Clinical trial NCT03346057
Conditions: Reversal of Neuromuscular Blockade
Keywords: arrhythmia, bradycardia, neuromuscular blocking agents, surgery, tachycardia
Sponsor: Merck Sharp & Dohme LLC
Start date: 2017-12-20; Completion date: 2019-09-04
Enrollment: 344 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial is to evaluate the safety of sugammadex for the reversal of neuromuscular blockade (NMB) induced by neuromuscular blockade agents (NMBA) rocuronium or vecuronium in adult American Society of Anesthesiologists (ASA) Physical Status Class 3 and 4 participants. The primary objectives of the study are to characterize the incidence of treatment emergent sinus bradycardia, treatment emergent sinus tachycardia, or other treatment emergent cardiac arrhythmias after administration of sugammadex and to evaluate the general safety of sugammadex in a population of ASA Class 3 and 4 participants in a surgical setting.

Detailed description:

Arms: arm 1: Sugammadex 2 mg/kg administered as a single intravenous (IV) dose arm 2: Sugammadex 4 mg/kg administered as a single IV dose arm 3: Sugammadex 16 mg/kg administered as a single IV dose arm 4: Neostigmine 50 μg/kg (up to 5 mg maximum dose) plus glycopyrrolate 10 μg/kg (up to 1 mg maximum dose) administered as a single IV dose
Interventions: intervention 1: Sugammadex 2 mg/kg intervention 2: Sugammadex 4 mg/kg intervention 3: Sugammadex 16 mg/kg intervention 4: Neostigmine + Glycopyrrolate intervention 5: Rocuronium intervention 6: Vecuronium
Intervention descriptions: intervention 1: Following administration of NMBA (Rocuronium or Vecuronium) to achieve moderate NMB, participants received a single i.v. bolus of Sugammadex 2 mg/kg for reversal of moderate NMB. Moderate block is a level of NMB in which peripheral nerve stimulation elicits one to four muscle twitches. intervention 2: Following administration of NMBA (Rocuronium or Vecuronium) to achieve deep NMB, participants received a single i.v. bolus of Sugammadex 4 mg/kg for reversal of deep NMB. Deep block is a level of NMB in which peripheral nerve stimulation elicits no muscle twitches and high-frequency muscle stimulation elicits minimal levels of muscle contraction. intervention 3: Following administration of NMBA (Rocuronium) to achieve deep NMB, participants received a single i.v. bolus of Sugammadex 16 mg/kg for reversal of deep NMB. Deep block is a level of NMB in which peripheral nerve stimulation elicits no muscle twitches and high-frequency muscle stimulation elicits minimal levels of muscle contraction. intervention 4: Following administration of NMBA (Rocuronium or Vecuronium) to achieve moderate NMB, participants received a single i.v. bolus of Neostigmine (50 μg/kg; 5 mg maximum) and Glycopyrrolate (10 μg/kg; 1 mg maximum) for reversal of moderate NMB. Moderate block is a level of NMB in which peripheral nerve stimulation elicits one to four muscle twitches. intervention 5: To achieve NMB, participants received steroidal NMBA Rocuronium Bromide administered via IV infusion and dosed according to participant body weight. NMBAs were concomitant medications used per label and at Investigator's discretion as an adjunct to general anesthesia. intervention 6: To achieve NMB, participants received steroidal NMBA Vecuronium Bromide administered via IV infusion and dosed according to participant body weight. NMBAs were concomitant medications used per label and at Investigator's discretion as an adjunct to general anesthesia.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03346057 
Document Date: 
05-Jul-2018
A Phase 4 Randomized, Active-Comparator Controlled Clinical 
Trial to Study the Safety of Sugammadex (MK-8616) for the 
Reversal of Neuromuscular Blockade Induced by Either 
Rocuronium Bromide or Vecuronium Bromide in American Society 
of Anesthesiologists (ASA) Class 3 or 4 Subjects 


Product:  MK-8616 
1
Protocol/Amendment No.: 145-01 
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5-Jul-2018
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase 4 Randomized, Active-Comparator Controlled Clinical Trial to Study the Safety of 
Sugammadex (MK-8616) for the Reversal of Neuromuscular Blockade Induced by Either 
Rocuronium Bromide or Vecuronium Bromide in American Society of Anesthesiologists 
(ASA) Class 3 or 4 Subjects
IND NUMBER:  68,029
EudraCT NUMBER:  2017-000187-15
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TABLE OF CONTENTS
SUMMARY OF CHANGES.................................................................................................. 9
1.0
TRIAL SUMMARY.................................................................................................. 15
2.0
TRIAL DESIGN........................................................................................................ 16
Trial Design ........................................................................................................... 16
2.1
Trial Diagram........................................................................................................ 19
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 20
Primary Objective(s) & Hypothesis(es) .............................................................. 20
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 20
3.2
4.0
BACKGROUND & RATIONALE.......................................................................... 20
Background ........................................................................................................... 20
4.1
Pharmaceutical and Therapeutic Background .................................................... 21
4.1.1
Rationale................................................................................................................ 21
4.2
Rationale for the Trial and Selected Subject Population .................................... 21
4.2.1
Rationale for Dose Selection/Regimen............................................................... 22
4.2.2
Rationale for the Use of Comparator........................................................... 23
4.2.2.1
Rationale for Endpoints ...................................................................................... 23
4.2.3
Efficacy Endpoints....................................................................................... 23
4.2.3.1
Safety Endpoints .......................................................................................... 23
4.2.3.2
Future Biomedical Research........................................................................ 24
4.2.3.3
Benefit/Risk ........................................................................................................... 25
4.3
5.0
METHODOLOGY ................................................................................................... 25
Entry Criteria........................................................................................................ 25
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 25
5.1.1
Subject Inclusion Criteria.................................................................................... 25
5.1.2
Subject Exclusion Criteria .................................................................................. 26
5.1.3
Trial Treatment(s) ................................................................................................ 28
5.2
Dose Selection .................................................................................................... 28
5.2.1
Dose Selection (Preparation) ....................................................................... 28
5.2.1.1
Timing of Dose Administration .......................................................................... 29
5.2.2
Trial Blinding...................................................................................................... 29
5.2.3
 
 
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Randomization ...................................................................................................... 30
5.3
Stratification.......................................................................................................... 31
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 31
5.5
Rescue Medications & Supportive Care............................................................. 31
5.6
Diet/Activity/Other Considerations..................................................................... 31
5.7
Subject Withdrawal from the Trial .................................................................... 31
5.8
Subject Replacement Strategy............................................................................. 32
5.9
Beginning and End of the Trial ........................................................................... 32
5.10
Clinical Criteria for Early Trial Termination ................................................... 32
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 33
7.0
TRIAL PROCEDURES ........................................................................................... 36
Trial Procedures ................................................................................................... 36
7.1
Administrative Procedures.................................................................................. 36
7.1.1
Informed Consent......................................................................................... 36
7.1.1.1
7.1.1.1.1
General Informed Consent.................................................................... 36
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 37
Inclusion/Exclusion Criteria ........................................................................ 37
7.1.1.2
Subject Identification Card .......................................................................... 37
7.1.1.3
Medical History ........................................................................................... 37
7.1.1.4
Prior and Concomitant Medications Review ............................................... 37
7.1.1.5
7.1.1.5.1
Prior Medications.................................................................................. 37
7.1.1.5.2
Concomitant Medications..................................................................... 37
Assignment of Screening Number............................................................... 38
7.1.1.6
Assignment of Treatment/Randomization Number ..................................... 38
7.1.1.7
Trial Compliance (Medication).................................................................... 38
7.1.1.8
Clinical Procedures/Assessments........................................................................ 38
7.1.2
Physical Examination................................................................................... 38
7.1.2.1
Body Weight and Height ............................................................................. 39
7.1.2.2
Body Mass Index ......................................................................................... 39
7.1.2.3
Electrocardiogram........................................................................................ 39
7.1.2.4
Vital Signs.................................................................................................... 39
7.1.2.5
 
 
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Administration of Neuromuscular Blocking Agents ................................... 41
7.1.2.6
Neuromuscular Monitoring.......................................................................... 41
7.1.2.7
Laboratory Procedures/Assessments .................................................................. 41
7.1.3
Laboratory Safety Evaluations (Hematology and Chemistry)..................... 42
7.1.3.1
Pregnancy Tests ........................................................................................... 42
7.1.3.2
Future Biomedical Research Samples ......................................................... 43
7.1.3.3
Other Procedures................................................................................................. 43
7.1.4
Withdrawal/Discontinuation........................................................................ 43
7.1.4.1
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 43
7.1.4.1.2
Lost to Follow-up.................................................................................. 43
7.1.4.1.3
Subject Blinding/Unblinding ................................................................ 44
Calibration of Equipment............................................................................. 44
7.1.4.2
Visit Requirements.............................................................................................. 44
7.1.5
Screening Visit (V1) .................................................................................... 45
7.1.5.1
Peri-anesthetic Visit (V2) ............................................................................ 45
7.1.5.2
Post-Anesthetic Visit (V3)........................................................................... 47
7.1.5.3
Follow-up Safety Contact (V4).................................................................... 48
7.1.5.4
Assessing and Recording Adverse Events and Patient/Device Events............. 48
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 49
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 50
7.2.2
Immediate Reporting of Adverse Events and Incidents to the Sponsor ............. 50
7.2.3
Serious Adverse Events and Incidents......................................................... 50
7.2.3.1
Events of Clinical Interest............................................................................ 52
7.2.3.2
Evaluating Adverse Events ................................................................................. 53
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 56
7.2.5
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 56
7.3
Clinical Adjudication Committee ....................................................................... 56
7.3.1
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 56
Statistical Analysis Plan Summary ..................................................................... 57
8.1
Interim Analyses ................................................................................................... 58
8.2
Responsibility for Analyses/In-House Blinding ................................................. 58
8.3
 
 
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Hypotheses/Estimation ......................................................................................... 58
8.4
Analysis Endpoints ............................................................................................... 58
8.5
Tier 1 Safety Endpoints ...................................................................................... 58
8.5.1
Tier 2 Safety Endpoints ...................................................................................... 59
8.5.2
Analysis Populations............................................................................................. 59
8.6
Statistical Methods................................................................................................ 59
8.7
Statistical Methods for Safety Analyses ............................................................. 60
8.7.1
Demographic and Baseline Characteristics ........................................................ 61
8.7.2
Multiplicity ............................................................................................................ 61
8.8
Sample Size and Power Calculations .................................................................. 62
8.9
Subgroup Analyses and Effect of Baseline Factors ........................................... 64
8.10
Compliance (Medication Adherence).................................................................. 64
8.11
Extent of Exposure................................................................................................ 64
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 64
Investigational Product ........................................................................................ 64
9.1
Packaging and Labeling Information ................................................................. 65
9.2
Clinical Supplies Disclosure................................................................................. 65
9.3
Storage and Handling Requirements.................................................................. 65
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 66
9.5
Standard Policies................................................................................................... 66
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 66
Confidentiality....................................................................................................... 66
10.1
Confidentiality of Data ....................................................................................... 66
10.1.1
Confidentiality of Subject Records ..................................................................... 66
10.1.2
Confidentiality of Investigator Information........................................................ 67
10.1.3
Confidentiality of IRB/IEC Information............................................................. 67
10.1.4
Compliance with Financial Disclosure Requirements....................................... 67
10.2
Compliance with Law, Audit and Debarment ................................................... 68
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 69
10.4
Quality Management System............................................................................... 70
10.5
Data Management................................................................................................. 70
10.6
 
 
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Publications ........................................................................................................... 70
10.7
11.0
LIST OF REFERENCES......................................................................................... 71
12.0
APPENDICES........................................................................................................... 73
Merck Code of Conduct for Clinical Trials........................................................ 73
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 75
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.3
by Sample Types ................................................................................................... 79
List of Abbreviations and Definitions of Terms................................................. 80
12.4
13.0
SIGNATURES........................................................................................................... 81
Sponsor's Representative ..................................................................................... 81
13.1
Investigator............................................................................................................ 81
13.2
 
 
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LIST OF TABLES
    
Table 1
Trial Treatments...................................................................................................... 28
Table 2
Vital Sign Measurements........................................................................................ 40
Table 3
Laboratory Tests ..................................................................................................... 42
Table 4
Evaluating Adverse Events..................................................................................... 54
Table 5
Analysis Strategy for Safety Parameters ................................................................ 61
Table 6
Estimate of Incidence of Any Treatment Emergent Arrhythmia and 95% 
Upper Confidence Bound Based on Hypothetical Number of Subjects with 
Any Treatment Emergent Arrhythmia Among 40 and 66 Subjects in the 
Sugammadex Group............................................................................................... 63
Table 7
Differences in Incidence in Any Treatment Emergent Arrhythmia between the 
Sugammadex and Neostigmine Groups (Assuming Two-Sided 5% alpha level 
with 66 Subjects in Sugammadex Group and 33 Subjects in Neostigmine 
Group) .................................................................................................................... 63
Table 8
Product Descriptions............................................................................................... 65
 
