Clinical trial NCT02296892
Conditions: Bronchoscopy
Keywords: Remimazolam, midazolam, bronchoscopy, procedural sedation
Sponsor: Paion UK Ltd.
Start date: 2015-04-01; Completion date: 2017-03-13
Enrollment: 446 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A prospective, double-blind, randomized, placebo and active controlled, multi-center, parallel group study comparing remimazolam to placebo, with an additional open label arm for midazolam, in patients undergoing a bronchoscopy.

Detailed description:

Arms: arm 1: Double-blind Remimazolam arm: 5 mg iv for sedation induction, and 2.5 mg iv top-ups for sedation maintenance.

Fentanyl pre-treatment: 25-50 μg (or less for elderly/disabled subjects), and 25 μg top-up doses arm 2: Double-blind placebo arm as inactive control

Fentanyl pre-treatment: 25-50 μg (or less for elderly/disabled subjects), and 25 μg top-up doses arm 3: Open-label Midazolam arm: 1.75 mg\* iv for sedation induction and 1.0 mg\* iv for sedation maintenance. \*1.0 mg for induction and 0.5 mg for maintenance in adults over 60, debilitated or chronically ill.

Fentanyl pre-treatment: 25-50 μg (or less for elderly/disabled subjects), and 25 μg top-up doses
Interventions: intervention 1: Remimazolam intervention 2: Placebo intervention 3: Midazolam
Intervention descriptions: intervention 1: For induction and maintenance of sedation intervention 2: Inactive control arm intervention 3: For induction and maintenance of sedation

Protocol documents:
Prot_000.pdf: 
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STUDY PROTOCOL 
A Phase III Study Evaluating the Efficacy and Safety of Remimazolam (CNS 7056) 
Compared to Placebo and Midazolam in Patients Undergoing Bronchoscopy 
PROTOCOL NUMBER: 
IND NUMBER: 
VERSION 
DATE OF ISSUE: 
SPONSORED BY: 
CNS7056-008 
102,486 
Protocol Amendment 5.0 
Previous Protocols 
Protocol Amendment 4.1, 10 November 2015 
Protocol Amendment 4.0, 28 October 2015 
Protocol Amendment 3.0, 20 July 2015 
Protocol Amendment 2.0, 08 May 2015 
Protocol Amendment 1.0, 17 March 2015 
Version 1.0, 10 November 2014 
03 March 2016 
PAION UK LIMITED 
UNIT D1 
BROOKMOUNT COURT 
KIRKWOOD ROAD 
CAMBRIDGE 
CB4 2QH, UK 
24-hour SAE FAX Line:
Email: P
Non-SAE Questions for the Medical Monitor: Dr. 
 Cell phone: 435- 
Email: Jom 
Information contained in this protocol is confidential in nature and may not be used, divulged, 
published or otherwise disclosed to others except to the extent necessary to obtain approval of 
the Institutional Review Board or Ethics Committee or as required by law. Persons to whom this 
information is disclosed should be informed that this information is confidential and may not be 
further disclosed without the express permission of PAION. 
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INSTITUTIONS AND LABORATORIES INVOLVED IN THE STUDY 
Contract Research Organization 
Safety 
Study Drug Packaging 
Safety Laboratory 
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INVESTIGATOR STATEMENT OF COMPLIANCE AND SIGNATURE PAGE 
I confirm that I have read this study protocol Study Number CNS7056-008, Amendment 5.0 as of March 3rd, 2016 
including appendices and agree to the performance of the study according to this protocol. I will perform the study 
in accordance with the procedures described in the protocol and potential later amendments, and will try to 
contribute to the study in such a way that the targeted time schedule will be fulfilled. 
By my professional education and experience I am licensed to practice medicine and qualified to execute this 
clinical study in patients. 
I will provide training and all necessary information including copies of the study protocol and the Investigator’s 
Brochure (IB) to the staff involved in the performance of the study. I will keep them informed about the general 
status of the study as communicated to me by PAION including the development and report of any new information 
learned about the Investigational Product which may influence willingness of the participants to participate/continue 
to participate in the study, and will verify that all tasks are fulfilled thoroughly and in a timely manner. 
I will perform the study according to the ICH-GCP Guidelines, the Declaration of Helsinki, national laws and 
regulations, and according to accepted moral, ethical and scientific standards within clinical research. 
I confirm that my facilities (equipment, laboratory, etc) are adequate to conduct the study according to the 
requirements of the study protocol. 
A patient will not be enrolled in the study without first providing his/her written informed consent. Only the versions 
of the “Patient Information Sheet/ Informed Consent Form” and “Condensed Patient Information Sheet/ Informed 
Consent Form” reviewed by PAION and subsequently approved by the central Institutional Review Board (IRB) 
will be used. 
I, or one of the sub-investigators delegated by me, will review each case report form (CRF) prior to forwarding to 
PAION appointed monitors/ and confirm the correctness of entries by signature. 
I agree to regular monitoring visits and to audits/inspections by PAION-appointed monitors/ and/or by local, 
national, and foreign authorities. I will provide original data (eg, medical records, ECGs) to the monitors and/or 
auditors/inspectors to allow Source Data Verification. I, sub-investigators or study coordinators (eg, study nurses) 
delegated by me will cooperate in data clarification procedures. 
All patients’ data will be treated as confidential; patient data will only be transferred in pseudonymous ways. All 
research data will be the property of PAION. 
Principal Investigator 
Printed Name: 
Position: 
Professional 
Address: 
Date/Signature: 
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PROTOCOL SYNOPSIS 
Protocol Title 
Phase 3 Study to Evaluate the Efficacy and Safety of Remimazolam (CNS 7056) 
Compared to Placebo and Midazolam in Patients Undergoing Bronchoscopy 
Protocol Number 
CNS7056-008 
Sponsor 
PAION UK Limited 
Unit D1, Brookmount Court 
Kirkwood Road 
CAMBRIDGE CB4 2QH 
United Kingdom 
Study Sites & Country 
Approximately 30 sites in the USA 
Principal Investigator 
 
Investigational Product 
Remimazolam (CNS 7056) 
Phase 
3 
Indication 
Conscious sedation in patients undergoing bronchoscopy 
Design 
A prospective, double-blind, randomized, placebo and active controlled, multi-center, 
parallel group study comparing remimazolam to placebo with an additional open-label 
arm for midazolam in patients undergoing bronchoscopy. 
Primary 
Endpoint/Objective 
This is a confirmatory study to assess the efficacy and safety of remimazolam in 
inducing and maintaining suitable sedation levels for patients undergoing 
bronchoscopy. 
Primary efficacy endpoint: 
To assess the success of the procedure, as measured by: 

Completion of the bronchoscopy procedure, AND

No requirement for a rescue sedative medication, AND

No requirement for more than 5 doses of study medication within any 15 minute
window
Secondary 
Endpoints/Objectives 
The following evaluations will be made: 
1.
The time to start of procedure after administration of the first dose of study
medication.
3.
The times to ready for discharge after the end of bronchoscopy procedure
(bronchoscope out) and after the last injection of study drug (defined as ability to
walk unassisted).
4.
The times to fully alert (first of three Modified Observer's Assessment of
Alertness/Sedation (MOAA/S) scores of 5 after the end of bronchoscopy procedure
(bronchoscope out) and after the last injection of study drug).
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Sample Size 
 
 
 
  
 
 
 
 
 
 
                   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A total of 420 patients will be randomized, 300 to receive remimazolam, 60 to receive 
placebo and 60 to receive midazolam. 
Study Duration 
The maximum study duration for any patient will be up to 28 days: patients will be 
screened within 21 days prior to the bronchoscopy, and a follow-up phone call will be 
performed on Day 4 (+3/-1 days) following the procedure. 
Study Population 
Patients undergoing bronchoscopy for diagnostic or therapeutic reasons. 
Key Inclusion Criteria 
Male and female patients, aged ≥18 years, scheduled to undergo a bronchoscopy. 
Key Exclusion Criteria 
Patients with a known allergy or sensitivity to benzodiazepines, flumazenil, opioids, 
naloxone, or a medical condition such that these agents are contraindicated. 
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Investigational Product 
Formulation 
 
 
 
Analgesic Medication 
Fentanyl will be administered as an analgesic pretreatment at a dose of 25-50 µg, 
immediately prior to administration of the initial dose of the study medication. (with 
suitable dose reductions at the investigator’s discretion for elderly and debilitated 
patients) Top-up doses of fentanyl of 25 µg are allowed q 5-10 minutes until analgesia 
is adequate or the maximum dose of 200 µg per procedure has been given. An opiate 
antagonist (eg naloxone) should be immediately available at the site. Topical 
anesthesia will be administered to all the patients prior to bronchoscopy by spraying 
the nostril (if nasal route is used), nasopharynx and oropharynx with 3 mL of 2% 
lidocaine. In addition, lidocaine 2% gel may be applied to the nasal passages for ease 
in inserting the bronchoscope if the nasal route is used. 
Rescue Medication 
After determination of treatment failure, only midazolam may be administered as 
rescue sedation, according to local practice, in order to perform the bronchoscopy. 
Other sedatives are not allowed in this study. 
The benzodiazepine reversal agent flumazenil should be immediately available at the 
site for use according to standard medical practice. 
In situations where the investigator considers the use of reversal agents as necessary, 
naloxone should be considered in cases where the initial dose of flumazenil has not 
provided the anticipated effect. 
Investigational and 
Reference Product  
In order to maintain the study blind, drug preparation will be performed by an 
unblinded pharmacist at each site, and the final material will be provided to the 
investigational staff in a blinded manner.  
Study Treatment Plan  
If the fluid status allows, patients will receive a up to 1000 mL 0.9% NaCl solution 
bolus prior to fentanyl administration followed by a normal saline infusion during the 
procedure at a rate of 50 mL/hr. The administration of supplemental oxygen 4 L/min 
will begin shortly before the procedure and will continue until the patient is fully alert.  
Immediately prior to the first dose of study medication, the patients will receive 25-
50 µg of fentanyl (with suitable dose reductions at the investigator’s discretion for 
elderly and debilitated patients). 
Patients will be randomized to manually receive in a blinded fashion an initial single 
intravenous (iv) dose over one minute of remimazolam or placebo or over 2 minutes of 
midazolam in the open-label arm at the following dose levels: 
Study Drug 
Initial Dose 
Top-up 
n 
Remimazolam 
5.0 mg 
2.5 mg 
300 
Placebo 
- 
- 
60 
Midazolam 
1.75 mg* 
1.0 mg§ 
1.0 mg* 
0.5mg§ 
60 
*Healthy adults <60 yrs; §adults ≥60 yrs, debilitated or chronically ill patients. 
Sedation initiation:  
 
Remimazolam or placebo group: After the initial dose, further doses may be 
applied at least two minutes apart, until adequate sedation is achieved  
 
Midazolam group: After the initial dose, further doses may be applied at least two 
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minutes apart, until adequate sedation is achieved. 
When adequate sedation for scope insertion has been achieved (MOAA/S ≤3) a 
flexible bronchoscope will be inserted after prior nasopharyngeal 2% lidocaine spray 
and the procedure will be performed according to the usual clinical practice. 
Sedation maintenance: 
Remimazolam or placebo group: Subsequent doses of study drug will be administered 
over 15 seconds, at least two minutes apart, to maintain the sedation (MOAA/S ≤4) as 
needed. The total number of doses of study drug throughout the procedure is not 
limited, as long as no more than 5 doses are administered within any 15 minute 
window. 
Midazolam group: Subsequent doses will be administered over two minutes, at least 
two minutes apart, to maintain the sedation (MOAA/S ≤4) as needed. The total number 
of doses of midazolam throughout the procedure is not limited, as long as no more than 
3 doses are administered within any 12 minute window.   
If adequate sedation cannot be achieved at the beginning or maintained throughout the 
bronchoscopy using the initial dose plus the maximum allowed number of top-ups 
within any 15 minute window (12 minutes for midazolam), this will be defined as 
treatment failure. After such determination, rescue medication (ie midazolam) will be 
administered in such cases according to local practice in order to start or finalize the 
bronchoscopy. 

Patients will be continuously monitored for early signs of hypoventilation, airway
obstruction, or apnea, and interventions must be conducted early enough in order
to maintain homeostasis and vital signs as close as normal for the patient as
possible.

Flumazenil as a reversal agent for benzodiazepines and naloxone for opioids will
be immediately available for injection, if required.
Bronchoscopy 
The bronchoscopy procedure will be performed using a flexible device according to 
standard practice at the site. All findings from bronchoscopy will be documented, but 
will not be defined as Adverse Events (AEs). 
Assessment of Efficacy 

The primary efficacy endpoint will be the successful completion of the procedure.

Efficacy will also be evaluated by time ready to discharge, time to fully alert,
Assessment of Safety 

Physical examination.

Venous blood samples will be collected for routine safety evaluation of
biochemistry and hematology.

Vital signs (body temperature, heart rate, systolic and diastolic blood pressure and
respiratory rate) will be measured throughout the study.

Oxygen saturation will be measured throughout the study.
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
12-lead ECGs will be performed when clinically indicated (eg arrhythmia) and
before, during and after the procedure. 3-lead ECG will be continuously monitored
during the procedure until the patient is fully alert.

AEs will be monitored by the investigator and study personnel and asked about or
evaluated using non leading questions throughout the study.


Concomitant medications will be documented to evaluate possible drug
interactions and also any AEs or pharmacodynamic data that could be associated
with periprocedural medications.

AEs with a focus on respiratory and cardiovascular parameters will be documented
and analyzed separately and will include the following:

Hypoxia

Bradycardia

Hypotension

Hypertension

Respiratory depression

Prolonged sedation

 
 
 
 
 
Statistics 
Efficacy and safety analysis: 
For the primary efficacy analsysis the following hypothesis will be tested: 
H0: πRemi ≤ πPLA vs. H1: πRemi > πPLA, 
where πRemi and πPLA denote the success rates for remimazolam and placebo, 
respectively. The primary efficacy analysis will be the comparison of these success 
rates between the remimazolam and placebo groups, using the Cochran-Mantel-
Haenszel test to account for the actual fentanyl, benzodiazepine and opioid use in the 
final analysis. 
Secondary efficacy analyses: 

Descriptive testing will be performed on the secondary efficacy parameters.

Pairwise comparisons for these endpoints will be performed between the
midazolam vs remimazolam groups and between the placebo vs. remimazolam
groups, in contrast to the primary endpoint, where the midazolam group serves as
an internal validation of the sedation assessment only.

.
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
Descriptive p-values will be presented as appropriate.
Safety analysis:

Safety variables will be summarized for the overall population and for each
treatment group by descriptive statistics according to their measurement scales.

For AEs with a respiratory and cardiovascular focus and interventions undertaken
to prevent or treat such AEs, nominal p-values derived by the χ²-test will be used
for treatment group comparisons.
Interim analysis: 
No interim analysis will be performed. 
Version and Date 
Protocol Amendment 5.0; Date 03 March 2016 
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TABLE OF CONTENTS 
1
Amended Protocol Approval Signature Page .......................................................................... 2
2
Investigator Statement of Compliance and Signature Page ..................................................... 4
3
4
Protocol Synopsis .................................................................................................................... 7
5
Table of Contents ................................................................................................................... 13
6
List of Abbreviations and Definitions of Terms .................................................................... 18
7
Introduction ............................................................................................................................ 20
7.1
Background and Rationale ......................................................................................... 20
7.2
Study Population ........................................................................................................ 20
7.3
Investigational Medicinal Product ............................................................................. 21
7.4
Treatment of Possible Overdose ................................................................................ 21
7.5
7.6
Clinical Experience .................................................................................................... 22
7.6.1
First-in-man Study (CNS7056-001) ............................................................... 22
7.6.2
Phase Ib Study (CNS7056-002) ..................................................................... 23
7.6.3
Phase IIa Study (CNS7056-003) .................................................................... 24
7.6.4
Phase IIb Study (CNS7056-004) .................................................................... 24
7.6.5
7.7
Summary of Potential Risks and Benefits.................................................................. 26
8 
Ethics ..................................................................................................................................... 28
9 
Objectives .............................................................................................................................. 29
9.1
Primary Objective ...................................................................................................... 29
9.2
Secondary Objectives ................................................................................................. 29
10 Study Design .......................................................................................................................... 30
10.1
Overall Design ........................................................................................................... 30
10.2
Duration of Study Participation ................................................................................. 31
11 Study Population: Selection and Withdrawal of Patients ...................................................... 33
11.1
Inclusion Criteria........................................................................................................ 33
11.2
Exclusion Criteria ...................................................................................................... 33
11.3
Removal of Patients from Therapy or Assessment/Stop of Recruitment .................. 34
11.4
Data Monitoring Committee ...................................................................................... 34
12 Study Procedures ................................................................................................................... 36
12.1
Screening Visit: Procedures and Assessments (up to 21 days prior to procedure 
day)............................................................................................................................. 36
12.2
Day 1 of Bronchoscopy - Procedures and Assessments ............................................ 36
12.3
Follow-up on Day 2 ................................................................................................... 43
12.4
Follow-up Telephone Interview Assessments (Day 4 [+3/-1 Days]) ........................ 43
12.5
Patient Completion/Discontinuation .......................................................................... 43
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12.6
Replacement of Patients ............................................................................................. 44
12.7
Prior and Concomitant Therapy ................................................................................. 44
12.8
Rescue Sedative Medication ...................................................................................... 45
12.9
Clinical Trial Material and Co-medication ................................................................ 45
12.9.1 Identity, Supply and Storage of Clinical Trial Material ................................. 45
12.9.1.1
Remimazolam .............................................................................. 45
12.9.1.2
Midazolam ................................................................................... 46
12.9.1.3
Placebo ........................................................................................ 46
12.9.1.4
Flumazenil ................................................................................... 46
12.9.1.5
Fentanyl ....................................................................................... 46
12.9.1.6
Naloxone ..................................................................................... 46
12.9.2 Dispensing, Accountability, and Destruction ................................................. 46
12.9.2.1
Recording of Receipt, Dispensing and Return/Destruction ........ 46
12.9.3 Dispensing ...................................................................................................... 47
12.9.3.1
12.9.3.2
Flumazenil Dispensing ................................................................ 47
12.9.3.3
Fentanyl Dispensing .................................................................... 47
12.9.3.4
Naloxone Dispensing .................................................................. 47
12.9.3.5
Accountability ............................................................................. 47
12.9.4 Destruction ..................................................................................................... 48
12.9.5 Blinding and Labeling .................................................................................... 48
12.9.6 Randomization and Unblinding ..................................................................... 48
12.9.7 Assessment of Compliance ............................................................................ 49
12.9.8 Study Patient Numbering ............................................................................... 49
13 Description of Assessments ................................................................................................... 50
13.1 
Efficacy Evaluations .................................................................................................. 50
13.1.1 Modified Observer's Assessment of Alertness and Sedation ......................... 50
13.1.2 
13.1.3 
13.1.4 
13.1.5 Process to Determine Time Ready for Discharge .......................................... 51
13.1.6 Readiness-for-Discharge Score ...................................................................... 51
13.1.7 Pharmacokinetic Procedures .......................................................................... 51
13.1.8 
13.2 
Safety Procedures ....................................................................................................... 52
13.2.1 Clinical Laboratory Tests ............................................................................... 52
13.2.2 Physical Examinations ................................................................................... 53
13.2.3 Vital Signs ...................................................................................................... 53
13.2.4 Electrocardiograms 
 Adverse Events ............................................................................................... 55
13.2.6.1 
Definitions ................................................................................... 55
13.2.6.2 
Assessment of Adverse Events ................................................... 56
13.2.6.3 
Collection and Recording of Adverse Events ............................. 58
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13.2.6.4
Reporting of Adverse Events ...................................................... 59
13.2.6.5
Treatment and Follow-up of Adverse Events ............................. 60
13.2.6.6
13.2.6.7
Adverse Events Related to Effects Seen with Medications Known 
to be Associated with Abuse ....................................................... 60
13.2.6.8
Pregnancy .................................................................................... 61
13.2.6.9
Special Procedures for Managing SAEs and Unblinding ........... 61
14 Study Management ................................................................................................................ 62
14.1
Regulatory Guidelines................................................................................................ 62
14.2
Institutional Review Board ........................................................................................ 62
14.3
Informed Consent ....................................................................................................... 62
14.4
Discontinuation of the Study by the Sponsor............................................................. 62
14.5
Changes to the Protocol ............................................................................................. 62
14.6
Deviations from the Protocol ..................................................................................... 63
14.7
Selection of Investigators and Study Sites ................................................................. 63
14.8
Data Collection .......................................................................................................... 63
14.9
Study Monitoring ....................................................................................................... 64
14.10 Inspections ................................................................................................................. 64
14.11 Audits ......................................................................................................................... 64
14.12 Retention of Records .................................................................................................. 65
14.13 Disclosure and Confidentiality................................................................................... 65
14.14 Use of Information and Publication ........................................................................... 65
15 Statistical Methods ................................................................................................................. 66
15.1
Randomization and Blinding ..................................................................................... 66
15.2
Statistical Analysis ..................................................................................................... 66
15.3
Analysis Populations .................................................................................................. 66
15.4
Disposition ................................................................................................................. 67
15.5
Patient Characteristics ................................................................................................ 67
15.6
Efficacy Analysis ....................................................................................................... 68
15.6.1 Primary Analysis ............................................................................................ 68
15.6.2 Secondary Analysis ........................................................................................ 69
15.7
Safety Analysis .......................................................................................................... 71
15.7.1 Adverse Events ............................................................................................... 71
15.7.2 Clinical Laboratory Tests ............................................................................... 71
15.7.3 Vital Signs and Pulse Oximetry ..................................................................... 71
15.7.4 Electrocardiograms ........................................................................................ 72
15.7.5 Physical Examinations ................................................................................... 72
15.7.6 Visual Analogue Scale ................................................................................... 72
15.8
Interim Analysis ......................................................................................................... 73
15.9
Sample Size and Power .............................................................................................. 73
16 Finance and Insurance ........................................................................................................... 74
16.1
Financial Contract ...................................................................................................... 74
16.2
Insurance .................................................................................................................... 74
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17 References .............................................................................................................................. 75
18 Appendices ............................................................................................................................ 78
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CONTACT INFORMATION FOR INVESTIGATIVE SITES 
Project Leader 
 
 
 
 
 
Phone: +52 
Fax: +58 
Medical Advisor/Medical Monitor 
 
 
 
 
 
Phone: 43 
Fax: +51 
Sponsor 
 
 
 
 
 
 Fax: +44 (0) 1  
Clinical Trial Leader 
 
 
 
 
 
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6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ASA-PS 
American Society of Anesthesiologists-Physical Status 
AST 
Aspartate aminotransferase 
BP 
Blood pressure 
bpm 
Beats per minute 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
°C 
Celsius 
CDA 
Confidentiality Disclosure Agreement 
CFR 
Code of Federal Regulations 
CNS 7056B 
CNS 7056 besylate 
Cl 
Clearance 
cm 
Centimeter(s) 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CS 
Clinically significant 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
EEG 
Electroencephalogram 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
 
 
GCP 
Good clinical practice 
GI 
Gastrointestinal 
hr 
Hour(s) 
HCG 
Human chorionic gonadotropin 
hERG 
Human Ether-a-Go-go Related Gene 
 
 
 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug Application 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
iv 
Intravenous(ly) 
IWRS 
Interactive web response system 
kg 
Kilogram(s) 
LDH 
Lactate dehydrogenase 
LRR 
Loss of righting reflex 
min 
Minute(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
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Abbreviation 
Definition 
µg 
Microgram 
mg 
Milligram 
mL 
Milliliter(s) 
mmHg 
Millimeters of mercury 
MOAA/S 
Modified Observer’s Assessment of Alertness and Sedation 
NaCl 
Sodium Chloride (0.9% NaCl solution) 
NDA 
New Drug Application 
PD 
Pharmacodynamic(s) 
Ph Eur 
European Pharmacopeia 
PI 
Principal investigator 
PID 
Patient identification (number) 
PP 
Per protocol 
PRN 
pro re nata (as needed) 
QTc 
Corrected QT interval 
RBC 
Red blood cells 
rpm 
Revolutions per minute 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SpO2 
Peripheral blood oxygen saturation (measured by pulse oximetry) 
TEAE 
Treatment-emergent adverse event 
t½ 
Mean terminal half-life 
USA 
United States of America 
 
 
Vd 
Volume of distribution 
Vss 
Volume of distribution at steady state 
WBC 
White blood cells 
WHO-UMC 
World Health Organisation - Uppsala Monitoring Centre 
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7 
INTRODUCTION 
7.1 
Background and Rationale 
Patients undergoing uncomfortable medical procedures of limited duration generally require 
some form of sedation and/or analgesia in order to minimize their discomfort and thereby aid in 
the performance of the procedure. Currently, either a benzodiazepine (sometimes in combination 
with a narcotic) or propofol is primarily used to obtain sedation for such procedures1-5. Among 
benzodiazepines, midazolam is the most commonly used agent. While both propofol and 
benzodiazepines have documented effectiveness for use in these procedures, each agent has 
disadvantages6, 7. 
 
