is re-administered. 
6.4.1.6 Follow-Up of Subjects Reporting Adverse Events 
Adverse events assessed as nonserious will be reported through the 7 days following the 
subject’s last dose of study drug (the follow-up safety phone call) or until the last study visit, 
whichever is later. Outcomes of any ongoing AEs will be discussed and recorded during the 
follow-up safety phone call and, if indicated, a visit to the study center for safety assessments 
will be scheduled. Nonserious AEs that are ongoing at the subject’s last study visit or follow-
up safety phone call must be followed until resolution or for 30 days after the subject’s last 
study drug dose, whichever comes first. 
6.4.2 Alcohol Screen 
Upon check-in to the study center at Visits 2, 3, 4, and 5, subjects subject will undergo an 
alcohol breath test. Any subject who tests positive for alcohol will not be administered study 
drug. 


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6.4.3 Urine Pregnancy Test 
Upon check-in to the study center at Visits 2, 3, 4, and 5, a urine pregnancy test will be 
performed for female subjects who are of childbearing potential. If a urine pregnancy test 
performed after assignment of study drug is positive, it should be confirmed by a serum 
pregnancy test. If a female subject is pregnant, she must be discontinued from the study. 
6.4.4 Karolinska Sleepiness Scale 
The KSS, completed on paper by each subject after waking at Visits 2 through 5, is a 
self-report instrument on which subjects rate their sleepiness on a 9-point, verbally anchored 
scale (Akerstedt T and Gillberg M 1990; Akerstedt T et al 2014). Categories and scores range 
from “extremely alert” (score = 1), “alert” (score = 3), “neither alert nor sleepy” (score = 5), 
“sleepy-but no difficulty remaining awake” (score = 7), and “extremely sleepy/fighting 
sleep” (score = 9). The steps in between have a scale value but no verbal label. An example 
of the KSS is presented in Appendix 12.4. 
6.4.5 Digit Symbol Substitution Test 
The DSST is a measure of attention, perceptual speed, motor speed, visual scanning, and 
memory. The DSST consists of 9 digit-symbol pairs, followed by a list (rows) of digits. 
Under each digit is an open field where the subject is asked to write down on paper the 
corresponding symbol as quickly as possible. The key outcome parameter for the DSST is the 
number of correct responses in 90 seconds. An example of the DSST is presented in 
Appendix 12.5. 
During the screening visit, subjects will be trained on how to complete the DSST until they 
are considered proficient. Subjects will then complete the DSST approximately 90 minutes 
before lights out in each treatment period (Visits 2, 3, 4, and 5) to provide a baseline 
assessment. The DSST will be repeated approximately 30 minutes after waking in each 
treatment period. 
6.4.6 Vital Sign Measurements 
Vital signs will be measured at check-in and before discharge from the study center at 
Visits 2, 3, 4, and 5. Details of the vital sign measurements are presented in Section 6.2.3. 


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6.4.7 Predischarge Evaluation 
Before leaving the study center at Visits 2, 3, 4, and 5, subjects will undergo a predischarge 
evaluation consisting of tandem gait and the Romberg test to assess whether they may be 
safely discharged from the study center. Subjects who pass this evaluation will be discharged 
from the study center. Failure will be considered an AE, and subjects will remain at the study 
center until they are able to pass. 
6.5 Pregnancy 
Pregnancy is not regarded as an AE unless there is a suspicion that an investigational product 
may have interfered with the effectiveness of a contraceptive medication. Any pregnancy that 
occurs during study participation must be reported to PPD Pharmacovigilance within 2 weeks 
of learning of its occurrence, using the EDC system (Section 6.4.1.3). The pregnancy must be 
followed-up to determine outcome (including spontaneous miscarriage, elective termination, 
normal birth, or congenital abnormality) and status of mother and child, even if the subject 
was discontinued from the study. Pregnancy complications and elective terminations for 
medical reasons must be reported as an AE or SAE. Spontaneous miscarriages must be 
reported as an SAE. 
Any SAE occurring in association with a pregnancy, brought to the investigator’s attention 
after the subject has completed the study, and considered by the investigator as possibly 
related to the study drug, must be promptly reported to PPD. 
6.6 Laboratory Analyses 
Clinically significant safety assessments and laboratory analyses that are associated with the 
underlying condition, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs. 
Laboratory analyses are reportable as AEs or SAEs if they are actionable, but not solely 
based on an abnormal result. 
6.7 Sample Collections 
Instructions for sample collection, handling, and shipping will be presented in a separate 
study manual that will be provided to study center as a separate document. 


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7 Statistical and Analytical Plan 
All personnel involved with the analysis of the study will remain blinded until database lock. 
A comprehensive statistical analysis plan will be prepared before unblinding. Any subsequent 
amendments will be documented, with final amendments completed before unblinding of the 
data.  
7.1 Primary Efficacy Endpoints 
The primary efficacy endpoint for this study is TST on an 8-hour PSG comparing SM-1 
versus placebo, SM-1 versus D+Z, and SM-1 versus D+L.  
7.2 Secondary Efficacy Endpoints 
The comparison of SM-1 versus placebo, SM-1 versus D+Z, and SM-1 versus D+L for data 
collected from PSG recordings and PSQ responses will be performed on WASO, LPS, NAW, 
sTST, sSOL, and TST by quarters of the night. The comparison of D+Z versus placebo and 
D+L versus placebo for data collected from PSG recordings and PSQ responses will be 
performed on TST, WASO, LPS, NAW, sTST, sSOL, and TST by quarters of the night. 
7.3 Safety and Other Endpoints 
Safety endpoints include: 
• Incidence, severity, and relationship to treatment of AEs 
• Karolinska Sleepiness Scale 
• Digit Symbol Substitution Test  
Other endpoints include percentage and number of minutes of sleep stages NI, N2, N3, and 
REM, and latency to REM sleep onset. 
7.4 Sample Size Calculations 
Sample size is estimated based on the following assumptions: 
1. The difference in TST between SM-1 and placebo is 120 minutes, 


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2. The difference in TST between SM-1 and each of the two 2-drug combination 
products is 44 minutes, 
3. The standard deviation of TST (defined as the square root of the within mean square 
error from a repeated measures analysis of variance [ANOVA]) is 88 minutes. 
A minimum of 68 blinded subjects will be able to ensure 80% power to detect treatment 
difference between SM-1 and all 3 controls (D+Z, D+L, and placebo) at a 2-sided 0.05 
significance level. Approximately 84 subjects will be randomly assigned to receive study 
drug. 
A blinded interim analysis will be performed after approximately 50% of blinded subjects 
have completed the study to allow for an option to increase the sample size (see Section 
7.7.5). 
7.5 Analysis Sets 
The following analysis sets will be used in the statistical analyses: 
Full analysis set (FAS): The FAS will consist of all subjects who were randomly assigned to 
receive double-blind study drug and have taken any study drug during the prescribed 
treatment period. All analyses using the FAS will group subjects according to randomized 
treatment. 
Modified FAS (mFAS): The mFAS will consist of all subjects included in the FAS, grouped 
according to randomized treatment. The mFAS will exclude any subjects from the FAS that 
may have become unblinded during the study. 
Per-protocol set (PPS): The PPS will consist of all FAS subjects who fulfill all eligibility 
criteria, have taken all 4 doses of study drug, have not taken any prohibited medication, and 
have no significant protocol deviations. All analyses using the PPS will group subjects 
according to actual treatment received. 
Safety set: The safety set will consist of all subjects who received any study drug. All 
analyses using the safety set will group subjects according to actual treatment received. 


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The mFAS will be used for the primary efficacy analyses. The FAS and PPS will be used for 
sensitivity analyses of the primary efficacy endpoint. The mFAS and FAS will be used for the 
secondary efficacy analyses and other analyses. The safety set will be used for the safety 
analyses. 
7.6 Description of Subgroups to be Analyzed 
Subgroup analysis of the primary efficacy endpoint will be performed by sex (male vs 
female) and age (greater than median vs less than median). 
7.7 Statistical Analysis Methodology 
Statistical analysis will be performed using SAS software Version 9.2 or later. Continuous 
variables will be summarized using the mean, SD, median, minimum value, and maximum 
value. Categorical variables will be summarized using frequency counts and percentages. 
Data will be provided in by-subject data listings. 
Details of the statistical analyses, methods, and data conventions are described in the 
statistical analysis plan. 
All statistical tests will be 2-sided and performed using a 5% significance level, leading to 
95% 2-sided CIs. The overall study wide type I error rate (alpha) will be 0.05. 
7.7.1 Analysis of Primary Efficacy Endpoint 
The analysis of the primary efficacy endpoint will be conducted using an ANOVA method 
with the TST as the response variable and treatment, sequence, center, and period as the fixed 
effects. The primary comparison will be SM-1 with placebo, followed by SM-1 with D+Z 
and SM-1 with D+L. 
Analyses will be performed to evaluate effect of sex and age on TST using the same ANOVA 
model with addition of sex and age (greater than median vs less than median) as fixed 
factors. 
7.7.2 Analysis of Secondary Efficacy Endpoint 
The data collected from PSG recordings and PSQ responses will be used for the comparisons 
of SM-1 versus placebo on WASO, LPS, NAW, sTST sSOL, and TST by quarters of the 


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night; SM-1 versus both D+Z and D+L on WASO, LPS, NAW, sTST, sSOL, and TST by 
quarters of the night; and both D+Z and D+L versus placebo on TST, WASO, LPS, NAW, 
sTST, sSOL, and TST by quarters of the night. These analyses will be performed using the 
same ANOVA model as for the primary efficacy endpoint. Endpoints that are not normally 
distributed will be log-transformed first. 
7.7.3 Safety Analyses 
Adverse events will be summarized by using count summaries. Adverse events will be listed 
for each subject and summarized by system organ class and preferred term assigned to the 
event by MedDRA. 
The KSS and DSST data will be analyzed using the same statistical methods used for the 
primary efficacy endpoint analysis. 
Vital sign measurements will be summarized and listed. Physical examination findings, 
alcohol breath test results, and urine pregnancy test results will be provided in by-subject 
data listings. 
7.7.4 Other Analyses 
Sleep stage will be summarized by the duration (in minutes) and percentage of each sleep 
stage. The latency to REM will be summarized. The duration and percentage of each sleep 
stage (NI, N2, N3) and the latency to REM will be analyzed using the same statistical 
methods as for the primary endpoint analysis. 
Disposition, demographics, medical history, sleep history, and concomitant medications will 
be summarized and listed. 
7.7.5 Interim Analyses 
To address the uncertainty about the estimate of the SD of the primary efficacy endpoint, the 
pooled SD will be monitored by a blinded interim analysis performed after approximately 
50% of blinded subjects have completed the study to allow for an option to increase the 
sample size to preserve power if the observed SD is different than was estimated for the 
a priori sample size calculation. 