 
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LIST OF FIGURES
          
Figure 1
Trial Design ........................................................................................................ 20
 
 
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SUMMARY OF CHANGES
PRIMARY REASON FOR THIS AMENDMENT:
Section 
Number
Section Title
Description of Change
Rationale
6.0
Trial Flow Chart
Update to Trial Flow Chart to allow Visit 1 
and Visit 2 to occur on the same day.
To provide flexibility to trial sites.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
2.1
Trial Design 
Added:
“The screening and peri-anesthetic visits 
may occur on the same day (see Section 
7.1.5.2).”
Text added for consistency with updates to 
the Trial Flow Chart and Section 7.1.5.2.
2.1
4.2.3.2
Trial Design
Safety Endpoints
Added additional formatting and minor 
textual clarifications for safety endpoints: 
treatment emergent sinus bradycardia, 
treatment emergent sinus tachycardia, and 
other 
treatment 
emergent 
cardiac 
arrhythmias
Added: Definition of baseline heart rate 
Additional text, formatting and definition of 
baseline heart rate added for clarity and 
alignment with Section 8.5.1 Tier 1 Safety 
Endpoints.
Note: 
the 
definition 
of 
these 
safety 
endpoints has not changed.
2.2
Trial Diagram
Dose units for neostigmine corrected from 
50 µ/kg to 50 µg/kg
Correction to dose units in Figure
2.2
6.0
Trial Diagram
Trial Flow Chart
Screening Visit (V1) window extended to 
21 days
Screening Visit (V1) window extended from 
14 to 21 days to allow greater flexibility for 
trial sites.
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
2.2
6.0
Trial Diagram
Trial Flow Chart
Visit 4: Follow-Up Visit/Phone Call occurs 
14 
days 
post 
study 
medication 
administration
Clarification provided for the timing of 
follow up visit/call.
5.1.3
Subject 
Exclusion 
Criteria
Added note to exclusion criteria #4:
If dialysis or severe renal insufficiency is 
not known or confirmed in the subject’s 
medical history, a creatinine clearance 
value should be calculated based upon the 
serum creatinine values obtained from 
local labs within the past 2 weeks prior to 
Visit 1 or local labs performed between V1 
and V2 (e.g., pre-operative testing).
Additional clarification provided to assist 
trial 
sites 
with 
determining 
subject 
eligibility.
5.2.2
Timing of Dose 
Administration
Previous wording stated: Sugammadex or 
neostigmine administration should not 
exceed 20 seconds.  
Updated for clarity: The total duration of 
administration for all study medication 
syringes (Dose 1 and Dose 2 syringe(s) as 
outlined in Study Drug Manual) should not 
exceed a total of 20 seconds.
Updated this language to clarify that all 
syringes, not just the syringes containing 
sugammadex or neostigmine, should be 
administered within 20 seconds. The 
standardization of timing for study 
medication administration across treatment 
arms is necessary to ensure consistency of 
dosing across sites and to maintain the 
treatment blind.
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.2.3
Trial Blinding
The 4th
bulleted item
regarding
BSA 
responsibilities:

Be required to sign a statement for each 
subject (after V4 or discontinuation)
confirming 
that 
the 
blind 
was 
maintained (treatment group, depth of 
block, drug preparation records).
Textual update to provide consistency with 
the BSA statement and other sections of the 
protocol and to clarify the BSA signs this 
statement 
after 
Visit 
4 
or 
subject 
discontinuation.
6.0
7.1.3.2
Appendix 12.3
Trial Flow Chart
Pregnancy Tests
Approximate 
Blood/Tissue Volumes 
Drawn/Collected 
by 
Trial 
Visit 
and 
by 
Sample Types
Protocol sections updated to show that a 
serum β-human chorionic gonadotropin (β-
hCG) pregnancy test (results analyzed at a
local lab) is acceptable for Visit 1 or within 
24 hours prior to surgery in place of a urine 
pregnancy test.
The serum β-hCG pregnancy test was added
as an acceptable method of testing for Visit 
1 or within 24 hours prior to surgery for 
sites that use this method of testing as a part 
of their standard of care process.
7.1.2.2
Body 
Weight 
and 
Height
The measurement of height and weight 
should be rounded to the nearest whole 
number.
Clarification
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.2.4
Electrocardiogram
Added: Historical ECGs done prior to 
informed consent are not acceptable for the 
Visit 1 ECG.
To assist sites with scheduling study 
procedures, the screening ECG may be 
performed 
at 
Visit 
2 
if 
necessary. 
However, it must be performed prior to 
induction of anesthesia or prior to 
administration of study medication.
Printing of the ECG trace is not required 
per protocol.
Clarification provided for Visit 1 and Visit 2
ECG requirements.
7.1.2.5
Vital Signs
Added : Table 2 Vital Sign Measurements
Timing 
and 
methods 
for 
vital 
sign 
measurements displayed in table format for 
additional clarity.
7.1.3.1
Laboratory 
Safety 
Evaluations
Changed: “Safety labs should be obtained 
pre-administration of study medication” to 
“Safety labs should be obtained pre-
administration of NMBA”
Correction
7.1.4.1.3
Subject 
Blinding/ 
Unblinding
Update:
Treatment/Vaccine 
identification 
information is to be unmasked ONLY if 
necessary for the welfare of the subject.  
Every effort should be made not to unblind 
the subject unless necessary.
Removal of redundant text
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.4.2
Calibration 
of 
Equipment
Removed reference to list of critical 
equipment.
Textual revisions were applied to clarify 
investigator responsibility for calibration 
and maintenance of study equipment.
2.1;
7.1.5.2
Trial Design
Peri-anesthetic 
Visit 
(V2)
Updated PTC value from PTC >1, to PTC
≥ 1
Typographical error that has been corrected
in order to be consistent with other sections 
of the protocol.
7.1.5.2
Peri-anesthetic 
Visit 
(V2)
Added text to describe the conduct of 
protocol procedures when Visit 1 and Visit 
2 occur on the same day. 
Section formatting updated (bullets and 
numbering).
Additional guidance provided on the order 
of 
trial 
procedures 
in 
relation 
to 
randomization in IRT, and new guidance for 
when Visit 1 and Visit 2 are performed on 
the same day.
7.2
Adverse Events
Removed:
“All device or patient events that occur 
after allocation/randomization must be 
reported by the investigator if they cause 
the subject to be excluded from the trial, or 
are the result of a protocol-specified 
intervention, including but not limited to 
washout 
or 
discontinuation of 
usual 
therapy, diet, placebo treatment or a 
procedure.”
Text was not applicable to the trial; the 
device used for neuromuscular monitoring 
(peripheral nerve stimulator or TOF-Watch
SX®)
is 
only 
used 
after 
subject 
randomization. Device incidents can only be 
reported for randomized subjects in this 
trial.
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.2.3.1
Serious Adverse Events 
and Incidents
Removed:
“For the time period beginning at treatment 
allocation/randomization, 
any 
incident, 
including follow up to an incident, 
including death due to any cause, that 
occurs to any subject must be reported 
within 24 hours to the Sponsor if it causes 
the subject to be excluded from the trial, or 
is the result of a protocol-specified 
intervention, including but not limited to 
washout
or 
discontinuation of 
usual 
therapy, diet, placebo treatment or a 
procedure.
Text was not applicable to the trial, the 
device used for neuromuscular monitoring 
(peripheral nerve stimulator or TOF-Watch
SX®)
is 
only 
used 
after 
subject 
randomization. Device incidents can only be 
reported for randomized subjects in this 
trial.
7.3.1
Clinical 
Adjudication 
Committee (CAC)
Previous 
wording 
stated:
Upon 
identification of an eligible event, the 
Sponsor will query the site to confirm that 
the event is eligible for adjudication based 
on the AE term and the timing of the event. 
Revised to: Upon identification of such an 
event, the Sponsor may query the site for 
additional information.
Removed language to be consistent with 
process; CAC will determine if an event is 
eligible for adjudication, not the site.
Throughout 
protocol
Throughout protocol
Minor typographical updates
For clarity
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Safety of Sugammadex for the Reversal of Neuromuscular Blockade 
in American Society of Anesthesiologists (ASA) Class 3 or 4 Subjects
Sponsor Product Identifiers
MK-8616
Sugammadex
Trial Phase
Phase 4
Clinical Indication
Reversal of neuromuscular blockade
Trial Type
Interventional
Type of control
Active control without placebo
Route of administration
Intravenous
Trial Blinding
Double-blind
Treatment Groups
Within the rocuronium stratum, the treatment groups are:
1)
Moderate block and reversal with sugammadex 2 mg/kg; or
2)
Moderate block and reversal with neostigmine (50 µg/kg up to 5 
mg maximum dose) + glycopyrrolate (10 µg/kg up to 1 mg 
maximum dose); or 
3)
Deep block and reversal with sugammadex 4 mg/kg; or
4)
Deep block and reversal with sugammadex 16 mg/kg
Within the vecuronium stratum, the treatment groups are:
1)
Moderate block and reversal with sugammadex 2 mg/kg; or
2)
Moderate block and reversal with neostigmine (50 µ g/kg up to 5 
mg maximum dose) + glycopyrrolate (10 µg/kg up to 1 mg 
maximum dose); or 
3)
Deep block and reversal with sugammadex 4 mg/kg;
Number of trial subjects
Approximately 331 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 3 years
from the time the first subject signs the informed consent until the last 
subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for approximately 30 days
from the time the subject signs the Informed Consent Form (ICF) 
through the final contact.  After the screening period, each subject will 
receive the assigned treatment on their operative day.  After treatment,
each subject will undergo a post-anesthetic visit a minimum of 4 hours 
or up to a maximum of 36 hours after administration of study 
medication. A
follow-up
safety
contact
will take place
at 
approximately 14 days post treatment to assess for AEs.
A list of abbreviations used in this document can be found in Section 12.4.
Randomization Ratio
2:1:2:2 for rocuronium and 2:1:2 for vecuronium 
 
 
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2.0 TRIAL DESIGN
Trial Design
2.1
This is a randomized, active comparator-controlled, parallel-group, multi-site, double-blind
safety trial of sugammadex for the reversal of neuromuscular blockade (NMB) induced by 
rocuronium or vecuronium in adult American Society of Anesthesiologists (ASA) Physical 
Status Class 3 and 4 subjects. The purpose of this study is to characterize the incidence of 
treatment emergent sinus bradycardia, treatment emergent sinus tachycardia, or other 
treatment emergent cardiac arrhythmias after administration of sugammadex. Approximately 
331 subjects will be enrolled (randomized) across multiple global sites.
The trial will consist of four visits: screening visit (V1), peri-anesthetic visit (V2), post-
anesthetic visit (V3), and a follow-up safety contact (V4). The screening and peri-anesthetic 
visits may occur on the same day (see Section 7.1.5.2).  Subjects will be in the trial for 
approximately 30 days.
Subjects will be stratified by ASA Physical Status Class by an Interactive Voice Response 
System (IVRS), to facilitate enrollment of the target number of randomized subjects into the 
ASA Class 4 stratum (approximately 25% of the overall planned study sample).
Subjects will also be stratified by neuromuscular blocking agent (NMBA), rocuronium or 
vecuronium. A total of ~30% of the total number of randomized subjects will be in the 
vecuronium stratum (i.e., ~100 subjects). Investigators will be permitted to select the NMBA,
for use as appropriate for the type of surgery provided that both NMBA strata remain open.
Subjects will be randomized to depth of NMB (moderate or deep) and reversal agent 
(sugammadex or neostigmine + glycopyrrolate). 
Within the rocuronium stratum, subjects will be randomized to one of four treatment groups
in a 2:1:2:2 ratio as follows (N=~231):
1. Moderate block and reversal with sugammadex 2 mg/kg 
2. Moderate block and reversal with neostigmine(50 µg/kg up to 5 mg maximum dose)  
+ glycopyrrolate (10 µg/kg up to 1 mg maximum dose)
3. Deep block and reversal with sugammadex 4 mg/kg
4. Deep block and reversal with sugammadex 16 mg/kg
Within the vecuronium stratum, subjects will be randomized to one of three treatment groups 
in a 2:1:2 ratio as follows (N=~100):
1. Moderate block and reversal with sugammadex 2 mg/kg 
2. Moderate block and reversal with neostigmine (50 µg/kg up to 5 mg maximum dose)  
+ glycopyrrolate (10 µg/kg up to 1 mg maximum dose)
3. Deep block and reversal with sugammadex 4 mg/kg 
 
 
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Depending on treatment assignment, subjects should be maintained, according to standard 
medical practice, in either moderate or deep NMB intraoperatively until the time of reversal:

Subjects randomized to moderate block should be maintained, according to standard 
medical practice, in moderate block until the time of reversal. Either sugammadex 2 
mg/kg or neostigmine + glycopyrrolate will be given after the last dose of 
administered NMBA and within 5 minutes of detection of reappearance of second 
twitch (T2) with a lower limit of train of four (TOF) count 1 and upper limit of TOF 
count of 4.

