Effectiveness of Nonspecific Methods of Treatment and Zopiclone for Chronic Insomnia
Phase: PHASE2
Conditions: Insomnia Chronic
Sponsor: I.M. Sechenov First Moscow State Medical University

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Clinical Research Protocol
Effectiveness of nonspecific methods of treatment and Zopiclone for chronic
insomnia
Protocol Number:
1
Version Date:
18th March, 2015
Investigational method:
Brief behavioral therapy program
Study Phase:
Sponsor-Investigator:
Name: Pchelina Polina
Address: 3/1-129, Ivanteevskaya str. 107150
City, State: Moscow, Russia
Funding Organization:
Site Investigator:
Name: Pchelina Polina
Telephone: +79036701725
Fax:
E-mail: polpchelina@gmail.com
Approval:
PI Signature (Name and Title)
Date

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PROTOCOL AGREEMENT
I have read the protocol specified below. In my formal capacity as Investigator, my duties
include ensuring the safety of the study subjects enrolled under my supervision.  It is
understood that all information pertaining to the study will be held strictly confidential.
Furthermore, on behalf of myself, I agree to maintain the procedures required to carry out
the study in accordance with accepted GCP principles and to abide by the terms of this
protocol.
Protocol Number: 1
Protocol Title: Effectiveness of nonspecific methods of treatment and Zopiclone for
chronic insomnia
Protocol Date: 18th March 2015
Investigator Signature
Date
Pchelina Polina, postgraduate student . Institute of professional education, Chair of
neurology. I.M.Sechenov First Moscow State Medical University
Print Name and Title
Site Name
Sleep Medicine department, University hospital №3
Address
11/1, Rossolimo st., Moscow, 119991, Russia
Phone Number
+79036701725

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TABLE OF CONTENTS
PURPOSE OF THE INVESTIGATION .........................................................................10
Name of investigational method......................................................................................10
Brief behavioral therapy program....................................................................................10
Imovan (zopiclone)..........................................................................................................10
Intended use of the investigational method .....................................................................10
Overview of Clinical Studies...........................................................................................10
STUDY RATIONALE.......................................................................................................10
Risk / Benefit Assessment ...............................................................................................11
STUDY OBJECTIVES......................................................................................................11
Primary Objective............................................................................................................11
Secondary Objectives.......................................................................................................11
STUDY DESIGN................................................................................................................11
Study Overview ...............................................................................................................11
Criteria for evaluation.......................................................................................................11
Primary Efficacy Endpoint ..............................................................................................11
Secondary Efficacy Endpoints.........................................................................................12
Safety Evaluations ...........................................................................................................12
SUBJECT SELECTION ...................................................................................................12
Study Population..............................................................................................................12
Inclusion Criteria .............................................................................................................13
Exclusion Criteria ............................................................................................................13
Allowed Medications and Treatments .............................................................................13
Prohibited Medications and Treatments ..........................................................................13
STUDY TREATMENTS...................................................................................................14
Method of Assigning Subjects to Treatment Groups.......................................................14
Blinding............................................................................................................................14
Formulation of Test and Control Products.......................................................................14
Formulation of Test Product 1.........................................................................................................................................14
Formulation of Test Product 2.........................................................................................................................................14
Packaging and Labeling...................................................................................................................................................14
Supply of Study Drug at the Site .....................................................................................15
Dosage/Dosage Regimen .................................................................................................................................................15
Dispensing ………………………………………………………………………………………………………….15

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Administration Instructions .............................................................................................................................................15
Storage
………………………………………………………………………………………………………....15
Study Drug Accountability ..............................................................................................15
Measures of Treatment Compliance................................................................................15
STUDY PROCEDURES AND GUIDELINES................................................................15
Clinical Assessments .......................................................................................................16
Concomitant Medications ................................................................................................................................................16
Demographics...................................................................................................................................................................16
Medical History ................................................................................................................................................................16
Physical Examination.......................................................................................................................................................16
Vital Signs…………........................................................................................................................................................16
Polysomnography.............................................................................................................................................................16
Questionnaire....................................................................................................................................................................16
Adverse Events .................................................................................................................................................................17
Clinical Laboratory Measurements..................................................................................17
EVALUATIONS BY VISIT..............................................................................................17
Visit 1 (Day 1/Week 1/ Month 1) ....................................................................................17
Visit 1.2 (for subjects of BBT-I-first group) (Day 8/Week 2/ Month 1) .........................17
Visit 2 (Day 14/Week 2/Month 1) ...................................................................................17
Visit  3 (Day 28/Week 4/Month 1) ..................................................................................18
Visit 3.2 (for subjects of zopiclone-first group) (Day 35/Week 5/ Month 2)..................18
Visit 4 (Day 42/Week 6/Month 2) ...................................................................................18
Visit 5 (Day 56/Week 8/Month 2) ...................................................................................18
Early Withdrawal Visit ....................................................................................................18
ADVERSE Experience REPORTING AND DOCUMENTATION..............................18
Adverse Events ................................................................................................................18
Medical Monitoring .........................................................................................................19
DISCONTINUATION AND REPLACEMENT OF SUBJECTS .................................19
Early Discontinuation of Study........................................................................................19
Replacement of Subjects..................................................................................................19
Protocol Violations.............................................................................................................19
DATA SAFETY MONITORING.....................................................................................19
STATISTICAL METHODS AND CONSIDERATIONS ..............................................20
Data Sets Analyzed..........................................................................................................20
Demographic and Baseline Characteristics .....................................................................20

