A Phase 4 Double-Blinded, Randomized, Active Comparator-Controlled Clinical Trial to Study the Efficacy, Safety, and Pharmacokinetics of Sugammadex (MK-8616) for Reversal of Neuromuscular Blockade in Pediatric Participants
Phase: PHASE4
Conditions: Neuromuscular Blockade
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03351608  
Document Date: 
18-Aug-2017
A Phase 4 Double-Blinded, Randomized, Active Comparator-
Controlled Clinical Trial to Study the Efficacy, Safety, and 
Pharmacokinetics of Sugammadex (MK-8616) for Reversal of 
Neuromuscular Blockade in Pediatric Participants

Product:  MK-8616 
1
Protocol/Amendment No.: 089-01
MK-8616-089-01 Final Protocol
18-Aug-2017
Confidential
Title Page
THIS PROTOCOL 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.
Protocol Title: A Phase 4 Double-Blinded, Randomized, Active Comparator-Controlled 
Clinical Trial to Study the Efficacy, Safety, and Pharmacokinetics of Sugammadex (MK-8616) 
for Reversal of Neuromuscular Blockade in Pediatric Participants 
Protocol Number: 089-01
Compound Number: MK-8616
Sponsor Name and Legal Registered Address: 
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.
Regulatory Agency Identifying Number(s):
IND NUMBER:   [68029]
EudraCT NUMBER: [2017-000692-92]
Approval Date:  18-Aug-2017
 
 
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Protocol/Amendment No.: 089-01
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18-Aug-2017
Confidential
Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent). 
Investigator Signatory
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.
Typed Name:
Title:
Date
 
 
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Product:  MK-8616 
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Protocol/Amendment No.: 089-01
MK-8616-089-01 Final Protocol
18-Aug-2017
Confidential
Protocol Amendment Summary of Changes
Amendment 01
Overall Rationale for the Amendment:
To clarify the safety endpoints of treatment-emergent bradycardia and provide information 
regarding the criteria for stopping the trial.
 
 
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Protocol/Amendment No.: 089-01
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18-Aug-2017
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Summary of Changes Table:
Section # and 
Name
Description of Change
Brief Rationale
Section 5.4.1.2 
Safety 
Endpoints
Clarification of safety 
endpoint: 
Treatment-emergent 
relative bradycardia
The definition of treatment-emergent relative 
bradycardia was added to align with regulatory 
requirements.
Section 5.4 
Scientific 
Rationale for 
Study Design; 
Section 5.4.1.2 
Safety 
Endpoints; 
Section 10.7 
Interim 
Analyses
Addition of text regarding 
trial stopping criteria
The eDMC charter will contain the details of the 
stopping criteria.
Section 10.2 
Responsibility 
for Analyses/ 
In-House 
Blinding
Added text to explain the 
role of the unblinded 
statistician and 
programmer
Clarification provided for role of the unblinded 
statistician and programmer
Throughout
Minor editorial and 
document formatting 
revisions
Minor, therefore have not been summarized
 
 
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Protocol/Amendment No.: 089-01
MK-8616-089-01 Final Protocol
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Confidential
Table of Contents
Protocol Amendment Summary of Changes ........................................................................ 3
1.
Synopsis...................................................................................................................... 13
2.
Schedule of Activities (SoA) ..................................................................................... 16
3.
Introduction............................................................................................................... 20
Study Rationale..................................................................................................... 20
3.1
Background ........................................................................................................... 20
3.2
Pharmaceutical and Therapeutic Background .................................................... 20
3.2.1
Pre-clinical and Clinical Trials ........................................................................... 21
3.2.2
Benefit/Risk Assessment....................................................................................... 21
3.3
4.
Objectives/Hypotheses and Endpoints.................................................................... 22
5.
Study Design.............................................................................................................. 23
Overall Design....................................................................................................... 23
5.1
Study Diagram .................................................................................................... 23
5.1.1
Number of Participants........................................................................................ 24
5.2
Beginning and End of Study Definition .............................................................. 24
5.3
Clinical Criteria for Early Trial Termination...................................................... 24
5.3.1
Scientific Rationale for Study Design.................................................................. 25
5.4
Rationale for Endpoints ...................................................................................... 26
5.4.1
Efficacy Endpoints....................................................................................... 26
5.4.1.1
Safety Endpoints .......................................................................................... 26
5.4.1.2
Pharmacokinetic Endpoints ......................................................................... 27
5.4.1.3
Pharmacodynamic Endpoints....................................................................... 27
5.4.1.4
Rationale for the Use of Comparator .................................................................. 27
5.4.2
Justification for Dose............................................................................................ 28
5.5
6.
Study Population....................................................................................................... 28
Inclusion Criteria.................................................................................................. 28
6.1
Exclusion Criteria................................................................................................. 29
6.2
Lifestyle Restrictions ............................................................................................ 30
6.3
Meals and Dietary Restrictions........................................................................... 30
6.3.1
 
 
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Protocol/Amendment No.: 089-01
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Caffeine, Alcohol, and Tobacco ......................................................................... 30
6.3.2
Activity ............................................................................................................... 30
6.3.3
Screen Failures...................................................................................................... 30
6.4
Participant Replacement Strategy ...................................................................... 30
6.5
7.
Treatments................................................................................................................. 30
Treatments Administered .................................................................................... 30
7.1
Medical Devices.................................................................................................. 31
7.1.1
Dose Modification (Escalation/Titration/Other)................................................ 32
7.2
Method of Treatment Assignment....................................................................... 32
7.3
Stratification........................................................................................................ 32
7.3.1
Blinding.................................................................................................................. 33
7.4
Preparation/Handling/Storage/Accountability .................................................. 34
7.5
Dose Preparation................................................................................................. 34
7.5.1
Handling, Storage and Accountability................................................................ 34
7.5.2
Treatment Compliance......................................................................................... 34
7.6
Concomitant Therapy........................................................................................... 35
7.7
Rescue Medications & Supportive Care ............................................................. 35
7.7.1
Treatment After the End of the Study................................................................ 35
7.8
Clinical Supplies Disclosure................................................................................. 35
7.9
8.
Discontinuation/Withdrawal Criteria..................................................................... 35
Withdrawal from the Study................................................................................. 35
8.1
Lost to Follow Up.................................................................................................. 36
8.2
9.
Study Assessments and Procedures......................................................................... 36
Administrative and General Procedures ............................................................ 37
9.1
Informed Consent/Assent.................................................................................... 37
9.1.1
General Informed Consent/Assent............................................................... 37
9.1.1.1
Inclusion/Exclusion Criteria ............................................................................... 37
9.1.2
Participant Identification Card............................................................................ 37
9.1.3
Medical History .................................................................................................. 38
9.1.4
Prior and Concomitant Medications Review ...................................................... 38
9.1.5
Prior Medications......................................................................................... 38
9.1.5.1
Concomitant Medications ............................................................................ 38
9.1.5.2
 
 
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Protocol/Amendment No.: 089-01
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Assignment of Screening Number ...................................................................... 38
9.1.6
Assignment of Treatment/Randomization Number ............................................ 38
9.1.7
Treatment Administration................................................................................... 39
9.1.8
Administration of Neuromuscular Blocking Agents ................................... 39
9.1.8.1
Timing of Dose Administration................................................................... 39
9.1.8.2
Withdrawal/Discontinuation ............................................................................... 39
9.1.9
Participant Blinding/Unblinding......................................................................... 40
9.1.10
Calibration of Critical Equipment....................................................................... 40
9.1.11
Efficacy Assessments ............................................................................................ 40
9.2
Neuromuscular Monitoring................................................................................. 40
9.2.1
Adverse Events, Serious Adverse Events and Other Reportable Safety Events41
9.3
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
9.3.1
Safety Event Information.................................................................................... 41
Method of Detecting AE, SAE and Other Reportable Safety Events ................. 43
9.3.2
Follow-up of AE, SAE and Other Reportable Safety Event Information........... 43
9.3.3
Regulatory Reporting Requirements for SAE .................................................... 43
9.3.4
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
9.3.5
AEs or SAEs ....................................................................................................... 43
Pregnancy and Exposure During Breastfeeding ................................................. 43
9.3.6
Events of Clinical Interest (ECI)......................................................................... 44
9.3.7
Assessing and Recording Patient/Device Events................................................ 44
9.3.8
Device Incidents........................................................................................... 45
9.3.8.1
Regulatory Reporting Requirements for Device Events and Incidents ....... 46
9.3.8.2
Treatment of Overdose......................................................................................... 46
9.4
Safety...................................................................................................................... 46
9.5
Physical Examinations ........................................................................................ 46
9.5.1
Height and Weight .............................................................................................. 47
9.5.2
Vital Signs........................................................................................................... 47
9.5.3
Electrocardiogram............................................................................................... 48
9.5.4
Clinical Safety Laboratory Assessments............................................................. 48
9.5.5
Pharmacokinetics.................................................................................................. 48
9.6
Blood Collection for Plasma Sugammadex ........................................................ 49
9.6.1
Pharmacodynamics............................................................................................... 49
9.7
 
 
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Protocol/Amendment No.: 089-01
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Future Biomedical Research Sample Collection................................................ 49
9.8
Biomarkers ............................................................................................................ 49
9.9
Medical Resource Utilization and Health Economics ....................................... 49
9.10
Visit Requirements ............................................................................................... 49
9.11
Screening (Visit 1) .............................................................................................. 50
9.11.1
Peri-anesthetic Visit (Visit 2).............................................................................. 50
9.11.2
Post-anesthetic Visit (Visit 3) ............................................................................. 50
9.11.3
Follow-up Contact (Visit 4)................................................................................ 51
9.11.4
10.
Statistical Analysis Plan ........................................................................................... 51
Statistical Analysis Plan Summary ..................................................................... 51
10.1
Responsibility for Analyses/In-House Blinding ................................................. 53
10.2
Hypotheses/Estimation ......................................................................................... 53
10.3
Analysis Endpoints ............................................................................................... 53
10.4
Efficacy Endpoints.............................................................................................. 53
10.4.1
Safety Endpoints ................................................................................................. 53
10.4.2
Pharmacokinetic Endpoints ................................................................................ 54
10.4.3
Derivations of Efficacy/Pharmacokinetics Endpoints ........................................ 54
10.4.4
Analysis Populations............................................................................................. 55
10.5
Efficacy Analysis Populations ............................................................................ 55
10.5.1
Safety Analysis Populations ............................................................................... 55
10.5.2
PK Analysis Populations..................................................................................... 55
10.5.3
Statistical Methods................................................................................................ 56
10.6
Statistical Methods for Efficacy Analyses .......................................................... 56
10.6.1
Statistical Methods for Safety Analyses ............................................................. 57
10.6.2
Statistical Methods for Pharmacokinetics Analyses........................................... 59
10.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 60
10.6.4
Demographic and Baseline Characteristics ................................................. 60
10.6.4.1
Interim Analyses ................................................................................................... 60
10.7
Multiplicity ............................................................................................................ 61
10.8
Sample Size and Power Calculations .................................................................. 61
10.9
Sample Size and Power Calculations for Efficacy Analyses.............................. 61
10.9.1
Sample Size and Power Calculations for Safety Analyses ................................. 62
10.9.2
 
 
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Protocol/Amendment No.: 089-01
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Sample Size and Power Calculations for Pharmacokinetic Analyses................. 64
10.9.3
Subgroup Analyses ............................................................................................... 64
10.10
Compliance (Medication Adherence).................................................................. 64
10.11
Extent of Exposure................................................................................................ 65
10.12
11.
References.................................................................................................................. 65
12.
Appendices................................................................................................................. 67
Appendix 1: Abbreviations and Trademarks .................................................... 67
12.1
Appendix 2: Clinical Laboratory Tests .............................................................. 69
12.2
Appendix 3: Study Governance Considerations ................................................ 71
12.3
Merck Code of Conduct for Clinical Trials.................................................................... 71
Financial Disclosure.......................................................................................................... 73
Data Protection ................................................................................................................. 73
Confidentiality of Data ..................................................................................................... 73
Confidentiality of Participant Records........................................................................... 73
Confidentiality of IRB/IEC Information ........................................................................ 74
Committees Structure....................................................................................................... 74
Data Monitoring Committee ........................................................................................... 74
Neuromuscular Monitoring Adjudication Committee .................................................... 74
Clinical Adjudication Committee ................................................................................... 75
Publication Policy ............................................................................................................. 75
Compliance with Trial Registration and Results Posting Requirements .................... 75
Compliance with Law, Audit and Debarment ............................................................... 76
Data Quality Assurance.................................................................................................... 76
Source Documents............................................................................................................. 77
Study and Site Closure ..................................................................................................... 77
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
12.4
Evaluating, Follow-up, and Reporting................................................................ 78
Definition of AE ................................................................................................................ 78
Definition of SAE .............................................................................................................. 79
Additional Events reported.............................................................................................. 80
Recording AE and SAE.................................................................................................... 80
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor............. 84
Appendix 5: Contraceptive Guidance and Pregnancy Testing ........................ 85
12.5
 
 
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Protocol/Amendment No.: 089-01
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Contraception Requirements........................................................................................... 85
Appendix 6: Bradycardia Definition by Age Range .......................................... 87
12.6
Appendix 7: Approximate Blood Volumes Collected by Trial Visit................ 88
12.7
 
 
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LIST OF TABLES
Table 1
Study Treatments ..................................................................................................... 31
Table 2
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events......................................................................................... 42
Table 3
Assessment Windows for Vital Signs Following Administration of Study 
Treatment ................................................................................................................. 48
Table 4
Analysis Strategy for Key Efficacy Variables Comparing Sugammadex to 
Neostigmine in the Setting of Moderate NMB........................................................ 57
Table 5
Analysis Strategy for Safety Parameters.................................................................. 59
Table 6
Time (in min) to Recovery to a TOF Ratio of ≥0.9 for Sugammadex 2 mg/kg 
and Neostigmine 50 mcg/kg for Moderate Block with Rocuronium....................... 61
Table 7
Power Estimates for Detecting Various Differences Between Sugammadex and 
Neostigmine in Moderate Block.............................................................................. 62
Table 8
Estimate of Incidence of a Tier 1 Adverse Event and 95% Upper Confidence 
Bound Based on Hypothetical Number of Participants with a Tier 1 Adverse 
Event Among 44 (2mg/kg) and 164 (4mg/kg) Participants in the Sugammadex 
Group ....................................................................................................................... 63
Table 9
Differences in Incidence in a Tier 1 Adverse Event between the Sugammadex 
and Neostigmine Groups (Assuming Two-Sided 5% alpha level with 44 
Participants in Sugammadex Group and 30 Participants in Neostigmine Group)... 63
Table 10
Protocol-Required Safety Laboratory Assessments.................................................. 70
Table 11
Contraceptive Methods ............................................................................................. 86
 
 
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LIST OF FIGURES
Figure 1
Study Diagram .......................................................................................................... 23
Figure 2
Study Treatment Randomization .............................................................................. 24
 
 
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1. Synopsis
Protocol Title:  
A Phase 4 Double-Blinded, Randomized, Active Comparator-Controlled Clinical Trial 
to Study the Efficacy, Safety, and Pharmacokinetics of Sugammadex (MK-8616) for 
Reversal of Neuromuscular Blockade in Pediatric Participants 
Short Title: 
PK, safety and efficacy of sugammadex in children 2 to <17 years of age
Objectives/Hypotheses and Endpoints:
For male/female participants between the ages of 2 to <17 years administered a NMBA
(rocuronium or vecuronium) for either moderate or deep block:
Objective/Hypothesis
Endpoint
Primary

Objective: To describe the 
pharmacokinetic parameters of 
sugammadex when used for reversal 
of moderate neuromuscular blockade 
(NMB) or deep NMB (Part A).

