Clinical trial NCT03346070
Conditions: Neuromuscular Blockade
Sponsor: Merck Sharp & Dohme LLC
Start date: 2018-01-01; Completion date: 2019-01-29
Enrollment: 207 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial is to evaluate the safety and efficacy of Sugammadex when administered according to actual body weight (ABW) as compared to ideal body weight (IBW) for the reversal of both moderate and deep neuromuscular blockade (NMB) induced by either Rocuronium or Vecuronium in morbidly obese participants. The primary hypothesis of this investigation is that, compared to obese participants dosed based on IBW, obese participants receiving Sugammadex according to ABW will demonstrate a faster time to recovery to a Train Of Four (TOF) ratio of ≥0.9 (i.e. faster NMB reversal), pooled across NMB depth and type of neuromuscular blocking agent (NMBA; Rocuronium or Vecuronium) administered.

Detailed description:

Arms: arm 1: Following administration of NMBA, participants received a single intravenous (i.v.) bolus of Sugammadex at 2 mg/kg as determined utilizing participant ABW. A treatment dose of 2 mg/kg was used for reversal of moderate NMB. arm 2: Following administration of NMBA, participants received a single i.v. bolus of Sugammadex at 2 mg/kg as determined utilizing participant IBW. A treatment dose of 2 mg/kg was used for reversal of moderate NMB. arm 3: Following administration of NMBA, participants received a single i.v. bolus of Sugammadex at 4 mg/kg as determined utilizing participant ABW. A treatment dose of 4 mg/kg was used for reversal of deep NMB. arm 4: Following administration of NMBA, participants received a single i.v. bolus of Sugammadex at 4 mg/kg as determined utilizing participant IBW. A treatment dose of 4 mg/kg was used for reversal of deep NMB. arm 5: Following administration of NMBA, participants received a single i.v. bolus containing both Neostigmine (50 µg/kg; up to 5 mg maximum dose) and Glycopyrrolate (10 µg/kg; up to 1 mg maximum dose) as determined utilizing participant ABW. Neostigmine/Glycopyrrolate was used for reversal of moderate NMB. Active comparator treatment for reversal for deep NMB was not available.
Interventions: intervention 1: Sugammadex 2 mg/kg ABW intervention 2: Sugammadex 2 mg/kg IBW intervention 3: Sugammadex 4 mg/kg ABW intervention 4: Sugammadex 4 mg/kg IBW intervention 5: Neostigmine + Glycopyrrolate intervention 6: Rocuronium or 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 by ABW) for reversal of moderate NMB.

Moderate NMB is defined as the reappearance of a second twitch (T2) in response to TOF stimulations. intervention 2: Following administration of NMBA (Rocuronium or Vecuronium) to achieve moderate NMB, participants received a single i.v. bolus of Sugammadex (2 mg/kg by IBW) for reversal of moderate NMB.

Moderate NMB is defined as the reappearance of T2 in response to TOF stimulations. intervention 3: Following administration of NMBA (Rocuronium or Vecuronium) to achieve deep NMB, participants received a single i.v. bolus of Sugammadex (4 mg/kg by ABW) for reversal of deep NMB.

Deep NMB is defined as no response to TOF stimulations (TOF=0) and a detection target of 1-2 post-tetanic counts (PTCs). intervention 4: Following administration of NMBA (Rocuronium or Vecuronium) to achieve deep NMB, participants will receive a single i.v. bolus of Sugammadex (4 mg/kg by IBW) for reversal of deep NMB.

Deep NMB is defined as no response to TOF stimulations (TOF=0) and a detection target of 1-2 post-tetanic counts (PTCs). intervention 5: 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), dosed according to participant ABW for reversal of moderate NMB.

Moderate NMB is defined as the reappearance of T2 in response to TOF stimulations. intervention 6: To achieve NMB, participants received steroidal NMBA Rocuronium Bromide or Vecuronium Bromide administered via i.v. infusion and dosed according to participant ABW. NMBAs were concomitant medications used per label as adjunct to general anesthesia.

Protocol documents:
Prot_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03346070 
Document Date: 
05-Jul-2018
A Phase 4 Randomized, Active-Comparator Controlled Trial to 
Study the Efficacy and Safety of Sugammadex (MK-8616) for the 
Reversal of Neuromuscular Blockade Induced by Either 
Rocuronium Bromide or Vecuronium Bromide in Morbidly Obese 
Subjects


Product:  MK-8616 
1
Protocol/Amendment No.: 146-01 
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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 Trial to Study the Efficacy and 
Safety of Sugammadex (MK-8616) for the Reversal of Neuromuscular Blockade Induced by 
Either Rocuronium Bromide or Vecuronium Bromide in Morbidly Obese Subjects
IND NUMBER:  68,029
EudraCT NUMBER:  2017-000188-33
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES.................................................................................................. 9
1.0
TRIAL SUMMARY.................................................................................................. 17
2.0
TRIAL DESIGN........................................................................................................ 18
Trial Design ........................................................................................................... 18
2.1
Trial Diagram........................................................................................................ 21
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 22
Primary Objective(s) & Hypothesis(es) .............................................................. 22
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 22
3.2
Exploratory Objectives......................................................................................... 23
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 23
Background ........................................................................................................... 23
4.1
Pharmaceutical and Therapeutic Background .................................................... 23
4.1.1
Rationale................................................................................................................ 24
4.2
Rationale for the Trial and Selected Subject Population .................................... 24
4.2.1
Rationale for Dose Selection/Regimen............................................................... 25
4.2.2
Rationale for the Use of Comparator........................................................... 26
4.2.2.1
Rationale for Endpoints ...................................................................................... 26
4.2.3
Efficacy Endpoints....................................................................................... 26
4.2.3.1
Safety Endpoints .......................................................................................... 26
4.2.3.2
Pharmacokinetic Endpoints ......................................................................... 28
4.2.3.3
Future Biomedical Research........................................................................ 28
4.2.3.4
Benefit/Risk ........................................................................................................... 28
4.3
5.0
METHODOLOGY ................................................................................................... 29
Entry Criteria........................................................................................................ 29
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 29
5.1.1
Subject Inclusion Criteria.................................................................................... 29
5.1.2
Subject Exclusion Criteria .................................................................................. 30
5.1.3
Trial Treatment(s) ................................................................................................ 32
5.2
Dose Selection .................................................................................................... 32
5.2.1
Dose Selection (Preparation) ....................................................................... 32
5.2.1.1
 
 
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Timing of Dose Administration .......................................................................... 33
5.2.2
Trial Blinding...................................................................................................... 33
5.2.3
Randomization or Treatment Allocation............................................................ 35
5.3
Stratification.......................................................................................................... 35
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 35
5.5
Rescue Medications & Supportive Care............................................................. 36
5.6
Diet/Activity/Other Considerations..................................................................... 36
5.7
Subject Withdrawal from the Trial .................................................................... 36
5.8
Subject Replacement Strategy............................................................................. 36
5.9
Beginning and End of the Trial ........................................................................... 36
5.10
Clinical Criteria for Early Trial Termination ................................................... 36
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 37
7.0
TRIAL PROCEDURES ........................................................................................... 40
Trial Procedures ................................................................................................... 40
7.1
Administrative Procedures.................................................................................. 40
7.1.1
Informed Consent......................................................................................... 40
7.1.1.1
7.1.1.1.1
General Informed Consent.................................................................... 40
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 41
Inclusion/Exclusion Criteria ........................................................................ 41
7.1.1.2
Subject Identification Card .......................................................................... 41
7.1.1.3
Medical History ........................................................................................... 41
7.1.1.4
Prior and Concomitant Medications Review ............................................... 41
7.1.1.5
7.1.1.5.1
Prior Medications.................................................................................. 41
7.1.1.5.2
Concomitant Medications..................................................................... 41
Assignment of Screening Number............................................................... 42
7.1.1.6
Assignment of Treatment/Randomization Number ..................................... 42
7.1.1.7
Trial Compliance (Medication).................................................................... 42
7.1.1.8
Clinical Procedures/Assessments........................................................................ 42
7.1.2
Physical Examination................................................................................... 42
7.1.2.1
Body Weight and Height ............................................................................. 43
7.1.2.2
Body Mass Index ......................................................................................... 43
7.1.2.3
 
 
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Electrocardiogram........................................................................................ 43
7.1.2.4
Vital Signs.................................................................................................... 43
7.1.2.5
Administration of Neuromuscular Blocking Agents ................................... 45
7.1.2.6
Neuromuscular Monitoring.......................................................................... 45
7.1.2.7
Laboratory Procedures/Assessments .................................................................. 45
7.1.3
Laboratory Safety Evaluations (Hematology and Chemistry)..................... 46
7.1.3.1
Pregnancy Tests ........................................................................................... 47
7.1.3.2
Pharmacokinetic Evaluations....................................................................... 47
7.1.3.3
7.1.3.3.1
Blood Collection for Plasma MK-8616................................................ 47
Future Biomedical Research Samples ......................................................... 47
7.1.3.4
Other Procedures................................................................................................. 48
7.1.4
Withdrawal/Discontinuation........................................................................ 48
7.1.4.1
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 48
7.1.4.1.2
Lost to Follow-up.................................................................................. 48
7.1.4.1.3
Subject Blinding/Unblinding ................................................................ 49
Calibration of Equipment............................................................................. 49
7.1.4.2
Visit Requirements.............................................................................................. 49
7.1.5
Screening (V1)............................................................................................. 49
7.1.5.1
Peri-anesthetic Visit (V2) ............................................................................ 50
7.1.5.2
Post-Anesthetic Visit (V3)........................................................................... 53
7.1.5.3
Follow-up Safety Contact (V4).................................................................... 53
7.1.5.4
Assessing and Recording Adverse Events and Patient/Device Events............. 53
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 55
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 55
7.2.2
Immediate Reporting of Adverse Events and Incidents to the Sponsor ............. 56
7.2.3
Serious Adverse Events and Incidents......................................................... 56
7.2.3.1
Events of Clinical Interest............................................................................ 57
7.2.3.2
Evaluating Adverse Events ................................................................................. 58
7.2.4
Sponsor Responsibility for Reporting Adverse Events and Patient/Device 
7.2.5
Events and Incidents ........................................................................................... 61
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 61
7.3
Data Monitoring Committee ............................................................................... 61
7.3.1
 
 
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Clinical Adjudication Committee ....................................................................... 61
7.3.2
Neuromuscular Monitoring Adjudication Committee ................................. 61
7.3.2.1
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 62
Statistical Analysis Plan Summary ..................................................................... 62
8.1
Responsibility for Analyses/In-House Blinding ................................................. 63
8.2
Hypotheses/Estimation ......................................................................................... 63
8.3
Analysis Endpoints ............................................................................................... 63
8.4
Efficacy Endpoints.............................................................................................. 64
8.4.1
Safety Endpoints ................................................................................................. 64
8.4.2
Pharmacokinetic Endpoints ................................................................................ 65
8.4.3
Derivations of Efficacy /Pharmacokinetics Endpoints ....................................... 66
8.4.4
Analysis Populations............................................................................................. 67
8.5
Efficacy Analysis Population.............................................................................. 67
8.5.1
Safety Analysis Population ................................................................................. 67
8.5.2
Pharmacokinetic Population ............................................................................... 67
8.5.3
Statistical Methods................................................................................................ 68
8.6
Statistical Methods for Efficacy Analyses .......................................................... 68
8.6.1
Statistical Methods for Safety Analyses ............................................................. 69
8.6.2
Statistical Methods for Pharmacokinetic Analysis ............................................. 71
8.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 72
8.6.4
Demographic and Baseline Characteristics ................................................. 72
8.6.4.1
Population PK Analyses .............................................................................. 72
8.6.4.2
Interim Analyses ................................................................................................... 73
8.7
Multiplicity ............................................................................................................ 73
8.8
Sample Size and Power......................................................................................... 73
8.9
Sample Size and Power for Efficacy Analyses................................................... 73
8.9.1
Sample Size for Safety Analyses ........................................................................ 75
8.9.2
Precision Estimates for Pharmacokinetic Parameters (AUC0-inf, Cmax) ......... 76
8.9.3
Subgroup Analyses and Effect of Baseline Factors ........................................... 76
8.10
Compliance (Medication Adherence).................................................................. 77
8.11
Extent of Exposure................................................................................................ 77
8.12
 
 
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9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 77
Investigational Product ........................................................................................ 77
9.1
Packaging and Labeling Information ................................................................. 77
9.2
Clinical Supplies Disclosure................................................................................. 78
9.3
Storage and Handling Requirements.................................................................. 78
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 78
9.5
Standard Policies................................................................................................... 78
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 79
Confidentiality....................................................................................................... 79
10.1
Confidentiality of Data ....................................................................................... 79
10.1.1
Confidentiality of Subject Records ..................................................................... 79
10.1.2
Confidentiality of Investigator Information........................................................ 79
10.1.3
Confidentiality of IRB/IEC Information............................................................. 80
10.1.4
Compliance with Financial Disclosure Requirements....................................... 80
10.2
Compliance with Law, Audit and Debarment ................................................... 80
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 82
10.4
Quality Management System............................................................................... 82
10.5
Data Management................................................................................................. 82
10.6
Publications ........................................................................................................... 83
10.7
11.0
LIST OF REFERENCES......................................................................................... 84
12.0
APPENDICES........................................................................................................... 85
Merck Code of Conduct for Clinical Trials........................................................ 85
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 87
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.3
by Sample Types ................................................................................................... 91
List of Abbreviations and Definitions of Terms................................................. 92
12.4
13.0
SIGNATURES........................................................................................................... 94
Sponsor's Representative ..................................................................................... 94
13.1
Investigator............................................................................................................ 94
13.2
 
 
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LIST OF TABLES
Table 1
Trial Treatment ....................................................................................................... 32
Table 2
Vital Sign Measurements........................................................................................ 44
Table 3
Laboratory Tests ..................................................................................................... 46
Table 4
Evaluating Adverse Events..................................................................................... 59
Table 5
Analysis Strategy for Key Efficacy Variables........................................................ 69
Table 6
Analysis Strategy for Safety Parameters ................................................................ 71
Table 7
Sample Size for Interim Analysis .......................................................................... 73
Table 8
Simulated power levels for the primary comparison and related subgroup 
analyses as a function of sample size..................................................................... 74
Table 9
Estimate of Incidence of Treatment Emergent Sinus Bradycardia/Tachycardia 
and 95% Upper Confidence Bound Based on Hypothetical Number of 
Subjects with Any Treatment Emergent Arrhythmia Among 20 Subjects in a 
Treatment Group .................................................................................................... 75
Table 10 Differences in Incidence in Any Treatment Emergent Arrhythmia between the 
Sugammadex and Neostigmine Groups Assuming Two-Sided 5% alpha level 
with 20 Subjects in a Treatment Group.................................................................. 76
Table 11 Product Descriptions............................................................................................... 77
 
 
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LIST OF FIGURES
          
Figure 1
Trial Design......................................................................................................... 22
Figure 2
Illustrative scenario of Time-to-Recovery to TOF ratio of 0.9 for ABW vs. 
IBW under the assumption of median time-to-recovery of 2.2 minutes in 
ABW group and of 3.3 minutes in IBW group. .................................................. 74
 