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Analysis of Primary Endpoint..........................................................................................20
Analysis of Secondary Endpoints....................................................................................20
Interim Analysis...............................................................................................................21
Sample Size and Randomization .....................................................................................21
DATA COLLECTION, RETENTION AND MONITORING......................................21
Data Collection Instruments ............................................................................................21
Data Management Procedures .........................................................................................21
Data Quality Control and Reporting................................................................................22
Archival of Data...............................................................................................................22
Availability and Retention of Investigational Records....................................................22
Subject Confidentiality ....................................................................................................22
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS.................22
Protocol Amendments......................................................................................................23
Institutional Review Boards and Independent Ethics Committees..................................23
Informed Consent Form...................................................................................................23
Publications......................................................................................................................24
Investigator Responsibilities............................................................................................24

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LIST OF ABBREVIATIONS
AE
adverse event
CRF
case report form
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
PI
Principal Investigator
BDI
Beck Depression Inventory
STAI
State-trait anxiety inventory
PSQI
Pittsburg Sleep Quality Index
DBAS
Dysfunctional beliefs about sleep scale
ISI
Insomnia Severity Index
SHI
Sleep hygiene index
PSG
Polysomnography
CI
Chronic insomnia
CBT-I
Cognitive-behavioral therapy of insomnia
BBT-I
Brief-behavioral therapy of insomnia

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PROTOCOL SYNOPSIS
TITLE
Effectiveness of nonspecific methods of treatment and
Zopiclone for chronic insomnia
SPONSOR
FUNDING
ORGANIZATION
NUMBER OF SITES
RATIONALE
Importance of chronic insomnia (CI) problem is determined by
its high prevalence rate, comorbidity and resistance to the
treatment. There are pharmacological and cognitive-behavioral
approaches to the CI treatment. Even after considering all the
specific advantages and drawbacks of both methods of CI
treatment a clinician would be still in question, which one
would be preferable in a particular case.
STUDY DESIGN
Prospective randomized crossover study
PRIMARY OBJECTIVE
to test the effectiveness of short BBT-I program for chronic
insomnia in comparison with zopiclone
SECONDARY
OBJECTIVES
to find anthropometric, psychological and polysomnographic
predictors of effectiveness of each method
NUMBER OF SUBJECTS
SUBJECT SELECTION
CRITERIA
Inclusion Criteria:
meeting the criteria for chronic insomnia according ICSD-3
wilingness to take part in the study and signed informed consent form
Exclusion Criteria:
(1) unability to stop taking medications that have a proven impact on
sleep at least one week before and during the study;
(2) history of alcohol or drug abuse;
(3) major depressive disorder or other severe mental disorder
identified by a clinical assessment and medical history;
(4) dementia;
(5) pregnancy or lactation;
(6) shift or night work;
(7) medical problems that would be a direct cause of sleep
complaints: moderate/severe sleep apnea, defined as an apnea–
hypopnea index of ≥15 events per hour, periodic limb movement
disorder defined as a periodic leg movement index ≥15 events per
hour or restless legs syndrome;
(8) other serious chronic conditions or exacerbation of chronic
disorder preventing further participation.

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TEST PRODUCT, DOSE,
AND ROUTE OF
ADMINISTRATION
2-week Brief behavioral therapy program includes a question-and-
answer part; a didactic presentation of sleep regulation mechanisms;
an examination of patient's sleep log; explanation of sleep restriction
method and prescription of individual regimen of sleep; explanation
of stimulus control method; sleep hygiene education; discussion of
relaxation techniques, providing with relaxation audio recording.
BBT-I first group
Will receive two-week brief behavioral therapy followed by
medication therapy (zopiclone).
CONTROL GROUP OR
OTHER STUDY ARMS (if
applicable)
Imovan (zopiclone) intake in a dose of 7,5 mg 30 minutes before
bedtime for two weeks
zopiclone first group
will get the medication therapy (zopiclone) for the first two weeks
followed by brief behavioral therapy
DURATION OF
SUBJECT
PARTICIPATION AND
DURATION OF
STUDY
Subjects will be on study for up to 8 weeks
Screening: every 2 weeks
Treatment: 2 treatment courses 2 weeks each
Follow-up: 2-week washout periods after each treatment course
The total duration of the study was 24 months
CONCOMMITANT
MEDICATIONS
Prohibited: substances affecting sleep (hypnotics, antidepressants,
anxiolytics, antihistamine)
EFFICACY EVALUATIONS
Questionnaires (ISI, BDI, STAI, PSQI, DBAS, SHI, Big Five
Questionnaire, TAS-20), Polysomnography, β-adrenoreactivity
test
PRIMARY ENDPOINT

ISI
SECONDARY ENDPOINTS

BDI, STAI, PSQI, DBAS, SHI, β-adrenoreactivity test
OTHER EVALUATIONS
Polysomnography, Big Five Questionnaire for evaluation of
personal traits
SAFETY EVALUATIONS
All subjects will be asked about well-being and possible
adverse effects of treatment, on each biweekly visit. In the case
of condition exclusionary for study participation (exacerbation
of disease, starting medicines, incompatible with zopiclone
etc.) when it is not in the subject’s best interest to continue the
subject may be discontinued from study
PLANNED INTERIM
ANALYSES
When approximately 50% of subjects have completed the study, an
interim analysis will be conducted by the investigator. Serious
adverse events will be monitored by the committee on an ongoing
basis throughout the study.