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7.8 Data Quality Assurance 
Standard operating procedures are available for all activities relevant to the quality of this 
study. Designated personnel will be responsible for implementing and maintaining quality 
assurance and quality control systems to ensure that the study is conducted and that data are 
generated, documented, and reported in compliance with the study protocol, Good Clinical 
Practice (GCP), and Good Laboratory Practice requirements as well as applicable regulatory 
requirements and local laws, rules, and regulations relating to the conduct of the clinical 
study. 
An authorized quality assurance auditor will audit the study data and procedures at periodic 
intervals as indicated. Regulatory authorities, the institutional review board (IRB), and a 
sponsor-authorized auditor may request access to all study documentation for an on-site 
inspection or audit. The investigator must notify Sequential Medicine, Ltd of any regulatory 
authority inspections and forward copies of the inspection report to Sequential Medicine, Ltd. 
Electronic data systems will be designed and used in accordance with applicable aspects of 
21 Code of Federal Regulations (CFR) Part 11, International Council for Harmonisation 
(ICH) Guidelines, GCP, local laws and legislation, and the Health Insurance Portability and 
Accountability Act. 
7.8.1 Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include laboratory reports, 
questionnaire results, or paper diaries. 
Electronic CRFs will be supplied by PPD for recording of all study data as specified by this 
protocol. Study center personnel will enter subject data into Medidata Rave (the eCRF 
program). The analysis data sets will be a combination of these data and data from other 
sources (e.g., data from laboratory reports). 
Clinical data management will be performed in accordance with applicable standards and 
data cleaning procedures to ensure the integrity of the data, e.g., removing errors and 


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inconsistencies in the data. Adverse events will be coded using MedDRA and concomitant 
medication terms will be coded using the World Health Organization Drug Dictionary. 
After database lock, each study center will receive a CDROM containing all their 
site-specific eCRF data as entered into Medidata Rave for the study, including full 
discrepancy and audit history. Additionally, a CDROM copy of all the study center’s data 
from the study will be created and sent to the sponsor for storage. PPD will maintain a 
duplicate CDROM copy for their records. In all cases, subject initials will not be collected or 
transmitted to the sponsor. 


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8 Ethics 
8.1 Independent Ethics Committee or Institutional Review Board 
Federal regulations and the ICH guidelines require that approval be obtained from an IRB 
before participation of human subjects in research studies. Before study onset, the protocol, 
informed consent, advertisements to be used for the recruitment of study subjects, and any 
other written information regarding this study to be provided to the subject must be approved 
by the IRB. Documentation of all IRB approvals and of the IRB compliance with ICH 
harmonised tripartite guideline E6(R2): Good Clinical Practice will be maintained by the 
study center and will be available for review by the sponsor or its designee. 
All IRB approvals should be signed by the IRB chairman or designee and must identify the 
IRB name and address, the clinical protocol by title or protocol number or both, and the date 
approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB. The 
investigator must promptly supply the sponsor or its designee, the IRB, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to subjects. 
8.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, and all applicable regulations. 
8.3 Subject Information and Consent 
A signed written informed consent in compliance with US Title 21 CFR Part 50 shall be 
obtained from each subject before entering the study or performing any unusual or 
nonroutine procedure that involves risk to the subject. An informed consent template may be 
provided by the sponsor to study centers. If any institution-specific modifications to study-
related procedures are proposed or made by the study center, the consent should be reviewed 
by the sponsor or its designee or both before IRB submission. Once reviewed, the consent 
will be submitted by the investigator to his or her IRB for review and approval before the 


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start of the study. If the ICF is revised during the course of the study, all active participating 
subjects must sign the revised form. 
Before recruitment and enrollment, each prospective subject will be given a full explanation 
of the study and be allowed to read the approved ICF. Once the investigator is assured that 
the subject understands the implications of participating in the study, the subject will be 
asked to give consent to participate in the study by signing the ICF. 
The investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the subject. 


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9 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB 
but will not result in protocol amendments. 
9.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the subject, except as necessary for monitoring and auditing by the sponsor, its 
designee, the US Food and Drug Administration (FDA), or the IRB. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
9.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 21 
CFR 54. In addition, the investigator must provide to the sponsor a commitment to promptly 
update this information if any relevant changes occur during the course of the investigation 
and for 1 year following the completion of the study. 
Neither the sponsor nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the sponsor nor PPD is financially responsible for 
further treatment of the subject’s disease. 


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9.3 Investigator Documentation 
Before beginning the study, the investigator will be asked to comply with ICH E6(R2) 8.2 
and Title 21 of the CFR by providing the following essential documents, including but not 
limited to: 
• 
IRB approval 
• 
Original investigator-signed investigator agreement page of the protocol 
• 
Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572 
• 
Curriculum vitae (CV) for the investigator and each subinvestigator listed on 
Form FDA 1572 
• 
Financial disclosure information to allow the sponsor to submit complete and 
accurate certification or disclosure statements required under 21 CFR 54. In 
addition, the investigators must provide to the sponsor a commitment to 
promptly update this information if any relevant changes occur during the 
course of the investigation and for 1 year after the completion of the study. 
• 
IRB-approved informed consent, samples of site advertisements for recruitment 
for this study, and any other written information regarding this study that is to 
be provided to the subject, and 
• 
Laboratory certifications and normal ranges for any local laboratories used by 
the study center, in accordance with 42 CFR 493 
9.4 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of ICH 
E6(R2). The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. Study information from this protocol will be 
posted on publicly available clinical registers before enrollment of subjects begins. 
9.5 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R2) and all applicable guidelines and regulations. 


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9.6 Adverse Events and Study Report Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in the protocol. In addition, the investigator agrees to 
submit annual reports to the study center IRB as appropriate. 
9.7 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB with a summary of the study’s 
outcome and the sponsor and regulatory authority(ies) with any reports required. 
9.8 Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained. 
9.9 Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues. The sponsor has approval authority over all such 
issues. 
Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 


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10 Study Management 
10.1 Monitoring 
10.1.1 Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, has the obligation to follow the study 
closely. In doing so, the monitor will visit the investigator and study center at periodic 
intervals, in addition to maintaining necessary telephone and letter contact. The monitor will 
maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
investigator and personnel. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
10.1.2 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records. 
In the event of an audit, the investigator agrees to allow the sponsor, representatives of the 
sponsor, or a regulatory agency (e.g., FDA) access to all study records. 
The investigator should promptly notify the sponsor and PPD of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
10.2 Management of Protocol Amendments and Deviations 
10.2.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the subject, must be reviewed and approved by the sponsor or its 
designee. Amendments to the protocol must be submitted in writing to the investigator’s IRB 
for approval before subjects can be enrolled into an amended protocol. 


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10.2.2 Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB for review and approval, to the sponsor for agreement, and to 
the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol by the 
subject or investigator that results in a significant, additional risk to the subject. Significant 
deviations can include nonadherence to inclusion or exclusion criteria, enrollment of the 
subject without prior sponsor approval, or nonadherence to FDA regulations or ICH GCP 
guidelines, and will lead to the subject being withdrawn from the study (Section 4.2). 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Principal investigators will be notified in writing by the monitor of 
deviations. The IRB should be notified of all protocol deviations in a timely manner. 
10.3 Study Termination 
Although Sequential Medicine, Ltd has every intention of completing the study, Sequential 
Medicine, Ltd reserves the right to discontinue the study at any time for clinical or 
administrative reasons. 
The end of the study is defined as the date on which the last subject completes the last visit 
(includes the follow-up safety phone call). 
10.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study reports are prepared and provided to the regulatory agency(ies) as required by 
the applicable regulatory requirement(s). The sponsor will also ensure that the clinical study 


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reports in marketing applications meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and content of clinical study reports. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results. 
Upon completion of the clinical study report, the sponsor will provide the investigator with 
the full summary of the study results. The investigator is encouraged to share the summary 
results with the study subjects, as appropriate. The study results will be posted on publicly 
available clinical trial registers. 


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11 Reference List 
Akerstedt T and Gillberg M. Subjective and objective sleepiness in the active individual. Int J 
Neurosci. 1990;52(1-2):29-37. 
Akerstedt T, Anund A, Axelsson J, et al. Subjective sleepiness is a sensitive indicator of 
insufficient sleep and impaired waking function. J Sleep Res. 2014;23(3):240-52. 
Johns MW. Epworth Sleepiness Scale (ESS) [Internet]. Lyon, France: Mapi Research Trust; 
1990. [updated 1997; cited 30 November 2017]. Available from:  
https://eprovide.mapi-trust.org/instruments/epworth-sleepiness-scale. 
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. 
Sleep. 1991;14(6):540-5. 
Johns MW. Reliability and factor analysis of the Epworth Sleepiness Scale. Sleep. 
1992;15(4):376-81. 
Johns MW. Sensitivity and specificity of the multiple sleep latency test (MSLT), the 
maintenance of wakefulness test and the Epworth sleepiness scale: failure of the MSLT as a 
gold standard. J Sleep Res. 2000;9(1):5-11. 
The official STOP-Bang website [Internet]. Toronto, Canada: Toronto Western Hospital, 
University Health Network, University of Toronto; 2012. STOP-Bang Questionnaire; 2012 
[cited 30 November 2017]; [about 2 screens]. Available from: 
http://www.stopbang.ca/osa/screening.php. 


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12 Appendices 
12.1 Appendix 1: STOP-Bang Questionnaire 
 
 
 


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12.2 Appendix 2: Epworth Sleepiness Scale 
 


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12.3 Appendix 3: Post-Sleep Questionnaire 
 
 


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12.4 Appendix 4: Karolinska Sleepiness Scale 
 
 


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12.5 Appendix 5: Digit Symbol Substitution Test 
 


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SAP_000.pdf: 
Sequential Medicine, Ltd
Draft Statistical Analysis Plan, Version 1.0
SM-A-05 
 
   Date Issued: 09FEB2018 
  
 
 
 
1
Sequential Medicine, Ltd 
 
SM-A-05 
 
A Randomized, Double-Blind, Single-Dose, 4-Way Crossover Study to Assess the Efficacy and Safety of 
SM-1 (50-mg Diphenhydramine, 5-mg Delayed-Release Zolpidem, and 0.5-mg Delayed-Release 
Lorazepam) versus 2 Comparators (50-mg Diphenhydramine and 5-mg Delayed-Release Zolpidem; 
50-mg Diphenhydramine and 0.5-mg Delayed-Release Lorazepam) and Placebo in a 5-Hour Phase 
Advance Model of Transient Insomnia 
 
09 FEB 2018 
 
 Statistical Analysis Plan 
Version 1.0 
 
Prepared by:  
PPD 
7551 Metro Center Drive, Suite 300 
Austin, TX 78744 
 
 
Prepared by: 
____________________________ 
 
 
 
James Pottala 
Lead Biostatistician, Biostatistics 
PPD 
 
Reviewed by: ____________________________ 
 
 
  
Raymond Claus 
Senior Reviewer, Biostatistics 
PPD 
 
 
Upon review of this document, including table, listing, and figure shells, the undersigned approves the 
statistical analysis plan. The analysis methods and data presentation are acceptable, and the table, listing, 
and figure production can begin. 
 