Pharmacokinetic parameters: Area under 
the plasma concentration-time curve 
(AUC), clearance (CL), apparent volume 
of distribution (Vz), maximum plasma 
concentration (Cmax), and half-life (t1/2)

Objective: To evaluate the safety and 
tolerability of sugammadex (data will 
be pooled across Part A and Part B of 
the study).

Number of participants experiencing 
adverse events.

Objective: To evaluate the efficacy 
of sugammadex in comparison to 
neostigmine for the reversal of 
moderate NMB (Part B).

Hypothesis: Sugammadex is 
superior to neostigmine in 
reversing moderate NMB as 
measured by time to recovery to a 
train-of-four (TOF) ratio of ≥0.9.

Time to recovery to a TOF ratio of ≥0.9.
Secondary

Objective: To evaluate the efficacy 
of sugammadex in comparison to 
neostigmine for the reversal of 
moderate NMB (Part B).

Time to recovery to a TOF ratio of ≥0.8.

Time to recovery to a TOF ratio of ≥0.7.
 
 
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Overall Design:
Trial Phase
Phase 4
Clinical Indication
Reversal of neuromuscular blockade (NMB)
Population
Pediatric participants aged 2 to <17 years who have received 
rocuronium or vecuronium for either moderate or deep 
block.
Trial Type
Interventional
Type of Design
Randomized, multi-site, parallel design, active comparator 
controlled
Type of Control
Active control without placebo
Trial Blinding
Double-blind
Estimated Duration 
of Trial
The Sponsor estimates that the trial will require 
approximately 4 years from the time the first participant 
signs the informed consent/assent until the last participant’s 
last study-related phone call or visit.
Number of Participants:
Approximately 238 participants will be enrolled.
Treatment Groups and Duration:
Treatment Groups
Treatment groups:
Part A:

Moderate block and reversal with sugammadex 
2 mg/kg; or

Deep block and reversal with sugammadex 4 mg/kg
Part B:

Moderate block and reversal with sugammadex 
2 mg/kg; or

Moderate block and reversal with neostigmine
50 mcg/kg; or

Deep block and reversal with sugammadex 4 mg/kg
 
 
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Duration of 
Participation
Each participant will participate in the trial for 
approximately 28 days from the time the participant (or
parent/legally acceptable representative) signs the informed 
consent form through the final contact. After a screening 
period of up to 14 days, each participant will receive a
single bolus dose of assigned study treatment. After the end 
of treatment, each participant will undergo a post-treatment 
safety visit between 4 and 36 hours after administration of 
study drug. A follow-up contact (phone call or visit) with 
the participant (and/or parent/legally acceptable 
representative) will take place at approximately 14 days 
post-treatment.
A list of abbreviations used in this document can be found in Appendix 1.
 
 
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2. Schedule of Activities (SoA)
Trial Period
Screening
Treatment
Follow-up
Notes
Visit Number/Title
1/Screening
2/Peri-anesthetic 
period
3/Post-anesthetic 
period
4/Follow-up contact
Visit 1 (Screening) and Visit 2 may 
occur on the same day
Follow-up contact may occur via 
telephone or visit dependent upon 
hospitalization status
Scheduled Day
Day -1
Day 1
Day 1 to 2
Day 14
Scheduling Window Days
-14 to -1 Days
±0 days
See Notes
+2 days
Visit 3 should occur between 4 and 
36 hours after administration of 
study treatment
Administrative Procedures
Informed Consent/Assent
X
Participant Identification Card
X
Screening Number Assignment
X
Medical History 
X
Inclusion/Exclusion Criteria
X
X
Visit 2: Inclusion/exclusion criteria 
will be reviewed for any changes 
from screening (Visit 1)
Prior/Concomitant Medication 
Review
X
X
X
X
Treatment Assignment or 
Randomization 
X
If needed to aid drug preparation, 
treatment assignment may be 
performed in IRT the day before 
Visit 2.  See Sections 9.1.7 and 
9.1.8.
Administration of NMBA
X
Administration of Study 
Treatment
X
For any given participant, the person 
who administers the study treatment
and the person who performs the
blinded safety assessments must be 
different qualified individuals.
 
 
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Trial Period
Screening
Treatment
Follow-up
Notes
Visit Number/Title
1/Screening
2/Peri-anesthetic 
period
3/Post-anesthetic 
period
4/Follow-up contact
Visit 1 (Screening) and Visit 2 may 
occur on the same day
Follow-up contact may occur via 
telephone or visit dependent upon 
hospitalization status
Scheduled Day
Day -1
Day 1
Day 1 to 2
Day 14
Scheduling Window Days
-14 to -1 Days
±0 days
See Notes
+2 days
Visit 3 should occur between 4 and 
36 hours after administration of 
study treatment
Efficacy Procedures
Neuromuscular Monitoring
X
Conducted using TOF-Watch® SX 
device.
Safety Procedures
Full Physical Examination 
X
Targeted Physical Examination
X
To be collected by the blinded safety 
assessor.
Vital Signs (heart rate, blood 
pressure, temperature, respiratory 
rate, oxygen saturation)
X
X
X
For Visit 2, scheduled vitals are to be 
performed prior to administration of
NMBA; prior to administration of
study treatment; and 2, 5, 10 and 
30 minutes after study treatment.
Height
X
Weight
X
X
Continuous ECG Monitoring
X
To occur at least 5 minutes before, 
during, and for 30 minutes following 
administration of study treatment.
 
 
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Trial Period
Screening
Treatment
Follow-up
Notes
Visit Number/Title
1/Screening
2/Peri-anesthetic 
period
3/Post-anesthetic 
period
4/Follow-up contact
Visit 1 (Screening) and Visit 2 may 
occur on the same day
Follow-up contact may occur via 
telephone or visit dependent upon 
hospitalization status
Scheduled Day
Day -1
Day 1
Day 1 to 2
Day 14
Scheduling Window Days
-14 to -1 Days
±0 days
See Notes
+2 days
Visit 3 should occur between 4 and 
36 hours after administration of 
study treatment
Urine Pregnancy Test, Serum 
β-hCG, as applicable
X
X
Urine or serum β-hCG test is 
required prior to surgery (or other 
clinical situation that requires 
administration of NMBA) in any 
young woman with onset of
menarche. Serum β-hCG pregnancy 
test is required only if urine is 
positive, unless local requirements 
require otherwise. If Visit 1 
(Screening) and Visit 2 occur on the 
same day, then the pregnancy test 
does not need to be repeated.
Hematology
X
X
Laboratory samples will be sent to a 
central laboratory for analysis.
Visit 2: Samples need not be drawn 
if local lab results are available 
within 14 days of randomization. 
Visit 3: Samples need not be drawn 
if local lab results are (or will be)
available within 24 hours after 
administration of study treatment.
Chemistry
X
X
Laboratory samples will be sent to a 
central laboratory for analysis.
Visit 2: Samples need not be drawn 
if local lab results are available 
within 14 days of randomization. 
Visit 3: Samples need not be drawn 
if local lab results are (or will be)
available within 24 hours after 
administration of study treatment.
 
 
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Trial Period
Screening
Treatment
Follow-up
Notes
Visit Number/Title
1/Screening
2/Peri-anesthetic 
period
3/Post-anesthetic 
period
4/Follow-up contact
Visit 1 (Screening) and Visit 2 may 
occur on the same day
Follow-up contact may occur via 
telephone or visit dependent upon 
hospitalization status
Scheduled Day
Day -1
Day 1
Day 1 to 2
Day 14
Scheduling Window Days
-14 to -1 Days
±0 days
See Notes
+2 days
Visit 3 should occur between 4 and 
36 hours after administration of 
study treatment
eGFR
X
Performed only for participants with 
history of renal impairment, eGFR to 
be calculated with revised Schwartz 
estimate using serum creatinine at
Visit 1 (Screening).
AE/SAE/ECI Review
X
X
X
X
Visit 3 only: Must be performed by 
blinded safety assessor.
Adverse Device Events 
Monitoring
X
TOF-Watch® SX device
Pharmacokinetics
PK Sampling
X
X
For PK, 5 to 6 samples will be drawn 
at approximately the following time 
points: 2, 15, 30, 60 minutes; 5, 
10 hours after study treatment
administration. (See Section 9.6 for 
details)
PK is required for Part A of the 
study only.
Abbreviations:  AE = adverse event, β-hCG = β-human chorionic gonadotropin, ECI = event of clinical interest, ECG = electrocardiogram, eGFR = estimated glomerular filtration 
rate, NMBA = neuromuscular blocking agent, SAE = serious adverse event, SCr = serum creatinine, TOF = train-of-four
 
 
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3. Introduction
Study Rationale 
3.1
Sugammadex sodium, herein referred to as sugammadex, has been demonstrated to be safe and 
effective in reversing rocuronium and vecuronium induced neuromuscular blockade (NMB) in 
adults; however, clinical trial data in children is limited. The current trial aims to demonstrate 
that sugammadex is generally safe and effective for reversing both moderate and deep block after 
rocuronium or vecuronium induced NMB in children and adolescents.
Part A of this trial will evaluate the pharmacokinetic (PK) parameters of the 2 mg/kg and 4mg/kg 
doses of sugammadex in children and adolescents.  The PK data that is generated from Part A 
will be evaluated to ensure that the doses intended to be administered in Part B (2mg/kg and 4 
mg/kg) demonstrate similar exposures to the approved doses in adults. Although limited, the 
pediatric data from a previous PK study [Trial 19.4.306 (P034)] [Plaud, B., et al 2009] provide
preliminary evidence that the intended doses will exhibit comparable exposures in the pediatric 
age groups when compared to adults.
Background
3.2
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information 
on MK-8616.
Pharmaceutical and Therapeutic Background
3.2.1
Neuromuscular blockade is an important component of many surgical and medical procedures, 
as it provides muscle relaxation and reduces patient movement. In current anesthesia practice, 
reversal agents of NMB are often administered at the end of the procedure to aid the recovery of 
muscle function and prevent residual NMB after the procedure. Prior to the availability of 
sugammadex, all clinically used reversal agents (eg, neostigmine, edrophonium) were 
acetylcholinesterase inhibitors. These agents achieved reversal of NMB, but at the cost of 
multiple side effects due to their nonselective potentiation of cholinergic neurotransmission.
Moreover, these agents are only able to reverse NMB at a moderate level of block, in which 
neuromuscular transmission is partially recovered, which limits their utility.
Sugammadex is a modified gamma-cyclodextrin administered at the end of surgical procedures 
to reverse paralysis induced by the steroidal neuromuscular blocking agents (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. Since this mechanism of action does not involve direct interaction with cholinergic 
systems, it circumvents undesired side effects associated with acetylcholinesterase inhibitors. 
Furthermore, sugammadex does not require the presence of neuromuscular activity before 
administration, and is therefore effective in reversal of both moderate and deep levels of NMB.
Sugammadex, as well as the complex of sugammadex and rocuronium or vecuronium, is cleared 
almost entirely via the kidney. In adults, there are no dose adjustments required for mild or 
 
 
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moderate renal impairment. The use of sugammadex in severe renal impairment is not 
recommended.
Sugammadex has been extensively studied in 58 clinical trials with a total of 5999 exposures to 
intravenous (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 countries and marketed in more than 50 countries, with an estimated >30 million 
exposures worldwide at the time of authoring this document.
In the pediatric population, sugammadex was studied in a randomized placebo-controlled trial
[Trial 19.4.306 (P034)] [Plaud, B., et al 2009] that evaluated reversal of rocuronium-induced 
moderate NMB (n=64). The trial evaluated children and adolescents across 3 age categories: 
infants (28 days to 23 months inclusive [n=8]); children (2 to 11 years inclusive [n=26]); 
adolescents (12 to 17 years inclusive [n=30]). The PK, efficacy, and safety results were generally 
consistent with the adult profile. No data on the use of sugammadex in neonates is available.
Pre-clinical and Clinical Trials
3.2.2
Refer to the IB for information on the pre-clinical and clinical development of sugammadex.
In addition, there are 2 other clinical trials planned to be conducted in an adult population:
1) A safety trial with adult participants who are categorized as American Society of 
Anesthesiologists (ASA) Class 3 or 4.
2) A safety and efficacy trial with adult participants who are morbidly obese.
Benefit/Risk Assessment
3.3
The Sponsor considers that the currently approved adult doses are appropriate for assessment to 
provide the optimal benefit/risk ratio in this trial, based on the adult Phase 3 trials, subsequent 
post marketing data, and the pediatric information collected to date in prior sugammadex trials.
Sugammadex has a positive benefit-risk profile and is well tolerated in the approved indications 
as described in the Investigator’s Brochure. It has specifically been shown to be superior (faster 
recovery as well as effective in a higher proportion of treated participants) to both placebo and 
neostigmine for reversal of moderate and deep NMB. Reversal of deep NMB is a unique benefit 
of sugammadex compared to other current treatments, which can only reverse moderate block. 
From a risk perspective, sugammadex has been shown to be generally safe and well tolerated. 
The use of sugammadex at recommended doses is associated with a low risk of residual NMB or 
recurrence of NMB compared with current treatment. 
Additional details regarding specific benefits and risks for participants in this clinical trial may 
be found in the accompanying IB and informed consent documents.
 
 
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4. Objectives/Hypotheses and Endpoints
For male/female participants between the ages of 2 to <17 years administered a NMBA for either 
moderate or deep block (rocuronium or vecuronium):
Objective/Hypothesis
Endpoint
Primary

Objective: To describe the 
pharmacokinetic parameters of 
sugammadex when used for reversal of 
moderate NMB or deep NMB (Part A).

Pharmacokinetic parameters: AUC, CL, 
Vz, Cmax, and t1/2.

Objective: To evaluate safety and 
tolerability of sugammadex (data will be 
pooled across Part A and Part B of the 
study).

Number of participants experiencing 
adverse events.

Objective: To evaluate the efficacy of 
sugammadex in comparison to 
neostigmine for the reversal of moderate 
NMB (Part B).

Hypothesis: Sugammadex is 
superior to neostigmine in 
reversing moderate neuromuscular 
blockade as measured by time to 
recovery to a train-of-four (TOF)
ratio of ≥0.9.

Time to recovery to a TOF ratio of ≥0.9.
Secondary

Objective: To evaluate the efficacy of 
sugammadex in comparison to 
neostigmine for the reversal of moderate 
NMB (Part B).

Time to recovery to a TOF ratio of ≥0.8.

Time to recovery to a TOF ratio of ≥0.7.
Tertiary/Exploratory

Objective: To evaluate the efficacy of 
sugammadex in comparison to 
neostigmine for the reversal of moderate 
NMB (Part B).

Time to extubation: Interval from 
administration of reversal agent to 
removal of the endotracheal tube.

Time to OR discharge

Time to PACU discharge

Time to hospital discharge

Incidence of delayed recovery
 
 
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5. Study Design 
Overall Design 
5.1
This is a randomized, active comparator-controlled, parallel group, multi-site, double-blinded
trial of sugammadex in pediatric participants from 2 to <17 years of age for the reversal of NMB.
The design of the trial consists of a two-part structure (Part A and Part B).  The purpose of the 
trial is to first identify the doses of sugammadex that will produce similar exposure in the 2 to 
<17 year old age group when compared to systemic exposure noted in adults following 
administration of the 2 mg/kg and 4 mg/kg doses (lead-in cohort Part A), followed by the 
assessment of safety and efficacy parameters (Part B). Once Part A of the study is complete, an 
interim analysis (IA) will be performed (prior to the commencement of enrollment in Part B) to 
evaluate PK and safety data. PK and safety data will be reviewed by a standing internal Data 
Monitoring Committee (siDMC) and safety data will be reviewed by an external Data 
Monitoring Committee (eDMC). Details are provided in Section 10.7.
All participants will receive a single dose of sugammadex or neostigmine to reverse NMB.
Potential trial participants will have a planned non-emergent surgical procedure or clinical 
situation that requires moderate or deep NMB. 
The sample size of the study is in alignment with the minimum number of participants required 
to obtain the relevant safety information for each level of NMB as specified by the Sponsor’s 
commitments under the Pediatric Research Equity Act (PREA).
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial SoA - Section 2. Details of each procedure are 
provided in Section 9 – Study Assessments and Procedures.
Study Diagram
5.1.1
The Study Diagram and Study Treatment Randomization are depicted in Figure 1 and Figure 2.
Figure 1
Study Diagram
 
 
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Figure 2
Study Treatment Randomization
Number of Participants
5.2
Approximately 238 participants will be enrolled in this study.
Beginning and End of Study Definition
5.3
The overall trial begins when the first participant signs the informed consent/assent form.  The 
overall trial ends when the last participant completes the last study-related phone-call or visit, 
withdraws from the trial or is lost to follow-up (i.e. the participant is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.3.1
The clinical trial may be terminated early if the extent (incidence and/or severity) of emerging 
effects/clinical endpoints is such that the risk/benefit ratio to the trial population as a whole is 
unacceptable.  In addition, further recruitment in the trial or at (a) particular trial site(s) may be 
stopped due to insufficient compliance with the protocol, GCP and/or other applicable regulatory 
requirements, procedure-related problems or the number of discontinuations for administrative 
reasons is too high.
 
 
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Scientific Rationale for Study Design 
5.4
In accordance with the Sponsor’s commitments under the PREA, pharmacokinetic, safety, and 
efficacy data will be collected in a two-part structure (Part A and Part B). The study will contain 
a lead-in cohort where PK parameters and safety will be assessed (Part A), before proceeding to 
the safety and efficacy portion of the protocol (Part B).
Part A:
Part A is a randomized, double-blinded, multi-site study evaluating PK, safety, and tolerability of 
sugammadex when used for reversal of NMB. The PK data that is collected in Part A will be 
used to accurately characterize the PK parameters in pediatric patients of 2 to <17 years of age, 
and identify the pediatric dose that will provide similar exposure to adults. Based on the known 
PK characteristics of sugammadex in children and adolescents, the 2 mg/kg and 4 mg/kg doses 
of sugammadex (for reversal of moderate and deep block, respectively) are predicted to achieve 
similar exposures to that of adults. However, if PK results of the interim analysis (IA) from Part 
A of the study are inconsistent with those previously established in pediatrics and/or adults, then
Part A and the subsequent IA will be repeated with modified doses until comparable doses are
obtained. Details regarding the planned IA are described in Section 10.7. 
Study enrollment will be paused after the completion of Part A to allow for review of the IA 
results by the siDMC and the eDMC. (Details are provided in Section 10.7 and Appendix 3).
Once the appropriate doses are confirmed for moderate and deep block, then Part B will 
commence. 
Part B:
Part B is a randomized, double-blinded, active-comparator controlled, multi-site study evaluating 
the safety and efficacy of sugammadex for reversal of moderate or deep NMB in pediatric 
participants.
To ensure that adequate safety data is obtained in the relevant age groups, Part B will enroll at 
least 40% of participants into the 2 to <6 year old age cohort.  Enrollment into the 12 to <17 
cohort will be capped at approximately 30%. 
For the entire pediatric program, including this study, the eDMC will also review accruing data 
on the protocol-specified ECI's of anaphylaxis and clinically relevant bradycardia.  Overall 
program-wide stopping criteria are in effect for these two ECI's.  The detailed criteria are 
described in the eDMC charter.
The dosing for each depth of block in this study will be based on the results from Part A. The 
currently predicted doses for Part B include sugammadex 2 mg/kg for moderate block and 
4 mg/kg for deep block. 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 to target maintenance at the 
assigned depth of block. For participants randomized to the moderate block arms of Part B,
either sugammadex 2 mg/kg or neostigmine 50 mcg/kg (up to 5mg maximum dose) 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. For participants randomized to the deep block arm of Part B, sugammadex 4 mg/kg 
 
 
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will be given after the last dose of administered NMBA and within 2 minutes of detection of 1 to
2 post-tetanic counts (PTC) with a range of 1-5 PTC at a TOF count of 0.
Quantitative monitoring will be performed using acceleromyography (eg, TOF-Watch® SX). The 
time to recovery to a TOF ratio of ≥0.9 will be the primary efficacy endpoint, consistent with the 
endpoint approach used in prior studies of sugammadex.
Rationale for Endpoints
5.4.1
Efficacy Endpoints
5.4.1.1
The primary efficacy endpoint for the study is the time to recovery of NMB from the 
administration of study medication to a TOF ratio of ≥0.9. During recovery of neuromuscular
transmission after blockade from an NMBA, 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, 
individuals 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 [Eriksson, L. I., 
et al 1993]. Conversely, recovery to a TOF ratio of 0.9 has been shown to correlate with 
essentially complete clinical recovery from the effects of NMB. [Eriksson, L. I. 1999]
Safety Endpoints
5.4.1.2
A primary objective of this study is an overall assessment of safety and tolerability of 
sugammadex in pediatric participants (2 to <17 years of age).
To ensure timely reporting and comprehensive data collection regarding events of clinical 
interest (ECI), the following types of events are pre-specified as ECIs:

Hypersensitivity and/or anaphylaxis (defined by Sampson et al.) [Sampson, H. A., et al 
2005]: Adjudication of potential hypersensitivity and/or anaphylaxis events will be 
conducted by an independent external Adjudication Committee.

Clinically relevant bradycardia, defined as any bradycardia event necessitating 
intervention, as determined by investigator judgment.
In addition, the incidence of any treatment-emergent bradycardia or treatment-emergent relative 
bradycardia after administration of study treatment will be assessed in this study. Continuous 
electrocardiogram (ECG) monitoring will be performed, beginning at least 5 minutes before and 
for at least 30 minutes after administration of study treatment to facilitate assessment of 
treatment-emergent bradycardia.  

Treatment-emergent relative bradycardia is defined as a heart rate that has decreased 
20% or greater as compared to the participant’s pre-dose baseline heart rate value, 
sustained for at least 30 seconds, [Butterworth, J. F., et al 2013] and occurring after the 
administration of study treatment.

Treatment-emergent bradycardia is defined as a heart rate generally below the 1st
percentile for age that has also decreased 20% or greater as compared to the participant’s 
pre-dose baseline heart rate value, sustained for at least 30 seconds, [Butterworth, J. F., et 
al 2013] and occurring after the administration of study treatment. Refer to Appendix 6: 
Bradycardia Definition by Age Range.
 
 
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Information regarding residual NMB, recurrence of NMB, and adverse respiratory events (eg, 
hypercapnia, dyspnea, hypoxia, and distress) will be collected via standard adverse event (AE)
reporting.
Standard safety assessments (ie, physical examination, laboratory assessments, and vital signs 
including heart rate and blood pressure) will be recorded at specified time points (refer to
Section 2).
Pharmacokinetic Endpoints
5.4.1.3
Pharmacokinetic sparse sampling will be conducted (Part A) to estimate model-based clearance 
and total exposure of sugammadex. Each participant is to provide at least 5 samples. 
Pharmacokinetic endpoints include AUC, Cmax, CL, Vz, and t1/2. Details are provided in Section 
9.6.
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 and the Clinical 
Director.
Information regarding the collection and shipping of plasma samples will be provided in the
administrative binder.
Pharmacodynamic Endpoints
5.4.1.4
There are no pharmacodynamic endpoints that will be collected in the current trial.
Rationale for the Use of Comparator
5.4.2
In the case of moderate NMB reversal, neostigmine is the most frequently used 
acetylcholinesterase inhibitor and is therefore the comparator for the moderate block arm of this 
trial. Neostigmine and glycopyrrolate (or neostigmine and atropine) will be administered 
intravenously according to current prescribing information. Where glycopyrrolate is not readily 
available or in situations where glycopyrrolate is contraindicated, atropine may be used. For the 
purposes of this study, any reference to the administration of neostigmine herein or in other study 
documents should be understood as a reference to the administration of neostigmine and 
glycopyrrolate, or neostigmine and atropine unless otherwise stated. The selected dose of 50 
mcg/kg (up to a maximum of 5 mg total dose) for neostigmine is within the range of 
recommended dosing for children and adolescents, is consistent with prior sugammadex trials,
and provides a standardized comparison to the sugammadex arm.
Based on a 50 mcg/kg dose of neostigmine, the following doses of glycopyrrolate and atropine 
are suggested:

Glycopyrrolate: 10mcg/kg (or a neostigmine:glycopyrrolate dose ratio of 5:1)

Atropine: 20 mcg/kg (or a neostigmine:atropine dose ratio of 2.5:1)
Because sugammadex is the only reversal agent indicated for reversal of deep NMB, no 
comparator is available for study in the setting of deep NMB in this trial.
 
 
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Justification for Dose 
5.5
Based on the available data from the sugammadex clinical trial program, no additional efficacy 
benefits are expected from higher doses than those recommended for adults (2 and 4 mg/kg, for 
reversal of moderate and deep NMB respectively). The use of lower doses in children is also 
unlikely to offer tangible benefits for patients; and based on trial data in adults, the use of doses 
lower than recommended (ie, <2 mg/kg) may lead to an increased risk of recurrence of NMB
after initial reversal. This study aims to provide evidence that the weight-based dosing approach 
established for sugammadex use in adults is also applicable for pediatric patients; thereby 
reducing the risk of pediatric patients being administered either supratherapeutic or inadequate 
doses.
Depending on the depth of NMB (moderate or deep), a sugammadex dose of either 2 or 4 mg/kg 
will be administered to reverse NMB. Sugammadex will be administered as a single IV bolus 
dose, in accordance with prescribing information, which states to administer a dose of 2 mg/kg 
sugammadex if neuromuscular recovery has occurred up to at least the reappearance of T2 
following the last dose of administered NMBA (ie, moderate blockade); or to administer a dose 
of 4 mg/kg sugammadex if neuromuscular recovery has reached at least 1 to 2 PTCs following 
the last administered dose of NMBA (ie, deep block).
6. Study Population
Male/Female participants between the ages of 2 and <17 years who will be administered NMBA 
for either moderate or deep block will be enrolled in this trial.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
Inclusion Criteria
6.1
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Must be categorized as ASA Physical Status Class 1, 2, or 3, as determined by the 
investigator.
2. Have a planned non-emergent surgical procedure or clinical situation (eg, intubation) that 
requires moderate or deep NMB with either rocuronium or vecuronium.
3. Have a planned surgical procedure or clinical situation that would allow objective 
neuromuscular monitoring techniques to be applied with access to the arm for 
neuromuscular transmission monitoring.
Demographics
4. Age between 2 to <17 years at Visit 2.
5. A female participant is eligible to participate if she is not pregnant (see Appendix 5), not 
breastfeeding, and at least one of the following conditions applies: 
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR 
 
 
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b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the 
treatment period and for at least 7 days after the last dose of study treatment.
Informed Consent/Assent
6. The participant (and/or legally acceptable representative, if applicable) provides written 
informed consent/assent for the trial.
Exclusion Criteria 
6.2
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has any clinically significant condition or situation (eg, 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.
2. Has a neuromuscular disorder that may affect NMB and/or trial assessments.
3. Is dialysis-dependent or has (or is suspected of having) severe renal insufficiency 
(defined as estimated glomerular filtration rate (eGFR) <30 ml/min; using revised 
Schwartz estimate as method of calculation).
4. Has or is suspected of having a family or personal history of malignant hyperthermia.
5. Has or is suspected of having an allergy to study treatments or its/their excipients, to 
opioids/opiates, muscle relaxants or their excipients, or other medication(s) used during 
general anesthesia.
6. Has received or is planned to receive toremifene and/or fusidic acid via IV administration 
within 24 hours before or within 24 hours after administration of study treatment.
7. A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose 
of study treatment (see Appendix 5).  If the urine test cannot be confirmed as negative, a 
serum pregnancy test is required.  In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
Prior/Concomitant Therapy
8. Use of medication expected to interfere with study treatments given in this trial, as per 
prescribing information. Refer to Section 7.7.
Prior/Concurrent Clinical Study Experience
9. Has been previously treated with sugammadex or has participated in a sugammadex 
clinical trial.
10. Is currently participating in or has participated in an interventional clinical trial with an 
investigational compound or device within 30 days of signing the informed 
consent/assent for this current trial.
 
 
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Other Exclusions
11. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
Lifestyle Restrictions
6.3
There are no lifestyle restrictions that are required for study participation.
Meals and Dietary Restrictions
6.3.1
There are no dietary restrictions required for this study.
Caffeine, Alcohol, and Tobacco
6.3.2
There are no restrictions on caffeine, alcohol, and tobacco for this study.
Activity
6.3.3
There are no activity restrictions for study participation.
Screen Failures
6.4
Screen failures are defined as participants who consent/assent to participate in the clinical study 
but are not subsequently randomized.  A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any adverse events or serious adverse events (SAE) meeting reporting requirements as 
outlined in the entry guidelines.
Participant Replacement Strategy
6.5
Recruitment will continue until the needed number of evaluable PK participants is obtained for 
each age cohort.
7. Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol.
Treatments Administered
7.1
The study treatments to be used in this trial are outlined below in Table 1.
 
 
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Table 1
Study Treatments
Study 
Treatment 
Name:
Sugammadex 
MK-8616
Neostigmine 
methylsulfate
Glycopyrrolate
Atropine sulfate
Dosage 
Formulation:
Solution for 
injection
Solution for 
injection
Solution for 
injection
Solution for 
injection
Unit Dose 
Strength(s):
100mg/ml
0.5mg/ml 
0.2mg/ml
0.4mg/ml
Dosage 
Level(s):
2mg/kg or 
4mg/kg 
50mcg/kg
5 to 15 mcg/kg
10 to 30 mcg/kg
Route of 
Administration:
Intravenous
Intravenous
Intravenous
Intravenous
Sourcing:
Provided 
centrally by the 
Sponsor
Provided 
centrally by the 
Sponsor 
Provided 
centrally by the 
Sponsor 
Provided 
centrally by the 
Sponsor 
Use:
Investigational
Comparator
Required to be 
used with 
comparator
Required to be 
used with 
comparator
All supplies indicated in Table 1 will be provided per the ‘Sourcing’ row depending upon local 
country operational requirements.  Every attempt should be made to source these supplies from a 
single lot/batch number. The trial site is responsible for recording the lot number, manufacturer,
and expiry date for any locally purchased product as per local guidelines unless otherwise 
instructed by the Sponsor.
Refer to section 9.1.8 for details regarding administration of the study treatment.
In the current study, neostigmine and glycopyrrolate (or neostigmine and atropine) will be used 
according to the applicable labeling, and administration of neostigmine, as in usual practice, will 
be accompanied by administration of glycopyrrolate (or atropine), used to counter the anticipated 
muscarinic effects of neostigmine. Where glycopyrrolate is not readily available, atropine may 
be used.
For the purposes of this study, any reference to the administration of neostigmine herein or in 
other study documents should be understood as a reference to the administration of neostigmine 
and glycopyrrolate or neostigmine and atropine, unless otherwise stated. Note that the target dose 
of neostigmine will be administered over 10 seconds; titration to effect is not allowed.
Medical Devices
7.1.1
●
Instructions for medical device use are provided in the TOF-Watch® SX Neuromuscular 
Transmission Monitoring Guidelines (provided separately).
 
 
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●
Device events, adverse device events and medical device incidents, including those 
resulting from malfunctions of the device must be detected, documented, and reported by 
the investigator throughout the study.  Refer to Section 9.3.8 for details.
Dose Modification (Escalation/Titration/Other) 
7.2
This section is not applicable to the study.
Method of Treatment Assignment 
7.3
Treatment randomization will occur centrally using interactive response technology (IRT).  
Participants will be allocated to 1 treatment group as indicated in Figure 2.
Participants in Part A of the study will be assigned randomly in a 1:1 ratio to the following 
treatment arms:

Moderate block and reversal with sugammadex 2 mg/kg; or

Deep block and reversal with sugammadex 4 mg/kg
Participants in Part B of the study will be assigned randomly in a 1:1:5 ratio to the following 
treatment arms:

Moderate block and reversal with sugammadex 2 mg/kg; or

Moderate block and reversal with neostigmine 50 mcg/kg; or

Deep block and reversal with sugammadex 4 mg/kg
Stratification
7.3.1
Treatment allocation/randomization will be stratified according to the following factors:
1. Age:
Participants will be enrolled into the following age cohorts: 12 to <17 years; 6 to <12 years; 2
to <6 years.
For Part B: To ensure that adequate safety data is obtained in the relevant age groups, Part B 
will target approximately 40% of participants into the 2 to <6 year old age cohort.  
Enrollment into the 12 to <17 cohort will be capped at approximately 30%.
Overall, participants in Part B of the study will be assigned randomly in a 1:1:5 ratio to three 
treatment arms. However, to ensure that adequate safety database sample sizes are reached 
within each age group, the allocation ratios will vary slightly by age:

1:1:4 ratio for the 12 to <17 year age cohort

1:1:5 ratio for the 6 to <12 year age cohort

1:1:6 ratio for the 2 to <6 year age cohort
2. Neuromuscular blocking agent: 

Rocuronium
 
 
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
Vecuronium
o
Note: Approximately 30% of the overall planned sample size will be enrolled in the 
vecuronium stratum.
Blinding 
7.4
Study Treatment:
With the exception of designated individuals (eg, unblinded Clinical Research Associates), all 
Sponsor study team personnel will be blinded to study treatment assignments. Refer to Section 
10.2 for details.
The site pharmacist (or delegate) will be unblinded to study treatment assignments in order to 
prepare study treatment. Study treatment will be provided to site staff in the operating room (OR)
(anesthesiologist) in masked syringe(s) to ensure that the contents of the syringe will not be 
revealed.
Site Personnel Roles:
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 syringe(s), OR staff aware of the depth of block will know the study treatment as there is 
no approved comparator for reversal of deep block.
The blinded safety assessor (BSA) will be an appropriately qualified health care professional 
(eg, 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 participant will be blinded to:
o
Study treatment assignment
o
The depth of NMB
o
Drug preparation records

The BSA for any given individual participant will:
o
Not be present during the operation and will not administer study treatment
o
Complete the post-anesthetic safety visit (Visit 3)
o
Complete the causality assessment for all AEs, including any perioperative AEs.
Note: if the BSA is not a physician, a blinded causality assessor who is a physician 
(MD, DO) will be responsible for completing the causality assessment for all AEs.
o
Be required to sign a statement confirming that the blind was maintained as to 
treatment group and relevant records

Of note, a BSA may, for any other participant, fill other study roles as appropriate for 
their qualifications.
 
 
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The anesthesiologist performing trial-related procedures during surgery (or other clinical 
situation requiring NMBA) and the BSA, must be 2 separate individuals and their roles and 
responsibilities must not overlap for any given individual participant. Given the complexity of 
maintaining the blind of the BSA for any given individual participant, any inadvertent unblinding 
of the BSA will be documented.
See Section 9.1.10 for a description of the method of unblinding a participant during the trial, 
should such action be warranted.
Preparation/Handling/Storage/Accountability
7.5
Dose Preparation
7.5.1
The rationale for selection of doses to be used in this trial is provided in Section 5.5. Specific 
calculations or evaluations which may be required to be performed in order to administer the 
proper dose to each participant are outlined in the Study Operations Manual.
Handling, Storage and Accountability
7.5.2
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
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.
The trial site is responsible for recording the lot number, manufacturer, and expiry date for any 
locally purchased product as per local guidelines unless otherwise instructed by 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 study 
treatments in accordance with the protocol and any applicable laws and regulations.
Treatment Compliance
7.6
Treatment compliance will be based on the actual dosage of study treatment assigned and the 
actual dose administered by the investigator.
Any dosage that deviates more than 10% from the planned dosage will be considered a 
medication error. No statistical tests will be performed with respect to treatment compliance.
 
 
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Concomitant Therapy
7.7
Medications specifically prohibited in the exclusion criteria are not allowed during the ongoing 
trial. If there is a clinical indication for any medication specifically prohibited during the 
trial, the investigator should discuss this with the Sponsor Clinical Director. The final decision 
on any supportive therapy rests with the investigator and/or the participant’s primary physician.
However, the decision to continue the participant in the trial requires the mutual agreement of the 
investigator, the Sponsor, and the participant.
Rocuronium or vecuronium are concomitant medications to be used per label as adjunct to 
general anesthesia. Besides rocuronium or vecuronium, a participant must not be administered 
any other NMBA during the trial, including:

Other steroidal NMBAs, such as pancuronium

Nonsteroidal NMBAs such as succinylcholine or benzylisoquinolinium compound (eg, 
cisatracurium)*

Toremifene or fusidic acid use within 24 hours before or within 24 hours after study 
treatment administration is prohibited.
*Except in the circumstance that renewed muscle relaxation is needed after 
administration of study treatment, in which case a non-steroidal NMBA should be 
administered.
Rescue Medications & Supportive Care
7.7.1
No rescue or supportive medications are specified to be used in this trial.
Treatment After the End of the Study 
7.8
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
7.9
The emergency unblinding call center will use the treatment/randomization schedule for the trial 
to unblind participants and to unmask study 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 (IRT) should be used in order to unblind participants and to 
unmask study treatment identity.  The Sponsor will not provide random code/disclosure 
envelopes or lists with the clinical supplies.
See Section 9.1.10, Participant Blinding/Unblinding, for a description of the method of 
unblinding a participant during the trial, should such action be warranted.
8. Discontinuation/Withdrawal Criteria 
Withdrawal from the Study
8.1
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
 
 
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If a participant withdraws from the study, they will not receive study treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the study
are outlined in Section 9.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 8.2.
Lost to Follow Up
8.2
If a participant fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the participant, the following procedures are to be performed:

The site must attempt to contact the participant and reschedule the missed visit.  If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, phone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Note:  A participant is not considered lost to follow-up until the last scheduled visit for 
the individual participant.  The amount of missing data for the participant will be 
managed via the pre-specified data handling and analysis guidelines.
9. Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. 

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
The maximum amount of blood drawn from each participant over the duration of the study will 
not exceed 6.5 mL.
According to current standards, the maximum blood volume collected from each participant 
should be based on weight and should generally not exceed 1% of total blood volume on a single
day (or 3% of total blood volume [2.4 mL blood per kg of body weight] during a given 4-week 
trial period), unless appropriate justification is documented by the investigator. [EMEA/CPMP 
2008] [Food and Drug Administration (CDER) 2014] In this trial, the maximum volume of blood 
drawn on any single day is 4 mL; this is within approximately 1% of total blood volume even for 
 
 
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eligible participants in this study whose weight falls within the lower ranges of the World Health 
Organization growth chart (ie, 2-year old girls in the 3rd percentile of growth).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. Refer to Appendix 7 for approximate blood volumes collected by trial visit.
Administrative and General Procedures
9.1
Informed Consent/Assent
9.1.1
The investigator or qualified designee must obtain documented consent, and assent if applicable,
from each potential participant or each participant’s legally acceptable representative prior to 
participating in a clinical trial. If there are changes to the participant’s status during the trial (eg, 
health or age of majority requirements), the investigator or qualified designee must ensure the 
appropriate consent/assent is in place. 
General Informed Consent/Assent
9.1.1.1
Consent/assent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent/assent form along with the dated 
signature of the person conducting the consent discussion. 
A copy of the signed and dated consent/assent form should be given to the participant before 
participation in the trial.
The initial informed consent/assent form, any subsequent revised written informed 
consent/assent form and any written information provided to the participant must receive the 
IRB/IEC’s approval/favorable opinion in advance of use.  The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
trial.  The communication of this information will be provided and documented via a revised 
consent/assent form or addendum to the original consent/assent form that captures the 
participant’s dated signature or by the participant’s legally acceptable representative’s dated 
signature.
Specifics about a trial and the trial population will be added to the consent/assent form template 
at the protocol level.  
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations and 
Sponsor requirements.  The assent, as applicable will adhere to IRB/ERC requirements, 
applicable laws and regulations and Sponsor requirements.
Inclusion/Exclusion Criteria
9.1.2
All inclusion and exclusion criteria will be reviewed at Visit 1 and Visit 2 by the investigator or 
qualified designee to ensure that the participant qualifies for the trial.
Participant Identification Card
9.1.3
All participants will be given a Participant 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 
 
 
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provide the participant with a Participant Identification Card immediately after the participant 
provides written informed consent/assent. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study treatment 
in emergency situations where the investigator is not available.
Medical History
9.1.4
A medical history will be obtained by the investigator or qualified designee. In addition to the 
evaluation of a participant’s medical history in terms of trial eligibility, all medical conditions 
since birth (including obstetrical history) will be documented on the appropriate electronic case 
report form (eCRF). The surgical procedure and medical indication for surgery (or other clinical 
situation that requires administration of NMBA) must be recorded in the Sponsor database.
Prior and Concomitant Medications Review
9.1.5
Prior Medications
9.1.5.1
The investigator or qualified designee will review prior medication use, and record prior 
medication taken by the participant within 30 days before starting the trial.
Concomitant Medications
9.1.5.2
The investigator or qualified designee will record medication taken by the participant during the 
trial. Refer to Section 7.7 for additional information on use of concomitant medications.
Rocuronium or vecuronium, are concomitant medications to be used per label as adjunct to 
general anesthesia.
Assignment of Screening Number
9.1.6
All consented participants will be given a unique screening number that will be used to identify 
the participant for all procedures that occur prior to treatment randomization.  Each participant 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details regarding the screening visit requirements (screening/rescreening) are provided 
in Section 9.11.1.
Assignment of Treatment/Randomization Number
9.1.7
All eligible participants will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the participant for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number is 
assigned to a participant, it can never be re-assigned to another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
 
 
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Treatment randomization in IRT may occur on the same day, or one day in advance of, the 
participant’s scheduled procedure. Sites should contact the Sponsor if a participant‘s procedure
is postponed for more than one day from the date of treatment randomization in IRT (eg, surgery 
postponed due to illness). Trial status of participants in these situations will be handled on a case 
by case basis in consultation with the Sponsor.
Treatment Administration
9.1.8
Administration of study treatment will be performed by the investigator or qualified designee.
Trial Treatment should begin within 1 day of treatment randomization.
Administration of Neuromuscular Blocking Agents
9.1.8.1
Rocuronium or vecuronium will be dosed as indicated as adjunct to general anesthesia, per 
prescribing information, for intubation purposes and maintenance of NMB by re-dosing or 
continuous infusion.
Neuromuscular block should be maintained within the assigned depth of block to ensure that the 
participant is at target depth of block at time of reversal. 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 (or other clinical situation that requires administration of NMBA) to target maintenance 
at the assigned depth of block. Only one NMBA should be used for the entire duration of surgery
(or other clinical situation that requires administration of NMBA), including the intubation dose. 
The NMBA used during surgery (or procedure) should be the NMBA noted in the IRT.
Timing of Dose Administration
9.1.8.2
Sugammadex or neostigmine is to be administered as a single bolus injection within 10 seconds, 
into a fast running existing IV line (per product label), on the day of surgery (or other clinical 
situation that requires administration of NMBA). After administration, site staff should perform a 
visual inspection of the line to ensure that study treatment was fully administered.
For participants randomized to moderate block, either sugammadex 2 mg/kg or neostigmine 50 
mcg/kg (up to 5mg maximum dose) 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 participants randomized to deep block, sugammadex 4mg/kg will be given after the last dose 
of administered NMBA and within 2 minutes of detection of a target of 1 to 2 PTC with a range 
of 1 to 5 PTC at a TOF count of 0.
Withdrawal/Discontinuation
9.1.9
Once a participant receives study treatment at Visit 2, all applicable procedures at subsequent 
visits should be performed as per Trial SoA - Section 2.
Any adverse events which are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 9.3 - Adverse Events.
 
 
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Participant Blinding/Unblinding
9.1.10
When the investigator or delegate needs to identify the drug used by a participant and the dosage 
administered in case of emergency eg, the occurrence of serious adverse events, 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 participant’s 
treatment assignment, the investigator or delegate must enter the intensity of the adverse events 
observed, the relation to study drug, the reason thereof, etc., in the medical chart etc.
Additionally, the investigator must go into the IRT system and perform the unblind in the IRT
system to update drug disposition.  In the event that the emergency unblinding call center is not 
available for a given site in this trial, IRT should be used for emergency unblinding in the event 
that this is required for participant safety.
Study treatment identification information is to be unmasked ONLY if necessary for the welfare 
of the participant.  Every effort should be made not to unblind the participant unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (eg, 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 participant’s code should be unblinded. Other trial site personnel and Sponsor 
personnel directly associated with the conduct of the trial should not be unblinded.
Calibration of Critical Equipment
9.1.11
The investigator or qualified designee has the responsibility to ensure that any critical device or 
instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or reproducible.  
Documentation of equipment calibration must be retained as source documentation at the trial 
site.
Critical Equipment for this trial includes:

TOF-Watch® SX device and accessories:  Details for device calibration and proper use 
can be found in supplemental documentation (Neuromuscular Transmission Monitoring 
Guidelines) provided separately.

Vital sign monitors: Alarm signals should be calibrated to the appropriate range
according to the participant’s age category.

ECG equipment: This equipment should be calibrated per manufacturer specifications 
and/or local guidelines/processes.
Efficacy Assessments 
9.2
Neuromuscular Monitoring
9.2.1
Details for NMTM training and site personnel qualification, set-up, calibration, data collection, 
etc. are provided in the Neuromuscular Transmission Monitoring Guidelines provided separately. 
 
 
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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 participant 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 
participant on clinical grounds is to be based on investigator judgment taking into account 
participant’s medical requirements. 
Adverse Events, Serious Adverse Events and Other Reportable Safety Events 
9.3
The definitions of an adverse event (AE) or serious adverse event (SAE), as well as the method 
of recording, evaluating, and assessing causality of AE and SAE and the procedures for 
completing and transmitting AE, SAE and other reportable safety event reports can be found in 
Appendix 4.
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator, who is a qualified physician, and any designees are responsible for detecting, 
assessing, documenting, and reporting events that meet the definition of an AE or SAE as well as 
other reportable safety events. Investigators remain responsible for following up AE, SAEs and 
other reportable safety events for outcome according to Section 9.3.3.
Time Period and Frequency for Collecting AE, SAE and Other Reportable Safety 
9.3.1
Event Information 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed but 
before treatment allocation/randomization must be reported by the investigator if the participant 
is receiving placebo run-in or other run-in treatment, if the event causes the participant 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, or a procedure. 
From the time of treatment allocation/randomization through 14 days following cessation of 
treatment, all AEs, SAEs and other reportable safety events must be reported by the investigator. 
Additionally, any SAE brought to the attention of an investigator at any time outside of the time 
period specified in the previous paragraph must be reported immediately to the Sponsor if the 
event is considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events in 
former study participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers the event to 
be reasonably related to the study treatment or study participation, the investigator must 
promptly notify the sponsor.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the sponsor or designee within the timeframes as indicated in Table 2.
 
 
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Table 2
Reporting Time Periods and Timeframes for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
Specified Follow-
up Period
Reporting Time Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome.)
Within 24 
hours of 
learning of 
event
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 5 days 
of learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- Potential DILI
- Require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 days 
of learning of 
event
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 days 
of learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
 
 
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Method of Detecting AE, SAE and Other Reportable Safety Events
9.3.2
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence.
Follow-up of AE, SAE and Other Reportable Safety Event Information 
9.3.3
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AE, SAE and other reportable safety events including 
pregnancy and exposure during breastfeeding, ECI, Cancer and Overdose will be followed until 
resolution, stabilization, until the event is otherwise explained, or the participant is lost to follow-
up (as defined in Section 8.2). In addition, the investigator will make every attempt to follow all 
non-serious AEs that occur in randomized participants for outcome.  Further information on 
follow-up procedures is given in Appendix 4.
Regulatory Reporting Requirements for SAE
9.3.4
●
Prompt notification (within 24 hours) by the investigator to the sponsor of SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are met.
●
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. All Adverse Events will be reported to regulatory authorities, IRB/IECs 
and investigators in accordance with all applicable global laws and regulations, i.e., per 
ICH Topic E6 (R1) Guidelines for Good Clinical Practice.
●
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
●
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or 
9.3.5
SAEs
This section is not applicable to the study.
Pregnancy and Exposure During Breastfeeding
9.3.6
Although pregnancy and infant exposure during breastfeeding are not considered adverse events, 
any pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported 
to the investigator or their designee) that occurs during the trial are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
 
 
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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.
Events of Clinical Interest (ECI)
9.3.7
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
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. Hypersensitivity or anaphylaxis
a.
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. 
b. 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, all potential cases of anaphylaxis (as defined by 
Sampson et al.) [Sampson, H. A., et al 2005] will be adjudicated.
3. Clinically relevant bradycardia, defined as any bradycardia event necessitating 
intervention, as determined by investigator judgment.
Refer to the ECI Guidance document (or equivalent) for reporting the ECIs of hypersensitivity or 
anaphylaxis, and clinically relevant bradycardia.
Assessing and Recording Patient/Device Events
9.3.8
Device and/or patient events include all untoward events related to the use of the TOF-Watch®
SX device. 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 participant caused by or suspected to be caused by the TOF-
Watch® SX.
All device or patient events that occur after allocation/randomization must be reported by the 
investigator (initial and follow-up) if they cause the participant to be excluded from the trial, or 
 
 
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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 allocation/randomization through 14 days following cessation of treatment, all 
device or patient events (initial and follow-up) 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 not meeting serious criteria, whether or not related to the 
Sponsor’s product must be reported within 5 calendar days of learning of event to the Sponsor. 
The reporting timeframe for events meeting any serious criteria is described in section 9.3.1. The 
investigator will make every attempt to follow all non-serious device or patient events for 
outcome.  
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
During the course of the trial, a participant may provide feedback related to the TOF-Watch®
SX.  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 the TOF-Watch® SX.  All reports of 
customer feedback must be reported to the Sponsor within 14 calendar days of awareness.  
Sponsor Contact information can be found in the Investigator Trial File Binder (or equivalent).
Device Incidents
9.3.8.1
An incident is any malfunction or deterioration in the characteristics and/or performance of the 
device (TOF-Watch® SX), 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 participant or user, or of 
other persons, or to a serious deterioration in their state of health.
A serious deterioration in the state of health can include:
●
Life-threatening illness, even if temporary in nature;
●
Permanent impairment of a body function or permanent damage to a body structure;
●
Any indirect harm as a consequence of an incorrect diagnostic or IVD test results when 
used within instructions for use;
●
Fetal distress, fetal death or any congenital abnormalities or birth defects;
●
Condition necessitating medical or surgical intervention, including hospitalization or 
prolongation or existing hospitalization to prevent one of the above;
●
Cases that are considered medically significant.
For the time period beginning at allocation/randomization, any incident, including follow up to 
an incident, including death due to any cause, that occurs to any participant must be reported 
within 24 hours to the Sponsor if it causes the participant 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. 
 
 
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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 participants involved with incidents must be followed up for outcome.
Regulatory Reporting Requirements for Device Events and Incidents 
9.3.8.2
Device Events and Incidents will be reported to regulatory authorities, IRB/IECs and 
investigators in accordance with all applicable global laws and regulations, ie, ICH Topic E6 
(R1) Guidelines for Good Clinical Practice.
Treatment of Overdose
9.4
In this trial, an overdose of sugammadex is considered a dose ≥2 times the intended dose to 
which the participant 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. An overdose of atropine is considered a dose of greater than 0.5 mg for participants up to 
age 11 years, and a dose of 1 mg for ages 12 to <17 years.
Safety 
9.5
Details regarding specific safety procedures/assessments to be performed in this trial are 
provided below. The total amount of blood to be drawn over the course of the trial, including 
approximate blood volumes drawn by visit and by sample type per participant can be found in 
Section 9.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
9.5.1
A complete physical examination will be conducted, per institutional standard.
The principal investigator or licensed clinician (ie, physician, physician’s assistant, or nurse 
practitioner) will perform a full physical examination of the following organ systems at 
screening (Visit 1):

Head, eyes, ears, nose, and throat

Neck

Respiratory system

Cardiovascular system

Abdomen
 
 
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
Skin and extremities

Neurological system, including mental status, motor strength, muscle tone, and reflexes.
Any medical conditions found during the full physical exam will be recorded in the Sponsor 
database.
A second physical examination (targeted physical exam) will be performed at the post-anesthetic 
visit (Visit 3) by the BSA. At a minimum, the following organ systems will be assessed in the 
targeted physical exam:

Respiratory system

Cardiovascular system

Neurological system, including mental status, motor strength, muscle tone, and reflexes.
Additional organ systems may be assessed at the discretion of the BSA. Any clinically 
significant change from the initial physical examination will be recorded in the Sponsor 
database.
Height and Weight
9.5.2
Height (cm) and weight (kg) will be measured and recorded. Measurements should be recorded 
to the nearest unit. Body weight will be obtained using a standardized digital scale without shoes 
and with heavy clothing (eg, jacket or coat) removed.
Vital Signs
9.5.3
Heart rate, blood pressure, respiratory rate, oxygen saturation, and core body temperature will be 
obtained, at the following time points:

Screening visit (Visit 1)

Prior to administration of NMBA

After the final dose of NMBA is administered, prior to administration of study treatment

At 2, 5, 10, and 30 minutes following administration of study treatment (refer to Table 3
for vital sign assessment windows)

Post-anesthetic visit (Visit 3)
Blood pressure and heart rate measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. The same 
method for heart rate and blood pressure (eg, manual or automated) should be used for all 
measurements for each individual participant, unless the clinical situation dictates otherwise.
Core body temperature must be measured; axillary or skin temperature measurements are 
unacceptable for core body temperature assessment, another method must be used. The 
investigator will maintain a record of the participant’s core body temperature during NMTM (the 
target core temperature is ≥ 35ºC [95ºF]).
 
 
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Table 3
Assessment Windows for Vital Signs Following Administration of Study Treatment
Time Point of Assessment for 
Vital Signs
Assessment Window*
2 minutes
(1, 3) minutes
5 minutes
(3, 7) minutes
10 minutes
(8, 12) minutes
30 minutes
(25, 35) minutes
*upper and lower limits are inclusive.
Electrocardiogram
9.5.4
During the peri-anesthetic visit (Visit 2), continuous ECG monitoring will occur at least 5 
minutes before, during, and for 30 minutes after administration of study treatment. 
Clinical Safety Laboratory Assessments
9.5.5
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for the 
timing and frequency. 
●
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.
●
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
●
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
●
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study treatment, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator. 
Pharmacokinetics
9.6
Pharmacokinetic samples are required for Part A of the study only; 5 to 6 samples will be drawn 
at the following time points:

At 2, 15, 30, and 60 minutes following administration of sugammadex

At 4 to 6 hours following administration of sugammadex
 
 
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
At 10 to 12 hours following administration of sugammadex*
*Note: depending on length of hospital stay, the 10 to 12 hour sample may not be drawn. 
However, if the participant remains hospitalized, then all attempts should be made to 
obtain the 10 to 12 hour sample.
Pharmacokinetic sampling windows are not provided because the PK samples will be analyzed 
using actual time. However, every effort should be made to adhere to the time points specified 
above.
Blood Collection for Plasma Sugammadex
9.6.1
Sample collection, storage and shipment instructions for plasma samples will be provided in the 
operations/laboratory manual.
For all participants, PK blood samples are to be drawn from a separate IV line other than the site 
used for study treatment administration. If the separate site is in the same limb, the second site 
must be distal to the site into which study treatment was administered. However, if available, a 
multi-lumen IV, peripherally inserted central catheter, or central venous catheter may be used to 
both administer study treatment and also draw PK blood samples, provided a different lumen is 
used and with adequate flushing (per standard hospital procedure) to ensure patency of the access 
line. Arterial access sites will not be suitable for drawing PK blood samples for this study.
Pharmacodynamics
9.7
Pharmacodynamic parameters will not be evaluated in this study.
Future Biomedical Research Sample Collection 
9.8
Future Biomedical Research Samples will not be collected in this study.
Biomarkers
9.9
Biomarkers are not evaluated in this study.
Medical Resource Utilization and Health Economics
9.10
Medical resource utilization and health economics data will be collected in the CRF by the 
investigator and study-site personnel for all participants throughout the study. Protocol-mandated 
procedures, tests, and encounters are excluded. 
The data collected may be used to conduct exploratory economic analyses and will include:

Hospital length of stay (including duration by wards [eg, OR, PACU])
Visit Requirements
9.11
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA).  Specific procedure-
related details are provided above in Section 9 – Study Assessments and Procedures.
 
 
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Screening (Visit 1)
9.11.1
Potential participants will be evaluated to determine that they fulfill the entry requirements as set 
forth in Section 6.1 and Section 6.2. If needed, a participant may repeat screening once; any 
additional rescreening will require consultation with the Sponsor.
Peri-anesthetic Visit (Visit 2)
9.11.2
The peri-anesthetic period begins when the participant is randomized and continues throughout 
the surgical period, ending just prior to 4 hours post-surgery (or other clinical situation that 
requires administration of NMBA).
Study staff will confirm that the participant still meets inclusion/exclusion criteria (eg, negative 
pregnancy test), review prior/concomitant medications, record the participant’s weight per SoA, 
and then randomize the participant using IRT. 
The pharmacist will prepare study treatment according to the Drug Preparation Manual.
An IV cannula for the administration of anesthetic drugs, NMBA, and study treatment will be 
inserted. A second IV cannula will be inserted into another vein (Refer to Section 9.6.1 for 
details) to allow collection of blood samples for safety and PK analysis at predefined time points.
Anesthesia will be induced and maintained according to the needs of the participant. Note: All 
medications, time of dose administration, and actual doses given to the participant are required to 
be recorded throughout the peri-anesthetic visit and transferred to Sponsor database.
At stable anesthesia, and before administration of the NMBA, the TOF-Watch® SX and 
accessories will be affixed to the participant’s arm according to the Neuromuscular Transmission 
Monitoring Guidelines. Neuromuscular monitoring will continue until recovery of the TOF ratio 
≥0.9. If a TOF ratio ≥0.9 is not reached, then monitoring should continue a minimum of 30 
minutes after the administration of study treatment. Refer to Section 9.2.1 for details.
Rocuronium or vecuronium will be administered; only 1 NMBA (either rocuronium or 
vecuronium per Investigator choice) should be used for the entire duration of surgery (or other 
clinical situation that requires administration of NMBA). The NMBA used during surgery (or 
procedure) will be the NMBA noted in the IRT. Additional doses of NMBA will be administered 
as clinically necessary, as determined by the Primary Investigator or designee, for the duration of 
the surgery to maintain assigned depth of block. Refer to Section 9.1.8, for details on the 
administration of NMBA and timing of dose administration.
Vital signs will be recorded per protocol. Blood samples for laboratory safety analyses and PK 
evaluation will be collected per protocol (refer to Section 2).
Post-anesthetic Visit (Visit 3)
9.11.3
Between at least 4 hours following study treatment administration and up to a maximum of 
36 hours after study treatment administration, the BSA will conduct Visit 3. Refer to Section 2
for more information.
The drug preparation records, depth of neuromuscular block, study treatment given, and 
TOF-Watch® SX traces will be sequestered from the BSA for any participant assessed by that 
given BSA.
 
 
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For any given individual participant, the BSA will be required to sign a statement confirming 
that the blind was maintained. Given the complexity of maintaining the blind of the BSA for any 
given individual participant, any inadvertent unblinding of the BSA will be documented.
Follow-up Contact (Visit 4)
9.11.4
Approximately 14 days post-study treatment administration, the participant/ participant’s legally 
acceptable representative will be contacted by designated site personnel by telephone (or in 
person if the participant is still in the hospital). New and ongoing AEs and concomitant 
medication(s) should be assessed and reported in the database.
10. 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 are 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 E9). Changes to exploratory or other non-confirmatory 
analyses made after the protocol has been finalized, but prior to final database lock, will be 
documented in a supplemental statistical analysis plan 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
10.1
Key elements of the statistical analysis plan are summarized below; the comprehensive plan is 
provided in Section 10.2 through Section 10.12.
Study Design Overview
A Phase 4 Double-Blinded, Randomized, Active Comparator-
Controlled Clinical Trial to Study the Efficacy, Safety, and 
Pharmacokinetics of Sugammadex (MK-8616) for Reversal of 
Neuromuscular Blockade in Pediatric Participants 
Treatment Assignment
In Part A, participants will be randomized to 2 doses of sugammadex 
in a 1:1 ratio with NMBA and age as stratification factors:

2 mg/kg sugammadex for moderate NMB and reversal

4 mg/kg sugammadex for deep NMB and reversal
In Part B, participants will be randomized to the following treatment 
groups in a 1:1:5 ratio (overall) with NMBA and age as stratification 
factors:

2 mg/kg sugammadex for moderate NMB and reversal

50 mcg/kg neostigmine for moderate NMB and reversal

4 mg/kg sugammadex for deep NMB and reversal
Analysis Populations
Pharmacokinetic:  Pharmacokinetic (PK) Set
Safety: All Participants as Treated (APaT)
Efficacy: All Participants Treated (APT)
 
 
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Primary Endpoint(s)
Pharmacokinetic: Area under the plasma concentration-time curve 
(AUC), clearance (CL), volume of distribution (Vz), maximum plasma 
concentration (Cmax), and half-life (t1/2)
Safety:  Adverse event (AE) reporting, laboratory and vital sign 
assessments.
Efficacy:  The time to recovery to a train-of-four (TOF) ratio of ≥0.9
Secondary Endpoints
The time to recovery to a TOF ratio of ≥0.8
The time to recovery to a TOF ratio of ≥0.7
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
Pharmacokinetic: Separately for each PK parameter, individual 
values of CL, AUC, Cmax, and Vz, will be natural log-transformed and 
evaluated with a fixed effects model containing terms dose and age 
group. At each dose, 95% CIs of geometric means for each parameter 
will be provided.  Descriptive summary statistics will be provided for 
PK parameters including AUC, Cmax, dnAUC, dnCmax, CL, Vz and t1/2.
Efficacy:  The efficacy hypothesis will be evaluated within Part B by 
comparing sugammadex to neostigmine in the setting of moderate 
block using log-transformed time-to-recovery values via Analysis of 
Variance (ANOVA), adjusting for neuromuscular blocking agent 
(NMBA) and age.
Statistical Methods for Key 
Safety Analyses
P-values (Tier 1 only) and 95% confidence intervals (Tier 1 and 
Tier 2) will be provided for between-treatment differences in the 
percentage of participants with events; these analyses will be 
performed using the stratified Miettinen and Nurminen method 
[Miettinen, O. and Nurminen, M. 1985] with NMBA and age group as 
stratification factors.
Interim Analyses
One interim analysis (IA) will be performed in this study to evaluate 
PK and safety data. PK and safety data will be reviewed by a standing 
internal Data Monitoring Committee (siDMC) and safety data will be 
reviewed by an external Data Monitoring Committee (eDMC). This 
interim analysis is summarized below. Details are provided in Section 
10.7.

Timing: When Part A has been completed, prior to the 
commencement of enrollment of Part B.

Testing:  IA will evaluate PK and safety data. No formal efficacy 
analyses are planned.
Multiplicity
No multiplicity adjustment is planned as there is a single comparison 
of sugammadex versus neostigmine in the setting of moderate block
using 1 endpoint in the primary efficacy hypothesis.
Sample Size and Power
The planned sample size is 238 participants, based on minimum safety 
database requirement. There will be 30 participants per treatment arm 
(sugammadex and neostigmine) in the setting of moderate block for 
efficacy analysis. For time to recovery to TOF ≥0.9, the trial has >99% 
power to demonstrate that sugammadex 2mg/kg is superior to 
neostigmine at an overall two-sided 5% alpha-level.
 
 
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Responsibility for Analyses/In-House Blinding
10.2
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor. The pharmacokinetic analyses and summaries 
described in Section 10.6.3 are the responsibility of Pharmacokinetics, Pharmacodynamics and 
Drug Metabolism – Quantitative Pharmacology and Pharmacometrics department of the Sponsor
and Early Clinical Development Statistics – Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. With 
the exception of designated Sponsor personnel (e.g., unblinded Clinical Research Associates 
[CRAs], and other designated individuals as required), all other Sponsor study team personnel 
will be blinded to study medication assignment. Separate functional unblinding for PK will be 
conducted in support of PK evaluations. A small team as specified in a separate unblinding 
memo will be unblinded for the purpose of preparing the PK analyses for Part A. An unblinded 
statistician and programmer will prepare the safety analyses in support of the eDMC (and siDMC 
for IA only).
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 in the IRT.
Hypotheses/Estimation
10.3
Objectives and hypotheses of the study are stated in Section 4.
Analysis Endpoints
10.4
Efficacy, safety and PK 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.
Efficacy Endpoints
10.4.1
The primary efficacy endpoint is time to recovery to a TOF ratio of ≥0.9. Please see Section
5.4.1.1 for a description of the efficacy endpoints.
Safety Endpoints
10.4.2
Safety will be assessed through descriptive statistics within the All Participants as Treated 
(APaT) population. Safety assessments will include AEs, laboratory evaluations, and physical 
exams including vital signs. Adverse events of clinical interest for this protocol include clinically 
relevant bradycardia, hypersensitivity, and anaphylaxis. Please see Section 5.4.1.2 for a 
description of safety endpoints.
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. Finally, for the cardiac endpoints 
of clinically relevant bradycardia and treatment emergent bradycardia, an analysis of events 
 
 
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occurring within the 1st 30 minutes after study medication administration will be conducted, as 
this is the time period during which continuous ECG monitoring will be conducted per protocol.
Pharmacokinetic Endpoints
10.4.3
Pharmacokinetic endpoints include AUC, CL, Vz, Cmax, and t1/2. Please see Section 5.4.1.3 for a 
description of PK endpoints.
Derivations of Efficacy/Pharmacokinetics Endpoints
10.4.4
For imputation of missing times for calculations of summary statistics from the start of 
administration of sugammadex or neostigmine to recovery of the TOF ratio of ≥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 throughout the sugammadex program. The following 
procedure will be used:
If the time from the start of administration of study drug to recovery of the TOF ratio ≥0.9 is 
missing, there are 3 cases of particular importance for imputation purposes:
1. Time to TOF ratio ≥0.8 is available:
a.
Sugammadex group: First, for all participants randomized to receive sugammadex and 
with times to recovery of the TOF ratio ≥0.8 and ≥0.9 available, the difference between 
these 2 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 ≥0.8 of the participants 
with missing times to recovery of the TOF ratio ≥0.9. This will be used as the imputed 
missing time to recovery of the TOF ratio ≥0.9.
b. Neostigmine group: Same as for the sugammadex group, but now only participants 
randomized to receive neostigmine will be used, and the 5th percentile (P5) of the 
differences in time to recovery of the TOF ratio of ≥0.8 and ≥0.9 will be calculated.
2. Time to TOF ratio ≥0.7 is available, but the time to TOF ratio ≥0.8 is missing:
a.
Sugammadex group: First, for all participants randomized to sugammadex and with 
times to recovery of the TOF ratio ≥0.7 and ≥0.9 available, the difference in time 
between these 2 recovery times will be calculated. Next, the P95 of these differences will 
be added to the time to recovery of the TOF ratio ≥0.7. This will be used as imputation of 
the missing time to recovery of the TOF ratio ≥0.9.
b. Neostigmine group: Same as for sugammadex group, but now only participants 
randomized to receive neostigmine will be used and the P5 of the differences in time to 
recovery of the TOF ratio ≥0.7 and ≥0.9 will be calculated.
3. Times to TOF ratio ≥0.7 and ≥0.8 are both missing:
a.
Sugammadex group: The P95 of the time to recovery in all participants randomized to 
sugammadex with an observed recovery time of the TOF ratio ≥0.9 will be imputed.
b. Neostigmine group:  The P5 of the time to recovery in all participants randomized to 
receive neostigmine with an observed recovery time of the TOF ratio ≥0.9 will be 
imputed.
 
 
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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 ≥0.8 (secondary efficacy variable). For 
imputation of missing times, P95 (sugammadex) or P5 (neostigmine) of the differences in time 
between recovery of the T4/T1 ratio ≥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 ≥0.7 (secondary efficacy variable), the P95 observed time for the participants 
randomized to the sugammadex group will be imputed. For participants 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 of ≥0.7, ≥0.8, and ≥0.9.
Analysis Populations
10.5
Efficacy Analysis Populations
10.5.1
The All Participants Treated (APT) population will serve as the primary population for the 
analysis of efficacy data in this study. The APT population consists of all randomized 
participants who receive at least 1 dose of study treatment.
Participants will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using the APT population. Details on the approach to handling missing 
data are provided in Section 10.4.4.
Safety Analysis Populations
10.5.2
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all randomized participants from both Part A and Part B who received a 
dose of study treatment. Participants will be included in the treatment group corresponding to the 
study treatment they actually received for the analysis of safety data using the APaT population. 
For most participants, this will be the treatment group to which they are randomized. Participants
who take incorrect study treatment will be included in the treatment group corresponding to the 
study treatment actually received.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 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 
10.6.
PK Analysis Populations
10.5.3
In Part A, evaluable PK population for PK data analysis is defined as all participants with 5 to 
6 time points approximately at 2 minutes, 15 minutes, 30 minutes, 60 minutes, 4 to 6 hours, and 
10 to 12 hours (10 to 12 hour sample is optional; refer to Section 9.6) after study treatment, with 
14 participants per dose level in Part A. For descriptive summaries of sugammadex, the 
population includes all participants with at least 1 measurable PK sample.
 
 
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Statistical Methods
10.6
Statistical testing and inference for efficacy and safety analyses are described in Section 10.6.1
and Section 10.6.2 respectively. Efficacy results that will be deemed to be statistically significant 
after consideration of the Type I error control strategy are described in Section 10.8. 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
10.6.1
This section describes the statistical methods that address the primary and secondary objectives. 
Methods related to exploratory objectives will be described in the supplemental statistical 
analysis plan.
The primary efficacy endpoint is the time to recovery, defined as a TOF ratio (ie, T4/T1 ratio)
>0.9. A formal test for efficacy in the comparison of sugammadex to neostigmine in the setting 
of moderate block will be conducted with data from Part B. Deep block data will not contribute 
to the primary efficacy analysis. Log-transformed time to recovery values will be analyzed by 
analysis of variance (ANOVA), adjusting for NMBA and age.
Additionally, supportive analyses will include a stratified log-rank test (adjusting for age group 
and NMBA) as well as a Kaplan-Meier curve for time to recovery to a TOF ratio of ≥0.9. The 
same set of analyses planned for the primary endpoint will be included for the secondary 
endpoints of times to recovery to a TOF ratio ≥0.8 and TOF ratio ≥0.7.
In addition, summary statistics and a Kaplan-Meier curve will be provided for sugammadex 2
mg/kg and 4 mg/kg from both Part A and Part B. Table 4 summarizes the key efficacy analyses
comparing sugammadex to neostigmine in the setting of moderate NMB.
 
 
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Table 4
Analysis Strategy for Key Efficacy Variables Comparing Sugammadex to 
Neostigmine in the Setting of Moderate NMB
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoints
Time to Recovery to TOF >0.9
P
Analysis of Variancea
APT
Explicit 
Imputationb
S
Stratified Log-Rank 
Test, Kaplan Meier 
Curves
APT
Censoredc
Secondary Endpoints
Time to Recovery to TOF >0.8
P
Analysis of Variancea
APT
Explicit 
Imputationb
S
Stratified Log-Rank 
Test, Kaplan Meier 
Curves
APT
Censoredc
Time to Recovery to TOF >0.7
P
Analysis of Variancea
APT
Explicit 
Imputationb
S
Stratified Log-Rank 
Test, Kaplan Meier 
Curves
APT
Censoredc
a
Analysis of Variance includes terms for age and NMBA.
b
Imputation approach described in Section 10.4.4.
c     Censored at the last time point from TOF observation period.
Abbreviations:  APT = All Participants Included, NMBA = neuromuscular blocking agent, P = primary, 
S = supportive, TOF = train-of-four
Statistical Methods for Safety Analyses
10.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs.
The analyses of safety results will follow a tiered approach (Table 5), and will be performed with 
data pooled across Part A and Part B. Comparisons between groups will be the 2 pairwise 
comparisons of the 2 mg/kg and 4 mg/kg sugammadex arms versus neostigmine. The tiers differ 
with respect to the analyses that will be performed. Safety parameters or AEs 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.
Adverse experiences (specific terms as well as system organ class terms) and predefined limits of 
change in laboratory or vital signs that are not pre-specified as Tier 1 endpoints will be classified 
 
 
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as belonging to "Tier 2" or "Tier 3", based on the number of events observed. Membership in 
Tier 2 requires that at least 4 participants 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% confidence interval for the 
between-group difference in percent incidence will always include 0 when treatment groups each 
have less than 4 events and thus, would add little to the interpretation of potentially meaningful 
differences. Because many 95% confidence intervals may be provided without adjustment for 
multiplicity, the confidence intervals should be regarded as a helpful descriptive measure to be 
used in review, not a formal method for assessing the statistical significance of the 
between-group differences in AEs and predefined limits of change.
Continuous measures such as changes from baseline in laboratory and vital sign parameters 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. 
For this protocol, clinically-relevant bradycardia, hypersensitivity, and anaphylaxis are 
considered Tier 1 events. In addition, treatment-emergent bradycardia and the broad clinical and 
laboratory AE categories consisting of the percentage of participants with any AE, a drug-related 
AE, a serious AE, an AE which is both drug-related and serious, and who discontinued due to an 
AE will be considered Tier 2 endpoints. P-values (Tier 1 only) and 95% confidence intervals 
(Tier 1 and Tier 2) will be provided for between-treatment differences in the percentage of 
participants with events; these analyses will be performed using the stratified Miettinen and 
Nurminen method [Miettinen, O. and Nurminen, M. 1985] with NMBA and age group as 
stratification factors. For the purposes of this analysis, treatment emergent bradycardia is defined 
as a heart rate generally below the 1st percentile of age that has also decreased 20% or greater as 
compared to the participant’s pre-dose baseline heart rate value, sustained for at least 30 seconds, 
[Butterworth, J. F., et al 2013] and occurring after the administration of study treatment. Refer to 
Appendix 6: Bradycardia Definition by Age Range.
 
 
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Table 5
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpointa
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Clinically-relevant bradycardia
X
X
X
Hypersensitivity (adjudicated)
X
X
X
Anaphylaxis (adjudicated)
X
X
X
Tier 2
Treatment-emergent bradycardia
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 participants in 1 of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCsb (incidence 
<4 participants in all of the treatment groups)
X
Change from Baseline Results (Labs, Vital Signs)
X
Decreased heart rate
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: AE = adverse event, CI = confidence interval, PDLC = pre-defined limit of change, SOC = system 
organ class, X = results will be provided.
Statistical Methods for Pharmacokinetics Analyses
10.6.3
For Part A, separately for each PK parameter, individual values of CL, AUC, Cmax, and Vz, will 
be natural log-transformed and evaluated with a fixed effects model containing terms dose and
age group (2 to <6 years, 6 to <17 years). Kenward and Roger's method will be used to calculate 
the denominator degrees of freedom for the fixed effects (DDFM=KR). At each dose, ninety-five 
percent (95%) CIs for the least squares means for each age group will be constructed on the 
natural log scale and will reference the t-distribution. Exponentiating the least-squares means
and their corresponding 95% CIs will yield estimates for the population geometric means and 
95% confidence intervals about the geometric means on the original scale at each dose level.
At each dose, plots with individual values, geometric means and corresponding 95% CIs will be 
provided for all PK parameters by age group.
For each dose, individual values will be listed for each PK parameter and the following 
descriptive statistics will be calculated for all plasma PK parameters (AUC, Cmax, dose-
normalized (dn) AUC, dnCmax, CL, Vz, and t1/2) for MK-8616 by age group. Sample size (N), 
arithmetic mean (AM), standard deviation (SD), arithmetic coefficient of variation (ACV), 
median (Med), minimum (Min), maximum (Max), geometric mean (GM), and geometric CV 
(GCV) will be provided for all PK parameters by age group.
 
 
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Additionally, the data from the previous pediatric studies may be pooled with the current study 
data and the pediatric data will be reclassified into the following age categories: (2 to <6 years, 6 
to <12 years, and 12 to <17 years for each dose. The above described fixed effect model 
containing terms dose and age group (2 to <6 years, 6 to <12 years, and 6 to <17 years) will be 
used to estimate the geometric means and corresponding 95% confidence intervals for each age 
group by dose. Also summary statistics for the PK parameters will be provided for these age 
groups by dose. Also, at each dose, plots with individual values, geometric means and 
corresponding 95% confidence intervals will be provided for all PK parameters by age group.
A separate population PK analysis utilizing all the pediatric data from Part A, historic pediatric,
and/or adult may be performed to characterize the PK in pediatric population.
The appropriate dose in different groups of pediatric participants will be determined following 
the evaluation of the safety, efficacy, and PK exposures.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
10.6.4
Demographic and Baseline Characteristics
10.6.4.1
The comparability of the treatment groups for each relevant characteristic will be assessed by the 
use of tables and/or graphs by Part A, Part B, and Part A and Part B combined. No statistical 
hypothesis tests will be performed on these characteristics. The number and percentage of 
participants screened, randomized, the primary reasons for screening failure, and the primary 
reason for discontinuation will be displayed. Demographic variables (eg, age, sex, race), baseline 
characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be 
summarized by treatment either by descriptive statistics or categorical tables.
Interim Analyses
10.7
One formal IA is planned for this trial, to occur after the completion of Part A, including 
evaluation of PK and safety results. Study enrollment will be paused for review of the IA results 
by the siDMC and the eDMC (Details are provided in Appendix 3). The eDMC will serve as the 
primary reviewer of the safety results of the IA and the siDMC will review the PK and safety 
results of the IA and make recommendations related to the acceptability of doses for this 
population. 
If PK results of IA from Part A of the study are inconsistent with those previous established in 
pediatrics and/or adults, then Part A and the subsequent IA will be repeated with modified doses 
until comparable doses are obtained.
Beyond the formal IA described above, the eDMC will also review the safety data periodically 
throughout the study. Additionally, selected ECIs (e.g., anaphylaxis and clinically-relevant 
bradycardia) will be monitored by the eDMC; program-wide (i.e., including all data across the 
pediatric trials) stopping criteria related to these ECIs are described in the eDMC charter.
If the study is stopped early for safety, the final CSR will comprise all available data up to and 
including the close-out visits, which includes the data used to draw the conclusion in the decisive 
IA plus the remaining data obtained afterwards (from additional visits and close-out visits). This 
approach to include all available information is in line with the ICH E9 guideline, the intent-to-
treat principle and the Committee for Medicinal Products for Human Use (CHMP) guideline on 
adaptive designs.
 
 
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Details of blinding are described in Section 10.2.
Multiplicity
10.8
No corrections for multiplicity are planned for this study as there is a single comparison of 
sugammadex versus neostigmine in the setting of moderate block using 1 endpoint in the primary 
efficacy hypothesis.
Sample Size and Power Calculations
10.9
The sample size of the study is in alignment with the number of participants required to obtain 
the relevant safety information for each level of block, as specified by the Sponsor’s 
commitments under the PREA. A 1:1 randomization ratio will be used for sugammadex 2 mg/kg 
and 4 mg/kg in the enrollment of 28 participants (14 in each treatment) in Part A, and an overall
1:1:5 randomization ratio will be used for sugammadex 2 mg/kg, neostigmine, and sugammadex 
4 mg/kg in the enrollment of approximately 210 participants in Part B (30 on sugammadex 2 
mg/kg, 30 on neostigmine 50mcg/kg, 150 on sugammadex 4 mg/kg). The study will enroll 
approximately 44 participants on sugammadex in moderate block, 164 participants on
sugammadex in deep block, and 30 participants on neostigmine in moderate block.
Sample Size and Power Calculations for Efficacy Analyses
10.9.1
Power calculations are based on the primary efficacy hypothesis, a comparison of 2 mg/kg of 
sugammadex versus neostigmine for moderate block. The database for recovery times in adults is 
extensive, while objective information in pediatric participants is sparse. Given this, as well as 
the fact that the limited information that has been obtained in pediatrics to date supports an 
assumption of similarity of efficacy and tolerability in those patients as compared to the adult 
population, the approach used for underlying assumptions in this trial is based primarily on the 
adult data. From the Integrated Summary of Efficacy performed in 2012, summary statistics (in 
minutes) for the time to recovery to a TOF ratio of ≥0.9 for sugammadex 2 mg/kg and 
neostigmine 50 mcg/kg for moderate block with rocuronium are noted below in Table 6.
Table 6
Time (in min) to Recovery to a TOF Ratio of ≥0.9 for Sugammadex 2 mg/kg and 
Neostigmine 50 mcg/kg for Moderate Block with Rocuronium
Sugammadex 
2 mg/kg
Neostigmine
50mcg/kg
Mean (SD)
2.2 (1.3)
14.6 (14.5)
Median
1.7
9.7
Geometric Mean
1.9
10.6
Min, Max
0.6, 12.0
2.5, 106.9
Comparisons will be conducted via ANOVA on the log scale, which assumes that the data in the 
original scale are lognormal (and thus the log-transformed data are normally distributed). Power 
estimates for detecting various differences between sugammadex and neostigmine in moderate 
block are obtained using a 2-sided α of 0.05 for a 2-sample t-test on log-transformed time to 
recovery to a TOF ratio of ≥0.9, are summarized in Table 7. These assumptions are judged to be 
 
 
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appropriately conservative, especially with respect to the sugammadex arm, given the limited 
experience in assessing the efficacy in pediatric participants.
Table 7
Power Estimates for Detecting Various Differences Between Sugammadex and 
Neostigmine in Moderate Block
Sugammadex
Mean (SD)
Neostigmine
Mean (SD)
Mean 
Difference
Powera
3 (3)
13 (15)
10
>99%
5 (4)
13 (15)
8
92%
6 (6)
13 (15)
7
81%
a  Based on N=27 for each treatment group to allow for 10% participants 
with non-evaluable data; 2-sided, 5%-level 2-sample t-test
Sample Size and Power Calculations for Safety Analyses
10.9.2
The probability of observing at least one Tier 1 AE (such as adjudicated hypersensitivity) in this 
study depends on the number of participants treated and the underlying percentage of 
participants with an AE in the study population. If the underlying incidence of a Tier 1 AE is 1% 
(ie, 1 of every 100 participants receiving the drug), there is a 35.7% chance of observing at least 
1 AE among 44 participants in the 2 mg/kg sugammadex treatment group, and a 80.8% chance of 
observing at least 1 AE among 164 participants in the 4mg/kg sugammadex treatment group.
The estimate of and the upper bound of the 95% confidence interval for the underlying 
percentage of participants with a  Tier 1 AE given various hypothetical observed number of 
participants with a Tier 1 AE within the sugammadex groups are provided in Table 8. These 
calculations are based on the exact binomial method proposed by Clopper and Pearson [Clopper, 
C. J. and Pearson, E. S. 1934].
 
 
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Table 8
Estimate of Incidence of a Tier 1 Adverse Event and 95% Upper Confidence Bound 
Based on Hypothetical Number of Participants with a Tier 1 Adverse Event Among 
44 (2mg/kg) and 164 (4mg/kg) Participants in the Sugammadex Group
Number of 
Participants in 
Sugammadex Group
Hypothetical Number 
of  Participants
With a Tier 1 Adverse 
Event
Estimate of 
Incidence
95% Upper Confidence 
Bounda
44 
(Sugammadex 
2mg/kg)
0
0.0%
8.0%
1
2.3%
12.0%
3
6.8%
18.7%
5
11.4%
24.6%
164
(Sugammadex 
4mg/kg)
0
0.0%
2.2%
3
1.8%
5.3%
9
5.5%
10.2%
15
9.1%
14.6%
a Based on the two-tailed exact confidence interval of a binomial proportion (Clopper and 
Pearson, 1934).
Table 9 summarizes the percentage point differences between the sugammadex and neostigmine 
groups for a variety of hypothetical underlying incidences of a Tier 1 AE. These calculations 
assume 44 participants in the sugammadex group and 30 participants in the neostigmine group 
and are based on a 2-sided 5% alpha level. The calculations are based on an asymptotic method 
proposed by Farrington and Manning (1990) [Farrington, C.P. 1990]; no multiplicity adjustments 
were made.
Table 9
Differences in Incidence in a Tier 1 Adverse Event between the Sugammadex and 
Neostigmine Groups (Assuming Two-Sided 5% alpha level with 44 Participants in 
Sugammadex Group and 30 Participants in Neostigmine Group)
Incidence of Adverse Event
Risk Difference
Sugammadex (%)
Neostigmine (%)
Percentage Points
95% CIa
2.3%
3.3%
1.0
(-14.6%, 8.9%)
6.8%
13.3%
6.5
(-23.8%, 7.4%)
Incidences presented here are hypothetical and do not represent actual adverse 
experiences in either group.
a Based on an asymptotic method (Farrington and Manning (1990)).
 
 
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Sample Size and Power Calculations for Pharmacokinetic Analyses
10.9.3
A sample size of 6 in each age group has approximately 91% power that 95% confidence interval
of the geometric mean of CL (Vz) in this age group will be within 60% and 140% of the 
geometric mean estimates of the clearance of MK-8616. A between-subject standard deviation of 
0.23 in log scale for CL (Vz) that was obtained from previous studies was used for these 
calculations. This calculation is based on the pediatric guidance proposed by Wang et al [Wang, 
Y., et al 2012].
Subgroup Analyses
10.10
To determine whether the treatment effect is consistent across various subgroups, the estimate of 
the between-group treatment effect (with a nominal 95% confidence interval) for the primary 
efficacy endpoint will be estimated and plotted within each category of each subgroup based on 
the primary efficacy analysis model (ANOVA) in the setting of moderate block. The following 
are examples of classification variables:

Age group (2 to <6, 6 to <12, 12 to <17 years)

Neuromuscular blocking agent (rocuronium or vecuronium)

Sex (female, male)

Race (white, other)

Region (United States, Ex-United States)
In addition, a Forest plot will be produced, which provides the estimated point estimates and 
confidence intervals for the treatment effect across the categories of subgroups listed above.
The consistency of the treatment effect will be assessed descriptively via summary statistics by 
category for the classification variables listed above.
In addition, a summary of safety parameters will be provided for each category of the following 
classification variables: 

Depth of block (moderate, deep)

Age group (2 to <6, 6 to <12, 12 to <17 years)

Neuromuscular blocking agent (rocuronium or vecuronium)

Sex (female, male)

Race (white, other)

Region (United States, Ex-United States)
Subgroup analyses/summaries will only be performed for those classification variables with 
≥10% participants in each subgroup.
Compliance (Medication Adherence)
10.11
Compliance with dosage (in mg/kg) will be assessed based on the actual dosage (mg) of study 
treatment administered and the reported body weight, per dosing occasion. Any dosage that 
 
 
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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
10.12
The extent of exposure to study drug will be summarized in a table presenting per treatment 
group the number of participants who were randomized and received the study drug (ie, were 
treated). If information on actual dose of study treatment is available, summary statistics will be 
provided on the actual dose of study treatment received (mg/kg).
11. References
[Butterworth, J. F., et al 2013]
Butterworth JF, Mackey DC, Wasnick JD. 
Morgan & Mikhail's clinical anesthesiology. 5th 
ed. New York: McGraw-Hill Education; 2013. 
Chapter 42, Pediatric Anesthesia; p. 877-905.
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[Clopper, C. J. and Pearson, E. 
S. 1934]
Clopper CJ, Pearson ES. The use of confidence 
or fiducial limits illustrated in the case of the 
binomial. Biometrika 1934;26(4):404-13.
03Q0LW
[EMEA/CPMP 2008]
EMEA/CPMP.  Ethical considerations for 
clinical trials on medicinal products conducted 
with the paediatric population.
00VKT0
[Eriksson, L. I. 1999]
Eriksson LI. The effects of residual 
neuromuscular blockade and volatile anesthetics 
on the control of ventilation. Anesth Analg 
1999;89:243-51.
00V282
[Eriksson, L. I., et al 1993]
Eriksson LI, Sato M, Severinghaus JW. Effect 
of a vecuronium-induced partial neuromuscular 
block on hypoxic ventilatory response. 
Anesthesiology 1993;78(4):693-9.
00V27Y
[Farrington, C.P. 1990]
Farrington CP, Manning G. Test statistics and 
sample size formulae for comparative binomial 
trials with null hypothesis of non-zero risk 
difference or non-unity relative risk. Stat Med 
1990;9:1447-54.
03T059
[Fleming, S., et al 2011]
Fleming S, Thompson M, Stevens R, Heneghan 
C, Plüddermann A, Maconochie I, et al. Normal 
ranges of heart rate and respiratory rate in 
children from birth to 18 years of age: a 
systematic review of observational studies. 
Lancet 2011;377:1011-8.
03RRBX
 
 
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[Food and Drug 
Administration (CDER) 2014]
Food and Drug Administration (CDER). 
General clinical pharmacology considerations 
for pediatric studies for drugs and biological 
products [Internet]. Silver Spring, MD: U.S. 
Department of Health and Human Services; 
2014. Available from: 
http://www.fda.gov/downloads/drugs/guidancec
omplianceregulatoryinformation/guidances/ucm
425885.pdf.
04JMPW
[Miettinen, O. and Nurminen, 
M. 1985]
Miettinen O, Nurminen M. Comparative 
analysis of two rates. Stat Med 1985;4:213-26.
00VV0G
[Plaud, B., et al 2009]
Plaud B, Meretoja O, Hofmockel R, Raft J, 
Stoddart PA, van Kuijk JHM, et al. Reversal of 
rocuronium-induced neuromuscular blockade 
with sugammadex in pediatric and adult surgical 
patients. Anesthesiology 2009;110(2):284-94.
00WB5V
[Sampson, H. A., et al 2005]
Sampson HA, Muñoz-Furlong A, Bock A, 
Schmitt C, Bass R, Chowdhury BA, et al. 
Symposium on the definition and management 
of anaphylaxis: Summary report. J Allergy Clin 
Immunol 2005;115:584-91.
00VPJQ
[Wang, Y., et al 2012]
Wang Y, Jadhav PR, Lala M, Gobburu JV. 
Clarification on precision criteria to derive 
sample size when designing pediatric 
pharmacokinetic studies. J Clin Pharmacol. 
2012 Oct;52(10):1601-6.
042QFB
 
 
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12. Appendices
Appendix 1: Abbreviations and Trademarks
12.1
Term
Definition
AE
adverse event
ANOVA
analysis of variance
ASA
American Society of Anesthesiologists
AUC
area under the plasma concentration-time curve
APaT
All Participants As Treated
APT
All Participants Treated
BSA
blinded safety assessor
CAC
Clinical Adjudication Committee
CL
clearance
Cmax
maximum plasma concentration
CRF
case report form
CSR
clinical study report
CTFG
Clinical Trial Facilitation Group
DMC
Data Monitoring Committee
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic case report form
EDC
electronic data capture
eDMC
External Data Monitoring Committee
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOC
Executive Oversight Committee
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
HRT
hormonal replacement therapy
IA
interim analysis
 
 
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Term
Definition
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
NMAC
Neuromuscular Adjudication Committee
NMB
neuromuscular blockade
NMBA
neuromuscular blocking agent
NSAE
non-serious adverse event
OR
operating room
PACU
Post-anesthesia care unit
PK
pharmacokinetic
PREA
Pediatric Research Equity Act
PTC
post-tetanic count
SAC
Scientific Advisory Committee
SAE
serious adverse event
SoA
Schedule of Activities
t1/2
half-life
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 (eg, 0.7 or 0.8 or 0.9)
TOF
train-of-four stimulation
Vz
apparent volume of distribution
WOCBP
woman of childbearing potential
 
 
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Appendix 2: Clinical Laboratory Tests 
12.2

The tests detailed in Table 10 will be performed by the central laboratory. Laboratory 
samples will be sent to a central laboratory for analysis unless local labs that satisfy the 
protocol requirements are already available.

Peri-anesthetic period (Visit 2): Samples need not be drawn if local lab results are available 
within 14 days of randomization.

Post-anesthetic period (Visit 3): Samples need not be drawn if local lab results are (or will 
be) available within 24 hours of randomization.

If local laboratory results are used, the results and normal ranges must be entered into the 
CRF.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations.
 
 
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Table 10
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistrya
BUN
Potassium
AST/SGOT
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above 
the upper limit 
of normal)
Albumin
Bicarbonate
Chloride
Total Protein
Creatinine
Sodium
ALT/SGPT
Alkaline 
phosphatase
Glucoseb
Other 
Screening 
Tests
Urine Pregnancy Test, Serum β-hCG, as applicable:  Urine or serum β-hCG 
test is required prior to surgery (or other clinical situation that requires 
administration of NMBA) in any young woman with onset of menarche. 
Serum β-hCG pregnancy test is required only if urine is positive, unless local 
requirements require otherwise
a For participants with history of renal impairment only: SCr will be required for Screening (Visit 1), to calculate
eGFR (using revised Schwartz estimate).
b Fasting or non-fasting glucose values are acceptable.
Abbreviations:  ALT/SGPT = alanine aminotransferase/serum glutamic-pyruvic transaminase, 
AST/SGOT = aspartate aminotransferase/serum glutamic-oxaloacetic transaminase, β-hCG  = β-human chorionic 
gonadotropin, BUN = blood urea nitrogen, eGFR = estimated glomerular filtration rate, MCH = mean corpuscular 
hemoglobin, MCV = mean corpuscular volume, RBC = red blood cell, SCr = serum creatinine, WBC = white 
blood cell
Investigators must document their review of each laboratory safety report.
 
 
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Appendix 3: Study Governance Considerations
12.3
Merck Code of Conduct for Clinical Trials
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 participant 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 (eg, 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 participant 
preferences, etc.  
The design (ie, participant population, duration, statistical power) must be adequate to address the specific purpose of 
the trial.  Research participants 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 participants, 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. Participant Protection
A. IRB/IEC review
All clinical trials will be reviewed and approved by an independent IRB/IEC before being initiated at each site.  Significant
changes or revisions to the protocol will be approved by the IRB/IEC prior to implementation, except that changes required 
urgently to protect participant safety and well-being may be enacted in anticipation of IRB/IEC approval. For each site, the 
IRB/IEC and Merck will approve the participant informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance.  Potential 
participants 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. Participants are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Participants are enrolled only after providing informed consent for
participation.  Participants 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 participant 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 participant 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 
participants 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 participant referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible participants.
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/IEC 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 (eg, 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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Financial Disclosure
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.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Confidentiality of Data
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/IEC) 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 Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, 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 participant 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the participant will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
 
 
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By signing this protocol, the investigator agrees to treat all participant data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and regulations.
Confidentiality of IRB/IEC Information
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.
Committees Structure
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data Monitoring 
Committee (DMC) will monitor the interim data from this trial.  The voting members of the 
committee are external to the Sponsor.  The members of the DMC must not be involved with the 
trial in any other way (eg, they cannot be trial investigators) and must have no competing 
interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 10.7 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles and 
responsibilities of the various members and the Sponsor protocol team; meeting facilitation; the 
trial governance structure; and requirements for and proper documentation of DMC reports, 
minutes, and recommendations will be described in the DMC charter that is reviewed and 
approved by all the DMC members.
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 interim analysis of Part A. 
The siDMC will generally serve in an advisory role and specifically communicate 
recommendations to the sugammadex development team to continue the study as originally 
planned or to amend the study to modify the dose of sugammadex. The siDMC will operate 
independently of the external Clinical Adjudication and Neuromuscular Monitoring Adjudication 
Committees. Specific details regarding responsibilities of the siDMC will be described in a 
separate charter that is reviewed and approved by the siDMC.
Neuromuscular Monitoring Adjudication Committee
Independent vendor personnel 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 Neuromuscular Transmission Monitoring Guidelines. In instances where there is no 
resolution between the vendor and site personnel regarding the interpretation of trace output, 
 
 
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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 the 
participant’s treatment or condition. The NMAC will provide the final decision by either 
confirming the acceptability of the investigative site TOF-operator’s interpretation or providing a 
separate interpretation to be used as part of the efficacy analysis.
Clinical Adjudication Committee
A Clinical Adjudication Committee (CAC) will evaluate the following events for the purposes of 
confirming them according to the criteria in Section 10 – Statistical Analysis Plan, as well as 
evaluating the presence of confounding factors.
This external committee of independent consultants will assess the following events:
1) Hypersensitivity 
2) Anaphylaxis
The BSA and/or Principal Investigator will identify events to be adjudicated based on their AE 
monitoring of their participants. In addition, the Sponsor will periodically review the blinded 
clinical database in order to identify events that may meet criteria for adjudication.
All personnel involved in the adjudication process will remain blinded to study treatment 
allocation throughout the trial. 
Publication Policy
The results of this study may be published or presented at scientific meetings. The sponsor will 
comply with the requirements for publication of study results. In accordance with standard 
editorial and ethical practice, the sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data. In this case, a coordinating 
investigator will be designated by mutual agreement.
If publication activity is not directed by the sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before submission.  This allows the sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.
Compliance with Trial Registration and Results Posting Requirements
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 participants to 
identify potentially appropriate trials for their disease conditions and pursue participation by 
 
 
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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.
Compliance with Law, Audit and Debarment
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 (eg, 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 this appendix 
under the Merck Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
The Investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting from 
regulatory authority inspection, and will provide the Sponsor with a copy of the proposed 
response for consultation before submission to the regulatory authority. 
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.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator or 
qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be provided 
separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
 
 
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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 or regulatory authority as a result of an audit or inspection to cure deficiencies in the 
trial documentation and worksheets/case report forms.
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available.
Study and Site Closure
The sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
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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Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
12.4
Follow-up, and Reporting
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the sponsor for human use in this study.
Events Meeting the AE Definition 
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in 
the medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.
●
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
●
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, the AE term should reflect the clinical symptoms or abnormal test 
result.  An overdose without any associated clinical symptoms or abnormal laboratory 
results is reported using the terminology “accidental or intentional overdose without 
adverse effect.”
●
Any new cancer or progression of existing cancer.
 
 
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Events NOT Meeting the AE Definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has 
not worsened.
●
Refer to section 9.3.5 for protocol specific exceptions
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met 
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing 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.
d.
Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.
●
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(eg, sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
 
 
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f.
Other important medical events:
●
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse.
Additional Events reported
Additional Events which require reporting 
●
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.
●
Is a cancer;
●
Is associated with an overdose.
Recording AE and SAE
AE and SAE Recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to the 
event.
●
The investigator will record all relevant AE/SAE information on the Adverse Event case 
report forms/worksheets at each examination.
●
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are requested by the 
Sponsor. In this case, all participant identifiers, with the exception of the participant number, 
will be blinded on the copies of the medical records before submission to the Sponsor.
●
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.
 
 
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Assessment of Intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and 
other reportable safety event) reported during the study and assign it to 1 of the 
following categories: 
●
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.  (for pediatric trials, 
awareness of symptoms, but easily tolerated)
●
Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities. (for pediatric trials, definitely acting like something is wrong)
●
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe 
(for pediatric trials, extremely distressed or unable to do usual activities).
Assessment of Causality
●
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 
product 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 participant 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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●
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 participant 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 PARTICIPANT THEN 
THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR, AND IF REQUIRED, THE INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study 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.
●
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. 
 
 
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●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant 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 participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
Follow-up of AE and SAE
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals.
●
New or updated information will be recorded in the CRF.
●
The investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt 
of the information.
 
 
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Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor 
AE, SAE, and Other Reportable Safety Event Reporting to Sponsor via Electronic 
Data Collection Tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.  
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.  
●
Reference section 9.3.1 – Time Period and Frequency for Collecting AE and 
SAE and Other Reportable Safety Event Information for reporting time 
requirements 
●
The site will enter the SAE data into the electronic system as soon as it becomes available.
●
After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data.
●
If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, then 
the site can report this information on a paper SAE form or by telephone (see next section).
●
Contacts for SAE reporting can be found in the Investigator Trial File Binder (or equivalent).
SAE Reporting to the Sponsor via Paper CRF
●
If the electronic data collection tool is not operational, facsimile transmission or secure e-mail 
of the SAE paper CRF is the preferred method to transmit this information to the Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service.
●
Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be found in 
the Investigator Trial File Binder (or equivalent).
 
 
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Product:  MK-8616 
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Protocol/Amendment No.:  089-01 
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Appendix 5: Contraceptive Guidance and Pregnancy Testing
12.5
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with two FSH measurements in the postmenopausal range 
is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
Contraception Requirements
Female Participants:
Female participants of childbearing potential are eligible to participate if they agree to use one of 
the contraception methods described in Table 11 consistently and correctly during the protocol-
defined time frame in Section 6.1.
 
 
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Protocol/Amendment No.:  089-01 
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Table 11
Contraceptive Methods
Acceptable Contraceptive Methods 
Failure rate of >1% per year when used consistently and correctly.
●
Male or female condom with or without spermicide
●
Cervical cap, diaphragm or sponge with spermicide
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing ) hormonal contraceptionb
○
Oral
○
Intravaginal
○
Transdermal
○
Injectable
●
Progestogen-only hormonal contraceptionb
○
Oral
○
Injectable
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen-only contraceptive implantb, c
●
Intrauterine hormone-releasing system (IUS)b
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. 
●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.) 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.
a) Typical use failure rates are higher than perfect-use failure rates (i.e. when used consistently and 
correctly). 
b) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation. 
 
 
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Product:  MK-8616 
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Protocol/Amendment No.: 089-01 
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Confidential
Appendix 6: Bradycardia Definition by Age Range 
12.6
Age Range
Heart Ratea
(beats per minute)
Median Heart Rate
(1st- 99th percentile)
2 to <3 years
<80
110 (76 – 142)
3 to <4 years
<70
104 (70 – 136)
4 to <6 years
<65
98 (65 – 131)
6 years and older
<60b
N/Ac
aHeart rates were rounded to the more conservative value (Adapted from Fleming, 2011) [Fleming, 
S., et al 2011]
bA heart rate of 60 bpm was selected for the 6 years and older age range; this is consistent with 
typical practice for adult and pediatric patients.
c Median heart rate for participants in the age range of 6 years and older varies by age group and is 
not presented in detail here.
 
 
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Product:  MK-8616 
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Protocol/Amendment No.: 089-01 
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18-Aug-2017
Confidential
Appendix 7: Approximate Blood Volumes Collected by Trial Visit
12.7
Screening
Visit 1
Peri-anesthetic visit 
Visit 2
Post anesthetic visit 
Visit 3
Blood Parameter
Approximate Blood Volume (mL)
Hematology
1
1
Serum/Plasma Chemistry
0.5
0.5
Serum β-Human 
Chorionic Gonadotropin 
(β-hCG)a
0.5
PK for sugammadexb
2.5
0.5
Expected Total (mL)
0.5
4
2
a For female participants of child bearing potential only. Sample taken only if the urine pregnancy test is positive 
at Visit 1.
b Required only for Part A of the study.
Abbreviations:  β-hCG = β-human chorionic gonadotropin, PK = pharmacokinetic
 
 
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