Subjects randomized to deep block should be maintained, according to standard 
medical practice, in deep block until the time of reversal. Either sugammadex 4 
mg/kg or 16 mg/kg will be given after the last dose of administered NMBA 
and within 5 minutes of detection of post-tetanic counts (PTC) ≥1 and a TOF count of 
0.
Safety endpoints include the incidence of treatment emergent sinus bradycardia, treatment 
emergent sinus tachycardia, or other treatment emergent cardiac arrhythmias after 
administration of sugammadex or neostigmine. For the purpose of this study: 

Treatment emergent sinus bradycardia is defined as meeting all of the following:
o
a heart rate <60 bpm 
o
a heart rate decreased more than 20% compared to the subject’s baseline heart 
rate value*
o
is sustained for at least 1 minute after administration of study medication.

Treatment emergent sinus tachycardia is defined as meeting all of the following:
o
a heart rate >100 bpm 
o
a heart rate increased more than 20% compared to the subject’s baseline heart 
rate value*
o
is sustained for at least 1 minute after administration of study medication.

Other treatment emergent cardiac arrhythmias are defined as meeting all of the 
following:
o
new or worsening arrhythmias (e.g., atrial fibrillation, atrial tachycardia, 
ventricular fibrillation, or ventricular tachycardia), 
o
is sustained for at least 1 minute after administration of study medication.
*Baseline heart rate is defined as the heart rate taken after the last dose of NMBA is 
administered and (approximately 5 minutes) prior to administration of study medication.
Safety assessments, including AEs, serious adverse events (SAEs), and events of clinical 
interest (ECIs), will be recorded during the trial as noted in the Trial Flow Chart in Section 
6.0. Any perioperative events that occur in the operating room (OR) or post-anesthesia care 
unit (PACU) will be recorded by study personnel that are present. 
 
 
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To ensure timely reporting and comprehensive data collection, the following types of events 
are pre-specified as ECIs:

Clinically relevant arrhythmias, inclusive of bradycardia and tachycardia, defined as 
events necessitating intervention, as determined by investigator judgment. 

Hypersensitivity and/or anaphylaxis
o
Potential cases of hypersensitivity and/or anaphylaxis will be adjudicated by an 
external expert Adjudication Committee.
For this study, the anesthesiologist (or comparable professionally qualified individual, such 
as certified nurse anesthetist), who is present during the operation and administers the study 
medication, will be blinded to the reversal agent in the moderate block arms. While 
sugammadex for the deep block arm (as for the moderate block arm) will be provided to the 
anesthesiologist in masked syringes, OR staff aware of the depth of block will know the 
study medication as there is no approved comparator for reversal of deep block.  However,
the dose of sugammadex in the rocuronium deep block groups will remain blinded.
This study will have a blinded safety assessor (BSA). For any given individual subject, the 
anesthesiologist performing study related procedures during the surgery and the BSA must be 
two separate individuals, and their roles and responsibilities must not overlap. The BSA, for 
any given individual subject, will not be present during the operation and will not administer 
study medication. The BSA will be blinded to study medication assignment, depth of NMB, 
and drug preparation records. Of note, a BSA may, for any other subject, fill other study roles 
as appropriate for his/her qualifications. Note: if the BSA is not a physician, a blinded 
physician (MD, DO) will be responsible for completing the causality assessment for all 
adverse events, including any perioperative adverse events. 
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
 
 
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Trial Diagram
2.2
The trial design is depicted in Figure 1.
Randomization Scheme
 
 
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Figure 1
Trial Design
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
1) Objective:  To characterize the incidence of treatment emergent sinus bradycardia,
treatment emergent sinus tachycardia,
or
other treatment emergent cardiac 
arrhythmias after administration of sugammadex in a population of ASA Class 3 and 
4 subjects in a surgical setting.
2) Objective:  To evaluate the general safety of sugammadex in a population of ASA 
Class 3 and 4 subjects in a surgical setting.
Secondary Objective(s) & Hypothesis(es)
3.2
There are no secondary objectives (or hypotheses) for this trial.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-8616.
 
 
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Pharmaceutical and Therapeutic Background
4.1.1
Sugammadex sodium, herein referred to as sugammadex is a modified gamma-cyclodextrin 
administered at the end of surgical procedures to reverse paralysis induced by the steroidal 
NMBAs rocuronium and vecuronium. Sugammadex accomplishes this reversal of 
neuromuscular blockade (NMB) through formation of high affinity sugammadex: NMBA 
complexes. Given the very high binding affinity and low dissociation rate of the complex, the 
bound NMBAs can no longer act at the neuromuscular junction, thereby restoring muscle 
function. The complex is then renally eliminated. Since this mechanism of action does not 
involve direct interaction with cholinergic systems, it circumvents undesired side effects 
associated with acetylcholinesterase inhibitors. Furthermore, sugammadex does not require 
the presence of neuromuscular activity before administration, and is therefore effective in 
reversal of both moderate and deep levels of NMB.
Sugammadex has been extensively studied in 58 clinical trials with a total of 5999 exposures 
to IV sugammadex in 4453 unique individuals, establishing a well characterized safety and 
efficacy profile in adults. It is currently approved in more than 83 countries and marketed in 
more than 50 countries with more than an estimated 30 million exposures worldwide at the 
time of authoring of this document.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
In adults, most demographic factors, such as age, body weight, or other factors related to the 
medical history or surgical procedures have not been found to affect sugammadex efficacy or 
safety. While sugammadex exposure is increased in the setting of renal impairment, the 
safety and efficacy of sugammadex has been shown to not be impacted by mild to moderate 
levels of renal impairment. 
In the combined clinical safety database, evaluation of cardiac arrhythmia AEs did not show 
increases in the incidence of arrhythmia-related AEs after sugammadex treatment as 
compared to placebo. Rates of reporting of arrhythmias after use of sugammadex in patients 
in the postmarketing environment were generally no higher than and in most cases were 
lower than the reported rates of peri/post-operative arrhythmias in the literature [1][2][3]. 
The only exception was rare observations of marked bradycardia in patients (following 
sugammadex administration for the reversal of NMBAs), which were readily detectable in 
the well-monitored post-operative setting, and typically responded well to usual
anticholinergic therapy.
The risk of bradycardia related to sugammadex appears to be lower than that associated with
the alternative usual treatment neostigmine, which, as a cholinesterase inhibitor, has
pronounced pro-cholinergic effects. However, given this risk patients should be closely
monitored for hemodynamic changes during and after reversal of neuromuscular blockade,
and treatment with anti-cholinergic agents such as atropine should be administered if
clinically significant bradycardia is observed.
 
 
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In terms of ASA class, the pharmacokinetic (PK), efficacy, and safety results were generally 
consistent across ASA class groups. However, the number of subjects in Phase 3 studies who 
met ASA class 3 or 4 was small. Since ASA class 3 or 4 subjects may have increased cardiac 
risk given their comorbidity and status, the current trial aims to demonstrate that 
sugammadex is generally safe for reversing rocuronium or vecuronium-induced NMB (both 
moderate and deep block) in subjects undergoing surgery who meet the ASA class 3 or 4 
criteria. 
Rationale for Dose Selection/Regimen
4.2.2
Depending on the selected NMBA and the randomly assigned depth of NMB (moderate or 
deep), a sugammadex dose of either 2 mg/kg, 4 mg/kg, or 16 mg/kg, based on actual body 
weight, will be administered as an intravenous (IV) bolus dose to reverse NMB. The 2 mg/kg 
and 4mg/kg dose has been established for reversal of moderate or deep block, respectively. 
The 16 mg/kg sugammadex dose is indicated for immediate reversal of rocuronium 1.2 
mg/kg. 
The 16 mg/kg dose has been evaluated as part of the extensive clinical development program 
for sugammadex in subjects receiving both NMBA and general anesthesia with a total of 98 
subjects receiving the 16 mg/kg dose. In placebo-controlled trials of subjects treated with 
NMBA and general anesthesia, the incidence of adverse events (AE) reported in those 
receiving sugammadex compared favorably with those receiving placebo. In the Pooled 
Phase 1-3 group, the following drug-related AEs as determined by the investigator associated 
with exposure to 16 mg/kg doses of sugammadex were reported at an incidence of ≥2%: 
anaesthetic complication (n=2, 2%), procedural complication (n=3, 3%), procedural 
hypertension (n=2,2%), nausea (n=3, 3%), bradycardia (n=2, 2%), and tachycardia (n=4, 
4%). There were no other drug-related AEs except nausea (2%) that occurred at ≥2% at 2 or 
4 mg/kg in the Pooled Phase 1-3 trials. 
Hypersensitivity reactions, including anaphylaxis, have occurred in both premarketing 
clinical trials and in post-marketing spontaneous reports. In a randomized, double-blind 
placebo-controlled study the incidence of drug hypersensitivity reactions in healthy subjects
not receiving anesthesia who received up to 3 doses of placebo (N=76), sugammadex 4 
mg/kg (N=151) or sugammadex 16 mg/kg (N=148), separated by approximately 5 weeks was 
examined.  The frequency of anaphylaxis in the sample of 299 healthy volunteers was 0.3%
(one incidence in 16 mg/kg group, none in 4 mg/kg or placebo group). These reactions varied 
from isolated skin reactions to serious systemic reactions (i.e., anaphylaxis, anaphylactic 
shock) and have occurred in patients with no prior exposure to sugammadex.
In the Pooled Phase 1-3 trials, the overall incidence of adverse events was balanced between 
groups, without evidence for a pro-arrhythmic effect of sugammadex. In the Broad and 
Narrow Standardized MedDRA Query (SMQ) for ‘Cardiac Arrhythmias’ there was a 
comparable incidence for total sugammadex (broad 4.6%, narrow 1%) and for placebo (broad 
4.0%, narrow 1.8%). However, the incidence of bradyarrhythmias (including conduction 
defects and disorders of sinus node function) was potentially dose-dependent (2%, 2.3%, 
1.3%, and 4.1% for placebo, 2 mg/kg, 4 mg/kg, and 16 mg/kg, respectively). Therefore, 
study of all three indicated doses of sugammadex is essential to further characterize the 
safety profile of sugammadex in ASA 3 and 4 subjects. Because it is not feasible to study the 
 
 
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safety of the 16 mg/kg dose in the emergent setting to reverse an intubating dose of 
rocuronium, for this study 16 mg/kg will be administered for reversal of deep block to enable 
characterization of its risk for arrhythmias.
Rationale for the Use of Comparator
4.2.2.1
For reversal of moderate NMB, neostigmine is selected as an active comparator because it is
the most frequently used acetylcholinesterase inhibitor indicated for reversal of moderate 
block. As per current prescribing information, neostigmine will be co-administered 
intravenously with
glycopyrrolate to counter the anticipated muscarinic effects of 
neostigmine. Neostigmine will be administered at the recommended dose of 50 µg/kg, up to 
a maximum dose of 5 mg, and glycopyrrolate will be administered at a dose of 10 µg/kg, up 
to a maximum dose of 1 mg. Hereafter, reference to the administration of "neostigmine" 
herein or in other study documents pertains to the administration of neostigmine +
glycopyrrolate as noted.
Because sugammadex is the only reversal agent indicated for reversal of deep NMB, no deep 
block comparator is available in this trial. However, the neostigmine group will provide a 
standard-of-care comparison for the sugammadex 4 and 16 mg/kg groups with respect to 
safety.
Rationale for Endpoints
4.2.3
Efficacy Endpoints
4.2.3.1
Not applicable as this is a safety trial.
Safety Endpoints
4.2.3.2
The primary safety endpoint in this trial is to characterize the incidence of treatment 
emergent sinus bradycardia, treatment emergent sinus tachycardia, or other treatment 
emergent cardiac arrhythmias after administration of sugammadex among ASA Class 3 and 4 
subjects. Other safety events (e.g., recurrence of NMB or respiratory events) and tolerability 
of sugammadex will be continuously assessed throughout the trial via standard AE reporting.
Thorough assessment for potential treatment related arrhythmias, inclusive of treatment
emergent sinus bradycardia, and treatment emergent sinus tachycardia, is planned. 
Continuous ECG monitoring will be performed, beginning at least 5 minutes before, during,
and for at least 30 minutes after administration of study medication to facilitate arrhythmia 
assessment. 
For the purpose of this study:

Treatment emergent sinus bradycardia is defined as meeting all of the following:
o
a heart rate <60 bpm
o
a heart rate decreased more than 20% compared to the subject’s baseline heart 
rate value*
o
is sustained for at least 1 minute after administration of study medication. 
 