 
 
Approved by: ____________________________ 
 
 
Date:  _12/FEB/2018_ 
Thomas Dahl 
Sequential Medicine, Ltd 
 
 
  


Sequential Medicine, Ltd
Draft Statistical Analysis Plan, Version 1.0
SM-A-05 
 
   Date Issued: 09FEB2018 
  
 
 
 
2
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... 4
1.
INTRODUCTION ............................................................................................................ 5
2.
OBJECTIVES ................................................................................................................... 5
2.1.
PRIMARY OBJECTIVES ........................................................................................................ 5
2.2.
KEY SECONDARY OBJECTIVES ........................................................................................... 5
2.3.
OTHER SECONDARY OBJECTIVES ....................................................................................... 5
2.4.
SAFETY OBJECTIVE ............................................................................................................ 6
2.5.
OTHER OBJECTIVES ............................................................................................................ 6
3.
INVESTIGATIONAL PLAN .......................................................................................... 6
3.1.
OVERALL STUDY DESIGN AND PLAN .................................................................................. 6
3.2.
STUDY ENDPOINTS ............................................................................................................. 7
3.2.1.
Primary Efficacy Endpoints ........................................................................................ 7
3.2.2.
Key Secondary Efficacy Endpoints ............................................................................. 7
3.2.3.
Other Secondary Efficacy Endpoints .......................................................................... 7
3.2.4.
Safety and Other Endpoints ........................................................................................ 8
4.
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 8
4.1.
SAMPLE SIZE ...................................................................................................................... 9
4.2.
RANDOMIZATION, STRATIFICATION, AND BLINDING .......................................................... 9
4.3.
ANALYSIS SET .................................................................................................................. 10
5.
SUBJECT DISPOSITION AND PROTOCOL DEVIATIONS ................................. 11
5.1.
DISPOSITION ..................................................................................................................... 11
5.2.
PROTOCOL DEVIATIONS ................................................................................................... 11
6.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 11
6.1.
DEMOGRAPHICS ................................................................................................................ 11
6.2.
ALCOHOL, TOBACCO, AND CAFFEINE USAGE ................................................................... 12
6.3.
MEDICAL HISTORY ........................................................................................................... 12
6.3.1.
General Medical History .......................................................................................... 12
6.3.2.
Disease-Specific History ........................................................................................... 12
6.4.
INCLUSION AND EXCLUSION CRITERIA ............................................................................. 12
7.
TREATMENTS AND THERAPY ................................................................................ 13
7.1.
PRIOR AND CONCOMITANT THERAPY ............................................................................... 13
7.2.
STUDY TREATMENTS ........................................................................................................ 13
7.2.1.
Treatment Compliance .............................................................................................. 13
8.
EFFICACY ANALYSIS................................................................................................. 14
8.1.
PRIMARY EFFICACY ENDPOINT ......................................................................................... 14
8.1.1.
Primary Analysis ....................................................................................................... 14
8.1.2.
Assumption Testing ................................................................................................... 15
8.2.
KEY SECONDARY EFFICACY ENDPOINTS .......................................................................... 15


Sequential Medicine, Ltd
Draft Statistical Analysis Plan, Version 1.0
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   Date Issued: 09FEB2018 
  
 
 
 
3
8.3.
OTHER SECONDARY EFFICACY ENDPOINTS ...................................................................... 17
8.4.
OTHER ENDPOINTS ........................................................................................................... 17
8.5.
FAMILY WISE ERROR RATE (FWER) CONTROL ............................................................... 18
9.
SAFETY ANALYSIS ..................................................................................................... 18
9.1.
ADVERSE EVENTS ............................................................................................................. 18
9.1.1.
Incidence of Adverse Events ..................................................................................... 19
9.1.2.
Relationship of Adverse Events to Study Drug ......................................................... 19
9.1.3.
Severity of Adverse Event.......................................................................................... 20
9.1.4.
Serious Adverse Events ............................................................................................. 20
9.1.5.
Adverse Events Leading to Study Discontinuation ................................................... 21
9.1.6.
Death ......................................................................................................................... 21
9.2.
CLINICAL LABORATORY EVALUATIONS ........................................................................... 21
9.2.1.
Hematology ............................................................................................................... 21
9.2.2.
Chemistry .................................................................................................................. 21
9.2.3.
Urinalysis .................................................................................................................. 22
9.3.
VITAL SIGN MEASUREMENTS ........................................................................................... 22
9.4.
PHYSICAL EXAMINATION ................................................................................................. 22
9.5.
OTHER SAFETY DATA ....................................................................................................... 22
10.
INTERIM ANALYSIS ................................................................................................... 23
11.
CHANGES IN PLANNED ANALYSIS ........................................................................ 24
12.
REFERENCES ................................................................................................................ 25
13.
APPENDICES ................................................................................................................. 26
13.1.
SCHEDULE OF EVENTS ................................................................................................... 26
13.2.
SLEEP STUDY EVENTS BY DAY FOR TREATMENT PERIODS ........................................... 29
13.3.
IMPUTATION FOR PARTIAL AND MISSING DATES .......................................................... 31
13.4.
SAMPLE SIZE RECALCULATION REPORT ........................................................................ 33
 
 
 


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List of Abbreviations 
AE                  adverse event 
ANOVA         analysis of variance 
BMI                body mass index 
D+L                50-mg diphenhydramine and 0.5-mg delayed-release lorazepam 
D+Z                50-mg diphenhydramine and 5-mg delayed-release zolpidem 
DSST              Digit Symbol Substitution Test 
eCRF              electronic case report form 
ESS                 Epworth Sleepiness Scale 
FAS                full analysis set 
FWER 
family-wise error rate 
IP 
Investigational Product 
IRB                 institutional review board 
KSS                Karolinska Sleepiness Scale 
LPS                 latency to persistent sleep 
LSMEANS 
least squares means 
MedDRA        Medical Dictionary for Regulatory Activities 
mFAS 
modified full analysis set 
MSE 
mean square error 
NAW              number of awakenings 
OSA               obstructive sleep apnea 
PPS                 per-protocol set 
PSG                polysomnography, polysomnographic 
PSQ                Post-Sleep Questionnaire 
PT                   preferred term 
REM              rapid eye movement 
SAE                serious adverse event 
SM-1              50-mg diphenhydramine, 5-mg delayed-release zolpidem, and 0.5-mg delayed-release lorazepam        
sNAW 
subjective number of awakenings 
SOC 
system organ class 
sQUALITY
subjective quality 
sSOL              subjective sleep onset latency 
sTST               subjective total sleep time 
TEAE 
treatment-emergent adverse event 
TST                total sleep time 
WASO            wakefulness after sleep onset 
 
 
 
 
 


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1. Introduction 
SM-1 is a 3-component investigational drug that is intended to increase total sleep time.  The formulation 
provides 50-mg immediate-release diphenhydramine, 5-mg delayed-release zolpidem, and 0.5 mg 
delayed-release lorazepam.  This combination is a unique approach to addressing the problem of transient 
insomnia. 
 
A Phase 2 clinical study of SM-1 was conducted in the target population.  The primary endpoint was the 
comparison of total sleep time (TST) between SM-1 and placebo.  This study showed that SM-1 had a 
significantly greater TST than placebo (P<0.001) as well as the 2-drug combination (zolpidem and 
lorazepam, P=0.014).  SM-1 also reduced wakefulness after sleep onset (WASO) significantly compared 
with placebo (P<0.001).  On waking, there were no residual drug effects as indicated by the Karolinska 
Sleepiness Scale (KSS), Digit Symbol Substitution Test (DSST), or predischarge neurological 
examination results. 
 
The current study will serve to confirm the efficacy, safety, and tolerability of SM-1 in subjects with 
transient insomnia.  In addition, the inclusion of additional drug combination arms will serve to generate 
data to assess the contribution of zolpidem and lorazepam to the overall efficacy of the investigational 
drug. 
2. Objectives 
2.1. Primary Objectives 
The primary objectives of this study are: 
 
To assess efficacy of SM-1 versus placebo as measured by polysomnographic (PSG)-defined TST 
 
To assess efficacy of SM-1 versus 2 additional combination products comprised of 2 of the 3 
components of SM-1 (diphenhydramine plus zolpidem; and diphenhydramine plus lorazepam) as 
measured by PSG-defined TST 
2.2. Key Secondary Objectives 
The secondary objectives of this study are: 
 
To assess activity of SM-1 versus placebo on additional PSG measures of sleep induction and 
maintenance 
 
To assess SM-1 versus placebo on subject-reported efficacy measures from the Post-Sleep 
Questionnaire (PSQ) 
2.3. Other Secondary Objectives 
Other efficacy objectives include comparisons with the two 2-drug combination products. 
 
To assess activity of SM-1 versus the two 2-drug combination products on additional PSG 
measures of sleep induction and maintenance 
 
To assess SM-1 versus the two 2-drug combination products on subject reported efficacy 
measures from the PSQ. 
 
To assess the activity of the two 2-drug combination products versus placebo on PSG-defined 
TST, and additional PSG measures of sleep induction and maintenance 


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2.4. Safety Objective 
The safety objective of this study is to assess safety of SM-1 in terms of adverse events (AEs) and 
morning measures of alertness (KSS and DSST). 
2.5. Other Objectives 
Other objectives include the assessment of the effect of SM-1 and the two 2-drug combination products 
on sleep stage distribution. 
3. Investigational Plan 
3.1. Overall Study Design and Plan 
This is a randomized, double-blind, single dose, 4-way crossover study to assess the efficacy and safety of 
SM-1 compared with placebo and two 2-drug combination products in subjects with a history of transient 
insomnia.  Subjects will be exposed to a 5-hour phase advance model of transient insomnia with 8 hours 
(960 30-second epochs) of PSG recording as the primary efficacy assay.  The primary efficacy endpoint is 
TST on an 8-hour PSG comparing SM-1 versus placebo, SM-1 versus D+Z, and SM-1 versus D+L (see 
Table 3-1 footnote for abbreviations). 
 
The study has the following periods: screening (at least 8 and no more than 21 days), treatment and PSG 
period, and a follow-up safety phone call.  There will be 84 subjects enrolled in 2 clinical centers in the 
study. The duration will be approximately 8 weeks, which includes 5 visits (screening period and 4 
treatment periods) and 1-week (minimum 5-day) washout intervals between each treatment period. 
 