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STATISTICS
Primary Analysis Plan
Analysis of insomnia treatment will be conducted only for patients
matching inclusion and exclusion criteria who will complete at least
one treatment course (BBT-I or medication) and fill in questionnaires
prior and after the treatment. Continuous variables will be presented
in means and standard deviation (M±SD). Categorical and rank
variables will be presented as percentages.
Statistical significance of differences between group for continuous
variables will be evaluated with Student’s t-test after confirmation of
normal variable distribution by Kolmogorov-Smirnov test.
For continuous variables with distribution other than normal Mann-
Whitney U-test will be used. For comparison of the proportions
Pearson chi-squared test will be performed.
Criterion of response to the treatment is defined as the reduction of
ISI score reduction of >7 points from baseline. Remission criterion is
defined as final ISI score of 7 points or less. Nonresponse criterion is
defined as ISI score decrease of ≤7 points from baseline. Based on
these dichotomic values participants will be divided into two groups:
responders and nonresponders for each method of treatment.
Comparison of responders and nonresponders baseline quantitative
characteristics will be performed using Student’s t-test (for normal
data distribution) or Mann-Whitney U-test (for abnormal data
distribution). Statistical significance will be set at a p-value less 0,05.
Rationale for Number of
Subjects
Study design allows to compare two therapeutic approaches with a
relatively small sample size and to determine the predictors of
effectiveness for each treatment. Thus 40 patients get 2 therapeutic
approaches. This is the representative sample size enough to produce
normal variable distribution for further parameter statistical analysis.

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PURPOSE OF THE INVESTIGATION
Name of investigational method
Brief behavioral therapy program
Imovan (zopiclone)
Intended use of the investigational method
2-week Brief behavioral therapy will be performed in two 1 hour session for treatment of
chronic insomnia (CI)
Imovan (zopiclone) in a dose of 7,5 mg has to be taken 30 minutes before bedtime for two
weeks
Overview of Clinical Studies
The main treatment approaches for chronic insomnia with proven efficacy are
pharmacologic and behavioral treatment. In accordance with the results of multiple
clinical trials and meta-analyses both methods have comparable effectiveness in
terms of sleep quality ranging between 64% (Buysse et.al., 2011) and 88% (Carson,
McDonagh, Thakurta, and Yen P. 2008).
GABA(a) agonists being the most widely used hypnotics could cause residual
daytime sedation and safety concerns like the risk of drug addiction, overdose and
intoxication along with cognitive toxicity, falls and hip fractures especially in
elderly persons (Pagel & Parnes, 2001)
The second approved treatment option for insomnia is cognitive-behavioral
treatment of insomnia combining behavioral and psychological techniques. Unlike
hypnotics this method has consistent long-term efficacy with few adverse effects
(Morin et.al., 2016). On the other hand it requires special training of therapist,
compliance of patient and noticeable time expenditures of both. Hence shortened
and simplified behavioral approaches have been developed. It includes brief
behavioral treatment for insomnia (BBT-I) lasting four weekly sessions instead of 6-
8, online sessions, telephone consultations, and self-help approaches. Although there
are no enough data for meta-analysis, BBT-I proved its efficacy in a number of
clinical comparative studies (Bootzin, 2004).
STUDY RATIONALE
Even after considering all the specific advantages and drawbacks of
pharmacological and cognitive-behavioral methods of CI treatment a clinician
would be still in question, which one would be preferable in a particular case.
There are still questions about the reason why CBT or pharmacotherapy or even
their combination didn’t reach 100% treatment response. So the treatment
response predictors identification is required for individualized treatment

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Risk / Benefit Assessment
Brief behavioral therapy has no potential adverse effects, risks of addiction or tolerance.
Zopiclone has possible hypersensitivity adverse effects as well as possible effects on
central nervous system: taste disturbance; less commonly nausea, vomiting, dizziness,
drowsiness, dry mouth, headache; rarely amnesia, confusion, depression, hallucinations,
nightmares; very rarely light headedness, incoordination, paradoxical effects. Nevertheless
it remains medication recommended for insomnia treatment in accordance with
international guidelines
STUDY OBJECTIVES
Primary Objective
To test the effectiveness of short BBT-I program for chronic insomnia in comparison with
zopiclone in Russian population.
Secondary Objectives
Identification of anthropometric, psychological and polysomnographic predictors of
effectiveness of each method.
STUDY DESIGN
Study Overview
Prospective randomized crossover study. In accordance with this design every patient will
receive two different treatment courses in random sequence: zopiclone or structured
educational program (BBT-I) delivered in two sessions. Patients of the zopiclone-first
group will receive the medication therapy for the first two weeks followed by educational
program. Patients of the BBT-I-first group will receive two-week educational program
followed by medication therapy.
Each treatment course will be separated by 2-weeks washout period that will provide the
opportunity to evaluate the sustainability of treatment effect.
The total duration of the study will be 8 weeks with 6 visits including 1 night
polysomnography (PSG), 2 face-to-face structured educational program sessions and 5
diagnostic interviews. Total duration of the study will be 2 years.
Criteria for evaluation
Primary Efficacy Endpoint
Proposed primary efficacy endpoint is change of insomnia severity index
(ISI) after treatment. Criterion of response to the treatment will be defined as the
reduction of ISI score reduction of >7 points from baseline. This criterion is
indicative of moderate improvement and validated as clinically significant
(Morin, Belleville & Belanger, 2011). Remission criterion will be defined as final