Propofol is an intravenous (iv) sedative/hypnotic agent with excellent sedative properties8. A 
second advantage is its extremely short half-life (t½), 9,10 which allows rapid recovery from 
sedation. 
 
A disadvantage of propofol or of fospropofol12,13,14, its pro drug, is due to its potential for 
respiratory depression and thus hypoxia11, thus requiring constant monitoring of patient’s vital 
signs and respiration rate. Consequently, a second physician or a nurse must be present to 
monitor the patient while the primary physician performs the procedure. 
 
Benzodiazepines are widely used sedative agents15 with a lower likelihood for respiratory 
depression than propofol, thus these drugs require less intensive vital sign monitoring than in 
case of propofol. 
 
Their main disadvantage is their long half life, eg even midazolam, the shortest acting 
benzodiazepine has a half-life of approximately one to three hours17. 
 
Remimazolam, with a considerably shorter half-life than even midazolam should combine the 
better safety profile of benzodiazepines over propofol with a rapid recovery and an early 
restoration of normal cognitive function16. 
 
For information regarding the concomitant use of fentanyl during bronchoscopy procedures, as 
well as regarding flumazenil, naloxone or midazolam, please refer to the full prescribing 
information for each product17, 26-28. 
 
7.2 
Study Population 
This is a study in patients undergoing flexible bronchoscopy. A total of 420 patients will be 
randomized, of which 300 will receive remimazolam, 60 will receive placebo (0.9% NaCl) in a 
blinded fashion and 60 patients will receive midazolam open label. 
 
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Randomization will be stratified by age group. The aim is to have 100 patients on remimazolam 
aged ≥ 65 years (at least 30 of these aged ≥ 75 years) across the three late stage clinical trials 
(CNS7056-006, CNS7056-008, and CNS7056-015). 
 
7.3 
Investigational Medicinal Product 
Remimazolam18,19 belongs to the class of benzodiazepines. It is an ester-based drug that is 
rapidly hydrolyzed in the body by esterases to an inactive carboxylic acid metabolite (CNS 
7054)20. 
 
 
 
 
 
7.4 
Treatment of Possible Overdose 
Flumazenil is a benzodiazepine antagonist used to reverse the effects of overdoses of 
benzodiazepines. 
Results from preclinical work have shown that treatment with flumazenil reverses loss of 
righting reflex (LRR) induced by remimazolam in rats21. In addition, during the dog maximum 
tolerated dose (MTD) study, flumazenil was administered to a dog suffering from paradoxical 
excitation following administration of remimazolam, and the animal recovered within minutes22. 
The efficacy of flumazenil as an antidote to remimazolam in humans has been shown in part A 
of the phase Ib study (CNS7056-002)23, in which flumazenil or placebo have been applied to 
subjects after administration of 0.25 mg/kg of remimazolam. While the median time to fully alert 
was 16.8 minutes after the administration of placebo, the time was shortened to 1.8 minutes after 
the administration of flumazenil. 
These data indicate that flumazenil is likely to be a suitable antidote to remimazolam in the case 
of accidental overdose and should be able to reverse the effects of remimazolam. Flumazenil will 
be immediately available on-site for use at the investigator’s discretion. In situations where the 
investigator considers the use of reversal agents as necessary, naloxone should be considered in 
cases where the initial dose of flumazenil has not provided the anticipated effect. Naloxone will 
also be available on-site for immediate use. 
Skilled personnel not participating in the procedure will provide for continuous monitoring of 
respiratory and cardiac function, i.e., pulse oximetry. Additionally, supervision by a person 
trained in Advanced Cardiac Life Support will be ensured to stay with the patient until the 
patient has recovered consciousness and has normal cardiovascular and respiratory function. 
Immediate availability of resuscitative drugs and age- and size-appropriate equipment for 
bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in 
airway management will be ensured. 
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7.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
7.6 
Clinical Experience 
7.6.1 First-in-man Study (CNS7056-001) 
In the first-in-man, double-blind, placebo- and midazolam-controlled Phase I study, 81 subjects 
received a bolus dose of 0.01 to 0.3 mg/kg of remimazolam, a dose of 0.075 mg/kg of 
midazolam, or placebo24, 25. 
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Remimazolam demonstrated the expected rapid onset and a quicker offset of sedation as 
compared to midazolam. Onset of sedation was within one to two minutes following bolus 
administration at sedative doses starting from 0.05 mg/kg. Depth and duration of sedation 
appeared to be sufficient at doses of 0.075 to 0.20 mg/kg to allow for a short-term procedure 
such as upper gastrointestinal (GI) endoscopy. Recovery from adequate sedation (MOAA/S ≤4) 
was rapid (about ten minutes) compared with midazolam (about 40 minutes). Higher doses of 
remimazolam (up to 0.30 mg/kg) appeared to safely induce loss of consciousness. 
There were minimal changes in oxygen saturation, even at doses that led to loss of 
consciousness. Airway patency was maintained throughout the study with no requirement for 
mechanical intervention. Vital signs remained stable throughout; there were no reports of hyper- 
or hypotension. The most commonly reported related adverse events (AEs) were headache (five 
events in four out of 54 subjects [9.3%] receiving remimazolam, and one event in one of 18 
subjects receiving midazolam [5.6%]) followed by bradycardia/sinus bradycardia (two events in 
two out of 54 subjects receiving remimazolam [3.7%], and four events in three out of nine 
subjects receiving placebo [33.3%]). There was no pain on injection. No serious AE (SAE) was 
reported. 
Remimazolam was rapidly cleared from plasma with a clearance that was approximately three-
fold greater than that observed for midazolam. The average percent dose cleared from plasma per 
cohort was 80 to 90% in one hour for remimazolam and 50% in one hour for midazolam. The 
elimination rate of the inactive metabolite CNS7054 was largely unchanged in the dose range 
studied, with linear PK. 
 
7.6.2 Phase Ib Study (CNS7056-002) 
This phase I dose-finding study evaluated the potential of flumazenil as an antidote to 
remimazolam (Part A), and the safety, pharmacokinetics and pharmacodynamics of multiple 
doses of remimazolam in volunteers undergoing colonoscopy (part B), in combination with a 
standard dose of fentanyl. 
The efficacy of reversal of sedation with flumazenil (0.5 mg three minutes after administration of 
remimazolam) was tested in six subjects who were sedated with a single dose of 0.25 mg/kg 
remimazolam (part A). The subjects (n=6) were randomized to receive either flumazenil or 
placebo at Day 1 and to receive the alternate treatment on Day 2. The median time to fully alert 
after administration of remimazolam and flumazenil or placebo was 1.3 minutes versus 16 
minutes, respectively. Therefore, flumazenil in the tested dose has been demonstrated to be a 
potent antidote to remimazolam. No re-sedation has been observed. 
In part B of the study, remimazolam in combination with a standard dose of fentanyl, has been 
studied to provide suitable sedation levels during a colonoscopy procedure. In this study, 
sedation was to be maintained for 30 minutes. The subjects received three initial doses of 
remimazolam (0.04, 0.075, or 0.10 mg/kg, in Cohorts of n=15 each), five or ten minutes after 
administration of 50 µg of fentanyl for analgesia. In order to maintain adequate sedation for 30 
minutes, up to six top-up doses of 0.04 mg/kg remimazolam each could have been administered. 
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Remimazolam demonstrated a rapid onset and rapid offset of sedation for all doses tested. The 
sedation success rate (defined as MOAA/S ≤4 on three consecutive measurements and 
completion of the procedure and no requirement for alternative sedative or ventilation) combined 
for the top two cohorts were found to be 83%. No dose dependency was found for time to fully 
alert, time to recovery and time to ready for discharge. 
Remimazolam demonstrated hemodynamic stability: no dose-dependent drops in systolic or 
diastolic blood pressure and oxygen-saturation have been observed. Only two patients needed 
airway interventions (chin lift, supplemental oxygen) although the patients were on room air. 
There was no need for ventilation at all. No serious or severe adverse events occurred; the rate of 
moderate adverse events was low. 
 
7.6.3 Phase IIa Study (CNS7056-003) 
The Phase IIa study was a randomized, controlled, double-blind, dose-finding study evaluating 
the efficacy and safety of remimazolam in patients undergoing diagnostic upper gastrointestinal 
(GI) endoscopy. One hundred and two patients were randomly assigned (1:1:1:1) to receive 
either midazolam at a single dose of 0.075 mg/kg, or a single injection of remimazolam at a dose 
of 0.1 mg/kg, 0.15 mg/kg, or 0.2 mg/kg. Midazolam (1-2 mg) was planned as rescue medication 
in the event that the single dose of study medication was insufficient to achieve the level of 
sedation needed for the upper GI endoscopy. The endoscopy procedure has been performed 
according to the study site practice. 
The primary objective, success of the procedure, defined as MOAA/S ≤4 on three consecutive 
measurements AND completion of the procedure AND no requirement for alternative sedative or 
ventilation, dose-dependently increased from 32% (remimazolam 0.10 mg/kg) and 56% 
(remimazolam 0.15 mg/kg) to 64% (remimazolam 0.20 mg/kg) compared to 44% for midazolam 
(0.075 mg/kg). A rapid recovery was observed in all patients. No dose dependency was seen in 
the mean time to fully alert for all remimazolam groups, and a slightly longer and more variable 
duration for midazolam-treated patients. 
Vital signs remained stable under treatment with any dose of remimazolam and Midazolam and 
no clinically relevant changes in ECG were observed. The rate of adverse events under treatment 
with remimazolam was comparable to the rate of Midazolam and did not show any dose-
dependency. No dose dependent drop of oxygen-saturation has been observed. No ventilation 
was necessary at any of the patients. No serious adverse events occurred. 
 
7.6.4 Phase IIb Study (CNS7056-004) 
The Phase IIb study was a randomized, controlled, double-blind, dose-finding study evaluating 
the efficacy and safety of remimazolam in patients undergoing standard colonoscopy. One 
hundred and sixty patients were randomly assigned (1:1:1:1) to receive either midazolam at a 
single dose 2.5 mg and 1.0 mg top-ups, or an initial injection of remimazolam at a dose of 8.0 
mg plus 3.0 mg top-ups, 7.0 mg plus 2.0 mg top-ups or 5.0 mg plus 3.0 mg top-ups. The 
colonoscopy procedure has been performed according to the study site’s practice. 
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The primary objective, sedation success rate (see Section 7.6.3 for definition) was superior for 
remimazolam over midazolam with a success rate of 92.5% for remimazolam 8.0 mg, 95% for 
7.0 mg remimazolam and 97.5% for 5.0 mg remimazolam (and their respective top-up doses) 
versus midazolam with a 75% success rate. A rapid recovery was observed in all patients. No 
dose dependency was seen in the mean time to fully alert for all remimazolam groups, and a 
slightly longer duration for midazolam-treated patients. Vital signs remained stable under 
treatment with any dose of remimazolam and midazolam and no clinically relevant changes in 
ECG were observed. Analysis of QT intervals using both a Bazett’s and a Fridericia correction 
showed statistically significant differences between the treatment groups favoring the 
remimazolam groups at 5 minutes: the point nearest the Cmax for remimazolam. 
The rate of adverse events under treatment with remimazolam was comparable to the rate of 
midazolam and did not show any dose-dependency. No dose dependent drop of oxygen-
saturation has been observed. No ventilation was necessary at any of the patients. No serious 
adverse events occurred. The data also indicated that a low initial dose of 5.0 mg of 
remimazolam and top-up doses of 2.5 mg are appropriate in colonoscopy to initiate and maintain 
an adequate sedation level. 
 
7.6.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
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8 
ETHICS 
This study will be conducted in compliance with the principles of the Declaration of Helsinki 
and its amendments, the International Conference on Harmonization (ICH) principles of Good 
Clinical Practice (GCP) (including archiving of essential study documents), and the applicable 
regulations of the country in which the study is conducted. 
A properly constituted, accredited Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) must review and approve the protocol, the patient information, and the patient 
informed consent document, and recruitment materials before the start of the study. The study 
will be conducted in compliance with all US IRB requirements. 
It is the responsibility of the investigator to ensure that written informed consent is obtained from 
the patient before any activity or procedure is undertaken that is not part of routine care. 
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9 
OBJECTIVES 
9.1 
Primary Objective 
The objective is to establish the superiority of remimazolam compared to placebo in inducing 
and maintaining suitable sedation levels for patients undergoing bronchoscopy and in 
comparison to an additional open-label midazolam group in combination with fentanyl as 
determined by sedation success. 
 
9.2 
Secondary Objectives 
The data will be evaluated to assess: 
1. 
The time to start of procedure after administration of the first dose of study medication. 
2. 
 
3. 
The times to ready for discharge after the end of bronchoscopy procedure (bronchoscope 
out) and after the last injection of study drug (defined as ability to walk unassisted). 
4. 
The times to fully alert (time to first of three consecutive Modified Observer's Assessment 
of Alertness/Sedation (MOAA/S) scores of 5 after the end of bronchoscopy procedure 
(bronchoscope out) and after the last injection of study drug).  
5. 
 
6. 
 
 
7. 
 
 
 
8. 
 
 
 
9. 
 
10. 
 
11. 
. 
12. 
. 
13. 
. 
14. 
 
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10 STUDY DESIGN 
10.1 Overall Design 
This study will be performed as a prospective, double-blind, randomized, multi-center, parallel 
group study assessing the efficacy and safety of remimazolam in patients undergoing 
bronchoscopy in comparison to placebo. An open-label midazolam group has been included as a 
validation measure for the tools to determine sedation as well as a comparator for safety. 420 
patients will be randomized, of which 300 patients belong to the remimazolam group, 60 to the 
placebo and 60 patients to the midazolam group. 
Bronchoscopy may be performed for diagnostic but as well as for therapeutic reasons, such as 
biopsies, lavage, brushings, and foreign body extraction for example. It is, however, limited to 
procedures usually performed in the bronchoscopy suite, but not the ICU (for detail see 
inclusion/exclusion criteria in Section 11). Subjects should follow fasting instructions as 
provided by the site.  
All patients will receive 0.9% NaCl solution up to 1000 mL drip starting prior to the procedure, 
if their fluid status allows. All patients will receive 25-50 µg of fentanyl immediately prior to the 
administration of study medication (with suitable dose reductions at the investigator’s discretion 
for elderly and debilitated patients). All infused fluid volumes will be recorded throughout the 
procedure. The administration of supplemental oxygen will be started shortly before the 
procedure and will be continued at a rate of 4 L/min until the patient is fully alert (three 
consecutive MOAA/S scores of 5). 
Patients will be randomized to manually receive an initial single intravenous (iv) dose over one 
minute of remimazolam 5.0 mg or an equal volume of placebo in a blinded manner and 
bronchoscopy will start when adequate sedation (MOAA/S ≤3) has been achieved.  
Sedation may be maintained by injection of further doses of remimazolam 2.5 mg or placebo in 
the same volume not earlier than two minutes apart after assessment of the sedative effect. The 
overall number of remimazolam/placebo doses is not limited as long as not more than 5 doses are 
administered in any 15 minute window. Should five doses within 15 minutes not be sufficient to 
obtain adequate sedation for the bronchoscopy, this is defined as a treatment failure. 
In the open-label midazolam arm, healthy adults <60 will receive 1.75 mg of midazolam as an 
initial dose over two minutes. Adults ≥60 years, debilitated or chronically ill patients will receive 
1.0 mg as an initial dose over two minutes. Sedation can be maintained by further doses of 
1.0 mg in healthy adults <60 years; in the case of adults ≥60 yrs, debilitated or chronically ill 
patients, the dose will be 0.5 mg. These subsequent doses should always be titrated slowly and 
administered over at least two minutes. At least two additional or more minutes should be 
allowed to fully evaluate the sedative effect. The overall number of midazolam doses is not 
limited as long as not more than three doses are administered in any 12 minute window. Should 
three doses within any 12 minute window not be sufficient to obtain adequate sedation for the 
bronchoscopy, this is to be considered a treatment failure. 
After determination of treatment failure, midazolam is defined as the only rescue sedative 
medication in such cases in order to perform or finalize the bronchoscopy. 
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If the pain is not adequately controlled by the initial dose of 25-50 µg fentanyl (with suitable 
dose reductions at the investigator’s discretion for elderly and debilitated patients), further top up 
doses of fentanyl of 25 µg q 5-10 minutes are allowed until adequate analgesia is achieved or the 
maximum dose of 200 µg per procedure has been reached. It is of note, that fentanyl is strictly to 
be applied for pain control only. 
The flexible bronchoscope will be inserted and the procedure will be performed according to the 
usual clinical practice. 
If the investigator does not proceed with the bronchoscopy or does not complete the 
bronchoscopy (eg for technical reasons), the reason will be documented. 
The primary efficacy endpoint is to assess the success of sedation of the bronchoscopy 
procedure. This composite endpoint will be determined for remimazolam and placebo by the 
following criteria: 
 Completion of the bronchoscopy procedure, AND  
 No requirement for a rescue sedative medication, AND 
 No requirement for more than 5 doses of study medication within any 15 minute 
window. 
With regard to the last point, in the case of midazolam a requirement for more than 3 doses 
doses within any 12 minute window defines a treatment failure.  
Skilled personnel not participating in the procedure will provide for continuous monitoring of 
respiratory and cardiac function, ie, pulse oximetry. Immediate availability of resuscitative drugs 
and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and 
personnel trained in their use and skilled in airway management will be ensured. A 
benzodiazepine reversal agent (flumazenil) as well as an opioid antagonist (naloxone) will be 
immediately available for use. See Appendix A for an overdose treatment protocol.  
Individuals trained in Advanced Cardiac Life Support will be present in the vicinity of the 
patient until he/she has recovered consciousness and has normal cardiovascular and respiratory 
function. 
 
10.2 Duration of Study Participation 
The maximum study duration for any patient will be up to 28 days. The patients will be screened 
within 21 days prior to the bronchoscopy. A follow-up phone call will be performed on Day 4 
(+3/-1 days) after the bronchoscopy has taken part (see Appendix B). 
 
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Screening (up to 21 days prior to procedure day):  
Patients will sign informed consent and undergo procedures to determine eligibility.  
Day of bronchoscopy (Day 1):  
After the completion of screening procedures patients will be randomly assigned to the 
remimazolam, placebo or midazolam group. Patients will receive their assigned treatment with 
25-50 µg fentanyl (with suitable dose reductions at the investigator’s discretion for elderly and 
debilitated patients) and the bronchoscopy will be performed according to the study procedures. 
Following completion of the bronchoscopy procedure, the patients will be discharged at the 
discretion of the investigator and completing the assessments after reaching fully alert status. 
Assessment of “time back to normal” in the patient’s subjective view (via telephone contact by 
study nurse on Day 2). 
 
Follow-up (Day 4 [+3/-1 days]):  
The site will telephone the patient for safety assessments. Study participation is considered 
complete after all Day 4 assessments have been performed and all Adverse Events have been 
followed-up until they resolve or become stable, or until they can be explained by another known 
cause(s). 
In case there has been any indication for the onset of a new AE since discharge, patients should 
come back to the site immediately (preferably the same day) to perform further assessments (eg 
clinically laboratory tests, 12 lead ECG, left to the discretion of the investigator). 
 
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11 STUDY POPULATION: SELECTION AND WITHDRAWAL OF PATIENTS 
A screening log of potential study candidates and an enrollment log of enrolled patients will be 
maintained by IWRS. No protected health information under the Health Insurance Portability 
and Accountability Act (HIPAA) regulations will be collected on the screening log. 
 
11.1 Inclusion Criteria 
A patient can be included into the study if he/she meets all of the following inclusion criteria: 
 Male and female patients, aged ≥18, scheduled to undergo a diagnostic or therapeutic 
flexible bronchoscopy in the bronchoscopy suite (therapeutic bronchoscopies may 
include lavage, biopsies, brushings, and foreign body extraction, for example). 
 American Society of Anesthesiologists Physical Status Score 1 through 333. 
 BMI ≤ 45. 
 SpO2 ≥ 90% in ambient air or with no more than 2L/min of O2 support. 
 For all female patients, negative result of urine pregnancy test. Additionally, for women 
of child-bearing potential only, use of birth control during the study period (from the time 
of consent until all specified observations are completed). 
 Patient voluntarily signs and dates an ICF that is approved by an IRB prior to the conduct 
of any study procedure, including screening procedures. 
 Patient is willing and able to comply with study requirements and available for a Follow-
up phone call on Day 4 (+3/-1 days) after the bronchoscopy. 
 
11.2 Exclusion Criteria 
A patient will not be included if he/she meets one or more of the following exclusion criteria: 
 Patients with a known sensitivity to benzodiazepines, flumazenil, opioids, naloxone, or a 
medical condition such that these agents are contraindicated. 
 Bronchoscopy outside the bronchoscopy unit (eg ICU). 
 Patients on mechanical ventilation. 
 Tracheal stenosis. 
 Planned Laser bronchoscopy, rigid scope bronchoscopy. 
 Use of unstable doses of benzodiazepines and opioids for any indication eg, insomnia, 
anxiety, spasticity. An unstable dose means dose changes of more than 50% of the 
previous dose within 30 days prior to day of procedure. 
 Female patients with a positive pregnancy test at screening or baseline and lactating 
female patients. 
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 Patients with positive drugs of abuse screen (unless explained by concomitant 
medication) or a positive ethanol test at baseline. 
 Patient with a history of drug or ethanol abuse within the past 2 years. 
 Patients in receipt of any investigational drug or use of investigational device within 30 
days or less than seven half-lives (whichever is longer) before the start of the study, or 
scheduled to receive one during the study period. 
 Participation in any previous clinical trial with remimazolam. 
 Patients with an inability to communicate well in English with the investigator, or 
deemed unsuitable according to the investigator (in each case providing a reason). 
 
11.3 Removal of Patients from Therapy or Assessment/Stop of Recruitment 
All patients are free to withdraw from participation in this study at any time, for any reason, and 
without prejudice. 
The investigator may terminate a patient from the study at any time for lack of therapeutic effect 
that is intolerable to the patient, or otherwise considered unacceptable; for intolerable or 
unacceptable AEs, intercurrent illness, noncompliance with study procedures, or administrative 
reasons; or in the investigator’s opinion, to protect the patient’s best interest. 
Irrespective of the investigator’s discretion, a subject will be immediately discontinued from the 
study for the following reasons: 
- Need for endotracheal intubation 
- Use of catecholamines 
If a patient is withdrawn before completing the study, the reason for withdrawal will be entered 
on the appropriate CRF page. Whenever possible and reasonable, the evaluations that were to be 
conducted at the completion of the study should be performed at the time of premature 
discontinuation. 
Patients who withdraw from the study after randomization will not be replaced. 
 
On the study level: the clinical investigation can be terminated due to either administrative or 
safety reasons. A regular review of aggregate study data will be performed by the Data 
Monitoring Committee (DMC). Based on their review, the DMC may recommend to continue, 
impose a temporary halt or stop the study.  
 
11.4 Data Monitoring Committee  
A DMC will be formed, to monitor the study data at regular intervals, and will comprise of three 
independent physicians and a statistician, all of whom have no involvement with the conduct of 
this clinical trial. The DMC will operate according to a specific charter. 
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12 STUDY PROCEDURES 
12.1 Screening Visit: Procedures and Assessments (up to 21 days prior to procedure day) 
The Screening Visit will take place within the 21 days prior to dosing; Day -21 to Day 1. 
During the Screening Visit, study procedures will be explained in detail by the investigator, 
informed consent will be obtained and the following evaluations will be performed (see 
Appendix B). 
 