After signing the informed consent, potential subjects will come in for screening visit (Visit 1) and 
specified procedures will be performed as in the schedule of events (Appendix 13.1).  The subjects who 
satisfy the eligibility criteria will be issued a paper diary to record the time they go to bed and the time 
they get up during the screening period. Information recorded will be given to study personnel to 
calculate median habitual bedtime for each subject.  At Visit 2, subjects will check-in at the study center 
7 hours earlier than their median habitual bedtime.  Once eligibility has been reconfirmed, subjects will be 
randomly assigned to 1 of 4 treatment sequences as shown in Table 3-1, and procedures will be performed 
per the schedule of events 
habitual bedtime (Appendix 13.2).  Each treatment and PSG period visit will last approximately 11 to 12 
hours.  
 
Table 3-1 Randomized Treatment Sequences 
 
Treatment 
Period 1 
Visit 2 
 
Treatment
Period 2 
Visit 3 
 
Treatment 
Period 3 
Visit 4 
 
Treatment
Period 4 
Visit 5 
Sequence 1 
SM-1 
D+Z 
D+L 
Placebo 
Sequence 2 
D+Z 
D+L 
Placebo 
SM-1 
Sequence 3 
D+L 
Placebo 
SM-1 
D+Z 
Sequence 4 
Placebo 
SM-1 
D+Z 
D+L 
SM-1 = 50-mg diphenhydramine, 5-mg delayed-release zolpidem, and 0.5-mg delayed-release lorazepam; 
D+Z = 50-mg diphenhydramine and 5-mg delayed-release zolpidem;  


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D+L = 50-mg diphenhydramine and 0.5-mg delayed-release lorazepam; 
Placebo = identical in appearance to SM-1, D+Z, and D+L and has the same excipients, but no diphenhydramine, zolpidem, 
lorazepam, or delayed-release coating materials 
 
  
Approximately 90 minutes before lights out, baseline DSST measurements will be obtained.  
Approximately 60 minutes before lights out, PSG electrodes will be applied. Subjects will be 
administered their assigned treatment by study personnel 30 minutes before lights out and an oral cavity 
check will be performed to assure compliance with treatment.  At the assigned lights out time, the subject 
will go to bed, PSG biocalibration will be performed, and PSG recording will begin.  The recording will 
continue for 8 hours. 
 
At the completion of the 8-hour PSG recording period, subjects will be awakened.  Approximately 30 
minutes after the end of PSG recording, subjects will complete the PSQ, KSS, and DSST.  Before leaving 
the study center, subjects will undergo a brief discharge evaluation consisting of tandem gait, the 
Romberg test, and an assessment of vital signs and AEs.  Subjects will remain at the study center until 
they are able to pass the discharge evaluation.  Upon discharge, subjects will be told the time and date to 
return for the next overnight visit, dispensed a daily washout interval diary, and instructed to maintain 
normal sleep patterns. 
 
Following a minimum 5 days washout, subjects will return to the study center and return their diary for 
review.  The schedule of procedures for Visits 3, 4, and 5 will be the same as for Visit 2 except that the 
subjects will be given the next treatment in their randomization sequence (Table 3-1) and lights out will 
occur at the time established at Visit 2 ±15 minutes. 
 
Within 7 days after completion of Treatment Period 4 (Visit 5), but at least 72 hours after the final dose, a 
follow-up safety phone call will be performed.  Outcomes of any AEs will be discussed and recorded.  If 
indicated, a visit to the study center for safety assessments will be scheduled. 
3.2. Study Endpoints 
3.2.1. Primary Efficacy Endpoints 
The primary efficacy endpoints for this study are TST on an 8-hour PSG comparing SM-1 versus placebo, 
SM-1 versus D+Z, and SM-1 versus D+L. 
3.2.2. Key Secondary Efficacy Endpoints 
The comparison of SM-1 versus placebo for data collected from PSG recordings and PSQ responses will 
be performed on WASO, latency to persistent sleep (LPS), number of awakenings (NAW), subjective 
TST (sTST), subjective sleep onset latency (sSOL), and TST by quarters of the night.   
3.2.3. Other Secondary Efficacy Endpoints 
The comparison of SM-1 versus D+Z and SM-1 versus D+L for data collected from PSG recordings and 
PSQ responses will be performed on WASO, latency to persistent sleep (LPS), number of awakenings 
(NAW), subjective TST (sTST), subjective sleep onset latency (sSOL), and TST by quarters of the night.   
 


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The comparison of D+Z versus placebo and D+L versus placebo for data collected from PSG recordings 
and PSQ responses will be performed on TST, WASO, LPS, NAW, sTST, sSOL, and TST by quarters of 
the night.  
3.2.4. Safety and Other Endpoints 
Safety endpoints include the following: 
 
 
Incidence, severity, and relationship to treatment of AEs 
 
Karolinska Sleepiness Scale 
 
Digit Symbol Substitution Test  
 
Discharge evaluation (tandem gait and Romberg) 
 
Other endpoints include percentage and number of minutes of sleep stages N1, N2, N3, and rapid eye 
movement (REM) and latency to REM sleep onset. 
4. General Statistical Considerations 
Continuous variables will be summarized using the mean, SD, median, minimum value, and maximum 
value.  Categorical variables will be summarized using frequency counts and percentages.  Data will be 
provided in by-subject data listings with center ID concatenated with subject ID. 
 
Unless specified otherwise, all statistical analyses will be performed using a 2-sided hypothesis test at the 
overall 5% level of significance leading to 95% (2-sided) CIs.  All p-values will be rounded to 4 decimal 
places. If a p-
.   If a p-value is greater than 
.  
 
Data will be displayed in all listings sorted as indicated in the specifications.  When count data are 
presented, the percent will be suppressed when the count is zero in order to draw attention to the non-zero 
counts.  
dropouts and missing values.  The denominator for all percentages will be the number of subjects in that 
treatment with nonmissing values within the analysis set of interest, unless otherwise stated. Non-zero 
percentages will be rounded to 1 decimal place, except 100% will be displayed without any decimal 
places.  Additional rounding rules are as follows: 
 
 
If the original value has 0 decimal places: mean, median, and CIs will have 1 decimal place and 
SD will have 2 decimal places.  
 
If the original value has 1 decimal place: mean, median, and CIs will have 2 decimal places and 
SD will have 3 decimal places.  
 
If the original value has 2 or more decimal places: mean, median, CIs, and SD will all have 3 
decimal places.  
 
Minimum and maximum will always have the same decimal places as the original measure, up to a 
maximum of 3 decimal places. 
 


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Study Day 1 is defined as date of first dose (i.e., date of study drug administration during Visit 2 = study 
Day 1); study day will be calculated as below: 
 
 
Study Day xx = date of measurement/observation  first dose date + 1; if date of 
measurement/observation is on or after first dose date.  
 
Study Day xx = date of measurement/observation  first dose date; if date of 
measurement/observation is prior to the first dose date.  
 
The duration of study participation will be summarized for all subjects.  If the date of the last visit on the 
Study Completion/Early Withdrawal page is missing, or if a subject is lost to follow-up, the latest 
available visit date will be used.  
4.1. Sample Size  
A total of 68 blinded subjects will be able to ensure 80% power to detect treatment differences on TST 
between SM-1 and all 3 controls (D+Z, D+L, and placebo) at a 2-sided 0.05 significance level with a 
fixed-sequence testing procedure using an effect size of at least 44 minutes between SM-1 and all three 
comparators.  
 
The assumptions in the sample size analysis included a 2x2 crossover design (since the 4x4 crossover 
design collapses to a 2x2 when making a comparison between 2 treatment groups), minimum of 80% 
power, 2-sided alpha=0.05, standard deviation (defined as the square root of the within mean square error 
(MSE) from a repeated measures analysis of variance (ANOVA) model) of 88 minutes, and effect sizes of 
120 minutes for SM-1 versus placebo and 44 minutes for SM-1 versus the 2-drug comparators with 0% 
loss to follow-up.  To maintain the family-wise error rate (FWER) alpha=0.05, the 3 primary efficacy 
hypotheses will be tested using a fixed-sequence procedure; more details are provided in Section 8.1.1. 
 
There is a sample size recalculation planned after approximately 50% of the subjects have completed the 
study.  The details are provided in Section 10, and the sample size recalculation report is included in 
Appendix 13.4.  The sample size recalculation allows increasing the sample size if the variability or loss 
to follow-up is greater than expected. 
4.2. Randomization, Stratification, and Blinding  
The study will be performed in a double-blind manner, with the subjects, investigator, and study center 
staff being blinded to the identity of study drug.  All study drug will be supplied in identical packaging 
and will be identical in color, smell, taste, and appearance to enable double-blind conditions.  Subjects 
will be randomly assigned to 1 of 4 treatment sequences shown in Table 3-1 by a manual randomization 
process.  When a center needs to randomly assign a subject, the lowest unused randomization number at 
that center will be selected from the randomization schedule.  The kit labeled with this randomization 
number will include 4 bottles each labeled with the randomization number and a visit number (i.e., Visit 2 
through Visit 5) to be dispensed at the corresponding visits.  The randomization schedule will use a block 
size, which will not be revealed to the staff responsible for the conduct of the study.  No stratification will 
be used in this study.   
 


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A subject will not be unblinded until the end of the study after database lock or if a medical treatment 
depends on knowing the study drug the subject received.  If the blind needs to be broken because of a 
medical emergency, the investigator may unblind a s
 via a set of blind 
breaking envelopes located at each center.  The investigator should make every effort to contact the 
medical monitor and/or sponsor prior to opening the envelope corresponding to the subject and visit, to 
reveal the actual treatment drug description.  
 
notified immediately.  Any subjects unblinded during the study will be summarized in a table and 
presented in a by-subject listing. 
4.3. Analysis Set 
The following analysis sets will be used in the statistical analyses: 
 
All enrolled subjects: A subject is considered enrolled when he/she signs informed consent, passes the 
screening criteria, and is eligible for first dose of drug to be administered. 
 
Full analysis set (FAS): The FAS will consist of all subjects who were randomly assigned to study drug at 
Visit 2 and have taken any study drug during the treatment period.  All analyses using the FAS will group 
subjects according to randomized treatment.  The FAS will be used as a sensitivity analysis for the 
primary, secondary, and other efficacy analyses. 
 
Modified FAS (mFAS): The mFAS will consist of all subjects from the FAS that did not have their 
treatment codes potentially unblinded during the study.  All analyses using the mFAS will group subjects 
according to randomized treatment.  The mFAS will be used for the primary, secondary, and other 
efficacy analyses and will be the principal efficacy population. 
 
Per-protocol set (PPS): The PPS will consist of all FAS subjects who fulfill all eligibility criteria, have 
taken all 4 doses of study drug, have not taken any prohibited medication, and have no significant 
protocol deviations that may affect the primary endpoint.  Significant protocol deviations and whether 
each results in excluding a subject from the PPS will be defined in a Study Deviation Rules Document 
and will be finalized prior to database lock and study unblinding.  All analyses using the PPS will group 
subjects according to actual treatment received.  The PPS will only be used as a sensitivity analysis for the 
primary efficacy analysis. 
 
