Conditions: HIV-1 Infection
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: yes

Brief summary:
The present study is designed to determine the effect of islatravir (ISL) \[MK-8591\] on methadone pharmacokinetics (PK). The primary objective is to assess whether ISL impacts the area under the plasma concentration time curve from dosing to 24 hours postdose (AUC0-24) of S-methadone and R-methadone in participants on oral methadone therapy. It is hypothesized that the plasma AUC0-24hr for S- and R-methadone will be similar after methadone alone compared to methadone and ISL 60 mg coadministration.

Detailed description:

Arms:
arm 1: Methadone-maintained participants (20 to 200 mg \[locally-provided\] once daily \[QD\] from Day -14 to Day -1 and Day 10 to Day 15) receive methadone 20 to 200 mg QD on Day 1 to Day 9; ISL 60 mg is co-administered with methadone on Day 2.

Interventions: intervention 1: Islatravir
Intervention descriptions: intervention 1: ISL 30 mg x 2 (60 mg total) capsules taken by mouth.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT04568603 
Document Date: 
28-Aug-2020
A Clinical Trial to Study the Effect of a Single Dose of Islatravir 
(MK-8591) on the Pharmacokinetics of Methadone


PRODUCT: MK-8591  
1
PROTOCOL/AMENDMENT NO.: 029-00 
MK-8591-029-00 FINAL PROTOCOL
28-AUG-2020
Title Page
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. (MSD).
Protocol Title: A Clinical Trial to Study the Effect of a Single Dose of Islatravir (MK-8591) 
on the Pharmacokinetics of Methadone
Protocol Number: 029-00
Compound Number: MK-8591
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
128,595
Approval Date: 28 August 2020
 
 
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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
Original Protocol
28-AUG-2020
Not applicable
 
 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
1
PROTOCOL SUMMARY ............................................................................................11
1.1
Synopsis.................................................................................................................11
1.2
Schema ..................................................................................................................15
1.3
Schedule of Activities...........................................................................................16
2
INTRODUCTION..........................................................................................................24
2.1
Study Rationale....................................................................................................24
2.2
Background ..........................................................................................................25
2.2.1
Pharmaceutical and Therapeutic Background .............................................25
2.2.2
Clinical Studies............................................................................................26
2.2.3
Ongoing Clinical Studies.............................................................................26
2.2.4
Information on Other Study-related Therapy ..............................................26
2.3
Benefit/Risk Assessment......................................................................................27
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................28
4
STUDY DESIGN............................................................................................................30
4.1
Overall Design......................................................................................................30
4.2
Scientific Rationale for Study Design.................................................................31
4.2.1
Rationale for Endpoints ...............................................................................32
4.2.1.1
Efficacy Endpoints.............................................................................32
4.2.1.2
Safety Endpoints................................................................................32
4.2.1.3
Pharmacokinetic Endpoints ...............................................................32
4.2.1.4
Pharmacodynamic Endpoints.............................................................33
4.2.1.5
Planned Exploratory Biomarker Research.........................................33
4.2.1.5.1
Planned Genetic Analysis ........................................................33
4.2.1.6
Future Biomedical Research..............................................................34
4.3
Justification for Dose...........................................................................................34
4.4
Beginning and End of Study Definition .............................................................34
4.4.1
Clinical Criteria for Early Study Termination .............................................35
5
STUDY POPULATION ................................................................................................35
5.1
Inclusion Criteria.................................................................................................35
5.2
Exclusion Criteria................................................................................................37
5.3
Lifestyle Considerations......................................................................................39
5.3.1
Meals and Dietary Restrictions....................................................................39
5.3.1.1
Diet Restrictions.................................................................................39
5.3.1.2
Fruit Juice Restrictions ......................................................................40
 
 
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5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................40
5.3.2.1
Caffeine Restrictions..........................................................................40
5.3.2.2
Alcohol Restrictions...........................................................................40
5.3.2.3
Tobacco Restrictions..........................................................................40
5.3.3
Activity Restrictions ....................................................................................40
5.4
Screen Failures.....................................................................................................40
5.5
Participant Replacement Strategy......................................................................41
6
STUDY INTERVENTION............................................................................................41
6.1
Study Intervention(s) Administered...................................................................41
6.2
Preparation/Handling/Storage/Accountability .................................................43
6.2.1
Dose Preparation..........................................................................................43
6.2.2
Handling, Storage, and Accountability........................................................43
6.3
Measures to Minimize Bias: Randomization and Blinding..............................44
6.3.1
Intervention Assignment..............................................................................44
6.3.2
Stratification.................................................................................................44
6.3.3
Blinding........................................................................................................44
6.4
Study Intervention Compliance..........................................................................44
6.5
Concomitant Therapy..........................................................................................44
6.5.1
Rescue Medications and Supportive Care ...................................................45
6.6
Dose Modification ................................................................................................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...........................................................46
7.3
Lost to Follow-up .................................................................................................46
8
STUDY ASSESSMENTS AND PROCEDURES........................................................47
8.1
Administrative and General Procedures ...........................................................48
8.1.1
Informed Consent.........................................................................................48
8.1.1.1
General Informed Consent.................................................................48
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................48
8.1.2
Inclusion/Exclusion Criteria ........................................................................49
8.1.3
Participant Identification Card.....................................................................49
8.1.4
Medical History ...........................................................................................49
8.1.5
Prior and Concomitant Medications Review...............................................49
 
 
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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
Timing of Dose Administration.........................................................50
8.1.9
Discontinuation and Withdrawal .................................................................50
8.1.9.1
Withdrawal From Future Biomedical Research ................................51
8.1.10
Participant Blinding/Unblinding..................................................................51
8.1.11
Domiciling ...................................................................................................51
8.1.12
Calibration of Equipment.............................................................................51
8.2
Efficacy/Immunogenicity Assessments ..............................................................51
8.3
Safety Assessments...............................................................................................52
8.3.1
Physical Examinations.................................................................................52
8.3.2
Vital Signs....................................................................................................52
8.3.2.1
Resting Vital Signs ............................................................................52
8.3.3
Electrocardiograms ......................................................................................53
8.3.4
Clinical Opiate Withdrawal Scale (COWS) ................................................54
8.3.5
Clinical Safety Laboratory Assessments .....................................................55
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................55
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......57
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...57
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............................................................................58
8.5
Treatment of Overdose........................................................................................59
8.6
Pharmacokinetics.................................................................................................59
8.6.1
Blood Collection for Plasma ISL and Plasma Methadone...........................59
8.7
Pharmacodynamics..............................................................................................59
8.8
Biomarkers ...........................................................................................................59
8.8.1
Planned Genetic Analysis Sample Collection..............................................59
8.9
Future Biomedical Research Sample Collection...............................................60
8.10
Visit Requirements...............................................................................................60
 
 
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8.10.1
Screening......................................................................................................60
8.10.2
Treatment Period..........................................................................................60
8.10.3
Discontinued Participants Continuing to be Monitored in the Study ..........60
8.10.4
Poststudy......................................................................................................60
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......61
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................62
9
STATISTICAL ANALYSIS PLAN .............................................................................63
9.1
Statistical Analysis Plan Summary.....................................................................63
9.2
Responsibility for Analyses.................................................................................65
9.3
Hypotheses/Estimation ........................................................................................65
9.4
Analysis Endpoints...............................................................................................66
9.5
Analysis Populations............................................................................................66
9.6
Statistical Methods...............................................................................................67
9.7
Interim Analyses ..................................................................................................69
9.8
Multiplicity ...........................................................................................................69
9.9
Sample Size and Power Calculations .................................................................69
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................71
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........71
10.1.1
Code of Conduct for Clinical Trials.............................................................71
10.1.2
Financial Disclosure.....................................................................................73
10.1.3
Data Protection.............................................................................................73
10.1.3.1
Confidentiality of Data ......................................................................74
10.1.3.2
Confidentiality of Participant Records...............................................74
10.1.3.3
Confidentiality of IRB/IEC Information............................................74
10.1.4
Publication Policy........................................................................................75
10.1.5
Compliance with Study Registration and Results Posting Requirements ...75
10.1.6
Compliance with Law, Audit, and Debarment ............................................75
10.1.7
Data Quality Assurance ...............................................................................76
10.1.8
Source Documents .......................................................................................77
10.1.9
Study and Site Closure.................................................................................77
10.2
Appendix 2: Clinical Laboratory Tests..............................................................78
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................79
10.3.1
Definition of AE ..........................................................................................79
10.3.2
Definition of SAE ........................................................................................80
10.3.3
Additional Events Reported.........................................................................81
 
 
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10.3.4
Recording AE and SAE ...............................................................................81
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................85
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................86
10.5
Appendix 5: Contraceptive Guidance................................................................87
10.5.1
Definitions....................................................................................................87
10.5.2
Contraception Requirements........................................................................89
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................90
10.7
Appendix 7: Country-specific Requirements....................................................95
10.8
Appendix 8: Blood Volume Table ......................................................................96
10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria ....................97
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values .....99
10.11 Appendix 11: Abbreviations .............................................................................100
11
REFERENCES.............................................................................................................102
 
 
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LIST OF TABLES
Table 1
Study Interventions..........................................................................................42
Table 2
Sample Allocation Schedule............................................................................44
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................56
Table 4
Pharmacokinetic Blood Collection Windows..................................................61
Table 5
Power and Precision Estimates........................................................................70
Table 6
Protocol-required Safety Laboratory Assessments..........................................78
 
 
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LIST OF FIGURES
Figure 1
Trial Diagram.............................................................................................15
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Clinical Trial to Study the Effect of a Single Dose of Islatravir (MK-8591) 
on the Pharmacokinetics of Methadone
Short Title: Islatravir and Methadone Drug Drug Interaction
Acronym:
Hypotheses, Objectives, and Endpoints:
Primary Objectives
Primary Endpoints
- To determine the effect of ISL on the 
plasma pharmacokinetics of methadone (eg, 
AUC0-24 for S- and R-enantiomers of 
methadone) following  co-administration of 
a single dose of methadone.  
Primary Hypothesis:  The methadone (R-
enantiomer) plasma AUC0-24 obtained 
after single dose co-administration of 
methadone with ISL is similar to the 
methadone (R-enantiomer) plasma AUC0-
24 obtained after single dose administration 
of methadone alone. That is, the true GMR 
(methadone and ISL/methadone alone) for 
the dose-normalized AUC0-24 (AUC0-
24/D) of methadone (R-enantiomer) is 
contained within (0.7, 1.43).
Primary Hypothesis: The methadone (S-
enantiomer) plasma AUC0-24 obtained 
after single dose co-administration of 
methadone with ISL is similar to the 
methadone (S-enantiomer) plasma AUC0-
24 obtained after single dose administration 
of methadone alone. That is, the true GMR 
(methadone and ISL/methadone alone) for 
the dose-normalized AUC0-24 (AUC0-
24/D) of methadone (S-enantiomer) is less 
than 2.0.
- Dose-normalized AUC0-24 (AUC0-24/D) 
of plasma methadone (R-, and S-
methadone).
 
 
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Secondary Objectives
Secondary Endpoints
- To determine the effect of ISL on the 
plasma pharmacokinetics of methadone (eg, 
Cmax, C24, and Tmax for the S- and R-
enantiomers and  AUC0-24, Cmax, C24, 
and Tmax for total methadone) following 
co-administration of methadone.
Secondary Hypothesis: The methadone (R-
enantiomer) plasma Cmax obtained after 
single dose co-administration of methadone 
with ISL is similar to the methadone (R-
enantiomer) plasma Cmax obtained after 
single dose administration of methadone 
alone. That is, the true GMR (methadone 
and ISL/methadone alone) for the dose-
normalized Cmax (Cmax/D) of methadone 
(R-enantiomer) is less than 1.43.
Secondary Hypothesis: The methadone (S-
enantiomer) plasma Cmax obtained after 
single dose co-administration of methadone 
with ISL is similar to the methadone (S-
enantiomer) plasma Cmax obtained after 
single dose administration of methadone 
alone. That is, the true GMR (methadone 
and ISL/methadone alone) for the dose-
normalized Cmax (Cmax/D) of methadone 
(S-enantiomer) is less than 2.0.
Estimation: The true GMR (methadone and 
ISL/ methadone alone) for the dose 
normalized C24 (C24/D) of methadone (R-
enantiomer and S-enantiomer) will be 
estimated.
Estimation: The true GMR (methadone and 
ISL/methadone alone) for the dose 
normalized AUC0-24 (AUC0-24/D), Cmax 
(Cmax/D) and C24 (C24/D) of methadone 
(total) will be estimated.
- Dose-normalized Cmax (Cmax/D), C24 
(C24/D), and Tmax of plasma methadone 
(R-, and S- enantiomer).
- Dose-normalized AUC0-24 (AUC0-24/D), 
Cmax (Cmax/D), C24 (C24/D), and Tmax 
of plasma methadone (total).
- To evaluate the safety and tolerability of 
ISL co-administered with methadone.
- Adverse experiences, laboratory safety 
tests, ECGs, VSs (HR, BP, RR, oxygen 
saturation).
 