Assign a screening number 
 
Review inclusion/exclusion criteria 
 
ASA Score33 
 
Record medical and medication history 
 
Record last participation/receipt of investigational product or use of investigational 
device 
 
Demographics: ethnicity (Hispanic/Latino, not Hispanic/Latino), race (White, American 
Indian/Alaska Native, Asian, Native Hawaiian or other Pacific Islander, Black/African 
American, biracial), gender, age (yrs) 
 
Complete physical examination (except rectal, breast or genitalia exams unless medically 
indicated); plus height, weight, and BMI 
 
Assess hemodynamics, after resting supine for more than five minutes (supine heart rate, 
systolic and diastolic blood pressure), record respiratory rate 
 
Take body temperature 
 
Perform supine single 12-lead ECG 
 
Perform clinical laboratory tests (serum chemistry, hematology)  
 
Perform urine drugs-of-abuse test (positive result will exclude from the study unless 
result can be explained by concomitant medication)  
 
Perform oral saliva test for ethanol (by presentation of a positive result the patient will be 
excluded from the study) 
 
Perform urine pregnancy test (HCG) for female patients  
 
Pulse oximetry  
 
12.2 Day 1 of Bronchoscopy - Procedures and Assessments  
The patient’s eligibility will be reconfirmed by a review of inclusion/exclusion criteria and the 
following procedures and assessments will be completed. 
Within five hours prior to the initial administration of trial medication: 
 
Review inclusion and exclusion criteria and verify that the patient continues to meet all 
study entry criteria. 
 
Update medical history (including adverse reactions experienced and concomitant 
medications taken, if applicable, since Screening). 
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 
Baseline physical examination (symptom-directed exam). 
 
Weight will be measured while patient is without shoes or heavy coat. 
 
Record vital signs (supine heart rate, systolic and diastolic BP, and temperature). 
 
Collect blood samples for clinical laboratory tests (hematology, serum chemistry). 
 
Collect a urine sample for the pregnancy test from female patients. 
 
Collect a urine sample for the drug screen. 
 
Perform ethanol saliva test. 
 
Perform a 12-lead ECG. 
If randomization is at the same day as screening, the above mentioned assessments do not need 
to be repeated. 
For all patients applicable: 
 
Adverse events and concomitant medications will be assessed. 
 
Assign a randomization number to each eligible patient. 
 
 
 
 
 
 
Within 30 minutes prior to initial administration of trial medication: 
 
Hemodynamic parameters (supine heart rate and systolic and diastolic blood pressure) as 
well as body temperature will be measured at pre-defined intervals and documented using 
an electronic recording device, body temperature will be determined. 
 
Administration of 0.9% NaCl solution will start, if the fluid status of the patient allows 
and in absence of contraindications eg renal failure, and should continue until the end of 
bronchoscopy. 
 
Within 15 minutes prior to initial administration of trial medication: 
 
Baseline MOAA/S score will be recorded. 
 
Continuous 3 lead ECG recording will commence and continue until fully alert. 
 
Baseline SpO2 measurement will be recorded and continuous SpO2 monitoring by pulse 
oximetry will commence.  
 
Baseline respiratory rate measurement will be recorded and continuous RR monitoring by 
a medical device will commence. 
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 
Administration of supplemental oxygen will be started at a rate of 4 L/min by nasal 
prongs (if standard) and will continue until the patient is fully alert. Oxygen may be 
increased if needed, according to oxygen saturation monitoring. 
 
Airway management assessment should be performed. (Immediate availability of oxygen, 
resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation 
and intubation, presence of skilled personnel for the maintenance of a patient airway and 
support of ventilation). 
 
Baseline hemodynamic parameters (supine heart rate and systolic and diastolic blood 
pressure) will be measured immediately before dosing of fentanyl. 
 
Topical airway anesthesia will be undertaken with 3 mL of 2% Lidocaine, administered 
either as a spray to upper airways or administered via nebulizer. 
 
Approximately one minute prior to initial administration of fentanyl and trial medication for 
sedation initiation: 
 
In case of nasal route, topical lidocaine 2% gel will be inserted into nostrils (or as 
standard) and patient will be asked to ‘sniff’ the lidocaine into the nose. 
 
Hemodynamic parameters (supine heart rate and systolic and diastolic blood pressure) 
will be measured and documented in the eCRF at defined time points. 
 
 
 
Respiratory rate will be recorded 
 
DOSING OF FENTANYL, DOUBLE BLIND STUDY MEDICATION, AND OPEN-LABEL MIDAZOLAM 
Preparation: 
Up to 1000mL normal saline will be administered if the fluid status of the patient allows.  In all 
subjects the details of fluid administration information will be documented including: the date 
and time of fluid initiation and end of infusion, volume infused at the time of sedation initiation, 
measurement of additional fluid and time administered during the procedure, as well as total 
volume infused. 
The dose and time of administration of all medication, as well as all MOAA/S scores, will be 
documented. 
After start of administration of the randomized study medication (t=0) MOAA/S scores will be 
recorded at 1, 1.5, 2, 2.5 and 3 minutes and further in 1-minute intervals until fully alert (fully 
alert is defined as the first of three consecutive MOAA/S measurements of 5). 
 
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Dosing of fentanyl: 
Immediately before administration of study sedative medication, 25-50 μg fentanyl or a suitably 
reduced dose for elderly or debilitated patients will be administered iv slowly over 1-2 minutes 
for analgesia.  
All patients receiving fentanyl will require close monitoring of respiratory rate and continuous 
oxygen saturation monitoring.  Neither initial nor subsequent doses should be administered to 
patients who have a respiratory rate of less than 8 breaths per minute or an oxygen saturation of 
less than 90%. 
Supplementary doses of 25 μg of fentanyl may be given until adequate analgesia is achieved or a 
maximum dose of 200 μg is reached.  Five to ten minutes should be allowed to assess the 
analgesic effect.  Such subsequent doses should ONLY be administered if the patient’s pain is 
not adequately controlled.  If depth of sedation is insufficient, ONLY the dose of the sedative 
should be adjusted. 
The dose and time of administration of any medication will be documented.  Patients should be 
observed closely for signs of adverse events and possible respiratory distress.  Naloxone should 
be close at hand for emergency administration (see Appendix A) 
Immediately after the dosing of fentanyl and depending on the allocated study arm, the following 
dose instructions for study sedative medication (blinded study arm or open label midazolam) 
have to be followed: 
 
Dosing of double blind study medication (remimazolam or placebo): 
Initiation of sedation (remimazolam or placebo): 
The initial dose of 2 mL double-blinded study medication will be administered manually by iv 
injection over one minute with watch control.  
MOAA/S scores will be recorded at 1, 1.5, 2, 2.5 and 3 minutes and further in 1-minute intervals, 
after start of blinded study drug dosing (t=0) until fully alert.  At least two additional minutes 
should be allowed to evaluate fully the sedative effect.  If there is sufficient sedation 
(MOAA/S ≤3) the procedure can start. 
If there is insufficient sedation (MOAA/S 4 or 5) to begin the procedure after the initial dose of 
blinded study medication, a supplementary dose of 1 mL of blinded study medication may be 
administered by slow iv injection (over approximately 15 seconds) at least two minutes after the 
end of the first dose and after MOAA/S assessment. 
If initial sedation is still insufficient, further supplementary doses of 1 mL of blinded study 
medication may be administered by slow iv injection (over approximately 15 seconds), at least 
two minutes apart. 
If there is still insufficient sedation to begin the procedure after the initial dose and a maximum 
of four additional doses within a 15 minute period, “treatment failure” is recorded and the patient 
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should receive midazolam rescue medication at the discretion of the investigator to start the 
procedure. 
 
Maintenance of sedation (remimazolam or placebo): 
If sedation from blinded study medication is sufficient to allow colonoscopy to begin, subsequent 
doses of 1mL double blind study medication can be administered to maintain the patient at an 
adequate sedation level (MOAA/S ≤4). 
If the MOAA/S is ≥4 additional doses (as manual bolus injections over 15 seconds) of 1mL 
remimazolam or placebo can be administered, at least two minutes apart, to maintain or again 
reach an adequate sedation level.  Two or more additional minutes should be allowed to evaluate 
fully the sedative effect. 
During the procedure “treatment failure” is recorded if adequate sedation (MOAA/S ≤4) cannot 
be maintained by blinded study medication despite five doses within any 15 minute period.  The 
patient should then receive midazolam rescue sedative medication at the discretion of the 
investigator to allow for completion of the procedure or for scope removal.  Only midazolam 
may be used as rescue sedative medication 
 
Dosing of open label midazolam: 
Initiation of sedation (midazolam): 
The initial midazolam dose will be administered manually by iv injection over two minutes with 
watch control.  In healthy adults <60 yrs, the initial dose will be 1.75 mL solution containing 
1.75 mg.  In the case of adults ≥60 yrs, or debilitated or chronically ill patients, the dose will be 
1mL solution containing 1.0 mg. 
MOAA/S scores will be recorded at 1, 1.5, 2, 2.5 and 3 minutes and further in one minute 
intervals, after start of the open label midazolam dosing (t=0) until fully alert.  At least two 
additional minutes should be allowed to evaluate fully the sedative effect.  If there is sufficient 
sedation (MOAA/S ≤3) the procedure can start. 
If there is insufficient sedation to begin the procedure after the initial dose of midazolam 
(MOAA/S 4 or 5), a supplementary dose of midazolam may be administered by iv injection over 
at least two minutes under watch control, at least two minutes after the end of the last dose and 
after MOAA/S assessment.  In the case of healthy adults <60 yrs, the dose will be 1 mL 
containing 1.0 mg.  In the case of adults ≥60 yrs, or debilitated or chronically ill patients, the 
dose will be 0.5 mL containing 0.5mg. 
If initial sedation is still insufficient, one further supplementary dose of midazolam may be 
given, at least two minutes apart. 
If there is still insufficient sedation to begin the procedure after the initial dose and a maximum 
of two further doses within a 12 minute period, “treatment failure” is recorded and the patient 
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should receive midazolam rescue medication at the discretion of the investigator to start the 
procedure. 
 
Maintenance of sedation (midazolam): 
If sedation from open label midazolam study medication is sufficient to allow colonoscopy to 
begin, subsequent doses can be administered to maintain the patient at an adequate sedation level 
(MOAA/S ≤4). 
If the MOAA/S is ≥4 additional doses (as manual injections over two minutes) of midazolam can 
be administered, at least two minutes apart, to maintain or again reach an adequate sedation 
level. 
For healthy adults <60 yrs, the dose of midazolam will be 1.0 mg (1mL); in the case of adults 
≥60 yrs, debilitated or chronically ill patients, the dose will be 0.5 mg (0.5mL).  These 
subsequent doses should always be administered as manual injections over at least two minutes, 
and two or more additional minutes should be allowed to evaluate fully the sedative effect. 
During the procedure “treatment failure” is recorded if adequate sedation (MOAA/S ≤4) cannot 
be maintained by midazolam study medication, despite three doses within any 12 minute period.  
The patient should then receive midazolam rescue sedative medication at the discretion of the 
investigator to allow for completion of the procedure or for scope removal.  Only midazolam 
may be used as rescue sedative medication. 
 
Sedation and analgesia reversal: 
The benzodiazepine reversal agent flumazenil should be immediately available for use at the site 
(see Appendix A). 
 
The opioid antagonist naloxone should be immediately available for use at the site (see 
Appendix A). 
 
Start of bronchoscopy: 
The scope will be inserted when sufficient sedation is achieved (MOAA/S ≤3). 
 
Post-dose assessments Day 1:  
All safety and PK post-dose assessments (where appropriate) will be performed based on the 
start time of the initial infusion of study medication: 
 
Hemodynamic parameters: Systolic and diastolic blood pressure will be recorded at 2, 5, 
10 and every five minutes thereafter for the duration of the procedure until the patient is 
fully alert and clinically stable. Heart rate will be monitored and recorded continuously 
using an electronic device (Nellcor, Covidien) and documented in the CRF at 2, 5, 10 and 
every 5 minutes thereafter for the duration of the procedure until the patient is fully alert 
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and clinically stable. The heart rate nadir will be determined and will also be recorded in 
the eCRF. In addition, these parameters will be recorded immediately prior to, and two 
minutes after each administration of fentanyl. 
 
Respiratory rate will be recorded and monitored continuously using an electronic device 
(Nellcor, Covidien) until fully alert. Values will be documented in the eCRF at 2, 5, 10 
and every five minutes thereafter for the duration of the procedure until the patient is 
fully alert and clinically stable. The respiratory rate nadir will be determined and will also 
be recorded in the eCRF. 
 
SpO2 will be monitored and recorded continuously from 15 minutes pre-dose, and values 
will be documented in the eCRF at 2, 5, 10, and every five minutes thereafter for the 
duration of the procedure until the patient is fully alert and clinically stable. The SpO2 
nadir will be determined and will also be recorded in the eCRF.  In addition, SpO2 will be 
recorded immediately prior to, and two minutes after each administration of fentanyl. 
 
Single 12-lead ECGs will be performed one minute after the first dose, five minutes after 
initial dosing, and every 10 minutes until the end of the procedure if possible, and also 5 
minutes after the end of procedure and at discharge or if clinically warranted, eg in case 
of arrhythmias. 3 lead ECG recording will be performed continually throughout the 
procedure with documentation of presence or absence of any arrhythmias 2 minutes post t 
= 0 and every 5 minutes until fully alert. Any patients with evidence of QT prolongation 
should be monitored until the ECGs return to baseline. 
 
MOAA/S scores will be recorded post t=0 at 1, 1.5, 2, 2.5 and 3 minutes and at 1-minute 
intervals thereafter until fully alert (fully alert is defined as the first of three consecutive 
MOAA/S measurements of 5). After fully alert, MOAA/S scores will be recorded every 5 
minutes until ready for discharge (see below), and after ready for discharge every 10 
minutes (up to 90 minutes) until actual discharge of patient. Following completion of the 
procedure and fully alert, patients will be allowed clear liquids and a meal at the 
discretion of the investigator. 
 
The time ready for discharge must be determined. 
 
Actual times of discharge from (a) the bronchoscopy suite, and (b) the recovery room 
after the last injection of study medication and after the end of the bronchoscopy will be 
recorded.  
 
At 30, 60 and 90 minutes post t=0, a ready-for-discharge score will be determined. 
 
 
 
 
 
Adverse events will be assessed. 
 
Any airway management procedures will be recorded. 
 
Concomitant medications will be reviewed.  
 
Blood samples for clinical laboratory tests (hematology, serum chemistry) will be 
collected at least 3 hrs after the procedure. 
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 
Body temperature will be determined 5 minutes after end of procedure, at fully alert and 
at discharge. 
 
 
 
 
 
In order tocapture the potential time differences between the main clock (used for assessment of 
time = 0) and the Nellcor device clock, both times shall be recorded simultaneously at some 
point within 30 minutes prior to the start of the procedure. 
 
Pharmacokinetic determinations: 
For patients ≥ 75 years at selected sities, venous blood samples (approximately 4 mL each) for 
plasma concentration analysis of remimazolam, will be collected in samples obtained at five 
accurately recorded time points during and after the procedure.  The first three during the 
procedure should be no closer than two minutes after the end of a dose, with the first sample 
taken after the initial dose.  The two samples after the anticipated last dose should be (a) between 
5 and 15 minutes later and (b) at least 20 minutes post dose, but no later than about 2 hours. 
 
12.3 Follow-up on Day 2 
Assessment of “time back to normal” in the patient’s subjective view (via telephone contact by 
study nurse on Day 2). 
 
12.4 Follow-up Telephone Interview Assessments (Day 4 [+3/-1 Days]) 
The following assessments will be undertaken via telephone interview at the Follow-Up Contact: 
 
 
 
Record any concomitant medications and AEs reported since Day 1. 
In case there has been any indication for the onset of a new AE since discharge, patients should 
come back to the site immediately (preferably the same day) to perform further assessments (eg 
clinically laboratory tests, 12 lead ECG, left to the discretion of the investigator). 
 
12.5 Patient Completion/Discontinuation 
A patient is considered to have completed the study once all Follow-up call assessments have 
been completed or the patient withdraws from the study prematurely. 
While patients are encouraged to complete all study evaluations, they may withdraw from the 
study at any time and for any reason. Every effort will be made to determine why any patient 
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withdraws from the study prematurely. This information will be recorded. If a patient withdraws 
prematurely after dosing, patients will be monitored until they are stable for discharge. All data 
normally collected at the End of Study Visit should be recorded at the time of premature 
discontinuation, or at the scheduled End of Study Visit. Patients’ participation may be terminated 
prior to completing the study for any of the following reasons: 
1. Adverse event 
2. Protocol violation 
3. Loss to follow-up 
4. Patient’s own request (withdrawal of consent) 
5. Endotracheal intubation 
6. Use of catecholamines 
7. Other 
If a patient is not reachable for the Follow-up call or is discontinued from the study, an attempt 
will be made to determine the reason(s). If the patient is unreachable by telephone, a registered 
letter will be sent to the patient requesting that he/she contact the clinic. 
All patients with an ongoing SAE at the End of Study call (scheduled or premature) must be 
followed until the event is resolved (with or without sequelae) or deemed stable. 
 
12.6 Replacement of Patients 
Patients who withdraw from the study before randomization will be replaced to ensure the 
planned number of patients can be randomized. 
Patients who withdraw from the study after randomization will not be replaced. A log of screen 
failures and subjects who are withdrawn prior to randomization that includes the reason(s) they 
were not enrolled or reason(s) for their pre-randomization withdrawal will be kept. 
 
12.7 Prior and Concomitant Therapy 
Treatment with the following medications and therapies before study entry or during the study is 
not allowed (see also Section 11): 
 Any investigational drug when taken within 30 days or less than seven half-lives (whichever 
is longer) before Screening. 
 Use of unstable doses of benzodiazepines or opioids for any indication eg, insomnia, anxiety, 
spasticity. An unstable dose is a dose change of more than 50% of the previous dose, within 
30 days prior to day of procedure. 
 Use of propofol within less than 5 half-lives prior to day of procedure 
 Diphenhydramine and other anti-histamines, unless they are administered on a regular dose 
and schedule (not PRN) for at least one week before the procedure in order to avoid any 
interference. 
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In case of nausea and vomiting, sites are allowed to administer 5HT3-antagonists, either as 
prophylaxis, or to treat an adverse event. 
 
12.8 Rescue Sedative Medication 
Rescue sedative medication is defined as any medication given, over and above that of the 
assigned treatment arm, in order to either induce or maintain a suitable sedation level to start or 
continue with the procedure.  Rescue sedative medication would thus be given if adequate 
sedation by the assigned study drug could not be induced or maintained.  The patient should 
receive midazolam as the rescue sedative at the discretion of the investigator, to allow for 
completion of the procedure or scope removal. In cases where the investigator regards it 
necessary to use antagonizing agents, naloxone should be considered if the patient does not react 
as expected to flumazenil. 
 
Sedation initiation:  
Rescue sedative medication may only be applied after five doses of double-blind study drug 
within any 15 minute window have been given and adequate sedation to start the procedure 
(MOAA/S ≤3) has not been achieved. In the case of midazolam, rescue sedative medication may 
be applied if adequate sedation cannot be achieved after three doses of open label study drug 
within any 12 minute window. 
 
Sedation maintenance:  
Rescue sedative medication during the procedure must be applied, if adequate sedation 
(MOAA/S ≤4) cannot be maintained despite five doses of blinded study drug within any 15 
minute window; or, in the case of midazolam, three doses within any 12 minute window. Any 
administration of rescue sedative medication will be defined as treatment failure. 
 
12.9 Clinical Trial Material and Co-medication 
12.9.1 Identity, Supply and Storage of Clinical Trial Material 
All study material will be stored at the clinical site in a secure room with access restricted to 
pharmacy personnel. 
12.9.1.1 Remimazolam 
The chemical designation for remimazolam besylate is 
 
All doses and concentrations in this protocol are expressed as the base, remimazolam, unless 
stated otherwise. 
Remimazolam is presented as a sterile, white-to-off-white lyophilized powder for reconstitution 
in a vial. 
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12.9.1.2 Midazolam  
Midazolam (1 mg/mL) will be provided by the Sponsor as study medication. Midazolam will be 
stored at controlled room temperature between 20 to 25°C (68 to 77°F). 
12.9.1.3 Placebo 
Placebo will consist of 0.9% NaCl solution and will be provided by the Sponsor. It will be 
prepared by the local pharmacy in syringes in the same volumes as the other study drugs. 
12.9.1.4 Flumazenil 
Flumazenil will be provided by the clinical site. Flumazenil is available in multiple-use glass 
vials containing 5 mL or 10 mL of a 0.1 mg/mL flumazenil sterile solution for injection. 
Flumazenil will be stored at 25°C (77°F) with excursions permitted (15 to 30°C [59 to 86°F]). 
12.9.1.5 Fentanyl 
Fentanyl citrate (50 µg/mL) will be provided by the Sponsor. Fentanyl citrate (2 mL ampoules) 
will be stored at room temperature (15 to 30°C [59 to 86°F]), protected from freezing, light, and 
extreme heat. 
12.9.1.6 Naloxone 
Naloxone is available as a 1, 2, and 4 mg/mL sterile solution and will be provided by the clinical 
site. Naloxone will be stored at controlled room temperature between 15 to 30°C (59 and 86°F). 
 
12.9.2 Dispensing, Accountability, and Destruction 
12.9.2.1 Recording of Receipt, Dispensing and Return/Destruction 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the study medication including the date, quantity, batch or code number, and 
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identification of patients (patient number and initials) who received the study medication. The 
investigator will not supply the study medication to any persons except those named as sub-
investigators on the FDA 1572, designated staff, and patients in this study. The investigator will 
not dispense the study drug from any sites other than those listed on the FDA 1572. Study 
drug(s) may not be relabeled or reassigned for use by other patients. Upon completion of the 
study, unused supplies of the study drug will be returned to PAION or destroyed as directed. 
 
12.9.3 Dispensing 
12.9.3.1 
 
 
 
 
 
 
 
 
12.9.3.2 Flumazenil Dispensing 
If needed, the investigator will prepare flumazenil (0.1 mg/mL) for iv administration. Flumazenil 
use as a rescue medication should be as per site practice (Appendix A). 
12.9.3.3 Fentanyl Dispensing 
The investigator will dispense 0.5 - 1.0 mL of the 0.05 mg/mL fentanyl solution for a total dose 
of 25-50 g. Appropriate reductions will be used for elderly and debilitated patients, at the 
discretion of the investigator. Five additional syringes will be prepared, containing 0.5 mL of the 
0.05 mg/mL fentanyl solution for follow-up doses of 25 g, for use only if needed for pain 
control during the procedure. Further details are given in the drug handling manual. 
12.9.3.4 Naloxone Dispensing 
Naloxone, an opioid antagonist, will be immediately available in the event of fentanyl over-
dosage. Naloxone use as a rescue medication should be as per site practice (Appendix A). 
12.9.3.5 Accountability 
Following dispensing, the remaining trial medication dilution will be stored in the pharmacy for 
subsequent analysis, according to the study manual. 
A drug accountability log that documents, among other appropriate information, patient number, 
amount dispensed, and amount returned to the pharmacy (if any) will be maintained. Study drug 
returned to the pharmacy will be stored according to the study manual. The returned study drug 
should be marked as ‘returned’ and kept separate from the study drug not yet dispensed. 
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If institutional policy requires destruction, used IP should be destroyed per policy. There will be 
accountability logs in place that document amount of destructed study drug and that are 
witnessed by one other person. 
All dispensing and accountability records will be available for Sponsor review. When the study 
monitor visits the participating centers, he/she will reconcile the drug accountability log with the 
study drug stored in the hospital or ambulatory center/bronchoscopic suite pharmacy. 
 
12.9.4 Destruction 
Upon completion of the study and after receiving Sponsor approval in writing, 
 
. will be responsible for destroying the remaining study drug or returning it to the sponsor’s 
vendor. 
 
12.9.5 Blinding and Labeling 
The study will be conducted as a randomized, double-blind study with respect to remimazolam 
and placebo. The midazolam arm will be open-label. The identity of the blinded study drugs 
(remimazolam or placebo) will not be revealed to study management or to anyone at the study 
site except for the pharmacist, the pharmacy staff 
 unblinded monitor until the 
study is completed. This exemption also applies to the DMC members. The pharmacist and staff 
will not participate in other study procedures. Patients will be blinded to treatment. 
Study-specific labeling meeting all applicable regulatory requirements can be found in the Drug 
Handling Manual for this study. 
 