Safety set: The safety set will consist of all subjects who received any study drug.  All analyses using the 
safety set will group subjects according to actual treatment received.  Each AE will be assigned to the 
actual treatment that was associated with the AE based on whether the start date of the AE was on or after 
the start date of the associated period, up through the day prior to the start date of the following period.  
The safety set will be used for all safety analyses. 
 
A by-subject listing will be provided for any randomization errors (i.e., a subject was randomized to the 
incorrect sequence) or dispensing errors where a subject was randomized to the correct sequence but the 
treatments were administered in an incorrect order. 


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5. Subject Disposition and Protocol Deviations 
5.1. Disposition 
A summary of all subjects screened (i.e., signed informed consent) will include the number and 
percentage of subjects screened, randomized, and the reasons for screen failures by center as the 
following: inclusion/exclusion criteria, subject withdrawn, lost to (screening) follow-up, sponsor decision, 
AE, and other.  A listing of screen-failed subjects will be provided as well.   
 
The primary reason for study discontinuation will also be listed by subject, and summarized in a table for 
the mFAS and FAS populations by treatment sequence group and overall.  The reason for study 
discontinuation may include any of the following: completed study, AE, death, lost to follow-up, 
physician decision, pregnancy, protocol violation, study terminated by sponsor, subject withdrawal, or 
other.  Only 1 reason for study discontinuation per subject will be entered.  The number of subjects in the 
mFAS, PPS, and SS populations and subjects completing all 4 treatment visits will be included. 
5.2. Protocol Deviations 
A deviation from the protocol is an unintended or unanticipated departure from the procedures or 
processes approved by the sponsor and the institutional review board (IRB)/independent ethics committee 
and agreed to by the investigator.  The investigator may implement a deviation from the protocol to 
eliminate an immediate hazard to study subjects without prior IRB approval.  A significant deviation 
occurs when there is nonadherence to the protocol by the patient or investigator that results in a 
significant, additional risk to the subject.  Descriptions and categories of significant protocol deviations 
will be defined in the Study Protocol Deviation Document and finalized prior to database lock and study 
unblinding.  The significant protocol deviations will be listed by subject and summarized in a table by 
categories for the mFAS and FAS by treatment sequence group and overall. 
6. Demographics and Baseline Characteristics 
6.1. Demographics 
Baseline demographics will be listed by subject and summarized by treatment sequence group and overall 
for subjects in the mFAS and FAS.  Demographic variables will include the following: 
 
Age at informed consent defined as the integer part of: [(date of informed consent  date of birth) 
/ 365.25] 
 
Age group (greater than median vs less than median) 
 
Sex 
 
If female: fertility status (i.e., postmenopausal, potentially able to bear children, or sterile) 
 
Race (i.e., white, African American, Asian, American Indian or Alaska Native, Native Hawaiian 
or other Pacific Islander, or other) 
 
Ethnicity (i.e., Hispanic or Latino, not Hispanic or Latino) 
 
Weight (kg) 
 
Height (cm) 
 
Body mass index (BMI) defined as: weight (kg) / [height (m)]2 
 


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Continuous descriptive statistics will be presented for age, weight, height, and BMI.  Frequency counts 
and percentages will be presented for age group, sex, fertility status, race, and ethnicity.   
6.2. Alcohol, Tobacco, and Caffeine Usage  
History of substance use for alcohol, caffeine, and tobacco/nicotine (type and amount) will be listed by 
subject.  Alcohol, caffeine, and tobacco use history will all be categorized as current, former, or never.  
For alcohol, the average number of units per week will be recorded.  A unit of alcohol is equivalent to 12 
ounces of beer, 4 ounces of wine, or 1 ounce of liquor.  The amount of caffeine will be recorded as 
mg/day.  The average use of tobacco is measured in units per day; and if the subject is a current smoker, 
then whether they smoke during the sleep period will be entered in the electronic case report form 
(eCRF). 
6.3. Medical History 
6.3.1. General Medical History 
Medical history and psychiatric history will be listed by subject and summarized for the FAS by treatment 
sequence group and overall.  The verbatim terms will be coded by the primary system organ class (SOC) 
and preferred term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.0 
or higher, and the summary will include the count and percentage of subjects with a significant history by 
SOC and PT.  The listing will include start date, end date, and ongoing status.   
6.3.2. Disease-Specific History 
Subject sleep history will be assessed at screening to confirm subject eligibility for the study using the 
STOP-Bang (STOP: snoring, tiredness, observed apnea, and high blood pressure; Bang: BMI, age, neck 
circumference, and gender) questionnaire [STOP-Bang 2012].  The questionnaire consists of 
8 dichotomous (yes/no) items related to the clinical features of obstructive sleep apnea (OSA).  The total 
score ranges from 0 to 8 
.  The STOP-Bang responses will be 
listed by subject.   
 
The Epworth Sleepiness Scale (ESS) [Johns 1997] will also be used at screening to measure a 
 
level of daytime sleepiness or their average sleep propensity in daily life.  Subjects rate, on a 4-point scale 
(0 to 3), their usual chances of dozing off or falling asleep in 8 different situations or activities that most 
people engage in as part of their daily lives.  The total ESS score is the sum of 8 item scores and can 
range between 0 and 24.  
 If a 
subject fails to answer any 1 of the 8 items, then the total score will be missing.  Responses to each 
question and the score totals will be listed by subject.   
6.4. Inclusion and Exclusion Criteria 
The investigator will certify that the subject satisfies all eligibility criteria at screening and continues to 
satisfy all inclusion and exclusion criteria prior to dosing at Visit 2.  A subject is considered enrolled 
when he/she signs informed consent, passes the screening criteria, and is eligible for first dose of drug to 
be administered.  Inclusion and exclusion criteria that are violated will be presented in a by-subject listing. 


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7. Treatments and Therapy 
7.1. Prior and Concomitant Therapy 
The use of concomitant medications during this study is discouraged, unless required to treat AEs.  The 
use of other concomitant medications should be approved by the investigator and sponsor (or designee) 
before subjects enroll in the study. 
 
Any prior therapy within the 30 days before enrollment (i.e., Visit 2) or concomitant therapy taken by a 
subject during the course of the study will be documented, along with the reason for its use.  Concomitant 
medications will include all prescription drugs, over-the-counter medications, herbal products, vitamins, 
minerals, and nutritional supplements.  WHO Drug Dictionary version 01JUN2017 will be used to code 
all concomitant medications, which will be summarized in a table for PT by treatment group for the safety 
set.  Partial dates for concomitant medication will be imputed as described in Appendix 13.3.  A 
concomitant medication will be assigned to the treatment in 1 or more periods if the start date of that 
medication is on or after the start date of that period, up through the day prior to the start date of the 
following period (or 7 days after last dose, for the last period).  Prior and concomitant medication data 
will be listed by subject for the safety set. 
7.2. Study Treatments 
The study includes the following 4 treatment arms that require each subject to take 1 pill orally from each 
of the arms during the 4 treatment periods, in a random sequence: 
 
 
SM-1 contains 50-mg diphenhydramine, 5-mg delayed-release zolpidem, and 0.5-mg 
delayed-release lorazepam  
 
D+Z contains 50-mg diphenhydramine and 5-mg delayed-release zolpidem 
 
D+L contains 50-mg diphenhydramine and 0.5-mg delayed-release lorazepam  
 
Placebo 
7.2.1. Treatment Compliance  
At Screening Visit 1, subjects who satisfy all eligibility criteria will be issued a pretreatment paper diary 
and instructed to record the time they went to bed with the intention of sleeping and the time they got up, 
during the screening period that lasts from 8 to 21 days.  Each diary entry day will be recorded as 
collected, not expected, or missing data.  The compliance rate will be calculated as the number of 
collected days divided by the number of days of collected + missing data multiplied by 100%.  There 
must be at least 5 entries and at least a 70% compliance rate at Visit 2 for a subject to be eligible for 
randomization.  The median habitual bedtime will be determined based on these pretreatment diary 
entries.  The sleep diary is reissued between treatment visits. 
 
Investigational product (IP) that is considered damaged will not be replaced and the data point for that 
particular visit will be missed for the subject.  When treatment is administered during Visits 2, 3, 4, and 5, 
an oral cavity check will be performed to assure compliance with treatment.  However, if the pill is 
vomited then the subject will not be given a replacement pill, and the subject will be required to take the 
next assigned treatment at the following visit.  The PSG will not be conducted for visits in which the 
subject did not take IP.  A minimum washout period of 5 days is required between treatment visits.   


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A table will summarize treatment compliance and washout period durations between visits by treatment 
group sequence and overall for the FAS; in addition, the diary compliance number of days collected, not 
expected, and missing with compliance rate will be reported.  Subject listings will be provided for sleep 
diary data and for treatment administrations. 
8. Efficacy Analysis 
All efficacy summaries will present data by treatment group (i.e., SM-1, D+Z, D+L, and placebo) for the 
mFAS.  The PPS will only be used for sensitivity analyses of the primary efficacy endpoint.  The FAS 
will be used as a sensitivity analysis for the primary and secondary efficacy analyses.  Subject level data 
will be provided in listings. 
8.1. Primary Efficacy Endpoint 
The primary endpoint is TST that will be determined at Visits 2, 3, 4, and 5 as the number of minutes the 
subject was in REM sleep + non-REM sleep during the 8-hour PSG recording, which will be scored at a 
central location blinded to treatment assignment.  The analysis of the primary efficacy endpoint will be 
conducted using a repeated measures ANOVA model.  The primary comparison will be SM-1 with 
placebo, followed by SM-1 with D+Z and SM-1 with D+L.  Since missing data are expected to be 
minimal, no formal imputation methods will be used.  Instead, missing data will be assumed to be missing 
at random, as handled by the Restricted Maximum Likelihood (REML) method in PROC MIXED. 
8.1.1. Primary Analysis 
The primary efficacy analysis will be conducted on the mFAS using a repeated measures ANOVA model 
with TST as the response variable. PROC MIXED in SAS® version 9.3 or higher will be used for the 
repeated measures ANOVA analysis and will include treatment, sequence, center, and period as fixed 
effects [Yarandi 2004].  The Kenward-Roger degrees of freedom approximation method will be used in 
the MODEL statement, which is less biased for small samples [Kenward and Roger 1997].  Restricted 
Maximum Likelihood method and the RANDOM intercept statement will be used to model the within-
subject correlation as subjects nested in sequence. 
 