 
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Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
- To determine the effect of methadone on 
the PK of coadministered ISL
- AUC0-24, AUC0-168, AUC0-672, 
AUC0-inf, Cmax, Tmax, t1/2 of plasma ISL
- To explore the relationship between 
genetic variation and response to the 
treatment(s) administered and mechanisms 
of disease. Variation across the human 
genome may be analyzed for association 
with clinical data collected in this study. 
- Germline genetic variation and association 
to clinical data collected in this study
Overall Design:
Study Phase
Phase 1
Primary Purpose
Other
Indication
Treatment of HIV infection
Population
Participants on oral methadone maintenance therapy Insert 
text here
Study Type
Interventional
Intervention Model
Single Group
This is a single-site study.
Type of Control
Internal control
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 5 months from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
Number of Participants:
Approximately 14 participants will be allocated/randomized.
 
 
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Regimen/ 
Treatment 
Period/
Regimen
Use
Methadone 
Maintenance
Methadone
20 – 200 
mg
QD
Oral
20 to 200 
mg from 
Day -14 to 
Day -1 and 
Day 10 to 
Day 15
Back-
ground 
Therapy
Study 
Intervention 
(Islatravir
60 mg, 
Individualized 
methadone)
ISL
30 mg
Once 
Oral
2 x 30 mg 
capsules on 
Day 2 
Experim
ental
Methadone
20 – 200 
mg
QD
Oral
20 to 200 
mg from 
Day 1 to 
Day 9
Experim
ental
Abbreviations: QD=Once Daily
Other current or former name(s) or alias(es) for study intervention(s) are as 
follows: ISL, MK-8591, EFdA
Total 
Number of 
Intervention 
Groups/ 
Arms
1
Duration of 
Participation
Each participant will participate in the study for approximately 6 weeks
from the time the participant signs the Informed Consent Form through the 
final contact.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 11.
 
 
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Trial Diagram
 
 
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1.3
Schedule of Activities
Screening – Day 1
Screening
Run-In
Intervention
Notes
Scheduled Day
Screening 
Day -
14 to 
Day   -
2
Day-1
Day 1
Scheduled Hour
Pre-
dose
0
0.5 1
1.5 2
3
4
6
12 16
24
Administrative/Study
Procedures
Informed Consent
X
The informed consent form 
must be signed prior to any 
protocol procedures being 
performed.
Informed Consent for Future 
Biomedical Research
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
X
Inclusion/Exclusion criteria
review may begin on Day-
1. Eligibility to be 
confirmed after completion 
of all predose assessments. 
Medical History
X
Prior/Concomitant Medication 
Review
  X---------------------------------------------------------------------------------------------------------X
Assignment of 
Treatment/Randomization 
Number
X
Methadone Maintenance 
Phase
X----------------X
Participants will receive 
their standard methadone 
therapy from their usual 
clinic during a minimum
14-day run-in phase ending 
on Day -1.
 
 
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Screening – Day 1
Screening
Run-In
Intervention
Notes
Scheduled Day
Screening 
Day -
14 to 
Day   -
2
Day-1
Day 1
Scheduled Hour
Pre-
dose
0
0.5 1
1.5 2
3
4
6
12 16
24
Methadone Administration
X
Participants will receive a 
maintenance dose of 
methadone with 
approximately 240 mL of 
water after an overnight 
fast of at least 8 hours. 
Participants will continue to 
fast for 4 hours postdose.
Standard Meals
X
X----------------X
A meal will be served on 
the evening of Day -1 and 
consumed at least 8 hrs
before dosing. Standard 
meals will be served per 
site processes beginning ~4 
hrs post-dose until 8 hrs 
prior to Day 2 dosing.
Domiciling
X----------------------------------------------------------------------------------X
Participants will check-in 
on Day -1.
Safety Procedures
Full physical examination
X
Height
X
Weight
X
Note: BMI to be calculated
only at screening
 
 
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Screening – Day 1
Screening
Run-In
Intervention
Notes
Scheduled Day
Screening 
Day -
14 to 
Day   -
2
Day-1
Day 1
Scheduled Hour
Pre-
dose
0
0.5 1
1.5 2
3
4
6
12 16
24
Vital Signs (heart rate, blood 
pressure, respiratory rate, 
oxygen saturation)
X
X
X
X
Participants should be 
resting in a semi-recumbent 
position for at least 10 mins 
prior to measurement. 
Respiratory rate and 
oxygen saturation will be 
measured as per SOPs. 
Predose VS should be 
measured within 3 hours of 
methadone dosing.
Vital Signs (temperature)
X
X
Predose VS should be 
measured within 3 hours of 
methadone dosing.
12-lead ECG
X
X
X
X
Participants should be 
resting in a semi-recumbent 
position for at least 10 mins 
prior to measurement. 
Screening and pre-dose 
ECGs should be performed 
in triplicate, 1 to 2 minutes 
apart. Predose ECGs should 
be measured within 3 hours 
of methadone dosing.
Serum hCG
X
X
Performed for women of 
childbearing potential.
Serum FSH 
X
Performed for 
postmenopausal women.
Hepatitis B and C screen (per 
site SOP)
X
 
 
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Screening – Day 1
Screening
Run-In
Intervention
Notes
Scheduled Day
Screening 
Day -
14 to 
Day   -
2
Day-1
Day 1
Scheduled Hour
Pre-
dose
0
0.5 1
1.5 2
3
4
6
12 16
24
HIV antigen/antibody screen
X
Participants must have 
negative HIV 
antigen/antibody test at 
screening.
STI Urine screen
X
Includes testing for 
gonorrhea, chlamydia, and 
trichomoniasis at minimum.
Syphilis serologic screening
X
UDS (per site SOP)
X
X
Screening and Day-1 UDS
is mandatory, any 
additional UDS are 
conducted per site SOP.
Hematology, Urinalysis, 
Chemistry
X
X
Collected after at least an 8 
hour fast at screening and 
predose.
AE/SAE review
X-----------------------------------------------------------------------------------------------------------X
 
 
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Screening – Day 1
Screening
Run-In
Intervention
Notes
Scheduled Day
Screening 
Day -
14 to 
Day   -
2
Day-1
Day 1
Scheduled Hour
Pre-
dose
0
0.5 1
1.5 2
3
4
6
12 16
24
Clinical Opiate Withdrawal 
Scale
X
X
To be administered at 
screening and within 1 hr 
predose to establish a 
baseline. May be 
administered if clinically 
indicated at other 
timepoints. Each participant 
should be assessed by the 
same clinic personnel 
throughout the study, if 
possible. Not all 
participants need to be 
assessed by the same 
individual.
Pharmacokinetics
Blood for Methadone PK
X
X
X
X
X
X
X
X
X
X
X
24 hr sample to be collected 
just prior to Day 2 
methadone administration.
Biomarkers
Blood for Genetic Analysis
X
Collect at any time up to 
24hrs post-dose on Day 1 in 
enrolled participants only.
See Section 8.8.
 
 
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Day 2 – Post-study
Intervention
Follow-
Up Call
Notes
Scheduled Day
Day 2
Day 3
Day 4
Day 
5
Day 
6
Day 
9
Day 
10 
to 
Day 
15
Day 16a
Scheduled Hour
0
0.25 0.5 1 1.5 2
3
4
6
12
16
24
48
72
96
168
Administrative/Study
Procedures
Prior/Concomitant 
Medication Review
X----------------------------------------------------------------------------------------------------------------------X
Methadone 
Maintenance Therapy
X
After the follow-up call on 
~Day 16, methadone 
maintenance therapy will 
continue as per the 
participant’s standard 
schedule. 
Methadone 
Administration
X
X
X------------------------X
On Day 2, participants will 
receive a maintenance dose 
of methadone after an 
overnight fast of at least 8 
hours with ~240 mL of 
water.b Participants will 
continue to fast for 4 hours 
postdose. From Day 3 (ie, 
Day 2, 24 hrs) to Day 9 (ie, 
Day 2, 168hrs), participants 
will receive methadone 
once daily at the clinic. 
Islatravir 
Administration
X
On Day 2, participants will 
receive a dose of ISL within 
5 minutes of the methadone 
dose with ~240 mL of 
water.b
 
 
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Day 2 – Post-study
Intervention
Follow-
Up Call
Notes
Scheduled Day
Day 2
Day 3
Day 4
Day 
5
Day 
6
Day 
9
Day 
10 
to 
Day 
15
Day 16a
Scheduled Hour
0
0.25 0.5 1 1.5 2
3
4
6
12
16
24
48
72
96
168
Standard Meals
X--------------------------------------------------------------X
Standard meals will be
served per site processes 
beginning approximately 4 
hrs post-dose until
discharge from the clinic on 
Day 9.
Domiciling
X---------------------------------------------------------------------------------------------------X
Safety Procedures
Full physical 
examination
X
Weight
X
Vital Signs (heart rate, 
respiratory rate, oxygen 
saturation)
X
X
X
X
X
Participants should be 
resting in a semi-recumbent 
position for at least 10 mins 
prior to measurement. 
Respiratory rate and oxygen 
saturation will be measured 
as per site standard 
operating procedures.
Predose VS on Day 2 
should be measured within 
3 hours of methadone 
dosing.
Vital Signs 
(temperature)
X
 
 
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Day 2 – Post-study
Intervention
Follow-
Up Call
Notes
Scheduled Day
Day 2
Day 3
Day 4
Day 
5
Day 
6
Day 
9
Day 
10 
to 
Day 
15
Day 16a
Scheduled Hour
0
0.25 0.5 1 1.5 2
3
4
6
12
16
24
48
72
96
168
12-lead ECG
X
X
X
X
X
Participants should be 
resting in a semi-recumbent 
position for at least 10 mins 
prior to measurement. 
Predose ECGs should be 
performed in triplicate, 1 to 
2 minutes apart. Predose 
ECGs on Day 2 should be 
measured within 3 hours of 
methadone dosing.
Serum hCG
X
Performed in women of 
child-bearing potential. 
Hematology, Urinalysis, 
Chemistry
X
X
Collected after at least an 8 
hour fast. Collected prior to 
methadone dosing.
AE/SAE review
X---------------------------------------------------------------------------------------------------------------------X
Pharmacokinetics
Blood for Plasma ISL
X
X
X
X
X
X
X
X
X
X
X
X
X
0 h sample to be collected 
just prior to ISL 
administration.
Blood for Methadone
X
X
X
X X
X
X
X
X
X
a Follow-up call will occur 14 days (+3 days) after the ISL dose.
b A total of 240 mL of water will be taken with the methadone AND ISL dose. Additional water may be provided in 50 mL increments as needed.
 
 
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2
INTRODUCTION
Islatravir (MK-8591, ISL) is a novel, potent NRTTI being developed both for treatment of 
HIV-1 infection and for prevention of HIV-1 infection in uninfected individuals at high risk
of becoming infected.  Currently, ISL is being evaluated in a Phase 2 trial at a dose of 0.75 
mg QD (in combination with 100 mg doravirine, DOR; NCT03272347) and in a Phase 2 trial 
at doses of 60 mg and 120 mg QM (NCT04003103). Additional programs with other doses 
and administration frequencies within the range of 0.75-120 mg are being considered as well. 
2.1
Study Rationale
According to the CDC, HIV infections due to IDU have declined, but injecting drugs remains 
a significant risk factor in becoming infected with HIV. In 2018, 7% (2,652) of the estimated 
37,881 new HIV infections in the United States were attributed to IDU[Centers for Disease 
Control and Prevention 2020]. Many PWID seek treatment for opioid addiction and receive
maintenance therapy with the opioid agonist methadone for substance dependence. 
Consequently, individuals on MMT may benefit from ISL either for treatment of existing 
HIV infection or prophylactically to prevent new infection. Success of MMT is sensitive to 
many factors and complicated by inter-subject variability in both methadone PK and PD. 
Titration of methadone dosing is necessary to balance the reduction of craving for opiates, 
the medical necessity of avoiding opiate withdrawal, and the effects associated with 
methadone toxicity. 
Methadone has been shown to be metabolized by multiple members of the cytochrome P450 
family including CYP3A4, 2B6, 2C19, 2D6, 2C9 and 2C8, with CYP3A4 usually cited as the 
most active member when using human microsomes in vitro[Volpe, D. A., et al 2018][Eap, 
C. B., et al 2002]. Interactions between HIV antiretrovirals and methadone have been widely 
reported, with methadone being affected by both induction and inhibition of metabolic 
enzymes by antiretrovirals. Generally, the interactions found to be clinically meaningful were 
due to decreases in methadone exposure[Volpe, D. A., et al 2018][Eap, C. B., et al 2002].
ISL is not anticipated to be a perpetrator of meaningful drug interactions. ISL is not an 
inhibitor of major CYP enzymes (eg, CYP2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) or inducer 
of CYP2B6 or CYP3A4.
There are reports of methadone affecting the pharmacokinetics of coadministered HIV 
antiretrovirals. Methadone decreases exposure of didanosine and stavudine (older HIV 
antiretrovirals), possibly due to delayed gastric emptying[Rainey, P. M., et al 2000]. In 
addition, there are reports of increased zidovudine exposure mediated through inhibition of 
glucuronidation or altered renal clearance[McCance-Katz, E. F., et al 1998][Schwartz, E. L., 
et al 1992][Volpe, D. A., et al 2018]. Methadone is also an inhibitor of P-glycoprotein (P-
gp). ISL is highly soluble and rapidly absorbed, is not metabolized via glucuronidation and is 
not a substrate of P-gp. Therefore, it is unlikely that methadone will affect the PK of ISL.
The concomitant use of ART to treat or prevent HIV-1 with MMT may interfere with the 
efficacy/safety of ART and/or with the ability to maintain stable methadone concentrations 
leading to symptoms of either opiate intoxication or withdrawal with serious or even life-
threatening consequences. While no interaction is expected, given the importance of ensuring 
 