 
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SUMMARY OF CHANGES
PRIMARY REASON FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
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
Trial Design
Added: Formula for calculation of 
Ideal Body Weight (IBW)
Clarification
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 
8.4.2 
Safety 
Endpoints.
Note: the definition of these safety endpoints 
has not changed.
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
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.
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 #5:
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.
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
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.
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, and TOF-
Watch SX® traces).
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.
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
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
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 
Measurement
Timing 
and 
methods 
for 
vital 
sign 
measurements displayed in table format for 
additional clarity.
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.2.7
Neuromuscular Monitoring
Added additional text regarding the 
management of the study subject if 
the TOF-Watch SX® data become 
unavailable 
due 
to 
a 
device 
malfunction.
To provide additional guidance to sites on 
the protocol requirements for neuromuscular 
monitoring.
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
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.
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 . 
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.5.2
Peri-anesthetic Visit (V2)
Added: Refer to Section 7.1.2.7 
Neuromuscular 
Monitoring 
for 
general guidance, in the event that 
TOF-Watch 
SX® 
data 
become 
unavailable 
due 
to 
device 
malfunction.
To 
reference 
the 
additional 
guidance 
provided in Section 7.1.2.7 for managing 
subjects in the event of a TOF-Watch SX®
malfunction.
7.1.5.2
Peri-anesthetic Visit (V2)
Updated Item #8: Administration of 
anesthesia
Anesthesia will be induced and 
maintained according to the need of 
the subject.  Note:  All drugs, date of 
administration
dosing time, and 
actual doses given to the subject will 
need to be recorded throughout the 
Peri-anesthetic visit and transferred to 
Sponsor database as required.
The date of medication administration will be 
recorded in the Sponsor database (dosing 
time is not required). 
However, investigator site personnel should 
follow site procedures with respect to 
documenting 
the 
date 
and 
time 
of 
medications administered during surgery.
7.1.5.2
Peri-anesthetic Visit (V2)
Items 5 and 6: The TOF-Watch SX®
accessories
(transducers 
and
electrodes) and/or device
can be 
affixed prior to administration of
anesthesia or after
induction of 
anesthesia but prior to administration 
of NMBA.
Clarification 
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
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 TOF-
Watch SX® device is only used after subject 
randomization. Device incidents can only be 
reported for randomized subjects in this trial.
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 TOF-
Watch SX® device 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
7.3.2
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.
8.4.3
Pharmacokinetic Endpoints
Added heading for this section 
Correction: Section heading was added, as it 
was missing from the Table of Contents in 
the original protocol
Appendix 12.3
Approximate Blood/Tissue 
Volumes Drawn/Collected 
by Trial Visit and by 
Sample Types
Correction to total blood volume 
values at Visit 2 and Visit 3
Assuming all parameters are collected, the 
minimum expected total blood volume 
collected:

At Visit 2 is 39.5 mL (45.5 mL 
maximum).

At Visit 3 is 15 mL (23 mL maximum)
Throughout 
protocol
Throughout protocol
Minor typographical updates
For clarity
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Efficacy and Safety of Sugammadex for the Reversal of 
Neuromuscular Blockade in Morbidly Obese 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 
each 
neuromuscular 
blocking 
agent
(rocuronium 
or 
vecuronium), the treatment groups are:
1)
Moderate block and reversal with sugammadex 2 mg/kg, based on 
actual body weight; or
2)
Moderate block and reversal with sugammadex 2 mg/kg, based on 
ideal body weight; or
3)
Moderate block and reversal with Neostigmine 50 µg/kg up to 5 
mg maximum dose) + glycopyrrolate glycopyrrolate (10 µg/kg up 
to 1 mg maximum dose); or
4)
Deep block and reversal with sugammadex 4 mg/kg, based on 
actual body weight; or
5)
Deep block and reversal with sugammadex 4 mg/kg, based on 
ideal body weight
Number of trial subjects
Approximately 200 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 14 
months 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 through 
the final contact.  After a screening period, each subject will receive
an 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 adverse events.
A list of abbreviations used in this document can be found in Section 12.4.
Randomization Ratio
1:1:1:1:1 per neuromuscular blocking agent (NMBA)
 
 
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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, 
efficacy and safety trial of sugammadex for the reversal of neuromuscular blockade (NMB) 
induced by rocuronium or vecuronium in morbidly obese adult subjects, where morbid 
obesity is defined as body mass index ≥ 40 kg/m2. The purpose of this study is to evaluate the 
efficacy of sugammadex when dosed according to actual body weight (ABW) as compared 
with ideal body weight (IBW), with the latter to be calculated based on the formula by 
Kammerer et al, 2015 [1] . The formula for IBW is as follows:
•
Males: 142 lb +3 lb/in over 63 inches (height) +1 lb/in over 71 inches (height) 
•
Females: 119 lb +3 lb/in. over 60 inches (height) 
Height will be rounded to the nearest whole integer before applying the Kammerer formula.
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.
Investigators will be permitted to select the NMBA for use as appropriate for the type of 
surgery, provided both the rocuronium and vecuronium strata remain open. Subjects will be 
stratified by NMBA by an Interactive Voice Response System (IVRS) to facilitate enrollment 
of the target number of randomized subjects into each stratum (approximately 30% of the 
overall planned sample size will be enrolled in the vecuronium stratum).
Subjects will be randomized to depth of NMB (moderate or deep) and reversal agent 
(sugammadex or neostigmine + glycopyrrolate). For each NMBA stratum (rocuronium or 
vecuronium), subjects will be randomized to one of five treatment groups in a 1:1:1:1:1 ratio 
as follows: 
1. Moderate block and reversal with sugammadex 2mg/kg, based on ABW
2. Moderate block and reversal with sugammadex 2 mg/kg, based on IBW 
3. Moderate block and reversal with neostigmine (50 µg/kg up to 5 mg maximum dose) 
+ glycopyrrolate based on ABW
4. Deep block and reversal with sugammadex 4 mg/kg, based on ABW 
5. Deep block and reversal with sugammadex 4 mg/kg, based on IBW 
 
 
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Subjects should be maintained in either moderate or deep NMB intra-operatively, according 
to treatment assignment, until the time of reversal. Depth of block is to be assessed as 
described elsewhere via continuous neuromuscular transmission monitoring (Section 
7.1.2.7). While fluctuations in depth of block are expected as matter of course to 
accommodate the needs of surgical procedures, additional doses of NMBA should be 
administered as clinically necessary for the duration of the surgery in order for target 
maintenance of the assigned depth of block as follows:

Subjects randomized to moderate block are to be maintained in moderate block until 
the time of reversal. Either sugammadex 2 mg/kg or neostigmine (50 µg/kg up to 5mg 
maximum dose) + glycopyrrolate will be given after the last dose of administered 
NMBA and within 2 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 are to be maintained in deep block until the time 
of reversal. Sugammadex 4 mg/kg will be given after the last dose of administered 
NMBA and within 2 minutes of detection of 1-2 post-tetanic counts (PTC) with a 
range of 1-5 PTC 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. 
 
 
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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 
(PACU) will be recorded by study personnel that are present. 
To ensure timely reporting and comprehensive data collection, the following types of events 
are prespecified 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, 
whether the dose of sugammadex is based on ABW or IBW in the deep block groups will be
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.
A PK-only interim analysis (IA) will be conducted in this study when PK data from 
approximately 64 evaluable sugammadex subjects becomes available. This IA will be 
conducted solely for the purpose of evaluating linearity of sugammadex exposures in 
morbidly obese adult subjects to inform need for study of the 16 mg/kg dose. No unblinding 
of safety or efficacy assessments will be done in support of this IA and enrollment will 
continue during the IA. A Standing Internal Data Monitoring Committee (siDMC) will 
review the results of the planned IA to make recommendations regarding the need to 
study  the 16 mg/kg sugammadex dose.  
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)
In male/female subjects aged 18 years or older who are morbidly obese.
Primary Objective(s) & Hypothesis(es)
3.1
1) Objective:  To evaluate the efficacy of sugammadex when dosed according to ABW 
as compared with IBW; specifically, to compare the distributions of recovery times 
pooled across depth of block and NMBA.
Hypothesis: The time to recovery to a train-of-four (TOF) ratio of ≥ 0.9 is faster in 
subjects dosed according to ABW as compared to subjects dosed according to IBW, 
pooled across depth of block and NMBA.
2) Objective:  To evaluate the safety of sugammadex when dosed according to ABW as 
compared with IBW pooled across depth of block and NMBA.
Secondary Objective(s) & Hypothesis(es)
3.2
1) Objective:  To evaluate the efficacy of sugammadex when dosed according to ABW 
as compared with IBW, by comparing:

The distributions of recovery times to TOFs of  ≥0.7, ≥0.8, and ≥0.9 via mean, 
standard deviation and geometric mean pooled across both depth of block and 
NMBA 

The proportions of subjects with prolonged recovery (>10 minutes) pooled 
across both depth of block and NMBA.
 
 
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Exploratory Objectives 
3.3
1) Objective: To evaluate the pharmacokinetics of sugammadex in morbidly obese 
subjects when dosed according to ABW and IBW by computing:

The geometric mean ratio (4 mg/kg versus 2 mg/kg) for the plasma dose-
normalized AUC 0-inf and dose normalized Cmax following administration of 
sugammadex based on ABW.

The geometric mean ratio (4 mg/kg versus 2 mg/kg) for the plasma dose-
normalized AUC 0-inf and dose normalized Cmax following administration of 
sugammadex based on IBW.
2) Objective:   To evaluate the efficacy of sugammadex and neostigmine; specifically to 
compare the distributions of recovery times in moderate depth of block pooled across 
NMBA.
3) Objective: To evaluate the efficacy of sugammadex when dosed according to ABW
as compared with IBW, by comparing:

The distributions of recovery times to TOFs of  ≥0.7, ≥0.8, and ≥0.9 via mean, 
standard deviation and geometric mean separately by depth of block and by 
NMBA 

The proportions of subjects with prolonged recovery (>10 minutes) separately by 
depth of block and by NMBA.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-8616.
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 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. Because 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.  Additionally, sugammadex is currently approved in more than 83
 
 
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countries and marketed in more than 50 countries, with 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
The pharmacokinetics of sugammadex following single doses from 0.1 mg/kg to 96 mg/kg 
mg, calculated based upon ABW, have been extensively evaluated across a heterogeneous 
population including the effects of intrinsic factors and extrinsic factors (drug-drug 
interactions) on sugammadex PK and/or pharmacodynamic (PD) taking into account the 
nature of the product, results of in vitro studies, and data obtained during the development 
program.  The analysis of PK-PD included population-based analyses across many of the 
clinical pharmacology studies and clinical trials to assess potential covariate effects on PK-
PD variability.  Sugammadex PK is linear over doses of 0.1 to 96 mg/kg and no clinically 
meaningful differences in sugammadex PK based upon intrinsic factors (i.e., weight, BMI, 
gender, age, race) have been observed. In addition, similar PK was observed for anesthetized 
surgical patients and non-anesthetized healthy subjects when administered sugammadex 
based on actual body weight, such that no dose adjustments are necessary based upon these 
factors, except in the setting of severe renal impairment or end stage renal disease. Following 
intravenous injection of sugammadex, elimination is rapid in adult and elderly subjects 
having normal renal function, with a mean half-life of ~2 hours. 
Body weight is the basis for determination of appropriate dose for many medications used in 
the practice of anesthesia. In adults, most demographic factors, such as age, body weight or 
other factors related to medical history or surgical procedures, have not been found to affect 
the efficacy or safety of sugammadex. 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 despite higher exposures. Although 
examination of the sugammadex clinical trial database did not reveal clinically meaningful 
differences in efficacy or safety based on subject body weight, the increasing prevalence of 
obesity and subsequently the number of morbidly obese patients undergoing surgical 
procedures requiring anesthesia
necessitates further evaluation of drug PK and 
pharmacodynamic properties in the morbidly obese (body mass index [BMI] >40 kg/m2). 
Factors to consider in anesthetizing morbidly obese individuals include the potential for 
physiological and anthropometric changes, such as increases in cardiac output, changes in 
regional blood flow, and increases in fat mass and lean mass that may affect PK properties. 
Additionally, respiratory pathophysiology, such as the increased incidence of obstructive 
sleep apnea and fat deposition in the oropharynx and chest wall, can alter the 
pharmacodynamic properties of anesthetics.
Due in part to these factors and the concern for potential overdose if drug administration in 
the morbidly obese is based on actual total body weight, alternative weight-based dosing 
scalars have been variously considered (e.g. IBW, body surface area, BMI, and lean body 
weight).  However, administration of drugs based on IBW, for example, can result in a 
subtherapeutic dose, because an IBW-based approach does not account for changes in body 
composition associated with obesity; namely, the calculated IBW of a morbidly obese patient 
 
 
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is less than their actual lean body weight that may therefore result in under-dosing (Ingrande 
and Lemmens, 2010, [2]).  
Dosing based on actual body weight was consistently applied across the clinical development 
program for sugammadex, both to mirror the ABW-based dosing of the NMBAs whose 
effects it reverses and to ensure a sufficient and consistent molar ratio of 
sugammadex:NMBA. The latter effects a reliable and rapid reversal of NMB with the goal of 
minimizing the occurrence of outliers experiencing prolonged recovery of NMB and to 
reduce the risk of residual block or recurrence of block.
In the pooled clinical trial 
experience, which included 157 obese patients (BMI ≥30 kg/m2), no meaningful differences 
in efficacy or safety were observed in the obese; therefore, no dose adjustment is needed in 
the setting of obesity. 
Data informing the use of sugammadex in the morbidly obese is limited. The purpose of the 
current trial is to therefore evaluate the efficacy and safety of ABW-based and IBW-based 
dosing of sugammadex in the morbidly obese, as well as to generate data to support potential 
dosing recommendations. 
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 or 4 mg/kg – established for reversal of moderate or 
deep block, respectively - will be administered as an intravenous (IV) bolus dose to reverse 
NMB, with the amount of sugammadex administered to be based on either ABW or IBW.
Sugammadex exerts its effect by forming very tight complexes at a 1:1 ratio with rocuronium 
and vecuronium, during rocuronium- or vecuronium -induced neuromuscular blockade, the 
IV administration of sugammadex results in rapid removal of free rocuronium molecules 
from the plasma; therefore, the molar ratios and resultant concentration gradient is an 
important consideration to contextualize the dosing, based upon ABW, of sugammadex 
across populations.  At all recommended doses, based upon ABW, of sugammadex (2 mg/kg 
at reappearance of T2, 4 mg/kg at 1-2 PTC, and 16 mg/kg at 3 minutes after 1.2 mg/kg 
rocuronium) the molar excess of sugammadex over rocuronium, at 2 minutes after 
sugammadex dosing, is about 5 to 8.  Within these 2 minutes, already enough rocuronium has 
flowed from the neuromuscular junction to the extracellular fluid (where the concentration of 
sugammadex is still increasing) and to the plasma (where sugammadex has encapsulated free 
rocuronium first) to achieve recovery.  This creates a concentration gradient favoring the 
movement of the remaining rocuronium molecules from the neuromuscular junction back 
into the plasma, where they are encapsulated by free sugammadex molecules, the 
neuromuscular blockade of rocuronium is terminated rapidly by the diffusion of rocuronium 
away from the neuromuscular junction back into the plasma.  Regarding situations where 
sugammadex is needed clinically to urgently reverse the effects of a large intubating dose of 
rocuronium, at 60 minutes after administration of the 16 mg/kg dose, a 4-to-1 molar excess 
of sugammadex over rocuronium is projected, thereby maximizing the likelihood of effective 
and timely reversal of NMB and minimizing risk of NMB recurrence over a sustained critical 
period in this setting.  
 