There are 3 two-sided hypotheses in this primary efficacy analysis: 
 
Null hypothesis: TSTSM-1 - TSTPlacebo = 0; alternative hypothesis: TSTSM-1 - TSTPlacebo 
 
 
Null hypothesis: TSTSM-1  TSTD+Z = 0; alternative hypothesis: TSTSM-1  TSTD+Z 
 
 
Null hypothesis: TSTSM-1  TSTD+L = 0; alternative hypothesis: TSTSM-1  TSTD+L 
 
 
To control the FWER, all above hypotheses will be tested using the fixed-sequence procedure with two-
sided alpha = 0.05 (the details of the fixed-sequence procedure are provided in Section 8.5) [Dmitrienko 
2013].  The p-values from the ESTIMATE statement used to test each hypothesis and 
the 95% CIs will be reported; however, significant p-values will be indicated with an asterisk.  The least 
squares means (LSMEANS) statement will be used to tabulate the mean estimate of TST and standard 
error for each treatment group.   
 
The following sensitivity and subgroup analyses will be performed: 
 
Center will be removed from the model effectively pooling the centers 


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Interaction between treatment and period will be added to the model to test 1st order 
carryover effects 
 
Use of PPS  
 
Subgroup by sex (male vs female) 
 
Subgroup by age group (median split) 
8.1.2. Assumption Testing 
The ANOVA model assumes residuals are normally distributed with constant variance.  The univariate 
distribution of all the TST measurements will be tested for skewness.  If skewness is greater than 2, then 
the responses will benefit from natural logarithm transformation; sSOL and LPS are expected to be 
logarithm transformed.  For repeated measures ANOVA, the variance assumption is compound 
symmetry, or less restrictively that Huynh-Feldt condition of equal variances for all possible differences 
between repeated measures (i.e., sphericity) [Kuehl 2000].  The Huynh-Feldt condition will be tested 
using PROC GLM with the PRINTE option in the REPEATED statement.  If sphericity is rejected, then 
these results should be interpreted with caution; the result from the sphericity test will be included in the 
table. 
8.2. Key Secondary Efficacy Endpoints  
The mFAS and FAS will be used for the key secondary efficacy endpoints, to compare SM-1 versus 
Placebo.  The secondary endpoints are derived from the PSG recordings and PSQ assessments at Visits 2, 
3, 4, and 5.  The following PSG secondary endpoints will be included in the analyses: WASO, LPS, 
NAW, TST by quarters of the night; and PSQ secondary efficacy endpoints: sTST, subjective quality 
(sQUALITY), sSOL, and subjective number of awakenings (sNAW).  Since the protocol was approved, 
sQUALITY and sNAW have been added as secondary efficacy endpoints. 
 
The PSG is scored by dividing the 8-hour recordings into 960, 30-second epochs of various sleep stages.  
The following are derived from the PSG data transfer from the clinical sleep laboratory.   
 
 
WASO = total wake time in minutes from persistent sleep onset to lights on 
 
LPS = duration in minutes from lights off to the first epoch of 20 consecutive nonwake epochs 
 
NAW = number of awakening from the onset of persistent sleep until lights on.  An awakening is 
defined as at least 2 consecutive epochs of wake.  Individual awakenings must be separated by at 
least 1 epoch of stage N2, N3, or REM sleep 
 
TST1Q = duration in minutes of total REM sleep + non-REM sleep as Hour 1 + Hour 2 
 
TST2Q = duration in minutes of total REM sleep + non-REM sleep as Hour 3 + Hour 4 
 
TST3Q = duration in minutes of total REM sleep + non-REM sleep as Hour 5 + Hour 6 
 
TST4Q = duration in minutes of total REM sleep + non-REM sleep as Hour 7 + Hour 8 
 
The PSQ is a self-assessment questionnaire that the centers enter into eCRF to assign the following 
secondary efficacy endpoints, which include the prefix s  for being subjective: 
 
 
sTST = response to 
ow much time in total did you sleep last night?  converted to minutes 
 
sQUALITY = response to 
ow would you describe the quality of your sleep last night? ; 
1=poor, 2=fair, 3=good, 4=excellent 


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sSOL = response to 
ow long did it take you to fall asleep?  converted to minutes 
 
sNAW = response to 
ow many times did you wake up during the night?  
 
There are 11 key secondary endpoints including the 3-drug combination treatment (i.e., SM-1); however 
only 2 hypotheses will be tested using the fixed-sequence procedure to strongly control the FWER at 
0.05.  The difference in treatment groups with 95% CI and p-values will be reported for each endpoint.  P-
values that are significant based on the fixed-sequence procedure will be identified with an asterisk (see 
Section 8.5). 
 
 
Key Secondary Endpoints Controlled with FWER: 
 WASOSM-1 versus WASOPlacebo  
 LPSSM-1 versus LPSPlacebo  
 
 
Key Secondary Endpoints Not Controlled with FWER: 
 sTSTSM-1 versus sTSTPlacebo  
 sQUALITYSM-1 versus sQUALITYPlacebo  
 sSOLSM-1 versus sSOLPlacebo  
 NAWSM-1 versus NAWPlacebo  
 sNAWSM-1 versus sNAWPlacebo  
 TST1QSM-1 versus TST1QPlacebo  
 TST2QSM-1 versus TST2QPlacebo  
 TST3QSM-1 versus TST3QPlacebo  
 TST4QSM-1 versus TST4QPlacebo  
 
Each secondary endpoint will be tested for normality as described above (except NAW, sNAW, and 
sQUALITY) and the measurements transformed using natural logarithm as appropriate.  If an endpoint 
includes a minimum measurement with zero minutes, then all the measurements for that endpoint will be 
increased by 1 minute prior to transformation.  Sphericity will also be tested and reported for each of the 
secondary endpoints.  These analyses will be performed using the same repeated measures ANOVA 
model as in the primary analysis, except for NAW, sNAW, and sQUALITY endpoints.  Since missing 
data are expected to be minimal, no formal imputation methods will be used. 
 
The NAW and sNAW endpoints will be modeled using PROC GENMOD with a Poisson distribution and 
a log link function in the MODEL statement.  However, a zero-inflated Poisson (ZIP) distribution model 
will also be used to test if there is a preponderance of zero counts, i.e., more than expected under the 
Poisson distribution.  The ZEROMODEL statement will be used with a logit link to test if the mixture 
model is required.  If so, these results will be reported in addition to the standard Poisson model.  The 
model goodness-of-fit will be reported as the deviance divided by the degrees of freedom, and if 
significant p<0.05 overdispersion (i.e., the variance is significantly larger than the mean) exists then the 
results including deviance scaling will also be reported.  The same fixed effects, LSMEANS and 
ESTIMATE statements included in the primary analysis will be used.  The REPEATED statement will be 
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The sQUALITY endpoint will be modeled using ordinal logistic regression in PROC GENMOD with a 
multinomial distribution and a cumulative logit link function.  The proportional odds assumption will be 
tested and the p-value reported.  The same fixed effects, LSMEANS and ESTIMATE statements included 
in the primary analysis will be used; however, odds ratio estimates with SE and 95% CI will be reported.  
The REPEATED statement will be used to induce a compound symmetry covariance structure. 
8.3. Other Secondary Efficacy Endpoints 
The mFAS and FAS will be used for the other secondary efficacy endpoints, to compare SM-1 versus 
D+Z and SM-1 versus D+L using the same methodology as described above for the following 
comparisons.   
 
 
Endpoint Comparisons: 
 WASOSM-1 versus WASOD+Z  
 WASOSM-1 versus WASOD+L 
 LPSSM-1 versus LPSD+Z 
 LPSSM-1 versus LPSD+L   
 sTSTSM-1 versus sTSTD+Z  
 sTSTSM-1 versus sTSTD+L  
 sQUALITYSM-1 versus sQUALITYD+Z  
 sQUALITYSM-1 versus sQUALITYD+L     
 sSOLSM-1 versus sSOLD+Z  
 sSOLSM-1 versus sSOLD+L  
 NAWSM-1 versus NAWD+Z  
 NAWSM-1 versus NAWD+L  
 sNAWSM-1 versus sNAWD+Z  
 sNAWSM-1 versus sNAWD+L  
 TST1QSM-1 versus TST1QD+Z  
 TST1QSM-1 versus TST1QD+L  
 TST2QSM-1 versus TST2QD+Z  
 TST2QSM-1 versus TST2QD+L  
 TST3QSM-1 versus TST3QD+Z  
 TST3QSM-1 versus TST3QD+L  
 TST4QSM-1 versus TST4QD+Z  
 TST4QSM-1 versus TST4QD+L  
 
In addition, D+Z versus placebo and D+L versus placebo for data collected from PSG recordings and 
PSQ responses on TST, WASO, LPS, NAW, sTST, sSOL, and TST by quarters of the night will be 
analyzed.  The ESTIMATE statement will be used to summarize a point estimate and 95% CI of the 
difference in treatment groups with p-values reported as described above.   
8.4. Other Endpoints 
The mFAS and FAS will be used for the other endpoints, which are derived from the PSG recordings at 
Visits 2, 3, 4, and 5.  Other endpoints include percentage and duration in minutes of sleep stages N1, N2, 
N3, and REM and latency to REM sleep onset (defined as the number of non-REM sleep epochs from 


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lights off to the first epoch of REM sleep).  These will be analyzed using the same repeated measures 
ANOVA models described above. 
8.5. Family Wise Error Rate (FWER) Control 
Only the 5 hypotheses listed in this section will be controlled at a FWER = 0.05 for this Phase III clinical 
trial.  Only the 5 p-values from these hypotheses, when conducted in the mFAS population, have the 
possibility of being deemed statistically significant.  All other p-values, e.g., in different populations, 
subgroups, sensitivity analyses, different endpoints, etc. will not be included in the FWER and thus any p-
value <0.05 may have occurred by chance, since no multiple testing procedures will be applied to these 
other hypotheses.   
 
The order of fixed-sequence testing is as follows: 
 
null hypothesis H1: TSTSM-1 - TSTPlacebo = 0;  
 alternative hypothesis K1: TSTSM-1 - TSTPlacebo 
 
 
null hypothesis H2: WASOSM-1  WASOPlacebo = 0 
 alternative hypothesis K2: WASOSM-1  WASOPlacebo 
 
 
null hypothesis H3: TSTSM-1  TSTD+Z = 0;  
 alternative hypothesis K3: TSTSM-1  TSTD+Z 
 
 
null hypothesis H4: TSTSM-1  TSTD+L = 0;  
 alternative hypothesis K4: TSTSM-1  TSTD+L 
 
 
null hypothesis H5: LPSSM-1  LPSPlacebo = 0 
 alternative hypothesis K5: LPSSM-1  LPSPlacebo 
 
 
Starting with H1, if the null hypothesis is rejected (i.e., p-
sequence (H2) will be tested at the same two-sided alpha = 0.05. However, if H1 is accepted (i.e. p-value 
>0.05), then all following null hypotheses are also accepted and testing stops.  This procedure is repeated 
in order from H1 to H5, or until a single test fails to reject the null hypothesis. 
 