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ISI score of 7 points or less. Nonresponse criterion will be defined as ISI score
decrease of ≤7 points from baseline.
Secondary Efficacy Endpoints
1. Insomnia severity index self reported insomnia symptoms severity . Each item is
scored 0 (no problem) - 4 (very big problem) with total between 0-28 (absence of
insomnia (0-7); sub-threshold insomnia (8-14); moderate insomnia (15-21); and
severe insomnia (22-28).
2. Beck Depression Inventory. 21-item questionnaire assessing (on 4-point Likert
scales) the intensity of depressive symptoms in the past week
3. State-trait anxiety inventory. 2-part questionnaire assessing state (situational) and
trait anxiety. Both situational and trait parts comprise 20 items rated on a 4-point
Likert scale.
4. Dysfunctional beliefs about sleep scale. questionnaire assessing sleep related
cognitions in 16 item rated on a 10-point Likert scale.
5. Sleep hygiene index. questionnaire assessing sleep related behavior in 13 item
rated on a 5-point Likert scale.
6. Pittsburg Sleep Quality Index. 19-item questionnaire evaluating sleep quality over
the past month. The first 4 items are open questions, items 5 to 19 are rated on a 4-
point Likert scale. A total score range from 0 to 21. A score > 5 suggests poor
sleep quality.
7. Big Five Questionnaire. questionnaire assessing personal traits in 134 item rated
on a 5-point Likert scale.
8. Toronto alexythymia scale, short version (TAS-20) - questionnaire assessing
alexythymia in 20 item rated on a 5-point Likert scale.
9. β-adrenoreactivity test - laboratory peripheral blood sample analysis for
evaluation of sympathetic activity
10. Polysomnography. the main variables used were sleep latency, total sleep time,
sleep efficiency, wake after sleep onset, number of awakenings, sleep stages
proportion
Safety Evaluations
All subjects will be asked about well-being and possible adverse effects of treatment, on
each biweekly visit. In the case of condition exclusionary for study participation
(exacerbation of disease, starting medicines, incompatible with zopiclone etc.) when it is
not in the subject’s best interest to continue the subject may be discontinued from study
SUBJECT SELECTION
Study Population
40 subjects with a diagnosis of chronic insomnia who meet the inclusion and exclusion
criteria will participate in this study.

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Inclusion Criteria
1.
14 males, 28 females from 18 to 80 years of age.
2.
Chronic insomnia diagnosis consistent with the criteria of International Classification
of Sleep Disorder, third version (ICSD-3):
any sleep complaints i.e. difficulties falling or staying asleep, nonrestorative sleep;
waking symptoms such as fatigue, impaired concentration, and mood disturbance
etc.;
adequate opportunity and circumstances for sleep.
relapse of the mentioned symptoms at least 3 nights per week for at least 3 months:
3.
Written informed consent (and assent when applicable) obtained from subject or
subject’s legal representative and ability for subject to comply with the requirements
of the study.
Exclusion Criteria
1. unability to stop taking medications that have a proven impact on sleep at least one
week before and during the study;
2. history of alcohol or drug abuse;
3. major depressive disorder or other severe mental disorder identified by a clinical
assessment and medical history;
4. dementia;
5. pregnancy or lactation;
6. shift or night work;
7. medical problems that would be a direct cause of sleep complaints:
moderate/severe sleep apnea, defined as an apnea-hypopnea index of ≥15 events
per hour, periodic limb movement disorder defined as a periodic leg movement
index ≥15 events per hour or restless legs syndrome;
8. other serious chronic conditions or exacerbation of chronic disorder preventing
further participation.
Allowed Medications and Treatments
Regular therapy for cardiovascular diseases (beta-blockers, ACE-inhibitors, antiplatelets,
antiarrhythmics).
Prohibited Medications and Treatments
The following medications are prohibited during the study and their administration will be
considered a protocol violation:
substances affecting sleep (hypnotics, antidepressants, anxiolytics, antihistamine)