 
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Based on assessments to date, including linear sugammadex PK across a dose range from 0.1 
to 96 mg/kg, this relationship of sugammadex-to-rocuronium stoichiometry is expected to 
remain similar across demographic factors and clinical settings.  Because of this, together 
with the fact that sugammadex does not act through other receptor systems, it is anticipated 
that linear PK will be confirmed in the PK-only IA conducted in approximately 64 morbidly 
obese subjects treated with sugammadex.  Any subsequent decision to evaluate the 16 mg/kg 
dose will be based upon evaluation of PK data only; no unblinding of safety or efficacy will 
occur during the IA. Results of the PK-only IA will be reviewed by an siDMC, who will 
make recommendations regarding the need for study of the 16 mg/kg sugammadex dose.
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 coadministered 
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. 
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 4mg/kg group with respect to safety.
Rationale for Endpoints
4.2.3
Efficacy Endpoints
4.2.3.1
During recovery of neuromuscular transmission after blockade from an NMBA such as
rocuronium, the TOF ratio rises from zero during deep NMB back to approximately 1.0 at 
total recovery. Research demonstrates that at TOF ratios of < 0.9, subjects are at potential 
risk for impaired pharyngeal function with associated risk of aspiration, and hypoxic 
ventilatory responses are impaired at TOF ratios of < 0.7 [3]. Conversely, recovery to a TOF
ratio of 0.9 has been shown to correlate with essentially complete clinical recovery from the 
effects of NMB [4]. Therefore, in order to provide a quantitative comparative assessment of 
ABW versus IBW based dosing of sugammadex in the setting of morbid obesity, the primary 
efficacy parameter in this study is the time to recovery of neuromuscular block to a TOF ratio 
of ≥0.9 following sugammadex administration.
Safety Endpoints
4.2.3.2
A primary safety objective of this study is an overall assessment of sugammadex safety when 
dosed according to ABW or IBW. Other safety events (e.g., residual NMB, recurrence of 
NMB, or respiratory events) and tolerability of sugammadex will be continuously assessed 
throughout the trial, via standard AE reporting. 
 
 
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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 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. 

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 one 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 prespecified 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 [5]) will 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. 
 
 
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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). 
Pharmacokinetic Endpoints
4.2.3.3
The intended use for sugammadex is single intravenous administration as needed.  Therefore, 
consistent with historical assessments and based upon its pharmacokinetic properties, 
pharmacokinetic sampling following sugammadex administration at selected time points 
through at least 4-5 hours post-dose will support evaluation of exposure (AUC0-inf, AUC0-
last, Cmax), as well as clearance (CL), volume of distribution (Vd), apparent terminal 
elimination half-life (t1/2), and assessment of PK linearity.  
Population-based methods of analysis may be explored at the completion of the study to 
further characterize the PK profiles within morbidly obese subjects and/or permit 
comparisons to historical data.  
For all subjects, blood samples will be collected at specific visits as indicated in the Trial 
Flow Chart (Section 6.0).
The final decision as to which plasma samples will be assayed will be made by the Sponsor's 
Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism PPDM and the 
Clinical Monitor.
Information regarding the collection and shipping of plasma samples will be provided in the
administrative binder.
Future Biomedical Research
4.2.3.4
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 
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 
 
 
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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 NM B or 
recurrence of NMB compared with other 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 are morbidly obese 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 BMI ≥ 40 kg/m2 (morbidly obese).
2. Be categorized as American Society of Anesthesiologists (ASA) Physical Status 
Class 3, as determined by the Investigator [6].
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). 
5. Have a planned surgical procedure that would allow objective neuromuscular 
monitoring techniques to be applied with access to the arm for neuromuscular 
transmission monitoring (NMTM).
6. 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). 
 
 
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7. 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.
8. 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 an actual body weight < 100 kg.
2. Has a pacemaker or automatic implantable cardioverter-defibrillator (AICD) that 
precludes the assessment of bradycardia or arrhythmias. 
3. Has
a medical condition or surgical procedure that precludes reversal of 
neuromuscular block at the end of surgery.
4. Has neuromuscular disorder(s) that may affect neuromuscular block and/or trial 
assessments.
 
 
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5. 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[yr]) x weight (kg)
        serum creatinine (mg/dL) x72
For Females:   Creatinine Clearance  =   0.85 x (140-age[yr]) x weight (kg)
          
serum creatinine (mg/dL) x72
6. Has or is suspected of having a personal history or family history (parents, 
grandparents, or siblings) of malignant hyperthermia.
7. 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.
8. Has received or is planned to receive toremifene within 24 hours before or within 24 
hours after study medication administration.
9. Has any condition that would contraindicate the administration of study medication.
10. Is pregnant, is attempting to become pregnant, or is lactating.
11. 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.
12. Is currently participating in or has participated in an interventional clinical trial with 
an investigational compound (including any other current or ongoing trial with a 
sugammadex treatment arm) or device within 30 days of signing the informed consent 
form of this current trial.
13. 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 treatment(s) to be used in this trial are outlined below in Table 1.
Table 1
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Treatment 
Period
Use
Sugammadex
2 mg/kg ABW
Single dose
IV
Peri-anesthetic 
period
Experimental
Sugammadex
2 mg/kg IBW
Single dose
IV
Peri-anesthetic 
period
Experimental
Sugammadex
4 mg/kg ABW
Single dose
IV
Peri-anesthetic 
period
Experimental
Sugammadex
4 mg/kg IBW
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.
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. Specific calculations or evaluations required to be performed in 
order to administer the proper dose to each subject are outlined in the Study Operations 
Manual (or equivalent).
Sugammadex will be given at 2mg/kg for moderate block or 4mg/kg for deep block based on 
randomly assigned level of block. Additionally, sugammadex will be dosed by ABW or 
 
 
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IBW, according to randomly assigned treatment group.
IBW will be calculated by IVRS 
based on the formula by Kammerer et al, 2015: Males: 142 lb +3 lb/in over 63 inches +1 
lb/in over 71 inches. Females: 119 lb +3 lb/in. over 60 inches [1]. Height will be rounded to 
the nearest whole integer before applying the Kammerer formula.
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 
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 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 2 minutes of detection of reappearance of T2
with a lower limit of train of four (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 2 minutes of detection of a target of 1-2 PTC with a range of 
1-5 PTC and a TOF count of 0.
Trial Blinding 
5.2.3
Study Medication Blinding
Sponsor study team personnel will be blinded to study medication assignments for 
randomized subjects, with the exception of designated Sponsor personnel (e.g., unblinded 
Clinical Research Associates [CRAs], the pharmacokineticist, statistician(s) not associated 
with the study who will complete the PK IA and provide the data to the siDMC, and other 
designated individuals as required).
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 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. 
 
 
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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, but will not 
know if sugammadex dosing is based on ABW or IBW. Regardless of level of block, study 
personnel in the OR will be blinded to the dose assignment.
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 

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
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 given subject, will be responsible for completing the 
causality assessment for all adverse events.
o
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, and TOF-Watch SX® traces).

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.
PK-only Interim Analysis Blinding
An IA of PK data will be conducted to inform the need for study of the 16 mg/kg dose after 
the completion of approximately 64 subjects treated with sugammadex. The IA will be 
performed by an unblinded pharmacokineticist and unblinded statistician separate from the 
sugammadex study team.  Only the unblinded pharmacokineticist and statistician will have 
 
 
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access to the interim dataset and the individual results. No unblinding of safety or efficacy 
will occur in support of this PK-only IA.
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 or Treatment Allocation
5.3
Randomization will occur centrally using IVRS. Within each NMBA stratum (rocuronium 
or vecuronium), subjects will be randomized to one of 5 treatment groups as indicated in the 
Trial Diagram (Figure 1 in Section 2.2). 
Subjects will be assigned randomly on Day 1 in a 1:1:1:1:1 ratio:
1. Moderate block and reversal with sugammadex 2 mg/kg, dosed by ABW
2. Moderate block and reversal with sugammadex 2 mg/kg, dosed by IBW
3. Moderate block and reversal with neostigmine 50µg/kg + glycopyrrolate 10 µg/kg by 
ABW
4. Deep block and reversal with sugammadex 4 mg/kg, dosed by ABW
5. Deep block and reversal with sugammadex 4 mg/kg, dosed by IBW
Stratification
5.4
Treatment allocation/randomization will be stratified according to the following factors:

NMBA (rocuronium or vecuronium)
Subjects will be stratified by NMBA by an IVRS System to facilitate enrollment of the target
number of randomized subjects into each stratum (approximately 30% of the overall planned 
sample size will be enrolled in the vecuronium stratum).
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.
 
 
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*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.
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 Visita
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, Days:
-21 to Day 1 
±0 days
See footnote “c”
+2 days
Visit 1 and Visit 2 may occur on the 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
Xa
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 Visita
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, Days:
-21 to Day 1 
±0 days
See footnote “c”
+2 days
Visit 1 and Visit 2 may occur on the 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
Xa
X
Adverse Device Events
X
Laboratory Procedures/Assessments
Hematologyi
X
X
Chemistryi
X
X
Blood Samples for Pharmacokinetics
Xj
Xj
Pregnancy Test k
X
Xk
Blood (DNA) for Future Biomedical Researchl
X
 
 
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Trial Period:
Screening
Treatment
Follow-up
Visit Number/Title:
1
Screening
2
Peri-anesthetic Visit
3 
Post-anesthetic Visita
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, Days:
-21 to Day 1 
±0 days
See footnote “c”
+2 days
Visit 1 and Visit 2 may occur on the 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 completed by the Blinded Safety Assessor (BSA) at V3. For any given individual subject, the anesthesiologist performing 
study related procedures during the surgery and the BSA must be 2 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 The 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 from  5 minutes before, during, and for at least 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, 30, 45, and 60 minutes after study medication 
administration. 
h Neuromuscular monitoring using TOF-Watch SX®: Until recovery of TOF to ≥ 0.9.
i Laboratory samples will be sent to a central laboratory for analysis. Baseline safety labs should be obtained from the same port and at the time of the first PK draw. Post-op 
safety labs should be obtained at the time of the 4-6 hour PK draw.
j PK: Sample drawn before NMBA administration, and at 2, 5, 15, 60, and 120 minutes, 4-6 hours and 10-12 hours after administration of study medication reversal agent. Note 
that the 10-12 hour PK draw may not be feasible depending on length of hospital stay; however, if the subject remains hospitalized then all attempts should be made to obtain the 
10-12 hour sample time points.
k 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 test 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.
l 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 surgical 
procedure and medical indication for surgery should be recorded in the Sponsor 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. 
IBW will be calculated by IVRS based on the formula by Kammerer et al, 2015: Males: 142 
lb +3 lb/in over 63 inches +1 lb/in over 71 inches.  Females: 119 lb +3 lb/in. over 60 inches 
[1].
Body Mass Index
7.1.2.3
Body mass index will be calculated at Visit 1 and Visit 2 (only once if V1 and V2 are 
conducted on the same day) to ensure that 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, clinical 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 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, 45, and 60 
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 as noted in the IVRS
confirmation.
Neuromuscular Monitoring 
7.1.2.7
Details for NMTM training and site personnel qualification, set-up, calibration, data 
collection, etc. are provided in the Neuromuscular Transmission Monitoring Guidelines
provided separately.  Neuromuscular monitoring will be performed using a TOF-Watch SX®, 
which will be provided to participating sites with all required accessories and components. 
After induction of anesthesia, neuromuscular monitoring will start before the administration 
of NMBA. Neuromuscular monitoring should remain ongoing until the subject reaches the 
endpoint of TOF ≥0.9, or for at least 30 minutes following administration of study drug. In 
instances where a return to TOF ≥0.9 fails to occur within 30 minutes, a decision to 
discontinue TOF monitoring and extubate the subject on clinical grounds is to be based on 
investigator judgment taking into account subject’s medical requirements.
In the event that TOF-Watch SX® data become unavailable due to device malfunction, follow 
the general guidance:

If prior to Study Medication administration the TOF-Watch SX® data become 
unavailable due to device malfunction, then the investigator should discontinue the 
study subject from the protocol and proceed per usual care.

If after Study Medication administration the TOF-Watch SX® data become 
unavailable due to device malfunction, the study subject should continue in the study, 
but the investigator should discontinue TOF-Watch SX® monitoring and use clinical 
judgment to determine when it is appropriate to extubate the subject. All other study 
procedures should be completed through Visit 4 (Follow-up Safety Contact).
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 postoperative 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.
 
 
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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 this is 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.
Pharmacokinetic Evaluations
7.1.3.3
Pharmacokinetic samples will be drawn at the following time points: 

Prior to administration of NMBA

At 2, 5, 15, 60, and 120 minutes following administration of sugammadex or 
neostigmine

At 4-6 hours following administration of sugammadex or neostigmine 

At 10-12 hours following administration of sugammadex or neostigmine*
*Note that depending on length of hospital stay, the 10-12 hour samples may not be 
drawn; however, if the subject remains hospitalized then all attempts should be made 
to obtain the 10-12 hour sample. For all subjects, blood samples for PK are to be 
drawn in the same arm, distal and upstream from where the study medication 
(sugammadex or neostigmine) is administered or in another location to ensure the 
study medication has passed through the heart and arteries before reaching the sample 
vein.
7.1.3.3.1 Blood Collection for Plasma MK-8616
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual. 
Future Biomedical Research Samples
7.1.3.4
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research
 
 
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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.
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.
 
 
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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.
Screening (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. 
 
 
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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 followed 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 (i.e., 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.
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
 
 
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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 1day 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.
6. A second IV with flush will be inserted distally and upstream in the same arm or from 
another location to allow collection of blood samples for safety and PK analyses at 
predefined time points.
Administration of anesthesia: 
7. Anesthesia will be induced and maintained according to the need of the subject. Note:  
All drugs, date of administration, and actual doses given to the subject will need to be 
recorded throughout the Peri-anesthetic visit and transferred to Sponsor database as 
required.
TOF-Watch SX® set-up, and before administration of the NMBA:
8. The TOF-Watch SX® accessories (transducers and electrodes) and/or device can be 
affixed prior to administration of anesthesia or after induction of anesthesia but prior to 
administration of NMBA.
9. Affix the TOF-Watch SX® and accessories (transducers and electrodes) according to the 
Neuromuscular Transmission Monitoring Guidelines (provided separately) to the arm 
contralateral to the arm used for study medication administration or blood draws. Check 
the equipment, stabilize, and calibrate. In the event that TOF-Watch SX® data become 
unavailable due to device malfunction follow the general guidance provided in Section 
7.1.2.7 Neuromuscular Monitoring.
10. Vital signs (per protocol) will be recorded
11. A baseline blood sample for safety and PK analysis will be obtained and sent to the 
central lab vendor.
12. A blood sample will be collected for future biomedical research (if consent obtained).
 