Vertical box plot figures will be created for TST, WASO, and LPS.  Each figure will include the raw data 
for the endpoint across the four treatment groups, i.e. SM-1, D+Z, D+L, and Placebo.  The box plots will 
include details for mean, 25th percentile, median, 75th percentile, with whiskers up to 1.5 times the 
interquartile range with more extreme observations indicated as outliers. 
9. Safety Analysis 
Safety and tolerability will be assessed in terms of the incidence, severity, and relationship to treatment of 
AEs and by morning measures of alertness (KSS and DSST).  In addition, safety assessments will include 
alcohol screening, urine pregnancy testing for women of childbearing potential, vital sign measurements, 
and predischarge evaluations.  A safety follow-up phone call is performed as Visit 6, 3 to 7 days after the 
final dose.  All safety analysis will be conducted on the safety set, and summaries will be presented by 
treatment group and overall.   
9.1. Adverse Events 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study regardless of 
its causal relationship to study drug.  A treatment-emergent AE (TEAE) is defined as any event not 


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present before exposure to study drug or any event already present that worsens in either intensity or 
frequency after exposure to study drug. 
 
A treatment-emergent AE is defined as an AE that meets any of the following conditions: 
 
 
Begins on or after Study Day 1 up to 7 days after the last dose of study drug 
 
Begins before Study Day 1 and worsens in severity or frequency on or after Study Day 1 up to 7 
days after the last dose of study drug 
 
Adverse events with unknown onset dates or unknown end dates will be counted as having occurred 
during the investigational drug period (i.e., as TEAEs) unless the event resolves before Study Day 1.  
Partial dates will be imputed as given in Appendix 13.3.  A TEAE will be assigned to the treatment in 1 
period if the start date of that TEAE is on or after the start date of that period, up through the day prior to 
the start date of the following period (or 7 days after last dose, for the last period).   
 
All AEs will be followed to adequate resolution.  The MedDRA Version 20.0 or higher will be used to 
code all AEs.  However, only TEAEs will be presented in AE tables, according to SOC and PT.  Any AEs 
that occur prior to Study Day 1 without worsening in severity should be recorded on the medical history 
eCRF and will be summarized as part of medical history. 
 
The overall summary of TEAEs by SOC and PT will be presented using counts and percentages for the 
following categories: 
 
Any TEAE  
 
Any study drug related TEAE 
 
Any severe TEAE 
 
Any serious TEAE 
 
Any study drug related serious TEAE 
 
Any TEAE leading to study discontinuation 
 
Any TEAE leading to death (listing only) 
9.1.1. Incidence of Adverse Events 
The total number of TEAEs will be summarized.  Also the number of subjects with at least 1 TEAE will 
be grouped by SOC and PT.  If a subject reports the same PT multiple times, then that PT will only be 
counted once per subject.  As with the PT, if a subject reports multiple TEAEs within the same SOC, then 
that SOC will only be counted once per subject.  For tables showing incidence by SOC and PT, PTs will 
be sorted within SOC in descending order of incidence in the total group.  All AEs will be presented in a 
by-subject listing; an asterisk will be used to indicate any AE that is not a TEAE. 
9.1.2. Relationship of Adverse Events to Study Drug 
Treatment-emergent AEs will be summarized by the total number of events and relationship.   
Treatment-emergent AEs will also be summarized by the number of subjects with at least 1 TEAE and 
will be grouped by SOC, PT, and relationship to study drug.  The relationships will be collected as the 
possibility that study drug caused the event.  
not related,
possibly 
related,
probably related,
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relation to 
not related.   In the TEAE relationship table, if a subject reports 
multiple occurrences of the same AE, only the most closely related occurrence will be presented for a 
given SOC or PT.  Treatment-emergent AEs that are missing relationship will be presented in the 
possibly related
  
The relationship or association of the study drug in causing or contributing to the AE will be 
characterized by the investigator using the following classification and criteria:    
 
Not 
Related: 
This relationship suggests that there is no association between the study drug and the 
reported event. 
Possibly 
Related: 
This relationship suggests that treatment with the study drug caused or contributed to 
the AE, i.e., the event follows a reasonable temporal sequence from the time of drug 
administration or follows a known response pattern to the study drug, but could also 
have been produced by other factors. 
Probably 
Related: 
This relationship suggests that a reasonable temporal sequence of the event with drug 
administration exists and, based upon the known pharmacological action of the drug, 
known or previously reported adverse reactions to the drug or class of drugs, or 
with the study drug seems likely. The event disappears or decreases on cessation or 
reduction of the dose of study drug. 
Definitely 
Related: 
This relationship suggests that a definite causal relationship exists between drug 
administration and the AE, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not 
appear to explain the event. The event reappears or worsens if the study drug is 
readministered. 
9.1.3. Severity of Adverse Event 
Treatment-emergent AEs will be summarized by the total number of events and severity.  
Treatment-emergent AEs will also be summarized by the number of subjects with at least 1 event and will 
be grouped by SOC, PT, and severity.  In the TEAE severity table, if a subject reported multiple 
occurrences of the same TEAE, only the most severe will be presented for a given SOC or PT.  
Treatment-emergent AEs 
s
presented in the data listing with a missing severity.  Treatment-emergent AEs will be classified by the 
investigator as follows: 
 
Mild: 
These events require minimal or no treat
daily activities. 
Moderate: 
These events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with normal functioning. 
Severe: 
therapy or other treatment. Severe events are usually incapacitating.  
9.1.4. Serious Adverse Events 
The seriousness of an AE should be assessed by the investigator independently from the severity of the 
AE.  A serious AE is defined as any untoward medical occurrence that at any dose results in death, is 
immediately life threatening, requires inpatient hospitalization or prolongation of existing inpatient 


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hospitalization, results in significant disability/incapacity, or is a congenital anomaly/birth defect.  
Important medical events that may not result in death, be life threatening, or require hospitalization may 
be considered serious AEs when, based upon medical judgment, they may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above.  
 
The total incidence of serious AEs and study drug related serious AEs will be presented in separate tables.  
Serious AEs and study drug related serious AEs will also be summarized by the number of subjects with 
at least 1 event and will be grouped by SOC and PT.  If a subject reported multiple occurrences of the 
same serious AE, only 1 event will be counted for a given SOC or PT.  Serious AEs will also be listed 
separately. 
9.1.5. Adverse Events Leading to Study Discontinuation 
All TEAE data collected with a 
study discontinuation?
 summarized in 
a table and presented in a listing.  There is not an option to discontinue treatment and remain in the study; 
therefore, treatment discontinuation and study discontinuation are equivalent. 
9.1.6. Death 
All subject deaths during this study will be collected and presented in a listing.  The information that is 
presented includes date of death, autopsy performed (yes/no), death certificate completed (yes/no), AE 
number, and relationship to study drug of the SAE that led to death. 
9.2. Clinical Laboratory Evaluations 
Clinical laboratory assessments will be conducted at screening only.  These will include hematology, 
chemistry, electrolytes, liver function tests, and renal function parameters.  The actual values for all 
laboratory measurements will be listed by subject and will include any scheduled and unscheduled visits. 
 
Laboratory assessments will be performed by a central laboratory.  All listings will be based on the SI 
units provided by the central laboratory.  Each subject
be flagged 
 
available.  Each subject
,
,  or if no value is 
.  
9.2.1. Hematology 
The following laboratory tests will be included at the screening assessment: red blood cell count, total 
white blood cell count (including basophils, eosinophils, lymphocytes, monocytes, and neutrophils), 
platelet count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, and 
mean corpuscular hemoglobin concentration. 
9.2.2. Chemistry 
The following laboratory tests will be included at the screening assessment: sodium, potassium, 
bicarbonate, chloride, calcium, blood urea nitrogen, random glucose, alkaline phosphatase, creatinine, 
alanine aminotransferase, aspartate aminotransferase, gamma glutamyltransferase, and total and direct 
bilirubin. 


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9.2.3. Urinalysis 
Urine drug screen test is only conducted at the screening visit.  If the test was performed, the date and 
result (positive/negative) of test will be included in a separate by-subject listing. 
9.3. Vital Sign Measurements 
Vital signs will be measured at screening and check-in and before discharge from the study center at 
Visits 2, 3, 4, and 5.  Vital sign measurements will include pulse, systolic and diastolic blood pressure, 
and respiration rate.  All vital signs will be measured after the subject has been supine for 5 minutes.  
Vital sign actual measurements and change from baseline measurements will be summarized by treatment 
group for scheduled visits; however, listings will also include any unscheduled visits. 
9.4. Physical Examination 
A brief physical examination will be performed at screening and should include evaluation of height 
(cm); body weight (kg); appearance; skin; head and neck; eyes, ears, nose, and throat; chest and lungs; 
heart; abdomen; and extremities.  Each appearance area result will be recorded as normal, abnormal, or 
not done.  
weight measured at screening will be used to calculate BMI used for 
the STOP-Bang questionnaire and to ensure that the subject meets the BMI entry criterion.  Physical 
examination findings will be provided in by-subject data listings. 
9.5. Other Safety Data 
The safety set will be used for additional safety endpoints, and summaries will be presented by treatment 
group and overall.  Data will also be presented in a by-subject data listing for the below endpoints. 
 
The KSS is completed after waking at Visit 2 through Visit 5.  The KSS [Akerstedt et al 2014] is 
self-reported 9-
extremely 
(score = 
 = 
 = 
-but no difficulty remaining 
 = 
extremely sleepy/ 
 = 9).  The steps in between have a scale 
value but no verbal label.  The KSS responses will be analyzed as a continuous variable using descriptive 
statistics and a repeated measures ANOVA model.  Due to anticipated variation in the duration between 
Lights On and completing the KSS test, the descriptive summary will subgroup the results by subjects 
Lights On and the KSS test will be included as a covariate in a separate repeated measures ANOVA 
model as a sensitivity analysis. 
 
The DSST will be completed prior to lights out and after waking at each treatment period Visit 2 through 
Visit 5.  DSST consists of 9 digit-symbol pairs, followed by a list (rows) of digits.  Under each digit is an 
open field where the subject is asked to write down on paper the corresponding symbol as quickly as 
possible.  The key outcome parameter for the DSST is the number of correct responses in 90 seconds.  
The descriptive summary will include after waking measurements following PSG assessment.  In 
addition, a repeated measures ANOVA model will be used to model the correct number of responses after 
waking as the dependent variable.  Due to anticipated variation in the duration between Lights On and 
completing the DSST  test, the descriptive summary will subgroup the results by subjects that completed 


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the DSST test will be included as a covariate in a separate repeated measures ANOVA model as a 
sensitivity analysis. 
 