 
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
Treatment emergent sinus tachycardia is defined as meeting all of the following:
o
a heart rate >100 bpm
o
a heart rate increased more than 20% compared to the subject’s baseline heart 
rate value*
o
is sustained for at least 1 minute after administration of study medication.

Other treatment emergent cardiac arrhythmias are defined as meeting all of the 
following:
o
new or worsening arrhythmias (e.g., atrial fibrillation, atrial tachycardia, 
ventricular fibrillation, or ventricular tachycardia)
o
is sustained for at least 1 minute after administration of study medication.
*Baseline heart rate is defined as the heart rate taken after the last dose of NMBA is 
administered and (approximately 5 minutes) prior to administration of study medication.
To ensure timely reporting and comprehensive data collection regarding ECIs, the following 
types of events are pre-specified as ECIs: 

Clinically relevant sinus bradycardia is defined as any bradycardia event 
necessitating intervention, as determined by investigator judgment

Clinically relevant sinus tachycardia
is defined as any tachycardia event 
necessitating intervention, as determined by investigator judgment

Other clinically relevant cardiac arrhythmias are defined as any arrhythmia event 
necessitating intervention, as determined by investigator judgment. 

Hypersensitivity and/or anaphylaxis
Events of hypersensitivity and anaphylaxis (defined by Sampson et al. [4]) will also 
be adjudicated by an independent external Adjudication Committee. 
Any perioperative events that occur in the OR or PACU will be recorded by study personnel 
that are present.
Lastly, standard safety assessments (e.g., physical examination, vital signs including heart 
rate and blood pressure) will be recorded at specified time points (see Trial Flow Chart –
Section 6.0). 
Future Biomedical Research
4.2.3.3
The Sponsor will conduct Future Biomedical Research on DNA specimens consented for 
future biomedical research during this clinical trial.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting/retaining specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
 
 
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of this Future Biomedical Research sub-trial are presented in Section 12.2 – Collection and 
Management of Specimens for Future Biomedical Research.
Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Sugammadex has a positive benefit-risk profile and is well tolerated in the approved 
indications as described in the Investigator’s Brochure. It has specifically been shown to be 
superior (faster and effective in a higher proportion of treated subjects) to both placebo and 
neostigmine for reversal of moderate and deep NMB. Reversal of deep NMB is a unique 
benefit of sugammadex unavailable with currently available treatments. From a risk 
perspective, sugammadex has been shown to be generally safe and well tolerated. The use of 
sugammadex at recommended doses is associated with a low risk of residual NMB or 
recurrence of NMB compared with current treatment. The clinical trial experience with 
sugammadex (with 5999 subject IV exposures) is consistent with and supported by post-
marketing data obtained in real world use in clinical practice (with more than an estimated 30 
million patients exposed in more than 50 countries).
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/female subjects aged 18 years or older who meet the American Society of 
Anesthesiologists Physical Status Class of 3 or 4 will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Have a body mass index (BMI) < 40 kg/m2.
2. Be categorized as ASA Physical Status Class 3 or 4, as determined by the Investigator
[5]. Note that subject should meet criteria for ASA Class 3 or 4, independent of the 
BMI > 40 kg/m2 criterion.
3. Have a planned surgical procedure that requires neuromuscular block with either 
rocuronium or vecuronium. 
4. Have a planned surgical procedure
(e.g., gastrointestinal [GI], urologic, or 
laparoscopic procedures) that in the opinion of the investigator does not preclude
maintenance of moderate or deep depth of NMB throughout the case (maintained by 
re-dosing or continuous infusion).
 
 
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5. If female, who is not of reproductive potential be one of the following: (1) 
postmenopausal (defined as at least 12 months with no menses in women ≥45 years 
of age); (2) has had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy, or bilateral tubal ligation/occlusion at least 6 weeks prior to screening; 
(3) has a congenital or acquired condition that prevents childbearing; or (4) is 
undergoing surgical sterilization as the planned surgical procedure associated with 
participation in this study (e.g., hysterectomy or tubal ligation). 
6. If female, who is sexually active and of child-bearing potential, agrees to use a 
medically accepted method of contraception through seven days after receiving 
protocol-specified medication. Medically accepted methods of contraception include 
condoms (male or female) with a spermicidal agent, diaphragm, or cervical cap with 
spermicide, medically prescribed intrauterine device (IUD), inert or copper-
containing 
IUD, 
surgical 
sterilization 
(e.g., 
hysterectomy 
or 
tubal 
ligation). Abstinence (relative to heterosexual activity) can be used as the sole method 
of contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs. 
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
7. Be able to provide (or the subject’s legally authorized representative, in accordance 
with local requirements), written informed consent for the trial. The subject or legally 
authorized representative may also provide consent for Future Biomedical Research. 
However, the subject may participate in the main trial without participating in Future 
Biomedical Research.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Has a pacemaker or automatic implantable cardioverter-defibrillator (AICD) that 
precludes the assessment of bradycardia or arrhythmias. 
2. Has a medical condition or surgical procedure that precludes reversal of 
neuromuscular block at the end of surgery.
3. Has a neuromuscular disorder(s) that may affect neuromuscular block and/or trial 
assessments.
 
 
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4. Is dialysis-dependent or has severe renal insufficiency.
Note:  If dialysis or severe renal insufficiency is not known or confirmed in the 
subject’s medical history, a creatinine clearance value should be calculated based 
upon serum creatinine values obtained from local labs within the past 2 weeks prior to 
Visit 1 or local labs performed between V1 and V2 (e.g., pre-operative testing). 
Severe renal insufficiency is defined as an estimated creatinine clearance of < 30 
mL/min using the formulas below. 
Cockcroft-Gault formula:
For Males:   Creatinine Clearance  =         (140-age [years]) x weight (kg)
              serum creatinine (mg/dL) x 72
For Females:   Creatinine Clearance  =   0.85 x (140-age [years]) x weight (kg)
              serum creatinine (mg/dL) x 72
5. Has or is suspected of having a personal history or family history (parents, 
grandparents, or siblings) of malignant hyperthermia.
6. Has or is suspected of having an allergy (e.g., hypersensitivity and/or anaphylactic 
reaction) to study treatments or its/their excipients, to opioids/opiates, muscle 
relaxants or their excipients, or other medication(s) used during general anesthesia.
7. Has received or is planned to receive toremifene within 24 hours before or within 
24 hours after study medication administration.
8. Has any condition that would contraindicate the administration of study medication.
9. Is pregnant, is attempting to become pregnant, or is lactating.
10. Has any clinically significant condition or situation (e.g., anatomical malformation 
that complicates intubation) other than the condition being studied that, in the opinion 
of the investigator, would interfere with the trial evaluations or optimal participation 
in the trial.
11. Is currently participating in or has participated in an interventional clinical trial
(including any other current or ongoing trial with a sugammadex treatment arm) with 
an investigational compound or device within 30 days of signing the informed 
consent form of this current trial.
12. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
 
 
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Trial Treatment(s)
5.2
The treatments to be used in this trial are outlined below in Table 1.
Table 1
Trial Treatments
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Treatment 
Period
Use
Sugammadex
2 mg/kg
Single dose
IV
Peri-anesthetic 
period
Experimental
Sugammadex
4 mg/kg
Single dose
IV
Peri-anesthetic 
period
Experimental
Sugammadex
16 mg/kg
Single dose
IV
Peri-anesthetic 
period
Experimental
Neostigmine
+ 
Glycopyrrolate 
50 µg/kg (up 
to 5 mg 
maximum 
dose)
10
µg/kg
(up to 1 mg 
maximum 
dose)
Single dose
IV
Peri-anesthetic 
period
Comparator/ 
Standard of 
Care
Trial Treatment should begin within 1 day of randomization. Randomization in IVRS may 
occur on the same day as a subject’s scheduled surgery or one day in advance of the 
scheduled surgery. Sites should contact the Sponsor if a subject‘s surgery is postponed for 
more than one day from the date the subject is randomized in IVRS (e.g., surgery postponed 
due to subject illness). Trial status of subjects in these situations will be handled on a case by 
case basis in consultation with the Sponsor.  See Section 7.1.5.2. 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection
5.2.1
Dose Selection (Preparation)
5.2.1.1
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale. 
Sugammadex, neostigmine and glycopyrrolate will be prepared by an unblinded pharmacist 
(or delegate) and supplied to OR staff in masked syringes for administration to study 
subjects.
The volume of study medication drawn into the syringes will be normalized between 
treatment groups by adding saline to allow for blinding of differences in volume and 
 
 
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concentrations for assigned doses. Instructions for normalizing the volumes are included in a 
separate Study Drug Manual.
Timing of Dose Administration
5.2.2
Trial treatment should begin within 1 day of randomization in IVRS.
The total duration of administration for all study medication syringes (Dose 1 and Dose 2 
syringe(s) as outlined in the Study Drug Manual) should not exceed a total of 20 seconds.  
The syringes should be administered as a bolus injection into a fast running intravenous line, 
on the day of surgery.  
For subjects randomized to moderate block, sugammadex or neostigmine will be given after 
the last dose of administered NMBA and within 5 minutes of detection of reappearance of T2 
(with a lower limit of TOF count 1 and upper limit of TOF count of 4). 
For subjects randomized to deep block, sugammadex will be given after the last dose of 
administered NMBA and within 5 minutes of detection of PTC >1 and a TOF count of 0.
Trial Blinding 
5.2.3
Study Medication Blinding
With the exception of designated individuals (e.g., unblinded Clinical Research Associates 
[CRAs]), all other Sponsor study team personnel will be blinded to study medication 
assignments for randomized subjects. 
The site pharmacist (or delegate) will be unblinded to study medication assignments in 
order to prepare study medication.  Study medication will be provided to site staff in the OR 
(anesthesiologist) in masked syringes to ensure that the contents of the syringes will not be 
revealed. 
Site Personnel Roles and Blinding  
The anesthesiologist (or comparable professionally qualified individual, such as certified 
nurse anesthetist), and other OR staff will be blinded to the reversal agent in the moderate 
block arms. While sugammadex for the deep block arm will be provided to the OR 
(anesthesiologist) in masked syringes, OR staff aware of the depth of block will know the 
study medication as there is no approved comparator for reversal of deep block.  However, 
the dose of sugammadex in the rocuronium deep block groups will remain blinded.
The blinded safety assessor (BSA) will be an appropriately qualified health care 
professional (e.g., a licensed physician, nurse practitioner, physician assistant, or certified 
registered nurse anesthetist [or comparable professional qualification in countries outside of 
the United States]) with training and experience in anesthesia or post-anesthesia care.

The BSA for any given individual subject will be blinded to:
o
Study medication assignment
o
The depth of NMB  
o
Drug preparation records 
 
 
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
The BSA for any given individual subject will:
o
Not be present during the operation and will not administer study 
medication
o
Conduct the required procedures (see Section 6.0 Trial Flow Chart) at the 
post-anesthetic safety visit (Visit 3)
o
Complete the causality assessment for all adverse events, including any 
perioperative adverse events. Note: if the BSA is not a physician, a blinded 
physician (MD, DO), not present during the surgical procedure, reversal 
dosing, or recovery for a given subject, will be responsible for completing 
the causality assessment for all adverse events.
o
Be required to sign a statement for each subject (V4 or discontinuation) 
confirming that the blind was maintained (treatment group, depth of block, 
drug preparation records).