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STUDY TREATMENTS
Method of Assigning Subjects to Treatment Groups
40 subjects meeting inclusion and exclusion criteria will be randomly assigned to one of
treatment sequences (zopiclone-first group or BBT-I-first group) by card sorting method.
Blinding
The study will be open-label
Formulation of Test and Control Products
Formulation of Test Product 1
Brief behavioral therapy program will include a question-and-answer part; a didactic
presentation of sleep regulation mechanisms; the review of causes of onset and
chronification of illness; an examination of patient's sleep log; explanation of sleep
restriction method and prescription of individual regimen of sleep; explanation of stimulus
control method; sleep hygiene education; discussion of relaxation techniques. Participants
will be supplied with 32 minute audio recording "Relaxation and refreshment session for
insomnia" created for this study by Dr. A.Tabidze with verbal relaxing instructions with
quiet musical composition behind it. Participants will be instructed to listen to this
recording in headphones each day for 2-week BBT-I period after laying into bed and
turning the light off.
Formulation of Test Product 2
Imovan is a trade name of ABC, developed by Sanofi winthrop industrie , for oral
administration in the management of CI patients. Imovan is a white-colored tablet
Table 2: Formulation and Measured pH of Imovan
Imovan
Active Ingredient, mg
Zopiclone, 7,5
Other ingredient, mg
Wheat amylum, 60; natrii hydrophosphate dehydrate, 60;
lactose monohydrate 31,575; sodium carboxymethyl
starch, 4,95; magnesia stearate 0,975
Packaging and Labeling
For BBT-I program doctor will use supporting data with illustrations of process S and
process C of sleep regulation, insomnia pathogenesis, sleep hygiene and behavioral
treatment techniques for didactic presentation. At the end of the first session patients will
be given reminder card containing sleep hygiene rules and condensed information about
normal regulation of sleep and insomnia pathogenesis. For the relaxation audio record

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listening all patients will be provided with mp3 players (with audio recorded) and
individual earphones.
Imovan is produced in 2 blisters containing 10 tablets each. The blisters are contained in
carton (1 extra pouch containing 4 ampoules in the event of breakage).
Supply of Study Drug at the Site
Supporting illustrations, mp3 players with audio records and other hand-outs will be
provided by the investigator
On the zopiclone treatment stage patients will be given Imovan prescription and buy it in a
pharmacy
Dosage/Dosage Regimen
Imovan (zopiclone) in a dose of 7,5 mg will be taken 30 minutes before bedtime for two
weeks
Dispensing
Investigator will have the responsibility for dispensing of drug prescriptions and BBT-I
handouts
Administration Instructions
BBT-I will be delivered in two weekly 1-hour sessions.
Imovan (zopiclone) will be prescribed in a dose of 7,5 mg to be taken 30 minutes before
bedtime for two weeks
Storage
Imovan (zopiclone) should be kept dry at controlled room temperature, to 30ºC.
Study Drug Accountability
There will be no special accounting of the dispensing and return of study drug for
subjects.
Measures of Treatment Compliance
Subjects will be asked to keep a sleep diary noting their bedtime, wake up time, sleep
latency time, arising time, possible causes of bed sleep, drug intake and any adverse
events. They will be asked to bring their diary to each biweekly study visit along with
questionnaires evaluating quality of sleep for that period
STUDY PROCEDURES AND GUIDELINES
A Schedule of Events representing the required testing procedures supposed to be
performed for the duration of the study is in Appendix 1.

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Prior to conducting any study-related activities, written informed consent will be signed
and dated by the subject.
Clinical Assessments
Concomitant Medications
All concomitant medication and concurrent therapies will be documented at baseline
examination and at visit days. Dose, route, unit frequency of administration, and
indication for administration and dates of medication will be captured.
Demographics
Demographic information (date of birth, gender) will be recorded at baseline examination.
Medical History
Relevant medical history, including history of current disease, other insomnia history, and
information regarding underlying diseases will be recorded at baseline examination.
Physical Examination
A complete physical and neurological examination will be performed by the investigator
who is a neurologist at baseline examination.
Vital Signs
Body temperature, blood pressure, pulse will be measured after resting for 5 minutes at
baseline examination.
Polysomnography
1-night in-lab PSG (without adaptation night) will be performed at baseline examination.
Standard polysomnography montage includes 6 monopolar electroencephalography (EEG)
channels Fp1A2, Fp2A1, C3A2, C4A1, O1A2, O2A1; 1 submental electromyogram (EMG)
channel; 2 electrooculogram (EOG) channels; 2 EMG channels of the right and left tibialis
anterior muscles; 1 electrocardiogram channel; oronasal airflow pressure; thoracic and
abdominal efforts; respiratory sound; oxygen saturation; body position with
videomonitoring
Questionnaire
Subjects will be asked to fill in self-report questionnaires: Beck Depression
Inventory (BDI), State-trait anxiety inventory (STAI), Toronto Alexithymia Scale –
short version TAS-20, Big Five Questionnaire (BFQ-2R), Pittsburg Sleep Quality
Index (PSQI), Insomnia Severity Index (ISI), Dysfunctional beliefs about sleep scale
(DBAS), Sleep hygiene index (SHI) at baseline examination.
During the next 4 visits participants will repeatedly undergo diagnostic tests
including BDI, STAI, PSQI, ISI, DBAS, SHI.