 
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appropriate exposures of both ISL and methadone, this study will evaluate the effect of ISL 
administration on methadone PK. Additionally, ISL PK in the presence of methadone will be 
evaluated.
2.2
Background
Refer to the IB/approved labeling for detailed background information on islatravir (ISL or 
MK-8591).
HIV-1 infection remains a global health challenge, with 38 million people living with 
HIV/AIDS worldwide and nearly 2 million people becoming newly infected[Joint United 
Nations Programme on HIV/AIDS 2020]. The use of ever-improving highly effective ART
has reformed the natural history of HIV infection, such that HIV infection has become a 
chronic illness, provided patients remain adherent in taking ART therapy. Furthermore, use 
of ART as pre-exposure prophylaxis to prevent new HIV infection (eg, PrEP) has been 
shown to reduce sexual transmission by up to 99% and transmission in intravenous drug 
users by up to 74%[Centers for Disease Control and Prevention 2020]. Islatravir is an NRTTI 
in development as a part of a complete ART regimen for the treatment of HIV-1 or as a 
stand-alone therapy for the prevention of new HIV-1 infection. Islatravir is differentiated 
from other ARTs because of its high potency, long half-life, favorable drug resistance profile 
and broad pharmacological distribution. Because of these properties, not only does ISL have 
the potential to be an effective treatment and prevention therapy, ISL is also well-suited to be 
delivered in less frequent dosing regimens.  
Understanding the effect of DDIs with ISL and medications used to manage common 
comorbidities is an important aspect of clinical development of the compound. One such 
medication which will be evaluated in this study is methadone, an opioid agonist indicated 
for treatment of moderate to severe pain and/or opioid addiction. 
2.2.1
Pharmaceutical and Therapeutic Background
Islatravir is a highly potent HIV-1 NRTTI. Unlike conventional NRTIs, ISL acts via multiple 
mechanisms, leading to both immediate and delayed chain termination. The inactive parent is 
phosphorylated to the active ISL-TP in PBMCs and other cells. In in vitro studies in PBMCs, 
ISL-TP demonstrated antiviral activity, with an IC50 of 0.21 nM, while other NRTIs 
demonstrated IC50s ranging from 10.1 to 144 nM. ISL demonstrates a favorable mutant 
selection profile compared to other NRTIs, selecting only for the M184V/I mutant, against 
which ISL is active but with a decrease in sensitivity of 7.3-to 9.5-fold.
ISL is not anticipated to be a victim or a perpetrator of meaningful drug interactions. 
Elimination of ISL is anticipated to be balanced between renal excretion and ADA-mediated 
metabolism. Metabolism via ADA is a non-CYP mediated pathway. ISL is not a substrate of 
P-gp. ISL is not an inhibitor of major drug transporters, inhibitor of CYP enzymes (eg, 
CYP2B6, 2C8, 2C9, 2C19, 2D6, and 3A4), inducer of CYP2B6 or CYP3A4, or an inhibitor 
of UGT1A1.
 
 
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2.2.2
Clinical Studies
Across Phase 1 studies, as of 30-Jun-2020, 218 adult participants (including 30 participants 
with HIV-1 infection) received an ISL single dose (up to 400 mg orally) or multiple doses 
(up to 100 mg QW for 3 weeks and up to 5 mg QD for 6 weeks orally).  In the Phase 1 
studies, single and multiple doses of ISL have been generally well tolerated, with no drug-
related SAEs and no discontinuations due to a drug-related AE. For all Phase 1 studies with 
oral administration, the most frequently reported drug-related AE (≥2% of participants in any 
protocol) was headache. 
Following oral administration, plasma PK data indicate that ISL was rapidly absorbed with a 
median Tmax of 0.5 hr, and an apparent terminal t½ of 47 to 64 hr after single doses. 
Intracellular ISL-TP levels reached Cmax between 6 to 24 hr and declined with an apparent 
terminal t½ of 79 to 214 hr. Over the entire Phase 1 clinical program, ISL plasma exposure 
and ISL-TP levels appeared to increase in an approximately dose-proportional manner 
between ISL doses of 0.25 and 400 mg. Following administration of 30 mg ISL with a high-
fat meal, PK of ISL and ISL-TP in PBMCs were largely unaffected. Examinations of DDIs 
between ISL and DTG/TDF, ISL and LNG/EE, ISL and DOR, and ISL and pantoprazole 
demonstrated no clinically meaningful interactions.
After ISL administration to treatment-naïve participants with HIV-1 infection at doses of 0.5 
mg, 1 mg, 2 mg, 10 mg, and 30 mg, viral load reduction data show greater than 1.0 log drop 
on average at all doses tested. Pharmacokinetic data in participants infected with HIV-1 
generally were consistent with the data in healthy participants.
2.2.3
Ongoing Clinical Studies
There are ten ongoing studies of oral ISL, including 4 Phase 1 trials, 2 Phase 2 trials and 4 
Phase 3 trials. To date, the ISL remains generally well tolerated. 
Protocol 011 (NCT03272347) is an ongoing Phase 2 trial in treatment-naive persons living 
with HIV-1, examining efficacy of daily ISL (0.25 mg, 0.75 mg, or 2.25 mg) in combination 
with DOR. As of 31-Mar-2020, ISL has been administered to ~90 HIV-1 positive individuals 
for at least 96 weeks. Protocol 016 (P016) is a double-blind, placebo-controlled Phase 2 PrEP
trial (NCT04003103), examining doses of 60 mg and 120 mg. As of 30-June-2020, 156 of a 
planned 250 participants (62%) have been randomized and 78 participants have received all 6 
planned once-monthly doses of study drug and 53 have received between 3-5 doses; the 
remaining 25 participants have received fewer than 3 doses.
The 4 Phase 3 trials initiated in early 2020; information on general tolerability is limited.
2.2.4
Information on Other Study-related Therapy
Methadone is an opioid agonist indicated for the management of pain for which alternative 
treatment options are inadequate and for the detoxification treatment of opioid addiction. 
Together with appropriate social and medical services, methadone is also used as MMT for 
the treatment of opioid addiction [U.S. Prescribing Information 2019].
 
 
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Methadone is a synthetic narcotic analgesic that acts as an opioid µ-receptor agonist with 
multiple actions quantitatively similar to those of morphine, the most prominent of which 
involve the central nervous system and organs composed of smooth muscle [U.S. Prescribing 
Information 2019]. Methadone is supplied and administered clinically as a racemate of R-
and S- enantiomers, though the R- enantiomer accounts for the majority of its 
pharmacological activity. Due to high intersubject variability both in PK and
pharmacological response, methadone dose must be individually titrated[Volpe, D. A., et al 
2018][Eap, C. B., et al 2002].
Following oral administration, the bioavailability of methadone ranges between 36 to 100% 
and peak plasma concentrations are achieved between 1 to 7.5 hours. While dose 
proportionality of methadone PK has not been definitively established, after administration of 
daily oral doses ranging from 10 to 225 mg, the steady-state plasma concentrations ranged 
from 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL.
These data suggest that generally, PK of methadone increases dose proportionally [U.S. 
Prescribing Information 2019]. Published reports indicate that after multiple dose 
administration the apparent plasma clearance of methadone ranged between 1.4 and 126 L/h, 
and the terminal half-life was highly variable and ranged between 8 to 59 hours in different 
studies [U.S. Prescribing Information 2019].
2.3
Benefit/Risk Assessment
Participants in clinical studies will not receive direct benefit from treatment during 
participation as clinical studies are designed to provide information about the safety and 
effectiveness of an investigational medicine.
The data generated will be used to support coadministration of ISL and methadone. Patients 
taking methadone have a high rate of HIV-infection or are at elevated risk for acquiring new 
HIV infection. Therefore, ISL may be an important therapy for HIV treatment or prevention 
in this population.
Additional details regarding specific benefits and risks for participants taking part in this 
clinical study may be found in the accompanying IB and informed consent documents.
 
 
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
The study population includes male and female participants from 18 years to 65 years of age, 
inclusive.
Objectives
Endpoints
Primary
•
To determine the effect of ISL on the 
plasma pharmacokinetics of methadone
(eg, AUC0-24 for R- and S-enantiomers
of methadone) following co-
administration of a single dose of 
methadone.
Primary Hypothesis: The methadone 
(R-enantiomer) plasma AUC0-24 
obtained after single dose co-
administration of methadone with ISL is 
similar to the methadone (R-enantiomer) 
plasma AUC0-24 obtained after single
dose administration of methadone alone.
That is, the true GMR (methadone and 
ISL/methadone alone) for the dose-
normalized AUC0-24 (AUC0-24/D) of 
methadone (R-enantiomer) is contained 
within (0.7, 1.43).
Primary Hypothesis: The methadone (S-
enantiomer) plasma AUC0-24 obtained 
after single dose co-administration of 
methadone with ISL is similar to the 
methadone (S-enantiomer) plasma 
AUC0-24 obtained after single dose 
administration of methadone alone. That 
is, the true GMR (methadone and 
ISL/methadone alone) for the dose-
normalized AUC0-24 (AUC0-24/D) of 
methadone (S-enantiomer) is less than 
2.0.
•
Dose-normalized AUC0-24 (AUC0-
24/D) of plasma methadone (R- and S-
methadone).
 
 
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Objectives
Endpoints
Secondary
•
To determine the effect of ISL on the 
plasma pharmacokinetics of methadone 
(eg, Cmax, C24, and Tmax for the R-
and S-enantiomers and AUC0-24, 
Cmax, C24, and Tmax for total 
methadone) following co-administration 
of methadone.
Secondary Hypothesis: The methadone 
(R-enantiomer) plasma Cmax obtained 
after single dose co-administration of 
methadone with ISL is similar to the 
methadone (R-enantiomer) plasma 
Cmax obtained after single dose 
administration of methadone alone. That 
is, the true GMR (methadone and 
ISL/methadone alone) for the dose-
normalized Cmax (Cmax/D) of 
methadone (R-enantiomer) is less than 
1.43.
Secondary Hypothesis: The methadone 
(S-enantiomer) plasma Cmax obtained 
after single dose co-administration of 
methadone with ISL is similar to the 
methadone (S-enantiomer) plasma Cmax 
obtained after single dose administration 
of methadone alone. That is, the true 
GMR (methadone and ISL/methadone 
alone) for the dose-normalized Cmax
(Cmax/D) of methadone (S-enantiomer) 
is less than 2.0.
Estimation: The true GMR (methadone 
and ISL/ methadone alone) for the dose 
normalized C24 (C24/D) of methadone 
(R-enantiomer and S-enantiomer) will 
be estimated.
Estimation: The true GMR (methadone 
and ISL/methadone alone) for the dose 
normalized AUC0-24 (AUC0-24/D), 
Cmax (Cmax/D) and C24 (C24/D) of 
methadone (total) will be estimated.
•
Dose-normalized Cmax (Cmax/D), C24 
(C24/D), and Tmax of plasma 
methadone (R- and S- enantiomer).
•
Dose-normalized AUC0-24 (AUC0-
24/D), Cmax (Cmax/D), C24 (C24/D), 
and Tmax of plasma methadone (total).
 
 
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Objectives
Endpoints
•
To evaluate the safety and tolerability of 
ISL co-administered with methadone.
•
Adverse experiences, laboratory safety 
tests, ECGs, VSs (HR, BP, RR, oxygen 
saturation).
Tertiary/Exploratory
•
To determine the effect of methadone on 
the PK of coadministered ISL.
•
AUC0-24, AUC0-168, AUC0-672, 
AUC0-inf, Cmax, Tmax, t1/2 of plasma 
ISL
•
To explore the relationship between 
genetic variation and response to the 
treatment(s) administered and 
mechanisms of disease. Variation across 
the human genome may be analyzed for 
association with clinical data collected in 
this study. 
•
Germline genetic variation and 
association to clinical data collected in 
this study
4
STUDY DESIGN
4.1
Overall Design
This is a nonrandomized, single-site, open-label study of ISL in adult male and female
participants on stable methadone therapy. 
Participants will receive their standard methadone therapy from their usual clinic during a 
minimum 14-day run-in phase. Dosing at the CRU will commence on Day 1, continuing on 
the same formulation and dose of methadone as from the run-in phase. On Day 1 and 2,
participants will receive their usual dose of methadone in the morning following an at least 8 
hr fast. Serial blood samples for methadone PK will be collected through 24 hours post dose. 
On Day 2, participants will also receive a single dose of ISL 60 mg concomitantly with their 
usual dose of methadone. Blood samples for methadone PK will be collected through 24 
hours post dose and for ISL PK through 168hrs post dose. Participants will remain domiciled 
in the CRU through 168 hrs post ISL dose. While domiciled, the site staff will administer 
participants their individualized methadone dose daily. After discharge from the CRU, 
participants will continue their standard MMT at their usual clinic. A follow-up call will be 
conducted at 14 days post ISL dose to assess for AEs. 
Safety and tolerability will be evaluated until the follow-up call. Opioid withdrawal 
symptoms will also be assessed prior to and following treatment with ISL and methadone. 
Approximately 14 participants will be enrolled.
 