 
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Neuromuscular monitoring: 
13. Neuromuscular monitoring will start before the administration of NMBA and recording 
will continue until the end of anesthesia. The laptop time (that is recorded in the TOF-
Watch SX® files) will be recorded for accounting with all trial-related assessments, such 
as administration of trial medication and blood sampling.  
Administration of NMBA until administration of study medication:
14. 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.
15. Additional doses of NMBA will be administered as clinically required for the duration of 
the surgery to maintain depth of block, as determined by the Primary Investigator or 
designee.  Fluctuations in depth of block are expected as matter of course to 
accommodate of the needs of surgical procedures, however additional doses of NMBA
should be administered as clinically necessary for the duration of the surgery for target 
maintenance of the assigned depth of block.
16. Monitor the subject with the TOF-Watch SX® and record all activities (e.g., 
administration of additional medications, time of blood samples) on the laptop during the 
entire duration of the surgery. 
17. Vital signs (per protocol) will be recorded.
18. Monitor and 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:
19. For subjects randomized to moderate block: after last dose of administered NMBA and 
within 2 minutes of reappearance of T2, study medication (sugammadex or neostigmine) 
will be administered.
20. For subjects randomized to deep block: after last dose of administered NMBA and within 
2 minutes of detection of a target of 1-2 PTC with a range of 1-5 PTC and TOF Count of 
0, study medication (sugammadex) will be administered.  
21. 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. 
22. Continuous ECG monitoring: at least 5 minutes before, during, and for 30 minutes after 
administration of study medication.
 
 
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23. The following additional study procedures should be done on the following schedule:
Time After 
Study 
Medication
2 
min
5 min
10 
min
15 
min
30 
min
45 min
60 
min
120 
min
4-6 hr
10-12 hr
Vital Signs
X
X
X
X
X
X
Blood 
Samples for 
PK analysis
X
X
X
X
X
X
X
Blood 
Samples for 
Safety Labs
X
24. Continue neuromuscular monitoring until the recovery of the TOF ratio ≥ 0.9; if TOF 
>=0.9 not reached, then monitoring should continue a minimum of 30 minutes after the 
administration of study medication. 
This enables the observation of recurrence of 
residual block should this occur.
25. 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 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: The drug preparation records, depth of 
neuromuscular block, study medication given, and TOF-Watch SX® traces.
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.
 
 
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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 
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).
 
 
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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 ≥2X 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 event 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).
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.
 
 
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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 
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.
 
 
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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.
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).
 
 
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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).
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. [5].
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 and Patient/Device Events 
7.2.5
and Incidents
All Adverse Events and Patient/Device Events and Incidents 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
Data Monitoring Committee
7.3.1
A standing internal Data Monitoring Committee (siDMC) consisting of Internal Sponsor 
personnel, unblinded to treatment groups for the purposes of reviewing analyses, will be 
responsible for reviewing the results of the PK-only interim analysis. 
The siDMC will review the results of the planned IA and make recommendations regarding
the need to study the 16 mg/kg dose of sugammadex. The siDMC will not be provided any 
safety or efficacy data and will operate independently of the external Clinical Adjudication 
and Neuromuscular Monitoring Adjudication Committees.
Clinical Adjudication Committee
7.3.2
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.
Neuromuscular Monitoring Adjudication Committee
7.3.2.1
An independent vendor will review all TOF traces to assess overall data quality and 
acceptability of investigative site TOF-operator’s interpretation of the efficacy variables and 
adherence to NMTM guidelines. In instances where resolution between the vendor and site 
personnel regarding the interpretation of trace output is needed, traces or data points will be 
reviewed by members of an independent Neuromuscular Monitoring Adjudication 
Committee (NMAC).
The NMAC will assess trace data objectively, independently, and without knowledge of 
subject treatment or condition, and either confirm the acceptability of investigative site TOF-
operator’s interpretation or provide a separate interpretation to be used as part of the efficacy 
analysis.
 
 
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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.
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 
efficacy and safety of sugammadex
when used
to reverse 
neuromuscular blockade induced by either rocuronium or vecuronium 
in morbidly obese subjects.
Treatment Assignment
Subjects will be stratified by NMBA and randomized to depth of 
NMB (moderate or deep) and reversal agent in a 1:1:1:1:1 ratio as 
follows:
1. Moderate block and reversal with sugammadex 2 mg/kg, based on 
ABW
2. Moderate block and reversal with sugammadex 2 mg/kg, based on 
IBW
3. Moderate block and reversal with neostigmine(0.05 mg/kg up to 5 
mg) + glycopyrrolate (10 µg/kg up to 1 mg maximum dose) based 
on ABW
4. Deep block and reversal with sugammadex 4 mg/kg, based on 
ABW
5. Deep block and reversal with sugammadex 4 mg/kg, based on 
IBW
Analysis Populations
Efficacy: All Subjects Treated (AST)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
The time to recovery to a TOF ratio of ≥0.9 for a comparison of ABW 
and IBW dosing of sugammadex pooled across depth of block and 
NMBA
Key Secondary Endpoint(s)
Distribution of time to recovery to a TOF ratio of ≥0.7, ≥0.8 and ≥0.9
as well as the proportions of subjects with prolonged recovery (>10 
minutes) pooled across depth of block and NMBA.
Statistical Methods for Key 
Efficacy Analyses
The primary hypothesis will evaluate the efficacy of sugammadex 
when dosed according to ABW as compared with IBW on time to 
recovery to a TOF ratio of ≥0.9 using a stratified log-rank test
(adjusted for the depth of block and NMBA). Event rates over time 
will be estimated within each treatment group using the Kaplan-Meier 
method. 
 
 
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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 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
A pharmacokinetic (PK) only IA will be conducted in this study when 
approximately 64 evaluable subjects treated with sugammadex
(approximately 16 subjects per treatment dose [2 mg/kg and 4 mg/kg] 
and weight-based dosing [ABW and IBW] categories) have been 
enrolled, in order to examine the PK profile of sugammadex in the 
setting of morbid obesity. No unblinding of safety or efficacy will 
occur in support of this PK-only IA. 
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power 
The total planned sample size is approximately 200 subjects. If 
subjects are equally allocated in each NMBA strata, there would be 
~100 subjects per NMBA with ~20 subjects in each of the 5 treatment 
arms. However, if approximately 30% of the total subjects (i.e., 60 
subjects) are enrolled in the vecuronium stratum, there would be ~12 
subjects in each of the 5 treatment groups in the vecuronium stratum.
Assuming the difference of median time-to-recovery in ABW and 
IBW groups is one minute based on the simulated data, a sample size 
of N ~80 per group (across both NMBA and depth of block) provides 
estimated power of > 99% to detect a shift in time-to-recovery.
Responsibility for Analyses/In-House Blinding
8.2
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
Sponsor study team personnel will be blinded to study medication assignments for 
randomized subjects, with the exception of designated Sponsor personnel (e.g., unblinded 
Clinical Research Associates [CRAs], the pharmacokineticist, statistician(s) not associated 
with the study who will complete the PK IA and provide the data to the siDMC, and other 
designated individuals as required).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
8.3
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
8.4
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected 
endpoints.
 
 
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Efficacy Endpoints
8.4.1
The primary efficacy endpoint is the time to recovery to a TOF ratio of ≥0.9 for a comparison 
of ABW and IBW based dosing of sugammadex. See Section 4.2.3.1 for more details.
Secondary efficacy endpoints are:

Summary statistics for the recovery times to TOFs of ≥0.7, ≥0.8 and ≥0.9 for ABW 
and IBW dosing groups pooled across both the depth of block and NMBA

The proportions of subjects with prolonged recovery (>10 minutes) for ABW and 
IBW dosing groups pooled across both the depth of block and NMBA
Exploratory efficacy endpoints are:

Summary statistics for the recovery times for sugammadex and neostigmine in the 
setting of moderate block pooled across NMBA

Summary statistics for the recovery times to TOFs of ≥0.7, ≥0.8 and ≥0.9 for ABW 
and IBW dosing groups separately by the depth of block and by NMBA

The proportions of subjects with prolonged recovery (>10 minutes) for ABW and 
IBW dosing groups by the depth of block and by NMBA.
Safety Endpoints
8.4.2
Safety endpoints that will be evaluated in each dosing group are listed below. For safety 
analyses other than the primary safety endpoint (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.
The primary 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 also increased 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 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.
 
 
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The baseline heart rate for the primary safety endpoints will be recorded approximately five 
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. In addition to the primary 
safety endpoints, 
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.
Pharmacokinetic Endpoints
8.4.3
The pharmacokinetics of sugammadex will be evaluated in obese patients when dosed 
according to ABW and IBW. 
Actual elapsed plasma sampling times relative to the time of dose will be used to estimate the 
pharmacokinetic 
parameters 
for 
each 
treatment 
in 
each 
subject. 
Sugammadex 
pharmacokinetic parameters will be calculated using noncompartmental methods.  The 
apparent terminal rate constant (λ) will be estimated by regression of the terminal log-linear 
portion of the plasma concentration time profile; apparent terminal t½ will calculated as the 
quotient of ln(2) and λ. AUC to the last time point with a quantifiable plasma concentration 
(AUC0-last) will be calculated using the linear trapezoidal method for ascending 
concentrations and the log trapezoidal method for descending concentrations up to the last 
quantifiable plasma concentration.  Total exposure (AUC0-inf) will be estimated as the sum 
of AUC0-last and the extrapolated area given by the quotient of the last quantifiable 
concentration and λ.  The maximum observed concentration (Cmax) will be obtained by 
inspection of the plasma concentration data.  Mean residence time (MRT) of sugammadex in 
the systemic circulation following IV administration will be estimated. Total clearance 
(CL=Dose/ AUC0-inf) and volume of distribution (Vd), defined as volume of distribution 
estimated at steady-state following a single IV dose administration (Vss=MRT x CL) and Vd 
during the terminal elimination phase (i.e. Dose/(AUC0-inf x λz) will be calculated.
No 
value for AUC0-∞, CL, λz, t1/2, Vz, MRT, Vss will be reported for concentration-time 
profiles where the terminal linear phase is not clearly defined.
 
 
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Additional pharmacokinetic analyses may be conducted if deemed appropriate.
Derivations of Efficacy /Pharmacokinetics Endpoints
8.4.4
For imputation of missing times from the start of administration of sugammadex or 
neostigmine to recovery of the TOF ratio to 0.7, 0.8 and 0.9, a worst case scenario for 
sugammadex and a best case scenario for neostigmine will be applied, consistent with the 
approach used in the adult program. For each of the two NMBAs, separately, the following 
procedure will be used:
If the time from the start of administration of study drug to recovery of the TOF ratio to 0.9 is 
missing, there are three cases of particular importance for imputation purposes: 
1. Time to TOF ratio to 0.8 is available: 

Sugammadex group: first, for all subjects randomized to receive sugammadex and 
with times to recovery of the TOF ratio to 0.8 and 0.9 available, the difference 
between these two recovery times will be calculated. Next, the 95th percentile 
(P95) of these differences will be added to the time to recovery of the TOF ratio 
to 0.8 of the subjects with missing times to recovery of the TOF ratio to 0.9. This 
will be used as the imputed missing time to recovery of the TOF ratio to 0.9.

Neostigmine group: same as for the sugammadex group but now only subjects 
randomized to receive neostigmine will be used, and the 5th percentile (P5) of the 
differences in time to recovery of the TOF ratio to 0.8 and 0.9 will be calculated.
2. Time to TOF ratio to 0.7 is available, but the time to TOF ratio to 0.8 is missing: 

Sugammadex group: first for all subjects randomized to sugammadex and with 
times to recovery of the TOF ratio to 0.7 and 0.9 available, the difference in time 
between these two recovery times will be calculated.
Next, the P95 of these 
differences will be added to the time to recovery of the TOF ratio to 0.7.
This 
will be used as imputation of the missing time to recovery of the TOF ratio to 0.9.

Neostigmine group: same as for sugammadex group but now only subjects 
randomized to receive neostigmine will be used and the P5 of the differences in 
time to recovery of the TOF ratio to 0.7 and 0.9 will be calculated. 
3. Times to TOF ratio to 0.7 and to 0.8 are both missing:

Sugammadex group: the P95 of the time to recovery in all subjects randomized to 
sugammadex with an observed recovery time of the TOF ratio to 0.9 will be 
imputed.

Neostigmine group: the P5 of the time to recovery in all subjects randomized to 
neostigmine with an observed recovery time of the TOF ratio to 0.9 will be 
imputed. 
A corresponding procedure will be followed for imputation of missing times from the start of 
administration of study drug to recovery of the TOF ratio to 0.8 (secondary efficacy 
variable). For imputation of missing times, P95 (sugammadex) or P5 (neostigmine) of the 
differences in time between recovery of the TOF ratio to 0.7 and 0.8 will be used.
 
 
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For imputation of missing times from the start of administration of study drug to recovery of 
the TOF ratio to 0.7 (secondary efficacy variable), the P95 observed time for the subjects 
randomized to the sugammadex group will be imputed. For subjects randomized to the 
neostigmine group the P5 observed time will be imputed. Imputation of missing times of the 
primary and secondary efficacy variables, however, should always result in a non-descending 
sequence of times to recovery of the TOF ratios to 0.7, 0.8, and 0.9.
Analysis Populations  
8.5
Efficacy Analysis Population
8.5.1
The All Subjects Treated (AST) population will serve as the primary population for the 
analysis of efficacy data in this study.  The AST population consists of all randomized
subjects who:

are dosed with both an NMBA and reversal agent (study treatment),

have at least one post-randomization efficacy assessment. 
Subjects will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using the AST population.  Details on the approach to handling 
missing data are provided in Section 8.6.1 Statistical Methods.
Safety Analysis Population
8.5.2
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.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.6.2 Statistical Methods.
Pharmacokinetic Population
8.5.3
Subjects with evaluable sugammadex concentrations at approximately 2, 5, 15, 60 min and 4-
6 hr post-dose will be included for pharmacokinetic analysis.
 
 
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Statistical Methods
8.6
Statistical testing and inference for efficacy and safety analyses are described in 8.6.1 and 
8.6.2 respectively.  Efficacy results that will be deemed to be statistically significant after 
consideration of the Type I error control strategy are described in Section 8.8, Multiplicity. 
Nominal p-values will be computed for other efficacy analyses, but should be interpreted 
with caution, due to potential issues of multiplicity, sample size, etc.  Unless otherwise 
stated, all statistical tests will be conducted at the α=0.05 (2-sided) level.
Statistical Methods for Efficacy Analyses
8.6.1
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the supplemental 
SAP.
All efficacy analyses will be based on the All Subjects Treated population.
The primary efficacy endpoint is the time to recovery, defined as a TOF ratio (i.e. T4/T1
ratio) ≥0.9 after sugammadex administration. The primary efficacy analysis is the stratified 
log-rank test adjusted for the depth of block and NMBA. Formal tests for efficacy, in 
comparison of sugammadex dosed according to ABW versus IBW, will be conducted across 
NMBA.
Secondary efficacy endpoints are summaries of time to recovery, including cumulative 
distribution plots, boxplots, and summary statistics (mean, standard deviation, median, 
geometric mean and its 95% CI) will be provided, as well as the proportions of subjects with 
prolonged time to recovery (>10 minutes) by treatment groups (pooled and separately by 
depth of block and by NMBA).
In addition, the 95% confidence intervals for pairwise 
differences will be provided for time to recovery and proportions (both overall and separately 
by depth of block and by NMBA).
Table 5 summarizes the key efficacy analyses.
 