12.9.6 Randomization and Unblinding 
Prior to dosing, patients will be randomly assigned in a 30:6:6 ratios to remimazolam, placebo or 
open-label midazolam. The randomization schedule will be computer-generated using a 
permuted block algorithm and will randomly allocate study drug to randomization numbers. The 
randomization numbers will be assigned sequentially as patients are entered into the study. The 
study site will not be stratified in the randomization schedule. Although the amount of chronic 
use of opioids and/or benzodiazepines will be known in advance, it is difficult to be able to 
stratify the randomization for amount of these drugs from a practical perspective. At Day 1 after 
confirming that a patient still meets entry criteria, the patient will get the next free random 
number in ascending order. The investigator will administer the trial medication corresponding 
to the random number. The doses of remimazolam or placebo will be visually indistinguishable.  
Treatment unblinding is discouraged if knowledge of the treatment assignment will not 
materially change the planned management of a medical emergency. Unblinding will be 
permitted in a medical emergency that requires immediate knowledge of the patient’s treatment 
assignment. Unblinding should be discussed in advance with the medical monitor if possible. For 
emergency unblinding, study site personnel will call the central IWRS. If the investigator is not 
able to discuss treatment unblinding in advance, then he or she must notify the medical monitor 
as soon as possible about the unblinding incident without revealing the patient’s treatment 
assignment. The central IWRS will capture the date and reason for the patient’s treatment 
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unblinding. In addition, the investigator or designee must record the date and reason for study 
discontinuation on the appropriate CRF for that patient. In all cases that are not emergencies, the 
investigator must discuss the event with the medical monitor prior to unblinding the patient’s 
treatment assignment. 
 
12.9.7 Assessment of Compliance 
Clinical trial materials will be received by pharmacy personnel at the study site, handled and 
stored safely and properly in a secure location. The PI or appropriate designee will administer 
study medication. The exact times of study medication administration will be captured in the 
electronic data capture system; compliance will be set to 100% if the patient received the initial 
dose of study medication. 
If dosing is not performed per protocol, details will be recorded as a protocol deviation. 
All incidents of abuse, misuse, overuse, or overdose (intentional or accidental) will be reported 
as AEs including case narrative. Study medication, that is lost, stolen, missing or unaccounted 
for will be thoroughly investigated and details related to such cases will also be narrated. 
 
12.9.8 Study Patient Numbering 
All consented patients are assigned unique patient identification (PID) numbers (screening 
number). The PID numbers are 6-digit numbers that identify study subjects from time of 
screening until time of randomization. 
Before the start of the study, a computer-generated randomization schedule will be prepared by 
 Based on the randomization schedule, patients at each study site will be 
randomly assigned by the central IWRS to one of the two treatment groups (Table 1) in the 
chronological order in which they were enrolled. 
 
Table 1 
Treatment Groups 
Group 
Trial medication 
Initial dose + Top-up dose 
Group 1 (N = 60) 
Placebo 
- 
Group 2 (N = 300) 
Remimazolam 
5.0 mg + 2.5 mg 
Group 3 (N = 60) 
Midazolam 
1.75 mg + 1.0 mg* or 
1.0 mg + 0.5 mg§ 
*Healthy adults <60 yrs; §adults ≥60 yrs, debilitated or chronically ill patients. 
 
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13 DESCRIPTION OF ASSESSMENTS 
13.1 Efficacy Evaluations 
13.1.1 Modified Observer's Assessment of Alertness and Sedation 
The MOAA/S is a measure of sedation based on the clinical evaluations of the practitioner and is 
also an accepted and commonly used method of assessing levels of sedation (see Appendix D)30. 
This method will be used in concert to present a comprehensive assessment of the efficacy 
profile of remimazolam. 
The MOAA/S Scores will be recorded pre-dose and then post-dose as follows: MOAA/S scores 
at 1, 1.5, 2, 2.5, 3 minutes after the start of trial medication injection and then, after the first 3 
minutes, at 1-minute intervals until patient is Fully Alert (first of three consecutive MOAA/S 
scores of 5). After Fully Alert, MOAA/S scores will be recorded every 5 minutes until ready for 
discharge, and after ready for discharge every 10 minutes (up to 90 minutes) until actual 
discharge of the patient. 
Time to peak sedation is defined as the time between start of the injection of the initial dose (t=0) 
until the lowest MOAA/S score is achieved for the first time. 
Close monitoring of MOAA/S levels will be undertaken by the sponsor on a patient level during 
the study to ensure patient safety, and any concerns notified to the DMC.  The blind will be 
maintained throughout. 
 
13.1.2 
 
 
 
 
 
 
 
 
 
 
 
13.1.3 
 
 
 
 
 
 
 
 
13.1.4 
 
 
 
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13.1.5 Process to Determine Time Ready for Discharge 
 
The patient will be instructed that after the procedure is completed and he is fully 
awake again, he has to indicate by himself as soon as possible once he feels ready to 
get up and walk again and that he has to pass a walking test before discharge29. 
 
Any attempts to wake the patient prematurely are not allowed. 
 
Prior to determine time ready to discharge, patient must be fully alert and meet the 
following criteria:  
- The patient must be free of nausea/vomiting and diaphoresis. 
- The patient must be free of dizziness in supine and in vertical position. 
- Vital signs must be within a reasonable and normal range of pre-procedure status. 
 
As soon as the patient indicates, that they feel ready to be discharged, the walking 
test will be started and patient must walk 16 ft. with a steady gait in a straight line, 
then turn and come back, in front of a blinded observer, eg the study coordinator. The 
patient is required to be able to walk as if they were leaving the recovery room 
unescorted. If the gait is still insecure, then the above must be repeated; if fulfilled, 
the patient is ready for discharge and time will be recorded. 
 
Patients will be discharged only with an accompanying person, even if they are able 
to walk unassisted. 
 
13.1.6 Readiness-for-Discharge Score 
Patients will be asked at 30, 60, and 90 minutes after time = 0 for their readiness-for-discharge34 
using the Visual Analogue Scale, where 0 denotes no readiness for discharge and 10 represents 
immediate readiness for discharge. 
 
 
 
 
 
 
 
 
 
 
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13.2 Safety Procedures 
Safety will be assessed by physical examination findings, vital signs (supine heart rate, systolic, 
diastolic and mean arterial BP, respiration rate and temperature), ECG findings, clinical 
laboratory test results, and the incidence of AEs. In addition, other procedures including pulse 
oximetry measurements, pain on injection intensity rating, and the assessment of interventions 
such as airway interventions (chin lift, jaw thrust, requirement of repositioning and/or manual or 
mechanical ventilation), administration of additional fluids or medication or any interventions 
necessary due to a clinically relevant change in ECG will also be performed. Concomitant 
medications will be documented to evaluate possible drug interactions and also any AEs or 
pharmacodynamic data that could be associated with peri-procedural medications. All 
observations will be followed from Baseline/Screening until the Follow-up on Day 4 (+3/-1 
days). Specific details on follow up of AEs can be found in Section 13.2.6.5. 
 
13.2.1 Clinical Laboratory Tests 
 
At Screening, blood/urine/saliva will be collected for the following tests:  
- 
Saliva test for alcohol. 
- 
Urine-pregnancy test in female subjects. 
- 
Urine-drug screen to include amphetamines, barbiturates, benzodiazepines, 
cocaine, opiates, phencyclidine, and cannabinoids.  
 
At Day 1 (if not the same day as Screening) sites will test for the following: 
- 
Saliva test for alcohol. 
- 
Urine pregnancy test in female subjects. 
- 
Urine drug screen to include amphetamines, barbiturates, benzodiazepines, 
cocaine, opiates, phencyclidine, and cannabinoids. 
 
Screening (if not the same as Day 1), Day 1 at least 3 hrs after the procedure: venous 
blood samples will be collected for routine safety evaluations (hematology, serum 
chemistry): 
- 
Hematology and Coagulation: hemoglobin, hematocrit, red blood cell (RBC) 
count, white blood cell (WBC) count with differential (both % and absolute), 
platelet count, activated Partial Thromboplastin Time (aPTT) and International 
Normalized Ratio (INR). 
- 
Serum Chemistry: AST, ALT, direct and total bilirubin, chloride, bicarbonate, 
calcium, magnesium, and phosphate, total protein, sodium, potassium, LDH, 
blood urea nitrogen (BUN), creatine phosphokinase (CPK), glucose, uric acid, 
albumin, creatinine, alkaline phosphatase. 
Clinical laboratory tests will be performed by 
 Details 
of blood sampling can be found in Appendix C. 
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Clinical laboratory values outside the normal range: 
Any value outside the normal range will be assessed by the principal investigator as to whether it 
is of clinical significance. Additional testing during the study may be done if medically 
indicated. If a clinically significant abnormality is found in the samples taken after 
administration of study drug or during the study, the abnormality will be recorded as an AE. 
 
13.2.2 Physical Examinations 
A complete physical examination (excluding rectal and genitourinary examination) will be 
performed at screening. A baseline physical examination will be performed on admission if 
screening and randomization is not at the same day. 
 
13.2.3 Vital Signs 
Hemodynamic parameters (heart rate and systolic and diastolic BP) will be measured using an 
electronic recording device after the patient has been resting supine for ≥5 minutes. 
Hemodynamics will be recorded at Screening and admission, with values recorded within five 
hours pre-dose, within 30 minutes pre-dose, within 15 minutes pre-dose, and 1 minute pre-dose 
and 2, 5, 10, and every five minutes thereafter for the duration of the procedure until the patient 
is fully alert and clinically stable. Continuous monitoring and recording of heart rate will take 
place on Day 1 from 15 minutes pre-dose until fully alert. 
Respiratory rate (breaths per minute) will be manually assessed at screening and on admission. 
Respiratory rate during the procedure will be continuously device-monitored and recorded 
(Nellcor, Covidien) on Day 1 and documented once within 15 minutes pre-dose (baseline) and at 
approximately 2, 5, 10, and every five minutes thereafter for the duration of the procedure until 
the patient is fully alert and clinically stable. 
Body temperature will be measured at screening, on Day 1, within 5 hours pre-dose, within 30 
minutes pre-dose and 5 minutes after the procedure, at fully alert and at discharge. 
A pulse oximeter for measurement of SpO2 will be placed 15 minutes prior to start of procedure 
and will be monitored and recorded continuously until fully alert and documented in the eCRF at 
the following time points: within 15 minutes of dosing of trial medication, and immediately 
before administration of fentanyl (baseline) and trial medication. Post-dose measurements will be 
made at the following time points: 2, 5, 10, and every five minutes thereafter for the duration of 
the procedure until the patient is fully alert and clinically stable. Any event occurring at the same 
time as a significant change in SpO2, such as a displaced sensor, will be recorded. 
A set of vital signs will additionally be recorded at the onset time of adverse events, if feasible or 
available and documented in the eCRF (if an AE occurs outside the medical practice / hospital 
setting [eg during the time from screening to day 1 or after discharge until follow up when the 
patient is sent home] data for vital signs might be unavailable).  
Systolic and diastolic BP, heart rate and SpO2 will also be recorded immediately prior to and 2 
minutes after each dose of fentanyl. 
 
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13.2.4 Electrocardiograms 
During the procedure a 3 lead ECG recording will be used to continuously record the cardiac 
rhythm throughout the procedure until the patient is fully alert. Post-dose measurements will be 
documented at the following time points: 2, 5, 10, and every five minutes thereafter for the 
duration of the procedure until the patient is fully alert and clinically stable. 
Single 12-lead ECGs will be performed within five hours pre-dose, 1 minute after the first dose, 
5 minutes after start of initial dosing and every 10 minutes until the end of the procedure (if 
possible), and five minutes after end of procedure and at discharge or in case of a clinical event, 
eg arrhythmias, where repeated ECG recordings are warranted. The ECG will include all twelve 
standard leads and a Lead II rhythm strip on the bottom of the tracing. The ECG will be recorded 
at a paper speed of 25 mm/sec. The following ECG parameters will be collected or calculated: 
PR interval, RR interval QRS interval, QT interval, and QTc interval (QT corrected, using Bazett 
[QTcB] and Fridericia [QTcF] formulae; correction may be done by 
 Any 
patients with evidence of QT prolongation should be monitored until the ECGs return to 
baseline. 
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All ECGs will be evaluated by a qualified physician for the presence of abnormalities and any 
significant finding will be documented as an AE. 
 
 
 
 
13.2.6 Adverse Events 
13.2.6.1 Definitions 
Adverse Event (AE): Any untoward medical occurrence in a clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with this treatment. 
An adverse event can therefore be any unfavorable and unintended sign (including clinically 
significant abnormal values from relevant tests, such as clinical safety laboratory tests, ECGs, 
vital signs), symptom, or disease temporally associated with the use of the study drug, whether or 
not considered related to the study drug.  
Diagnostic findings during the bronchoscopy procedure will not be reported as AEs, but 
documented as findings of the bronchoscopy in a specific section of the CRF. 
 
Serious adverse event: 
Any untoward medical occurrence or effect that at any dose results in death, is life-threatening, 
requires hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability or incapacity, is a congenital anomaly or birth defect, or is a medical 
important event. 
 
Adverse reaction: 
Any untoward and unintended response to an investigational medicinal product related to any 
dose administered. 
 
Suspected adverse reaction: 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 'Reasonable possibility' means that there is evidence to suggest a causal relationship 
between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug. 
 
Unexpected suspected adverse reaction: 
A suspected adverse reaction, not listed in the applicable product information (eg investigator’s 
brochure 
for 
an 
unauthorized 
investigational 
product, 
or 
summary 
of 
product 
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characteristics/product insert for an authorized product) or the specificity or severity of which is 
not consistent with the applicable product information. 
 
Suspected unexpected serious adverse reaction (SUSAR): 
A suspected adverse reaction related to an investigational medicinal product (the tested 
investigational medicinal products and comparators) which occurs in a clinical trial, and that is 
both unexpected and serious. 
 
13.2.6.2 Assessment of Adverse Events 
Assessment of intensity: 
There are three intensity categories: 
 Mild: the adverse event causes minimal discomfort and does not interfere in a significant 
manner with the subject’s normal activities. 
 Moderate: the adverse event is sufficiently uncomfortable to produce some impairment of 
the subject’s normal activities. 
 Severe: the adverse event is incapacitating, preventing the subject from participating in 
his/her normal activities. 
When changes in the intensity of an AE occur, the maximum intensity for the experience should 
be noted. 
 
Assessment of causality:  
Criteria for classifying AEs by causality (suspected relationship to IMP35) are presented below. 
Causality term  
Assessment criteria* 
Certain 
• Event or laboratory test abnormality, with plausible time relationship to drug intake 
• Cannot be explained by disease or other drugs 
• Response to withdrawal plausible (pharmacologically, pathologically) 
• Event definitive pharmacologically or phenomenologically (ie an objective and specific 
medical disorder or a recognized pharmacological phenomenon) 
• Re-challenge satisfactory, if necessary 
Probable / Likely 
• Event or laboratory test abnormality, with reasonable time relationship to drug intake 
• Unlikely to be attributed to disease or other drugs 
• Response to withdrawal clinically reasonable 
• Re-challenge not required 
Possible 
• Event or laboratory test abnormality, with reasonable time relationship to drug intake 
• Could also be explained by disease or other drugs 
• Information on drug withdrawal may be lacking or unclear 
Unlikely 
• Event or laboratory test abnormality, with a time to drug intake that makes a relationship 
improbable (but not impossible) 
• Disease or other drugs provide plausible explanations 
Conditional/ 
Unclassified 
• Event or laboratory test abnormality 
• More data for proper assessment needed, or 
• Additional data under examination 
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Unassessable/ 
Unclassifiable 
• Report suggesting an adverse reaction 
• Cannot be judged because information is insufficient or contradictory 
• Data cannot be supplemented or verified 
* All points should be reasonably complied with 
 
Assessment of outcome: 
The outcome at the time of last observation will be classified as: 
 Resolved: the subject has recovered completely, and no symptoms remain. 
 Resolved: with sequelae – the subject has recovered, but some symptoms remain. 
 Resolving: the subject’s condition is improving, but symptoms still remain. 
 Not resolved: the subject’s condition has not improved and the symptoms are unchanged 
or worsening. 
 Death. 
Death should only be selected as an outcome when the AE results in death. If more than one AE 
is possibly related to the patient’s death, the outcome of death should be indicated for each such 
AE. 
 
Assessment of seriousness: 
For the purpose of assessing seriousness of an AE, the occurrence at any dose of any the 
following will be considered as qualifying the event as an SAE: 
 Fatality. 
 A life-threatening event. 
 Hospitalization or prolongation of hospitalization. 
 Persistent or significant disability/incapacity. 
 A congenital abnormality or birth defect. 
 An important medical event that requires immediate medical intervention to prevent the 
above outcomes. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result 
in hospitalization, or development of drug dependency or drug abuse. 
 All AEs that require any of the following interventions will be considered SAEs: 
o Instrumentation of the airway  
o Administration of flumazenil 
In-patient hospitalization or prolongation of existing hospitalization means that hospital inpatient 
admission and/or prolongation of hospital stay were required for treatment of the AE, or 
occurred as a consequence of the event. It does not refer to pre-planned elective hospital 
admission for treatment of a pre-existing condition (before signing the informed consent) that 
has not significantly worsened, or to diagnostic procedures. It does not refer to findings during 
the bronchoscopy that might lead to further follow-up requiring hospitalization. 
 
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Assessment of expectedness: 
The expectedness of an adverse reaction is determined by the sponsor. This should be done from 
the perspective of events previously observed, not on the basis of what might be anticipated from 
the pharmacological properties of a medicinal product. For the study drug, the reference safety 
information is found in the current IB. For the comparator, the information is found in the current 
package insert (Summary of Product Characteristics). An unexpected suspected adverse reaction 
is one for which the specificity or severity is not consistent with the current version of the IB. 
For example, hepatic necrosis would be unexpected (of greater severity) if the IB only listed 
elevated hepatic enzymes or hepatitis. Likewise, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (of greater specificity) if the current version of the IB only listed 
cerebral vascular accidents. 
Furthermore, adverse events listed in the investigator brochure as occurring with members of the 
same class of drugs, or as anticipated from the pharmacological properties of the drug, would be 
considered unexpected until they have been observed with the drug under investigation. For 
example, although angioedema is anticipated to occur in some patients exposed to drugs in the 
angiotensin-converting enzyme (ACE) inhibitor class and angioedema would be described in the 
investigator brochure as a class effect, a case of angioedema observed with the drug under 
investigation should be considered unexpected for reporting purposes until it is included in the 
investigator brochure as occurring with the drug under investigation. 
13.2.6.3 Collection and Recording of Adverse Events 
An AE may be reported spontaneously by the patient, discovered on physical examination, or 
uncovered as a result of general questioning by the study staff. From signing the informed 
consent to admission then discharge and again at the Follow-up Visit, the patient will be asked 
non-leading questions such as, “How have you been since you were last asked?” All AEs will be 
recorded. 
For all AEs, the Investigator or designee must obtain enough information to both determine the 
outcome of the AE and to assess whether the AE meets the criteria for classification as a SAE. 
All AEs will be recorded in the study subject’s own words (“verbatim”) as well as by the 
diagnostic term assigned by the PI or designee. The term will subsequently be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Adverse events should be recorded 
individually unless the AEs constitute a condition, disease, or syndrome. In that case, separate 
AEs should not be recorded for individual symptoms; rather, the condition, disease or syndrome 
should be recorded as one AE.  
Each AE will also be described in terms of seriousness, start and stop times and dates, frequency, 
maximum intensity, causality (suspected relationship to trial medication), actions taken, and 
outcome. 
All incidents of abuse, misuse, overuse, or overdose (intentional or accidental) will be reported 
as AEs including case narrative. 
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13.2.6.4 Reporting of Adverse Events 
Adverse event (AE) reporting will begin upon signing of the informed consent and will continue 
through the Follow-up visit. 
Any SAE, whether deemed IMP-related or not, must be reported to the Sponsor's local safety 
management organization as soon as possible after the Investigator or Coordinator has become 
aware of its occurrence. The Investigator/Coordinator must complete an SAE form and submit it 
within 24 hours of becoming aware of the event. 
SAE Reporting Contact Information: 
24-hour SAE Fax Line: 88
Email: PAm
The Investigator must be prepared to supply the local safety management organization with the 
following information: 
a.
Investigator's name and site number
b.
Patients number
c.
Patients initials
d.
Patients demographics
e.
Clinical event:
1.
description
2.
date of onset
3.
severity
4.
treatment (including hospitalization)
5.
relationship to IMP (causality)
6.
action taken regarding IMP
7.
outcome
f.
If the AE was fatal:
1.
cause of death (whether or not the death was related to the IMP)
2.
autopsy findings (if available)
Additional information about any SAE should be forwarded by the site within 24 hours of the 
information becoming available. Under the Sponsor’s Standard Operating Procedures (SOPs), 
the safety management organization is responsible for immediately informing the Sponsor’s 
Medical Monitor of the occurrence of any SAEs. 
Any new SAE that occurs after the study period and is considered to be possibly related to the 
IMP or study participation should be handled in the same manner as that for SAEs that occur 
during the study. 
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13.2.6.5 
 
 
 
 
 
13.2.6.6 
  
 
13.2.6.7 
 
 
 
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• 
  
 
 
 
 
 
 
 
 
  
 
  
 
  
 
13.2.6.8 Pregnancy 
A pregnancy occurring in the study is not considered an AE but should be recorded as an AE on 
the Adverse Event Form and reported to Sponsor using the Pregnancy Form and within the same 
timelines as those for SAEs. The investigator must monitor the subject for the duration of the 
pregnancy and until three months after the child is born, and report the outcome of the pregnancy 
to 
. 
 
13.2.6.9 Special Procedures for Managing SAEs and Unblinding 
When a patient has a serious adverse event (SAE) that is a medical emergency requiring 
immediate knowledge of the patient’s treatment assignment, study site personnel will call the 
central interactive web response system (IWRS) to obtain the treatment assignment. In all other 
cases, prior to unblinding, the investigator must discuss the SAE with the medical monitor. The 
procedure for unblinding a patient’s treatment assignment is described in Section 12.9.6. 
In addition, in the event of SUSARs, which are subject to expedited reporting, the Sponsor/CRO 
Pharmacovigilance will unblind the affected cases in order to fulfill reporting requirements. For 
such cases, unblinding will be performed according to documented procedures and the unblinded 
information will be kept to authorized safety personnel. 
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14 STUDY MANAGEMENT 
14.1 Regulatory Guidelines 
The study will be conducted in accordance with the ethical principles of the Declaration of 
Helsinki (64th WMA assembly, Fortaleza, Brazil 10/2013; including amendments in effect up to 
the time the study was conducted) and in compliance with Good Clinical Practices (GCPs), local 
regulatory requirements, and U.S. Food and Drug Administration (FDA) Investigational New 
Drug (IND) regulations (21 CFR 56). 
 
14.2 Institutional Review Board 
Conduct of the study must be approved by an appropriately constituted institutional review board 
(IRB). Approval is required for the study protocol, protocol amendments, informed consent 
forms (ICFs), patient information sheets, and advertising materials. 
 
14.3 Informed Consent 
For each patient, written informed consent will be obtained prior to any protocol-related 
activities. As part of this procedure, the PI or designee must explain orally and in writing the 
nature, duration, and purpose of the study, and the action of the drug in such a manner that the 
patient is aware of the potential risks, inconveniences, or adverse effects that may occur. The 
patient will be informed that he/she is free to withdraw from the study at any time. The patient 
will receive all information that is required by federal regulations and International Conference on 
Harmonization (ICH) guidelines. The PI or designee will provide the Sponsor with a copy of the 
IRB-approved ICF prior to the start of the study. 
 
14.4 Discontinuation of the Study by the Sponsor 
The Sponsor reserves the right to discontinue the study for safety or administrative reasons at 
any time. Should the study be terminated and/or a site closed for whatever reason, all 
documentation and IMP pertaining to the study must be returned to the Sponsor. Any actions 
required to assess or to maintain patient safety will continue as required, in spite of termination 
of the study by the Sponsor. 
 
14.5 Changes to the Protocol 
Any change or addition to this protocol requires a written protocol amendment or administrative 
letter that must be approved by the Sponsor and the Investigator before implementation. 
Amendments significantly affecting the safety of patients, the scope of the investigation, or the 
scientific quality of the study, require additional approval by the IRB and FDA. Examples of 
amendments requiring such approval are: 
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
An increase in drug dosage or duration of exposure of subjects.

A significant change in the study design (eg addition or deletion of a control group).

An increase in the number of invasive procedures to which subjects are exposed.

Addition or deletion of a test procedure for safety monitoring.

Change in the inclusion or exclusion criteria that may increase the risk to the subjects.