 
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Because this is a Phase 1 assessment of ISL in humans, the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is therefore written 
with flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Refer to Section 8.11.6 for examples of modifications permitted within the protocol 
parameters.
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.
4.2
Scientific Rationale for Study Design
This study will evaluate the potential drug-drug interaction between methadone and ISL. The 
study design was chosen to optimally assess the objectives of the study.
A fixed-sequence design was selected for operational efficiency given the half-life of plasma 
ISL and intracellular ISL-TP.
Population: Steady state methadone disposition cannot be evaluated safely in participants
not on methadone for the duration specified in this trial without a substantial risk of causing 
methadone addiction. Participants without HIV infection will be enrolled to avoid 
interactions between ISL and other ART or to avoid exposing HIV infected individuals not 
on ART to HIV monotherapy. Participants will be screened for illicit drug use (except 
cannabis) and STIs as use of injection drugs and presence of STIs may indicate increased risk 
of contracting HIV during the study[Centers for Disease Control and Prevention 
2020][Centers for Disease Control and Prevention 2015].
Run-in Period: Methadone dose must be individually titrated and periodically adjusted to 
maintain optimal therapeutic effect. In addition, methadone has the potential to be both an 
inducer and autoinducer. To ensure that evaluation of a DDI on Day 1 and 2 in this study is 
done at steady-state concentrations of methadone and at steady-state levels of metabolic 
enzymes, a 14-day run-in period at a stable methadone dose will proceed the active treatment 
period in this study.
Doses: Methadone doses are individually titrated. Participants will remain on their stable 
methadone dose. A wide range of doses will be evaluated in this study (20 to 200 mg). Lower 
doses may not be clinically relevant, while increases in QTc prolongation were observed at 
doses >200 mg [U.S. Prescribing Information 2019]. 
A dose of 60 mg ISL has been selected to be administered as a one-time oral dose in this 
trial. This dose of ISL is the anticipated highest clinical dose being considered for
development, and ISL has demonstrated dose-proportional PK over the entire range studied 
to date (0.25 mg – 400 mg). While no drug interaction between ISL and methadone is 
anticipated, it is desirable to test this hypothesis at the upper end of the clinically relevant 
dose range as a lack of effect at this dose could be extrapolated to lower doses. As plasma 
accumulation of ISL is low and no induction or time dependent inhibitory effect is 
 
 
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anticipated, a single dose paradigm is considered adequate to assess the DDI with 
methadone.
Food: The effect of food on the bioavailability of methadone has not been evaluated [U.S. 
Prescribing Information 2019]. There is no clinically relevant effect of food on ISL
pharmacokinetics. However, dosing on Days 1 & 2 will be conducted under fasting 
conditions to decrease variability and because historical comparator data for ISL PK were 
also obtained under fasted conditions. Participants will be domiciled in the clinic from the 
night prior to dosing which will ensure that the protocol-specified overnight fast is 
completed.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
There are no efficacy endpoints.
4.2.1.2
Safety Endpoints
Participants will be observed at the clinical trial site where they are housed. Symptoms of 
CNS or respiratory depression that would be associated with enhanced effects of opiates will 
be observed by staff trained in the management of opiate overdose and/or critical care. 
Respiratory rate and oxygen saturation via pulse oximetry will be measured at select 
timepoints including near Tmax. A baseline COWS assessment will be done at screening and 
prior to dosing on Day 1; in the event that overt signs of opiate withdrawal are observed 
during the study, additional COWS assessments may be conducted as clinically indicated 
[Wesson, D. R. 2003]. 
In addition, safety laboratory evaluations (hematology and chemistry), ECGs and vital signs 
will be conducted to monitor subject safety throughout the study. Particular attention will be 
paid to the QTc interval of participants as methadone is known to cause QTc prolongation. 
No effects of ISL on QTc is predicted based on the electrophysiologic studies of ISL in vitro 
and in vivo animal models or clinical trials.
4.2.1.3
Pharmacokinetic Endpoints
To characterize the pharmacokinetics of methadone (R- and S-enantiomers and total) and 
determine if there is a clinically meaningful change in methadone pharmacokinetics when co-
administered with ISL, AUC0-24, Cmax, C24 and Tmax will be evaluated on Day 1 (without 
ISL administration) and on Day 2 (following co-administration with ISL). AUC0-24 will be 
evaluated since the PK evaluations are under steady-state conditions. 
Methadone is supplied and administered clinically as a racemic mixture, although only one 
enantiomer (R-) accounts for the majority of its pharmacological activity. Therefore, lower 
clinical significance bounds are set around PK of the R-enantiomer. The level to which 
methadone concentrations may safely change in any given patient is complicated by high 
interindividual variability in both PK and PD. Literature surveys have shown that mean 
 
 
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reductions in methadone exposure on the order of ~30% to ~50% are associated with 
withdrawal symptoms in at least some individuals (eg, due to interaction with efavirenz or 
nevirapine). Therefore, the lower bound in this study for the R-enantiomer is being set at 0.7. 
While methadone intoxication/toxicity related to on-target pharmacological activity has been 
less widely reported with inhibition, increases in drug levels are associated with QT 
prolongation. An increase of 47% of the R-enantiomer and 103% of the S-enantiomer in the 
presence of voriconazole are accompanied by cautionary QT label language [U.S. 
Prescribing Information 2019][Maremmani, I., et al 2005][Eap, C. B., et al 2002]. Based on 
this, the upper bound of clinical significance for AUC is set symmetrically at 1.43 for R-
methadone and an upper bound of 2.0 is set for S-methadone. Upper bounds of 1.43 for R-
methadone Cmax and 2.0 for S-methadone Cmax will be tested as a secondary hypothesis.
As participants will remain on their stable dose of methadone during the study, each 
participant may be taking a different dose of methadone. As such, dose normalized PK will 
be reported. Within participant comparisons are not impacted by dose as individuals will be 
on a stable dose.
For ISL, AUC0-24, AUC0-168, AUC0-672, AUC0-inf, Cmax, and Tmax will be evaluated. 
Both AUC0-672 and AUC0-inf will be estimated by extrapolation of the terminal phase of 
the measured profile. Efficacy is most closely associated with intracellular ISL-TP 
concentrations at trough (C168). Because ISL-TP has been shown to correlate closely with 
plasma ISL AUC which can be more readily measured, plasma ISL AUC is being assessed as 
a surrogate associated with efficacy. It is also considered the most relevant parameter for 
toxicity. Given the range of dosing frequencies being evaluated in ISL development, AUC0-
24 (daily), AUC0-168 (weekly), and AUC0-672 (monthly) will all be estimated. It is not 
possible to remove MMT patients from their established dosing regimen without substantial 
risk of inducing withdrawal symptoms and their attendant psychological sequelae. As a 
consequence, it is not possible to include an ISL alone treatment period for comparison to the 
methadone + ISL coadministration. Therefore, ISL plasma PK will be evaluated in this study 
with methadone coadministration and compared in an exploratory way to historical ISL PK 
data.
4.2.1.4
Pharmacodynamic Endpoints
No pharmacodynamic endpoints will be evaluated.
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
 
 
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DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.6
     Future Biomedical Research
The Sponsor will conduct FBR on DNA specimens for which consent was provided during 
this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
FBR is to explore and identify biomarkers that inform the scientific understanding of 
diseases and/or their therapeutic treatments. The overarching goal is to use such information 
to develop safer, more effective drugs/vaccines, and/or to ensure that participants receive the 
correct dose of the correct drug/vaccine at the correct time. The details of FBR are presented 
in Appendix 6.
4.3
Justification for Dose
The rationale for dose is detailed in Section 4.2.
As this is a Phase 1 assessment of ISL in humans, and the PK, pharmacodynamic and safety 
profiles of the compound are still being evaluated, modifications to the dose or dosing 
regimen may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants. Details of allowed 
modifications are provided in Section 8.11.6.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
 
 
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study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Males and females meeting the criteria outlined below will be enrolled.
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. Has a BMI > 18 and ≤ 35 kg/m2. See Section 8.3.1 for criteria on rounding to the 
nearest whole number. BMI=weight (kg)/height (m)2.
2. Is in good health based on laboratory safety tests obtained at the screening visit and 
prior to administration of study drug. Appendix 2 provides a table of laboratory safety 
tests to be performed. Appendix 10 provides an algorithm for the assessment of out of 
range laboratory values. 
Note: participants infected with Hepatitis C or Hepatitis B may be included if 
Screening and Baseline ALT is <2-fold the upper limit of normal and direct bilirubin 
is <2-fold the upper limit of normal. Participants slightly exceeding these limits may 
be retested and enrolled upon consultation with Sponsor.
3. Is in good health based on medical history, physical examination, VS measurements 
and ECGs performed prior to randomization. Appendix 9 provides a table of the 12-
Lead Electrocardiogram Abnormality Criteria.
4. Has a negative HIV antigen/antibody test at screening.
Demographics
5. Is male or female, from 18 years to 65 years of age, inclusive, at the time of signing 
the informed consent.
 
 
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Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.
Female Participants
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least one of the following conditions applies: 
•
Is not a WOCBP
OR
•
Is a WOCBP and using an acceptable contraceptive method, or be abstinent from 
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term 
and persistent basis), as described in Appendix [5] during the intervention period and for 
at least 21 days after the last dose of study intervention. The investigator should evaluate 
the potential for contraceptive method failure (ie, noncompliance, recently initiated) in 
relationship to the first dose of study intervention.
•
A WOCBP must have a negative highly sensitive pregnancy test (serum) as required by 
local regulations within 24 hours before the first dose of study intervention.
•
Additional requirements for pregnancy testing during and after study intervention are in 
Section 8.3.5.
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
•
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
6. The participant provides written informed consent for the study. The participant may 
also provide consent for FBR. However, the participant may participate in the main 
study without participating in FBR.
Additional Categories
7. Is reliably participating in a methadone maintenance program for at least two (2) 
months prior to Day 1. Subjects are required to be on a documented stable dose of 
methadone for at least 14 days prior to Day 1.
8. Agrees to not change their current maintenance methadone dose of 20-200 mg 
administered as a single daily dose (unless for safety reasons) from screening until 
 
 
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collection of the last PK sample. Subjects must agree to have their daily methadone 
dose administration observed and documented during the period of the study during 
which they are domiciled.
9. Agrees to take the following precautions to reduce the risk of acquiring HIV infection 
from the time of signing the informed consent until 3 months after the last dose of 
study medication:
a.
Use a male or female condom (but not both together) during all occurrences of 
penetrative vaginal or anal intercourse.
b. Avoid coming into contact with another individual’s blood (eg, by sharing a 
hypodermic needle).
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, 
hematological, hepatic, immunological, renal, respiratory, genitourinary, or major 
neurological (including stroke and chronic seizures) abnormalities or diseases. 
Participants with a remote history of uncomplicated medical events (eg, uncomplicated 
kidney stones, as defined as spontaneous passage and no recurrence in the last 5 years, or 
childhood asthma) may be enrolled in the study at the discretion of the investigator.
Exception: Subjects infected with hepatitis B or hepatitis C virus may participate if they 
meet Inclusion Criteria 2 and 3.
2. Is mentally or legally incapacitated, has significant emotional problems at the time of 
prestudy (screening) visit or expected during the conduct of the study or has a history of 
clinically significant psychiatric disorder of the last 5 years. Participants who have had 
situational depression may be enrolled in the study at the discretion of the investigator. 
3. Has a history of cancer (malignancy).
Exceptions: (1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in 
situ of the cervix or; (2) Other malignancies which have been successfully treated with 
appropriate follow up and therefore unlikely to recur for the duration of the study, in the 
opinion of the investigator and with agreement of the Sponsor (eg, malignancies which 
have been successfully treated ≥10 years prior to the prestudy [screening] visit).
4. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), 
or has had an anaphylactic reaction or significant intolerability (ie, systemic allergic 
reaction) to prescription or non-prescription drugs or food.
 