Of note, a BSA may, for any other subject, fill other study roles as appropriate for 
his/her qualifications.
The anesthesiologist performing study-related procedures during surgery and the BSA must 
be 2 separate individuals, and their roles and responsibilities must not overlap for any given 
individual subject.  
Any inadvertent unblinding of the BSA will be documented.
See Section 7.1.4.1.3, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization
5.3
Randomization will occur centrally using the IVRS. 
Within the rocuronium stratum, subjects will be randomized to 1 of 4 treatment groups as 
indicated in the Trial Diagram (Figure 1 in Section 2.2).
Subjects will be assigned randomly on Day 1 in a 2:1:2:2 ratio:
1. Moderate block and reversal with sugammadex 2 mg/kg
2. Moderate block and reversal with neostigmine 50 µg/kg + glycopyrrolate 10 µg/kg
3. Deep block and reversal with sugammadex 4 mg/kg
4. Deep block and reversal with sugammadex 16 mg/kg
Within the vecuronium stratum, subjects will be randomized to one of three treatment groups 
as indicated in the Trial Diagram (Figure 1 in Section 2.2). 
Subjects will be assigned randomly on Day 1 in a 2:1:2 ratio:
1. Moderate block and reversal with sugammadex 2 mg/kg
2. Moderate block and reversal with neostigmine 50 µg/kg + glycopyrrolate 10 µg/kg
3. Deep block and reversal with sugammadex 4 mg/kg
 
 
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Stratification
5.4
Treatment allocation/randomization will be stratified according to the following factors:

NMBA (rocuronium or vecuronium)

ASA Physical Status Class 3 or 4
A total of ~30% of the total number of randomized subjects will be in the vecuronium 
stratum (i.e., ~100 subjects). 
Subjects will be stratified by ASA Physical Status Class by an IVRS system, which will 
ensure the target number of randomized subjects are enrolled in the ASA Class 4 stratum 
(approximately 25% of the overall planned study sample).
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, the investigator should discuss this with the Sponsor 
Clinical Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.
Rocuronium or vecuronium are concomitant medications to be used per label as adjunct to 
general anesthesia. Besides rocuronium and vecuronium, a subject must not be administered 
any other NMBAs during the trial, including:

Other steroidal NMBAs such as pancuronium 

Nonsteroidal NMBAs such as succinylcholine or benzylisoquinolinium compound
(e.g., cisatracurium)*
Toremifene use within 24 hours before or within 24 hours after study medication 
administration is prohibited.
*Except in the circumstance that renewed muscle relaxation is needed after administration of 
study medication, in which case a non-steroidal NMBA should be administered.
Rescue Medications & Supportive Care
5.6
No rescue or supportive medications are specified to be used in this trial.
Diet/Activity/Other Considerations
5.7
There are no dietary or activity restrictions required for this protocol.
Subject Withdrawal from the Trial
5.8
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will not receive treatment or be followed at 
scheduled protocol visits.
 
 
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Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject fail to return for scheduled visits 
and/or if the study site is unable to contact the subject, as well as specific details regarding 
withdrawal from Future Biomedical Research are outlined in Section 7.1.4 – Other 
Procedures.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.11
There are no pre-specified criteria for terminating the trial early.
 
 
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6.0 TRIAL FLOW CHART
Trial Period:
Screening
Treatment
Follow-up
Visit Number/Title:
1
Screening
2
Peri-anesthetic Visit
3 
Post-anesthetic Visit a
4
Follow-up Safety 
Contactb
Scheduled Day:
Between Days
-21 to 1
Day 1
(Day of Surgery)
Days 1 to 2
(4 to 36 hours post study 
medication administration)
14 days post study 
medication administration
Scheduling Window:
-21 to Day 1 
±0 days
See footnote “c”
+2 days
Visit 1 and Visit 2 may occur on same day. 
Visit 2 may occur across 2 days.
Refer to Section 7.1.5.2.
Administrative Procedures
Informed Consent
X
Informed Consent for Future Biomedical Research
X
Inclusion/Exclusion Criteria
X
X
Subject Identification Card
X
Xd
Medical History
X
Concomitant Medication Review
X
X
X
X
Screening Number Assignment
X
Randomizatione
X
Clinical Procedures/Assessments
Physical Examination
X
X a
Height
X
Weight and BMI calculation
X
X
12-Lead Electrocardiogram
X
 
 
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Trial Period:
Screening
Treatment
Follow-up
Visit Number/Title:
1
Screening
2
Peri-anesthetic Visit
3 
Post-anesthetic Visit a
4
Follow-up Safety 
Contactb
Scheduled Day:
Between Days
-21 to 1
Day 1
(Day of Surgery)
Days 1 to 2
(4 to 36 hours post study 
medication administration)
14 days post study 
medication administration
Scheduling Window:
-21 to Day 1 
±0 days
See footnote “c”
+2 days
Visit 1 and Visit 2 may occur on same day. 
Visit 2 may occur across 2 days.
Refer to Section 7.1.5.2.
Continuous ECG Monitoring
Xf
Vital Signs (heart rate, respiratory rate, O2 saturation, 
blood pressure, temperature)
X
Xg
X
Administration of NMBA
X
Administration of Study Medication 
X
Neuromuscular Monitoringh
X
Adverse Events/ ECI Monitoring
X
X
X a
X
Laboratory Procedures/Assessments
Hematologyi
X
X
Chemistryi
X
X
Pregnancy Testj
X
Xj
Blood (DNA) for Future Biomedical Researchk
X
 
 
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Trial Period:
Screening
Treatment
Follow-up
Visit Number/Title:
1
Screening
2
Peri-anesthetic Visit
3 
Post-anesthetic Visit a
4
Follow-up Safety 
Contactb
Scheduled Day:
Between Days
-21 to 1
Day 1
(Day of Surgery)
Days 1 to 2
(4 to 36 hours post study 
medication administration)
14 days post study 
medication administration
Scheduling Window:
-21 to Day 1 
±0 days
See footnote “c”
+2 days
Visit 1 and Visit 2 may occur on same day. 
Visit 2 may occur across 2 days.
Refer to Section 7.1.5.2.
a
The physical exam and adverse event review must be conducted by the BSA at V3. For any given individual subject, the anesthesiologist performing study-related 
procedures during the surgery and the BSA must be two separate individuals and their roles and responsibilities will not overlap.
b
Should occur via phone, however, may be performed in person if the subject is still in the hospital.
c
Post-anesthetic visit will be completed a minimum of 4 hours or up to a maximum of 36 hours after administration of study medication or discharge, whichever 
occurs first.
d
Randomization number to be added at Visit 2.
e
Trial treatment should begin within 1 day of randomization. Randomization in IVRS may occur on the same day or one day in advance of the subject’s scheduled 
surgery (except when V1 and V2 occur on the same day).  Sites should contact the Sponsor if a subject‘s surgery is postponed for more than 1 day from the date the 
subject is randomized in IVRS (e.g., surgery postponed due to subject illness).  Trial status of subjects in these situations will be handled on a case by case basis in 
consultation with the Sponsor. 
f
To occur at least 5 minutes before, during, and for 30 minutes following administration of study medication. 
g
To be performed pre-administration of NMBA, approximately 5 minutes prior to study medication administration, and at 2, 5, 10, and 30 minutes following 
administration of study medication.
h
Neuromuscular monitoring is to be done using locally available NMTM (e.g., objective NMTM or subjective NMTM using a PNS).
i
Laboratory samples will be sent to a central laboratory for analysis.  Baseline safety labs should be obtained pre-NMBA administration and post-op safety labs are 
to be drawn 4-6 hours post-administration of sugammadex/neostigmine.
j
For females of childbearing potential, a urine or serum β-hCG pregnancy test is required within 24 hours prior to surgery. A serum β-hCG pregnancy test 
(performed locally) is required if the urine pregnancy test is positive, unless local requirements require otherwise. Note that if the pregnancy test is done within 24 hours 
prior to surgery at Visit 1, it does not have to be repeated at Visit 2.
k
Informed consent for future biomedical research samples must be obtained to collect the DNA sample. The blood (DNA) for future biomedical research sample 
should be taken on Day 1 at the same time as other blood collections.  If the sample cannot be taken at this visit, it can be taken at the next scheduled blood draw.
Abbreviations:  BMI = Body mass index; NMBA = Neuromuscular blocking agent; ECI = Events of clinical interest; β-hCG = Serum beta human chorionic 
gonadotropin; DNA = Deoxyribonucleic acid; BSA = Blinded Safety Assessor
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
Informed Consent
7.1.1.1
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
Inclusion/Exclusion Criteria
7.1.1.2
All inclusion and exclusion criteria will be reviewed at Visit 1 and 2 by the investigator or 
qualified designee to ensure that the subject qualifies for the trial.
Subject Identification Card
7.1.1.3
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
7.1.1.4
A medical history will be obtained by the investigator or qualified designee.
The medical indication for surgery and corresponding surgical procedure will be entered into 
the database.
Prior and Concomitant Medications Review
7.1.1.5
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 14 days before starting the trial. See Section 5.5 for concomitant medication 
information. 
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record any medication (e.g., beta-blockers, 
calcium channel blockers, anti-arrhythmic agents) taken by or administered to the subject 
during surgery and up to 14 days after surgery. See Section 5.5 for concomitant medication 
information. Rocuronium or vecuronium, are concomitant medications to be used per label as 
adjunct to general anesthesia.
 
 
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Assignment of Screening Number
7.1.1.6
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
Assignment of Treatment/Randomization Number
7.1.1.7
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Trial Compliance (Medication)
7.1.1.8
Compliance with dosage will be based on the actual dosage of study medication 
administered versus assigned dosage. For further information, refer to Section 8.11.
Clinical Procedures/Assessments
7.1.2
Physical Examination
7.1.2.1
The principal investigator or licensed clinician (i.e., physician, physician’s assistant, or nurse 
practitioner) will perform a general physical examination of the following organ systems at 
Visit 1: 

Head, Eyes, Ears, Nose, and Throat

Neck

Respiratory system

Cardiovascular system

Abdomen

Skin and extremities

Neurological system, including mental status, motor strength, muscle tone, sensation,
and reflexes. 
Any medical conditions found during the screening physical exam will be recorded in the 
Sponsor database.
 
 
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A second physical examination will be performed at the post-anesthetic visit by the BSA. 
Any clinically significant change from the first physical examination (screening) will be 
recorded in the Sponsor database.
Body Weight and Height
7.1.2.2
Body weight and height will be collected and recorded in the Sponsor database. 
Measurements should be rounded to the nearest whole number. Body weight will be obtained 
without shoes and with heavy clothing (e.g., jacket or coat) removed.
Body Mass Index
7.1.2.3
Body mass index will be calculated at Visit 1 and Visit 2 to ensure subjects meet eligibility 
criteria. The formula for BMI is weight in kilograms divided by height in meters squared 
(kg/m2). 
Electrocardiogram 
7.1.2.4
Visit 1:
A 12-lead ECG will be performed at Visit 1 for documentation of baseline rhythm and 
cardiac disease. Historical ECGs (those done prior to informed consent) are not acceptable.  
To assist sites with scheduling study procedures, the screening ECG may be performed at 
Visit 2 if necessary. However, it must be performed prior to induction of anesthesia or prior 
to administration of study medication. 
Visit 2:
During the peri-anesthetic visit, continuous ECG monitoring will occur at least 5 minutes 
before, during, and for 30 minutes after administration of study medication (sugammadex or 
neostigmine) to identify events of treatment emergent sinus bradycardia, treatment emergent 
sinus tachycardia, or other treatment emergent cardiac arrhythmias, which will be recorded in 
the Sponsor database. Sites should also record the heart rate and associated blood pressure 
for these events.
Events of clinically relevant sinus bradycardia, clinically relevant sinus tachycardia, or other
clinically relevant cardiac arrhythmias, (according to the definitions in Section 4.2.3.2),
should be reported as ECIs in the Sponsor database.
Printing of the ECG trace is not required per protocol.
Vital Signs
7.1.2.5
Heart rate, blood pressure, respiratory rate, oxygen saturation, and temperature will be 
obtained at the following time points as shown in Table 2.
 
 
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Table 2
Vital Sign Measurements
Vital Sign
Measurement
Visit 1
Visit 2
Visit 3
Prior to 
administration of 
NMBA
After the last dose of NMBA is 
administered and (approximately 5 
minutes) prior to administration of 
study medication
At 2, 5, 10, 30  minutes 
following administration 
of study medication
HR
X
X
X
X
X
BP
X
X
X
X
X
RR
X
X
X
X
X
O2 saturation
X
X
X
X
X
Body 
Temperature: 
Obtained per local 
guidelines/standard 
methods, 
except 
when noted*.
X
X
X
*Required: core body 
temperaturea, b
X
X
a The target core body temperature is ≥35ºC (95ºF). 
b The only acceptable locations for core body temperature measurement are:  nasopharynx, esophagus, bladder, pulmonary artery branch, or rectum. 
Abbreviations: BP= blood pressure, HR= heart rate, NMBA = neuromuscular blocking agent, 02= oxygen, RR= respiratory rate
 
 
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Administration of Neuromuscular Blocking Agents 
7.1.2.6
NMBAs will be dosed as indicated per prescribing information for intubation purposes and 
maintenance of neuromuscular block by re-dosing or continuous infusion.
Only one NMBA should be used for the entire duration of surgery, including the intubation 
dose. The NMBA used during surgery should be the NMBA noted in the IVRS confirmation.
Neuromuscular Monitoring 
7.1.2.7
Neuromuscular monitoring will be performed using locally available neuromuscular 
transmission monitoring (NMTM, e.g., objective NMTM using a quantitative TOF-Watch or 
subjective NMTM using a peripheral nerve stimulator).
For subjects randomized to moderate block, after the last dose of NMBA and within 5 
minutes of reappearance of T2, sugammadex or neostigmine will be given, according to the 
randomization schedule. 
For subjects randomized to deep block, after the last dose of NMBA and within 5 minutes of 
detection of PTC >1, sugammadex will be given. 
Clinical evidence of recovery will be assessed using the standard practice for monitoring in 
effect at the site.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood to be drawn/collected over the course of the trial 
(from pre-trial to post-trial visits), including approximate blood volumes drawn/collected by 
visit and by sample type per subject can be found in Section 12.3.
 