Addition of patients to the study.
These requirements for approval should in no way prevent any immediate action from being 
taken by the Investigator or by the Sponsor in the interests of preserving the safety of all patients. 
If an immediate change to the protocol is felt to be necessary by the Investigator and is 
implemented by him/her for safety reasons, the Sponsor and the monitor should be notified 
within 24 hours and the IRB and FDA should be informed within five working days. 
Changes affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB approval, but the IRB and FDA must be kept informed of such changes. 
Examples of administrative changes not requiring formal protocol amendments or IRB approval 
that can be treated as administrative amendments (eg file notes) include: 

Changes in the staff used to monitor trials (eg Sponsor staff or CRO staff).

Minor changes in the packaging or labeling of study drug.
14.6 Deviations from the Protocol 
The Investigator will not deviate from this protocol for any reason without prior written approval 
from the Sponsor/Medical Monitor, except in cases of medical emergencies. The Investigator 
may deviate from the protocol without prior approval only when the change is necessary to 
eliminate an apparent immediate hazard to a patient. In that event, the Investigator will notify the 
Sponsor immediately by phone, notify the IRB, and confirm notification to the Sponsor in 
writing within five working days after the change is implemented. 
14.7 Selection of Investigators and Study Sites 
The investigators and study sites will be selected by 
 and PAION UK Ltd. 
A pre-study site qualification visit will be performed by 
 Ltd. at all selected 
sites to assess the willingness and ability to perform the study in compliance with the protocol 
and current GCP- and regulatory guidelines. 
14.8 Data Collection 
An electronic data capture system will be used and provided by 
 for the 
clinical study. The Investigator will ensure the accuracy, completeness, and timeliness of the data 
reported to the Sponsor. Data collection processes and procedures will be reviewed and validated 
to ensure completeness, accuracy, reliability, and consistency. A complete audit trail will be 
maintained of all data changes. The Investigator or designee will cooperate with the Sponsor’s 
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representative(s) for the periodic review of study documents to ensure the accuracy and 
completeness of the data capture system at each scheduled monitoring visit. 
Electronic consistency checks and manual review will be used to identify errors or 
inconsistencies. This information will be provided to the study site by means of electronic or 
manual queries. 
The Investigator or designee will prepare and maintain adequate and accurate study documents 
(medical records, ECGs, AE, and concomitant medication reporting, raw data collection forms, 
Airway Assistance CRF, etc.), including a record of anesthesia designed to record all 
observations and other pertinent data for each patient receiving IMP. 
The Investigator will allow Sponsor representatives, contract designees, authorized regulatory 
authority inspectors, and the IRB to have direct access to all documents pertaining to the study. 
14.9 Study Monitoring 
All aspects of the study will be carefully monitored with respect to GCP and Standard Operating 
Procedures for compliance with applicable government regulations. The study monitor will be an 
authorized individual designated by the Sponsor. The study monitor will have access to all 
records necessary to ensure integrity of the data and will periodically review the progress of the 
study with the PI. 
Frequent communication between the study site and the Sponsor is essential to ensure that the 
safety of the study is monitored adequately. The Investigator will make all appropriate safety 
assessments on an ongoing basis. 
14.10  Inspections 
Inspections by local, regional, national, or central authorities may potentially take place at any 
study site. The investigator is obliged to cooperate during these inspections and make sure that 
study documents are available and that source data will be available for inspection. PAION or 
 might also be inspected. 
14.11  Audits 
Audits are routinely conducted as an overall quality check to ensure sites are adhering to the 
protocol and following the regulations. On-site audits may be performed at any study site and at 
any time (during the study or after the study is closed). Audits will take place after notification to 
the investigator. In the same way, audits can take place at PAION or 
. 
Study sites to be audited will be randomly selected, but may also be chosen for specific reasons, 
eg high number of patients recruited, research-naïve sites, a particularly high or low number of 
AEs or SAEs compared to other sites, monitor’s reports about data quality, and noncompliance 
with the study protocol. 
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14.12  Retention of Records 
It is the responsibility of the Investigator to maintain a comprehensive and centralized filing 
system of all relevant documentation. The Investigator will be instructed to retain all study 
records required by the Sponsor as well as the regulatory documents in a secure facility with 
limited access for the following required period: a minimum of two 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 after at least two years have elapsed since the formal 
discontinuation of clinical development of the IMP. 
 
14.13  Disclosure and Confidentiality 
By signing the protocol, the Investigator agrees to keep all information provided by the Sponsor 
in strict confidence and to request similar confidentiality from his staff and the IRB. Study 
documents (protocols, Investigator’s Brochures and other material) will be stored appropriately 
to ensure their confidentiality. The information provided by the Sponsor to the Investigator may 
not be disclosed to others without direct written authorization from the Sponsor, except to the 
extent necessary to obtain informed consent from patients who wish to participate in the trial or 
to comply with regulatory requirements. 
 
14.14  Use of Information and Publication 
The information developed in this study will be used by PAION in connection with the 
continued development of PAION and thus may be disclosed as required to other clinical 
investigators or government regulatory agencies. 
Publication or other public presentation of remimazolam data resulting from this study requires 
prior review and written approval of PAION. Abstracts, manuscripts, and presentation materials 
should be provided to PAION for review at least 30 days prior to the relevant submission 
deadline. Neither party shall have the right to unreasonably prohibit publication unless such 
publishing can be shown to affect possible patent filings, applications, rights or violate the terms 
set forth under separate Confidentiality Disclosure Agreement (CDA) or Clinical Trial 
Agreement (CTA). 
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15 STATISTICAL METHODS 
Statistical summaries will be provided for all demographic, efficacy, and safety parameters, as 
described in Sections 15.6 and 15.7. The data from all study sites will be combined for analysis. 
All data will be provided in listings. Descriptive summaries will be provided where applicable. 
15.1 Randomization and Blinding 
Prior to dosing, patients will be randomly assigned in a 30:6:6 ratio to remimazolam, placebo 
and open-label midazolam. The randomization schedule will be computer-generated using a 
permuted block algorithm and will randomly allocate study drug randomization numbers. The 
randomization numbers will be assigned sequentially as patients are entered into the study. 
Randomization will be stratified by age group. The aim is to have at least 100 patients on 
remimazolam aged ≥ 65 yrs (at least 30 of these aged ≥ 75 years or older) across the three late 
stage clinical trials (CNS7056-006, CNS7056-008, and CNS7056-015). Study site will not be 
stratified in the randomization schedule. Although the amount of chronic use of opioids and/or 
benzodiazepines will be known in advance, it is difficult to be able to stratify the randomization 
for amount of these drugs from a practical perspective. At Study Day 1, after confirming that a 
patient still meets entry criteria, study personnel will inform the pharmacist that the subject 
qualifies for randomization. The unblinded pharmacist will call the central IWRS and enter the 
requested information. The IWRS will then assign the next randomization number in the 
sequence and inform the pharmacist of the study treatment assignment. Thereafter, the 
pharmacist will dispense the corresponding treatment. For treatment unblinding please refer to 
Section 12.9.6. 
15.2 Statistical Analysis 
This section presents a summary of the planned statistical analyses. A Statistical Analysis Plan 
(SAP) describing in detail the analyses to be conducted will be written and approved prior to 
unblinding. All statistical analyses will be performed in SAS®. This study is a superiority study 
whose sample size was determined based on the results of previous studies. 
15.3 Analysis Populations 
The analysis populations include the following: 
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
The safety population will consist of all randomized patients who receive any amount of
study drug and will be analyzed as treated.

The intent-to-treat analysis set (ITT) will include all patients who were randomized and
will be analyzed as randomized.

The modified intent-to-treat analysis set (mITT) will include all patients included in the
ITT population who received at least one complete dose of study medication.

The per-protocol analysis set (PP) will include all patients from the ITT analysis set who:

received randomized treatment according to their randomization and the planned
treatment schedule.

did not have any major protocol violations.
Membership in the analysis populations will be determined prior to unblinding. 
All safety analyses will be conducted on patients in the safety population and will be based on 
the actual treatment administered. 
All efficacy analyses will be conducted on patients in the ITT, mITT and PP populations and will 
be based on the treatment assigned at randomization. 
15.4 Disposition 
The number of patients randomized, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated for the overall population and by treatment group. Additionally, the 
disposition of patients may be given by study site. 
15.5 Patient Characteristics 
Demographic variables will include age, sex, race, ethnicity, height, weight, and BMI. Baseline 
patient characteristics will include physical examination findings, medical history, vital signs, 
clinical laboratory test results, and 12-lead ECG. Baseline and post-baseline patient 
characteristics will include prior and concomitant medications, including additional sedative 
medications administered during the study procedure. 
The number and percentage of patients taking prior and concomitant medications will be 
summarized by treatment group. Medications will be classified using the most current World 
Health Organization Drug Dictionary (WHO-DD) Anatomical Therapeutic Chemical (ATC) 
classes and preferred terms. 
The remaining patient characteristic variables will be summarized descriptively by treatment 
group and for the overall population. Summary statistics will consist of sample size (n), mean, 
median, standard deviation (SD), minimum, and maximum for continuous measurements; and 
numbers and percentages of patients for categorical measurements. For categorical variables, 
percentages will be based on the number of the patients in the analysis population. 
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15.6 Efficacy Analysis 
15.6.1 Primary Analysis 
The primary efficacy variable is success of the bronchoscopy procedure; a composite endpoint 
consisting of the following: 

Completion of the bronchoscopy procedure, AND

No requirement for a rescue sedative medication, AND

No requirement of more than 5 doses of study medication within any 15 minute
window, ie 0-15, 1-16, 2-17 minutes, etc.  (For midazolam only: no requirement for
more than 3 doses within any 12 minute window, ie 0-12, 1-13,2-14 minutes, etc).
Exceeding 5 doses within any sliding 15 minute window in the blinded (remimazolam or 
placebo) arm will be considered a treatment failure. Exceeding 3 doses within any 12 minute 
sliding window in the open label midazolam arm will be considered a treatment failure. 
The primary efficacy analysis (success of the procedure using a composite endpoint) will be 
summarized descriptively for overall success and within each category for treatment group, with 
summaries to include the number and percentage of patients.  
For the primary efficacy analysis, the following primary hypothesis will be tested: 
H0: πRemi ≤ πPLA vs. H1: πRemi > πPLA, 
where πRemi and πPLA denote the success rates for Remimazolam and placebo, respectively. The 
primary efficacy analysis will be the comparison of these success rates between the 
remimazolam and placebo groups, using the Cochran-Mantel-Haenszel (CMH) test to account 
for fentanyl, opioid and benzodiazepine dose strata. Three strata will be formed based on amount 
of fentanyl given during the study, chronic opioid dose, and chronic benzodiazepine dose. The 
details of the strata will be decided at the end of the study by examination of completely blinded 
data. 
The primary efficacy analysis will be based on the ITT, mITT and PP populations, with the 
mITT and PP population planned to confirm the results of the ITT population. 
In the case that one of the strata contains all but 10 patients for the remimazolam or the placebo 
group, the other strata will be pooled if they are adjacent. If they are not adjacent, an unstratified 
2 test will be used for the primary analysis. Similarly, if one of the strata contains all but 5 
patients for either the remimazolam or the placebo group, an unstratified ² test will be used for 
the primary analysis. 
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15.6.2 Secondary Analysis 
Comparisons between treatment groups will be performed in a descriptive manner on the 
following parameters: 
1.
The time to start of procedure after administration of the first dose of study medication.
2.
3.
The time to ready for discharge (defined as ability to walk unassisted) after the last
injection of study drug and after the end of bronchoscopy procedure (bronchoscope out).
4.
The time to fully alert (time to first of three Modified Observer's Assessment of
Alertness/Sedation (MOAA/S) scores of 5 after the last injection of study drug and after
the end of bronchoscopy procedure (bronchoscope out).
5.
6.
7.
8.
9.
10.
11.
All secondary efficacy variables will be compared between the three treatment groups. For the 
key secondary variables, only the pairwise comparison between midazolam and remimazolam 
will be used for efficacy significance testing. 
Variables 1-4 will be analyzed using the logrank test. Median time to event with the 
corresponding 95% confidence interval will be presented. Additional quartiles (25% and 75%) 
and confidence intervals will be presented. All the time to event analyses will also be presented 
in Kaplan-Meier curves. Patients who do not reach the fully alert or ready for discharge criteria 
will be censored at the time of their last assessment. To account for the different sedation 
properties of remimazolam and midazolam, the following additional stratification factors will be 
added: For variables 3 and 4, the mean MOAA/S score for the last 3 minutes before last injection 
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of study drug or the mean MOAA/S score for the 3 minutes prior to bronchoscope out. For 
variables 1 and 2, such covariates will not be added as they aim at comparing the different 
sedation properties of remimazolam and midazolam. 
For secondary efficacy variables 5, 7-9 and 11 descriptive summaries (n, mean, SD, median, 
minimum, and maximum), and summary graphs (mean ± SD) against assessment times will be 
provided. Overall and pairwise comparisons at each time point using ANOVA models with 
treatment as the main effect will be conducted for descriptive purposes.  
For secondary efficacy variables 6 and 10, which is binary/categorical, descriptive summaries 
will be provided to include the number and percentage of patients within each category for each 
treatment group.  
 
 
 
 
 
 
 
 
 
 
Further secondary objective: 
Assessment of the population PK in patients (a minimum of 15 patients ≥ 75 years). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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15.7 Safety Analysis 
Safety variables that will be analyzed as safety endpoints include AEs, clinical laboratory test 
results, vital signs (supine heart rate, systolic and diastolic BP, respiration rate, temperature), 
pulse oximetry measurements, ECG findings, physical examination findings, and pain on 
injection intensity rating on a verbal score, airway interventions (chin lift, jaw thrust, 
requirement of repositioning and/or manual or mechanical ventilation), administration of 
additional fluids or medication or any interventions necessary due to a clinically relevant change 
in ECG. All analyses will be performed on the Safety population. 
15.7.1 Adverse Events 
Treatment-emergent AEs are defined as AEs reported during treatment (at or after the start time 
of initial fentanyl injection administration) that are not present at Baseline, or that represent an 
exacerbation of an event that is present at Baseline. Any AE with an unknown start date and time 
will be considered treatment-emergent if the event does not discontinue prior to study drug 
administration. The number and percentage of patients with TEAEs will be displayed for each 
treatment group by system organ class and preferred term using the current version of the 
Medical Dictionary for Regulatory Activities (MedDRA). Pre-treatment AEs (reported from 
signing informed consent to before administration of study treatment) will be analyzed and 
displayed in a similar manner to TEAEs. 
Summaries in terms of severity and relationship to study drug will also be provided. Summaries 
of SAEs similar to those of AEs will be provided separately. By-patient listings of AEs causing 
discontinuation of study drug and SAEs will be produced. 
15.7.2 Clinical Laboratory Tests 
For qualitative clinical laboratory tests, the number and percentage of patients in each category 
will be displayed for each treatment group at each time point. 
For all laboratory tests, a shift table will be produced summarizing changes from baseline to the 
end of the treatment period by treatment group. 
Individual data listings of laboratory results will be presented for each patient at all study visits 
(scheduled and non-scheduled), including normal range limits for each laboratory test. Out-of-
range results will be flagged, and determinations of whether the results were considered to be of 
clinical significance by the investigator will be included. Clinically significant laboratory test 
abnormalities that are considered AEs by the investigator will be presented in the AE summaries. 
15.7.3 Vital Signs and Pulse Oximetry 
Individual data listings of vital signs (supine heart rate, systolic and diastolic blood pressure, 
calculated mean arterial pressure, temperature, and respiration rate) will be presented for each 
patient at all visits (scheduled and non-scheduled). Pulse oximetry data (SpO2) will be presented 
by patient for pre-defined time points, and as oxygen saturation over time (AUC). 
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Descriptive statistics (n, mean, SD, median, minimum, and maximum) will be used to summarize 
the observed values at each time point, and the changes from baseline, for each treatment group. 
Graphic presentations of heart rate, blood pressure, and respiration rate may be presented by 
patients and as means by treatment over time. Vital sign and SpO2 findings that were considered 
AEs by the Investigator will be presented by treatment in the AE summaries. In addition, the 
respiratory rate, heart rate and SpO2 nadirs, as well as the duration of any bradycardia and 
desaturation period(s) will be presented. Instances of airway assistance will be summarized by 
treatment and by technique employed. Categorical summaries of endpoints of interest may be 
presented. 
 
 
15.7.4 Electrocardiograms 
The number and percentage of patients with normal and abnormal 12 lead ECG findings will be 
displayed for each treatment group at each time point. Additionally, patients with normal ECG 
findings at baseline and abnormal ECG findings at each time point will also be summarized by 
treatment group. For quantitative ECG variables (PR interval, QRS interval, QT interval, and 
QTc interval [corrected using the Bazett and Fridericia formulae]), descriptive statistics 
including the n, mean, SD, median, minimum, and maximum will be given for the values 
themselves as well as for change from baseline, by treatment group at each time point. In 
continuous 3 lead ECG recording, all episodes of bradycardia or other arrhythmias, and any 
interventions that were instituted, even if the event had not been deemed an adverse event will be 
displayed. 
15.7.5 Physical Examinations 
The number and percentage of patients with normal and abnormal ECG findings will be 
displayed for each treatment group at each time point. Additionally, patients with normal ECG 
findings at baseline and abnormal ECG findings at each time point will also be summarized by 
treatment group. 
 
 
 
 
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15.8 Interim Analysis 
No interim analyses are planned. 
15.9 Sample Size and Power 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The midazolam group, which will not be part of the primary confirmatory analysis but is 
included for assay sensitivity, will be set to 60 patients. 
A total of 420 patients will be randomized, 300 to receive remimazolam, 60 to receive open-label 
midazolam, and 60 to receive placebo. 
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16 FINANCE AND INSURANCE 
16.1 Financial Contract 
 
16.2 Insurance 
 
 
 
 
 
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17 REFERENCES 
1. Cohen LB, Wecsler JS, Gaetano JN et al; Endoscopic sedation in the United States: results 
from a nationwide survey. Am J Gastroenterol, 2006; 101(5):967-974. 
2. Green SM; Research advances in procedural sedation and analgesia. Ann Emerg Med, 2007; 
49(1):31-36. 
3. Wahidi MM, Jain P, Jantz M, Lee P, Mackensen GB, Barbour SY, Lamb C, Silvestri GA. 
American College of Chest Physicians consensus statement on the use of topical anesthesia, 
analgesia, and sedation during flexible bronchoscopy in adult patients. Chest. 2011 Nov; 
140(5):1342-1350. 
 
4. José RJ, Shaefi S, Navani N. Sedation for flexible bronchoscopy: current and emerging 
evidence. Eur Respir Rev. 2013 Jun 1; 22(128):106-116. 
 
5. Diaz-Fuentes G and Venkatram SK (2012). Role of Flexible-Bronchoscopy in Pulmonary 
and Critical Care Practice; in Global Perspectives on Bronchoscopy, Dr. Sai P. Haranath 
(Ed.), ISBN: 978-953-51-0642-5. 
6. Heuss LT, Inauen W; The dawning of a new sedative: propofol in gastrointestinal endoscopy. 
Digestion, 2004; 69(1):20-26. 
7. Miner JR, Danahy M, Moch A, Biros M; Randomized clinical trial of etomidate versus 
propofol for procedural sedation in the emergency department. Ann Emerg Med, 2007; 
49(1):15-22. 
8. Sacchetti A, Senula G, Strickland J, Dubin R; Procedural sedation in the community 
emergency department: initial results of the ProSCED registry. Acad Emerg Med, 2007; 
14(1):41-46. 
9. Dunn T, Mossop D, Newton A, Gammon A; Propofol for procedural sedation in the 
emergency department. Emerg Med J, 2007; 24(7):459-461. 
10. Frank LR, Strote J, Hauff SR, Bigelow SK, Fay K; Propofol by infusion protocol for ED 
procedural sedation. Am J Emerg Med, 2006; 24(5):599-602. 
11. Miller MA, Levy P, Patel MM; Procedural sedation and analgesia in the emergency 
department: what are the risks? Emerg Med Clin North Am, 2005; 23(2):551-572. 
12. Garnock-Jones KP, Scott LJ. Fospropofol. Drugs. 2010 Mar 5; 70(4):469-477. 
13. Fospropofol Package Insert (Eisai Inc., LUSEDRA™): 
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=8cc837aa-14f0-4809-9ca1-
6cc7ff84646b Accessed 05/2014. 
14. Silvestri GA, Vincent BD, Wahidi MM, Robinette E, Hansbrough JR, Downie GH. A phase 
3, randomized, double-blind study to assess the efficacy and safety of fospropofol disodium 
injection for moderate sedation in patients undergoing flexible bronchoscopy. Chest. 2009 
Jan; 135(1):41-47. 
15. Bahn EL, Holt KR; Procedural sedation and analgesia: a review and new concepts. Emerg 
Med Clin North Am, 2005; 23(2):503-517.  
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16.
17. Midazolam Package Insert:
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=737361a0-8db1-4d3c-ba5e-
44df3f49fa22 . Accessed 05/2014.
18. CNS 7056X-besylate: Modulatory Effects on Recombinant GABA Currents Recorded from
Stably Transfected Cells. bSys Report 99802, 2006.
19. Kilpatrick GJ, McIntyre MS, Cox RF et al.; remimazolam: A Novel Ultra-short-acting
Benzodiazepine. Anesthesiology, 2007; 107(1):60-66.
20. Rogers WK, McDowell TS. Remimazolam, a short-acting GABA(A) receptor agonist for
intravenous sedation and/or anesthesia in day-case surgical and non-surgical procedures.
IDrugs. 2010 Dec; 13(12):929-937.
21. Influence of the benzodiazepine receptor antagonist, flumazenil, on the sedative effects of
ONO 2745BS (remimazolam) and existing drugs. ONO Report EO8QA010, 2008.
22. Intravenous maximum tolerated dose (MTD) and 7 day repeat dose study in the Beagle Dog.
Aptuit Report RMN1017, 2006.
23. Worthington MT, Antonik LJ, Goldwater DR, Lees JP, Wilhelm-Ogunbiyi K, Borkett KM,
Mitchell MC. A phase Ib, dose-finding study of multiple doses of remimazolam (CNS 7056)
in volunteers undergoing colonoscopy. Anesth Analg. 2013 Nov; 117(5):1093-1100.
24. Antonik LJ, Goldwater DR, Kilpatrick GJ, Tilbrook GS, Borkett KM. A placebo- and
midazolam-controlled phase I single ascending-dose study evaluating the safety,
pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part I. Safety,
efficacy, and basic pharmacokinetics. Anesth Analg. 2012 Aug; 115(2):274-283.
25. Wiltshire HR, Kilpatrick GJ, Tilbrook GS, Borkett KM. A placebo- and midazolam-
controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and
pharmacodynamics of remimazolam (CNS 7056): Part II. Population pharmacokinetic and
pharmacodynamic modeling and simulation. Anesth Analg. 2012 Aug; 115(2):284-296.
26. Fentanyl Package Insert: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f969e2bc-
6297-4e29-89d3-a3685a2c7c6b Accessed 05/2014.
27. Flumazenil Package Insert:
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=11882e93-aa62-4d24-895c-
6f01d97fc730  Accessed 05/2014.
28. Naloxone Package Insert: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=76f7eee1-
d524-43a4-a868-ffa9f29638a6  Accessed 05/2014.
29. Mandel JE, Tanner JW, Lichtenstein GR, Metz DC, Katzka DA, Ginsberg GG, Kochman
ML. A randomized, controlled, double-blind trial of patient-controlled sedation with
propofol/remifentanil versus midazolam/fentanyl for colonoscopy. Anesth Analg. 2008 Feb;
106(2):434-439.
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30. Chernik DA, Gillings D, Laine H, et al.; Validity and reliability of the Observer’s
Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin
Psychopharmacol 1990; 10:244-251.
31.
32.
33. Dripps RD. New classification of physical status. Anesthesiol. 1963; 24:111.
34. Stolz D, Kurer G, Meyer A, Chhajed PN, Pflimlin E, Strobel W, Tamm M. Propofol versus
combined sedation in flexible bronchoscopy: a randomised non-inferiority trial. Eur Respir J.
2009 Nov; 34(5):1024-1030.
35. The Uppsala Monitoring Centre. The use of the WHO-UMC system for standardised case
causality assessment: http://www.who-umc.org/Graphics/26649.pdf. Accessed 04/2015.
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18 APPENDICES 
Appendix A Rescue Medication Protocol 
Flumazenil 
For the reversal of the sedative effects of benzodiazepines flumazenil should be administered as 
per site practice in accordance with the label.  
Naloxone 
For the reversal of any opiate related effects, naloxone should be administered as per site practice 
in accordance with the label.  
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Appendix B Schedule of Assessments 
All days 
Day -21 to 
Day 1 
Day 1 
Day 4 Phone Call5 
(+3/-1 days) 
Screening 
Treatment Day 
Follow-up 
Informed consent 
X 
See next 
schedule 
Eligibility criteria/medical and medication 
history/demographics 
X 
Physical examination1 
X 
Clinical laboratory samples2 
X 
Urine HCG (females) 
X 
Drugs of abuse screen 
X 
Blood ethanol screen 
X 
Hemodynamics3 
X 
Height and BMI 
X 
Weight 
X 
Supine respiratory rate 
Body temperature 
X 
Supine 12-lead ECG 
X 
Fast4 
Fentanyl administration 
Administration of trial medication 
3-lead ECG telemetry
Pulse oximetry monitoring/recording 
X 
Respiratory rate recordings 
X 
MOAA/S scale score monitoring/recording 
 