 
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5. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 
weeks prior to the screening visit. 
6. Tests positive for a sexually transmitted infection at screening. Participants with a past 
history of syphilis may be enrolled if, in the opinion of the investigator, clinical evidence 
do not indicate presence of a new infection.
Prior/Concomitant Therapy
7. With the exception of methadone, is unable to refrain from or anticipates the use of any 
medication, including prescription and non-prescription drugs or herbal remedies 
beginning approximately 2 weeks (or 5 half-lives) prior to the first dose of the 14 day 
methadone maintenance run-in phase prior to Day 1, throughout the trial, until the AE 
follow-up call (Day 16). Upon discussion with the Sponsor, concomitant use of 
benzodiazepines may be permitted during the study provided that the subject has been 
receiving a stable benzodiazepine dose prescribed by a physician for at least 2 months 
prior to administration of the first dose of study drug in this trial. In addition, there may 
be certain prescription and non-prescription drugs that are permitted, see Section 6.5.
Prior/Concurrent Clinical Study Experience
8. Has participated in another investigational study within 4 weeks (or 5 half-lives) prior to 
the prestudy (screening) visit. The window will be derived from the date of the last visit 
in the previous study.
Diagnostic Assessments
9. Has a QTc interval >450 msec (males) or >470 msec (females), has a history of risk 
factors for Torsades de Pointes (eg, heart failure/cardiomyopathy or family history of 
long QT syndrome), has uncorrected hypokalemia or hypomagnesemia, is taking 
concomitant medications that prolong the QT/QTc interval other than methadone.
Other Exclusions
10. Is under the age of legal consent.
11. Does not limit smoking to no more than 10 cigarettes per day while in the CRU. No 
smoking will be permitted from 2 hours predose to 2 hours postdose on Days 1 and 2. In 
addition, participant must agree to follow the smoking restrictions defined by the CRU.
12. Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 
mL/1 ounce]) per day. Participants who consume 4 glasses of alcoholic beverages per day 
may be enrolled at the discretion of the investigator. Participants must have a negative 
alcohol breath test at check-in.
 
 
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13. Consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or 
other caffeinated beverages per day.
14. With the exception of THC, has a positive screen for drugs with a high potential for 
abuse such as cocaine, amphetamines, MDMA, barbiturates, benzodiazepines (with the 
exception noted in exclusion criteria 7), or opiates/opioids on Day -1 that cannot be 
explained by concomitant medications, unless at the discretion of the principal 
investigator and the sponsor.
Subjects must have a negative UDS prior to randomization, with the exception of THC 
and prescription benzodiazepines.
15. Presents any concern by the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study.
16. Has a COWS score of ≥ 5 at screening or prior to randomization.
17. Is unwilling to comply with the study restrictions (see Section 5.3 for a complete 
summary of study restrictions).
18. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
Fasting requirements for study procedures, such as but not limited to laboratory safety 
evaluations are specified in Appendix 2.
On full pharmacokinetic sampling days, ie, Days 1 and 2, participants will fast from all food 
and drinks, except water, for at least 8 hours prior to study drug administration until the first 
scheduled meal at approximately 4 hours postdose. Otherwise, meals and snack(s) will be 
provided by the investigator per site standards during domiciling in the clinic. Participants 
will fast from all food and drinks except water between meals and snacks. The caloric 
content and composition of meals will be the same on Day 1 and Day 2. After the 24-hour 
postdose procedures have been completed, subsequent meals and snacks will be unrestricted 
in caloric content, composition and timing.
Water will be provided during study drug administration. With the exception of water 
provided with treatments, water will be restricted 1 hour prior to and 1 hour after study drug 
administration on Days 1 and 2.
 
 
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5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks prior to administration of the first dose of the 
14day methadone maintenance run-in phase prior to Day 1 until discharge from the clinic on 
Day 9. 
On full pharmacokinetic sampling days, ie, Days 1 and 2, participants will refrain from the 
consumption of all fruits and fruit juices 24 hours prior to and 4 hours following trial drug 
administration. On all other days during the study, consumption of fruits and fruit juices 
(except for grapefruit, grapefruit juices, and grapefruit products) is allowed.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from 12 hours prior to the prestudy visit until after the visit, from 12 hours prior to 
and after study drug administration on Days 1 and 2, and from 12 hours prior to the Day 9
(ie, 168hr post ISL dose) procedures. At all other times, caffeinated beverages or xanthine-
containing products will be limited to no more than 6 units per day (1 unit = 120 mg of 
caffeine).
5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours prior to the prestudy visit until 
after the visit, and from 24 hrs prior to Day -1 until the completion of Day 9 (ie, 168hr post 
ISL dose) procedures. At all other times, alcohol consumption is limited to no more than 
approximately 3 alcoholic beverages or equivalent (1 glass is approximately equivalent to: 
beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per 
day.
5.3.2.3
Tobacco Restrictions
Smoking will be limited to no more than 10 cigarettes per day while in the CRU. No smoking 
will be permitted from 2 hours predose to 2 hours post dose on Days 1 and 2. In addition, 
participants will follow the smoking restrictions defined by the CRU.
5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (ie, weightlifting, running, 
bicycling, etc.) from the prestudy (screening) visit until discharge from the clinic on Day 9.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized in the study. A minimal set of screen failure information 
may be included, as outlined in the eCRF entry guidelines. Minimal information may include 
 
 
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demography, screen failure details, eligibility criteria, and any AEs or SAEs meeting 
reporting requirements.
5.5
Participant Replacement Strategy
If a participant withdraws from the study a replacement participant may be enrolled if 
deemed appropriate by the investigator and Sponsor. The replacement participant will 
generally receive the same intervention or intervention sequence (as appropriate) as the 
participant being replaced. The replacement participant will be assigned a unique 
treatment/randomization number. The study site should contact the Sponsor for the 
replacement participant’s treatment/randomization number.
The replacement participant may begin dosing at the subsequent dose level for that panel, 
based on investigator and Sponsor review and discussion.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies of ISL will be packaged to support enrollment and replacement participants 
as required. When a replacement participant is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement participant. 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
Inter-
vention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Run-in 
Experi
mental
Methadone
Drug
Per Local 
Guidelines
Varies
20-200 
mg
Oral
Once daily for 
14 days prior to 
Day 1
Experi
mental
NIMP
Provided 
Locally by 
Outpatient 
Clinic
Maintenance 
Therapy
Experi
mental
Methadone
Drug
Per Local 
Guidelines
Varies
20-200 
mg
Oral
Once daily 
Days 2-9
Experi
mental
IMP
Provided 
Locally by 
Site
Maintenance 
Therapy
Experi
mental
Methadone
Drug
Per Local 
Guidelines
Varies
20-
200mg
Oral
Once daily 
Days 10-15
Experi
mental
NIMP
Provided 
Locally by 
Outpatient 
Clinic
ISL
Experi
mental
ISL
Drug
Capsule
30 mg
60 mg
Oral
Single Dose 
Day 2
Experi
mental
IMP
Provided 
Centrally by 
Sponsor
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
 
 
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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.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
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 4.2.
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.
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.
 
 
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this trial will be allocated by non-random assignment as shown in Table 2. 
Table 2
Sample Allocation Schedule
Subjects
Day 1
Day 2 
N=14
Single oral dose of methadone 20 
– 200 mg 
Single oral dose of methadone 20 –
200 mg + ISL 60 mg
6.3.2
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
6.3.3
Blinding
This is a single treatment arm open-label study; therefore, the Sponsor, investigator, and 
participant will know the intervention administered.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
6.5
Concomitant Therapy
If a participant does not discontinue all prior medications within 14 days or 5 half-lives of the 
first dose of methadone run-in therapy, they may be included in the study if the investigator 
can rationalize that the specific use of a prior medication is not clinically relevant within the 
context of the study.
Concurrent use of any prescription or nonprescription medication, or concurrent vaccination,
during the ongoing study (ie, after run-in maintenance phase begins) until the follow-up call
must first be discussed between the investigator and Sponsor prior to administration, unless 
appropriate medical care necessitates that therapy or vaccination should begin before the 
investigator and Sponsor can consult. The participant will be allowed to continue in the study 
if both the Sponsor and the investigator agree.
Paracetamol/acetaminophen at ≤2000 mg total daily dose may be used for minor ailments 
without prior consultation with the Sponsor.
In addition, the following concomitant medications are permitted:
1.
The participants’ prescribed methadone treatment.
 
 
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2.
The concomitant use of benzodiazepines may be permitted during the study provided 
the participant has been receiving a stable benzodiazepine dose (as prescribed by a 
physician) for at least 2 months prior to the first dose of study drug administered in 
this trial. Use must be discussed with Sponsor prior to enrollment.
3.
Truvada® or Descovy® for the prevention of HIV-infection, provided the participant 
initiates use of these products no later than the start of the 14-day run-in period or 
after the Day 9 clinic discharge.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification
Not applicable.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
6.9
Standard Policies
For studies using controlled substances, all Federal, State, Province, Country, etc., 
regulations must be adhered to in regard to their shipping, storage, handling, and dispensing
of controlled substances. Additionally, the investigator should have the appropriate 
controlled drug license(s) as mandated by Federal, State, Province, Country, etc., laws in 
which the study is being conducted.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.1.9, or if available, a protocol clarification letter.
 
 
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Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Sections 8.1.9.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
The participant requires a dose adjustment to their methadone treatment which, in the 
opinion of the investigator and/or Sponsor, would interfere with the scientific integrity of 
the trial.
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.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, 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 and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
 
 
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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 missing data for the participant will be managed via the 
prespecified statistical 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 study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
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), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 241 mL [Appendix 8].
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
 
 
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8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or future biomedical 
research. 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 consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s dated signature or by the participant’s legally acceptable 
representative’s dated signature.
If the investigator recommends continuation of study intervention beyond disease
progression, the participant or his/her legally acceptable representative will be asked to sign 
consent.
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.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to future biomedical research. A copy of the 
informed consent will be given to the participant.
 
 
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8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, 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 study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention allocation, 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 
intervention 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.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before the start of the methadone run-in phase.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
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 intervention allocation on Day 1. 
Each participant will be assigned only 1 screening number. Screening numbers must not be 
re-used for different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation.  Once a 
 
 
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treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
During the methadone run-in phase, participants will retrieve the stable daily dose of 
methadone from their usual local methadone clinic and self-administer as directed for 14 
days. 
On Days 1-9, administration of study medication will be witnessed by the investigator and/or 
study staff. Approximately 240 mL of water will be provided during trial drug 
administration. Additional water may be provided in ~50 mL increments if necessary. Water 
will be restricted 1 hour prior to and 1 hour after study drug administration. Details on water 
and dietary restrictions are outlined in Section 5.3.1.
Once discharged from the CRU, participants will continue to retrieve their methadone 
therapy from their usual local methadone clinic and self-administer at least until the follow-
up call.
8.1.8.1
Timing of Dose Administration
Methadone will be administered in the morning of Day 1 after an overnight fast with 
approximately 240 mL of water (regardless of formulation). Participants should continue to 
fast until at least 4 hours postdose. 
On Day 2, participants will receive an oral dose of ISL 60 mg once within 5 minutes of their 
dose of methadone after an overnight fast (methadone to be administered first at 
approximately the same time as on Day 1). A total of 240 mL of water will be used for ISL 
and methadone dosing. Additional water may be provided if needed. Participants should 
continue to fast until at least 4 hours postdose.
The time of methadone administration will be deemed Time “0” and study assessments will 
be relative to this.  
8.1.9
Discontinuation and Withdrawal
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study and/or intervention. If a participant discontinues for 
any reason at any time during the course of the study and/or intervention, the participant may 
be asked to return to the clinic (or be contacted) for a poststudy visit as per the number of 
days described in Section 8.4.1 after the last dose of study intervention to have the applicable 
procedures conducted. However, the investigator may decide to perform the poststudy 
procedures at the time of discontinuation or as soon as possible after discontinuation. If the 
poststudy visit occurs prior to the safety follow-up time frame as specified in Section 8.4.1, 
the investigator should perform a follow-up telephone call at the end of the follow-up period 
 
 
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( Section 8.4.1) to confirm if any AEs have occurred since the poststudy clinic visit. Any 
AEs that are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
Domiciling
Participants will report to the CRU on Day -1 and remain in the unit until 168 hrs postdose of 
concomitant methadone and ISL administration (ie, Day 9). At the discretion of the 
investigator, participants may be requested to remain in the CRU longer.
8.1.12
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.
8.2
Efficacy/Immunogenicity Assessments
There are no direct efficacy assessments in this study.
 
 
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn/collected over the course of the study (from 
prestudy to poststudy visits), including approximate blood volumes drawn 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.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
BMI
BMI equals a person's weight in kilograms divided by height in meters squared 
(BMI=kg/m2). BMI will be rounded to the nearest whole number according to the standard 
convention of 0.1 to 0.4 round down and 0.5 to 0.9 round up.
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
8.3.2
Vital Signs
Temperature, HR, BP, RR and oxygen saturation (via pulse oximeter) will be assessed.
8.3.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate, Blood Pressure, Respiratory Rate, Oxygen 
Saturation)
Participants should be resting in a quiet setting without distractions in a semirecumbent 
position for at least 10 minutes prior to having VS measurements obtained with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. Semirecumbent VS will include HR, systolic and diastolic BP, oxygen saturation,
and RR at timepoints indicated in the SoA. The correct size of the BP cuff and the correct 
positioning on the participant’s arm is essential to increase the accuracy of BP measurements.
The predose (baseline) HR and BP will be a single measurement obtained within 2 hours of 
dosing methadone on Day 1. These measurements will be used as the baseline to calculate 
change from baseline for safety evaluations (and for rechecks, if needed). Postdose VS 
measurements will also be single measurements.
 