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Adverse Events
Information regarding occurrence of adverse events will be captured throughout the study.
Duration (start and stop dates and times), severity, outcome, treatment and relation to
study drug will be recorded on the case report form (CRF).
Clinical Laboratory Measurements
-adrenoreactivity test
Peripheral blood sample will be collected in a sterile tube and tested in lab for erytrosyte
membranes β-adrenoreactivity by a method based on detection of adrenoreceptor
sensitivity to-endogenous catecholamines
EVALUATIONS BY VISIT
Visit 1 (Day 1/Week 1/ Month 1)
1.
Review the study with the subject and obtain written informed consent.
2.
Record demographics data.
3.
Record medical history, including a history of insomnia, diagnosis date, and prior
treatments.
4.
Record concomitant medications.
5.
Perform a complete physical and neurological examination.
6.
Perform and record vital signs.
7.
Perform and record Polysomnography
8.
Perform questionnaire completion
9.
Perform and record results of β-adrenoreactivity testing.
10.
Randomize subject for zopiclone-first or BBT-I-first group.
11.
Writing Imovan prescription for zopiclone-first group subjects
12.
First BBT-I session BBT-I-first group subjects
13.
Initiate subject diary.
Visit 1.2 (for subjects of BBT-I-first group) (Day 8/Week 2/ Month 1)
1.
Second BBT-I session
Visit 2 (Day 14/Week 2/Month 1)
1.
Record any Adverse Experiences and/or Review subject diary for adverse
experiences and dosing compliance.
2.
Perform questionnaire completion
3.
Perform and record results of β-adrenoreactivity testing.

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Visit 3 (Day 28/Week 4/Month 1)
1.
Record any Adverse Experiences and/or Review subject diary for adverse
experiences and dosing compliance.
2.
Perform questionnaire completion
3.
Perform and record results of β-adrenoreactivity testing.
4.
Writing Imovan prescription for BBT-I-first group subjects
5.
First BBT-I session for zopiclone-first group subjects
Visit 3.2 (for subjects of zopiclone-first group) (Day 35/Week 5/ Month 2)
1. Second BBT-I session
Visit 4 (Day 42/Week 6/Month 2)
1. Record any Adverse Experiences and/or Review subject diary for adverse experiences
and dosing compliance.
2. Perform questionnaire completion
3. Perform and record results of β-adrenoreactivity testing.
Visit 5 (Day 56/Week 8/Month 2)
1. Record any Adverse Experiences and/or Review subject diary for adverse experiences
and dosing compliance.
2. Perform questionnaire completion
3. Perform and record results of β-adrenoreactivity testing.
4. Medical consultation for treatment and health maintenance
Early Withdrawal Visit
1. Record any Adverse Experiences and/or Review subject diary for adverse experiences
and dosing compliance.
2. Perform questionnaire completion
3. Perform and record results of β-adrenoreactivity testing.
4. Medical consultation for treatment and health maintenance
ADVERSE Experience REPORTING AND DOCUMENTATION
Adverse Events
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal
laboratory finding), symptom or disease temporally associated with the administration of
an investigational product, whether or not related to that investigational product.  The
Investigator will discuss with the subject, possible AEs during each subject visit and
record the information in the patient CRF.  Adverse events will be described by duration
(start and stop dates and times), severity, outcome, treatment and relation to study drug, or
if unrelated, the cause.

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All reported adverse effects will be graded as mild in accordance with the Common
Terminology Criteria for Adverse Events (CTCAE) Version 3.0.
Medical Monitoring
Pchelina Polina should be contacted directly at these numbers to report medical concerns
or questions regarding safety.
Phone: +79036701725
DISCONTINUATION AND REPLACEMENT OF SUBJECTS
Early Discontinuation of Study
A subject may be discontinued from study treatment at any time if the subject or the
investigator, feels that it is not in the subject’s best interest to continue.  The following is a
list of possible reasons for study treatment discontinuation:

Subject withdrawal of consent (or assent)

Subject had a condition exclusionary for study participation

Subject is not compliant with study procedures

Adverse event that in the opinion of the investigator would be in the best interest of the
subject to discontinue study treatment
If a subject is withdrawn from treatment due to an adverse event, the subject will be
followed and treated by the Investigator until the abnormal parameter or symptom has
resolved or stabilized.
All subjects who discontinue study treatment will be recommended to come in for an early
discontinuation visit as soon as possible and then will be encouraged to complete all
remaining scheduled visits and procedures.
All subjects are free to withdraw from participation at any time, for any reason, specified
or unspecified, and without prejudice.
Reasonable attempts will be made by the investigator to provide a reason for subject
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in
the subject’s CRF. Subjects withdrawn after Visit 5 but prior to Visit 6 will be encouraged
to come in for a final visit (pass the procedures supposed for their next scheduled visit).
Replacement of Subjects
Subjects withdrawn from the study treatment will be replaced. Subjects withdrawn from
the study after Visit 5 but prior to Visit 6 won’t be replaced.
Protocol Violations
Protocol violations for this study include, but are not limited to, the following:

Failure to meet inclusion/exclusion criteria

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
Use of a prohibited concomitant medication