 
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Table 5
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method‡
Analysis 
Population
Missing Data 
Approach
Primary Endpoint/Hypothesis
Time to recovery to a TOF ratio ≥ 
0.9 for ABW and IBW dosing 
groups pooled across depth of 
block and NMBA
P
Stratified Log-rank test
AST
Censored
Secondary Endpoints
Distribution of time to recovery of 
TOFs of ≥0.7, ≥0.8 and ≥0.9
S
Descriptive statistics
(cumulative 
distribution plots, 
boxplots, mean, 
standard deviation, 
median,  geometric 
mean and its 95% CI)
AST
Explicit
Imputation
Distribution of time to recovery of 
TOFs of ≥0.7, ≥0.8 and ≥0.9 for 
ABW and IBW dosing groups, 
pooled across depth of block and 
NMBA
S
Pairwise difference in 
geometric mean and 
95% CI
AST
Explicit 
Imputation
Proportion of subjects with 
prolonged time to recovery (> 10 
minutes) for ABW and IBW 
dosing groups, pooled across 
depth of block and NMBA
S
Pairwise difference in 
proportion and 95% CI 
using the stratified 
Miettinen and 
Nurminen method
AST
Explicit 
Imputation
Distribution of time to recovery of 
TOFs of ≥0.7, ≥0.8 and ≥0.9 for 
ABW and IBW dosing groups, 
separately by depth of block and
by NMBA
S
Pairwise difference in 
geometric mean and 
95% CI
AST
Explicit 
Imputation
Proportion of subjects with 
prolonged time to recovery (> 10 
minutes) for ABW and IBW 
dosing groups, separately by 
depth of block and by NMBA
S
Pairwise difference in 
proportion and 95% CI 
using the stratified 
Miettinen and 
Nurminen method
AST
Explicit
Imputation
† P=Primary approach; S=Supportive approach.
Imputation approach described in Section 8.4.4.
‡ Statistical models are described in Section 8.6.1.
Statistical Methods for Safety Analyses
8.6.2
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 6).  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 
 
 
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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.
The incidence of safety parameters will be summarized by treatment group and preferred 
term across all 5 dosing groups. Between-group comparisons will be made for each ABW 
and IBW dosing group of sugammadex and neostigmine pooled across NMBA, as well as 
separately by NMBA. The primary safety endpoints, as well as other supportive 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 [7]. 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 [8] with 
NMBA as a stratification factor.
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 AEs and predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% CI 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% CIs may be provided without adjustment for 
multiplicity, the CIs 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 AE 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 6 summarizes the safety tier and level of analysis for the safety endpoints.
 
 
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Table 6
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
X
X
Adjudicated anaphylaxis
X
X
Clinically relevant sinus bradycardia
X
X
Clinically relevant sinus tachycardia
Other clinically relevant cardiac arrhythmia
X
X
X
X
Any AE
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.
Statistical Methods for Pharmacokinetic Analysis
8.6.3
For the following analysis all the subjects that have evaluable sugammadex concentrations 
will be included. 
Individual dose normalized (dn) AUC0-inf and dnCmax values for each of the sugammadex
treatments (4mg/kg, 2mg/kg) will be natural log-transformed and evaluated with a linear 
fixed effect model having fixed terms for treatment and mode (IBW, ABW) and an 
interaction term for mode x treatment. Kenward and Roger's method will be used to calculate 
the denominator degrees of freedom for the fixed effects.  Both interaction term (mode x 
treatment) and mode will be tested for statistical significance at alpha=0.05 for each of the 
pharmacokinetic parameters.  If either one or both of these terms for any or both of the
pharmacokinetic parameters (dnAUC0-inf and dnCmax) are statistically significant, then 
appropriate contrasts will be used to construct 90% confidence intervals (CIs) for the 
difference in least-squares (LS) means on the log scale for dnAUC0-inf and dnCmax for each 
of the modes of administration. These CIs will then be exponentiated to obtain a 90% CIs for 
the true dnAUC0-inf geometric mean ratio, GMR (4mg/kg versus 2mg/kg) and true dnCmax 
GMR (4mg/kg versus 2mg/kg) for each of the modes of administration. 
 
 
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If both interaction (mode x treatment) and mode terms of the model for both dnAUC0-  and 
dnCmax are not statistically significant at alpha=0.05, then the data for both modes of 
administration will be pooled and the final model will include treatment as fixed effect. 
Ninety percent (90%) CIs for the true dnAUC0-inf GMR (4mg/kg versus 2mg/kg) and true 
dnCmax GMR (4mg/kg versus 2mg/kg) will be obtained from the model.  For each mode of 
administration LS means and corresponding 95% CI obtained from the model will also be 
reported for dnAUC0-inf and dnCmax by treatment. 
Additionally, individual CL and Vd will be natural log-transformed and analyzed separately
using linear effects model as previously described. For each mode of administration, LS 
means and corresponding 95% CIs for CL and Vd will be provided for each treatment.
For each mode of administration, individual values will be listed for each PK parameter 
(AUC0-inf, AUC0-last, Cmax, dnAUC0-inf, dnCmax, CL, Vss, Vd, MRT, and t1/2) by 
treatment and the following (non-model-based) descriptive statistics will be provided: N 
(number of subjects with non-missing data), arithmetic mean, standard deviation, arithmetic  
percent CV (calculated as 100 x standard deviation/arithmetic mean), median, minimum, 
maximum, geometric mean, and geometric percent CV (calculated as 100 x sqrt( exp(s2) - 1), 
where s2 is the observed variance on the natural log-scale).
Mean (standard error) and median (interquartile range) concentration-time plots for each 
treatment and mode of administration will be provided.  Additionally for each mode of 
administration, individual ratios overlaid with GMR and corresponding 90% CI for each 
treatment for dnAUC0-inf and dnCmax will be provided. Plots of dnAUC0-inf versus ABW, 
dnAUC0-inf versus IBW, dnCmax versus ABW ABW, dnCmax versus IBW will also be 
provided.  
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.4
Demographic and Baseline Characteristics
8.6.4.1
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.
Population PK Analyses
8.6.4.2
Population-based methods of analysis may be explored at the completion of the study to 
further characterize the PK profiles within morbidly obese subjects and/or permit 
comparisons to historical data.  
 
 
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Interim Analyses
8.7
An interim pharmacokineticist and an interim statistician separate from the sugammadex
development team, both of whom will be unblinded during the IA, will perform the IA. Only 
the available data from the subjects (approximately 64 subjects total treated with 
sugammadex [~16 per combination of dose (2mg/kg, 4mg/kg) and weight-based dosing 
([ABW, IBW)], Table 7) for whom evaluable sugammadex PK samples are available will be 
included in the IA. 
Table 7
Sample Size for Interim Analysis
Approximate Number of Subjects that will Trigger Interim Analysis
2 mg/kg (ABW)
4 mg/kg (ABW)
2 mg/kg (IBW)
4 mg/kg (IBW)
16
16
16
16
The IA of the pharmacokinetic parameters will be performed as previously described in 
section 8.6.3.  In addition to the model-based analysis, the interim unblinded statistician will 
also provide descriptive statistics for the pharmacokinetic parameters as previously specified 
in 8.6.3. No individual listings for the PK parameters will be provided from the IA for 
decision making
The siDMC will review the results of the planned IA to make recommendations regarding the 
need to study the 16 mg/kg sugammadex dose. The decision about a 16 mg/kg dose will be 
based upon the evaluation of the 90% confidence intervals of the geometric mean ratio for 
both the Area Under the Curve0-inf (AUC0-inf) and Maximum Concentration (Cmax) form 
the IBW and ABW data.
Multiplicity
8.8
In this study, the primary hypothesis is a single comparison of sugammadex dosed with 
ABW and IBW using one endpoint in the primary hypothesis; therefore, no corrections of 
multiplicity are required. Sample Size and Power Calculations.
Sample Size and Power
8.9
Sample Size and Power for Efficacy Analyses
8.9.1
This study will enroll approximately 200 subjects in total. If subjects are equally enrolled in
each NMBA strata, there would be ~20 subjects in each of the five treatment groups within 
NMBA. However, due to enrollment kinetics, an effort will be made to enroll approximately 
30% of vecuronium-treated subjects. Therefore, ~12 subjects will be randomized to each of 
the 5 treatment groups in the vecuronium stratum. The primary approach to the assessment 
of sample size is via simulation using the primary efficacy model to compare time to 
recovery for sugammadex dosed to ABW versus IBW. Time–to-recovery data are simulated 
using distributional assumptions derived from dose-ranging efficacy data within the 
sugammadex clinical program, assuming that dosing according to IBW would result in 
weight-based dosing approximately half of that from dosing according to ABW for either 
depth of block. In addition, the general conclusion in phase 2 studies shows that patients 
 
 
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administered 1 mg/kg in moderate block and 2 mg/kg in deep block would have time to 
recovery increased by roughly 1 minute comparing to 2 mg/kg and 4 mg/kg, respectively.
Based on that assumption, subjects in the ABW group have a median time-to-recovery of 
~2.2 minutes with a standard deviation of ~1.3, while subjects in the IBW have median time 
to recovery of ~3.3 minutes with a standard deviation of ~2.3. Figure 2 illustrates data 
simulated from the above assumption. 
Figure 2
Illustrative scenario of Time-to-Recovery to TOF ratio of 0.9 for ABW vs. IBW 
under the assumption of median time-to-recovery of 2.2 minutes in ABW group and of 3.3 
minutes in IBW group.
The power calculation is based on a log-rank test, with an alpha level of 0.05 based on 1000 
simulated samples and a function of sample size per group expected to be included in the 
analysis, and is carried out using [SAS v9.3].
Simulated power levels for the primary 
comparison as a function of sample size are shown in Table 8.
Table 8
Simulated power levels for the primary comparison and related subgroup analyses
as a function of sample size
N/arm
15
30
40
50
60
70
80
Power
51%
81%
89%
95%
98%
99%
>99%
 
 
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Assuming the difference of median time-to-recovery in ABW and IBW groups is one minute 
based on the simulated data, a sample size of N~80 per group (across both NMBA and depth 
of block) provides estimated power of > 99% to detect a shift in time-to-recovery, as well as 
sufficient subject exposure to characterize safety and tolerability profiles of the distinct 
dosing paradigms. Although this study is well-powered for an efficacy comparison of 
sugammadex ABW and IBW, the subgroup analyses by NMBA and depth of block are likely 
underpowered, given the range of simulated power levels in Table 8.
Sample Size for Safety Analyses
8.9.2
The probability of observing at least one event of any treatment emergent arrhythmia in this 
study depends on the number of subjects treated and the underlying percentage of subjects 
with an AE in the study population.  If no events are observed among the 20 subjects in a 
treatment group, an upper bound of 95% CI for subjects with any treatment emergent 
arrhythmia is ~16.8% (1 in every 6 subjects) in a treatment group. If no events are observed 
in an arm with 12 subjects, an upper bound of the 95% CI would change to ~ 26.5%.
The estimate of incidence and the upper bound of the 95% CI for the underlying percentage 
of subjects with any treatment emergent arrhythmia within a treatment group are provided in
Table 9.  These calculations are based on the exact binomial method proposed by Clopper 
and Pearson (1934) [7]. The 95% CIs are provided in Table 10 for the difference in incidence 
in any treatment emergent arrhythmia between the sugammadex and neostigmine groups
although neostigmine is primarily an active control in this study as opposed to an active 
comparator and the main interest in this study is an estimation of the absolute incidence of 
AEs in the sugammadex arms.
Table 9
Estimate of Incidence of Treatment Emergent Sinus Bradycardia/Tachycardia and 
95% Upper Confidence Bound Based on Hypothetical Number of Subjects with Any 
Treatment Emergent Arrhythmia Among 20 Subjects in a Treatment Group
Hypothetical Number of  Subjects
With Any Treatment Emergent 
Arrhythmia
Estimate of 
Incidence
95% Upper Confidence 
Bound†
1
5%
24.9%
2
10%
31.7%
3
15%
37.9%
4
20%
43.7%
5
25%
49.1%
† Based on the two-tailed exact confidence interval of a binomial proportion (Clopper and 
Pearson, 1934) [7].
 
 
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Table 10
Differences in Incidence in Any Treatment Emergent Arrhythmia between the 
Sugammadex and Neostigmine Groups Assuming Two-Sided 5% alpha level with 20 
Subjects in a Treatment Group 
Incidence of Adverse Event
Risk Difference
Sugammadex 
(%)
Neostigmine 
(%)
Percentage 
Points
95% CIa
5%
10%
5
(-26%, 15.2%)
10%
20%
10
(-33.7%, 13.7%
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)).
Precision Estimates for Pharmacokinetic Parameters (AUC0-inf, Cmax)
8.9.3
The precision of the estimated ratios of geometric means (4 mg/kg versus 2 mg/kg) of 
pharmacokinetic parameters obtained from this study can be assessed by calculating the half-
width of the 90% confidence intervals expected for the given sample size and assumed 
variability. The between-subject geometric coefficient of variation (GCV) for sugammadex
AUC0-inf obtained from the population analysis is approximately 23%. Assuming a sample 
size of 16 subjects per treatment and observed pooled between-subject standard deviation of 
0.23 for AUC0-inf on the natural log scale, then the half width of the 90% confidence 
intervals of GMRs for AUC0-inf on the log scale will be 0.138. The lower and upper 90% 
confidence limits for the true GMRs will be given by OBS/1.148 and OBS*1.148 for AUC0-
inf, respectively, where OBS is the observed GMR. Thus, for example, if the observed GMR 
for AUC0-inf was 1.00, then the 90% CIs for the GMR would be 0.87 to 1.15.  These 
calculations also apply to the precision of the estimated geometric mean ratios for Cmax as 
the between-subject GCV for Cmax was assumed to be similar to that of AUC0-inf.
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 
endpoint will be estimated pooled across depth of block and NMBA within each category of 
each subgroup.  The following are classification variables: 

Age category (18-64, 65-74, >74 years)

Sex (female, male)

Race (white, other)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Region (United States, Non-United States)
Subgroup analyses/summaries will only be performed for those classification variables with 
≥10% participants in each subgroup.
 