 
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Respiratory rate and oxygen saturation (via pulse oximeter) will be measured per the site 
standard operating procedures. Participants should be resting in a semi-recumbent position 
for at least 10 minutes prior to having RR and oxygen saturation measurements obtained.
Body Temperature
Body temperature will be measured. The same method must be used for all measurements for 
each individual participant and should be the same for all participants.
8.3.3
Electrocardiograms
•
12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. Refer to Appendix 10.9 for evaluation and withdrawal criteria and additional 
QTc readings that may be necessary.
•
At each time point when triplicate ECGs are required (ie, screening and Day 1 and 2 
predose), 3 individual ECG tracings should be obtained as close as possible in 
succession, but no more than 2 minutes apart. The full set of triplicates should be 
completed in less than 4 minutes.
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry prior to lead placement. Participants may need to be shaved to ensure proper 
lead placement. Participants may need to remove interfering garments.
Participants should be resting in the semi-recumbent position for at least 10 minutes prior to 
each ECG measurement.
The correction formula to be used for QTc is Fridericia.
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in 
place or mark the position of the electrodes for subsequent ECGs. To mark the position of the 
electrodes, 12-lead electrode sites will be marked on the skin of each participant with an 
ECG skin marker pen to ensure reproducible electrode placement.
Predose ECGs will be obtained in triplicate at least 1-2 minutes apart within 2 hours prior to 
dosing on Days 1 and 2. The mean of these measurements will be used as the baseline to 
calculate change from baseline for safety evaluations (and for rechecks, if needed).
If a participant demonstrates an increase in QTc interval ≥60 msec compared with mean 
predose baseline measurement, the ECG will be repeated twice within 5 minutes. The mean 
value of the QTc interval from the 3 ECGs will represent the value at that time point. If the 
mean QTc interval increase from baseline for any postdose time point is ≥60 msec, the
participant will continue to be monitored by repeat 12-lead ECGs every 15 minutes for at 
least 1 hour or until the QTc is within 60 msec of baseline. If prolongation of the QTc 
 
 
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interval ≥60 msec persists, a consultation with a study cardiologist may be appropriate and 
the Sponsor should be notified.
If the QRS duration from any postdose ECG is 20% greater than the mean baseline QRS 
duration and is >120 msec (and change is not considered rate-related or pacing-induced) or 
there appears to be new onset intermittent bundle branch block, then the ECG will be 
immediately repeated twice within 5 minutes. The mean value of the QRS interval from the 3 
ECGs will represent the value at that time point. If the mean QRS interval increase from 
baseline for any postdose time point is >20%, the participant will continue to be monitored 
by repeat 12-lead ECGs every 15 minutes for at least 1 hour or until the QRS is within 20% 
of baseline. If a >20% prolongation of the QRS interval persists, a consultation with a 
cardiologist may be appropriate and the Sponsor should be notified.
If the QTc interval is ≥500 msec on any postdose ECG, the Sponsor should be notified and 
the ECGs should be reviewed by a cardiologist. The participant should be telemetry-
monitored (until the QTc is <500 msec) or should be considered for transfer to a location 
where closer monitoring and definitive care (eg, a cardiac or intensive care unit) is available.
If the QRS duration is prolonged by more than 20% compared to the mean baseline, and is 
≥200 msec (and change is not considered rate-related or pacing-induced), then the Sponsor 
should be notified. The ECGs should be reviewed by a cardiologist and the participant should 
be considered for transfer to a location where closer monitoring and definitive care (eg, a 
cardiac or intensive care unit) is available.
If the participant has unstable hemodynamics, or has any clinically significant dysrhythmias 
noted on telemetry, the participant should be immediately transferred to an acute care setting 
for definitive therapy.
If prolongation of the QTc is noted, concomitant medications that prolong QTc should be 
held until the QTc is within 60 msec of baseline and the QTc is <500 msec.
A cardiologist will be consulted by the investigator as needed to review ECG tracings with 
significant abnormalities.
8.3.4
Clinical Opiate Withdrawal Scale (COWS)
The COWS will be administered at screening and at predose on Day 1 to establish a baseline.
COWS will only be administered at other timepoints if overt signs of withdrawal are 
observed and it is determined clinically appropriate to administer COWS assessment. To 
minimize variability, it is preferred (but not required) that a participant be assessed by the 
same clinic personnel throughout the trial. Instructions on administering the COWS 
assessment can be found in the operations/laboratory manual.
 
 
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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 which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from 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).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 7 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, Serious Adverse Events, 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.
Adverse events, 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 AEs, 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.
 
 
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
AEs, SAEs, and other reportable safety events that occur after the consent form is signed but 
before intervention allocation, must be reported by the investigator for randomized 
participants only if the event is the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo, or a procedure.
From the time of intervention allocation through 14 days following cessation of intervention, 
all AEs, SAEs and other reportable safety events must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator any time outside of the time 
period specified in the previous paragraph also 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.
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 3.
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time Period:
Consent to 
Randomization/ 
Allocation
(Randomized 
participants only)
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:
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
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
 
 
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Type of Event
Reporting Time Period:
Consent to 
Randomization/ 
Allocation
(Randomized 
participants only)
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:
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout or 
run-in treatment 
including placebo run-
in)
Report all
Previously 
reported – Follow 
to 
completion/termin
ation; report 
outcome
Within 24 hours 
of learning of 
event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
ECI (do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 calendar 
days of learning 
of event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning 
of event
(unless serious)
Overdose
Report if:
- receiving placebo run-
in or other run-in 
medication 
Report all
Not required
Within 24 hours 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event
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,
including pregnancy and exposure during breastfeeding, 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 allocated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
 
 
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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 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
Information in this section is not applicable since participants are males and non-pregnant, 
non-breastfeeding females.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include: 
1.
An overdose of Sponsor's product, as defined in Section 8.5.
2.
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 must trigger 
an additional evaluation for an underlying etiology. The study site guidance for 
 
 
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assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any drug administered 
as part of the study exceeding the dose prescribed by the protocol. It is up to the investigator 
or the reporting physician to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.
8.6
Pharmacokinetics
The decision as to which plasma samples collected will be assayed for evaluation of 
PK/pharmacodynamics will be collaboratively determined by the Sponsor (eg, samples at 
lower doses may not be assayed if samples at higher doses reveal undetectable drug 
concentrations). If indicated, these samples may also be assayed and/or pooled for assay in an 
exploratory manner for metabolites and/or additional pharmacodynamic markers.
8.6.1
Blood Collection for Plasma ISL and Plasma Methadone
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Blood for Genetic Analysis
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
 
 
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leftover extracted DNA will be stored for future biomedical research. If the planned genetic 
analysis is not approved, but future biomedical research is approved, this sample will be 
collected for the purpose of future biomedical research.
Sample collection, storage, and shipment instruction for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
8.9
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:
•
Leftover DNA for future research
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Approximately 4 weeks prior to intervention allocation, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5.
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the SoA, including consent review. Rescreen 
procedures cannot be conducted the day prior to intervention allocation if there are Day -1 
procedures planned per protocol.
8.10.2
Treatment Period
Refer to Schedule of Activities (Section 1.3).
8.10.3
Discontinued Participants Continuing to be Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, a subset of study procedures specified in the SoA may be completed at the discretion 
of the investigator and with Sponsor agreement. The subset of study procedures completed 
will be communicated in a PCL.
8.10.4
Poststudy
Participants will receive a follow-up call 14 days (+3 days) after receiving the dose of ISL for 
assessment of AEs and reporting of concomitant medications.
 
 
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8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, blood samples for methadone and ISL pharmacokinetics are the critical 
procedures.
The blood collection for ISL pharmacokinetics should be based upon the time of ISL
administration. The blood collection for methadone should be based upon the time of 
methadone administration.
At any postdose timepoint, the blood samples for methadone and ISL need to be collected as 
close to the exact timepoint as possible. All other procedures should be completed as close to 
the prescribed/scheduled time as possible.
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
The following variance in procedure collection times will be permitted.
•
PK Collection as outlined in Table 4.
Table 4
Pharmacokinetic Blood Collection Windows
PK Collection
PK Collection Window
0 - <1 hr
± 5 min
1 - <24 hr
± 15 min
24 - <48 hr
± 1 hr
48 - 168 hr
± 2 hr
•
Predose standard safety evaluations: vital signs and ECG within 3 hrs prior to dosing on 
Days 1 and 2; COWS within 1 hr predose on Days 1 and 2; laboratory safety tests and 
physical exam within 24 hrs prior to dosing on Day 1
•
Postdose standard safety evaluations: vital signs, ECG, laboratory safety tests <24 hr 
postdose (Day 1 and Day 2) may be obtained within ±15 min of the theoretical sampling 
time
-
24 hr - <48 hr postdose (Day 2) may be obtained within ± 1 hr of the theoretical 
sampling time
-
48 hr – 168 hr postdose (Day 2) may be obtained within ± 2 hr of the theoretical 
sampling time
 
 
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-
>168 hr postdose (Day 2) may be obtained within ± 24 hr of the theoretical sampling 
time
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of ISL in humans, and the PK, pharmacodynamic, and safety 
profiles of the compound are still being elucidated. This protocol is written with some 
flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Modifications to the dose, dosing regimen, and/or clinical or laboratory procedures currently 
outlined may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants.
As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed those 
currently outlined in the protocol.
•
Decrease in the dose of the study intervention administered
•
Instructions to take study intervention with or without food or drink may also be modified 
based on newly available data
•
Modification of the PK/pharmacodynamic sample processing and shipping details based 
on newly available data
The PK/pharmacodynamic sampling scheme currently outlined in the protocol may be 
modified during the study based on newly available PK or pharmacodynamic data (eg, to 
obtain data closer to the time of peak plasma concentrations). If indicated, these collected 
samples may also be assayed in an exploratory manner for metabolites and/or additional 
pharmacodynamic markers.
Up to an additional 50 mL of blood may be drawn for safety, PK, and/or pharmacodynamic 
analyses. The total blood volume withdrawn from any single participant will not exceed the 
maximum allowable volume during his/her participation in the entire study (Appendix 8).
The timing of procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests, etc.) may be modified during the study based on newly available data. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information. These changes will not increase the number of study 
procedures for a given participant during his/her participation in the entire study.
It is understood that the current study may employ some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study File and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
 
 
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9
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
This section contains a summary of the statistical analyses for this trial. Full detail is in the 
Statistical Methods (Section 9.6).
Effect of ISL on Methadone 
Primary Hypotheses
AUC0-24 for methadone R-enantiomer will be dose-normalized by each subject’s methadone 
dose before the statistical analyses. A natural log transformation will be applied to the R-
methadone AUC0-24/D prior to the analysis. A linear mixed-effects model will be used to 
evaluate the primary hypothesis.  The model includes a fixed effect term for treatment.  An 
unstructured covariance matrix will be used to allow for unequal treatment variances and to 
model the correlation between the two treatment measurements within each subject via the 
REPEATED statement in SAS PROC MIXED.  Kenward and Roger's method will be used to 
calculate the denominator degrees of freedom for the fixed effects (DDFM=KR).  A ninety 
percent (90%) confidence interval (CI) will be constructed for the difference in LS means on 
the log scale R-methadone AUC0-24/D.  Exponentiating the log-scale 90% CI will provide a 
90% CI for the AUC0-24/D geometric mean ratio (GMR) (methadone+ISL/methadone 
alone). The hypothesis that the methadone (R-enantiomer) AUC0-24 obtained after single 
dose co-administration of methadone with ISL is similar to the methadone (R-enantiomer) 
AUC0-24 obtained after single dose administration of methadone alone will be supported if 
the 90% CI for the AUC0-24/D GMR of R-methadone is contained within the interval (0.70, 
1.43). 
AUC0-24 for methadone S-enantiomer will be analyzed based on the same model. The GMR 
(methadone+ISL/methadone alone) and 90% CI for methadone S-enantiomer will be 
estimated. The hypothesis that the methadone (S-enantiomer) AUC0-24 obtained after single 
dose co-administration of methadone with ISL is similar to the methadone (S-enantiomer) 
AUC0-24 obtained after single dose administration of methadone alone will be supported if 
the 90% CI for the AUC0-24/D GMR of S-methadone is below 2.0. 
Secondary Hypotheses
Dose normalized Cmax of R- and S- enantiomer will also be analyzed based on the same 
model. The GMRs (methadone+ISL/methadone alone) and 90% CIs for each parameter will 
be estimated. The hypothesis that the methadone (R-enantiomer) Cmax obtained after single 
dose co-administration of methadone with ISL is similar to the methadone (R-enantiomer) 
Cmax obtained after single dose administration of methadone alone will be supported if the 
90% CI for the Cmax/D GMR of R-methadone is below 1.43. The hypothesis that the 
methadone (S-enantiomer) Cmax obtained after single dose co-administration of methadone 
with ISL is similar to the methadone (S-enantiomer) Cmax obtained after single dose 
administration of methadone alone will be supported if the 90% CI for the Cmax/D GMR of 
S-methadone is below 2.0.  
 