 
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Laboratory Safety Evaluations (Hematology and Chemistry)
7.1.3.1
Laboratory tests for hematology and chemistry are specified in Table 3.
Table 3
Laboratory Tests
Hematology
Chemistry
Other
Hematocrit
Albumin
Urine pregnancy test
Hemoglobin
Alkaline phosphatase
Serum β-human chorionic 
gonadotropin (β-hCG)
Platelet count
Alanine aminotransferase
WBC (total and 
differential)
Aspartate aminotransferase 
Bicarbonate
Calcium
Chloride
Creatinine
Glucose
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total bilirubin is 
elevated above the upper limit of normal
Total protein
Blood Urea Nitrogen
All laboratory samples will be collected as per Section 6.0 – Trial Flow Chart. Safety 
laboratory samples will be sent to a central laboratory for analysis. Safety labs should be 
obtained pre-administration of NMBA and post-operative safety labs should be obtained 
within 4-6 hours after administration of study medication. Detailed instructions for specimen 
collection, packaging, and shipment will be provided in a Laboratory Manual by the Central 
Laboratory.
Pregnancy Tests
7.1.3.2
Female subjects of child-bearing potential are required to have a negative pregnancy test 
within 24 hours prior to surgery. At Visit 1, sites may test female subjects using a urine 
pregnancy test (provided by central lab) or a serum β-human chorionic gonadotropin
pregnancy test if part of their standard of care process (results analyzed at a local lab).
If Visit 1 occurs more than 24 hours prior to surgery, the pregnancy test will need to be 
repeated within 24 hours prior to surgery.
If a urine pregnancy test is positive, then a serum β-hCG pregnancy test is required unless 
local requirements require otherwise. This test may be performed locally. Results (negative 
for pregnancy) must be received by site staff before the subject is given study medication.
If serum pregnancy is positive, the subject is to be discontinued from the trial.
 
 
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Future Biomedical Research Samples
7.1.3.3
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research
Other Procedures
7.1.4
Withdrawal/Discontinuation
7.1.4.1
Once a subject receives study medication at Visit 2, all applicable procedures at subsequent 
visits should be performed as per study flow chart.
Any adverse events which are present at the time of withdrawal should be followed in
accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research.  Subjects may 
withdraw consent at any time by contacting the principal investigator for the main trial.  If 
medical records for the main trial are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com).  Subsequently, 
the subject's consent for Future Biomedical Research will be withdrawn.  A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the subject of completion of withdrawal.  Any analyses in progress at 
the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research trial data and results.  
No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
7.1.4.1.2 Lost to Follow-up
If a subject fails to complete a required study visit (e.g., follow-up safety contact) and/or if 
the site is unable to contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit.

The investigator or designee must make every effort to regain contact with the 
subject (e.g., phone calls and/or a certified letter to the subject’s last known 
mailing address or locally equivalent methods). These contact attempts should be 
documented in the subject’s medical record.
 
 
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Note:  A subject is not considered lost to follow-up until the last scheduled visit for the 
individual subject.  The amount of missing data for the subject will be managed via the 
pre-specified data handling and analysis guidelines.
7.1.4.1.3 Subject Blinding/Unblinding
When the investigator or delegate needs to identify the drug used by a subject and the dosage 
administered in case of emergency e.g., the occurrence of serious adverse experiences, he/she 
will contact the emergency unblinding call center by telephone and make a request for 
emergency unblinding.  As requested by the investigator or delegate the emergency 
unblinding call center will provide the information to him/her promptly and report unblinding 
to the sponsor.  Prior to contacting the emergency unblinding call center to request 
unblinding of a subject’s treatment assignment, the investigator or delegate must enter the 
intensity of the adverse experiences observed, the relation to study drug, the reason thereof, 
etc., in the medical chart etc. Subjects whose treatment assignment has been unblinded by the 
investigator/delegate and/or non-study treating physician must be discontinued from study 
drug, but should continue to be monitored in the trial.
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
Treatment/Vaccine identification information is to be unmasked ONLY if necessary for the 
welfare of the subject.  Every effort should be made not to unblind the subject.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. Only the principal investigator or 
delegate and the respective subject’s code should be unblinded. Other trial site personnel and 
Sponsor personnel directly associated with the conduct of the trial should not be unblinded.
Subjects whose treatment assignment has been unblinded by the investigator/delegate and/or 
non-study treating physician must be discontinued from study drug, but should continue to 
be monitored in the trial.
Calibration of Equipment
7.1.4.2
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
 
 
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Screening Visit (V1)
7.1.5.1
Potential subjects will be evaluated to determine if they fulfill the entry requirements as set 
forth in Section 5.1. Screening procedures may be repeated after consultation with the 
Sponsor.
A subject may be rescreened, but the Sponsor should be consulted prior to any rescreen. 
Rescreens will be handled on a case by case basis. Only one rescreen is allowed per subject.
Peri-anesthetic Visit (V2)
7.1.5.2
The following procedures will be performed during the Peri-anesthetic visit:
1. Confirm the subject still meets inclusion/exclusion criteria. 
2. Measure subject weight
3. Randomize the subject using IVRS.  Trial treatment should begin within 1 day of 
randomization.  
a) Randomization 1 day before surgery (Visit 2 performed across 2 days)
In certain situations (e.g., if surgery is scheduled for early morning), randomization in 
IVRS may occur 1 day in advance of the scheduled surgery only if the following 
procedures are completed prior to calling into IRT for randomization:
1. Confirm the subject meets inclusion/exclusion criteria (including recalculation 
of BMI using new weight measurement)
2. Take subject weight and recalculate BMI
If procedures above cannot be completed prior to randomizing the subject in IVRS,
then randomization in IVRS cannot occur 1 day in advance of the surgery.
*Visit 1 (V1) and Visit 2 (V2) should be conducted on separate days however in certain 
situations this may not be possible. For these exceptions, V1 and V2 may be conducted 
on the same day. Refer to guidance below.  
b) *V1 and V2: both visits performed in full on the same day
If V1 and V2 are conducted on the same day (including surgery), the following 
procedures need only be done once:
1. Inclusion/exclusion criteria review
2. Concomitant medication review
3. Weight measurement and BMI calculation
All other protocol procedures (e.g., vital signs, safety labs) must be conducted as 
indicated in the trial flow chart (Section 6.0) and as outlined in Section 7.1.5.2.
 
 
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c) *V1 and V2: part of Visit 2 performed same day as V1 but surgery is scheduled 
for the next day (i.e., Visit 2 performed across 2 days)
If V1 and part of V2 are conducted on the same day (not including surgery), the 
following procedures should be conducted prior to calling into IRT and only need to 
be done once.
1. Inclusion/exclusion criteria review
2. Concomitant medication review
3. Weight measurement and BMI calculation
All other protocol procedures (e.g., vital signs, safety labs) must be conducted as 
indicated in the trial flow chart (Section 6.0) and as outlined as outlined in Section 
7.1.5.2.
d) If surgery is postponed more than one day after randomization in IVRS:

Sites must contact the Sponsor if a subject‘s surgery is postponed for more than 
one day from the date the subject is randomized in IVRS (e.g., surgery postponed 
due to subject illness).

Trial status of subjects in these situations will be handled on a case by case basis 
in consultation with the Sponsor.
4. Pharmacist (or delegate) prepares study medication (refer to Study Drug Manual for 
details)
5. Insert an IV cannula for the administration of anesthetic drugs, NMBA, and study 
medication.
Administration of anesthesia: 
6. Anesthesia will be induced and maintained according to the need of the subject. 
Before administration of the NMBA:
7. Vital signs (per protocol) will be recorded.
8. A baseline blood sample for safety analysis will be obtained and sent to the central lab 
vendor. 
9. A blood sample will be collected for future biomedical research (if consent obtained).
10. Neuromuscular monitoring will be performed using locally available NMTM (e.g.,
objective NMTM or subjective NMTM using a peripheral nerve stimulator [PNS]).  
Administration of NMBA until administration of study medication:
11. Administer NMBA for intubation. Only one NMBA should be used for the entire 
duration of surgery.  The NMBA used during surgery should be the NMBA noted in the 
IVRS.
12. Additional doses of NMBA will be administered as clinically required for the duration of 
the surgery to target maintenance of the assigned depth of block, as determined by the 
Primary Investigator or designee. 
 
 
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13. Vital signs (per protocol) will be recorded.
14. Record a core body temperature after the last dose of NMBA is administered and at the 
time depth of block is assessed prior to administration of sugammadex or neostigmine.
From administration of study medication (sugammadex or neostigmine) until the end of 
anesthesia:
15. For subjects randomized to moderate block: after last dose of administered NMBA and 
within 5 minutes of reappearance of T2 (with a lower limit of TOF count 1 and upper 
limit of TOF count of 4), study medication (sugammadex or neostigmine) will be 
administered.
16. For subjects randomized to deep block: after last dose of administered NMBA and within 
5 minutes of detection of PTC ≥1 and TOF Count of 0, study medication (sugammadex) 
will be administered.
17. Study staff should NOT record ‘sugammadex’ or ‘neostigmine’ for annotation of study 
medication administration. To maintain blinding in the anesthetic chart, only indicate 
‘study medication’ or ‘SM’ in the place of sugammadex or neostigmine.
18. Continuous ECG monitoring: at least 5 minutes before, during, and for 30 minutes after 
administration of study medication.
19. The following additional study procedures should be done on the following schedule:
Time After Study 
Medication
2 mins
5 mins
10 mins
30 mins
4-6 hrs
Vital Signs
X
X
X
X
Blood Samples for 
Safety Labs
X
20. Continue neuromuscular monitoring using locally available NMTM (e.g., objective
NMTM using a quantitative TOF watch or subjective NMTM using a peripheral nerve 
stimulator) until the subject is ready to be extubated.
21. Adverse event(s) and concomitant medication(s) will be recorded.
Post-Anesthetic Visit (V3)
7.1.5.3
Visit 3 should be conducted at least 4 hours following study medication administration up to 
a maximum of 36 hours after study medication administration (or before discharge, 
whichever is earlier) (see Trial Flowchart – Section 6.0).
The BSA will review the subject’s medical records in order to properly assess the subject at 
this visit with the following exceptions: study medication assignment, depth of NMB, and 
drug preparation records.
 
 
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Follow-up Safety Contact (V4)
7.1.5.4
Approximately 14 days post study medication administration, subjects will be contacted by
designated site personnel by telephone (or in person if the subject is still in the hospital).
New and ongoing AEs and concomitant medication(s) should be assessed and reported in the 
database.
Assessing and Recording Adverse Events and Patient/Device Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Device and/or patient events include all untoward events related to the use of the device or 
device-like features of a drug delivery system. Device events include any malfunction or 
deterioration in the characteristics and/or performance of the device, as well as any 
 
 
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inadequacy in the labeling or the instructions for use, that led to or could have led to an 
untoward event for the user or any person. Patient events are adverse events experienced by 
the subject caused by or suspected to be caused by the device or device-like features of a 
drug delivery system.
From the time of allocation/randomization through 14 days following cessation of treatment, 
all device or patient events must be reported by the investigator. Such events will be recorded 
at each examination on the Adverse Event case report forms/worksheets. The reporting 
timeframe for events meeting any serious criteria is described in section 7.2.3.1. The 
investigator will make every attempt to follow all non-serious device or subject events for 
outcome.  
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
During the course of the trial, a subject may provide feedback related to the device or device-
like features of a drug delivery system.  This "customer feedback" is defined as a report that 
does not allege a product quality complaint or defect and has no relevant safety 
information/untoward event associated with it (e.g., goodwill or courtesy replacement, 
consumer preference or suggestion, remark which may suggest an improvement in the 
functionality or quality of a medical device or device-like features of a drug delivery system).  
All reports of customer feedback must be reported to the Sponsor.  Sponsor Contact 
information can be found in the Investigator Trial File Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose of sugammadex is considered a dose ≥ 2 X the intended dose to 
which the subject was randomized. In this trial, an overdose of neostigmine is any dose 
greater than 5.0 mg as indicated in the labeling of neostigmine. An overdose of 
glycopyrrolate is considered a dose of greater than 2.0 mg.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a non-serious adverse event, unless other serious
criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious adverse events using the terminology “accidental or intentional 
overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies  must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events and Incidents to the Sponsor
7.2.3
Serious Adverse Events and Incidents
7.2.3.1
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. 
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 4 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
 
 
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to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
An incident is any malfunction or deterioration in the characteristics and/or performance of 
the device, as well as any inadequacy in the labeling or the instructions for use that, directly 
or indirectly, led to or could have led to, the death of a subject or user, or of other persons, or 
to a serious deterioration in their state of health.
A serious deterioration in the state of health can include:

Life-threatening illness, even if temporary in nature;

Permanent impairment of a body function or permanent damage to a body structure;

Any indirect harm as a consequence of an incorrect diagnostic or IVD test results 
when used within instructions for use;

Fetal distress, fetal death or any congenital abnormalities or birth defects;

Condition necessitating medical or surgical intervention, including hospitalization or 
prolongation or existing hospitalization to prevent one of the above;

Cases that are considered medically significant
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any incident, or follow-up to an incident, whether or not 
related to the device, must be reported within 24 hours to the Sponsor either by electronic 
media or paper.   Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any incident considered by an investigator who is a qualified physician to be 
related to the Sponsor's product that is brought to the attention of the investigator at any time 
outside of the time period specified above also must be reported immediately to the Sponsor.
All subjects involved with incidents must be followed up for outcome.
 