 
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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 11.
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.
Table 11
Product Descriptions
Product Name & Potency
Dosage Form
Source/Additional Information
Sugammadex 100 mg/ml
Injection
Provided centrally by the Sponsor.
Neostigmine
methylsulfate
0.5 mg/ml
Injection
Provided centrally by the Sponsor.
Glycopyrrolate 0.2 mg/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 sufficient number of vials or ampoules to support treatment. Clinical Supplies will 
be masked by the pharmacist (or delegate) as needed.
 
 
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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.
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.
 
 
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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.
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.
 
 
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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.
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.
 
 
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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 
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.
 
 
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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.  
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.
 
 
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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 
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 
 
 
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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]
Kammerer MR, Porter MM, Beekley AC, Tichansky DS. Ideal Body Weight 
Calculation in the Bariatric Surgical Population. J Gastrointest Surg. 2015 
Oct;19(10):1758-62.
[2]
Ingrande J, Lemmens HJ. Dose adjustment of anaesthetics in the morbidly obese. 
Br J Anaesth. 2010 Dec;105 Suppl 1:i16-23.
[3]
Eriksson LI, Sato M, Severinghaus JW. Effect of a vecuronium-induced partial 
neuromuscular 
block 
on 
hypoxic 
ventilatory 
response. 
Anesthesiology 
1993;78(4):693-9.
[4]
Eriksson LI. The effects of residual neuromuscular blockade and volatile 
anesthetics on the control of ventilation. Anesth Analg 1999;89:243-51.
[5]
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.
[6]
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.
[7]
Clopper CJ, Pearson ES. The use of confidence or Fiducial limits illustrated in the 
case of the binomial. Biometrika 1934;26(4):404-13.
[8]
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 
1985;4:213-26.
 
 
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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 7.1.3.4 –
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
2
2
Serum/Plasma Chemistry
5
5
Serum β-Human Chorionic 
Gonadotropin (β-hCG)a
3.5
PK for sugammadex
24-30
8-16
Blood (DNA) for Future 
Biomedical Research 
8.5
Expected Total (mL)
3.5
39.5 to 45.5
15 to 23
a.
For female subjects 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
ABW
Actual body weight
AE
Adverse Event
ASaT
All Subjects as Treated
AUC0-inf
Area under the concentration-time curve from 0 extrapolated to infinity
AUC0-last
Area under the concentration-time curve from 0 to the time of the last 
quantifiable concentration
BMI
Body mass index
BSA
Blinded Safety Assessor
Cmax
Maximum Observed Concentration
CL
Clearance
CI
Confidence Interval
CSR
Clinical Study Report
ECG
Electrocardiogram
ECI
Event of Clinical Interest
EDC 
Electronic Data Capture
GMR
Geometric Mean Ratio
hCG
Human chorionic gonadotropin
IA
Interim Analysis
IBW
Ideal body weight
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
PK
Pharmacokinetic
 
 
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Term
Definition
PTC
Post-Tetanic Count
siDMC
Standing Internal Data Monitoring Committee
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)
T1/2
Apparent Terminal Elimination Half-Life
TOF
Train-of-Four Stimulation 
Vd
Volume of Distribution
λ
Apparent First Order Terminal Elimination Rate Constant
 
 
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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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SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
NCT03346070 
Document Date: 
20-Feb-2019
A Phase 4 Randomized, Active-Comparator Controlled Trial to 
Study the Efficacy and Safety of Sugammadex (MK-8616) for the 
Reversal of Neuromuscular Blockade Induced by Either 
Rocuronium Bromide or Vecuronium Bromide in Morbidly Obese 
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SUPPLEMENTAL SAP
20 Feb 2019 – AMENDMENT #3
Supplemental Statistical Analysis Plan (sSAP)
 
 
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TABLE OF CONTENTS
1
INTRODUCTION............................................................................................................3
2
SUMMARY OF CHANGES...........................................................................................3
3
ANALYTICAL AND METHODOLOGICAL DETAILS ...........................................4
3.1
Statistical Analysis Plan Summary.......................................................................4
3.2
Responsibility for Analyses/In-House Blinding ..................................................5
3.3
Hypotheses/Estimation ..........................................................................................6
3.4
Analysis Endpoints.................................................................................................6
3.4.1
Efficacy Endpoints.........................................................................................6
3.4.2
Safety Endpoints ............................................................................................6
3.4.3
Pharmacokinetic Endpoints ...........................................................................8
3.4.4
Derivations of Efficacy /Pharmacokinetics Endpoints ..................................8
3.5
Analysis Populations............................................................................................10
3.5.1
Efficacy Analysis Population.......................................................................10
3.5.2
Safety Analysis Population..........................................................................11
3.5.3
All Subjects Treated Population ..................................................................11
3.5.4
Pharmacokinetic Population ........................................................................11
3.6
Statistical Methods...............................................................................................11
3.6.1
Statistical Methods for Efficacy Analyses ...................................................12
3.6.2
Statistical Methods for Safety Analyses ......................................................15
3.6.3
Statistical Methods for Pharmacokinetic Analysis ......................................17
3.6.4
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................18
3.7
Interim Analyses ..................................................................................................18
3.8
Multiplicity ...........................................................................................................19
3.9
Sample Size and Power Calculations .................................................................19
3.9.1
Sample Size and Power for Efficacy Analyses............................................19
3.9.2
Sample Size for Safety Analyses .................................................................21
3.9.3
Precision Estimates for Pharmacokinetic Parameters (AUC0-inf, Cmax) ..22
3.10
Subgroup Analyses and Effect of Baseline Factors ..........................................23
3.11
Compliance (Medication Adherence).................................................................23
3.12
Extent of Exposure...............................................................................................23
3.13
Time Synchronization..........................................................................................23
4
REFERENCES...............................................................................................................25
 
 
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1
INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of 
confirmatory analyses for this trial, this supplemental SAP provides additional statistical 
analysis details/data derivations and documents modifications or additions to the analysis 
plan that are not “principal” in nature and result from information that was not available at 
the time of protocol finalization.     
2
SUMMARY OF CHANGES 
These changes are being made:

Imputations of missing recovery time are clarified to be done by actual body weight
(ABW) and ideal body weight (IBW) for sugammadex group and by pooling NMBA
and depth of block across all participants. Refer to Section 3.4.4 for details.

The All Subject Treated (AST) population in Protocol 8616-146-00 is renamed as
Full Analysis Set (FAS) and remains as the population for efficacy analysis. The AST
population is re-defined for treated subjects, i.e., the only requirement to be included
in the AST population is to receive NMBA and reversal agent (study treatment).
AST is used for reporting baseline characteristics. In addition, the criterion that will
be utilized to identify subjects that were potentially cross treated on the basis of ABW
versus IBW, is added to the safety analysis population. Refer to Section 3.5 for
details.

The stratification stratum used in the analysis is clarified in Section 3.6. All the
analyses will be based on the real stratification stratum that a subject belongs to. The
weighting scheme of the stratified Miettinen and Nurminen method is clarified in
Section 3.6.

More details are added about the assessment of the treatment effect on the endpoint –
time to recovery to TOF ratio (i.e. T4/T1 ratio) ≥0.9 after sugammadex administration.
Refer to Section 3.6.1 for details.

More details are added for calculating the 95% confidence interval (CI) of the
pairwise comparison between two treatment arms in geometric means. Refer to
Section 3.6.1. To note, in the previously published sSAP, the pairwise comparison
between two treatment arms in geometric means, were interpreted as the pairwise
geometric mean difference. However, as the distribution of recovery time (in minutes)
is highly skewed and as the recovery time (in minutes) could be short for both
treatment arms in certain pairwise comparison, e.g. ABW versus IBW, the pairwise
geometric mean ratio of the recovery time between two treatment arms (i.e. the
exponential transformation of the pairwise geometric mean difference in the
logarithmic scale) is deemed by the sponsor as more interpretable or meaningful than
the pairwise geometric mean difference. Therefore, the pairwise geometric mean ratio
 
 
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is implemented in the corresponding key secondary analyses within this sSAP 
version.

One exploratory analysis (i.e. a sensitivity analysis for key secondary analysis) is 
added for conservatively assessing the recovery time of subjects who received 
sugammadex ABW as compared to subjects who received sugammadex IBW. Refer 
to Section 3.6.1 for details.

To provide the comparable overall incidences with the label-based preferred terms of 
adverse events (AEs) used in the prior submission, the summary of the grouped AE 
preferred terms is added to the safety analysis. It is clarified that 95% confidence 
interval by treatment groups using Clopper-Pearson method will be provided to the 
estimates of Tier 1 endpoints and Tier 2 events of clinical interest. Refer to Section 
3.6.2 for details.

Section 3.13 is added for describing how to execute time synchronization in the 
analysis. 

Due to Health Insurance Portability and Accountability Act (HIPPA) regulations, the
trial collects partial birthday (year and month). This could make some participants 
(who are not less than 18 years old) have calculated age < 18 years. To include these 
eligible participants in the analyses, the youngest age group is updated to < 65 years
in this analysis plan and these participants will be discussed in the clinical study 
report. 

Corrections are made to ensure that the sSAP is consistent with the analysis plan in 
Protocol NO. 146-1.
3
ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 3.2-3.12.  
Study Design Overview
A randomized, active comparator-controlled trial evaluating the 
efficacy and safety of sugammadex when used to reverse 
neuromuscular blockade induced by either rocuronium or vecuronium 
in morbidly obese subjects.
Treatment Assignment
Subjects will be stratified by NMBA and randomized to depth of 
NMB (moderate or deep) and reversal agent in a 1:1:1:1:1 ratio as 
follows:
1. Moderate block and reversal with sugammadex 2 mg/kg, based on 
ABW
2. Moderate block and reversal with sugammadex 2 mg/kg, based on 
IBW
3. Moderate block and reversal with neostigmine(0.05 mg/kg up to 5 
mg) + glycopyrrolate (10 µg/kg up to 1 mg maximum dose) based 
on ABW
4. Deep block and reversal with sugammadex 4 mg/kg, based on 
 
 
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ABW
5. Deep block and reversal with sugammadex 4 mg/kg, based on IBW 
Analysis Populations
Efficacy: Full Analysis Set (FAS)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
The time to recovery to a TOF ratio of ≥0.9 for a comparison of ABW 
and IBW dosing of sugammadex pooled across depth of block and 
NMBA
Key Secondary Endpoint(s)
Distribution of time to recovery to a TOF ratio of ≥0.7, ≥0.8 and ≥0.9 
as well as the proportions of subjects with prolonged recovery (>10 
minutes) pooled across depth of block and NMBA.
Statistical Methods for Key 
Efficacy Analyses
The primary hypothesis will evaluate the efficacy of sugammadex 
when dosed according to ABW as compared with IBW on time to 
recovery to a TOF ratio of ≥0.9 using a stratified log-rank test 
(adjusted for the depth of block and NMBA). Event rates over time 
will be estimated within each treatment group using the Kaplan-Meier 
method. 
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 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
A pharmacokinetic (PK) only interim analyses (IA) will be conducted 
in this study when approximately 64 evaluable subjects treated with 
sugammadex (approximately 16 subjects per treatment dose [2 mg/kg 
and 4 mg/kg] and weight-based dosing [ABW and IBW] categories) 
have been enrolled, in order to examine the PK profile of 
sugammadex in the setting of morbid obesity. No unblinding of safety 
or efficacy will occur in support of this PK-only IA.
Multiplicity
No multiplicity adjustment is planned. 
Sample Size and Power 
The total planned sample size is approximately 200 subjects. If 
subjects are equally allocated in each NMBA strata, there would be 
~100 subjects per NMBA with ~20 subjects in each of the 5 treatment 
arms. However, if approximately 30% of the total subjects (i.e., 60 
subjects) are enrolled in the vecuronium stratum, there would be ~12 
subjects in each of the 5 treatment groups in the vecuronium stratum. 
Assuming the difference of median time-to-recovery in ABW and 
IBW groups is one minute based on the simulated data, a sample size 
of N ~80 per group (across both NMBA and depth of block) provides 
estimated power of  > 99% to detect a shift in time-to-recovery. 
3.2
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
Sponsor study team personnel will be blinded to study medication assignments for 
randomized subjects, with the exception of designated Sponsor personnel (e.g., unblinded 
Clinical Research Associates [CRAs], the pharmacokineticist, statistician(s) not associated 
with the study who will complete the PK IA and provide the data to the siDMC, and other 
designated individuals as required).The official final database will not be unblinded until 
 
 
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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.
3.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0 of the protocol.
3.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected 
endpoints.
3.4.1
Efficacy Endpoints
The primary efficacy endpoint is the time to recovery to a TOF ratio of ≥0.9 for a comparison 
of ABW and IBW based dosing of sugammadex.  See Section 4.2.3.1 of the protocol for 
more details.
Secondary efficacy endpoints are:
Summary statistics for the recovery times to TOFs of ≥0.7, ≥0.8 and ≥0.9 for ABW and 
IBW dosing groups pooled across both the depth of block and NMBA
The proportions of subjects with prolonged recovery (>10 minutes) for ABW and IBW 
dosing groups pooled across both the depth of block and NMBA
Exploratory efficacy endpoints are:

Summary statistics for the recovery times for sugammadex and neostigmine in the 
setting of moderate block pooled across NMBA 

Summary statistics for the recovery times to TOFs of ≥0.7, ≥0.8 and ≥0.9 for ABW 
and IBW dosing groups separately by the depth of block and by NMBA

The proportions of subjects with prolonged recovery (>10 minutes) for ABW and IBW 
dosing groups by the depth of block and by NMBA.
3.4.2
Safety Endpoints
Safety endpoints that will be evaluated in each dosing group are listed below. For safety 
analyses other than the primary safety endpoint (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 
 
 
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supplemental summary of all AEs occurring up to 14 days post administration of study 
medication will also be included.
The primary 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 also increased 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 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 five 
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. In addition to the primary 
safety endpoints, 
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.
 
 
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3.4.3
Pharmacokinetic Endpoints
The pharmacokinetics of sugammadex will be evaluated in obese participants when dosed 
according to ABW and IBW.  
Actual elapsed plasma sampling times relative to the time of dose will be used to estimate the 
pharmacokinetic 
parameters 
for 
each 
treatment 
in 
each 
subject. 
Sugammadex 
pharmacokinetic parameters will be calculated using noncompartmental methods.  The 
apparent terminal rate constant (λ) will be estimated by regression of the terminal log-linear 
portion of the plasma concentration time profile; apparent terminal t½ will calculated as the 
quotient of ln(2) and λ. AUC to the last time point with a quantifiable plasma concentration 
(AUC0-last) will be calculated using the linear trapezoidal method for ascending 
concentrations and the log trapezoidal method for descending concentrations up to the last 
quantifiable plasma concentration.  Total exposure (AUC0-inf) will be estimated as the sum 
of AUC0-last and the extrapolated area given by the quotient of the last quantifiable 
concentration and λ.  The maximum observed concentration (Cmax) will be obtained by 
inspection of the plasma concentration data.  Mean residence time (MRT) of sugammadex in 
the systemic circulation following IV administration will be estimated. Total clearance 
(CL=Dose/ AUC0-inf) and volume of distribution (Vd), defined as volume of distribution 
estimated at steady-state following a single IV dose administration (Vss=MRT x CL) and Vd 
during the terminal elimination phase (i.e. Dose/(AUC0-inf x λz) will be calculated. No 
value for AUC0-∞, CL, λz, t1/2, Vz, MRT, Vss will be reported for concentration-time 
profiles where the terminal linear phase is not clearly defined.
Additional pharmacokinetic analyses may be conducted if deemed appropriate.
3.4.4
Derivations of Efficacy /Pharmacokinetics Endpoints
For imputation of missing times from the start of administration of sugammadex or 
neostigmine to recovery of the TOF ratio to 0.7, 0.8 and 0.9, a worst case scenario for 
sugammadex and a best case scenario for neostigmine will be applied, consistent with the 
approach used in the adult program.  For each of the two NMBAs, separately, the following 
explicit imputation procedure (i.e. the primary imputation method) will be used:
If the time from the start of administration of study drug to recovery of the TOF ratio to 0.9 is 
missing, there are three cases of particular importance for imputation purposes: 
1. Time to TOF ratio to 0.8 is available: 

Sugammadex group: first, for all subjects randomized to receive sugammadex and 
with times to recovery of the TOF ratio to 0.8 and 0.9 available, the difference 
between these two recovery times will be calculated.  Next, the 95th percentile (P95) 
of these differences will be added to the time to recovery of the TOF ratio to 0.8 of 
the subjects with missing times to recovery of the TOF ratio to 0.9.  This will be used 
as the imputed missing time to recovery of the TOF ratio to 0.9.
 