 
 
X 
Airway management 
Assessment of adverse events and concomitant 
medication 
X 
X 
Note: Dosing day procedures described in the table on the next page. 
1.
Screening physical examination will include ASA-PS score.
2.
Biochemistry, hematology.
3.
Supine heart rate and systolic and diastolic BP.
4.
Fast to begin from midnight of the day before dosing (no food or water).
5.
In case there has been any indication for the onset of a new AE since discharge, patients should come back to the site immediately 
(preferably the same day) to perform further assessments (e.g.clinically laboratory tests, 12 lead ECG, left to the discretion of the
investigator)
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Day 1 – Assessments Based on Dosing Time 
Procedures  
Pre-dose 
Dosing of 
trial 
medication2 
Post-dose 
within 
5 hr 
within 
30 min 
within 
15 min 
within 
1min 
1 
min 
1.5 
min 
2 
min 
2.5 
min 
3 
min 
5 
min 
10 
min 
Every 5 minutes until fully alert 
Medical & medication 
histories 
X 
Adverse events 
X 
Concomitant 
medication 
X 
Physical examination 
x (B) 
Weight 
x (B) 
Body temperature 
x (B) 
x  
 x (5min 
post 
procedure) 
x  
(at fully 
alert) 
x (at actual 
discharge) 
Clinical laboratory tests 
x (B) 
 x (at least 
3hrs after the 
procedure  
12-lead ECG 7 
x (B) 
x 
x 
 x7 
x7 
x7 
x (at actual 
discharge) 
3-lead ECG 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
3-lead ECG 
documentation in CRF6
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine pregnancy test 
X 
Urine drug-of abuse test 
X 
Ethanol saliva test 
X 
Randomization 
X 
 
 
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Procedures  
Pre-dose 
Dosing of 
trial 
medication2 
Post-dose 
 
within 
5 hr 
within 
30 min 
within 
15 min 
within 
1min 
 
1 
min 
1.5 
min 
2 
min 
2.5 
min 
3 
min 
5 
min 
10 
min 
Every 5 minutes until fully alert 
Hemodynamic 
parameters (HR,  BP) 8, 
9 
x  
x 
 X (B) 
X  
  
  
  
x 
  
  
x 
x 
x 
x 
 x 
x 
 x 
x 
0.9% NaCl infusion   
(up to 1,000 mL, if 
fluid status allows) 
  
xx 
xx 
xx  
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
until end of procedure 
MOAA/S1,3 
  
  
x (B) 
  
  
x 
x 
x 
x 
x 
every minute until fully alert, then every 5 min until ready for discharge, 
then every 10 min until actual discharge 
Respiratory rate,9 
x (B) 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
RR documentation in 
CRF 
 
 
x (B) 
x 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
SpO2 (pulse oximetry) 
  
  
x (B) 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 xx 
xx  
SpO2 documentation in 
CRF8,9 
  
  
x (B) 
  
  
  
  
x 
  
  
x 
x 
x 
x 
x 
x 
 x 
x 
Airway management 
assessment 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Supplemental O2 
  
  
xx  
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx  
xx  
xx  
Fentanyl (25-50 µg) 
  
  
  
 x 
Supplemental doses of 25 mcg q 5-10 min until adequate analgesia or 200 mcg maximum dose  
 
 
  
  
  
 
     
 
 
  
  
 
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Readiness for discharge 
score5 
 
 
 
 
 
 
 
 
 
 
 
 
30 
 
60 
 
 
90 
NOTE: 
1. 
Bronchoscopy starts at sufficient sedation (MOAA/S ≤3), duration as necessary (MOAA/S ≤4), at the discretion of the investigator. 
2. 
Trial medication: Loading dose of randomized study drug start defines t0, supplemental doses as per protocol. 
 
3. 
See also schedules next page. 
 
4. 
If patient is capable, do not awake on purpose. 
 
5. 
30, 60 90 min post dose t=0. 
 
6. 
Running a strip to document presence or absence of arrhythmias. 
 
7. 
After first dose, 5 mins after dosing and every 10 minutes until the end of the procedure if possible, and also 5 minutes after the end of the procedure and at discharge 
 
8. 
In addition to times specified above, blood pressure, heart rate & SpO2 will be recorded immediately prior to, & two minutes after each additional dose of fentanyl 
 
9. 
Vital signs (heart rate, systolic & diastolic BP, respiratory rate and SpO2) will be recorded when an AE with a respiratory or cardiovascular focus has been observed. 
 
(B) Baseline values, x single action, xx continuous action. 
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Day 1 – Further Assessments 
 
Procedures 
after fully alert 
5 min. 
10 min. 
20 min. 
30 min. 
40 min. 
50 min. 
60 min. 
…..90 min. 
MOAA/S 
After fully alert every five minutes until ready for discharge, then every 10 min until actual discharge 
 
 
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
Time ready for discharge1 
After end of procedure 
 
Procedures 
after procedure 
ECG (single) 
5 min after end of 
procedure 
Adverse Events 
after procedure 
Concomitant medication 
after procedure 
Documentation of airway management 
after procedure 
“Time back to normal” assessment 
Day 2 
Notes: 1. Ability to walk unassisted. No attempt to prematurely awake patient. Walking 16 ft. (5 meters) on a straight line with turn back, documented by a blinded observer, or, if 
unable to walk, back to baseline state of mobility. 
 
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Appendix C Blood Sampling, Storage, and Shipping Instructions 
Clinical Laboratory Tests 
Clinical laboratory tests will be performed by 
 
 
 
Hematology: Blood (3 mL) will be collected into a lavender-top tube. 
 
Biochemistry: Blood (7.5 mL) will be collected into a red/black marble-top tube. 
 
Total Blood Sample Volume  
Test 
Volume/sample 
(mL) 
Number of samples 
Total volume/test 
(mL) 
Hematology 
3 
3 
9.0 
Biochemistry 
7.5 
3 
22.5 
Total 
 
 
31.5 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix D Modified Observer’s Assessment of Alertness and Sedation Scale 
 
Responds readily to name spoken in normal tone 
5 (alert) 
Lethargic response to name spoken in normal tone 
4 
Responds only after name is called loudly and/or repeatedly 
3 
Responds only after mild prodding or shaking 
2 
Responds only after painful trapezius squeeze 
1 
Does not respond to painful trapezius squeeze 
0 
Cohen LB. Clinical trial: a dose-response study of fospropofol disodium for moderate sedation during colonoscopy. 
Aliment Pharmacol Ther. 2008 Apr 1; 27(7):597-60830. 
 
 
 
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SAP_001.pdf: 
CNS7056-008 Integrated Clinical and Statistical Report 
Paion UK Limited
16.1.9 Documentation of Statistical Methods 
Paion UK Ltd., Statistical Analysis Plan, Final Version 1.0, dated 09-Jun-2017 
Paion UK Ltd., Statistical Analysis Plan Tables Figures, Listing TOCs, Final Version 1.0, dated 
09-Jun-2017
16.1 Trial Information 
1


STATISTICAL ANALYSIS PLAN 
Title: 
A Phase III Study Evaluating the Efficacy and Safety of 
Remimazolam (CNS 7056) Compared to Placebo and Midazolam 
in Patients Undergoing Bronchoscopy 
Protocol Number: 
CNS7056-008 
Compound: 
Remimazolam 
Phase: 
III 
Sponsor: 
PAION UK Ltd 
Author: 
 
 
Date: 
09  June 2017 
Version: 
Final 1.0 
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Table of Contents 
 
1 
OVERVIEW .................................................................................................................... 10 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................... 11 
2.1 
Primary Objective .................................................................................... 11 
2.2 
Secondary Objectives .............................................................................. 11 
2.3 
Safety and Efficacy Endpoints ................................................................. 11 
2.3.1 
Efficacy Endpoints ................................................................................... 11 
2.3.1.1 
Primary Efficacy Endpoints ..................................................................... 11 
2.3.1.2 
Secondary Efficacy Endpoints ................................................................. 11 
2.3.2 
Safety Endpoints ...................................................................................... 12 
2.3.3 
 
3 
OVERALL STUDY DESIGN AND PLAN .................................................................... 14 
3.1 
Study Population ...................................................................................... 15 
3.2 
Method of Assigning Patients to Treatment Groups ............................... 15 
3.3 
Treatment Blinding .................................................................................. 16 
3.4 
Schedule of Assessments ......................................................................... 16 
3.5 
Sample Size Calculation .......................................................................... 16 
4 
ANALYSIS AND REPORTING ..................................................................................... 18 
4.1 
Software and general statistical methods ................................................. 18 
4.2 
Interim Analyses and Data Monitoring ................................................... 18 
4.3 
Final Analysis .......................................................................................... 18 
5 
ANALYSIS POPULATIONS ......................................................................................... 19 
6 
GENERAL ISSUES FOR STATISTICAL ANALYSIS ................................................. 20 
6.1 
General Statistical Methodology ............................................................. 20 
6.1.1 
Adjustments for Multiple Comparisons ................................................... 20 
6.1.2 
Methods for Dropouts or Missing Data ................................................... 20 
6.1.3 
Pooling of Centers ................................................................................... 20 
6.1.4 
Analysis Visit Windows .......................................................................... 20 
6.1.5 
Data Handling Conventions ..................................................................... 20 
6.1.5.1 
Baseline Definitions ................................................................................. 20 
6.1.5.2 
Start Date, End Date of Study Treatment, and Study Day....................... 21 
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6.1.5.3 
Early Termination (ET) Visit ................................................................... 21 
6.1.5.4 
Unscheduled Visits .................................................................................. 21 
6.1.5.5 
Incomplete Date and Time Imputation for Adverse Events and 
Concomitant Medications ........................................................................ 21 
6.1.6 
By Patient Data Listings .......................................................................... 23 
6.2 
Derived and Computed Variables ............................................................ 23 
7 
STUDY PATIENTS AND DEMOGRAPHICS .............................................................. 28 
7.1 
Disposition of Patients and Withdrawals ................................................. 28 
7.2 
Protocol Deviations .................................................................................. 28 
7.3 
Demographics and Baseline Characteristics ............................................ 28 
7.4 
Medical History ....................................................................................... 28 
8 
EFFICACY ANALYSIS ................................................................................................. 29 
8.1 
Primary Efficacy ...................................................................................... 29 
8.1.1 
Primary Efficacy Endpoint ...................................................................... 29 
8.1.2 
Primary Analysis ...................................................................................... 29 
8.1.3 
 
8.2 
Secondary Efficacy .................................................................................. 30 
9 
SAFETY AND TOLERABILITY ANALYSIS .............................................................. 33 
9.1 
Adverse Events ........................................................................................ 33 
9.1.1 
 
9.1.5.1 
 
9.1.2 
Adverse Events Related to Effects Seen with Medications Known to be 
Associated with Abuse ..................................................................................................... 35 
9.2 
Clinical Laboratory Tests ......................................................................... 35 
9.3 
Vital Signs, Pulse Oximetry ..................................................................... 36 
9.3.1 
Continuous Monitoring ............................................................................ 36 
9.3.2 
Continuous Monitoring – Exploratory Analyses ..................................... 37 
9.4 
Electrocardiograms .................................................................................. 37 
9.4.1 
12-Lead ECG ........................................................................................... 37 
9.4.2 
3-Lead ECG ............................................................................................. 37 
9.5 
Physical Examinations ............................................................................. 37 
9.6 
 
9.7 
Prior and Concomitant Medications ........................................................ 38 
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9.7.1 
Prior and Concomitant Medications ........................................................ 38 
9.7.2 
Rescue Sedative Medications .................................................................. 38 
9.8 
 
10 CHANGES TO PLANNED ANALYSES ....................................................................... 40 
11 REFERENCES ................................................................................................................ 41 
12 ATTACHMENTS ............................................................................................................ 42 
APPENDIX A: Details of AEs with a Respiratory or Cardiovascular Focus.............. 43 
APPENDIX B: Diseases of Interest for Drug-Disease Interaction Analysis ............... 55 
 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
² 
chi-squared 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANOVA 
Analysis of variance 
ASA-PS 
American Society of Anesthesiologists-Physical Status 
ATC 
Anatomical Therapeutic Class 
AUC 
Area under the curve 
BP 
Blood pressure 
bpm 
Beats per minute 
BMI 
Body mass index 
CMH 
Cochran-Mantel-Haenszel 
CNS 7056B 
CNS 7056 besylate 
cm 
Centimeter(s) 
CM 
Concomitant medication 
CRF 
Case report form 
CS 
Clinically significant 
CSR 
Clinical study report 
CTA 
Clinical Trial Agreement 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
ET 
Early termination 
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Abbreviation 
Definition 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
h 
Hour(s) 
 
 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
ITT 
Intent-to-treat 
IWRS 
Interactive web response system 
kg 
Kilogram(s) 
LOCF 
Last observation carried forward 
LS 
Least squares 
max 
maximum 
µg 
Microgram 
mg 
Milligram 
min 
Minute(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-treat 
MOAA/S 
Modified Observer’s Assessment of Alertness and Sedation 
MON 
Month 
NDA 
New Drug Application 
NRS 
Numeric rating scale 
PP 
Per protocol 
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Abbreviation 
Definition 
QTc 
Corrected QT interval 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SMQ 
Standardised MedDRA query 
SOC 
System organ class 
SpO2 
Peripheral blood oxygen saturation (measured by pulse oximetry) 
TEAE 
Treatment-emergent adverse event 
TRTM 
Month of start of study treatment 
TRTY 
Year of start of study treatment 
USA 
United States of America 
 
 
yr 
Year 
YYYY 
Year 
WHO-DD 
World Health Organization – Drug Dictionary 
 
 
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1 OVERVIEW 
This document presents a detailed statistical analysis plan for the available data from Paion’s 
protocol CNS7056-008, Amendment 5.0, dated 3 March 2016 (A Phase III Study Evaluating 
the Efficacy and Safety of Remimazolam (CNS 7056) Compared to Placebo and Midazolam 
in Patients Undergoing Bronchoscopy).  
Reference materials for this statistical plan include Protocol CNS7056-008 version 1.0 
Amendment 5.0, dated 03-Mar-2016 and the accompanying SDTM and ADaM specification 
documents. Operational aspects related to collection and timing of planned clinical 
assessments are not repeated in this statistical analysis plan (SAP) unless relevant to the 
planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in 
Clinical Trials [1]. All work planned and reported for this SAP will follow internationally 
accepted guidelines, published by the American Statistical Association [2] and the Royal 
Statistical Society [3], for statistical practice. 
All planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analysis not 
necessarily identified in this SAP may be performed to further examine study data. Any post-
hoc, or unplanned, exploratory analyses performed will be clearly identified as such in the 
final CSR. 
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2 STUDY OBJECTIVES AND ENDPOINTS  
2.1 Primary Objective 
The objective is to establish the superiority of remimazolam compared to placebo in inducing 
and maintaining suitable sedation levels for patients undergoing bronchoscopy and to assess 
data from an additional open-label midazolam group in combination with fentanyl as 
determined by sedation success. 
2.2 Secondary Objectives 
Secondary objectives include assessing time to event endpoints (as described in detail under 
Section 2.3.1.2 Secondary Efficacy Endpoints). 
2.3 Safety and Efficacy Endpoints 
2.3.1 Efficacy Endpoints 
2.3.1.1 Primary Efficacy Endpoints 
The primary efficacy endpoint is to assess the success of sedation of the bronchoscopy 
procedure. This composite endpoint will be determined for remimazolam and placebo by the 
following criteria: 
 Completion of the bronchoscopy procedure, AND  
 No requirement for a rescue sedative medication, AND 
 No requirement for more than 5 doses of study medication within any 15 
minute window in the blinded arms (remimazolam/placebo) or no requirement 
for more than 3 doses within any 12 minute window in the open-label 
midazolam arm. 
2.3.1.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints are: 
1. The time to start of procedure after administration of the first dose of study medication. 
2. 
 
 
3. The time to ready for discharge (defined as ability to walk unassisted) after the end of 
bronchoscopy procedure (bronchoscope out). 
4. The time to ready for discharge after the last injection of study drug. 
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5. The times to fully alert (time to first of three consecutive Modified Observer's 
Assessment of Alertness/Sedation (MOAA/S) scores of 5) after the end of bronchoscopy 
procedure (bronchoscope out)). 
6. The times to fully alert (time to first of three consecutive MOAA/S scores of 5) after the 
last injection of study drug).  
7. 
 
8. 
 
 
9. 
 
 
 
10. 
 
11. 
 
12. 
 
13. 
 
14. 
 
2.3.2  Safety Endpoints 
Safety endpoints include: 
1. Adverse events (AEs) 
2. Clinical laboratory test results 
3. Vital signs (supine heart rate, systolic and diastolic blood pressure (BP), calculated mean 
arterial pressure, respiration rate, temperature) 
4. Pulse oximetry measurements (presented by patient for pre-defined time points, and as 
oxygen saturation over time (AUC)) 
5. Electrocardiogram (ECG) findings 
6. Physical examination findings 
7. 
 
8. 
 
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9. 
 
 
 
10. The safety of multiple doses (initial dose and additional top-up doses) of remimazolam 
including oxygen saturation and no need for mechanical ventilation following 
administration of a standard dose of fentanyl. 
2.3.3 
 
 
 
 
 
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3 OVERALL STUDY DESIGN AND PLAN 
This study is a prospective, randomized, placebo and active controlled, multi-center, parallel 
group study comparing remimazolam to placebo in a double-blind manner, with an additional 
open-label midazolam arm, in patients undergoing bronchoscopy. 420 patients will be 
randomized into one of three possible study groups: placebo (n=60), midazolam (n=60), and 
remimazolam (n=300). 
All patients will receive 0.9% NaCl solution up to 1000 mL drip starting prior to the 
procedure, if their fluid status allows. All patients will receive 25-50 µg of fentanyl 
immediately prior to the administration of study medication (with suitable dose reductions at 
the investigator’s discretion for elderly and debilitated patients). All infused fluid volumes 
will be recorded throughout the procedure. The administration of supplemental oxygen will 
be started shortly before the procedure and will be continued at a rate of 4 L/min until the 
patient is fully alert (first of three consecutive MOAA/S scores of 5). 
Blinded arms: 
Patients will be randomized to manually receive an initial single intravenous (iv) dose over 
one minute of remimazolam 5.0 mg or an equal volume of placebo in a blinded manner and 
bronchoscopy will start when adequate sedation (MOAA/S ≤3) has been achieved.  
Sedation may be maintained by injection of further doses of remimazolam 2.5 mg or placebo 
in the same volume not earlier than two minutes apart after assessment of the sedative effect. 
The overall number of remimazolam/placebo doses is not limited as long as not more than 5 
doses are administered in any 15 minute window. Should five doses within 15 minutes not 
be sufficient to obtain adequate sedation for the bronchoscopy, this is defined as a treatment 
failure. 
Open-label arm: 
In the open-label midazolam arm, healthy adults <60 years will receive 1.75 mg of 
midazolam as an initial dose over two minutes. Adults ≥60 years, debilitated or chronically ill 
patients will receive 1.0 mg midazolam as an initial dose over two minutes. Sedation can be 
maintained by further doses of 1.0 mg in healthy adults <60 years; in the case of adults ≥60 
years, debilitated or chronically ill patients, the dose will be 0.5 mg. These subsequent doses 
should always be titrated slowly and administered over at least two minutes. At least two 
additional or more minutes should be allowed to fully evaluate the sedative effect. The 
overall number of midazolam doses is not limited as long as not more than three doses are 
administered in any 12 minute window. Should three doses within any 12 minute window 
not be sufficient to obtain adequate sedation for the bronchoscopy, this is to be considered a 
treatment failure. 
After determination of treatment failure, midazolam is defined as the only rescue sedative 
medication in such cases in order to perform or finalize the bronchoscopy. 
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If the pain is not adequately controlled by the initial dose of 25-50 µg fentanyl (with suitable 
dose reductions at the investigator’s discretion for elderly and debilitated patients), further 
top up doses of fentanyl of 25 µg q 5-10 minutes are allowed until adequate analgesia is 
achieved or the maximum dose of 200 µg per procedure has been reached. It is of note, that 
fentanyl is strictly to be applied for pain control only. 
3.1 Study Population 
This is a study in patients undergoing a bronchoscopy for diagnostic or therapeutic purposes 
(e.g. biopsies, lavage, brushings, and foreign body extraction). A total of 420 patients will be 
randomized, of which 300 will receive remimazolam, 60 will receive placebo (0.9% NaCl) in 
a blinded fashion, and 60 patients will receive midazolam open label.  
3.2 Method of Assigning Patients to Treatment Groups 
Before dosing, patients will be randomly assigned in a 30:6:6 ratio to remimazolam, placebo 
or open-label midazolam.  The randomization schedule will be computer-generated using a 
permuted block algorithm and will randomly allocate study drug to randomization numbers. 
The randomization numbers will be assigned sequentially as patients are entered into the 
study. The study site will not be stratified in the randomization schedule. Although the 
amount of chronic use of opioids and/or benzodiazepines will be known in advance, it is 
difficult to be able to stratify the randomization for amount of these drugs from a practical 
perspective. 
Randomization will be stratified by age group. The aim is to have at least 100 patients on 
remimazolam aged ≥ 65 years (at least 30 of these aged ≥ 75 years or older) across the three 
late stage clinical trials (CNS7056-006, CNS7056-008, and CNS7056-015). The CNS7056-
008 study will be included as part of an integrated analysis plan where age group will be 
assessed as above. 
On Study Day 1, after confirming that a patient still meets entry criteria, study personnel will 
inform the pharmacist that the patient qualifies for randomization. The unblinded pharmacist 
will call the central interactive web response system (IWRS) and enter the requested 
information. The IWRS will then assign the next randomization number in the sequence and 
inform the pharmacist of the study treatment assignment. Thereafter, the pharmacist will 
dispense the corresponding treatment. 
Group  
Trial medication  Initial dose + Top up dose  
Group 1 (N = 60)  
Placebo  
Volume to match group 2 
Group 2 (N = 300)  
Remimazolam 
5.0 mg + 2.5 mg 
Group 3 (N = 60)  
Midazolam  
1.75 mg + 1.0 mg* or 1.0 mg + 0.5 mg§ 
*Healthy adults <60 years; §adults ≥60 years, debilitated or chronically ill patients. 
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3.3 Treatment Blinding 
The study will be conducted as a randomized, double-blind study with respect to 
remimazolam and placebo. The midazolam arm will be open-label. The identity of the 
blinded study drugs (remimazolam or placebo) will not be revealed to study management or 
to anyone at the study site except for the pharmacist, the pharmacy staff and 
 
unblinded monitor until the study is completed. This exemption also applies to the data 
monitoring committee (DMC) members. The pharmacist and staff will not participate in other 
study procedures. Patients will be blinded to treatment. 
3.4 Schedule of Assessments 
The maximum study duration for any patient will be up to 28 days. The patients will be 
screened within 21 days prior to the bronchoscopy. A follow-up phone call will be performed 
on Day 4 (+3/-1 days) following the bronchoscopy. 
Screening (Day -21 to Day 1): Patients will sign informed consent and undergo procedures to 
determine eligibility. 
Day of Bronchoscopy (Day 1): After the completion of screening procedures patients will be 
randomly assigned to the remimazolam, placebo or midazolam group. All patients will receive 
25-50 μg of fentanyl immediately prior to the administration of study medication (with suitable 
dose reductions at the investigator’s discretion for elderly and debilitated patients).Following 
completion of the bronchoscopy procedure, the patients will be discharged at the discretion of 
the investigator and complete the assessments after reaching fully alert status. Assessment of 
“time back to normal” in the patient’s subjective view will be collected via telephone contact 
by study nurse on Day 2. 
Follow-up (Day 4 [+3/-1 days]): The site will telephone the patient for safety assessments. 
Study participation is considered complete after all Day 4 assessments have been performed 
and all AEs have been followed-up until they resolve or become stable, or until they can be 
explained by another known cause(s). 
In case there has been any indication for the onset of a new AE since discharge, patients 
should come back to the site immediately (preferably the same day) to perform further 
assessments (e.g.clinically laboratory tests, 12 lead ECG, left to the discretion of the 
investigator). 
3.5  Sample Size Calculation 
 
 
  
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A total of 420 patients will be randomized, 300 to receive remimazolam, 60 to receive open-
label midazolam, and 60 to receive placebo. 
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4 ANALYSIS AND REPORTING 
4.1 Software and general statistical methods 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.3 or higher) for 
Windows. If the use of other software is warranted, the final statistical methodology report 
will detail what software was used for what purposes. 
All measured variables and derived parameters will be listed individually and, if appropriate, 
tabulated by descriptive statistics. 
For continuous variables, summary statistics including number of patients with data, mean, 
standard deviation (SD), median, minimum and maximum will be provided. For categorical 
variables, the number of patients and percentage for each category will be presented.  
A blinded data review will be performed before the database is locked and the study groups 
are unblinded.  
Study medication is defined as any of fentanyl or remimazolam, placebo or midazolam 
administered for the initial dosing or top-up doses.  
Randomized study medication is defined as the Investigational Medicinal Product IMP 
(remimazolam, placebo or midazolam). The start of the initial dose of randomized study drug 
infusion will be considered Time 0 (t=0). 
4.2 Interim Analyses and Data Monitoring 
No interim analyses are planned for this study. 
4.3 Final Analysis 
All final, planned, analyses identified in the protocol and in this SAP will be performed only 
after the last patient has completed the last study visit and end of study assessments, all 
relevant study data have been processed and integrated into the analysis data base, and the 
clinical database has been locked and the randomization code has been unblinded. In 
addition, no database may be locked, randomization code unblinded, or analyses completed 
until this SAP has been approved.  
All statistics and study results will be made available to Paion after database lock and 
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5 ANALYSIS POPULATIONS 
Eight analysis populations are defined: 
 The Safety Population will consist of all randomized patients who receive any amount of 
study drug and will be analyzed as treated. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 The Intent-to-treat analysis set (ITT) will include all patients who were randomized and 
will be analyzed as randomized. 
 The Modified Intent-to-treat analysis set (mITT) will include all patients included in the 
ITT population who received at least one complete dose of randomised study medication. 
These will be analysed as randomized. 
 The Per-Protocol analysis set (PP) will include all patients from the ITT analysis set who 
 received randomized treatment according to their randomization and the planned 
treatment schedule. 
 did not have any major protocol deviations  
Protocol deviations to be considered are defined in the Protocol Deviation Guidance Plan. 
Membership in the analysis populations will be determined before unblinding at the blinded 
data review meeting. 
 