 
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Events of Clinical Interest
7.2.3.2
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
2. Clinically relevant arrhythmias, inclusive of clinically relevant sinus bradycardia and
clinically relevant sinus tachycardia

Clinically relevant sinus bradycardia is defined as any bradycardia event
necessitating intervention, as determined by investigator judgment. 

Clinically relevant sinus tachycardia is defined as any tachycardia event
necessitating intervention, as determined by investigator judgment. 

Other clinically relevant cardiac arrhythmia is defined as any arrhythmia event
necessitating intervention, as determined by investigator judgment (i.e., new or 
worsening atrial fibrillation, atrial tachycardia, ventricular tachycardia, or 
ventricular fibrillation, etc).
 
 
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3. Hypersensitivity and/or anaphylaxis

Hypersensitivity: The term hypersensitivity describes objectively reproducible 
symptoms and signs of allergic disease initiated by exposure to a defined stimulus 
at a dose tolerated by normal persons. Refer to the ECI Guidance document (or 
equivalent) for more information.

Anaphylaxis: The term anaphylaxis is an umbrella term for a serious, life-
threatening generalized or systemic hypersensitivity reaction that is rapid in onset. 
For the purpose of this study, adjudication of potential cases of anaphylaxis is 
defined by Sampson et al. [4].
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 4. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 4 for instructions in evaluating adverse events.
 
 
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Table 4
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.   (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Overdose, although not serious per ICH definition, whether accidental or intentional, with or without an accompanying adverse event/serious adverse event, is 
reportable to the Sponsor within 24 hours to meet certain local requirements.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event?   The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor's 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Clinical Adjudication Committee
7.3.1
A Clinical Adjudication Committee (CAC) will evaluate the following events for the 
purposes of confirming them according to the criteria in Section 8.0 – Statistical Analysis 
Plan, as well as evaluating the presence of confounding factors.
This external committee of independent consultants will assess the following events:

Hypersensitivity and/or anaphylaxis
The BSA and/or Principal Investigator (or delegate) will identify events to be adjudicated. In 
addition, the Sponsor will periodically review the blinded clinical database in order to 
identify events that may meet criteria for adjudication. Upon identification of such an event, 
the Sponsor may query the site for additional information.
All personnel involved in the adjudication process will remain blinded to treatment allocation 
throughout the trial.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding, changes made to primary and/or key secondary 
hypotheses, or the statistical methods related to those hypotheses, then the protocol will be 
amended (consistent with ICH Guideline E-9). Changes to exploratory or other non-
confirmatory analyses made after the protocol has been finalized, but prior to unblinding, 
will be documented in a supplemental statistical analysis plan (sSAP) and referenced in the 
clinical study report (CSR) for the study. Post hoc exploratory analyses will be clearly 
identified in the CSR.
 
 
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Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2-8.12.  
Study Design Overview
A randomized, active comparator-controlled trial evaluating the safety 
of sugammadex when used to reverse neuromuscular blockade 
induced by either rocuronium or vecuronium in ASA Class 3 or 4 
subjects.
Treatment Assignment
Subjects will be stratified by NMBA (rocuronium or vecuronium) and
ASA Class. Subjects will be randomized to depth of NMB (moderate 
or deep) and reversal agent (sugammadex or neostigmine + 
glycopyrrolate) as follows:
Within the rocuronium stratum, the treatment groups are:
1)
Moderate block and reversal with sugammadex 2 mg/kg; or
2)
Moderate block and reversal with neostigmine (50 µg/kg up to 5 
mg maximum dose) + glycopyrrolate (10 µg/kg up to 1 mg 
maximum dose); or 
3)
Deep block and reversal with sugammadex 4 mg/kg; or
4)
Deep block and reversal with sugammadex 16 mg/kg
Within the vecuronium stratum, the treatment groups are:
1)
Moderate block and reversal with sugammadex 2 mg/kg; or
2)
Moderate block and reversal with neostigmine (50 µg/kg up to 5 
mg maximum dose) + glycopyrrolate (10 µg/kg up to 1 mg 
maximum dose); or 
3)
Deep block and reversal with sugammadex 4 mg/kg;
Analysis Populations
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
1)
The proportion of subjects with treatment emergent sinus 
bradycardia
2)
The proportion of subjects with treatment emergent sinus 
tachycardia
3)
The proportion of subjects with other treatment emergent cardiac
arrhythmias
Key Secondary Endpoints
N/A
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
As the trial is focused on the evaluation of safety, no statistical 
evaluation for efficacy will be performed.
Statistical Methods for Key 
Safety Analyses
A tiered approach will be used to safety analyses. Tier 1 parameters 
will be subject to inferential testing for statistical significance with 
95% confidence intervals (CI) for between-group comparisons. Tier 
2 parameters will be assessed via point estimates with 95% 
confidence intervals provided for between-group comparisons; only 
point estimates by treatment group are provided for Tier 3 safety 
parameters.
Interim Analyses
No interim analyses are planned for this study.
Multiplicity
No multiplicity adjustment is planned.
 
 
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Sample Size and Power 
The total planned sample size is approximately 331 subjects. 
Approximately 30% of the total number of randomized subjects will 
be enrolled in the vecuronium stratum. Therefore, approximately 100 
subjects will be enrolled in the vecuronium stratum and randomized to 
the 3 treatment arms in a 2:1:2 ratio; thus, there would be 
approximately 40 subjects in each of the sugammadex arms and 
approximately 20 subjects in the neostigmine arm. Approximately 231 
subjects will be enrolled in the rocuronium stratum and randomized to 
the 4 treatment arms in a 2:1:2:2 ratio; thus, approximately 66 subjects 
will be in each of the sugammadex arms (i.e., 2 mg/kg, 4 mg/kg and 
16 mg/kg) and approximately 33 subjects will be in neostigmine arm.
Interim Analyses
8.2
No interim analyses are planned for this study.
Responsibility for Analyses/In-House Blinding
8.3
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
With the exception of designated individuals (i.e., unblinded CRAs), all Sponsor study team 
personnel will be blinded to study medication assignment. The official, final database will 
not be unblinded until medical/scientific review has been performed, protocol deviations 
have been identified, and data have been declared final and complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented using an IVRS.
Hypotheses/Estimation
8.4
Objectives of the study are stated in Section 3.0.
Analysis Endpoints
8.5
Only safety endpoints will be evaluated in this study. For safety analyses other than the 
primary safety endpoints (which includes events up to 30 minutes post administration of 
study medication), the primary approach to the summary of AEs will include all events that 
occur up to 7 days post administration of study medication.  A supplemental summary of all 
AEs occurring up to 14 days post administration of study medication will also be included.
Tier 1 Safety Endpoints
8.5.1
The primary endpoints, which are considered as Tier 1 safety endpoints, are:

Proportion of subjects with treatment emergent sinus bradycardia defined as a heart 
rate <60 bpm that has also decreased more than 20% compared to the subject’s 
baseline heart rate value, sustained for at least 1 minute after administration of study 
medication.

Proportion of subjects with treatment emergent sinus tachycardia defined as a heart 
rate ≥100 bpm that has increased more than 20% compared to the subject’s baseline 
heart rate value, sustained for at least 1 minute after administration of study 
medication.
 
 
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
Proportion of subjects with other treatment emergent cardiac arrhythmias defined as
new or worsening arrhythmias (e.g., atrial fibrillation, atrial tachycardia, ventricular 
fibrillation, or ventricular tachycardia), sustained for at least 1 minute after 
administration of study medication.
The baseline heart rate for the primary safety endpoints will be recorded approximately 5 
minutes before administration of study medication (sugammadex or neostigmine) to 
determine events of treatment emergent sinus bradycardia, treatment emergent sinus 
tachycardia, or other treatment emergent cardiac arrhythmias. 
Tier 2 Safety Endpoints
8.5.2
Some supportive safety endpoints considered as Tier 2 endpoints are listed below:

Proportion of subjects with adjudicated hypersensitivity.

Proportion of subjects with adjudicated anaphylaxis.

Proportion of subjects with at least one clinically relevant sinus bradycardia event 
defined as any bradycardia event necessitating intervention, as determined by 
investigator judgment.

Proportion of subjects with at least one clinically relevant sinus tachycardia event 
defined as any tachycardia event necessitating intervention, as determined by 
investigator judgment.

Proportion of subjects with a least one other clinically relevant cardiac arrhythmia 
defined as any other cardiac arrhythmia event necessitating intervention, as 
determined by investigator judgment.
In addition, proportion of subjects with any AE, serious AE, drug-related AE, serious and 
drug-related AE, discontinuation due to AE and specific AEs, SOCs, or PDLCs (incidence≥4 
of subjects in one of the treatment group) will be considered as Tier 2 safety endpoints.
Analysis Populations
8.6
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be included in the treatment group corresponding 
to the study treatment they actually received for the analysis of safety data using the ASaT 
population. For most subjects this will be the treatment group to which they are randomized. 
Subjects who take incorrect study treatment will be included in the treatment group 
corresponding to the study treatment actually received.
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Statistical Methods
8.7
Statistical testing and inference for safety analyses are described in Section 8.7.1. Unless 
otherwise stated, all statistical tests will be conducted at the α=0.05 (2-sided) level.
 
 
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Statistical Methods for Safety Analyses
8.7.1
All safety analyses will be based on the All Subjects as Treated population. 
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs.
The analysis of safety results will follow a tiered approach (Table 5). The tiers differ with 
respect to the analyses that will be performed. Safety parameters or adverse experiences of
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p-values and 95% confidence 
intervals provided for between-group comparisons. Other safety parameters will be 
considered Tier 2 or Tier 3. Tier 2 parameters will be assessed via point estimates with 95% 
confidence intervals provided for between-group comparisons; only point estimates by 
treatment group are provided for Tier 3 safety parameters. Between-group comparisons will 
be made for each dosing group of sugammadex and neostigmine pooled across NMBA and 
separately by NMBA.
The incidence of safety parameters will be summarized by treatment group and preferred 
term across all 4 dosing groups. The primary safety endpoints are considered Tier 1 events. 
Both Tier 1 and Tier 2 endpoints will be estimated with 95% confidence interval by 
treatment groups using Clopper-Pearson method [6]. P-values (Tier 1 only) and 95% 
confidence interval (Tier 1 and Tier 2) will be provided for between-treatment differences
using the stratified Miettinen and Nurminen method [7] with NMBA and ASA class as 
stratification factors.
Adverse experiences (specific terms as well as System Organ Class terms) and predefined 
limits of change in laboratory and vital signs that are not pre-specified as Tier-1 endpoints 
will be classified as belonging to Tier 2 or Tier 3, based on the number of events observed. 
Membership in Tier 2 requires that at least 4 subjects in any treatment group exhibit the 
event; all other adverse experiences and predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have fewer than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences 
and predefined limits of change.
Continuous measures such as changes from baseline in laboratory and vital signs that are not 
pre-specified as Tier-1 endpoints will be considered Tier 3 safety parameters. Summary 
statistics for baseline, on-treatment, and change from baseline values will be provided by 
treatment group in table format. In addition, blood pressure will be evaluated in participants 
with Tier 1 safety events.
Table 5 summarizes the safety tier and level of analysis for the safety endpoints.
 