Before being discharged from the study center after waking at Visits 2 through Visit 5, the subjects must 
pass the tandem gait and the Romberg test to assess whether they may be safely discharged. Failure to 
pass either test will be considered an AE, and subjects will remain at the study center until they are able to 
pass.  Test results will be summarized for both tests. 
At the screening visit and upon check-in to the study center at Visits 2, 3, 4, and 5, a urine or serum 
pregnancy test will be performed for female subjects who are of childbearing potential. Data will be listed 
by subject only. 
 
At the screening visit and upon check-in to the study center at Visits 2, 3, 4, and 5, subjects will undergo 
an alcohol breath test.  Any subject who tests positive for alcohol will not be administered study drug.  
Data will be listed by subject only. 
10. Interim Analysis 
After approximately 50% of the subjects have completed the study, the sample size to achieve at least 
80% power for the primary endpoint analysis will be recalculated based on the current blinded data.  
These data will have undergone routine data cleaning, but the data will not be expected to be 100% 
cleaned nor will the data be frozen or locked, and the blind will not be revealed.  A data extraction will be 
coordinated by the team 
 (i.e., 
final safety follow-up call).   
 
The treatment group will remain blinded and will not be included in the repeated measures ANOVA 
model, thereby pooling the variance across treatment groups.  The mFAS will be used with TST as the 
response variable.  PROC MIXED in SAS® version 9.3 or higher will only include period as a fixed 
effect.  Restricted Maximum Likelihood method and the REPEATED statement will be used to model the 
within-subject correlation as a homogenous compound symmetry matrix.  The total variance will be 
partitioned into within-subject and between-subject components using the COVTEST option in the PROC 
MIXED statement.  The square root of the within-subject variance will be entered into the Sample Size 
Recalculation Report given in Appendix 13.4; and the sample size required to maintain 80% power for 
the primary efficacy analysis.  The revised power estimate maintaining 68 subjects using the revised 
variability estimate will also be provided.     
 
To determine the amount of missing information in the data, the number of subjects will be multiplied by 
4 to determine the number of expected TST measurements.  The percentage of missing data will be 
calculated as [1  (actual number of TST measurements / expected number of TST measurements)] * 
100%.  For example, if 34 subjects completed the study at the time of the data import from the clinical 
sleep laboratory, and 3 subjects had missed their last visit and 1 subject 
eturn after their initial 
visit, then 6 TST measurements would be missing and the percent of missing data would be calculated as 
[1  (130/136)] * 100% = 4.4% missing data.  The calculated percentage of missing data will be entered 
into the Sample Size Recalculation Report. 
 


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Any additional considerations regarding the Sample Size Recalculation recommendation will be provided 
in the 
Comments  field of the report, and an overall recommendation to increase the total 
blinded sample size to a specific count or to continue the trial without modifying the sample size will be 
recorded in the report. 
11. Changes in Planned Analysis 
Since the protocol was approved, sQUALITY and sNAW based on the PSQ have been added as 
secondary efficacy endpoints with analyses described in Section 8.2 and Section 8.3.   
 
A sensitivity analysis was removed from the primary endpoint, i.e., the effects of sex and age group 
(median split) were not added to the model as fixed factors for a covariate adjustment.  However, the 
separate subgroup analyses with age group (median split) and sex were conducted. 
 
Sleep history was not summarized, but was listed. 
 
 
 


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12. References 
Akerstedt T, Anund A, Axelsson J, et al. Subjective sleepiness is a sensitive indicator of insufficient sleep 
and impaired waking function. J Sleep Res. 2014;23(3):240-52. 
 Sr. Traditional multiplicity adjustment methods in clinical trials. Stat Med. 
2013;32(29):5172-218. 
Johns MW. Epworth Sleepiness Scale (ESS) [Internet]. Lyon, France: Mapi Research Trust; 1990. 
[updated 1997; cited 30 November 2017]. Available from:  
https://eprovide.mapi-trust.org/instruments/epworth-sleepiness-scale 
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum likelihood. 
Biometrics. 1997;53(3):983-97. 
Kuehl RO. Design of experiments: statistical principles of research design and analysis, 2nd ed. Pacific 
Grove: Duxbury; 2000. 
The official STOP-Bang website [Internet]. Toronto, Canada: Toronto Western Hospital, University 
Health Network, University of Toronto; 2012. STOP-Bang Questionnaire; 2012 [cited 
30 November 2017] [2 screens]. Available from: http://www.stopbang.ca/osa/screening.php 
Yarandi HN. Crossover designs and proc mixed in SAS. Paper SD04. Proceedings of the SouthEast SAS 
Users Group, Nashville, TN; 2004. 
 
 


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13. Appendices 
13.1. 
Schedule of Events  
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 
Potential subjects will be evaluated during a screening period lasting at least 8 and no more than 21 days before the first day of the first treatment period. 
b Example study days are shown for a 1-week washout interval. Washout intervals must be no less than 5 days. Actual study days for Treatment Periods 2, 3, and 4 and the 
follow-up safety phone call will depend on the length of interdose washout intervals. 
c 
Sleep history will be assessed using the STOP-Bang questionnaire, which includes 4 subjective items (STOP: snoring, tiredness, observed apnea, and high blood pressure) and 
4 demographics items (Bang: body mass index, age, neck circumference, and gender). 
d A brief physical examination will include evaluation of height (meters); body weight (kg); appearance; skin; head and neck; eyes, ears, nose, and throat; chest and lungs; heart; 
abdomen; and extremit
 
e 
Vital sign measurements will include pulse, blood pressure, and respiration rate. All vital signs will be measured after the subject has been supine for 5 minutes. On 
polysomnography recording days, vital signs will be measured at check-
 bedtime and again before 
discharge from the study center. 
f 
Clinical laboratory assessments wil include hematology, chemistry, electrolytes, liver function tests, and renal function parameters. 
g Subjects are to record the time they go to bed with the intention of sleeping and the time they get up in a pretreatment paper diary for a minimum of 7 days during the screening 
period, with at least 5 entries completed over the 7 days ( 70% compliance). Information recorded in the diary will be communicated to study personnel no later than 24 hours 
before check-in at Visit 2 to allow the calculation of 
 paper diary to study personnel at each visit during the 
treatment and PSG period. Upon discharge from the study center at Visits 2, 3, and 4, subjects will be dispensed a new daily washout interval diary to record the time they went 
to bed with the intention of sleeping and the time they got up. Subjects will be instructed to maintain their normal sleep patterns. 


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h Before Visit 2, subjects will be contacted by study personnel and told the time and date to present for their first overnight visit. Appendix 13.2 describes the timing of study 
procedures upon check in to the study center. Upon discharge from the study center at Visits 2, 3, and 4, subjects will be told the time and date to return for the next overnight 
visit. 
i 
Subjects will be contacted by phone for a safety follow-up within the 7 days after completion of Treatment Period 4 (Visit 5) but at least 72 hours after administration of the 
final dose of study drug. Subjects who discontinue study drug or withdraw from the study prematurely will be contacted within 24 hours of the final dose of study drug. 
Outcomes of any adverse events will be discussed and recorded. If indicated, a visit to the study center for safety assessments will be scheduled. 
j 
Once eligibility has been reconfirmed at Visit 2, subjects will be randomly assigned to 1 of 4 treatment sequences. Subjects will be crossed-over to their next treatment at each 
visit based on their treatment sequence randomization. 
k Before leaving the study center at Visits 2, 3, 4, and 5, subjects will undergo a brief discharge evaluation consisting of tandem gait and the Romberg test. 


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13.2. 
Sleep Study Events by Day for Treatment Periods 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
-
 
2. 
 
3. 
 


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Abbreviation: PSG, polysomnography  
a 
Procedures must be conducted in the order they appear in the bulleted list. 
 
 
 
 
 


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13.3. 
Imputation for Partial and Missing Dates 
Adverse Event   
A TEAE will be assigned to the treatment in 1 period if the start date of that TEAE is on or after the start 
date of that period, up through the day prior to the start date of the following period (or 7 days after last 
dose, for the last period).   
 
If onset date is completely missing: 
 If TEAE end date is missing or on/after the date of first dose, then onset date is set to date 
of first dose. 
 If TEAE end day is missing, but the month and year of the TE
and year of the first dose date, then the onset date is set to the 1st day of the month and 
year. 
 If TEAE end month is missing, but the year of the TE
first dose date, then the onset date is set to January 1.  
 If TEAE end date is prior to the date of the first dose, then onset date is not imputed. 
 
If onset year is present, but month is missing: 
 If year = year of first dose, then set onset month and day to month and day of first dose. 
 If year < year of first dose, then set onset month and day to December 31st. 
 If year > year of first dose, then set onset month and day to January 1st. 
 
If month and year are present, but day is missing: 
 If year = year of first dose and 
 
If month = month of first dose, then set day to day of first dose date. 
 
If month < month of first dose, then set day to last day of month. 
 
If month > month of first dose, then set day to 1st day of month. 
 If year < year of first dose, then set day to last day of month. 
 If year > year of first dose, then set day to 1st day of month. 
 
For all other cases, set onset date to date of first dose. 
 
Concomitant Medications 
A concomitant medication will be assigned to the treatment in 1 or more periods if the start date of that 
medication is on or after the start date of that period, up through the day prior to the start date of the 
following period (or 7 days after last dose, for the last period).  
 
If start date is completely missing or year is missing, then start date will not be imputed. 
 
If start year is present and month and day are missing, then set start month and start day to 
January 1. 
 
If start year and day are present and month is missing, then set start month to January. 
 
If start year and start month are present and start day is missing, then set start day to 1st day of 
month. 


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If end date is completely missing or year is missing, then end date will not be imputed.
 
If end year is present and month and day are missing, then set end month and day to 
December 31. 
 
If end year and day are present and month is missing, then set end month to December. 
 
If end year and end month are present and end day is missing, then set end day to last day of the 
month. 
 


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13.4. 
Sample Size Recalculation Report  
 
PPD Biostatistics review of sample size for the Sequential Medicine SM-A-05 Phase 3 trial, with data 
extracted on [_____________]. 
 
The original assumption included the square root of the within mean square error from the ANOVA 
model to be 88 minutes with an effect size of 44 minutes between SM-1 and D+Z.  However, the blinded 
analysis estimated the variability at [________minutes], which resulted in a required sample size of 
[_______] to maintain a minimum of 80% power for the primary efficacy endpoint.  The current power 
under the new variability estimate with 68 subjects is [________%].   
 
The original assumption did not include any loss of power due to subjects lost to follow-up or missed 
visits.  The number of data points expected in the analysis were 4 visits times 68 subjects completed the 
study = 272 pieces of information.  However, [________%] of the data points were missing in the blinded 
analysis from the subjects up to the time of the sample size recalculation.  While these missing data have 
already inflated the variance in the ANOVA model, the assumption is made that this missing data rate 
will remain similar at the end of the study. 
 
As a result, the recommendation is: 
 
To continue the trial unmodified. 
 
To continue the trial and increase the total blinded sample size to [________subjects] 
 
 
Additional Comments: