Conditions: Neuromuscular Blockade
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 145
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy, safety, and pharmacokinetics (PK) of sugammadex (MK-8616) for reversal of both moderate and deep neuromuscular blockade (NMB) in pediatric participants aged birth to \<2 years. The primary hypothesis of this study is that sugammadex is superior to neostigmine in reversing moderate NMB as measured by time to neuromuscular recovery.

Detailed description:
This trial will be conducted in two parts: Part A and Part B. In Part A, PK sampling will be conducted to identify the pediatric dose providing sugammadex exposure comparable to the next oldest age cohort. For Part B participants, the efficacy of sugammadex (i.e. neuromuscular recovery / time to extubation) will be assessed. Further, safety analyses will be conducted in both Parts A and B. Following completion of Part A, an interim analysis (IA) of the PK and safety data will be performed. Once the appropriate doses are confirmed and safety data is assessed for the 2 doses of sugammadex, then Part B will commence.

Arms:
arm 1: Participants received a single intravenous (IV) bolus of sugammadex at 2 mg/kg for moderate NMB reversal. arm 2: Participants received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal. arm 3: Participants received a single IV bolus of sugammadex at 2 mg/kg for moderate NMB reversal. arm 4: Participants received a single IV bolus of sugammadex at 4 mg/kg for deep NMB reversal. arm 5: Participants received a single IV bolus containing neostigmine (50 μg/kg; up to 5 mg maximum dose) in combination with either glycopyrrolate (10 μg/kg) or atropine sulfate (20 μg/kg) based on availability and/or contraindications, for moderate NMB reversal.

Interventions: intervention 1: Sugammadex 2 mg/kg intervention 2: Sugammadex 4 mg/kg intervention 3: Neostigmine + Glycopyrrolate intervention 4: Neostigmine + Atropine
Intervention descriptions: intervention 1: For moderate NMB reversal, a single IV bolus of sugammadex (2 mg/kg) will be given after final dose of neuromuscular blocking agent (NMBA; rocuronium or vecuronium) and within 2 minutes of the reappearance of a second twitch (T2) in response to train-of-four (TOF) stimulations. intervention 2: For deep NMB reversal, a single IV bolus of sugammadex (4 mg/kg) will be given after final dose of NMBA (rocuronium or vecuronium) and within 2 minutes of detection of a target of 1 to 2 post-tetanic counts and no response to TOF stimulations (TOF=0). intervention 3: For moderate NMB reversal, a single i.v. bolus containing both neostigmine (50 μg/kg; up to 5 mg maximum dose) as well as glycopyrrolate (10 μg/kg) will be given after final dose of NMBA (rocuronium or vecuronium) and within 2 minutes of the reappearance of T2 in response to TOF stimulations. intervention 4: For moderate NMB reversal, a single i.v. bolus containing both neostigmine (50 μg/kg; up to 5 mg maximum dose) as well as atropine (20 μg/kg) will be given after final dose of NMBA (rocuronium or vecuronium) and within 2 minutes of the reappearance of T2 in response to TOF stimulations.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03909165 
Document Date: 
27-OCT-2022
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 Aged Birth to
<2 Years


PRODUCT: MK-8616  
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
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 Aged Birth to <2 
Years
Protocol Number: 169-02
Compound Number: MK-8616
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
68029
EudraCT
2017-000693-11
Approval Date: 27 October 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study 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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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 2
27-OCT-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck Sharp 
& Dohme LLC, Rahway, NJ, USA. This conversion resulted only in an entity name change 
and update to the address.
Amendment 1
17-MAR-2020
Study endpoint of “time to neuromuscular recovery” moved to primary efficacy endpoint.
Study endpoint of “time to extubation” moved to secondary efficacy endpoint.
Protocol updated to assist sites with managing participant assignment in the case of delayed or 
rescheduled surgeries or clinical procedures
Original 
Protocol
05-FEB-2019
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendments:
Sponsor underwent an entity name change and update to the address.
Summary of Changes Table:
Section # and Name
Description of 
Change 
Brief Rationale 
Title Page
10.1.1. Code of Conduct 
for Clinical Trials
Sponsor entity name 
and address change.
Merck Sharp & Dohme Corp. underwent an entity name and address change 
to Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted 
only in an entity name change and update to the address.
1.3 Schedule of Activities 
(SoA)
8.3.3 Vital Signs
At Visit 2, after 
extubation or if 
decision is made not 
to extubate and the 
required 30-minute
postdose NMTM is 
complete, body 
temperature can be 
measured according to 
routine care (eg, 
axillary/skin 
thermometer is 
acceptable).  
“Core temperature” is required for assessing the ERA question for core 
temperature and to ensure accuracy of NMTM. Once the participant is 
extubated or if the participant will not be extubated and neuromuscular 
recovery has been monitored for at least 30 minutes after administration of 
study treatment, core temperature is no longer required and routine body 
temperature may be obtained.
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Section # and Name
Description of 
Change 
Brief Rationale 
4.1 Overall Design
5.1 Inclusion Criteria
Section 4.1 second 
paragraph and 
inclusion criterion #2:
added clarification 
that “non-emergent” 
refers to a surgical 
procedure or clinical 
situation that is not an 
acute life-threatening 
emergency.  
Clarification was needed to explain exactly what “non-emergent” refers to.
1.1 Synopsis
4.4  Beginning and End of 
Study Definition
5.1 Inclusion Criteria
8.1.1 Informed 
Consent/Assent
8.1.3 Participant 
Identification Card
8.4.1 Time Period and 
Frequency for Collecting 
AE, SAE and Other 
Reportable Safety Event 
Information
10.1.8 Data Quality 
Assurance
Changed “written 
consent/assent” to 
“documented 
informed 
consent/assent”
To align with text updates and legal language updates.
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Section # and Name
Description of 
Change 
Brief Rationale 
8.3.3 Vital Signs
Changed “must” to 
“should” in sentence
regarding blood 
pressure measurement
method.
Typographical error where blood pressure measurement method should be 
consistent across visits, but is not a requirement.
8.4.1: Table 4 Reporting 
Time Periods and Time 
Frames for Adverse Events 
and Other Reportable 
Safety Events
Event of Clinical 
Interest (do not 
require regulatory 
reporting) – the last 
column for time frame 
to report event and 
follow-up information 
to Sponsor was listed 
incorrectly as 5 days 
and is now changed to 
24 hours.
24 hours is the requirement for pediatric study ECI reporting, even if 
regulatory reporting is not required.
10.4: Appendix 4: Device 
Events, Adverse Device 
Events, and Medical 
Device Incidents: 
Definitions, Collection, and 
Documentation
Changed this section 
from “Not 
Applicable” to the 
standard text 
regarding medical 
device reporting.
This section was inadvertently shown as “Not Applicable” when it should 
have included standard medical device text, as the study includes a medical 
device.
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Section # and Name
Description of 
Change 
Brief Rationale 
Throughout Document
Minor administrative, 
formatting, 
grammatical, and/or 
typographical changes 
were made throughout 
the document.
To ensure clarity and accurate interpretation of the intent of the protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities (SoA)................................................................................20
2
INTRODUCTION..........................................................................................................25
2.1
Study Rationale....................................................................................................25
2.2
Background ..........................................................................................................25
2.2.1
Pharmaceutical and Therapeutic Background .............................................25
2.2.2
Preclinical and Clinical Studies ...................................................................26
2.2.3
Ongoing Clinical Studies.............................................................................26
2.3
Benefit/Risk Assessment......................................................................................26
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................27
4
STUDY DESIGN............................................................................................................28
4.1
Overall Design......................................................................................................28
4.2
Scientific Rationale for Study Design.................................................................31
4.2.1
Rationale for Endpoints ...............................................................................31
4.2.1.1
Efficacy Endpoints.............................................................................31
4.2.1.2
Safety Endpoints................................................................................32
4.2.1.3
Pharmacokinetic Endpoints ...............................................................33
4.2.1.4
Pharmacodynamic Endpoints.............................................................34
4.2.2
Rationale for the Use of Comparator/Placebo .............................................34
4.3
Justification for Dose...........................................................................................34
4.4
Beginning and End of Study Definition .............................................................35
4.4.1
Clinical Criteria for Early Study Termination .............................................35
5
STUDY POPULATION ................................................................................................35
5.1
Inclusion Criteria.................................................................................................35
5.2
Exclusion Criteria................................................................................................36
5.3
Lifestyle Considerations......................................................................................37
5.3.1
Meals and Dietary Restrictions....................................................................37
5.3.2
Activity Restrictions ....................................................................................37
5.4
Screen Failures.....................................................................................................37
5.5
Participant Replacement Strategy......................................................................38
6
STUDY INTERVENTION............................................................................................38
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6.1
Study Intervention(s) Administered...................................................................38
6.1.1
Medical Devices...........................................................................................40
6.2
Preparation/Handling/Storage/Accountability .................................................40
6.2.1
Dose Preparation..........................................................................................40
6.2.2
Handling, Storage, and Accountability........................................................40
6.3
Measures to Minimize Bias: Randomization and Blinding..............................41
6.3.1
Intervention Assignment..............................................................................41
6.3.2
Stratification.................................................................................................42
6.3.3
Blinding........................................................................................................43
6.4
Study Intervention Compliance..........................................................................44
6.5
Concomitant Therapy..........................................................................................44
6.5.1
Rescue Medications and Supportive Care ...................................................45
6.6
Dose Modification (Escalation/Titration/Other)...............................................45
6.7
Intervention After the End of the Study............................................................45
6.8
Clinical Supplies Disclosure................................................................................45
6.9
Standard Policies..................................................................................................45
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................45
7.1
Discontinuation of Study Intervention...............................................................45
7.2
Participant Withdrawal From the Study...........................................................45
7.3
Lost to Follow-up .................................................................................................46
8
STUDY ASSESSMENTS AND PROCEDURES........................................................46
8.1
Administrative and General Procedures ...........................................................47
8.1.1
Informed Consent/Assent.............................................................................47
8.1.1.1
General Informed Consent/Assent.....................................................47
8.1.2
Inclusion/Exclusion Criteria ........................................................................48
8.1.3
Participant Identification Card.....................................................................48
8.1.4
Medical History ...........................................................................................48
8.1.5
Prior and Concomitant Medications Review...............................................49
8.1.5.1
Prior Medications...............................................................................49
8.1.5.2
Concomitant Medications..................................................................49
8.1.6
Assignment of Screening Number...............................................................49
8.1.7
Assignment of Treatment/Randomization Number.....................................49
8.1.8
Study Intervention Administration ..............................................................50
8.1.8.1
Administration of Neuromuscular Blocking Agents .........................50
8.1.8.2
Timing of Dose Administration.........................................................50
8.1.9
Discontinuation and Withdrawal .................................................................50
8.1.10
Participant Blinding/Unblinding..................................................................51
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8.1.11
Calibration of Equipment.............................................................................51
8.2
Efficacy Assessments ...........................................................................................52
8.2.1
Monitoring Time to Neuromuscular Recovery............................................52
8.2.2
Monitoring Time to Extubation ...................................................................52
8.2.3
Neuromuscular Monitoring..........................................................................52
8.3
Safety Assessments...............................................................................................53
8.3.1
Physical Examinations.................................................................................53
8.3.2
Height and Weight .......................................................................................54
8.3.3
Vital Signs....................................................................................................54
8.3.4
Electrocardiograms ......................................................................................55
8.3.5
Clinical Safety Laboratory Assessments .....................................................55
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................56
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................56
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......58
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...58
8.4.4
Regulatory Reporting Requirements for SAE .............................................58
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................58
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................58
8.4.7
Events of Clinical Interest (ECIs)................................................................58
8.4.8
Device Events, Patient Events, and Medical Device Incidents (Including 
Malfunctions)...............................................................................................59
8.4.8.1
Prompt Reporting of Medical Device Incidents to Sponsor..............60
8.4.8.2
Assessing and Recording Patient/Device Events...............................60
8.4.8.3
Device Incidents.................................................................................60
8.4.8.4
Regulatory Reporting Requirements for Medical Device Incidents..61
8.5
Treatment of Overdose........................................................................................61
8.6
Pharmacokinetics.................................................................................................62
8.6.1
Blood Collection for Plasma MK-8616 .......................................................62
8.7
Pharmacodynamics..............................................................................................62
8.8
Biomarkers ...........................................................................................................62
8.9
Future Biomedical Research Sample Collection...............................................62
8.10
Health Economics Medical Resource Utilization and Health Economics.......63
8.11
Visit Requirements...............................................................................................63
8.11.1
Screening (Visit 1).......................................................................................63
8.11.2
Peri-anesthetic Visit (Visit 2).......................................................................63
8.11.3
Post-anesthetic Visit (Visit 3)......................................................................64
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8.11.4
Follow-up Contact (Visit 4).........................................................................64
9
STATISTICAL ANALYSIS PLAN .............................................................................64
9.1
Statistical Analysis Plan Summary.....................................................................64
9.2
Responsibility for Analyses/In-house Blinding .................................................66
9.3
Hypotheses/Estimation ........................................................................................66
9.4
Analysis Endpoints...............................................................................................66
9.4.1
Efficacy Endpoints.......................................................................................66
9.4.2
Safety Endpoints..........................................................................................67
9.4.3
Pharmacokinetic Endpoints .........................................................................67
9.4.4
Derivations of Efficacy Endpoints...............................................................67
9.5
Analysis Populations............................................................................................67
9.5.1
Efficacy Analysis Populations.....................................................................67
9.5.2
Safety Analysis Populations ........................................................................67
9.5.3
PK Analysis Populations..............................................................................68
9.6
Statistical Methods...............................................................................................68
9.6.1
Statistical Methods for Efficacy Analyses...................................................68
9.6.2
Statistical Methods for Safety Analyses ......................................................70
9.6.3
Statistical Methods for Pharmacokinetics Analyses....................................71
9.6.4
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................72
9.6.4.1
Demographic and Baseline Characteristics .......................................72
9.7
Interim Analyses ..................................................................................................72
9.8
Multiplicity ...........................................................................................................73
9.9
Sample Size and Power Calculations .................................................................73
9.9.1
Sample Size and Power for Efficacy Analyses............................................73
9.9.2
Sample Size and Power for Safety Analyses ...............................................74
9.9.3
Sample Size and Power for Pharmacokinetic Analyses ..............................76
9.9.4
Sample Size and Power for Efficacy Data Comparison with Adults (for 
Dose Selection)............................................................................................76
9.10
Subgroup Analyses...............................................................................................76
9.11
Compliance (Medication Adherence).................................................................77
9.12
Extent of Exposure...............................................................................................78
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................79
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........79
10.1.1
Code of Conduct for Clinical Trials.............................................................79
10.1.2
Financial Disclosure.....................................................................................81
10.1.3
Data Protection.............................................................................................81
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10.1.3.1
Confidentiality of Data ......................................................................82
10.1.3.2
Confidentiality of Participant Records...............................................82
10.1.3.3
Confidentiality of IRB/IEC Information............................................82
10.1.4
Committees Structure...................................................................................82
10.1.4.1
Executive Oversight Committee........................................................82
10.1.4.2
External Data Monitoring Committee ...............................................82
10.1.4.3
Clinical Adjudication Committee (CAC) ..........................................83
10.1.5
Publication Policy........................................................................................83
10.1.6
Compliance with Study Registration and Results Posting Requirements ...83
10.1.7
Compliance with Law, Audit, and Debarment ............................................84
10.1.8
Data Quality Assurance ...............................................................................84
10.1.9
Source Documents .......................................................................................85
10.1.10
Study and Site Closure.................................................................................86
10.2
Appendix 2: Clinical Laboratory Tests..............................................................87
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................88
10.3.1
Definition of AE ..........................................................................................88
10.3.2
Definition of SAE ........................................................................................89
10.3.3
Additional Events Reported.........................................................................90
10.3.4
Recording AE and SAE ...............................................................................90
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................93
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................95
10.4.1
Definitions....................................................................................................95
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions ....96
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing........................97
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................98
10.7
Appendix 7: Country-specific Requirements....................................................99
10.8
Appendix 8: Abbreviations ...............................................................................100
10.9
Appendix 9: Bradycardia Definition by Age Range.......................................102
10.10 Appendix 10: Extubation Readiness Assessment............................................103
11
REFERENCES.............................................................................................................105
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LIST OF TABLES
Table 1
Study Interventions....................................................................................39
Table 2
Number of Participants Required for Part B (Minimum/Maximum 
Enrollment) ................................................................................................42
Table 3
Assessment Windows for Vital Signs Following Study Treatment 
Administration ...........................................................................................55
Table 4
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................57
Table 5
Analysis Strategy for Key Efficacy Variables Comparing 
Sugammadex to Neostigmine in the Setting of Moderate NMB ...............69
Table 6
Analysis Strategy for Safety Parameters....................................................71
Table 7
Time (in Minutes) to Recovery to a TOF Ratio of ≥0.9 for 
Sugammadex 2 mg/kg and Neostigmine for Moderate Block with 
Rocuronium................................................................................................74
Table 8
Power Estimates for Detecting Various Differences in Time to 
Neuromuscular Recovery (in Minutes) Between Sugammadex and 
Neostigmine in Moderate Block................................................................74
Table 9
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 42 (2 mg/kg) and 54 (4 mg/kg) 
Participants in the Sugammadex Group.....................................................75
Table 10
Differences in Incidence in a Tier 1 Adverse Event Between the 
Sugammadex and Neostigmine Groups (Assuming 2-sided 5% Alpha 
Level With 42 Participants in Sugammadex Group and 30 Participants 
in Neostigmine Group) ..............................................................................76
Table 11
Protocol-required Safety Laboratory Assessments....................................87
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LIST OF FIGURES
Figure 1
Study Diagram ...........................................................................................18
Figure 2
Sequence of Study Enrollment and Timing of Interim Analyses ..............19
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1
PROTOCOL SUMMARY
1.1
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 Aged Birth to <2 
Years
Short Title: PK, safety, and efficacy of sugammadex in children aged birth to <2 years
Acronym: Not Applicable
Hypotheses, Objectives, and Endpoints:
For male/female participants between the ages of birth to <2 years undergoing a surgery or 
clinical procedure requiring a neuromuscular blocking agent (rocuronium or vecuronium) for 
either moderate or deep block:
Primary Objectives
Primary Endpoints
- Objective: To describe the pharmacokinetic 
parameters of sugammadex when used for 
reversal of moderate NMB or deep NMB 
(Part A). 
- Pharmacokinetic parameters:  Area under 
the plasma concentration-time curve (AUC), 
clearance (CL), apparent volume of 
distribution (Vz and Vss), maximum plasma 
concentration (Cmax), and half-life (t1/2) 
- Objective: To evaluate the time to 
neuromuscular recovery 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 neuromuscular 
recovery.
- Time to neuromuscular recovery: Interval 
from administration of reversal agent to time 
to neuromuscular recovery. 
- 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. 
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Secondary Objectives
Secondary Endpoints
- Objective: To evaluate the time to 
extubation 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.
Overall Design:
Study Phase
Phase 4
Primary Purpose
Treatment
Indication
Reversal of neuromuscular blockade (NMB)
Population
Pediatric participants aged birth to <2 years undergoing a 
surgery or clinical procedure requiring an NMBA 
(rocuronium or vecuronium) for either moderate or deep 
block.
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active control without placebo
Study Blinding
Double-blind
Masking
Participant or Subject
Care Provider
Investigator
Outcomes Assessor
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 5 years from the time the first participant’s 
legally acceptable representative provides documented
informed consent/assent through the last participant’s final 
contact. 
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Number of Participants:
Approximately 126 participants will be enrolled.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Administration
Treatment 
Period
Use
Part A-
Panel 1
Sugammadex
2 mg/kg
Once
Intravenous
Treatment
Experimental 
Treatment
Part A-
Panel 2
Sugammadex
4 mg/kg
Once
Intravenous
Treatment
Experimental 
Treatment
Part B
Sugammadex
2 mg/kg
Once
Intravenous
Treatment
Experimental 
Treatment
Sugammadex
4 mg/kg
Once
Intravenous
Treatment
Experimental 
Treatment
Neostigmine 
methylsulfate
50 mcg/kg
Once
Intravenous
Treatment
Treatment
kg=kilogram; mcg=microgram; mg=milligram
Total 
Number
5
Duration of 
Participation
Each participant will participate in the study for approximately 28 days from 
the time the participant’s 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 
posttreatment safety visit between 4 and 36 hours after administration of study 
treatment. A follow-up contact (phone call or visit) with the participant’s 
parent/legally acceptable representative will take place at approximately 14 
days posttreatment.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
Yes
Study governance considerations are outlined in Appendix 1.
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Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
1.2
Schema
The study design is depicted in Figure 1 and Figure 2.
Figure 1
Study Diagram
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Figure 2
Sequence of Study Enrollment and Timing of Interim Analyses
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1.3
Schedule of Activities (SoA)
Study Period
Screening
Treatment
Follow-up
Notes
Visit Number/Title
Visit 1/Screening
Visit 2/Peri-
anesthetic period
Visit 3/Post-
anesthetic period
Visit 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 on
hospitalization status.
Scheduled Day 
Day -1
Day 1
Day 1 to 2
Day 14
Scheduling Window Days
Day -14 to Day 1
±0 days
See Notes
+2 days
Visit 3 should occur between 4 and 
36 hours after administration of 
study treatment.
Administrative Procedures
Informed Consent
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 8.1.7 and 8.1.8.
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 will be 
different qualified individuals.
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Study Period
Screening
Treatment
Follow-up
Notes
Visit Number/Title
Visit 1/Screening
Visit 2/Peri-
anesthetic period
Visit 3/Post-
anesthetic period
Visit 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 on
hospitalization status.
Scheduled Day 
Day -1
Day 1
Day 1 to 2
Day 14
Scheduling Window Days
Day -14 to Day 1
±0 days
See Notes
+2 days
Visit 3 should occur between 4 and 
36 hours after administration of 
study treatment.
Efficacy Procedures
Extubation Readiness Assessment
X
Assessment performed by OR 
anesthesiologist or other medically 
qualified clinician fully trained on 
the protocol requirements.
Neuromuscular Monitoring
X
NMTM will be performed to assess 
depth of block. Sites may use a 
locally available device
(TOF-Watch®SX or PNS). See 
Section 8.2.2.
Safety Procedures
Full Physical Examination 
X
Targeted Physical Examination
X
To be collected by the blinded safety 
assessor. 
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Study Period
Screening
Treatment
Follow-up
Notes
Visit Number/Title
Visit 1/Screening
Visit 2/Peri-
anesthetic period
Visit 3/Post-
anesthetic period
Visit 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 on
hospitalization status.
Scheduled Day 
Day -1
Day 1
Day 1 to 2
Day 14
Scheduling Window Days
Day -14 to Day 1
±0 days
See Notes
+2 days
Visit 3 should occur between 4 and 
36 hours after administration of 
study treatment.
Vital Signs (heart rate, blood 
pressure, temperature, respiratory 
rate, oxygen saturation)
X
X
X
For Visit 2, collect core body 
temperature (after extubation or if 
the participant will not be extubated 
and neuromuscular recovery has 
been monitored for at least 30 
minutes after administration of study 
treatment, body temperature can be 
measured according to routine care); 
scheduled vitals are to be performed 
before administration of NMBA; 
after the final dose of NMBA is 
administered, before administration 
of study treatment; and 2, 5, 10, and 
30 minutes after study treatment.
Height
X
To be measured before study 
treatment preparation.
Weight
X
To be measured at the time of 
randomization and before study 
treatment preparation. Refer to 
Section 8.3.2.
Continuous Heart Rate 
Monitoring (ECG)
X
To occur at least 5 minutes before, 
during, and for 30 minutes after
administration of study treatment.
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Study Period
Screening
Treatment
Follow-up
Notes
Visit Number/Title
Visit 1/Screening
Visit 2/Peri-
anesthetic period
Visit 3/Post-
anesthetic period
Visit 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 on
hospitalization status.
Scheduled Day 
Day -1
Day 1
Day 1 to 2
Day 14
Scheduling Window Days
Day -14 to Day 1
±0 days
See Notes
+2 days
Visit 3 should occur between 4 and 
36 hours after administration of 
study treatment.
Hematology
X
X
Laboratory samples will be collected 
and analyzed by the local laboratory. 
Visit 2: Samples will be drawn 
before study treatment 
administration and need not be 
drawn if other local laboratory
results are available within 14 days 
of randomization. Visit 3: Samples 
need not be drawn if other local 
laboratory results are (or will be) 
available within 36 hours after 
administration of study treatment.
Chemistry
X
X
Laboratory samples will be collected 
and analyzed by the local laboratory. 
Visit 2: Samples will be drawn 
before study treatment 
administration and need not be 
drawn if other local laboratory
results are available within 14 days 
of randomization. Visit 3: Samples 
need not be drawn if other local 
laboratory results are (or will be) 
available within 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 SCr at Visit 1 
(Screening).
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Study Period
Screening
Treatment
Follow-up
Notes
Visit Number/Title
Visit 1/Screening
Visit 2/Peri-
anesthetic period
Visit 3/Post-
anesthetic period
Visit 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 on
hospitalization status.
Scheduled Day 
Day -1
Day 1
Day 1 to 2
Day 14
Scheduling Window Days
Day -14 to Day 1
±0 days
See Notes
+2 days
Visit 3 should occur between 4 and 
36 hours after administration of 
study treatment.
AE/SAE/ECI Review
X
X
X
X
Visit 3 only: Must be collected by 
blinded safety assessor.
Adverse Device Events 
Monitoring
X
X
X
For sites using TOF-Watch®SX 
only.
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; 4 to 6, 
10 to 12 hours after study treatment 
administration. (See Section 8.6 for 
details).
PK is required for Part A of the 
study only.
Abbreviations:  AE = adverse event, ECI = event of clinical interest, eGFR = estimated glomerular filtration rate, NMBA = neuromuscular blocking agent, 
NMTM = neuromuscular transmission monitoring; PK = pharmacokinetics; SAE = serious adverse event, SCr = serum creatinine, TOF = train-of-four.
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2
INTRODUCTION
Note that the terms “study intervention”, “study medication”, and “study treatment” are used 
interchangeably in this document.
2.1
Study Rationale
Sugammadex sodium, herein referred to as sugammadex, has been demonstrated to be safe 
and effective in reversing rocuronium and vecuronium induced NMB in adults; however, 
clinical trial data in children is limited. The current study aims to show that sugammadex is 
generally safe and effective for reversing both moderate and deep block after rocuronium or 
vecuronium induced NMB in term neonates and young children.
Part A of this study will evaluate the pharmacokinetic (PK) parameters of the 2 and 4 mg/kg 
doses of sugammadex in pediatric participants between the age of birth and <2 years. The PK 
data that is generated from Part A will be evaluated to ensure that the doses intended to be 
administered in Part B (2 mg/kg and 4 mg/kg) show comparable exposures to the next oldest 
age cohort or efficacy to the approved doses in adults. The pediatric data from prior studies 
[Trial 19.4.306 (P034) and P089 Part A PK analysis] [Plaud, B., et al 2009] provide evidence 
that the intended doses will show comparable exposures or efficacy across the pediatric age 
groups under study when compared with adults and to older children.
2.2
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-8616.
2.2.1
Pharmaceutical and Therapeutic Background
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. Before 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 moderate 
NMB, a degree of block that requires partial spontaneous recovery of neuromuscular 
transmission, 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 
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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 moderate renal impairment. The use of sugammadex in severe renal impairment is 
not recommended.
Sugammadex has been extensively studied in 59 clinical trials with a total of 6149 exposures 
to intravenous (IV) sugammadex in 4603 unique individuals, establishing a well-
characterized safety and efficacy profile in adults. Additionally, sugammadex is currently 
registered and approved in more than 90 countries, with an estimated 53,490,227 vials sold 
worldwide as of 30-SEPT-2019.
In the pediatric population, sugammadex was studied in a randomized placebo-controlled 
study [Trial 19.4.306 (P034)] [Plaud, B., et al 2009] that evaluated reversal of rocuronium-
induced moderate NMB (n=64). The study evaluated children and adolescents over 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.
2.2.2
Preclinical and Clinical Studies
Refer to the IB for information on the preclinical and clinical development of sugammadex.
2.2.3
Ongoing Clinical Studies
An ongoing 2-part clinical study (P089) evaluating the PK, safety, and efficacy of 
sugammadex 2 mg/kg and 4 mg/kg for the reversal of moderate and deep block in pediatric 
participants 2 to <17 years of age is being conducted; as of 01-FEB-2020, unblinded data is 
not yet available. However, the PK and efficacy data from Part A of P089 support the doses 
being evaluated in this study, and the external data monitoring committee’s (eDMC’s)
recommendation was that P089 should continue without modification.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
The Sponsor considers that the currently approved adult doses are appropriate for assessment 
to provide the optimal benefit/risk ratio in this study, based on the adult Phase 3 studies, 
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subsequent post marketing data, and the pediatric information collected to date in prior 
sugammadex studies.
Sugammadex has a positive benefit-risk profile and is well tolerated in the approved 
indications as described in the IB. 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 with 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 participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
For male/female participants between the ages of birth to <2 years undergoing a surgery or 
clinical procedure requiring a neuromuscular blocking agent (rocuronium or vecuronium) for 
either moderate or deep block:
Objectives
Endpoints
Primary
Objective: To describe the pharmacokinetic 
parameters of sugammadex when used for 
reversal of moderate NMB or deep NMB 
(Part A).
Pharmacokinetic parameters:  Area under 
the plasma concentration-time curve 
(AUC), clearance (CL), apparent volume of 
distribution (Vz and Vss), maximum plasma 
concentration (Cmax), and half-life (t1/2)
Objective: To evaluate the time to 
neuromuscular recovery 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 neuromuscular 
recovery.
Time to neuromuscular recovery: Interval 
from administration of reversal agent to 
time to neuromuscular recovery. 
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. 
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Objectives
Endpoints
Secondary
Objective: To evaluate the time to 
extubation 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.
Tertiary/Exploratory
Objective: To evaluate the time to 
discharge, incidence of delayed recovery
and proportion of participants with 
neuromuscular recovery after the first 5 
minutes of administration of sugammadex 
in comparison to neostigmine for the 
reversal of moderate NMB (Part B).
Time to OR discharge
Time to PACU discharge
Time to hospital discharge
Incidence of delayed recovery (any 
observation that is >3 times the geometric 
mean recovery time of neuromuscular 
recovery using readiness for extubation 
assessment)
Proportion of participants with 
neuromuscular recovery after the first 5 
minutes of study medication administration
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, active comparator-controlled, parallel-group, multisite, double-blinded 
trial to evaluate the PK, safety, and efficacy of sugammadex in pediatric participants aged 
birth to <2 years for the reversal of moderate and deep NMB. 
The design of this study consists of a 2-part structure (Part A and Part B). Part A will be 
open-label, while Part B will be double-blinded. Part A will evaluate safety and confirm the 
doses of sugammadex that will produce comparable exposure in children from birth to <2 
years of age when compared with systemic exposure noted in the next oldest age cohort or 
comparable efficacy to adults after administration of the 2 mg/kg and 4 mg/kg doses. In Part 
B of this study, the safety and efficacy parameters of sugammadex 2 mg/kg and 4 mg/kg will 
be assessed. Potential study participants will have a planned non-emergent (not an acute life-
threatening emergency) surgical procedure or clinical situation that can be conducted under 
both moderate and/or deep NMB.
Enrollment into the study will begin with Part A, which is further divided into Panel 1 and 
Panel 2. First, Panel 1 will evaluate the PK and safety of sugammadex 2 mg/kg in the setting 
of moderate block; next, Panel 2 will evaluate the PK and safety of sugammadex 4 mg/kg in 
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the deep block setting. Panels 1 and 2 will run in succession and consecutively within each 
age cohort (Figure 1).
Participants will be enrolled within 1 of the following 4 age cohorts in a sequential approach 
(within each Part), beginning with the eldest age cohort. Enrollment within each age cohort 
will be based on the participant’s age at time of treatment allocation (age will be defined as 
the anniversary date of the participant’s actual birthdate): 

6 months to <2 years

3 months to <6 months

28 days to <3 months

Birth to 27 days
Part A:
Part A is a 2-panel, open-label, single-arm, multisite study evaluating PK and safety of 
sugammadex when used for reversal of NMB. Within Part A, Panel 1 and Panel 2 will run in 
succession within each age cohort to evaluate the dose of sugammadex appropriate for 
moderate and deep block, respectively. An interim analysis (IA) of safety and PK data will 
occur after the completion of each age cohort within Part A (ie, on completion of Panels 1 
and 2) before beginning enrollment of the next age cohort and simultaneous initiation of Part 
B (see Figure 2).
The PK data that is collected in Part A will be used to accurately characterize the PK 
parameters in pediatric participants aged birth to <2 years, and identify the pediatric dose that 
will provide comparable exposure to the next oldest age cohort. 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 exposures comparable to that of adults. However, if PK results of an IA from Part A 
of the study are substantially different with those in the next oldest age cohort, then efficacy 
data will also be taken into consideration. If the efficacy data are substantially different with 
those previously established in adults, then Part A and the subsequent IAs may be repeated 
with modified doses until comparable exposure and/or efficacy are obtained. Details 
regarding the planned IAs are described in Section 9.7.
Study enrollment will be paused after the completion of each age cohort within Part A to 
allow for review of the PK data by the Sponsor (and efficacy if PK is substantially different) 
and safety data by the eDMC (details are provided in Section 9.7 and Appendix 1). Once the 
appropriate doses are confirmed for moderate and deep block within each age cohort, then 
Part B will begin for that particular age cohort (as shown in Figure 2).
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Part B:  
Part B is a randomized, double-blinded, active comparator-controlled, multisite study 
evaluating the efficacy and safety of sugammadex for reversal of NMB as determined by 
time to neuromuscular recovery (TTNMR) in the moderate and deep block setting. 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 and medical procedures, additional doses of NMBA 
should be administered for the duration of the procedure to target maintenance at the 
assigned depth of block. The active control, neostigmine methylsulfate 50 mcg/kg (up to 5 
mg maximum dose), will be used to evaluate TTNMR in comparison with the sugammadex 2 
mg/kg treatment arm for moderate 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). The study will 
target an approximately even distribution of participants across the birth to < 2 years age 
range, with each age cohort contributing at least 20% to the total study enrollment.
The minimum number of participants required in each age cohort to obtain relevant PK (and 
efficacy, if PK is substantially different) and safety data in Part A:

Panel 1 (moderate block and reversal with 2 mg/kg sugammadex): 3 participants/age 
cohort  

Panel 2 (deep block and reversal with 4 mg/kg sugammadex): 6 participants/age 
cohort  
The minimum number of participants required to obtain relevant efficacy and safety data in 
each treatment arm of Part B:

Moderate block and reversal with 2 mg/kg sugammadex: 30 participants

Moderate block and reversal with 50 mcg/kg neostigmine: 30 participants

Deep block and reversal with 4 mg/kg sugammadex: 30 participants
The study will consist of 4 visits: screening visit, perianesthetic visit, postanesthetic visit, and 
a follow-up safety contact.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
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4.2
Scientific Rationale for Study Design
In accordance with the Sponsor’s commitments under the PREA, PK, safety, and efficacy 
data will be collected in a 2-part structure (Part A and Part B). The study will contain a lead-
in cohort where PK parameters (and efficacy, if PK is substantially different) and safety will 
be assessed (Part A), before proceeding to the safety and efficacy portion of the protocol 
(Part B).
Four age cohorts will be enrolled sequentially beginning with the eldest age group. The 
eldest age group will be enrolled first to ensure that safety data from older age cohorts have 
been reviewed and confirmed before initiating the study in the younger age cohorts. 
For the entire pediatric program, including this study, the eDMC will also review accruing 
data on the protocol-specified events of clinical interest (ECIs) of anaphylaxis and clinically
relevant bradycardia. Overall program-wide stopping criteria are in effect for these 2 ECIs. 
The detailed criteria are described in the eDMC charter.
This study will allow the use of either awake or deep endotracheal extubation. Published data 
describes the safety and potential advantages associated with use of deep endotracheal 
extubation in children and infants less than 2 years old. These results have been summarized 
in a recent systematic review and meta-analysis, which supported the safety of deep 
endotracheal extubation as a way to “minimize overall airway complications except airway 
obstruction” [Koo, C. H., et al 2018]. In addition, for certain clinical circumstances, such as 
in cardiac catheterization where patients must be recumbent and nonambulatory during 
recovery, use of deep endotracheal extubation under anesthesia confers advantages during 
recovery over extubation while awake [Gautam, N. K., et al 2019]. In an observational study
conducted in a US children’s hospital in pediatric participants undergoing 
adenotonsillectomy, investigators made the clinical decision to perform deep endotracheal 
extubation in 66.6 of subjects versus awake extubation in 33.4% of subjects, indicating that 
deep endotracheal extubation is a common practice in pediatrics. No differences were noted 
in the incidence of peri-operative respiratory complications between the 2 extubation 
methods [Baijal, R. G., et al 2015]. To accommodate flexibility and consistency with real 
world practice, in this study the choice of extubation method will be made based on 
investigator judgment. 
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The primary and secondary efficacy endpoints of this study will evaluate the efficacy of 
sugammadex in comparison to neostigmine for the reversal of NMB.

Primary endpoint: Time to neuromuscular recovery (TTNMR), defined as the interval 
from administration of reversal agent to time to neuromuscular recovery. 

Secondary endpoint: Time to extubation, defined as the interval from administration of 
reversal agent to removal of the endotracheal tube.
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The primary endpoint in this study is TTNMR, as it is the most proximal measure available 
to estimate the time to NMB reversal. In 2 prior pediatric studies evaluating NMBAs in this 
age group, data collected using quantitative NMTM with the TOF-Watch® SX has shown 
considerable interpatient variability. In addition, quantitative NMTM involves technical 
challenges in obtaining and maintaining adequate calibration in the youngest age groups 
given their small size. Therefore, in this study, recovery endpoint data assessment methods 
are not limited to quantitative NMTM to TOF ratio ≥0.9. Instead, the endpoint of TTNMR 
may be assessed by 1 of 4 methods selected by the investigator, based on their judgment of 
what is technically feasible and clinically appropriate for the participant’s procedure. These 
are inclusive of both clinical signs (head lift or hip flexion) and neuromuscular transmission 
monitoring (using either a standard PNS or the technically challenging quantitative 
neuromuscular monitoring to TOF ratio ≥0.9, as stipulated in the ERA).
If clinically necessary, the recovery assessment method may be adjusted during management 
of the case, based on investigator judgment, as long as TTNMR is established by 1 of the 4
allowable approaches. When a change is made to the assessment method after administration 
of study medication, the method is to be reflected in the ERA eCRF. For further information, 
refer to MK-8616 P169 Guidance Document for Extubation Readiness Assessment. To 
assess for potential bias due to switch in recovery assessment method, a sensitivity analysis 
will be performed (see Section 9.6.1 for details).
Investigator sites will be trained on the use of their chosen NMTM device to conduct the 
protocol-required intraoperative monitoring (see Section 8.2.3), as guided by study-specific 
guidelines. NMTM training will be supportive of neuromuscular recovery data quality, for 
applicable participants. As flexibility in NMTM assessment method is allowed in this study, 
it is acknowledged that increased variability in TTNMR data may be observed in comparison 
to the pivotal studies where quantitative TOF NMTM was exclusively used.
While neuromuscular recovery is a major determinant for extubation readiness in surgeries 
where NMB is used, it is not the sole factor influencing timing to extubation. Thus, given its 
clinical relevance, “time to extubation” is the secondary endpoint of this study. The ERA will 
be used to ensure all clinically relevant elements are evaluated consistently across all sites 
(neuromuscular recovery, mental status, return of spontaneous ventilation, adequate 
oxygenation, hemodynamically stabile, and core body temperature; refer to Appendix 10 for 
details). Either awake or deep endotracheal extubation will be allowed and the investigator 
will determine which method is the most appropriate for each participant, such as occurs in 
real world clinical practice. Regardless of extubation method, the ERA will be used to assess 
and document extubation readiness in all participants, with modification for those undergoing 
deep endotracheal extubation.
4.2.1.2
Safety Endpoints
The overall assessment of safety and tolerability of sugammadex in pediatric participants 
between the ages of birth to <2 years is the primary safety objective of this study. The 
number of participants experiencing AEs will be evaluated as the primary safety endpoint. 
Safety data will be pooled across Part A and Part B of the study.
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To ensure timely reporting and comprehensive data collection regarding ECIs, the following 
types of events are prespecified as ECIs: 

Hypersensitivity and/or anaphylaxis (as 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 that occurs after 
administration of study treatment and requires 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. 
While these outcomes could be reported at any time after study treatment administration, 
continuous heart rate 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 with the participant’s predose 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 first 
percentile for age that has also decreased 20% or greater as compared to the 
participant’s predose 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 9: Bradycardia Definition by Age Range.
Information regarding residual NMB, recurrence of NMB, and adverse respiratory events 
(eg, hypercapnia, dyspnea, hypoxia, distress) will be collected via standard AE reporting. 
Additional clarifying information regarding these events may also be collected.
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).
4.2.1.3
Pharmacokinetic Endpoints
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, Vss, and t1/2. Details are 
provided in Section 8.6. 
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.
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Information regarding the collection and shipping of plasma samples will be provided in the 
administrative binder.
4.2.1.4
Pharmacodynamic Endpoints
There are no pharmacodynamic endpoints that will be collected in the current study.
4.2.2
Rationale for the Use of Comparator/Placebo
For Part B: The active control, neostigmine methylsulfate 50 mcg/kg (up to 5 mg maximum 
dose), will be used to evaluate TTNMR in comparison with the sugammadex 2 mg/kg 
treatment arm for moderate NMB.
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 study. 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 studies, 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: 10 mcg/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 study.
4.3
Justification for Dose
Based on the available data from the sugammadex 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; based on data in adults, sugammadex labeling 
states that the use of doses lower than recommended (ie, <2 mg/kg) may lead to an increased 
risk of recurrence of NMB after initial reversal. In light of the well-established safety and 
efficacy profile and extensive postmarketing experience associated with the approved adult 
doses, this study aims to confirm that the doses established for sugammadex use in adults 
show a comparable profile when administered to pediatric patients. This comparability is 
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initially suggested by the results of the prior pediatric study (19.4.306) and further supported 
by the results from P089 Part A. Confirmation of dose comparability will provide important 
information to practitioners for the appropriate use of sugammadex in pediatric patients, 
thereby minimizing administration of 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 after the last dose of administered rocuronium or vecuronium (ie, 
moderate block); or to administer a dose of 4 mg/kg sugammadex if neuromuscular recovery 
has reached at least 1 to 2 post-tetanic counts (PTC) after the last administered dose of 
NMBA (ie, deep block).
4.4
Beginning and End of Study Definition
The overall trial begins when the first participant’s legally acceptable representative provides 
documented informed consent/assent. The overall trial ends when the last participant’s
legally acceptable representative completes the last study-related contact, withdraws consent,
or is lost to follow-up (ie, the participant’s legally acceptable representative is unable to be 
contacted by the investigator).
4.4.1
Clinical Criteria for Early Study Termination
The clinical study 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 study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Male/Female participants between the ages of birth and <2 years undergoing a procedure 
requiring an NMBA for either moderate or deep block will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Is categorized as ASA Physical Status Class 1, 2, or 3 as determined by the investigator. 
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2. Has a planned non-emergent (not an acute life-threatening emergency) surgical procedure 
or clinical situation (eg, intubation) that requires moderate or deep NMB with either 
rocuronium or vecuronium. 
3. Has a surgical procedure or clinical situation that would allow neuromuscular monitoring 
techniques to be applied for neuromuscular transmission monitoring.
Demographics
4. Is male or female, between birth and <2 years of age at Visit 2.
Informed Consent/Assent
5. The participant’s legally acceptable representative for the study participant provides 
documented informed consent/assent for the trial.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Is a preterm infant or neonate <36 weeks gestational age at birth.
2. Has any clinically significant condition or situation (eg, anatomical malformation that 
complicates intubation) other than the condition requiring the use of NMBA that, in the 
opinion of the investigator, would interfere with the trial evaluations or optimal 
participation in the trial.
3. Has a neuromuscular disorder that may affect NMB and/or trial assessments.
4. 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). 
5. Has or is suspected of having a family or personal history of malignant hyperthermia.
6. 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.
7. Is expected to require mechanical ventilation after the procedure.
8. 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. 
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Prior/Concomitant Therapy
9. Use of medication expected to interfere with study treatments given in this trial, as per 
prescribing information. 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). (Except in the 
circumstance that renewed muscle relaxation is needed after 
administration of study treatment, in which case a nonsteroidal
NMBA should be administered)
Prior/Concurrent Clinical Study Experience
10. Has been previously treated with sugammadex or has participated in a sugammadex 
clinical trial within 30 days of providing documented informed consent/assent for this 
current trial.
11. Is currently participating in or has participated in an interventional clinical trial with an 
investigational compound or device within 30 days of providing documented informed 
consent/assent for this current trial
Other Exclusions
12. Is or has an immediate family member (eg, parent/legal guardian, or sibling) who is 
investigational site or Sponsor staff directly involved with this study. 
5.3
Lifestyle Considerations
There are no lifestyle restrictions required for study participation.
5.3.1
Meals and Dietary Restrictions
There are no dietary restrictions required for this study.
5.3.2
Activity Restrictions
There are no activity restrictions for study participation.
5.4
Screen Failures
Screen failures are defined as participants whose legally acceptable representative provides
consent to participate in the clinical study but are not subsequently enrolled/randomized.  A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
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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.
5.5
Participant Replacement Strategy
A participant who withdraws from the study will not be replaced. (see Section 7.2 for 
additional information regarding participants that withdraw from the study).
For Part A, recruitment will continue until the number of participants with evaluable PK 
samples is obtained for each age cohort.
For Part B, recruitment will continue until at least the minimum number of treated 
participants for each age cohort is obtained (refer to Table 2 in Section 6.3.2).
6
STUDY INTERVENTION
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.
Clinical supplies (study intervention[s] provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 1.
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Table 1
Study Interventions
Arm Name
Arm 
Type
Intervention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period/
Use
IMP/
NIMP
Sourcing
Sugammadex 
MK-8616
Experi-
mental
Sugammadex 
MK-8616
Drug
Solution 
for 
injection
100 mg/ml
2 mg/kg 
or 4 
mg/kg
IV 
Injection
Once
Experi-
mental
IMP
Provided 
centrally by 
the Sponsor
Neostigmine 
methylsulfate
Active 
Com-
parator
Neostigmine 
methylsulfate
Drug
Solution 
for 
injection
0.5 mg/ml
50 
mcg/kg
IV 
Injection
Once
Experi-
mental
IMP
Provided 
centrally by 
the Sponsor
Glycopyrrolate
Other
Glycopyrrolate
Drug
Solution 
for 
injection
0.2 mg/ml
5 to 15 
mcg/kg
IV 
Injection
Once
Experi-
mental
IMP
Provided 
centrally by 
the Sponsor 
or locally by 
the study 
site, 
subsidiary, 
or designee
Atropine sulfate
Other
Atropine sulfate
Drug
Solution 
for 
injection
0.5 mg/ml
10 to 30 
mcg/kg
IV 
Injection
Once
Experi-
mental
IMP
Provided 
centrally by 
the Sponsor 
or locally by 
the study 
site, 
subsidiary, 
or designee
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European 
Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
Other Arm Type:  Required to be used with active comparator.
Glycopyrrolate may be labeled as Glycopyrronium Bromide depending on source and will be used interchangeably in this study
Unit Dose Strength concentration/presentation may vary based on market availability for glycopyrrolate and/or atropine sulfate
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All supplies indicated in Table 1 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc.).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
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.
6.1.1
Medical Devices
For any site using the TOF-Watch®SX: 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 8.4.8 for 
details.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions 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.
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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study 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 study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) 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 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Treatment allocation/randomization will occur centrally using IRT. Participants will be 
allocated to 1 treatment group.
Participants in Part A will be assigned the following treatment regimen:

Panel 1: Moderate block and reversal with sugammadex 2 mg/kg

Panel 2: Deep block and reversal with sugammadex 4 mg/kg
Participants in Part B of the study will be assigned randomly in a 1:1:1 ratio to 1 of the 
following treatment groups:

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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6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:
1. Age: Four age cohorts will be enrolled sequentially, beginning with the eldest age group: 
6 months to <2 years; 3 months to <6 months; 28 days to <3 months; Birth to 27 days.
Safety data from older age cohorts will be reviewed before initiating the study in the 
younger age cohorts. To ensure that approximately even age distributions are met, this 
study will target a minimum of approximately 20% of participants within each age 
cohort.
Part A enrollment:

Part A- Panel 1 will enroll a minimum of 3 participants with evaluable PK in each age 
cohort.
Part -A- Panel 2 will enroll a minimum of 6 participants with evaluable PK in each age 
cohort.
Part B enrollment:
Table 2
Number of Participants Required for Part B (Minimum/Maximum Enrollment)
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2. Neuromuscular blocking agent:

Rocuronium

Vecuronium
o Note: Approximately 30% of the overall planned sample size will be enrolled 
in the vecuronium stratum
6.3.3
Blinding
Study Treatment 
With the exception of designated individuals (eg, unblinded Clinical Research Associates, 
etc.), Sponsor study team personnel will be blinded to study treatment assignments and depth 
of block in Part B. Refer to Section 9.2 for details.
The site pharmacist (or delegate) will be unblinded to study treatment assignments to
prepare study treatment. Study treatment will be provided to site staff in the operating room 
(OR) (anesthesiologist) in a masked syringe 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 during Part B. While sugammadex for the deep block arm will be provided to the 
OR (anesthesiologist) in a masked syringe, 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 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)
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NOTE: Vital signs may be administered by appropriate staff; however, the BSA 
should review the vital signs to determine if findings are clinically significant and 
report any related adverse events.
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, but may not fulfill any roles that would grant them access to
Inform™.
The anesthesiologist performing study-related procedures 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 8.1.10 for a description of the method of unblinding a participant during the trial, 
should such action be warranted.
6.4
Study Intervention Compliance
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.
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study. If there is a clinical indication for any medication specifically prohibited, 
discontinuation from study intervention may be required. The investigator should discuss any 
questions regarding 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 on study intervention requires the mutual 
agreement of the investigator, the Sponsor, and the participant.
Listed below are specific restrictions for concomitant therapy or vaccination:
1. 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 study, including:

Other steroidal NMBAs, such as pancuronium
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
Nonsteroidal NMBAs such as succinylcholine or benzylisoquinolinium 
compound (eg, cisatracurium) (except in the circumstance that renewed muscle 
relaxation is needed after administration of study treatment, in which case a 
nonsteroidal NMBA should be administered)
2. Toremifene or fusidic acid use within 24 hours before or within 24 hours after study 
treatment administration is prohibited.
6.5.1
Rescue Medications and Supportive Care 
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
This section is not applicable to the study.
6.7
Intervention After the End of the Study
There is no study-specified treatment following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind participants and to unmask study treatment identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). 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 8.1.10, Participant Blinding/Unblinding, for a description of the method of 
unblinding a participant during the trial, should such action be warranted.
6.9
Standard Policies
Not applicable.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Not applicable.
7.2
Participant Withdrawal From the Study
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 8.1.9. 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 7.3.
7.3
Lost to Follow-up
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’s legally acceptable representative and 
reschedule the missed visit. If the participant’s legally acceptable representative is 
contacted, the participant’s legally acceptable representative 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’s legally acceptable representative at each missed visit (eg, telephone calls 
and/or a certified letter to the participant’s legally acceptable representative 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.
8
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.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
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 
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purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C, etc.), and thus local 
regulations may require that additional informed consent, and assent if applicable, be 
obtained from the participant. In these cases, such evaluations/testing will be performed 
in accordance with those regulations.
The blood volume required for each PK sample is 0.5 mL, which is the minimum amount 
needed for an accurate evaluation of the sample.
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 during a given 4-week study period (unless 
appropriate justification is documented by the investigator). [EMEA/CPMP 2008] [Food and 
Drug Administration (CDER) 2014]
The total volume drawn is within an allowable amount of 3% of total blood volume (2.4 mL 
blood per kg of body weight), even for the smallest neonates allowed in this study.
While larger volumes may be collected per local laboratory policies for laboratory testing in 
older children, no more than 3% of the total blood volume should be drawn during the course 
of this study.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent, and assent if applicable, from each participant’s legally 
acceptable representative prior to participating in this clinical study. If there are changes to 
the participant’s status during the study (eg, health or age of majority requirements), the 
investigator or medically qualified designee must ensure the appropriate documented
consent/assent is in place.
8.1.1.1
General Informed Consent/Assent
Consent/assent must be documented 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 informed consent/assent form should be given to the 
participant's legally acceptable representative before participation in the study.
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The initial informed consent/assent form, any subsequent revised 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’s 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 study. 
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 legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent 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/IEC requirements, 
applicable laws and regulations and Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
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 study.
8.1.3
Participant Identification Card
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 provide the participant with a Participant Identification Card 
immediately after the participant's legally acceptable representative  provides documented 
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.
8.1.4
Medical History
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 study eligibility, all active 
medical conditions since birth will be documented on the appropriate electronic case report 
form (eCRF). The surgical procedure and medical indication for the procedure must be 
recorded in the Sponsor database.
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8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, and record prior 
medication taken by the participant within 30 days before starting the study.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication taken by the participant during 
the study. Refer to Section 6.5 for additional information on use of concomitant medications. 
Rocuronium or vecuronium are concomitant medications to be used per label as adjunct to 
general anesthesia.
8.1.6
Assignment of Screening Number
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 allocation. Each 
participant will be assigned a screening number. Refer to Section 8.1.7 if surgery is delayed 
for more than one day. 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 on the screening/rescreening visit 
requirements are provided in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will receive a treatment/randomization number; participants will be 
randomly allocated in Part B of the study. 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 reassigned to 
another participant.
After a participant is screened and randomized, unexpected events such as a delay in the 
surgery or the clinical procedure may occur that prevent administration of study treatment 
and lead to discontinuation. In these situations, it may be permissible, after consultation with 
the Sponsor, for the participant to be reassigned to a new allocation number if the original 
one is no longer appropriate due to either enrollment closure or participant’s age. A 
consultation with the Sponsor will be required. Depending on the time that has elapsed since 
the participant’s initial visit, the Sponsor may require that some of the screening assessments 
be repeated before randomization.
Treatment allocation 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 allocation in IRT 
(eg, procedure 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.
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8.1.8
Study Intervention Administration
Administration of study treatment will be performed by the investigator or qualified 
designee.
Study treatment should begin within 1 day of treatment randomization.
8.1.8.1
Administration of Neuromuscular Blocking Agents
Rocuronium or vecuronium will be dosed as indicated as adjunct to general anesthesia, per 
prescribing information, for intubation purposes and maintenance of NMB by redosing or 
continuous infusion. 
NMB should be maintained within the assigned depth of block for the entire duration of the 
procedure 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 the needs of 
surgical procedures. Only one NMBA should be used for the entire duration of the procedure, 
including the intubation dose (if NMBA is used for intubation). The NMBA used during the 
procedure should be the NMBA noted in the IRT.
8.1.8.2
Timing of Dose Administration
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 the procedure. 
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, sugammadex 2 mg/kg or neostigmine 50 
mcg/kg (up to 5 mg maximum dose) will be given after the last dose of administered NMBA 
and within 2 minutes of detection of reappearance of T2.  
For participants randomized to deep block, sugammadex 4 mg/kg will be given after the last 
dose of administered NMBA and within 2 minutes of detection of a target of 1 to 5 PTC.
8.1.9
Discontinuation and Withdrawal
Once a participant receives study treatment at Visit 2, all applicable procedures at subsequent 
visits should be performed as per Study SoA in Section 1.3.
During the procedure and before administration of study medication, if the participant is no
longer planned to be extubated, then study medication should not be administered and the 
participant should be discontinued from the study. Additional information regarding these 
situations should be collected and communicated to the clinical team.
Any adverse events, which are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4.
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8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, 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 intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc., in 
the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
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.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Additionally, the investigator or medically qualified designee 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 study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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8.2
Efficacy Assessments
8.2.1
Monitoring Time to Neuromuscular Recovery
The methods used to confirm the TTNMR are outlined by item #1 of the ERA (Appendix 
10). In all circumstances, the investigator must select 1 of the 4 methods of assessment of 
TTNMR assessment that is appropriate for the participant and method of extubation: 
1) able to sustain head lift against resistance for at least 5 seconds, 
2) able to sustain hip flexion against resistance for at least 5 seconds, 
3) 4 twitches without fade (or, for neonates, 4 twitches comparable to pre-op baseline) 
observed in response to TOF via NMTM device, or 
4) TOF ratio ≥0.9 observed on objective NMTN.
If clinically necessary, the recovery assessment method may be adjusted midprocedure, 
based on investigator judgment, as long as it is by 1 of the above 4 approaches. When the 
adjustment is made after administration of study medication, then the method should be 
reflected in the ERA eCRF. For participants undergoing deep endotracheal extubation, 
neuromuscular recovery must be assessed by either 4 twitches without fade (or, for neonates, 
4 twitches comparable to pre-op baseline) observed in response to TOF via NMTM device or 
TOF ratio ≥0.9 observed on objective neuromuscular transmission monitoring. 
Neuromuscular recovery is expected to be achieved before extubation; in addition, if the 
participant will not be extubated, all efforts should be made to monitor for neuromuscular 
recovery every minute for at least 30 minutes after administration of study treatment. For 
further information, refer to MK-8616 P169 Guidance Document for Extubation Readiness 
Assessment.
8.2.2
Monitoring Time to Extubation 
Monitoring of time to extubation will be achieved using the Extubation Readiness 
Assessment (Appendix 10). The OR anesthesiologist or other medically qualified clinician 
fully trained on the protocol requirements will be responsible for assessing extubation 
readiness beginning about 1 minute after study treatment administration and reassessing 
every 60 seconds until time of extubation readiness is achieved. Beginning 30 minutes after 
study treatment administration, readiness for extubation must be assessed at least every 5 
minutes until time of extubation readiness is achieved.
Extubation readiness should be assessed until either the removal of the endotracheal tube or 
the clinical decision is made that the participant will not be extubated after the procedure as 
planned. (Refer to Section 8.1.9.) Refer to MK-8616 P169 Guidance Document for 
Extubation Readiness Assessment for further information.
8.2.3
Neuromuscular Monitoring
Neuromuscular monitoring will be performed to maintain the target depth of block 
throughout the surgical procedure and to ensure appropriate timing of dose administration of 
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study medication. Neuromuscular monitoring will be performed using a locally available 
NMTM device (eg, TOF-Watch®SX or PNS). Refer to Section 8.1.8.1 and Section 8.1.8.2 for 
details regarding the administration of neuromuscular blocking agents and timing of dose 
administration. Depth of block must be assessed and recorded at depth appropriate intervals
to ensure appropriate timing of dose administration. Refer to MK-8616 P169 Neuromuscular 
Transmission Monitoring Guidelines for further information regarding neuromuscular 
monitoring procedures and requirements.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard. Height and weight 
will also be measured and recorded.
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

Skin and extremities

Neurological system, including mental status, motor strength, muscle tone, and reflexes.
Any medical conditions found during the full physical examination will be recorded in the 
Sponsor database.
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A second physical examination (targeted physical examination) 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 examination:

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.
8.3.2
Height and Weight
Height (cm) and weight (kg) will be measured and recorded at Visit 2 before study treatment 
preparation. If randomization occurs on the day before the procedure, then weight will be 
collected at the time of randomization to permit study treatment preparation. 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. Refer to 
Section 8.1.7 if surgery is delayed more than one day.
8.3.3
Vital Signs
Heart rate, blood pressure, respiratory rate, oxygen saturation, and body temperature will be 
obtained at the following time points: 

Screening visit (Visit 1)

Before administration of NMBA

After the final dose of NMBA is administered, before administration of study treatment 

At 2, 5, 10, and 30 minutes after 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 blood pressure (eg, manual or automated, position, and location) should be 
used for all measurements for each individual participant as clinically appropriate.
Core body temperature must be measured at Visit 2. Axillary or skin temperature 
measurements are unacceptable for core body temperature assessment; therefore, another 
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method must be used. However, after extubation or if the participant will not be extubated 
and neuromuscular recovery has been monitored for at least 30 minutes after administration 
of study treatment, body temperature can be measured according to routine care (eg, 
axillary/skin measurements are acceptable). The investigator or delegate will maintain a 
record of the participant’s core body temperature during NMTM (the target core temperature 
is ≥35 ºC [95 ºF]).
Table 3
Assessment Windows for Vital Signs Following Study Treatment Administration
Time Point of Assessment for Vital Signs
Assessment Windowa
2 minutes
(1, 3) minutes
5 minutes
(3, 7) minutes
10 minutes
(8, 12) minutes
30 minutes
(25, 35) minutes
aupper and lower limits are inclusive.
8.3.4
Electrocardiograms
During the perianesthetic visit (Visit 2), continuous heart rate monitoring will occur at least 5 
minutes before, during, and for 30 minutes after administration of study treatment to 
facilitate assessment of treatment-emergent bradycardia, treatment-emergent relative 
bradycardia, and clinically relevant bradycardia (according to definitions in Section 4.2.1.2).
8.3.5
Clinical Safety Laboratory Assessments
•
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 or medically qualified designee (consistent with local requirements) 
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 that 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 nonprotocol-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).
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•
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 intervention, 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.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or 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 3.
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 and any designees are responsible for detecting, 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 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant’s legally 
acceptable representative provides documented informed consent but before intervention 
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 study, 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 intervention 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 related to study intervention. 
Investigators are not obligated to actively seek AEs or SAEs 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 intervention or study participation, 
the investigator must promptly notify the Sponsor.
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All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 4.
Table 4
Reporting Time Periods and Time Frames 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
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious 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
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
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- Potential drug-
induced liver injury 
(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 24 
hours of 
learning of 
event
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days
of learning of 
event
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 5 
calendar days
of learning of 
event
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
events of clinical interest (ECIs), 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 7.3). In addition, the investigator will make every attempt to follow all 
nonserious AEs that occur in randomized participants for outcome. Further information on 
follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
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 intervention 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 intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
This section is not applicable to the study.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This section is not applicable to the study.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
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Events of clinical interest for this study 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 study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Study File 
Binder (or equivalent). 
2. Hypersensitivity and/or anaphylaxis:
Adjudication of potential hypersensitivity and/or anaphylaxis events will be conducted by an 
independent external Adjudication Committee.
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. Refer to the ECI Guidance document (or 
equivalent) for more information. 
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 that occurs after 
administration of study treatment and requires 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.
8.4.8
Device Events, Patient Events, and Medical Device Incidents (Including 
Malfunctions)
In order to fulfill regulatory reporting obligations worldwide, the investigator is responsible 
for the detection and documentation of events meeting the definitions of device events, 
patient events, and medical device incidents including malfunctions that occur during the 
study with such devices.
Device and/or patient events include all untoward events related to the use of the TOF-
Watch®SX device.
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8.4.8.1
Prompt Reporting of Medical Device Incidents to Sponsor
Medical device incidents will be reported to the Sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a medical device 
incident.
8.4.8.2
Assessing and Recording Patient/Device Events
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 AEs experienced by the participant caused by or suspected to be 
caused by the TOF-Watch®SX device.
For the time period before allocation/randomization through 14 days after 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 AE CRF/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 8.4.1. The investigator will make every attempt to follow all nonserious 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 study, 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 (eg, 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).
8.4.8.3
Device Incidents
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;
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
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 before treatment allocation/randomization through 14 days after 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 the time period specified above also must be reported immediately to the Sponsor.
All participants involved with incidents must be followed up for outcome.
8.4.8.4
Regulatory Reporting Requirements for Medical Device Incidents
The investigator will within 24 hours report all medical device incidents occurring with any 
medical device as defined in the study protocol in order for the Sponsor to fulfill the legal 
responsibility to notify appropriate regulatory authorities and other entities about certain 
safety information relating to medical devices being used in clinical studies.
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements relating to the reporting of incidents to the IRB/IEC.
8.5
Treatment of Overdose
In this study, an overdose of sugammadex is considered a single dose ≥2 times the intended 
dose to which the participant was allocated.
In this study, an overdose of neostigmine is any single dose greater than 5.0 mg as indicated 
in the labeling of neostigmine. An overdose of glycopyrrolate is considered a single dose of 
greater than 2.0 mg. An overdose of atropine is considered a single dose of greater than 
0.5 mg.
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8.6
Pharmacokinetics
Pharmacokinetic samples are required for Part A of the study only; 5 to 6 samples will be 
drawn at the following time points: 

4 samples:  At 2, 15, 30, and 60 minutes after administration of sugammadex 

1 sample:  At 4 to 6 hours after administration of sugammadex 

1 sample:  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.
8.6.1
Blood Collection for Plasma MK-8616
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 multilumen 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. If venous access is not feasible, then 
collection from an arterial site will be considered acceptable for drawing PK blood samples 
for this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Future Biomedical Research Sample Collection
Future biomedical research samples will not be collected in this study.
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8.10
Health Economics Medical Resource Utilization and Health Economics
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])
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3 – Schedule of Activities (SoA).  Specific 
procedure-related details are provided above in Section 8 – Study Assessments and 
Procedures.
8.11.1
Screening (Visit 1)
Potential participants will be evaluated to determine that they fulfill the entry requirements as 
set forth in Section 5.1 and Section 5.2. If needed, a participant may repeat screening once; 
any additional rescreening will require consultation with the Sponsor. Depending on the time 
that has elapsed since the participant’s initial visit, the Sponsor may require that some of the 
screening assessments be repeated before randomization.
8.11.2
Peri-anesthetic Visit (Visit 2)
The peri-anesthetic period begins when the participant is assigned a treatment 
allocation/randomization number and continues throughout the surgical period, ending just 
before 4 hours post procedure. Refer to Section 8.1.7 for situations such as a delay in surgery.
Study staff will confirm that the participant still meets inclusion/exclusion criteria, review 
prior/concomitant medications, record the participant’s height and weight per the SoA 
(Section 1.3). 
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 8.6.1 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.
Rocuronium or vecuronium will be administered; only 1 NMBA (either rocuronium or 
vecuronium) should be used for the entire duration of the procedure. The NMBA used during 
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the procedure will be the NMBA noted in the IRT. Additional doses of NMBA will be 
administered as clinically required to maintain depth of block for the entire duration of the 
procedure, as determined by the Primary Investigator or designee. Refer to Section 8.1.8, 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 1.3). 
Extubation readiness will be assessed per protocol by the OR anesthesiologist or other 
qualified clinician.
8.11.3
Post-anesthetic Visit (Visit 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 
1.3 and Section 6.3.3 for more information.
The drug preparation records, depth of neuromuscular block, and study treatment given will 
be sequestered from the BSA for any participant assessed by that given BSA.
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.
8.11.4
Follow-up Contact (Visit 4)
Approximately 14 days post-study treatment administration, the 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.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but before 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 nonconfirmatory analyses made after the protocol has been finalized, but before final 
database lock, will be documented in a supplemental statistical analysis plan (SAP) and 
referenced in the Clinical Study Report (CSR) for the study. Post hoc exploratory analyses 
will be clearly identified in the CSR.  
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below; the comprehensive plan is provided in 
Section 9.2 through Section 9.12.  
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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 Aged Birth to <2 Years
Treatment Assignment
In Part A, participants will be sequentially enrolled to 2 doses of 
sugammadex within each age cohort (6 months to <2 years; 3 months to 
<6 months; 28 days to <3 months; birth to 27 days) with NMBA 
(Rocuronium and Vecuronium) as a stratification factor.
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 with a 1:1:1 ratio with NMBA (Rocuronium and Vecuronium) 
and age cohort (6 months to <2 years; 3 months to <6 months; 28 days to 
<3 months; birth to 27 days) as stratification factors:
Sugammadex 2 mg/kg and Moderate NMB 
Neostigmine and Moderate NMB 
Sugammadex 4 mg/kg and Deep NMB 
Analysis Populations
Pharmacokinetic (Part A): Pharmacokinetic (PK) set.
Safety (Part A and Part B): All Participants as Treated (APaT)
Efficacy (Part B): All Participants Treated (APT)
Primary Endpoint(s)
Pharmacokinetic (Part A): AUC, Cmax, CL, Vz, Vss, and t1/2
Safety (Part A and Part B): AE reporting, vital sign assessments
Efficacy (Part B): TTNMR
Key Secondary Endpoints
Time to extubation (Part B)
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
Pharmacokinetic: Individual values will be listed for each PK parameter 
and descriptive statistics will be calculated for all plasma PK parameters 
(ie, AUC, CL, Cmax, Vz, Vss , and t1/2) by dose.
Efficacy: The primary efficacy analysis is Cox Proportional Hazards 
model comparing sugammadex and neostigmine in the setting of moderate 
block (adjusting for age, stratified by NMBA) with TTNMR censored at 
the time of last assessment of neuromuscular recovery if neuromuscular 
recovery is not achieved.
Statistical Methods for Key 
Safety Analyses
p-values (Tier 1 only) and 95% CIs (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 (1985) with NMBA and age group as 
stratification factors.
Interim Analyses
In Part A, 4 IAs will be performed in this study. Each IA will include the 
evaluation of the PK data by an internal group of the Sponsor and the 
evaluation of the safety data by an eDMC. If PK results of an IA from Part 
A of the study are substantially different with those in the next oldest age 
cohort, then efficacy data will also be taken into consideration. If the 
efficacy data are substantially different with those previously established in 
adults, then Part A and the subsequent IAs may be repeated with modified 
doses until comparable exposure and/or efficacy are obtained.
The timing of each IA is after the completion of the older age cohort, 
before the commencement of enrollment of the next younger age cohort.
Multiplicity
No multiplicity adjustment is needed.
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Sample Size and Power 
The planned sample size is 126 participants. There will be 30 
participants per treatment arm (sugammadex and neostigmine) in the 
setting of moderate block for efficacy analysis. For TTNMR, the study
has >99% power to show that sugammadex 2 mg/kg is superior to 
neostigmine at an overall 2-sided 5% alpha level under the assumption 
that mean and standard deviation are 3 and 2 for sugammadex 2 mg/kg
and 13 and 15 for neostigmine.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor. The PK analyses and summaries described 
in Section 8.6 are the responsibility of PK, Pharmacodynamics and Drug Metabolism –
Quantitative Pharmacology and Pharmacometrics department of the Sponsor and Early 
Clinical Development Statistics – Clinical Biostatistics of the Sponsor.
Part A will be conducted as an open-label study, while Part B will be conducted as a double-
blind study under in-house blinding procedures. With the exception of designated unblinded 
Sponsor personnel (eg, unblinded Clinical Research Associates [CRAs], and other designated 
individuals as required), all other Sponsor study team personnel will be blinded to study 
treatment assignment in Part B. An internal unblinded statistician and programmer will 
prepare the safety analyses in support of the eDMC as needed. Part B data will remain 
blinded until final database lock.
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.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
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.
9.4.1
Efficacy Endpoints
The primary efficacy endpoint is TTNMR. The secondary efficacy endpoint is time to 
extubation. Please see Section 4.2.1.1 for a description of the efficacy endpoints.
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9.4.2
Safety Endpoints
Safety will be assessed through descriptive statistics within the APaT population. Safety 
assessments will include AEs, laboratory evaluations, and physical exams including vital 
signs. AEs of clinical interest for this protocol include clinically relevant bradycardia, 
hypersensitivity, and anaphylaxis. Please see Section 4.2.1.2 for a description of safety 
measures.
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 (clinically relevant bradycardia and treatment-emergent bradycardia), an analysis 
of events occurring within the first 30 minutes after study medication administration will be 
conducted, as this is the time period during which continuous heart rate monitoring will be 
conducted per protocol.
9.4.3
Pharmacokinetic Endpoints
The PK endpoints include AUC, CL, Cmax, Vz, Vss, and t1/2. Please see Section 4.2.1.3 for a 
description of PK endpoints.
9.4.4
Derivations of Efficacy Endpoints
The primary efficacy endpoint, TTNMR, is defined as the interval from administration of 
reversal agent to TTNMR (refer to Section 4.2.1). The secondary efficacy endpoint, time to 
extubation, is defined as the interval from administration of reversal agent to removal of the 
endotracheal tube. It is a relevant measure of neuromuscular recovery. TTNMR will be 
censored at the time of last assessment of neuromuscular recovery if neuromuscular recovery 
is not achieved. Also, time to extubation will be censored at the time of last assessment of 
extubation readiness if extubation readiness is not achieved. 
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The 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 
one 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 9.6.
9.5.2
Safety Analysis Populations
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all enrolled/randomized participants from both Part A and Part B who 
received a dose of study treatment. Participants will be included in the treatment group 
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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 are given incorrect study treatment will be included in 
the treatment group corresponding to the study treatment actually received.  
At least one laboratory or vital sign measurement obtained after at least one dose of study 
treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section
9.6.
9.5.3
PK Analysis Populations
In Part A, the evaluable PK population for the PK data analysis is defined as all participants 
with at least 5 samples at the time points of approximately 2 minutes, 15 minutes, 30 
minutes, 60 minutes, and 4 to 6 hours (with an additional optional time point of 10 to 12 
hours; refer to Section 8.6) after study treatment, with 6 participants per age group in Part A. 
For descriptive summaries of sugammadex, the population includes all participants with at 
least one measurable PK sample.
9.6
Statistical Methods
Statistical testing and inference for efficacy and safety analyses are described in Section 9.6.1 
and Section 9.6.2, respectively. Efficacy results that will be deemed to be statistically 
significant after consideration of the Type I error control strategy are described in Section 9.8. 
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. All statistical tests will 
be conducted at the α=0.05 (2-sided) level.
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the supplemental 
SAP.
The primary efficacy endpoint is the TTNMR and the secondary efficacy endpoint is the time 
to extubation. 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. TTNMR and time to 
extubation will be analyzed by a Cox PH model, adjusting age (continuous) and stratified by 
NMBA (rocuronium and vecuronium). In addition, the Cox PH model for time to extubation 
will include a covariate of endotracheal extubation type (deep and not deep). A sensitivity 
analysis will be performed for TTNMR including participants with neuromuscular recovery
assessment using TOF/PNS devices only.
Additionally, supportive analyses will include a stratified log-rank test (adjusting for age 
cohort and NMBA) as well as a Kaplan-Meier (KM) curve for TTNMR and time to 
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extubation. If a model does not converge for analysis of a particular endpoint, the stratified 
log-rank test will be stratified by age cohort only.
For both the primary and supportive analyses, TTNMR will be censored at the time of last 
assessment of neuromuscular recovery if neuromuscular recovery is not achieved, and time 
to extubation will be censored at the time of last assessment of extubation readiness if 
extubation readiness is not achieved. In addition, descriptive statistics including geometric 
means, medians, and 95% confidence intervals, as well as a KM curve will be provided for 
the primary and secondary efficacy endpoints for sugammadex 2 mg/kg and sugammadex 4 
mg/kg from both Part A and Part B (combined) and neostigmine from Part B. Table 5
summarizes the key efficacy analyses comparing sugammadex to neostigmine in the setting 
of moderate NMB.
Table 5
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 Neuromuscular 
Recovery
P
Cox Proportional 
Hazards Modela
APT
Censoredb
S
Stratified Log-rank 
Testc, Kaplan-Meier 
Curves
APT
Censoredb
Secondary Endpoints
Time to Extubation
P
Cox Proportional 
Hazards Modeld
APT
Censorede
S
Stratified Log-rank 
Testc, Kaplan-Meier 
Curves
APT
Censorede
a
Cox Proportional Hazards model includes terms for age and stratified by NMBA.
b
Censored at the time of last assessment of neuromuscular recovery if neuromuscular recovery is not 
achieved.
c
Stratified by age cohort and NMBA.
d
Cox Proportional Hazards model includes terms for age and extubation type, stratified by NMBA.
e
Censored at the time of last assessment of extubation readiness if extubation readiness is not achieved.
Abbreviations:  APT = All Participants Treated, NMBA = neuromuscular blocking agent, P = primary, 
S = supportive, TOF = train-of-four.
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9.6.2
Statistical Methods for Safety Analyses
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 6) and will be performed 
pooled across Part A and Part B (and across age cohorts). 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% CIs 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% 
CIs provided for between-group comparisons; only point estimates by treatment group are 
provided for Tier 3 safety parameters. In addition, the 2 pairwise (between-group)
comparisons will also be performed for Tier 1 safety endpoints using just Part B data.
AEs (specific terms as well as system organ class terms) and predefined limits of change in 
laboratory or vital signs that are not prespecified as Tier-1 endpoints will be classified as 
belonging to “Tier 2" or “Tier 3," based on the number of events observed. Membership in 
Tier 2 requires that at least 4 participants in any treatment group show the event; all other 
AEs and predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% CI for the between-group 
difference in percent incidence will always include 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% CIs may be provided without adjustment for multiplicity, the 
CIs should be regarded as a helpful descriptive measure to be used in review, not a formal 
method for assessing the statistical significance of the between-group differences in AEs and 
predefined limits of change.
Continuous measures such as changes from baseline in laboratory and vital sign parameters 
that are not prespecified as Tier-2 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 will be 
considered Tier 1 events. In addition, treatment-emergent bradycardia, the broad clinical and 
laboratory AE categories consisting of the percentage of participants with any AE, a drug-
related AE, an SAE, an AE that 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% CIs (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 cohort as stratification 
factors. 
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Table 6
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpointa
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Clinically relevant bradycardia 
X
X
X
Hypersensitivity (adjudicated)
X
X
X
Anaphylaxis (adjudicated)
X
X
X
Tier 2
Treatment-emergent bradycardia
Any AE
X
X
X
X
Any serious AE
X
X
Any drug-related AE
X
X
Any serious and drug-related AE
X
X
Discontinuation due to AE
X
X
AE (specific or SOCs) or PDLCsb (incidence ≥4 
participants in one of the treatment groups)
X
X
Tier 3
AEs (specific or SOCs), or PDLCsb (incidence <4 
participants in all of the treatment groups)
X
Change from baseline results (laboratory test 
results, vital signs)
Treatment-emergent relative bradycardia
X
X
a
Adverse events references refer to both clinical and laboratory AEs.
b
Includes only those endpoints not prespecified as Tier 1 or not already prespecified as Tier-2 endpoints.
Abbreviations: AE = adverse event; CI = confidence interval; PDLC = Predefined Limit of Change; SOC = 
System Organ Class; X = results will be provided.
9.6.3
Statistical Methods for Pharmacokinetics Analyses
Separately for each PK parameter, individual values of CL, AUC, Cmax, Vss, and Vz, will be 
natural log-transformed and evaluated with a fixed effects model containing fixed terms, 
dose, and age cohort (6 months to <2 years; 3 months to <6 months; 28 days to <3 months; 
birth to 27 days) and an interaction term, dose by age cohort. (Note: if the variability in PK 
parameters is markedly different in the age groups then the analysis will be performed 
separately for each age cohort with a fixed effects model containing dose as a fixed term). 
Kenward and Roger’s method will be used to calculate the denominator degrees of freedom 
for the fixed effects (DDFM=KR). At each dose, 95% CIs for the least-squares means for 
each age cohort 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 GMs and 95% CIs about the GMs on the original scale at 
each dose level. 
At each dose, plots with individual values, GMs, and corresponding 95% CIs will be 
provided for all PK parameters by age cohort.
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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, CL, Cmax, Vz, 
Vss, t1/2, and other PK parameters as appropriate) for MK-8616 by age cohort. Sample size 
(N), arithmetic mean (AM), standard deviation (SD), arithmetic coefficient of variation 
(ACV), median (Med), minimum (Min), maximum (Max), GM, and geometric CV (GCV) 
will be provided for all PK parameters by age cohort.
For exploratory purposes, summary statistics for additional PK parameters not listed here 
may be evaluated. 
A separate population PK analysis utilizing all the pediatric data from the current study, 
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 after the 
evaluation of the safety, efficacy, and PK exposures.
9.6.4
Summaries of Baseline Characteristics, Demographics, and Other Analyses
9.6.4.1
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed 
for APT using 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.
9.7
Interim Analyses
Four IAs are planned for this study, including evaluation of PK and safety results. To ensure 
that the safety data from older age cohorts has been reviewed by the eDMC (details are 
provided in Appendix 1) before initiating the study in the younger age cohorts, beginning 
with the eldest age cohort, the IA for each age cohort will occur before the enrollment of the 
next younger age cohort. The eDMC will serve as the primary reviewer of the safety results 
of each IA and will make recommendations as to whether to continue the study as planned. 
The PK results will be reviewed by an internal group of the Sponsor. If PK results of an IA 
from Part A of the study are substantially different with those in the next oldest age cohort,
then efficacy data will also be taken into consideration. If the efficacy data are substantially 
different with those previously established in adults, then Part A and the subsequent IAs may 
be repeated with modified doses until comparable exposure and/or efficacy are obtained.
Beyond the formal IAs described above, the eDMC will also review the safety data 
periodically throughout the study. Additionally, selected ECIs (eg, hypersensitivity, 
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anaphylaxis, and clinically relevant bradycardia) will be monitored by the eDMC; program-
wide (ie, including all data across the pediatric studies) 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 ITT principle, and the CHMP guideline on adaptive designs.
Details of blinding are described in Section 9.2.
9.8
Multiplicity
No corrections for multiplicity are planned for the primary efficacy hypothesis of this study 
as there is a single comparison of sugammadex versus neostigmine in the setting of moderate 
block using one endpoint. 
9.9
Sample Size and Power Calculations
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 1:1:1 randomization ratio will be used for sugammadex 
2 mg/kg, neostigmine, and sugammadex 4 mg/kg in the enrollment of approximately 90 
participants in Part B (30 in each treatment group). Along with 12 participants on 
sugammadex 2 mg/kg and 24 participants on sugammadex 4 mg/kg in Part A, the study will 
enroll approximately 42 participants on sugammadex in moderate block, 54 participants on 
sugammadex in deep block, and 30 participants on neostigmine in moderate block.
9.9.1
Sample Size and Power for Efficacy Analyses
Power calculations are based on the primary 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 participants as 
compared with the adult population, the approach used for underlying assumptions in this 
study 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 for moderate block with rocuronium are 
noted below in Table 7.
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Table 7
Time (in Minutes) to Recovery to a TOF Ratio of ≥0.9 for Sugammadex 2 mg/kg 
and Neostigmine for Moderate Block with Rocuronium
Sugammadex 2 mg/kg
Neostigmine
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
SD = standard deviation; TOF = train-of-four.
TTNMR is correlated with time to recovery to a TOF ratio of ≥0.9 in adults; however, 
TTNMR in this study is expected to be more variable than time to recovery to a TOF ratio of 
≥0.9 as 4 different methods will be allowed to determine neuromuscular recovery. In 
addition, as clinical signs require the participant to be awake, TTNMR in these participants 
may be longer. Therefore, the assumptions for power calculations will be made appropriately 
conservative compared with the summary statistics listed in the table above. Power estimates 
for detecting various differences with respect to TTNMR between sugammadex and 
neostigmine in moderate block are obtained based on a Cox PH model using a 2-sided, 
5%-level test, and are summarized in Table 8. 
Table 8
Power Estimates for Detecting Various Differences in Time to Neuromuscular 
Recovery (in Minutes) Between Sugammadex and Neostigmine in Moderate Block
Sugammadex 
Mean (SD)
Neostigmine 
Mean (SD)
Hazard 
Ratio
Powera
3 (2)
13 (15)
6.96
>99%
5 (3)
13 (15)
3.39
97%
6 (4)
13 (15)
2.55
85%
SD = standard deviation
a Based on N=27 for each treatment group to allow for 10% participants not treated with study medication using 
Cox PH model; 2-sided, 5%-level Chi-Square Test;
Data are simulated based on log-normal distribution.
9.9.2
Sample Size and Power for Safety Analyses
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 
hypersensitivity is, eg, 1% (1 of every 100 participants receiving the study treatment), there 
is a 34.4% chance of observing at least 1 AE among 42 participants in the 2 mg/kg 
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sugammadex treatment group, and a 41.9% chance of observing at least 1 AE among 54 
participants in the 4 mg/kg sugammadex treatment group.  
The estimate of the upper bound of the 95% CI for the underlying percentage of participants 
with a Tier 1 AE within the sugammadex groups are provided in Table 9. These calculations 
are based on the exact binomial method proposed by Clopper and Pearson [Clopper, C. J. 
1934].
Table 9
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 
42 (2 mg/kg) and 54 (4 mg/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
42 
(Sugammadex 
2 mg/kg)
0
0.0%
8.4%
1
2.4%
12.6%
3
7.1%
19.5%
5
11.9%
25.6%
54
(Sugammadex 
4 mg/kg)
0
0.0%
6.6%
1
1.9%
9.9%
3
5.6%
15.4%
5
9.3%
20.3%
a Based on the 2-tailed exact confidence interval of a binomial proportion (Clopper and Pearson, 1934).
Table 10 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 42 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.
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Table 10
Differences in Incidence in a Tier 1 Adverse Event Between the Sugammadex and 
Neostigmine Groups (Assuming 2-sided 5% Alpha Level With 42 Participants in 
Sugammadex Group and 30 Participants in Neostigmine Group)
Incidence of Adverse Event
Risk Difference
Sugammadex (%)
Neostigmine (%)
Percentage Points
95% CIa
2.4%
3.3%
1.1
(-14.5%, 9.5%)
7.1%
13.3%
6.2
(-23.5%, 8.2%)
CI = confidence interval
a Based on an asymptotic method (Farrington and Manning [1990]).
Incidences presented here are hypothetical and do not represent actual AEs in either group
9.9.3
Sample Size and Power for Pharmacokinetic Analyses
A sample size of 6 in each age group has approximately 91% likelihood that the 95% CI of 
the GM of CL in that particular age group will be within 60% and 140% of the GM estimates 
of the clearance of MK-8616. A between-subject SD of 0.23 in log scale for CL that was 
obtained from previous studies was used for these calculations. These calculations are also 
applicable to Vz. This calculation is based on the pediatric guidance proposed by Wang et al. 
[Wang, Y., et al 2012].
9.9.4
Sample Size and Power for Efficacy Data Comparison with Adults (for Dose 
Selection)
If PK results of an IA from Part A of the study are substantially different with those in the 
next oldest age cohort, comparison of efficacy data with those from adults will also be taken 
into consideration. The efficacy data comparison will be made between TTNMR in each age 
cohort of Part A and TOF ratio of ≥0.9 in adults. In each of the age cohorts, participants in 
both Panels will be pooled since the difference in time to recovery to a TOF ratio of ≥0.9
between moderate and deep block is clinically insignificant in adults.
From the Integrated Summary of Efficacy performed in 2012, GM and its 95% CI for the 
time to recovery to a TOF ratio of ≥0.9 for sugammadex 2 mg/kg is 1.9 (1.8, 2.0). TTNMR is 
similar to time to recovery to a TOF ratio of ≥0.9; however, TTNMR in pediatrics is 
expected to be slightly longer and more variable than time to recovery to a TOF ratio of ≥0.9
as 4 different methods of assessments will be used, 2 of which require an awake and 
cooperative participant. Thus, we assume the TTNMR (in seconds) in pediatrics follows a 
log-normal distribution with mean and SD of 5.7 and 2.0 (the corresponding GM is 5 
minutes). With a sample size of 9 participants there is 85% probability that the estimated GM
in pediatrics is <10 minutes under the above assumptions.
9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a 95% CI) for the primary and 
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secondary efficacy endpoints will be estimated and plotted within each subgroup of each 
classification variable below based on the primary efficacy analysis model (Cox PH) in the 
setting of moderate block (age or NMBA will not be in the model for subgroup analysis of 
that classification variable). The following are the classification variables:
•
Age cohort (6 months to <2 years, 3 months to <6 months, 28 days to <3 months, 
Birth to 27 days)
•
Neuromuscular blocking agent (rocuronium or vecuronium)
•
Sex (female, male)
•
Race (white, other)
•
Region (US, Ex-US)
In addition, a Forest plot will be produced, which provides the estimated point estimates and 
CIs for the treatment difference across the categories of subgroups listed above.
In addition, a summary of Tier 1 safety parameters will be provided for each subgroup of the 
following classification variables: 
•
Depth of block (moderate, deep)
•
Age cohort (6 months to <2 years, 3 months to <6 months, 28 days to <3 months, 
Birth to 27 days)
•
Neuromuscular blocking agent (rocuronium or vecuronium)
•
Sex (female, male)
•
Race (white, other)
•
Region (US, Ex-US)
Subgroup analyses/summaries will only be performed for those classification variables with 
at least 5 participants in each subgroup.
9.11
Compliance (Medication Adherence)
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 differs by more than 10% from the planned dosage will be listed. No statistical tests will 
be performed with respect to treatment compliance.
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9.12
Extent of Exposure
The extent of exposure to study treatment will be summarized in a table presenting per 
treatment group the number of participants who were randomized and received the study 
treatment (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).
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, 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 participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD 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 that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
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 MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. 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 such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). 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. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD 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.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD 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
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD 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.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
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B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD 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.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
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. 
10.1.3
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 that 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.
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10.1.3.1
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 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 study 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.
10.1.3.2
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 study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. 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.
10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The Executive Oversight Committee (EOC) is comprised of members of Sponsor Senior 
Management. The EOC will receive and decide upon any recommendations made by the 
eDMC regarding the study.
10.1.4.2
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
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The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 -Interim 
Analysis) and recommend to the EOC whether the study 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 study 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.
10.1.4.3
Clinical Adjudication Committee (CAC)  
A Clinical Adjudication Committee (CAC) will evaluate the following events for the 
purposes of confirming them according to the criteria in Section 9, as well as evaluating the 
presence of confounding factors.
AE of hypersensitivity
Events of anaphylaxis
All personnel involved in the adjudication process will remain blinded to study intervention 
allocation throughout the study.
10.1.5
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.
10.1.6
Compliance with Study 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 study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
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entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study 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 study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
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 studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
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.
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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.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study 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 any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
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 participants’ legally acceptable representatives' 
documented informed consent, 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.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). 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/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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10.1.10
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 study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 11 will be collected and analyzed by the local laboratory.
•
Perianesthetic period (Visit 2): Samples will be drawn before study treatment 
administration and need not be drawn if local laboratory results are available within 14 
days of randomization.
•
Post-anesthetic period (Visit 3): Samples need not be drawn if local laboratory results are 
(or will be) available within 36 hours after administration of study treatment.
•
The results and normal ranges of protocol-required safety laboratory assessments from 
local laboratories must be entered into the CRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 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.
Table 11
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
Reticulocytes (% or 
numeric), if locally 
available
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistrya
BUN or urea per 
local regulations
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
Abbreviations:  ALT/SGPT = alanine aminotransferase/serum glutamic-pyruvic transaminase, AST/SGOT = aspartate 
aminotransferase/serum glutamic-oxaloacetic transaminase, 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.
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 nonfasting glucose values are acceptable.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
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 intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), 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, 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 intervention 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 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, 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 8.4.6 for protocol-specific exceptions.
10.3.2
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.
An 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 an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’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.
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•
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) that 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.
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 1 
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.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs 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 
10.3.4
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 AE 
CRFs/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.
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•
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.
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 studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, 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 used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE 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 AE 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 AE:
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-
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 studies 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.
-
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 study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
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 study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
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 
IRB/IEC.
•
Consistency with study intervention 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.
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•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
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 1 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.
10.3.5
Reporting of AEs, SAEs, 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.
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-
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 8.4.1 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 EDC 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 EDC 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 Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC 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 Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
The recording and follow-up procedures described in this protocol apply to all medical 
devices as described below. For purposes of this section, medical devices in scope for device 
information collection include devices intended to be used by a study participant according to 
the study protocol, that are manufactured by the Sponsor or for the Sponsor by a third party, 
licensed by the Sponsor for human use as listed in Section 6.1.1. Product Quality 
Complaints/Malfunctions must be reported to the Sponsor.
10.4.1
Definitions
Customer Feedback - A report that does not allege a PQC or defect and has no relevant 
safety information/untoward event associated with it (eg, goodwill or courtesy replacement, 
consumer preference or suggestion, remark which may suggest an improvement in the 
functionality or quality of a medical device or device-like features of a drug delivery system).
Device Events - 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.
Device Incident - Any malfunction or deterioration in the characteristics and/or performance 
of the device, as well as any inadequacy in the labeling or the instructions for use that, 
directly or indirectly, led to or could have led to, the death of a 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.
Malfunction - The failure of a device to meet its performance specifications or otherwise 
perform as intended.
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Medical Device - Any instrument, apparatus, appliance, material or other article, whether 
used alone or in combination, including the software necessary for its proper application 
intended by the MANUFACTURER to be used for human beings for the purpose of: 
•
diagnosis, prevention, monitoring, treatment or alleviation of disease, 
•
diagnosis, monitoring, treatment, alleviation of or compensation for an injury or 
handicap, 
•
investigation, replacement or modification of the anatomy or of a physiological process,
•
control of conception, 
and which does not achieve its principal intended action in or on the human body by 
pharmacological, immunological or metabolic means, but which may be assisted in its 
function by such means.
Participant Events - AEs experienced by the participant caused by or suspected to be caused 
by the medical device.
PQC - Any communication that describes a potential defect related to the identity, strength, 
quality, purity or performance of a product identified by external customers. This includes 
potential device malfunctions. Note: A report of Lack or Limited Efficacy is considered an 
AE rather than a PQC.
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions
Recording
Refer to Section 8.4.8.
Assessing Causality
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship.
•
The investigator will use clinical judgement to determine the relationship.
•
Alternative causes such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration should be considered and investigated.
Follow-up
•
The investigator will perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Sponsor to elucidate the 
nature and/or causality of the event as complete as possible.
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
Not applicable.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable.
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: Abbreviations
Term
Definition
AE
Adverse event
ALT
Alanine aminotransferase
APaT
All participants as treated
APT
All participants treated
ASA
American Society of Anesthesiologists
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve  
BSA
Blinded safety assessor
CAC
Clinical Adjudication Committee
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence interval
CL
Clearance  
Cmax
Maximum plasma concentration
Cox PH
Cox Proportional Hazards
CRF
Case report form
CSR
Clinical study report
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
ERA
Extubation readiness assessment
FDAAA
Food and Drug Administration Amendments Act
GCP
Good Clinical Practice
GM
Geometric mean
IA
Interim analysis
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive response technology
ITT
Intention-to-treat
IV
Intravenous
IVD
In vitro diagnostic
KM
Kaplan-Meier (curve)
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Term
Definition
NMB
Neuromuscular blockade
NMBA
Neuromuscular blocking agent
NMTM
Neuromuscular transmission monitoring 
NSAE
Nonserious adverse event
OR
Operating room
PACU
Post-anesthesia care unit
PK
Pharmacokinetic
PNS
Peripheral nerve stimulator
PREA
Pediatric Research Equity Act
PTC
Post-tetanic count
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SLAB
Supplemental laboratory
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 
TTNMR
Time to Neuromuscular Recovery
Vz
Apparent volume of distribution 
Vss
Apparent volume of distribution at steady state 
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10.9
Appendix 9: Bradycardia Definition by Age Range
Age Range
Heart Ratea
(beats per minute)
Median Heart Rate
(1st- 99th percentile)
0 to 3 months
<110
143 (107-181)
3 to 6 months
<105
140 (104-175)
6 to 12 months
<95
128-134 (93-168)
12 to 24 months
<85
116-123 (82-156)
a Heart rates were rounded to the more conservative value (Adapted from Fleming, 2011) [Fleming, S., et al 
2011]
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10.10 Appendix 10: Extubation Readiness Assessment
EXTUBATION READINESS ASSESSMENT (PEDIATRIC)
Instructions:  ALL core questions (Bolded Yes/No) must be answered. For the supporting 
data elements, assess and document any/all that apply. Refer to MK8616 P169 Guidance 
Document for Extubation Readiness Assessment for further details.
1) Neuromuscular Recovery
[   ] Yes     [   ] No
•
Able to sustain head lift against resistance for at least 5 seconds
•
Able to sustain hip flexion against resistance for at least 5 seconds
•
4 twitches without fade (or, for neonates, 4 twitches comparable to pre-op baseline) 
observed in response to TOF via NMTM device*
•
TOF ratio ≥0.9 observed on objective neuromuscular transmission monitoring*
*If deep endotracheal extubation is performed, then neuromuscular recovery must be 
assessed by 4 twitches without fade (or, for neonates, 4 twitches comparable to pre-op 
baseline) observed in response to TOF via NMTM device or TOF ratio ≥0.9 observed on 
objective neuromuscular transmission monitoring
----------------------------------------------------------------------------------------------------------------
2) Mental Status appropriate for extubation
[   ] Yes     [   ] No

Awake

Eye opening

Purposeful movements
Note: If deep endotracheal extubation is performed, mental status at the time of extubation 
should be confirmed to be appropriate. The core question should be answered as “yes” with 
the supporting data to be “other – extubation at deep sedation”.
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3) Return of Spontaneous ventilation
[   ] Yes     [   ] No
•
Spontaneous ventilation with clinically adequate tidal volume and regular respiratory 
rate as per individual’s age and weight
•
Spontaneous ventilation and no evidence of increased work of breathing (eg, no 
tracheal tug, no nasal flaring, no use of accessory muscles) 
•
End tidal CO2 <50mm Hg
----------------------------------------------------------------------------------------------------------------
4) Adequate Oxygenation 
[   ] Yes     [   ] No

SpO2 >92%

SpO2 <92%, but within 5% points of pre-operative baseline
----------------------------------------------------------------------------------------------------------------
5) Hemodynamically stable
[   ] Yes     [   ] No
•
Systolic and diastolic blood pressure at or above acceptable minimum for age
•
Systolic and diastolic blood pressure within 30% of baseline post-induction levels
•
Heart rate at or above acceptable minimum for age
•
Heart rate within 30% of baseline post-induction levels
----------------------------------------------------------------------------------------------------------------
6) Core Body Temperature at least 35 degrees Celsius
[   ] Yes     [   ] No
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11
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