 
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Table 5
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpointa
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Treatment emergent sinus bradycardia
X
X
X
Treatment emergent sinus tachycardia
X
X
X
Other treatment emergent cardiac arrhythmias
X
X
X
Tier 2
Adjudicated hypersensitivity
Adjudicated anaphylaxis
Clinically relevant sinus bradycardia
Clinically relevant sinus tachycardia
Other clinically relevant cardiac arrhythmia
Any AE
X
X
X
X
X
X
X
X
X
X
X
X
Any serious AE
X
X
Any drug-related AE
X
X
Any serious and drug-related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs, or PDLCsb (incidence ≥4 
of subjects in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCsb (incidence <4 
of subjects in all of the treatment groups)
X
Change from Baselinec Results (Labs, Vital 
Signs)
X
a
Adverse experience references refer to both clinical and laboratory AEs.
b
Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier 2 endpoints.
c    Baseline measurements are taken at Visit 1.
Abbreviations: CI = Confidence interval; SOC = System Organ Class; PDLC = Pre-defined limit of change; X  = 
Results will be provided.
Demographic and Baseline Characteristics
8.7.2
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs.  No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed.  
Demographic variables (e.g., age, gender, BMI, race, ethnicity), baseline characteristics, 
surgical procedures, primary and secondary diagnoses, and prior and concomitant therapies 
will be summarized by treatment either by descriptive statistics or categorical tables.
Multiplicity
8.8
This study is to evaluate the safety profile of treatment. P-values and 95% confidence 
intervals for the primary safety endpoints (e.g., incidence of treatment emergent sinus 
bradycardia, treatment emergent sinus tachycardia, or other treatment emergent cardiac 
arrhythmia) will be provided for clinical interpretation, but there will not be any formal 
hypothesis. Therefore, no corrections for multiplicity are planned for this study. 
 
 
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Sample Size and Power Calculations
8.9
This study will enroll approximately 331 subjects in total. Approximately 30% of the total 
number of randomized subjects (100 subjects) will be administered vecuronium with a 
maximum of 70% of the total number of randomized subjects (231 subjects) to be 
administered rocuronium. The following calculations are conducted assuming these to be the 
numbers of subjects in each stratum.
Assuming 100 subjects will be enrolled in the vecuronium stratum and randomized to the 3 
treatment arms in a 2:1:2 ratio, there would be 40 subjects in each of the sugammadex arms 
and 20 subjects in the neostigmine arm. If no events are observed among the 40 subjects in a 
given sugammadex group, an upper bound of the 95% confidence interval for subjects with 
any treatment emergent arrhythmia is ~8.8% (1 in every 11 subjects) in a treatment group.
Assuming 231 subjects will be enrolled in the rocuronium stratum and randomized to the 4 
treatment arms in a 2:1:2:2 ratio, there would be 66 subjects in each of the sugammadex arms 
(i.e., 2 mg/kg, 4 mg/kg, and 16 mg/kg) and 33 subjects in the neostigmine arm. If no events 
are observed among the 66 subjects in a given sugammadex group, an upper bound of the 
95% CI for subjects with any treatment emergent arrhythmia is ~5.0% (1 in every 20 
subjects) in a treatment group. 
The estimate of incidence and the upper bound of the 95% CI for the underlying percentage 
of subjects with any treatment emergent arrhythmia within the sugammadex group are 
provided in Table 6. These calculations are based on the exact binomial method proposed by 
Clopper and Pearson (1934) [6].
 
 
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Table 6
Estimate of Incidence of Any Treatment Emergent Arrhythmia and 95% Upper 
Confidence Bound Based on Hypothetical Number of Subjects with Any Treatment
Emergent Arrhythmia Among 40 and 66 Subjects in the Sugammadex Group
Number of 
Subjects in 
Sugammadex 
Group
Hypothetical Number of 
Subjects With Any 
Treatment Emergent 
Arrhythmia
Estimate 
of 
Incidence
95% Upper Confidence 
Bounda
40
1
2.5%
13.2%
3
7.5%
20.4%
5
12.5%
26.8%
7
17.5%
32.8%
10
25.0%
41.2%
66 
1
l.5%
8.2%
3
4.6%
12.7%
5
7.6%
16.8%
7
10.6%
20.6%
10
15.2%
26.1%
a Based on the two-tailed exact CI of a binomial proportion (Clopper and Pearson, 1934).
Table 7 summarizes the percentage point differences between the sugammadex and 
neostigmine groups for a variety of hypothetical underlying incidences of any treatment 
emergent arrhythmia.  These calculations assume 66 subjects in the sugammadex group and 
33 subjects in the neostigmine group and are based on a 2-sided 5% alpha level.  The 
calculations are based on an asymptotic method proposed by Farrington and Manning (1990) 
[8]; no multiplicity adjustments were made.
Table 7
Differences in Incidence in Any Treatment Emergent Arrhythmia between the 
Sugammadex and Neostigmine Groups (Assuming Two-Sided 5% alpha level with 66
Subjects in Sugammadex Group and 33 Subjects in Neostigmine Group)
Incidence of Adverse Event
Risk Difference
Sugammadex (%)
Neostigmine (%)
Percentage Points 
95% CIa
1.5%
3.0%
1.5
(-13.9%, 5.5%)
3.0%
9.1%
6.1
(-20.9%, 3.2%)
Incidences presented here are hypothetical and do not represent actual adverse experiences 
in either group.
a Based on an asymptotic method (Farrington and Manning (1990)).
 
 
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Subgroup Analyses and Effect of Baseline Factors
8.10
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
safety endpoint will be estimated across NMBA within each category of each subgroup. In 
addition, the consistency of the treatment effect on the primary endpoints will be assessed 
descriptively via summary statistics by category of subgroups for classification variables
listed below: 

Age category (18-64, 65-74, or >74 years)

Sex (female, male)

BMI (<30 or ≥30 - <40 kg/m2)

Race (white, other)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

ASA class (3, 4)

Region (United States, non-United States)
Subgroup analyses/summaries will only be performed for those classification variables with 
≥10% participants in each subgroup.
Compliance (Medication Adherence)
8.11
Compliance with dosage (in mg/kg) will be assessed based on the actual dosage (mg) of 
study medication administered and the reported body weight, per dosing occasion. Any 
dosage that differs by more than 10% from the planned dosage will be listed. No statistical 
tests will be performed with respect to treatment compliance.
Extent of Exposure
8.12
The extent of exposure to study medication will be summarized in a table presenting per 
treatment group the number of subjects who were randomized and received the study 
medication (i.e., were treated). If information on actual dose of study medication is available, 
summary statistics will be provided on the actual dose of study medication received (mg/kg).
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 8.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
 
 
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Table 8
Product Descriptions
Product Name & Potency
Dosage Form
Source/Additional Information
Sugammadex 100 mg/ml
Injection
Provided centrally by the Sponsor 
Neostigmine methylsulfate 
0.5mg/ml
Injection
Provided centrally by the Sponsor
Glycopyrrolate 0.2mg/ml
Injection
Provided centrally by the Sponsor
Sugammadex, neostigmine, and glycopyrrolate will be supplied to OR staff in masked 
syringes for administration to study subjects. 
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Clinical sites will receive open label single and multiple dose vials and kits. Each kit will 
contain the sufficient number of vials or ampoules to support treatment. Clinical supplies will 
be masked by the pharmacist (or delegate) as needed.
Clinical Supplies Disclosure
9.3
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind subjects and to unmask treatment identity. In the event that the emergency 
unblinding call center is not available for a given site in this trial, the central electronic 
treatment allocation/randomization system (IVRS/IWRS) should be used in order to unblind 
subjects and to unmask treatment/vaccine identity.  The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.  Only the principal investigator or 
delegate and the respective subject’s code should be unblinded.  Trial site personnel and 
Sponsor personnel directly associated with the conduct of the trial should not be unblinded to 
treatment assignment. Subjects whose treatment assignment has been unblinded (by the 
investigator, Merck subsidiary, or through the emergency unblinding call center) must be 
discontinued from study drug, but should continue to be monitored in the trial.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
 
 
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Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
9.6
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
 
 
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Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
 
 
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Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
 
 
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when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
 
 
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By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
 
 
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and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
[1]
Fasting S, Gisvold SE. Serious intraoperative problems - a five-year review of 83,844 
anesthetics. Can J Anesth 2002;49(6):545-53.
[2]
Sprung J, Flick RP, Gleich SJ, Weingarten TN. Perioperative cardiac arrests. Signa 
Vitae 2008;3(2):8-12.
[3]
Sprung J, Warner ME, Contreras MG, Schroeder DR, Beighley CM, Wilson GA, et 
al. Predictors of Survival following Cardiac Arrest in Patients Undergoing 
Noncardiac Surgery: A Study of 518,294 Patients at a Tertiary Referral Center. 
Anesthesiology 2003;99(2):259-69.
[4]
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson J, Bock SA, Branum A, et 
al. Second symposium on the definition and management of anaphylaxis: Summary 
report: Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117(2):391-7.
 
 
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[5]
American Society of Anesthesiologists. ASA physical status classification system 
[Internet]. 
Schaumburg, 
IL: 
ASA; 
2017. 
Available 
from. 
https://www.asahq.org/resources/clinical-information/asa-physical-status-
classification-system.
[6]
Clopper CJ, Pearson ES. The use of confidence or Fiducial limits illustrated in the 
case of the binomial. Biometrika 1934;26(4):404-13.
[7]
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985;4:213-
26.
[8]
Farrington CP, Manning G. Test statistics and sample size formulae for comparative 
binomial trials with null hypothesis of non-zero risk difference or non-unity relative 
risk. Stat Med 1990;9:1447-54.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this trial as outlined in Section 7.1.3.3 –
Future Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on the visit designated in the 
trial flow chart.  If delayed, present consent at next possible Subject Visit.  Consent 
forms signed by the subject will be kept at the clinical trial site under secure storage 
for regulatory reasons.  
 
 
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens.  This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between subject identifiers 
and this unique code will be held at the trial site.  No personal identifiers will appear on 
the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and ask that their 
biospecimens not be used for Future Biomedical Research.  Subjects may withdraw 
consent at any time by contacting the principal investigator for the main trial. If medical 
records for the main trial are still available, the investigator will contact the Sponsor 
using 
the 
designated 
mailbox 
(clinical.specimen.management@merck.com). 
 
 
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Subsequently, the subject's specimens will be flagged in the biorepository and restricted 
to main study use only. If specimens were collected from study participants specifically 
for Future Biomedical Research, these specimens will be removed from the biorepository 
and destroyed. Documentation will be sent to the investigator confirming withdrawal 
and/or destruction, if applicable. It is the responsibility of the investigator to inform the 
subject of completion of the withdrawal and/or destruction, if applicable.  Any analyses 
in progress at the time of request for withdrawal/destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and subjects.  Subjects will not be identified by 
 
 
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name in any published reports about this study or in any other scientific publication or 
presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial.
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
 
 
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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
12.3
Sample Types
Trial Visit
Screening
Visit 1
Peri-anesthetic visit
Visit 2
Post anesthetic visit
Visit 3
Blood Parameter 
Approximate Blood Volume (mL)
Hematology
0
2
2
Serum Chemistry
0
5
5
Serum β-Human Chorionic 
Gonadotropin (β-hCG)a
3.5
Blood (DNA) for Future 
Biomedical Research 
0
8.5
Expected Total (mL)
3.5
15.5
7
a.
For females of child bearing potential only. Sample taken only if the urine pregnancy test is 
positive at Visit 1 or if performed locally as part of standard of care.
 
 
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List of Abbreviations and Definitions of Terms
12.4
Term
Definition
AE
Adverse event
ASA
American Society of Anesthesiologists
ASaT
All subjects as treated
BMI
Body mass index
BSA
Blinded Safety Assessor
CI
Confidence interval
CSR
Clinical study report
ECG
Electrocardiogram
ECI
Event of clinical interest
EDC 
Electronic data capture
hCG
Human chorionic gonadotropin
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IV
Intravenous
IVRS
Interactive Voice Response System 
NMB
Neuromuscular blockade
NMBA
Neuromuscular blocking agent
NMTM
Neuromuscular Transmission Monitoring
OR
Operating room
PNS
Peripheral Nerve Stimulator
PTC
Post-tetanic count
SAE
Serious adverse event
T1, T2, T3, T4
First (T1),second (T2), third (T3), or fourth (T4) twitch in response to 
TOF stimulation
T4/T1 ratio
TOF ratio: Ratio of the height of T4 over the height of T1 in the 
recording of the response to TOF stimulation. Ratio expressed in 
decimals (e.g., 0.7 or 0.8 or 0.9)
TOF
Train of four stimulation 
 
 
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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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