 
 
 
 
 
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6 GENERAL ISSUES FOR STATISTICAL ANALYSIS 
6.1 General Statistical Methodology 
6.1.1 Adjustments for Multiple Comparisons 
No adjustment for multiple testing is required for the primary endpoint as only one pairwise 
comparison will be performed between the remimazolam and placebo groups. Analyses of the 
remimazolam and placebo groups for all secondary parameters will be considered to be 
descriptive only as it is likely that most of the patients in the placebo group will have taken 
midazolam as rescue sedative medication. Therefore, these analyses will need to be interpreted 
with caution. 
Comparison between the remimazolam and midazolam groups will be descriptive only, a 
95% confidence interval of the difference will be presented but no further analysis will be 
performed. 
6.1.2 Methods for Dropouts or Missing Data 
 
 
 
Incomplete dates and times for AEs and concomitant medications will be imputed as 
described in section 6.1.5.5 below. 
Time to event variables will be censored as described in section 6.2 below if the event did not 
occur. 
6.1.3  Pooling of Centers 
The study will include data from all centers.  
Centers who recruit fewer than 20 patients will be pooled into one “Other” center. 
6.1.4 Analysis Visit Windows 
Analyses of all variables for this study will use the nominal visit or time point as collected in 
the case report form (CRF) and/or database.  
6.1.5 Data Handling Conventions 
6.1.5.1 Baseline Definitions 
For all analyses, the baseline value is defined as the value recorded ‘Within 5 hrs’ or ‘Within 
15 minutes’ before first dosing of study medication as shown in Appendix B Schedule of 
Assessments of the protocol. The most recent pre-dose value will be taken as baseline. Where 
a value is missing, the next previous value will be used.  
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The date/time of the first dose (t=0) for the efficacy analyses is defined as the start date/time 
of first administration of randomized study medication. 
Change from baseline will be defined as the Value – Baseline.  
6.1.5.2 Start Date, End Date of Study Treatment, and Study Day  
The start date of study treatment is defined as the first date when study medication was 
taken (Day 1).  
The study day for all assessments will be calculated using the start date of study treatment as 
the origin (Day 1): 
study day = (date of assessment) – (start date of study treatment) + 1  
For assessments/events with a date preceding the start date of study treatment, the following 
formula will be applied: 
study day = (date of assessment) – (start date of study treatment)  
6.1.5.3 Early Termination (ET) Visit 
Patients who discontinue from the study after randomization and before the Day 4 visit 
should be scheduled for an ET visit during which all assessments listed for the Day 4 visit 
will be performed.  
6.1.5.4 Unscheduled Visits 
Data (such as laboratory tests and vital signs) collected at unscheduled visits will not be 
included in the analyses by scheduled visits, but may be used for baseline and for safety shift 
tables from baseline to most extreme value.  
6.1.5.5 Incomplete Date and Time Imputation for Adverse Events and Concomitant 
Medications 
For partial AE/concomitant medication (CM) start dates the imputation rules are described in 
the following table.  
Partial start date 
Date imputation 
YYYY missing 
 
No imputation 
YYYY ≠ TRTY  
MON missing 
Imputed date = 01JANYYYY 
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Partial start date 
Date imputation 
YYYY ≠ TRTY  
MON not missing, 
DAY missing 
Imputed date = 01MONYYYY 
YYYY = TRTY  
MON missing 
Imputed date = start date of study 
treatment 
YYYY = TRTY  
MON < TRTM, 
DAY missing 
Imputed date = 01MONYYYY 
YYYY = TRTY  
MON ≥ TRTM, 
DAY missing 
Imputed date = max (01MONYYYY, start 
date of study treatment) 
YYYY=Year of AE/CM start date, MON=Month of AE/ CM start date, DAY=day of AE/ CM start date, 
TRTY=Year of start date of study treatment, TRTM=Month of start date of study treatment 
For partial AE (or CM) end dates the imputation rules are defined as the following:  
 If month or year of an AE (or medication) end date is missing, the AE (or medication) 
end date is set to the date of study completion/early termination. 
 If day of an AE (or medication) end date is missing, but month and year of the AE (or 
medication) end date are not missing, the AE (or medication) end date is set to 
minimum of (end date of study treatment, last day of the month). 
If an imputed AE (or CM) end date is earlier than the AE (or CM) start date, the AE (or CM) 
start date will be used as the imputed AE (or CM) end date. 
After applying the rules above the following rules will be used to determine whether an AE is 
‘treatment emergent’ or not and whether a medication is ‘concomitant’ or ‘prior’:  
 If the start date is missing and the end date is either missing or on or after the start 
date of study treatment, then the AE (or medication) is considered to be treatment 
emergent (or concomitant). 
 If the start time is missing and the start date is either on the same day as the start of 
study treatment or has been imputed as the same day as the start of study treatment, 
then the AE (or medication) is considered to be treatment emergent (or concomitant) 
 If the start date is missing and the end date is before the start date of study treatment, 
then the AE (or medication) is considered to be not treatment emergent (or prior). 
 If the start date is not missing and the end date is missing, then the medication is 
considered to be concomitant while the treatment emergent status is determined by the 
start date. 
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 If the start time in seconds is missing, then the seconds is replaced by a half-minute or 
50 seconds. 
6.1.6 By Patient Data Listings 
All data available will be presented in listings. Data not subject to analysis according to this 
plan will not appear in any tables or graphs, but will be included in the data listings. 
6.2 Derived and Computed Variables  
The following derived and computed variables have been initially identified as important for 
the analysis of the primary and secondary target variables. It is expected that additional 
variables will be required. The SAP will not be amended for additional variables that are not 
related to the primary target or key secondary target variables. Any additional derived or 
computed variables will be identified and documented in the SAS programs that create the 
analysis files. In all cases, incomplete dates will be completed for the analysis using a 
conservative/worst case solution.  
Variable 
Name  
Description  
Valid 
Values 
(Ranges)  
Computation Methods, Notes, or Equation(s)  
SUCCESS  
Overall Success 
of the 
Bronchoscopy 
Procedure  
1 = Yes  
0 = No  
SUCCESS = 1 if and only if all the following criteria are met:  
 
Completion of the bronchoscopy procedure  
 
No requirement for an alternative sedative medication  
 
No requirement for more than 5 doses of study medication (these 5 
doses may include the initial dose) within any rolling 15 minute 
window in the double-blind arms or no requirement for more than 3 
doses within any rolling 12 minute window in the open midazolam 
arm. 
Otherwise SUCCESS = 0  
The criterion of no more than 5 doses for a 15 minute window means 
that if any dose has a further 4 doses within the following 900 seconds 
inclusive, then SUCCESS = 0. The criterion for 3 doses within 12 
minutes is defined similarly. 
T2START 
Time to start of 
procedure 
 
T2START=1 + (start time of procedure) - (first dose of randomized 
study medication start time) in minutes 
For patients who do not start a procedure, this time will be censored at 
the time of dropout. 
CENSOR2TS 
Censor indicator 
for time to start 
of procedure 
1 = Yes  
0 = No 
If T2START was censored, CENSOR2TS = 1, else CENSOR2TS = 0. 
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Variable 
Name  
Description  
Valid 
Values 
(Ranges)  
Computation Methods, Notes, or Equation(s)  
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
  
T2FAP  
Time to Fully 
Alert after the 
end of the 
procedure 
 
T2FAP = 1 + (time fully alert achieved) – (end time of procedure) in 
minutes, if patient reaches fully alert. Fully alert is defined as the first of 
three consecutive MOAA/S measurements of 5 after the end of the 
procedure.  
If a patient withdraws early, and/or does not reach Fully Alert at the end 
of the study, the patient’s T2FAP will be censored using a patient’s last 
MOAA/S assessment date.  
CENSORAP 
Censor Indicator 
for Fully Alert 
after the end of 
the procedure  
1 = Yes  
0 = No  
If T2FAP was censored: CENSORAP=1; Else CENSORAP=0.  
T2FAD  
Time to Fully 
Alert from the 
end of the last 
dose of study 
drug or rescue 
sedative drug 
 
T2FAD = 1+ (time fully alert achieved) – (end time of last dose of 
randomized study medication or rescue sedative medication) in minutes, 
if patient reaches fully alert. Fully Alert is defined as the first of three 
consecutive MOAA/S measurements of 5 after the start time of the last 
dose of study or rescue drug.  
If a patient withdraws early, and/or does not reach Fully Alert at the end 
of the study, the patient’s T2FAD will be censored using a patient’s last 
MOAA/S assessment. 
CENSORAD 
Censor Indicator 
for Fully Alert 
from the end of 
the last dose of 
study drug 
1 = Yes  
0 = No  
If T2FAD was censored: CENSORAD=1; Else CENSORAD=0.  
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Variable 
Name  
Description  
Valid 
Values 
(Ranges)  
Computation Methods, Notes, or Equation(s)  
T2RDB 
Time to Ready 
for Discharge 
from the end of 
bronchoscopy 
procedure  
 
T2RDB = 1 + (time ready for discharge) – (end time of bronchoscopy 
procedure) in minutes, if patient is ready for discharge. Ready for 
discharge is defined as ready to walk unassisted. 
If a patient withdraws early, and/or does not reach Ready for Discharge 
at the end of the study, the patient’s T2RDB will be censored using the 
patient’s last assessment.   
CENSORDB 
Censor Indicator 
for Ready for 
Discharge from 
the end of 
bronchoscopy 
procedure 
1 = Yes 
0 = No 
If T2RDB was censored: CENSORDB = 1; Else CENSORDB = 0. 
T2RDD 
Time to Ready 
for Discharge 
from the end of 
the last dose of 
study drug. 
 
T2RDD = 1 + (time ready for discharge) – ( end time of last dose of 
randomized study medication or rescue sedative medication) in minutes, 
if patient is ready for discharge. Ready for discharge is defined as ready 
to walk unassisted. 
If a patient withdraws early, and/or does not reach Ready for Discharge 
at the end of the study, the patient’s T2RDD will be censored using the 
patient’s last assessment. 
CENSORDD 
Censor Indicator 
for Ready for 
Discharge from 
the end of the 
last dose of 
study drug. 
1 = Yes 
0 = No 
If T2RDD was censored: CENSORDB = 1; Else CENSORDB = 0. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
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Variable 
Name  
Description  
Valid 
Values 
(Ranges)  
Computation Methods, Notes, or Equation(s)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HRNADC 
Lowest post-
dose value of 
Heart Rate 
 
Lowest recorded post-dose value of Heart Rate in CRF on treatment day 
RRNADC 
Lowest post-
dose value of 
Respiratory 
Rate 
 
Lowest recorded post-dose value of Respiratory Rate in CRF on 
treatment day 
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Variable 
Name  
Description  
Valid 
Values 
(Ranges)  
Computation Methods, Notes, or Equation(s)  
OXYNADC 
Lowest post-
dose value of 
SpO2 
 
Lowest recorded post-dose value of SPO2 in CRF on treatment day 
RRPEAK 
Peak post-dose 
value of 
Respiratory 
Rate 
 
Highest recorded post-dose value of Respiratory Rate in CRF on 
treatment day. 
HRNADN 
Lowest post-
dose value of 
Heart Rate 
 
Lowest value of Heart Rate from Nellcor data on treatment day in the 
interval between the first dose of study medication and the time when 
the patient becomes fully alert 
RRNADN 
Lowest post-
dose value of 
Respiratory 
Rate 
 
Lowest value of Respiratory Rate from Nellcor data on treatment day in 
the interval between the first dose and the time when the patient 
becomes fully alert 
OXYNADN 
Lowest post-
dose value of 
SpO2 
 
Lowest value of SpO2 from Nellcor data on treatment day in the interval 
between the first dose and the time when the patient becomes fully alert 
RRPEAKN 
Peak post-dose 
value of 
Respiratory 
Rate 
 
Highest value of Respiratory Rate from Nellcor data on treatment day in 
the interval between the first dose and the time when the patient 
becomes fully alert 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7 STUDY PATIENTS AND DEMOGRAPHICS 
7.1 Disposition of Patients and Withdrawals 
The number of patients included in each analysis set (Safety, each Safety [Nellcor], ITT, 
mITT, PP) will be presented by treatment group and overall. 
The number and percentage of patients who completed the study treatment period, who 
discontinued the study prior to the end of treatment and the reason for discontinuation, along 
with the number who completed the Follow-up Visit will be presented for each treatment 
group and overall, using the safety population. 
All disposition summaries will also be presented by study center. 
7.2 Protocol Deviations 
A list of protocol deviations that could affect the primary objective will be identified by the 
Clinical and Medical Monitors. This list will be finalized prior to database lock and 
unblinding of the study. The incidence of each protocol deviation will be presented for the 
ITT population.  
7.3 Demographics and Baseline Characteristics 
Demographics variables and baseline characteristics will be summarized for the safety 
population overall and by treatment group.  
Demographic variables will include age, sex, race, ethnicity, height, weight, and body mass 
index (BMI). Baseline patient characteristics will include ASA status, physical examination 
findings, medical history, vital signs, clinical laboratory test results, and 12-lead ECG. 
Baseline patient characteristics will include prior medications. 
7.4 Medical History 
The number and percentage of patients with at least one medical history item in each System 
Organ Class (SOC) and preferred term will be presented overall and by treatment group, 
using the safety population. 
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8 EFFICACY ANALYSIS  
8.1 Primary Efficacy 
8.1.1 Primary Efficacy Endpoint 
The primary efficacy variable is success of the bronchoscopy procedure; a composite 
endpoint consisting of the following: 
 Completion of the bronchoscopy procedure, AND  
 No requirement for a rescue sedative medication, AND 
 No requirement of more than 5 doses of study medication within any 15 minute window. 
For midazolam only: no requirement of more than 3 doses within any 12 minute window. 
(See section 6.2 for definition of how doses within a window are defined.) 
Exceeding 5 doses within any sliding 15 minute window in the blinded (remimazolam or 
placebo) arm will be considered a treatment failure. Exceeding 3 doses within any 12 minute 
sliding window in the open-label midazolam arm will be considered a treatment failure. 
8.1.2 Primary Analysis 
The primary efficacy analysis (success of the procedure using the composite endpoint) will 
be summarized descriptively for overall success for each treatment group, with summaries to 
include the number and percentage of patients. 
Comparison of remimazolam and placebo 
For the primary efficacy analysis, the following primary hypothesis will be tested: 
 
H0: πRemi ≤ πPLA vs. H1: πRemi > πPLA, 
 
where πRemi and πPLA denote the success rates for Remimazolam and placebo, respectively. 
The primary efficacy analysis will be the comparison of these success rates between the 
remimazolam and placebo groups, using the Cochran-Mantel-Haenszel (CMH) test 
 
 
 
 
 
 
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The primary efficacy analysis will be based on the ITT, mITT and PP populations, with the 
mITT and PP population planned to confirm the results of the ITT population.Comparison of 
remimazolam and midazolam 
A 95% confidence interval of the comparison of success rates between midazolam and 
remimazolam will be presented but there will be no significance testing. 
8.1.3 
 
 
 
 
 
 
 
 
 
 
 
8.2 Secondary Efficacy 
The following secondary efficacy variables will be presented with descriptive statistics by 
treatment group:  
1. The time to start of procedure after administration of the first dose of randomized 
study medication. 
2. 
 
3. The time to ready for discharge (defined as ability to walk unassisted) after the end 
of bronchoscopy procedure (bronchoscope out). 
4. The time to ready for discharge (defined as ability to walk unassisted) after the last 
injection of study drug. 
5. The time to fully alert (time to first of three consecutive MOAA/S scores of 5) after 
the end of bronchoscopy procedure (bronchoscope out)). 
6. The time to fully alert (time to first of three consecutive MOAAA/S scores of 5) after 
the last injection of study drug).  
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7. 
   
8. 
 
9. 
 
 
10. 
 
11. 
 
 
12. 
 
13. 
 
 
14. 
 
 
All secondary efficacy variables will be compared between the three treatment groups. For 
the key secondary variables (variables 1-6), only the pairwise comparison between placebo 
and remimazolam will be used for exploratory efficacy significance testing. The time to event 
variables (variables 1-6, 13 above) will be analyzed by the logrank test. Kaplan-Meier graphs 
will also be fitted for each treatment group. Patients who do not reach fully alert will be 
censored at the time of their last MOAA/S assessment. Patients who do not reach ready for 
discharge criteria will be censored at the time of their last assessment. Median time to event 
with the corresponding 95% confidence interval will be presented. Additional quartiles (25% 
and 75%) and confidence intervals will be presented. A Cox’s proportional hazard model 
including age group (<65, ≥65) will be fitted separately to the remimazolam and placebo, and 
the remimazolam and midazolam groups and the 95% confidence interval of the hazard ratio 
will be presented 
 
 
 
 
 
 
 
 
 
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For the Readiness for Discharge score (variable 10) a value of 100 (= immediate readiness for 
discharge) will be used if the patient has already been discharged at the defined timepoint of 
analysis.  
 
   
 
 
 
 
 
 
 
 
As a measure of discharge readiness, the proportion of the readiness for discharge score at 30, 
60 and 90 minutes after t=0 will be compared across the treatment groups.  
 
 
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9 SAFETY AND TOLERABILITY ANALYSIS 
All safety analyses will be performed on the Safety Population, apart from the analyses of the 
Nellcor data which will use the Safety (Nellcor) populations. 
All safety variables will be summarized descriptively. No statistical inference will be applied 
to the safety variables. 
Safety variables that will be analyzed as safety endpoints include  
 AEs, including adverse events with focus on respiratory and cardiovascular 
parameters and prolonged sedation (see Appendix A) and AEs potentially related to 
abuse (see Appendix D) 
 Concomitant medication 
 Clinical laboratory test results 
 Vital signs (supine heart rate, systolic, diastolic and mean BP, respiration rate, 
temperature) 
 Pulse oximetry measurements 
 12-lead and 3-lead ECG findings 
 Physical examination finding 
 
 
 
 
 
 
 
 
 
 
9.1 Adverse Events 
Treatment-emergent AEs (TEAEs) are defined as AEs reported at or after the start time of 
initial fentanyl administration or IMP, whatever is earlier, that are not present at Baseline, or 
that represent an exacerbation of an event that is present at Baseline. Any AE with an 
unknown start date and time will be considered treatment-emergent if the event does not 
discontinue prior to study drug administration.  
The number and percentage of patients with TEAEs will be displayed for each treatment 
group by system organ class and preferred term using the current version of the Medical 
Dictionary for Regulatory Activities (MedDRA). Pretreatment AEs (reported from signing 
informed consent to before administration of study treatment) will be analyzed and displayed 
in a similar manner to TEAEs. 
Summaries in terms of maximum severity and strongest relationship to study drug will also 
be provided.  
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Summaries of serious adverse events (SAEs) similar to those of AEs will be provided 
separately. By-patient listings of AEs causing discontinuation of study drug and SAEs will be 
produced. 
At each level of summarization (SOC or preferred term) a patient will be counted only once 
at the most severe or most related category. Patients with missing severity or relationship will 
be counted in the most severe and related category. 
In addition, tachycardia (defined as heart rate recorded as >100 bpm, or an increase of 20% or 
more in the heart rate from baseline) will be analyzed. 
 