 
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Estimations
Dose normalized C24 of R-methadone and S-methadone, and dose normalized AUC0-24, 
Cmax and C24 of methadone total will be analyzed similarly using the above model.  The 
GMR (methadone+ISL/methadone alone) and 90% CI for every afore-mentioned parameter 
will be estimated. Geometric means (GMs) and corresponding 95% CIs will also be provided
for AUC0-24/D, Cmax/D and C24/D of methadone (R-, S-, and total methadone) by 
treatment.  Plots with the individual ratios, GMR and 90% confidence interval will be 
provided for AUC0-24/D, Cmax/D and C24/D of methadone (R-, S-, and total methadone). 
Exploratory - Effect of Methadone on ISL
ISL AUC0-24 will be compared with the most appropriate available historical data following 
administration of MK-8591 60 mg alone. Potential historical data to be used include MK-
8591 P026 and P030. ISL AUC0-24 following co-administration of methadone and ISL and 
the historical data will be natural log transformed and analyzed using an ANOVA model with 
a factor for treatment (methadone+ISL, ISL alone). A ninety percent (90%) CI will be 
constructed for the difference in LS means on the log scale ISL AUC0-24. Exponentiating 
the log-scale 90% CI will provide a 90% CI for the AUC0-24 GMR (methadone+ISL/ISL 
alone). Similarly, ISL AUC0-168, AUC0-672, AUC0-inf, and Cmax will be analyzed and 
compared with historical data. GMs and corresponding 95% CIs will also be provided by 
treatment.  
Safety
Summary statistics and plots will be generated for raw laboratory safety tests, ECGs, and/or
VS as well as for change from baseline, as deemed clinically appropriate. Depending on the
safety parameter, the difference from baseline will either be computed on the original scale
(raw change from baseline) or on the log scale and back-transformed for reporting (percent
change from baseline). AEs will be listed and tabulated.
Sample Size and Power Calculations 
The following power estimates are based on within-subject SD obtained from MK-1439 
Protocol 045. With a sample size of 12 completers, if the true GMR of R-methadone AUC0-
24hr/D (methadone+ISL/methadone alone) is 1.00, then there is a greater than 99% 
probability of observing the 90% CI for the GMR within (0.70, 1.43) for R-methadone 
AUC0-24hr/D; if the true GMR of S-methadone AUC0-24hr/D (methadone+ISL/methadone 
alone) is 1.00, then there is a greater than 99% probability of observing the 90% CI for the 
GMR below 2.0 for S-methadone AUC0-24hr/D. Overall, there is a 98% probability to meet 
the two primary hypotheses. With a sample size of 12 completers, if the true GMR of R-
methadone AUC0-24hr is between 0.77 to 1.30 then there is at least 80% probability that the 
90% CI for R-methadone AUC0-24hr/D is between (0.70, 1.43); if the true GMR of S-
methadone AUC0-24hr is less than 1.76 then there is at least 80% probability that the 90% 
CI for S-methadone AUC0-24hr/D is less than 2.0. A total of 14 participants will be recruited 
for enrollment in case of discontinuations.
 
 
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9.2
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Early Clinical Development Statistics Department in collaboration 
with the Quantitative Pharmacology and Pharmacometrics Department and Translational 
Pharmacology Department of the Sponsor.
If, after the study has begun, changes are made to the statistical analysis plan stated below, 
then these deviations to the plan will be listed, along with an explanation as to why they 
occurred, in the Clinical Study Report.
9.3
Hypotheses/Estimation
Primary Hypotheses: 
The methadone (R-enantiomer) plasma AUC0-24 obtained after single dose co-
administration of methadone with ISL is similar to the methadone (R-enantiomer) plasma 
AUC0-24 obtained after single dose administration of methadone alone. That is, the true 
GMR (methadone and ISL/methadone alone) for the dose-normalized AUC0-24 (AUC0-
24/D) of methadone (R-enantiomer) is contained within (0.7, 1.43).
The methadone (S-enantiomer) plasma AUC0-24 obtained after single dose co-
administration of methadone with ISL is similar to the methadone (S-enantiomer) plasma 
AUC0-24 obtained after single dose administration of methadone alone. That is, the true 
GMR (methadone and ISL/methadone alone) for the dose-normalized AUC0-24 (AUC0-
24/D) of methadone (S-enantiomer) is less than 2.0.
Secondary Hypotheses: 
The methadone (R-enantiomer) plasma Cmax obtained after single dose co-
administration of methadone with ISL is similar to the methadone (R-enantiomer) plasma 
Cmax obtained after single dose administration of methadone alone. That is, the true 
GMR (methadone and ISL/methadone alone) for the dose-normalized Cmax (Cmax/D) of 
methadone (R-enantiomer) is less than 1.43.
The methadone (S-enantiomer) plasma Cmax obtained after single dose co-
administration of methadone with ISL is similar to the methadone (S-enantiomer) plasma 
Cmax obtained after single dose administration of methadone alone. That is, the true 
GMR (methadone and ISL/methadone alone) for the dose-normalized Cmax (Cmax/D) of 
methadone (S-enantiomer) is less than 2.0.
Estimations: 
The true GMR (methadone and ISL/ methadone alone) for the dose normalized C24 
(C24/D) of methadone (R-enantiomer and S-enantiomer) will be estimated.
The true GMR (methadone and ISL/methadone alone) for the dose normalized AUC0-24 
(AUC0-24/D), Cmax (Cmax/D) and C24 (C24/D) of methadone (total) will be estimated.
 
 
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9.4
Analysis Endpoints
Primary Endpoints
The primary PK endpoints include dose-normalized AUC0-24 (AUC0-24/D) of plasma 
methadone (R- and S-methadone).
Secondary Endpoints 
The secondary PK endpoints include dose-normalized Cmax (Cmax/D), C24 (C24/D), and 
Tmax of plasma methadone (R-, and S- enantiomer), and dose-normalized AUC0-24 (AUC0-
24/D), Cmax (Cmax/D), C24 (C24/D), and Tmax of plasma methadone (total).
The secondary safety endpoints include adverse experiences, laboratory safety tests, ECGs, 
and VSs (HR, BP, RR, oxygen saturation).
Exploratory Endpoints
The exploratory PK endpoints include AUC0-24, AUC0-168, AUC0-672, AUC0-inf, Cmax, 
Tmax and t1/2 of plasma ISL. 
9.5
Analysis Populations 
The following populations are defined for the analysis and reporting of data. All participants 
will be reported, and their data analyzed, according to the treatment(s) they actually received.
All Subjects as Treated (ASaT): The All Subjects as Treated Population consists of all 
participants who receive at least one dose of treatment. This population will be used for 
assessments of safety and tolerability.
Per-Protocol (PP): The Per-Protocol Population consists of the subset of participants who 
comply with the protocol sufficiently to ensure that generated data will be likely to exhibit 
the effects of treatment, according to the underlying scientific model. Compliance covers 
such considerations as exposure to treatment, availability of measurements and absence of 
important protocol deviations. Important protocol deviations will be identified to the extent 
possible prior to unblinding by individuals responsible for data collection/compliance, and its 
analysis and interpretation. Any participants or data values excluded from analysis will be 
identified, along with their reason for exclusion, in the CSR. At the end of the study, all 
participants who are compliant with the study procedure as aforementioned and have 
available data considered sufficient to exhibit the effect of treatment will be included in the 
Per-Protocol dataset. This population will be used for the PK analyses.
 
 
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9.6
Statistical Methods 
Pharmacokinetics
Effect of ISL on Methadone 
Primary Hypotheses
AUC0-24 for methadone R-enantiomer will be dose-normalized by each subject’s methadone 
dose before the statistical analyses. A natural log transformation will be applied to the R-
methadone AUC0-24/D prior to the analysis. A linear mixed-effects model will be used to 
evaluate the primary hypothesis.  The model includes a fixed effect term for treatment.  An 
unstructured covariance matrix will be used to allow for unequal treatment variances and to 
model the correlation between the two treatment measurements within each subject via the 
REPEATED statement in SAS PROC MIXED.  Kenward and Roger's method will be used to 
calculate the denominator degrees of freedom for the fixed effects (DDFM=KR).  A ninety 
percent (90%) confidence interval (CI) will be constructed for the difference in LS means on 
the log scale R-methadone AUC0-24/D.  Exponentiating the log-scale 90% CI will provide a 
90% CI for the AUC0-24/D geometric mean ratio (GMR) (methadone+ISL/methadone 
alone).  The hypothesis that the methadone (R-enantiomer) AUC0-24 obtained after single
dose co-administration of methadone with ISL is similar to the methadone (R-enantiomer) 
AUC0-24 obtained after single dose administration of methadone alone will be supported if 
the 90% CI for the AUC0-24/D GMR of R-methadone is contained within the interval (0.70, 
1.43). 
Sample SAS code is given below:
proc mixed data=dataset;
   class treatment subject;
   model y = treatment/ddfm=kr;
   repeated treatment / subject=subject type=un;
run;
AUC0-24 for methadone S-enantiomer will be analyzed based on the same model. The GMR 
(methadone+ISL/methadone alone) and 90% CI for methadone S-enantiomer will be 
estimated. The hypothesis that the methadone (S-enantiomer) AUC0-24 obtained after single 
dose co-administration of methadone with ISL is similar to the methadone (S-enantiomer) 
AUC0-24 obtained after single dose administration of methadone alone will be supported if 
the 90% CI for the AUC0-24/D GMR of S-methadone is below 2.0. 
Secondary Hypotheses
Dose normalized Cmax of R- and S- enantiomer will also be analyzed based on the same 
model. The GMRs (methadone+ISL/methadone alone) and 90% CIs for each parameter will 
be estimated. The hypothesis that the methadone (R-enantiomer) Cmax obtained after single 
dose co-administration of methadone with ISL is similar to the methadone (R-enantiomer) 
Cmax obtained after single dose administration of methadone alone will be supported if the 
 
 
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90% CI for the Cmax/D GMR of R-methadone is below 1.43. The hypothesis that the 
methadone (S-enantiomer) Cmax obtained after single dose co-administration of methadone 
with ISL is similar to the methadone (S-enantiomer) Cmax obtained after single dose 
administration of methadone alone will be supported if the 90% CI for the Cmax/D GMR of 
S-methadone is below 2.0.  
Estimations
Dose normalized C24 of R-methadone and S-methadone, and dose normalized AUC0-24, 
Cmax and C24 of methadone total will be analyzed similarly using the above model.  The 
GMR (methadone+ISL/methadone alone) and 90% CI for every aforementioned parameter 
will be estimated. Geometric means (GMs) and corresponding 95% CIs will also be provided 
for AUC0-24/D, Cmax/D and C24/D of methadone (R-, S-, and total methadone) by 
treatment. Plots with the individual ratios, GMR and 90% confidence interval will be 
provided for AUC0-24/D, Cmax/D and C24/D of methadone (R-, S-, and total methadone). 
Exploratory - Effect of Methadone on ISL
ISL AUC0-24 will be compared with the most appropriate available historical data following 
administration of MK-8591 60 mg alone. Potential historical data to be used include MK-
8591 P026 and P030. ISL AUC0-24 following co-administration of methadone and ISL and 
the historical data will be natural log transformed and analyzed using an ANOVA model with 
a factor for treatment (methadone+ISL, ISL alone). A ninety percent (90%) CI will be 
constructed for the difference in LS means on the log scale ISL AUC0-24. Exponentiating 
the log-scale 90% CI will provide a 90% CI for the AUC0-24 GMR (methadone+ISL/ISL 
alone). Similarly, ISL AUC0-168, AUC0-672, AUC0-inf, and Cmax will be analyzed and 
compared with historical data. GMs and corresponding 95% CIs will also be provided by 
treatment.  
Individual values will be listed for each PK parameter by treatment and analyte including 
dose-normalized AUC0-24 (AUC0-24/D), Cmax (Cmax/D), C24 (C24/D), and Tmax of 
plasma methadone (total, R-, and S-methadone), and AUC0-24, AUC0-168, AUC0-672, 
AUC0-inf, Cmax, Tmax and t1/2 of plasma ISL, and the following (non-model-based) 
descriptive statistics will be provided: N (number of subjects with non-missing data), 
arithmetic mean, standard deviation, arithmetic percent CV (calculated as 100 x standard 
deviation/arithmetic mean), median, minimum, maximum, geometric mean, and geometric 
percent CV (calculated as  100 x sqrt( exp(s2) - 1), where s2 is the observed variance on the 
natural log-scale. 
Safety:
Summary statistics and plots will be generated for raw laboratory safety tests, ECGs, and/or
VS as well as for change from baseline, as deemed clinically appropriate. Depending on the
safety parameter, the difference from baseline will either be computed on the original scale
(raw change from baseline) or on the log scale and back-transformed for reporting (percent
change from baseline). AEs will be listed and tabulated.
 