Non-compliance with study drug regimen, and questionnaires completion
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a
protocol violation. If a protocol violation occurs, a Protocol Violation Form detailing the
violation will be generated.
DATA SAFETY MONITORING
There will be no data monitoring committee
STATISTICAL METHODS AND CONSIDERATIONS
A Statistical Analysis Plan (SAP) is written describing all analyses that will be performed.
Data Sets Analyzed
All subjects matching inclusion and exclusion criteria who will complete at least one
treatment course (BBT-I or medication) and fill in questionnaires prior and after the
treatment will be included in the safety analysis.
Demographic and Baseline Characteristics
The following demographic variables at screening will be summarized by dose level:
gender, age, height and weight. Continuous variables will be presented in means and
standard deviation (M±SD).
Analysis of Primary Endpoint
Statistical significance of differences between ISI level before and after treatment for both
treatment methods will be evaluated with Student’s t-test after confirmation of normal
variable distribution by Kolmogorov-Smirnov test. For continuous variables with
distribution other than normal Mann-Whitney U-test will be used. For comparison of the
proportions Pearson chi-squared test will be performed.
Criterion of response to the treatment is defined as the reduction of ISI score reduction of
>7 points from baseline. This criterion is indicative of moderate improvement and
validated as clinically significant (Morin, Belleville & Belanger, 2011). As well the
criterion corresponds to approximately 1 standard deviation of the pretreatment values
(Cohen effect size of approximately 1.0). Remission criterion is defined as final ISI score
of 7 points or less. Nonresponse criterion is defined as ISI score decrease of ≤7 points
from baseline.
Analysis of Secondary Endpoints
Statistical significance of differences between BDI, STAI, PSQI, DBAS, SHI, β-
adrenoreactivity level, sleep diary data before and after treatment for both treatment
methods will be evaluated with Student’s t-test after confirmation of normal variable
distribution by Kolmogorov-Smirnov test. For continuous variables with distribution

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other than normal Mann-Whitney U-test will be used. For comparison of the proportions
Pearson chi-squared test will be performed.
Based on the response criterion participants will be divided into two groups: responders
and nonresponders for each method of treatment. Comparison of responders and
nonresponders baseline quantitative characteristics (polysomnographic, antropometric,
psychometric) will be performed using Student’s t-test (for normal data distribution) or
Mann-Whitney U-test (for abnormal data distribution). Statistical significance will be set
at a p-value less 0,05.
Safety and tolerability data will be summarized by treatment group. Adverse events will
be tabulated by treatment group and include the number of patients for whom the event
occurred, the rate of occurrence, and the severity and relationship to study drug.
Interim Analysis
Interim statistical analysis will be performed after 20 patients complete the study
protocol.
Sample Size and Randomization
The number of subjects planned to be enrolled is 40. This is a representative sample for
study of treatment effects. The crossover design of the study will allow us to compare two
therapeutic approaches with a relatively small sample size and to determine the predictors
of effectiveness for each treatment.
DATA COLLECTION, RETENTION AND MONITORING
Data Collection Instruments
The Investigator will prepare and maintain adequate and accurate source documents
designed to record all observations and other pertinent data for each study subject. The
information corresponding to each visit will be entered to the study database and to paper
CRF.
The Investigator is responsible for all information collected on subjects enrolled in this
study.  All data collected during the course of this study will be reviewed and verified for
completeness and accuracy by the Investigator.
Data Management Procedures
The data will be entered into a validated database.  The Investigator is responsible for data
processing, in accordance with procedural documentation.
All procedures for the handling and analysis of data will be conducted using Microsoft
Office Excel 2007 and STATISTICA 7

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Data Quality Control and Reporting
The Investigator is responsible for data collection, validation, processing and reporting in
accordance with procedural documentation.
Archival of Data
The database is safeguarded against unauthorized access by established security
procedures; appropriate backup copies of the database and related software files will be
maintained. Databases will be backed up by the Investigator in conjunction with any
updates or changes to the database.
Availability and Retention of Investigational Records
The Investigator must make study documents (patient files, signed informed consent
forms, copies of CRFs, questionnaires, sleep diaries) accessible to the monitor, IRB/IEC,
and Regulatory Agency inspectors upon request. A file for each subject will be
maintained that includes the signed Informed Consent, HIPAA Authorization and Assent
Form and copies of all source documentation related to that subject.  The Investigator
must ensure the reliability and availability of source documents from which the
information on the CRF is derived.
All study documents (patient files, signed informed consent forms, copies of CRFs,
questionnaires, sleep diaries) must be kept secured for the whole study period and two
years after study completion.
Subject Confidentiality
The study is open-label. All subjects will give written consent allowing their personal data
to be maintained and used for scientific purposes and published. In order to maintain
subject confidentiality, only a subject number will identify all study subjects on data
reports.
ADMINISTRATIVE, ETHICAL, REGULATORY
CONSIDERATIONS
The study will be conducted according to the WMA Declaration of Helsinki - Ethical
Principles for Medical Research Involving Human Subjects October 2013; Ethical Issues
in Patient Safety Research: Interpreting existing guidance, WHO, 2013; Сonsolidated
Guideline for good clinical practice (ICH), 1996; European Union Council and Parliament
guidelines (for instance, Guidelines on the practice of ethics committees in medical
research, 2007;  The Constitution of the Russian Federation (Article 21); OrderN 323-FZ
«About the Fundamentals of Health Protection of the Russian Federation citizens» 21
November 2011; Order N 61-FZ “About the drug use” from 22 December 2014; The
Russian Federation National Standard «Good Clinical Practice» (National Standard Р
52379-2005); and local regulations