 
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
Neostigmine group: same as for the sugammadex group but now only subjects 
randomized to receive neostigmine will be used, and the 5th percentile (P5) of the 
differences in time to recovery of the TOF ratio to 0.8 and 0.9 will be calculated.
2. Time to TOF ratio to 0.7 is available, but the time to TOF ratio to 0.8 is missing: 

Sugammadex group: first for all subjects randomized to sugammadex and with times 
to recovery of the TOF ratio to 0.7 and 0.9 available, the difference in time between 
these two recovery times will be calculated.  Next, the P95 of these differences will 
be added to the time to recovery of the TOF ratio to 0.7.  This will be used as 
imputation of the missing time to recovery of the TOF ratio to 0.9.

Neostigmine group: same as for sugammadex group but now only subjects 
randomized to receive neostigmine will be used and the P5 of the differences in time 
to recovery of the TOF ratio to 0.7 and 0.9 will be calculated. 
3. Times to TOF ratio to 0.7 and to 0.8 are both missing:

Sugammadex group: the P95 of the time to recovery in all subjects randomized to 
sugammadex with an observed recovery time of the TOF ratio to 0.9 will be imputed.

Neostigmine group: the P5 of the time to recovery in all subjects randomized to 
neostigmine with an observed recovery time of the TOF ratio to 0.9 will be imputed. 
A corresponding procedure will be followed for imputation of missing times from the start of 
administration of study drug to recovery of the TOF ratio to 0.8 (secondary efficacy 
variable).  For imputation of missing times, P95 (sugammadex) or P5 (neostigmine) of the 
differences in time between recovery of the TOF ratio to 0.7 and 0.8 will be used.
For imputation of missing times from the start of administration of study drug to recovery of 
the TOF ratio to 0.7 (secondary efficacy variable), the P95 observed time for the subjects 
randomized to the sugammadex group will be imputed.  For subjects randomized to the 
neostigmine group the P5 observed time will be imputed. Imputation of missing times of the 
primary and secondary efficacy variables, however, should always result in a non-descending 
sequence of times to recovery of the TOF ratios to 0.7, 0.8, and 0.9.
Note that, 

the imputation will be across NMBA and depth of blocks,

the imputation will be by ABW and IBW for the sugammadex group,

the imputation of missing time generated from the above procedures will be 
calibrated with the time of last reliable TOF ratio time as:
maximum of: 1) the imputed time from the above procedures and 2) the time to the 
last reliable ratio
 
 
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This will be used in the analysis with “Explicit Imputation”. Refer to Section 3.6.1.
In addition, the exploratory sensitivity analyses will be conducted for the key secondary 
efficacy analyses using an imputation method that is conservative for evaluating the recovery 
time of participants dosed with sugammadex according to ABW as compared to participants 
dosed with sugammadex according to IBW. The “conservative” imputation method is similar 
to the imputation described in this section, but uses the P5 (instead of P95 as described in the 
explicit imputation) for imputing the missing recovery time for participants who received 
sugammadex IBW and is for the analysis with “Conservative Imputation” in Section 3.6.1:

If the time from the start of administration of study drug to recovery of the TOF ratio 
to 0.9 is missing but the time to TOF ratio to 0.8 is available: 
First, for all subjects randomized to receive sugammadex IBW with times to recovery 
of the TOF ratio to 0.8 and 0.9 available, the difference between these two recovery 
times will be calculated.  Next, the P5 of these differences will be added to the time to 
recovery of the TOF ratio to 0.8 of the subjects with missing times to recovery of the 
TOF ratio to 0.9.  This will be used as the conservatively imputed missing time to 
recovery of the TOF ratio to 0.9. 

If the time from the start of administration of study drug to recovery of the TOF ratio 
to 0.9 is missing, the time to TOF ratio to 0.7 is available, but the time to TOF ratio to 
0.8 is missing: 
First, for all subjects randomized to sugammadex IBW with times to recovery of the 
TOF ratio to 0.7 and 0.9 available, the difference in time between these two recovery 
times will be calculated.  Next, the P5 of these differences will be added to the time to 
recovery of the TOF ratio to 0.7. This will be used as conservative imputation of the 
missing time to recovery of the TOF ratio to 0.9.

If the time from the start of administration of study drug to recovery of the TOF ratio 
to 0.9 is missing, and the times to TOF ratio to 0.8 and to 0.7 are also missing: the P5 
of the time to recovery in all subjects randomized to sugammadex IBW with an 
observed recovery time of the TOF ratio to 0.9 will be imputed.

A corresponding procedure will be followed for imputation of missing times from the 
start of administration of study drug to recovery of the TOF ratio to 0.8 and to 0.7.  
3.5
Analysis Populations
3.5.1
Efficacy Analysis Population
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study.  The FAS population consists of all randomized subjects who:

are dosed with both an NMBA and reversal agent (study treatment),

have at least one post-randomization efficacy assessment. 
 
 
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Subjects will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using the FAS population.  Details on the approach to handling 
missing data are provided in Section 3.6.1 Statistical Methods.
3.5.2
Safety Analysis Population
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 for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received. Percentage of the 
assigned dose criterion will be utilized to identify subjects that were potentially cross treated 
on the basis of ABW versus IBW. The criterion is as follows:

<70% of the assigned dose would be utilized to reclassify subjects randomized to 
ABW as IBW subjects.

>143% of the assigned dose would be utilized to reclassify subjects randomized to 
IBW as ABW subjects.
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.
Details on the approach to handling missing data for safety analyses are provided in Section 
3.6.2 Statistical Methods.
3.5.3
All Subjects Treated Population
The All Subjects Treated (AST) population consists of all randomized subjects who are 
dosed with both an NMBA and reversal agent (study treatment). Subjects will be included in 
the treatment group to which they are randomized for the analysis using the AST population.  
The AST population is used for reporting baseline characteristics.
3.5.4
Pharmacokinetic Population
Subjects with evaluable sugammadex concentrations at approximately 2, 5, 15, 60 min and 4-
6 hr post-dose will be included for pharmacokinetic analysis. 
3.6
Statistical Methods
Statistical testing and inference for efficacy and safety analyses are described in Section 3.6.1
and 3.6.2 respectively.  Efficacy results that will be deemed to be statistically significant 
after consideration of the Type I error control strategy are described in Section 3.8, 
Multiplicity.  Nominal p-values will be computed for other efficacy analyses, but should be 
interpreted with caution, due to potential issues of multiplicity, sample size, etc.  Unless 
otherwise stated, all statistical tests will be conducted at the α=0.05 (2-sided) level. All the 
 
 
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analyses will be based on the real stratification stratum (i.e. rocuronium or vecuronium) that 
a subject actually received.
3.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. 
All efficacy analyses will be based on the Full Analysis Set.
The primary efficacy endpoint is the time to recovery, defined as a TOF ratio (i.e. T 4/T1
ratio) ≥0.9 after sugammadex administration.  The primary efficacy analysis is the stratified 
log-rank test adjusted for the depth of block and NMBA.  Formal tests for efficacy, in 
comparison of sugammadex dosed according to ABW versus IBW, will be conducted across 
NMBA. A stratified [stratification factors are depth of block and NMBA] Cox proportional 
hazards model, with Efron method of tie handling, will be used to assess the magnitude of the 
treatment difference between treatment arms. For the treatment effect, the hazard ratio and its 
95% confidence interval will be reported from the same Cox model. Furthermore, to 
understand the impact of the depth of block and NMBA on the time to recovery to TOF ratio 
≥0.9 after sugammadex administration, the efficacy analyses on the time to recovery to TOF 
ratio ≥0.9 stratified by depth of block and NMBA, are repeated separately by depth of block 
and by NMBA.
Secondary efficacy endpoints and some exploratory efficacy endpoints are summaries of 
time to recovery, including cumulative distribution plots, boxplots, and summary statistics 
(mean, standard deviation, median, geometric mean and its 95% CI) will be provided, as well 
as the proportions of subjects with prolonged time to recovery (>10 minutes) by treatment 
groups ABW versus IBW (pooled and separately by depth of block and by NMBA).  In 
addition, the 95% confidence intervals for pairwise comparisons will be provided for time to 
recovery and proportions (both overall and separately by depth of block and by NMBA).
 
 
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Table 1 summarizes the key efficacy analyses. For other exploratory efficacy endpoints, the 
summary statistics (mean standard deviation, median, geometric mean and its 95% CI) will 
be provided for the comparison of time to recovery for each sugammadex dose group and 
neostigmine in the setting of moderate block across NMBA. To note, the pairwise 
comparisons between two treatment arms in geometric means for time to recovery, is through 
the pairwise geometric mean ratio of the recovery time between two treatment arms and its 
95% CI, which can be obtained from following:

Take the logarithm of the recovery time and calculate the mean of the recovery time 
in the logarithmic scale for each treatment arm.

Calculate the mean difference between the two treatment arms and its 95% CI based 
on t-distribution.  

Take the exponential transformation of the pairwise geometric mean difference in the 
logarithmic scale and its 95% CI. 
Additional exploratory sensitivity analyses will be conducted for the key secondary efficacy 
analyses. These analyses are the same as the ones for the key secondary endpoints in Table 1, 
but with an imputation method that is conservative for evaluating the recovery time of 
participants dosed with sugammadex according to ABW as compared to participants dosed 
with sugammadex according to IBW. The “conservative” imputation method used in the 
sensitivity analyses is described in Section 3.4.4.  
 
 
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Table 1
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method‡
Analysis 
Population
Missing Data 
Approach
Primary Endpoint/Hypothesis
Time to recovery to a TOF 
ratio ≥ 0.9 for ABW and IBW 
dosing groups pooled across 
depth of block and NMBA
P
Stratified Log-rank 
test
FAS
Censored
Secondary Endpoints
Time to recovery to a TOF 
ratio ≥ 0.9 for ABW and IBW 
dosing groups, separately by 
depth of block and by NMBA
S
Stratified Log-rank 
test
FAS
Censored
Distribution of time to recovery 
of TOFs of ≥0.7, ≥0.8 and 
≥0.9
S
Descriptive statistics 
(cumulative 
distribution plots, 
boxplots, mean, 
standard deviation, 
median, geometric 
mean and its 95% 
CI)
FAS
Explicit
Imputation,  
Conservative
Imputation 
Distribution of time to recovery 
of TOFs of ≥0.7, ≥0.8 and 
≥0.9 for ABW and IBW 
dosing groups, pooled across 
depth of block and NMBA
S
Pairwise comparison 
via the ratio of 
geometric mean and
95% CI
FAS
Explicit 
Imputation,  
Conservative
Imputation 
Proportion of subjects with 
prolonged time to recovery (> 
10 minutes) for ABW and 
IBW dosing groups, pooled 
across depth of block and 
NMBA 
S
Pairwise difference in 
proportion and 95% 
CI using the 
stratified Miettinen 
and Nurminen 
method
FAS
Explicit 
Imputation,  
Conservative 
Imputation 
Distribution of time to recovery 
of TOFs of ≥0.7, ≥0.8 and 
≥0.9 for ABW and IBW 
dosing groups, separately by 
depth of block and by NMBA
S
Pairwise comparison 
via the ratio of
geometric mean and 
95% CI
FAS
Explicit 
Imputation,  
Conservative 
Imputation 
Proportion of subjects with 
prolonged time to recovery (> 
10 minutes) for ABW and 
IBW dosing groups, 
separately by depth of block 
and by NMBA
S
Pairwise difference in 
proportion and 95% 
CI using the 
stratified Miettinen 
and Nurminen 
method
FAS
Explicit 
Imputation,  
Conservative 
Imputation 
† P=Primary approach; S=Supportive approach.
Imputation approaches described in Section 3.4.4.
‡ Statistical models are described in Section 3.6.1.
The stratified Miettinen and Nurminen method uses the sample-size weighting scheme.
 