 
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9.7
Interim Analyses
Not applicable. 
9.8
Multiplicity
Since both primary hypotheses (R- and S-methadone plasma AUC0-24) must be supported in 
order for the overall clinical hypothesis to be supported, there is no need for a multiplicity 
adjustment. 
9.9
Sample Size and Power Calculations
The following power estimates are based on within-subject SD obtained from MK-1439 
Protocol 045. 
With a sample size of 12 completers, if the true GMR of R-methadone AUC0-24hr/D
(methadone+ISL/methadone alone) is 1.00, then there is a greater than 99% probability of 
observing the 90% CI for the GMR within (0.70, 1.43) for R-methadone AUC0-24hr/D; if 
the true GMR of S-methadone AUC0-24hr/D (methadone+ISL/methadone alone) is 1.00, 
then there is a greater than 99% probability of observing the 90% CI for the GMR below 2.0
for S-methadone AUC0-24hr/D. Overall, there is a 98% probability to meet the two primary 
hypotheses. 
With a sample size of 12 completers, if the true GMR of R-methadone AUC0-24hr is 
between 0.77 to 1.30 then there is at least 80% probability that the 90% CI for R-methadone 
AUC0-24hr/D is between (0.70, 1.43); if the true GMR of S-methadone AUC0-24hr is less 
than 1.76 then there is at least 80% probability that the 90% CI for S-methadone AUC0-
24hr/D is less than 2.0. 
Similar power calculations for R-, S-methadone Cmax/D and the precision estimations for
R-, S-methadone C24/D and total-methadone AUC0-24/D, Cmax/D, and C24/D are provided 
in Table 5. 
A total of 14 participants will be recruited for enrollment in case of discontinuations.
 
 
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Table 5
Power and Precision Estimates
Hypotheses 
Parameter
Within subject
SD estimate
(log scale)
Bounds
Power if 
the True 
GMR is 
1.00 
Lowest and/or 
Highest True GMR 
to Maintain 80% 
Power
Primary Hypotheses 
R-methadone
AUC0-24/D
0.088
(0.7, 1.43)
99%
(0.77, 1.30)
S-methadone
AUC0-24/D
0.116
<2.0
99%
<1.76
Secondary Hypotheses
R-methadone
Cmax/D
0.076
<1.43
99%
<1.32
S-methadone
Cmax/D
0.106
<2.0
99%
<1.78
Estimations 
Parameter
Within subject
SD estimate
(log scale)
Half-width of 90% CI 
(log scale)
90% CI if the 
Estimated GMR is 
1.00
R-methadone
C24/D
0.119
0.087
(0.92, 1.09) 
S-methadone
C24/D
0.183
0.134
(0.87, 1.14) 
Total-methadone
AUC0-24/D
0.095
0.070
(0.93, 1.07) 
Cmax/D
0.087
0.064
(0.94, 1.07) 
C24/D
0.140
0.103
(0.90, 1.11) 
 
 
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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 and Dohme Corp., a subsidiary of Merck & Co., Inc. (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 and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also 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 (e.g., 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 (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. 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 (or individuals acting on behalf of MSD) 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 Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
 
 
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source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified 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. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
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, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), 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.
 
 
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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 and medical evaluation to identify potentially eligible participants.
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 (e.g., 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
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
 
 
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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.
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.
 
 
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10.1.4
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.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the 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 
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.
10.1.6
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 Council on Harmonisation 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 Trials.
 
 
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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.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
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 
 
 
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study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.8
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.
10.1.9
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 or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 6 will be performed by the local laboratory.
•
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 6
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)
Total and direct 
bilirubin 
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)
Total Protein
Glucose (fasting)
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
•
Follicle-stimulating hormone (as needed in women of nonchildbearing potential 
only)
•
Urine drug screen (to include at minimum: amphetamines, barbiturates, cocaine, 
opiates, cannabinoids and benzodiazepines) 
•
Highly sensitive serum pregnancy test (for WOCBP)
•
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody)
•
Syphilis testing per standard of care (eg, treponemal and/or nontreponemal testing)
•
Urine STI screen (to include at minimum: gonorrhea, chlamydia, trichomoniasis)
NOTES: Laboratory safety assessments will be performed after an 8- hour fast; however, in case of
discontinuation or rechecks, a non-fasting assessment may be performed at the discretion of the Investigator.
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, medical device, combination product, 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.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
 
 
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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.
    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 
 
 
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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/toxicity
    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) by recording the grade according to the NIH DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, version 2.1. Any AE which 
changes DAIDS grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
- Grade 1 Mild event: Mild symptoms causing no or minimal interference with usual 
social and functional activities with intervention not indicated.
- Grade 2 Moderate event: Moderate symptoms causing greater than minimal 
interference with usual social and functional activities with intervention indicated.
- Grade 3 Severe event: Severe symptoms causing inability to perform usual social and 
functional activities with intervention or hospitalization indicated.
- Grade 4 Potentially life-threatening event: Potentially life-threatening symptoms 
causing inability to perform basic self-care funtions with intervention indicated to 
prevent permanent impairment, persistent disability, or death.
- Grade 5 Death: Deaths related to an AE.
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 
 
 
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their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
- 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.
 
 
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•
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.
•
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.
 
 
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    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 EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
◦
Reference Section 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: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
 
 
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required. 
- Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
 
 
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Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
 
 
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen- only contraceptive implantc,d
•
IUSc,e
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
- Oral
- Intravaginal
- Transdermal
- Injectable
•
Progestogen-only hormonal contraceptionc,d
- Oral
- Injectable
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
•
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of action
•
Male or female condom with or without spermicide
•
Cervical cap, diaphragm, or sponge with spermicide
•
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods)f
a   Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b   Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-  Male and female condom should not be used together (due to risk of failure with friction).
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.  Definitions
a.   Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b   Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.   Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d.   DNA: Deoxyribonucleic acid.
e.   RNA: Ribonucleic acid.
2.  Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways with which drugs/vaccines may interact
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3.  Summary of Procedures for Future Biomedical Research
a.   Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in future 
biomedical research.
 
 
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b.   Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study visit 
by the investigator or his or her designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
delayed, present consent at next possible Participant Visit. Consent forms signed by the 
participant will be kept at the clinical study site under secure storage for regulatory 
reasons.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c.   eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d.   Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.  Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
 
 
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5.  Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6.  Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7.  Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
 
 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8.  Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9.  Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
 
 
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13. References
1.  National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.   International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3.   Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4.  Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
 
 
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
 
 
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10.8
Appendix 8: Blood Volume Table
Participants
Pre-study
Treatment 
Periods
Total 
Collections
mL Per 
Collection
Total mL/ Test
Laboratory Safety Tests
      Chemistrya
     Hematology
1
1
2
2
3
3
8.5
4
25.5
12
Blood for Planned Genetic 
Analysis
1
1
8.5
8.5
HIV Antigen/Antibody & 
/Hepatitis Screen
1b
1
8.5
8.5
Blood for syphilis screen
1
1
5
5
Blood for methadone
21
21
6
126
Blood for ISL
13
13
4
52
Total Blood Volume per Participant:
237.5 mLc
a Includes serum FSH (WONCBP only) and serum β-hCG (WOCBP only).
b  Hepatitis screen conducted at pre-study visit only.
c If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up 
to 50 mL) may be obtained. Note: never to exceed 50 mL.
 
 
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10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria
12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant 
Postrandomization Findings 
(clarification on action to take)
RHYTHM
Sinus Tachycardia
110 bpm
HR >110 bpm and HR increase of 
≥25 bpm from baseline
Sinus Bradycardia
<40 bpm
HR <40 bpm and HR decrease of 
≥5 bpm from baseline
Sinus Pause/Arrest
>2.0 seconds
>2.0 seconds
Atrial Premature Complex
1 beat
3 beats
Ventricular Premature Complex
All
3 beats
Ectopic Atrial Rhythm 
None
None
Junctional Rhythm
Junctional Rhythm with HR <40 
bpm
Junctional Rhythm with HR <40 
bpm
Idioventricular Rhythm
All
All
Atrial Fibrillation
All
All
Atrial Flutter
All
All
Supraventricular Tachycardia
All
All
Ventricular Tachycardia
All
All
AXIS
Left Axis Deviation
RBBB With Left Anterior 
Hemiblock (LAHB)
New Onset LAHB
Right Axis Deviation
RBBB With Left Posterior 
Hemiblock (LPHB)
New Onset LPHB
CONDUCTION
1st Degree AV Block
PR 230 ms
PR 230 ms  + Increase of 15 ms; 
or PR Increase of >25%
2nd Degree AV Block
Mobitz Type II
Mobitz Type II
3rd Degree AV Block
All
All
LBBB
All
All
RBBB
RBBB With LAHB/LPHB as 
Defined Above
New Onset RBBB (Not Including 
Rate-related)
Incomplete Right BBB 
(ICRBBB) (QRS <120 ms)
No Exclusion
Nothing
Short PR/ Preexcitation 
Syndrome
Delta Wave + PR <120 ms
Delta Wave + PR <120 ms
Other Intra-Ventricular 
Conduction Delay
QRS 130 ms
QRS 130 ms + Increase of 10 ms
QTc (B or F)
Male
QTc 450 ms
QTc 500 ms or Increase of 60 ms 
From Baseline
Female
QTc 470 ms
QTc 500 ms or Increase of 60 ms 
From Baseline
 
 
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12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant 
Postrandomization Findings 
(clarification on action to take)
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P Mitrale or 
P Pulmonale
Definite Evidence of P Mitrale or P 
Pulmonale
Ventricular Abnormalities
Voltage Criteria for LVH Plus 
Strain Pattern
Voltage Criteria  for LVH Plus 
Strain Pattern
MYOCARDIAL INFARCTION
Acute or Recent
All
All
Old
All
All
ST/T MORPHOLOGY
ST Elevation Suggestive of 
Myocardial Injury 
In 2 or more contiguous leads
In 2 or more contiguous leads
ST Depression Suggestive of
Myocardial Ischaemia 
In 2 or more contiguous leads
In 2 or more contiguous leads
T-wave Inversions Suggestive of 
Myocardial Ischaemia 
In 2 or more contiguous leads
In 2 or more contiguous leads
Non-specific ST-T Changes 
(In 2 or More Leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
Baseline is defined as Predose Day 1; ms=milliseconds, mm=millimeter
 
 
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10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the participant will be 
excluded from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
1.
The participant may be excluded from the study;
2.
The participant may be included in the study if the abnormal value(s) is NCS 
(the investigator must annotate the laboratory value “NCS” on the laboratory 
safety test source document).
3.
The participant may be included in the study if the abnormality is consistent 
with a pre-existing medical condition which is not excluded per protocol (eg, 
elevated eosinophil count in a participant with asthma or seasonal allergies),
the medical condition should be annotated on the laboratory report.
OR
4.
The abnormal test may be repeated (refer items a. and b. below for 
continuation of algorithm for repeated values).
a.   If the repeat test value is within the normal range, the participant may 
enter the study.
b.   If the repeat test value is still abnormal, the study investigator will 
evaluate the potential participant with a complete history and physical 
examination, looking especially for diseases that could result in the 
abnormal laboratory value in question. If such diseases can be ruled out, 
and if the abnormal laboratory value is not clinically relevant, then the 
participant may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
 
 
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
ADA
Adenosine deaminase
AE
adverse event 
APaT
All-Participants-as-Treated
AR
adverse reaction
ART
anti-retroviral therapy
BDS
blood drug screen
β-hCG
β-human chorionic gonadotropin
BID
twice daily
BMI
body mass index
BP
blood pressure
CG
Cockcroft-Gault
CNS
central nervous system 
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
clearance
CrCl
creatinine clearance
CRF
Case Report Form 
CRU
clinical research unit
CSR
Clinical Study Report
DAIDS
Division of AIDS
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
doravarine
DTG
dolutegravir
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
FSH
follicle stimulating hormone 
GCP
Good Clinical Practice 
HbsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IRB
Institutional Review Board
ISL
Islatravir
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
LNG/EE
Levonorgestrel/ethinyl estradiol
 
 
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Abbreviation
Expanded Term
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MMT
Methadone maintenance therapy
NCS
not clinically significant
NRTI
Nucleoside reverse transcriptase inhibitor
NRTTI
Nucleoside reverse transcriptase translocation inhibitor
NOAEL
no observed adverse effect level 
OTC
over-the-counter
PBMC
Peripheral mononuclear blood cells
PK
pharmacokinetic
PP
per-protocol
PrEP
Pre-exposure prophylaxis
PWID
People who inject drugs
QM
Once monthly
QW
Once a week
QP2
department of quantitative pharmacology and pharmacometrics
RNA
ribonucleic acid
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
TDF
Tenofovir disoproxil fumarate
TP
triphosphate
UDS
urine drug screen
V 
volume of distribution
VS
vital sign
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
WONCBP
Woman/women of nonchildbearing potential
 
 
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11
REFERENCES
[Centers for Disease Control 
and Prevention 2015]
Centers for Disease Control and Prevention. 
Factors increasing the risk of acquiring or 
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Department of Health and Human Services 
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[Centers for Disease Control 
and Prevention 2020]
Centers for Disease Control and Prevention 
[Internet]. Washington (DC): Department of 
Health and Human Services (HHS). 
Diagnoses of HIV infection in the United 
States and dependent areas, 2018: 
diagnoses: diagnoses of HIV infection; 
[cited 2020 Aug 24]; [about 19 screens]. 
Available from: 
https://www.cdc.gov/hiv/library/reports/hiv-
surveillance/vol-31/content/diagnoses.html.
[05KS5B]
[Centers for Disease Control 
and Prevention 2020]
Centers for Disease Control and Prevention 
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[Centers for Disease Control 
and Prevention 2020]
Centers for Disease Control and Prevention 
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https://www.cdc.gov/hiv/risk/idu.html.
[05KS5D]
[Eap, C. B., et al 2002]
Eap CB, Buclin T, Baumann P. 
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[Rainey, P. M., et al 2000]
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[Schwartz, E. L., et al 1992]
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