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All study records will be kept in a locked file. Only a subject number will identify all
study subjects on data reports The Investigator is responsible for confidentiality of
subjects personal data.
Protocol Amendments
Any amendment to the protocol will not be implemented without prior written IRB/IEC
approval.
Institutional Review Boards and Independent Ethics Committees
The protocol will be reviewed and approved by the IRB/IEC of I.M. Sechenov Moscow
State Medical University on 18th March, 2015. Serious adverse experiences regardless of
causality will be reported to the IRB/IEC in accordance with the standard operating
procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC
informed as to the progress of the study. The Investigator will obtain assurance of
IRB/IEC compliance with regulations.
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol,
protocol amendments, Investigator’s Brochure, consent forms, etc.) will be submitted to
the IRB/IEC. The IRB/IECs written unconditional approval of the study protocol and the
informed consent form will be in the possession of the Investigator before the study is
initiated.  This approval must refer to the study by exact protocol title and number and
should identify the documents reviewed and the date of review.
Protocol and/or informed consent modifications or changes may not be initiated without
prior written IRB/IEC approval.  Such modifications will be submitted to the IRB/IEC and
written verification that the modification was submitted and subsequently approved
should be obtained.  The IRB/IEC must be informed of revisions to other documents
originally submitted for review; serious and/or unexpected adverse experiences occurring
during the study in accordance with the standard operating procedures and policies of the
IRB; new information that may affect adversely the safety of the patients of the conduct of
the study.
Informed Consent Form
Informed consent will be designed in accordance with the WMA Declaration of Helsinki -
Ethical Principles for Medical Research Involving Human Subjects October 2013; Ethical
Issues in Patient Safety Research: Interpreting existing guidance, WHO, 2013;
Consolidated Guideline for good clinical practice (ICH), 1996; European Union Council
and Parliament guidelines (for instance, Guidelines on the practice of ethics committees in
medical research, 2007;  The Constitution of the Russian Federation (Article 21); OrderN
323-FZ «About the Fundamentals of Health Protection of the Russian Federation citizens»
21 November 2011; Order N 61-FZ “About the drug use” from 22 December 2014; The
Russian Federation National Standard «Good Clinical Practice» (National Standard Р
52379-2005); and local regulations
The consent form generated by the Investigator will be approved by the IRB/IEC of I.M.
Sechenov Moscow State Medical University on 18th March, 2015.  The written consent

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document embodies the elements of informed consent as described in the International
Conference on Harmonisation and comply with local regulations.
A properly executed, written, informed consent will be obtained from each subject prior to
entering the subject into the trial.  Information should be given in both oral and written
form and subjects must be given ample opportunity to inquire about details of the study.
A copy of the signed consent form will be given to the subject and the original will be
maintained with the subject’s records.
Publications
The preparation and submittal for publication of manuscripts containing the study results
shall comply with all applicable privacy laws, including, but not limited to, the Health
Insurance Portability and Accountability Act of 1996.
Investigator Responsibilities
By signing the Agreement of Investigator form, the Investigator agrees to:
1.
Conduct the study in accordance with the protocol, except when to protect the safety,
rights or welfare of subjects.
2.
Personally conduct the study
3.
Ensure that the requirements relating to obtaining informed consent and IRB review
and approval meet federal guidelines.
4.
Ensure that all associates, colleagues and employees assisting in the conduct of the
study are informed about their obligations in meeting the above commitments.
5.
Maintain adequate and accurate records and to make those records available for
inspection of IRB/IEC.
6.
Ensure that an IRB will be responsible for initial and continuing review and approval
of the clinical study.
7.
Promptly report to the IRB all changes in the research activity and all unanticipated
problems involving risks to subjects or others.
8.
Seek IRB approval before any changes are made in the research study, except when
necessary to eliminate hazards to the subjects.
9.
Comply with all other requirements regarding the obligations of clinical investigators
and all other pertinent requirements listed in regulatory documents.

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APPENDIX 1. SCHEDULE OF STUDY VISITS
VISIT 1
(Day1/Week1/Mo
nth 1)a
VISIT 2
(Day14/Week2
/Month 1)a
VISIT 3
(Day28/Week4
/Month 1)a
VISIT 4
(Day42/Week6
/Month 2)a
VISIT 5
(Day56/Week8
/Month 2)
Informed Consent
X
Medical History
X
Complete Physical and
neurological Exam
X
Abbreviated Physical Exam
X
X
X
X
Height
X
Weight
X
Vital Signs
X
Polysomnography
X
β-adrenoreactivity test
X
X
X
X
X
BDI, STAI, PSQI,
DBAS, SHI
X
X
X
X
X
Big five questionnaire, TAS-
20
X
Randomization
X
Administration of Study Drug
X
X
BBT-Ib
X
X
Initiate Subject Diary
X
Subject Diary Review
X
X
X
X
Adverse Experiences
X
X
X
X
a
2 day
b
BBT-I was delivered in two weekly sessions, so during BBT-I phase each subject had additional (1.2 or 3.2) visit
for BBT-I session

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Study design