9.1.1 
  
 
  
 
 
 
 
 
  
 
  
 
  
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
The number and percentage of patients with AEs with a respiratory or cardiovascular focus 
will be displayed for each treatment group by system organ class (SOC) and preferred term, 
and also by standardised MedDRA query (SMQ) and preferred term. The preferred terms 
relating to these are shown in Appendix A. 
The related AEs with a respiratory or cardiovascular focus will be displayed for each treatment 
group by system organ class and preferred term. 
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The AEs with a respiratory or cardiovascular focus will be summarized split by time of onset 
(Day 1, after Day 1).The vital signs observed when a patient experienced a respiratory-
cardiovascular AE will be summarized. The frequency of vital signs falling outside the normal 
range (as defined in the AE definitions above) will be given. 
Interventions taken to prevent or treat these AEs are collected in the CRF. The number of 
patients requiring intervention and the type of interventions will be summarized. 
9.1.5.1 
 
 
 
 
 
 
  
 
 
 
 
 
 
9.1.2 
 
 
 
 
 
 
 
9.2 Clinical Laboratory Tests 
For qualitative clinical laboratory tests, the number and percentage of patients in each 
category will be displayed for each treatment group at each time point. 
For all laboratory tests, a shift table will be produced summarizing changes from baseline to 
the end of the treatment period by treatment group. 
Individual data listings of laboratory results will be presented for each patient at all study 
visits (scheduled and non-scheduled), including normal range limits for each laboratory test. 
Out-of-range results will be flagged, and determinations of whether the results were 
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considered to be of clinical significance by the investigator will be included. Clinically 
significant laboratory test abnormalities that are considered AEs by the investigator will be 
presented in the AE summaries. 
9.3 Vital Signs, Pulse Oximetry 
Individual data listings of vital signs (supine heart rate, systolic and diastolic blood pressure, 
calculated mean arterial pressure, temperature, and respiration rate) will be presented for each 
patient at all visits (scheduled and non-scheduled). Pulse oximetry data (SpO2) will be 
presented by patient for pre-defined time points, and as the area under the oxygen 
desaturation curve (AUCDesat) over time from 1 minute before the first dose of randomized 
study drug to fully alert (AUCalert) and from 1 minute pre-dose to 20 minutes post dose 
(AUC20min). Desaturation is defined as an SpO2 below 90%. 
Descriptive statistics will be used to summarize the observed values at each time point, and 
the changes from baseline, for each treatment group. Graphic presentations of heart rate, 
blood pressure, and respiration rate may be presented by patients and as means by treatment 
over time. Vital sign and SpO2 findings that were considered AEs by the Investigator will be 
presented by treatment in the AE summaries. The number of heart rate and SpO2 findings 
(defined as being under the threshold value) that were not considered AEs as they did not 
meet the duration criteria will be presented by treatment, along with the duration. 
The nadirs of heart rate, respiratory rate, and SpO2, after the first dose of randomized study 
drug of the data recorded in the CRF on the treatment day will be calculated and summarized 
by treatment group.  
9.3.1 Continuous Monitoring 
The data from the Nellcor device used to perform continuous monitoring of heart rate, 
respiratory rate and SpO2 (taken every second) during the procedure will be downloaded for 
analysis. All analyses of the Nellcor data will use the Safety (Nellcor) Populations. 
The observational period will be from the first dose of any study medication (Fentanyl or 
IMP) until fully alert on the treatment day. Baseline will be defined as the pre-treatment 
values recorded in the CRF. 
The nadirs and the peak for respiratory rate in the observational period will be identified and 
summarized by treatment group. If a “0” occurs then these values will be treated as missing 
data. Similarly, nadirs of heart rate and SpO2 will be identified and summarized by treatment 
group. 
All episodes of hypoxia (SpO2 <90%), bradycardia (heart rate <40 bpm),  HR decreased (a 
drop in heart rate of 20% or more from baseline), respiratory depression (<8 breaths per 
minute) and respiratory increase (increase to >25 breaths per minute) in the observational 
period will be identified from the continuously recorded data. In addition, tachycardia (heart 
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rate >100 bpm or increase of heart rate of 20% or more from baseline) will be analyzed. The 
number of patients reporting each type of AE and the duration will be summarized. 
Further, those episodes of hypoxia, bradycardia or HR decreased which last long enough to 
match the protocol definitions of an AE above will be identified. The number of patients 
reporting episodes with a duration matching the AE definition and the number of patients 
with episodes with a duration that does not match the AE definition will be summarized, 
along with a summary of the durations of the episodes. Subgroup analyses of those AEs will 
be done as described in section 9.1.1 above. 
The sites were asked whether they agreed that AEs identified in this way were actually AEs 
and whether they had been clinically observed and recorded in the CRF. The number of 
patients reporting each type of episode will be summarized by whether the investigator 
agreed. 
9.3.2 Continuous Monitoring – Exploratory Analyses 
Further, exploratory analyses of the data collected with the Nellcor device may also be done 
after the main analyses of this study, and if so, those analyses will be described in a separate 
Exploratory SAP. 
9.4 Electrocardiograms 
9.4.1 12-Lead ECG 
The number and percentage of patients with normal and abnormal 12 lead ECG findings will 
be displayed for each treatment group at each time point. Additionally, patients with normal 
ECG findings at baseline and abnormal ECG findings at each time point will also be 
summarized by treatment group. For quantitative ECG variables (PR interval, RR interval, 
QRS interval, QT interval, and QTC interval [corrected using the Bazett and Fridericia 
formulae]), descriptive statistics will be given for the values themselves as well as for change 
from baseline, by treatment group at each time point. 
9.4.2 3-Lead ECG 
The number and percentage of patients with normal and abnormal 3 lead ECG findings will 
be displayed for each treatment group at each time point. Additionally, patients with normal 
ECG findings at baseline and abnormal ECG findings at each time point will also be 
summarized by treatment group. 
All episodes of bradycardia or other arrhythmias, captured in continuous 3-lead ECG 
recording, and any interventions that were instituted, will be documented and analyzed 
regardless of whether or not the event had been reported as an adverse event. 
9.5 Physical Examinations 
The number and percentage of patients with normal and abnormal physical examination 
findings will be displayed for each body system and treatment group at each time point. 
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Additionally, patients with normal physical examination findings at baseline and abnormal 
physical examination findings at each time point will also be summarized by treatment group. 
9.6 
 
 
 
 
 
9.7 Prior and Concomitant Medications 
9.7.1 Prior and Concomitant Medications 
Prior and concomitant medication analyses will be provided for the safety population. Data 
on sedation rescue medication (which should only be midazolam) will be collected and 
presented separately from concomitant therapy as described in section 9.7.2. 
All prior and concomitant medications will be coded using World Health Organization Drug 
Dictionary (WHO-DD) Version March 2015. Prior medications are defined as any 
medications taken prior to the start date of study treatment (whether stopped or continued 
after the start date of study treatment). Concomitant medications are defined as those used 
between the start date of study medication and the date of study completion or early 
termination. A medication could be flagged both as prior and concomitant if it was started 
prior to the patient’s start date and continued on or after the start date of study medication. 
Prior and concomitant medications will be summarized by treatment group in separate tables. 
Medications will be presented in alphabetical order, by Anatomical Therapeutic Class (ATC) 
(ATC Level 4) and preferred term. Tables will also show the overall number and percentage 
of patients receiving at least one medication. At each level of summarization (ATC class or 
preferred term) patients will be counted only once. 
9.7.2 Rescue Sedative Medications  
The patient should receive midazolam as the rescue sedative at the discretion of the 
investigator, to allow for completion of the procedure or scope removal. The patient should 
also receive flumazenil as a reversal medication in case of remimazolam or midazolam 
overdose, or naloxone as a fentanyl antagonist. The number and percentage of patients 
receiving it will be summarized for all patients in the safety population by treatment group. 
A patient reporting rescue medication more than once will be counted once when 
calculating the number and percentage of patients.  
 
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9.8 
 
 
 
 
The number of patients where the number of doses of double-blind IMP was more than 5 
within any 15 minute window or more than 3 doses within any 12 minute window in the 
midazolam arm will be considered a treatment failure, and will be calculated and summarized 
by treatment group. 
 
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10 
 
 
 
 
 
 
 
 
 
  
 
 
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11 REFERENCES 
1. US Department of Health and Human Services. International Conference on 
Harmonization; Guidance on Statistical Principles for Clinical Trials. Rockville, MD: 
September 16, 1998. Federal Register;63(179):49583-49598..
2. ASA. (1999) Ethical Guidelines for Statistical Practice. Prepared by the Committee 
on Professional Ethics, August 7, 1999.
http://www.amstat.org/about/ethicalguidelines.cfm
3. The Royal Statistical Society: Code of Conduct, April 1993.
http://www.rss.org.uk/main.asp?page=1875. 
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12 ATTACHMENTS 
The table shells will be attached in a separate document. 
 
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APPENDIX A: Details of AEs with a Respiratory or Cardiovascular Focus 
LOW OXYGEN SATURATION/RESPIRATORY DEPRESSION 
SMQ: Acute Central Respiratory Depression 
Acute central respiratory depression (SMQ) [20000116] 
Name 
Code 
Level 
Scope 
Acute respiratory failure 
10001053 
PT 
Narrow 
Apnoea 
10002974 
PT 
Narrow 
Apnoea neonatal 
10002976 
PT 
Narrow 
Apnoeic attack 
10002977 
PT 
Narrow 
Bradypnoea 
10006102 
PT 
Narrow 
Breath holding 
10006322 
PT 
Narrow 
Breath sounds abnormal 
10064780 
PT 
Narrow 
Breath sounds absent 
10062285 
PT 
Narrow 
Central-alveolar hypoventilation 
10007982 
PT 
Narrow 
Hypopnoea 
10021079 
PT 
Narrow 
Hypoventilation 
10021133 
PT 
Narrow 
Hypoventilation neonatal 
10021134 
PT 
Narrow 
Neonatal respiratory arrest 
10028968 
PT 
Narrow 
Neonatal respiratory depression 
10028970 
PT 
Narrow 
Neonatal respiratory failure 
10028975 
PT 
Narrow 
Postoperative respiratory failure 
10072651 
PT 
Narrow 
Respiratory arrest 
10038669 
PT 
Narrow 
Respiratory depression 
10038678 
PT 
Narrow 
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Acute central respiratory depression (SMQ) [20000116] 
Respiratory depth decreased 
10038681 
PT 
Narrow 
Respiratory failure 
10038695 
PT 
Narrow 
Respiratory paralysis 
10038708 
PT 
Narrow 
Respiratory rate decreased 
10038710 
PT 
Narrow 
Alveolar oxygen partial pressure abnormal 
10068420 
PT 
Broad 
Alveolar oxygen partial pressure decreased 
10068419 
PT 
Broad 
Anoxia 
10002660 
PT 
Broad 
Apnoea test abnormal 
10074913 
PT 
Broad 
Asphyxia 
10003497 
PT 
Broad 
Bilevel positive airway pressure 
10064530 
PT 
Broad 
Blood gases abnormal 
10005539 
PT 
Broad 
Blood pH abnormal 
10005705 
PT 
Broad 
Blood pH decreased 
10005706 
PT 
Broad 
Capnogram abnormal 
10067661 
PT 
Broad 
Carbon dioxide abnormal 
10064156 
PT 
Broad 
Carbon dioxide increased 
10007225 
PT 
Broad 
Cardiac arrest 
10007515 
PT 
Broad 
Cardiac arrest neonatal 
10007516 
PT 
Broad 
Cardiopulmonary failure 
10051093 
PT 
Broad 
Cardio-respiratory arrest 
10007617 
PT 
Broad 
Cardio-respiratory arrest neonatal 
10007618 
PT 
Broad 
Cardio-respiratory distress 
10049874 
PT 
Broad 
Cheyne-Stokes respiration 
10008501 
PT 
Broad 
Continuous positive airway pressure 
10052934 
PT 
Broad 
Cyanosis 
10011703 
PT 
Broad 
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Acute central respiratory depression (SMQ) [20000116] 
 
 
 
 
Cyanosis central 
10011704 
PT 
Broad 
 
Death neonatal 
10011912 
PT 
Broad 
Dependence on respirator 
10057482 
PT 
Broad 
 
Dyspnoea 
10013968 
PT 
Broad 
 
End-tidal CO2 abnormal 
10067663 
PT 
Broad 
 
End-tidal CO2 decreased 
10067665 
PT 
Broad 
 
Hyperbaric oxygen therapy 
10057480 
PT 
Broad 
 
Hypercapnia 
10020591 
PT 
Broad 
 
Hypercapnic coma 
10072597 
PT 
Broad 
 
Hypoxia 
10021143 
PT 
Broad 
 
Intermittent positive pressure breathing 
10052959 
PT 
Broad 
 
Life support 
10024447 
PT 
Broad 
 
Mechanical ventilation 
10067221 
PT 
Broad 
 
Mechanical ventilation complication 
10066821 
PT 
Broad 
 
Neonatal anoxia 
10028921 
PT 
Broad 
 
Neonatal asphyxia 
10028923 
PT 
Broad 
Neonatal hypoxia 
10050081 
PT 
Broad 
Neonatal respiratory acidosis 
10028966 
PT 
Broad 
Neonatal respiratory distress syndrome prophylaxis 
10054933 
PT 
Broad 
Oxygen saturation abnormal 
10033317 
PT 
Broad 
Oxygen saturation decreased 
10033318 
PT 
Broad 
Oxygen saturation immeasurable 
10051197 
PT 
Broad 
 
Oxygen supplementation 
10050322 
PT 
Broad 
 
PaO2/FIO2 ratio decreased 
10065413 
PT 
Broad 
 
PCO2 abnormal 
10058982 
PT 
Broad 
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Acute central respiratory depression (SMQ) [20000116] 
 
 
 
 
PCO2 increased 
10034183 
PT 
Broad 
 
PO2 abnormal 
10062087 
PT 
Broad 
PO2 decreased 
10035768 
PT 
Broad 
 
Positive end-expiratory pressure 
10059890 
PT 
Broad 
 
Respiration abnormal 
10038647 
PT 
Broad 
 
Respiratory acidosis 
10038661 
PT 
Broad 
 
Respiratory disorder 
10038683 
PT 
Broad 
 
Respiratory disorder neonatal 
10061484 
PT 
Broad 
 
Respiratory distress 
10038687 
PT 
Broad 
 
Respiratory fume inhalation disorder 
10061485 
PT 
Broad 
 
Respiratory gas exchange disorder 
10062105 
PT 
Broad 
 
Respiratory therapy 
10059828 
PT 
Broad 
 
Sleep apnoea syndrome 
10040979 
PT 
Broad 
 
Venous oxygen partial pressure abnormal 
10068424 
PT 
Broad 
 
Venous oxygen partial pressure decreased 
10068423 
PT 
Broad 
 
Venous oxygen saturation abnormal 
10068428 
PT 
Broad 
Venous oxygen saturation decreased 
10068427 
PT 
Broad 
Ventilation perfusion mismatch 
10069675 
PT 
Broad 
Ventilation/perfusion scan abnormal 
10047265 
PT 
Broad 
Wean from ventilator 
10056353 
PT 
Broad 
Weaning failure 
10066829 
PT 
Broad 
 
 
 
BRADYCARDIA: 
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-
Bradyarrhythmias (incl conduction defects and disorders of sinus node function,
SMQ):
Bradyarrhythmia
-
Conduction defects (SMQ):
Atrial conduction time prolongation, Atrioventricular block, Atrioventricular
block complete, Atrioventricular block first degree, Atrioventricular block second
degree, atrioventricular dissociation, Bifascicular block, Bundle branch block,
Bundle branch block bilateral, Bundle branch block left, Bundle branch block
right, Conduction disorder, Defect conduction intraventricular,
Electrocardiogram PQ interval prolonged, Electrocardiogram PR prolongation,
Electrocardiogram QRS complex prolonged, Electrocardiogram QT prolonged,
Long QT syndrome, Sinoatrial block, Trifascicular block, heart rate decreased
-
Disorders of sinus node function (SMQ):
Sinus arrest, Sinus bradycardia, Sinus node dysfunction,
Should add: PT Bradycardia 
HYPOTENSION: 

PTs:  Blood pressure ambulatory decreased, blood pressure decreased, blood
pressure diastolic decreased, blood pressure orthostatic decreased, blood pressure
systolic decreased, mean arterial pressure decreased, pulmonary arterial pressure
decreased, diastolic hypotension, hypotension, orthostatic hypotension, procedural
hypotension, vasoplegia syndrome, orthostatic intolerance, presyncope, syncope
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HYPERTENSION: 
SMQ: Hypertension 
Hypertension (SMQ) [20000147] 
Name 
Code 
Level 
Scope 
Accelerated hypertension 
10000358 
PT 
Narrow 
Blood pressure ambulatory increased 
10005732 
PT 
Narrow 
Blood pressure diastolic increased 
10005739 
PT 
Narrow 
Blood pressure inadequately controlled 
10051128 
PT 
Narrow 
Blood pressure increased 
10005750 
PT 
Narrow 
Blood pressure management 
10063926 
PT 
Narrow 
Blood pressure orthostatic increased 
10053355 
PT 
Narrow 
Blood pressure systolic increased 
10005760 
PT 
Narrow 
Diastolic hypertension 
10012758 
PT 
Narrow 
Eclampsia 
10014129 
PT 
Narrow 
Endocrine hypertension 
10057615 
PT 
Narrow 
Essential hypertension 
10015488 
PT 
Narrow 
Gestational hypertension 
10070538 
PT 
Narrow 
HELLP syndrome 
10049058 
PT 
Narrow 
Hyperaldosteronism 
10020571 
PT 
Narrow 
Hypertension 
10020772 
PT 
Narrow 
Hypertension neonatal 
10049781 
PT 
Narrow 
Hypertensive angiopathy 
10059238 
PT 
Narrow 
Hypertensive cardiomegaly 
10020801 
PT 
Narrow 
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Hypertension (SMQ) [20000147] 
Hypertensive cardiomyopathy 
10058222 
PT 
Narrow 
Hypertensive cerebrovascular disease 
10077000 
PT 
Narrow 
Hypertensive crisis 
10020802 
PT 
Narrow 
Hypertensive emergency 
10058179 
PT 
Narrow 
Hypertensive encephalopathy 
10020803 
PT 
Narrow 
Hypertensive heart disease 
10020823 
PT 
Narrow 
Hypertensive nephropathy 
10055171 
PT 
Narrow 
Labile hypertension 
10049079 
PT 
Narrow 
Malignant hypertension 
10025600 
PT 
Narrow 
Malignant hypertensive heart disease 
10025603 
PT 
Narrow 
Malignant renal hypertension 
10026674 
PT 
Narrow 
Maternal hypertension affecting foetus 
10026924 
PT 
Narrow 
Mean arterial pressure increased 
10026985 
PT 
Narrow 
Metabolic syndrome 
10052066 
PT 
Narrow 
Neurogenic hypertension 
10067598 
PT 
Narrow 
Orthostatic hypertension 
10065508 
PT 
Narrow 
Page kidney 
10076704 
PT 
Narrow 
Pre-eclampsia 
10036485 
PT 
Narrow 
Prehypertension 
10065918 
PT 
Narrow 
Procedural hypertension 
10062886 
PT 
Narrow 
Renal hypertension 
10038464 
PT 
Narrow 
Renal sympathetic nerve ablation 
10074864 
PT 
Narrow 
Renovascular hypertension 
10038562 
PT 
Narrow 
Retinopathy hypertensive 
10038926 
PT 
Narrow 
Secondary aldosteronism 
10039808 
PT 
Narrow 
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Hypertension (SMQ) [20000147] 
 
 
 
 
Secondary hypertension 
10039834 
PT 
Narrow 
 
Systolic hypertension 
10042957 
PT 
Narrow 
Withdrawal hypertension 
10048007 
PT 
Narrow 
 
Aldosterone urine abnormal 
10061625 
PT 
Broad 
 
Aldosterone urine increased 
10001653 
PT 
Broad 
 
Angiotensin converting enzyme increased 
10049530 
PT 
Broad 
 
Angiotensin I increased 
10002488 
PT 
Broad 
 
Angiotensin II increased 
10002495 
PT 
Broad 
 
Blood aldosterone abnormal 
10005294 
PT 
Broad 
 
Blood aldosterone increased 
10005296 
PT 
Broad 
 
Blood catecholamines abnormal 
10005412 
PT 
Broad 
 
Blood catecholamines increased 
10005414 
PT 
Broad 
 
Blood pressure abnormal 
10005728 
PT 
Broad 
 
Blood pressure ambulatory abnormal 
10005730 
PT 
Broad 
 
Blood pressure diastolic abnormal 
10005736 
PT 
Broad 
 
Blood pressure fluctuation 
10005746 
PT 
Broad 
Blood pressure orthostatic abnormal 
10053354 
PT 
Broad 
Blood pressure systolic abnormal 
10005757 
PT 
Broad 
Catecholamines urine abnormal 
10061747 
PT 
Broad 
Catecholamines urine increased 
10061034 
PT 
Broad 
Diuretic therapy 
10053073 
PT 
Broad 
Ectopic aldosterone secretion 
10014148 
PT 
Broad 
 
Ectopic renin secretion 
10014171 
PT 
Broad 
 
Epinephrine abnormal 
10061845 
PT 
Broad 
 
Epinephrine increased 
10015064 
PT 
Broad 
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Hypertension (SMQ) [20000147] 
Labile blood pressure 
10023533 
PT 
Broad 
Metanephrine urine abnormal 
10062193 
PT 
Broad 
Metanephrine urine increased 
10027445 
PT 
Broad 
Non-dipping 
10065226 
PT 
Broad 
Norepinephrine abnormal 
10061874 
PT 
Broad 
Norepinephrine increased 
10029752 
PT 
Broad 
Normetanephrine urine increased 
10049097 
PT 
Broad 
Pseudoaldosteronism 
10037113 
PT 
Broad 
Renin abnormal 
10038556 
PT 
Broad 
Renin increased 
10038559 
PT 
Broad 
Renin-angiotensin system inhibition 
10049415 
PT 
Broad 
Tyramine reaction 
10067895 
PT 
Broad 
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PROLONGED SEDATION 
SMQ: Anticholinergic Syndrome plus single PTs 
Anticholinergic syndrome (SMQ) [20000048] 
Name 
Code 
Level 
Scope 
Anticholinergic syndrome 
10002757 
PT 
Narrow 
Ataxia 
10003591 
PT 
Broad 
Autonomic nervous system imbalance 
10003840 
PT 
Broad 
Balance disorder 
10049848 
PT 
Broad 
Coordination abnormal 
10010947 
PT 
Broad 
Depressed level of consciousness 
10012373 
PT 
Broad 
Dizziness 
10013573 
PT 
Broad 
Hyporesponsive to stimuli 
10071552 
PT 
Broad 
Loss of consciousness 
10024855 
PT 
Broad 
Presyncope 
10036653 
PT 
Broad 
Sedation 
10039897 
PT 
Broad 
Slow response to stimuli 
10041045 
PT 
Broad 
Somnolence 
10041349 
PT 
Broad 
Stupor 
10042264 
PT 
Broad 
Agitation 
10001497 
PT 
Broad 
Confusional state 
10010305 
PT 
Broad 
Delirium 
10012218 
PT 
Broad 
Disorientation 
10013395 
PT 
Broad 
Hallucination 
10019063 
PT 
Broad 
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Anticholinergic syndrome (SMQ) [20000048] 
 
 
 
 
Hallucination, auditory 
10019070 
PT 
Broad 
 
Hallucination, gustatory 
10019071 
PT 
Broad 
Hallucination, olfactory 
10019072 
PT 
Broad 
 
Hallucination, synaesthetic 
10062824 
PT 
Broad 
 
Hallucination, tactile 
10019074 
PT 
Broad 
 
Hallucination, visual 
10019075 
PT 
Broad 
 
Hallucinations, mixed 
10019079 
PT 
Broad 
 
Restlessness 
10038743 
PT 
Broad 
 
Thinking abnormal 
10043431 
PT 
Broad 
 
Abasia 
10049460 
PT 
Broad 
 
Accommodation disorder 
10000389 
PT 
Broad 
 
Anhidrosis 
10002512 
PT 
Broad 
 
Blindness transient 
10005184 
PT 
Broad 
 
Cycloplegia 
10011719 
PT 
Broad 
 
Dry eye 
10013774 
PT 
Broad 
 
Dry mouth 
10013781 
PT 
Broad 
Dysphagia 
10013950 
PT 
Broad 
Gait disturbance 
10017577 
PT 
Broad 
Hemifacial anhidrosis 
10075470 
PT 
Broad 
Hyperaemia 
10020565 
PT 
Broad 
Hyperpyrexia 
10020741 
PT 
Broad 
Hypohidrosis 
10021013 
PT 
Broad 
 
Mydriasis 
10028521 
PT 
Broad 
 
Pyrexia 
10037660 
PT 
Broad 
 
Tachycardia 
10043071 
PT 
Broad 
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Anticholinergic syndrome (SMQ) [20000048] 
 
 
 
 
Thirst 
10043458 
PT 
Broad 
 
Toxicity to various agents 
10070863 
PT 
Broad 
Urinary retention 
10046555 
PT 
Broad 
 
Vision blurred 
10047513 
PT 
Broad 
 
Visual acuity reduced 
10047531 
PT 
Broad 
 
Visual acuity reduced transiently 
10047532 
PT 
Broad 
 
 
Add PTs: Sedation, Post-injection delirium sedation syndrome, Reversal of sedation 
 
 
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APPENDIX B: Diseases of Interest for Drug-Disease Interaction Analysis  
 
Disease 
Preferred Terms 
Congestive Heart Failure 
Cardiac failure (SMQ) 
Arterial Hypertension 
Hypertension (SMQ) 
Coronary artery disease 
 
Ischaemic heart disease (SMQ), including 
both Myocardial infarction (SMQ) and 
Other ischaemic heart disease (SMQ) 
In addition other coronary artery diseases, 
not related with ischaemic heart disease 
include: Arteritis coronary, Coronary artery 
aneurysm, Coronary artery perforation, 
Coronary artery dilatation, Coronary artery 
stent removal, Chest discomfort, and Chest 
pain. 
Chronic obstructive pulmonary disease 
 
Chronic obstructive pulmonary disease, 
Bronchitis chronic, Infective exacerbation 
of chronic obstructive airways disease, 
asthma. 
Pre-existing mental impairment (e.g. 
dementia) 
 
Mental disability, Mental retardation, Mild 
mental retardation, Moderate mental 
retardation, Profound mental retardation, 
Severe mental retardation, Mental status 
changes postoperative, Mental disorder due 
to a general medical condition. 
Dementia (SMQ) 
Psychosis and psychotic disorders (SMQ) 
Gastrointestinal disorder 
GI non-specific inflammation and 
dysfunctional conditions (SMQ) and GI 
perforation, ulceration, haemorrhage or 
obstruction (SMQ) 
 
 
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