 
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3.6.2
Statistical Methods for Safety Analyses
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, vital signs, and ECG measurements. To provide the 
comparable overall incidences with the label-based preferred terms of adverse events (AEs) 
used in the prior submission, the AE preferred terms are grouped based on BRIDION label 
for the United States: 

Nausea includes preferred terms nausea and procedural nausea

Vomiting includes preferred terms vomiting and procedural vomiting

Abdominal pain includes preferred terms abdominal pain, abdominal pain upper, 
abdominal discomfort, abdominal pain lower, and epigastric discomfort

Pain includes preferred terms pain and procedural pain

Red blood cell count decreased includes preferred terms red blood cell count 
decreased, hemoglobin decreased, and hematocrit decreased

Electrocardiogram QT interval abnormal includes preferred terms electrocardiogram 
QT interval abnormal and electrocardiogram QT interval prolonged

Hypertension includes preferred terms hypertension, procedural hypertension, and 
blood pressure increased

Hypotension includes preferred terms hypotension, procedural hypotension, and 
blood pressure decreased

Tachycardia includes preferred terms tachycardia and heart rate increased

Bradycardia includes preferred terms bradycardia and heart rate decreased
The analysis of safety results will follow a tiered approach (Table 2).  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. 
The incidence of safety parameters will be summarized by treatment group and preferred 
term across all 5 dosing groups.  Between-group comparisons will be made for each ABW 
and IBW dosing group of sugammadex and neostigmine pooled across NMBA, as well as 
separately by NMBA. The primary safety endpoints, as well as other supportive safety 
 
 
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endpoints are considered Tier 1 events. Both Tier 1 endpoints and Tier 2 events of clinical 
interest (i.e. adjudicated hypersensitivity, adjudicated anaphylaxis, clinically relevant sinus 
bradycardia, clinically relevant sinus tachycardia, other clinically relevant cardiac 
arrhythmia) will be estimated with 95% confidence interval by treatment groups using 
Clopper-Pearson method [1]. 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 [2] with NMBA as a stratification factor. The sample-size weighting 
scheme is used for the stratified Miettinen and Nurminen method.
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 AEs and predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% CI 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% CIs may be provided without adjustment for 
multiplicity, the CIs 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 AE 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 2 summarizes the safety tier and level of analysis for the safety endpoints.
Table 2 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
X
X
Adjudicated anaphylaxis
X
X
Clinically relevant sinus bradycardia
X
X
Clinically relevant sinus tachycardia
Other clinically relevant cardiac arrhythmia
X
X
X
X
Any AE
X
X
Any serious AE
X
X
Any drug-related AE
X
X
Any serious and drug-related AE
X
X
 
 
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Discontinuation due to AE
X
X
Grouped AE
Specific AEs, SOCs, or PDLCsb (incidence ≥4 
of subjects in one of the treatment groups)
X
X
X
X
Tier 3
Specific AEs, SOCs or PDLCsb (incidence <4 
of subjects in all of the treatment groups)
X
Change from Baseline 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.
Abbreviations: CI = Confidence interval; SOC=System Organ Class; PDLC=Pre-Defined Limit of 
Change; X  = results will be provided.
3.6.3
Statistical Methods for Pharmacokinetic Analysis
For the following analysis all the subjects that have evaluable sugammadex concentrations 
will be included.
Individual dose normalized (dn) AUC0-inf and dnCmax values for each of the sugammadex 
treatments (4mg/kg, 2mg/kg) will be natural log-transformed and evaluated with a linear 
fixed effect model having fixed terms for treatment and mode (IBW, ABW) and an 
interaction term for mode x treatment. Kenward and Roger's method will be used to calculate 
the denominator degrees of freedom for the fixed effects.  Both interaction term (mode x 
treatment) and mode will be tested for statistical significance at alpha=0.05 for each of the 
pharmacokinetic parameters.  If either one or both of these terms for any or both of the 
pharmacokinetic parameters (dnAUC0-inf and dnCmax) are statistically significant, then 
appropriate contrasts will be used to construct 90% confidence intervals (CIs) for the 
difference in least-squares (LS) means on the log scale for dnAUC0-inf and dnCmax for each 
of the modes of administration. These CIs will then be exponentiated to obtain a 90% CIs for 
the true dnAUC0-inf geometric mean ratio, GMR (4mg/kg versus 2mg/kg) and true dnCmax 
GMR (4mg/kg versus 2mg/kg) for each of the modes of administration. 
If both interaction (mode x treatment) and mode terms of the model for both dnAUC0-  and 
dnCmax are not statistically significant at alpha=0.05, then the data for both modes of 
administration will be pooled and the final model will include treatment as fixed effect. 
Ninety percent (90%) CIs for the true dnAUC0-inf GMR (4mg/kg versus 2mg/kg) and true 
dnCmax GMR (4mg/kg versus 2mg/kg) will be obtained from the model.  For each mode of 
administration LS means and corresponding 95% CI obtained from the model will also be 
reported for dnAUC0-inf and dnCmax by treatment. 
Additionally, individual CL and Vd will be natural log-transformed and analyzed separately 
using linear effects model as previously described. For each mode of administration, LS 
means and corresponding 95% CIs for CL and Vd will be provided for each treatment. 
For each mode of administration, individual values will be listed for each PK parameter 
(AUC0-inf, AUC0-last, Cmax, dnAUC0-inf, dnCmax, CL, Vss, Vd, MRT, and t1/2) by 
treatment and the following (non-model-based) descriptive statistics will be provided: N 
 
 
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(number of subjects with non-missing data), arithmetic mean, standard deviation, arithmetic  
percent CV (calculated as 100 x standard deviation/arithmetic mean), median, minimum, 
maximum, geometric mean, and geometric percent CV (calculated as 100 x sqrt( exp(s2) - 1), 
where s2 is the observed variance on the natural log-scale).
Mean (standard error) and median (interquartile range) concentration-time plots for each 
treatment and mode of administration will be provided.  Additionally for each mode of 
administration, individual ratios overlaid with GMR and corresponding 90% CI for each 
treatment for dnAUC0-inf and dnCmax will be provided. Plots of dnAUC0-inf versus ABW, 
dnAUC0-inf versus IBW, dnCmax versus ABW, dnCmax versus IBW will also be provided.  
3.6.4
Summaries of Baseline Characteristics, Demographics, and Other Analyses
3.6.4.1
Demographic and Baseline Characteristics
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.
3.6.4.2
Population PK Analyses
Population-based methods of analysis may be explored at the completion of the study to 
further characterize the PK profiles within morbidly obese subjects and/or permit 
comparisons to historical data.  
3.7
Interim Analyses
An interim pharmacokineticist and an interim statistician separate from the sugammadex
development team, both of whom will be unblinded during the interim analysis, will perform 
the interim analysis. Only the available data from the subjects (approximately 64 subjects 
total treated with sugammadex [~16 per combination of dose (2mg/kg, 4mg/kg) and weight-
based dosing ([ABW, IBW)], Table 3) for whom evaluable sugammadex PK samples are 
available will be included in the interim analysis. 
Table 3 Sample Size for Interim Analysis
Approximate Number of subjects that will trigger Interim analysis
2 mg/kg (ABW)
4 mg/kg (ABW)
2 mg/kg (IBW)
4 mg/kg (IBW)
16
16
16
16
The interim analysis of the pharmacokinetic parameters will be performed as previously 
described in Section 3.6.3.  In addition to the model-based analysis, the interim unblinded 
statistician will also provide descriptive statistics for the pharmacokinetic parameters as 
 
 
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previously specified in Section 3.6.3. No individual listings for the PK parameters will be 
provided from the interim analysis for decision making.
The siDMC will review the results of the planned IA to make recommendations regarding the 
need to study the 16 mg/kg sugammadex dose. The decision about a 16 mg/kg dose will be 
based upon the evaluation of the 90% confidence intervals of the geometric mean ratio fo r 
both the Area Under the Curve0-inf (AUC0-inf) and Maximum Concentration (Cmax) form 
the IBW and ABW data.
3.8
Multiplicity
In this study, the primary hypothesis is a single comparison of sugammadex dosed with 
ABW and IBW using one endpoint in the primary hypothesis; therefore, no corrections of 
multiplicity are required. Sample Size and Power Calculations.
3.9
Sample Size and Power Calculations
3.9.1
Sample Size and Power for Efficacy Analyses
This study will enroll approximately 200 subjects in total.  If subjects are equally enrolled in 
each NMBA strata, there would be ~20 subjects in each of the five treatment groups within 
NMBA.  However, due to enrollment kinetics, an effort will be made to enroll approximately 
30% of vecuronium-treated subjects.  Therefore, ~12 subjects will be randomized to each of 
the 5 treatment groups in the vecuronium stratum.  The primary approach to the assessment 
of sample size is via simulation using the primary efficacy model to compare time to 
recovery for sugammadex dosed to ABW versus IBW.  Time–to-recovery data are simulated 
using distributional assumptions derived from dose-ranging efficacy data within the 
sugammadex clinical program, assuming that dosing according to IBW would result in 
weight-based dosing approximately half of that from dosing according to ABW for either 
depth of block. In addition, the general conclusion in phase 2 studies shows that participants 
administered 1 mg/kg in moderate block and 2 mg/kg in deep block would have time to 
recovery increased by roughly 1 minute comparing to 2 mg/kg and 4 mg/kg, respectively.  
Based on that assumption, subjects in the ABW group have a median time-to-recovery of 
~2.2 minutes with a standard deviation of ~1.3, while subjects in the IBW have median time 
to recovery of ~3.3 minutes with a standard deviation of ~2.3.  Figure 1 illustrates data 
simulated from the above assumption. 
 
 
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Figure 1: Illustrative Scenario of Time-to-Recovery to TOF ratio of 0.9 for ABW vs. IBW
The power calculation is based on a log-rank test, with an alpha level of 0.05 based on 1000 
simulated samples and a function of sample size per group expected to be included in the 
analysis, and is carried out using [SAS v9.3].  Simulated power levels for the primary 
comparison as a function of sample size are shown in Table 4.
Table 4: Simulated power levels for the primary comparison and related subgroup analyses 
as a function of sample size
N/arm
15
30
40
50
60
70
80
Power
51%
81%
89%
95%
98%
99%
>99%
Assuming the difference of median time-to-recovery in ABW and IBW groups is one minute 
based on the simulated data, a sample size of N~80 per group (across both NMBA and depth 
of block) provides estimated power of > 99% to detect a shift in time-to-recovery, as well as 
sufficient subject exposure to characterize safety and tolerability profiles of the distinct 
dosing paradigms.  Although this study is well-powered for an efficacy comparison of 
sugammadex ABW and IBW, the subgroup analyses by NMBA and depth of block are likely 
underpowered, given the range of simulated power levels in Table 4. 
 
 
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3.9.2
Sample Size for Safety Analyses
The probability of observing at least one event of any treatment emergent arrhythmia in this 
study depends on the number of subjects treated and the underlying percentage of subjects 
with an AE in the study population. If no events are observed among the 20 subjects in a 
treatment group, an upper bound of 95% CI for subjects with treatment emergent sinus 
bradycardia/tachycardia is ~16.8% (1 in every 6 subjects) in a treatment group. If no events 
are observed in an arm with 12 subjects, an upper bound of the 95% CI would change to ~ 
26.5%.
The estimate of incidence and the upper bound of the 95% CI for the underlying percentage 
of subjects with any treatment emergent arrhythmia within a treatment group are provided in 
Table 5.  These calculations are based on the exact binomial method proposed by Clopper 
and Pearson (1934) [1]. The 95% CIs are provided in Table 6 for the difference in incidence 
in any treatment emergent arrhythmia between the sugammadex and neostigmine groups 
although neostigmine is primarily an active control in this study as opposed to an active 
comparator and the main interest in this study is an estimation of the absolute incidence of 
AEs in the sugammadex arms.
 
 
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Table 5
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 20 Subjects in a Treatment Group
Hypothetical Number of  Subjects 
With Any Treatment Emergent 
Arrhythmia
Estimate of 
Incidence
95% Upper Confidence 
Bound†
1
5%
24.9%
2
10%
31.7%
3
15%
37.9%
4
20%
43.7%
5
25%
49.1%
† Based on the two-tailed exact confidence interval of a binomial proportion 
(Clopper and Pearson, 1934) [7].
Table 6
Differences in Incidence in Any Treatment Emergent Arrhythmia between the 
Sugammadex and Neostigmine Groups Assuming Two-Sided 5% alpha level with 20 
Subjects in a Treatment Group 
Incidence of Adverse Event
Risk Difference
Sugammadex 
(%)
Neostigmine 
(%)
Percentage 
Points
95% CIa
5%
10%
5
(-26%, 15.2%)
10%
20%
10
(-33.7%, 13.7%)
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)).
3.9.3
Precision Estimates for Pharmacokinetic Parameters (AUC0-inf, Cmax)
The precision of the estimated ratios of geometric means (4 mg/kg versus 2 mg/kg) of 
pharmacokinetic parameters obtained from this study can be assessed by calculating the half-
width of the 90% confidence intervals expected for the given sample size and assumed 
variability. The between-subject geometric coefficient of variation (GCV) for sugammadex 
AUC0-inf obtained from the population analysis is approximately 23%. Assuming a sample 
 
 
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size of 16 subjects per treatment and observed pooled between-subject standard deviation of 
0.23 for AUC0-inf on the natural log scale, then the half width of the 90% confidence 
intervals of GMRs for AUC0-inf on the log scale will be 0.138. The lower and upper 90% 
confidence limits for the true GMRs will be given by OBS/1.148 and OBS*1.148 for AUC0-
inf, respectively, where OBS is the observed GMR. Thus, for example, if the observed GMR 
for AUC0-inf was 1.00, then the 90% CIs for the GMR would be 0.87 to 1.15.  These 
calculations also apply to the precision of the estimated geometric mean ratios for Cmax as 
the between-subject GCV for Cmax was assumed to be similar to that of AUC0-inf.
3.10
Subgroup Analyses and Effect of Baseline Factors
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 
endpoint will be estimated pooled across depth of block and NMBA within each category of 
each subgroup.  The following are classification variables: 

Age category (<65, 65-74, >74 years)

Sex (female, male)

Race (white, other)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Region (United States, Non-United States)
Subgroup analyses/summaries will only be performed for those classification variables with 
≥10% participants in each subgroup.
3.11
Compliance (Medication Adherence)
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.
3.12
Extent of Exposure
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).
3.13
Time Synchronization
During the course of the trial, there were two sources that might be used to reflect time of 
day. One source of time is from the laptop used for recording the TOF monitoring trace, and 
the other is the wall clock used for collecting other information. All the efficacy endpoints
(recovery times to TOF ratios of 0.9, 0.8, 0.7, etc.), and the treatment start and stop times are
 
 
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from the laptop, and all the other times (e.g. AE start time, start and stop times of cardiac 
arrhythmia events etc.) are collected based upon the wall clock. 
Sites are instructed to synchronize the time on the laptop and the time on the wall clock 
before conducting TOF monitoring. The wall clock time at a reference moment and the 
corresponding laptop time are collected during the surgery for capturing any time difference 
between the laptop and the wall clock at the reference moment. If the sites synchronize the 
laptop time and the reference wall clock time as instructed, the reference wall clock time and 
the corresponding laptop time should be the same, and no time adjustment is needed. If the 
sites do not synchronize the two times correctly, the reference wall clock time and the laptop 
time are not the same and their difference could be used for adjusting the time points as 
follows:

Compare the reference wall clock time collected through eCRFs and the 
corresponding laptop time collected on the TOF monitoring trace. Obtain the 
difference between the two times. We expect all data to be collected at least to the 
level of minutes.  If the reference wall clock time has missing seconds, we will 
impute 00 for the seconds, which is the most conservative imputation. The reason 
imputing 00 for the seconds of reference wall clock time is considered the most 
conservative is because:
o
Adjusted start time of treatment = Collected start time of treatment + 
Reference wall clock time – corresponding laptop time
o
To make the adjusted start time of treatment as early as possible means 
imputing 00 which is the smallest value for seconds of reference wall clock 
time.
o
The reason to impute in a manner that creates the earliest adjusted start time is 
to attribute any safety findings that may occur during this unknown (and 
imputed) time frame to the treatment period.

Use the time difference between the reference wall clock time and the corresponding 
laptop time to adjust all the time points from the laptop (including all the efficacy 
TOF time points, and the treatment start and stop times) to the wall clock time.

All the other times collected directly through the wall clock remain unchanged. 
Through this adjustment, all the analyses are consistently based on the wall clock time. The 
adjustment will be incorporated into the SDTM datasets, so that the SDTM variables (e.g. 
EPOCH) based on these timing variables are derived properly and provide linear traceability 
from SDTM to ADaM to TLFs. 
 
 
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4
REFERENCES
[1] Clopper C, and Pearson ES. (1934). "The use of confidence or fiducial limits illustrated in 
the case of the binomial". Biometrika 26: 404–413
[2] Miettinen OS, and Nurminen M. (1985). “Comparative analysis of two rates”, Statistics 
in Medicine 4: 213—226      
 
 
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