Clinical trial NCT02720081
Conditions: Asthma
Sponsor: Merck Sharp & Dohme LLC
Start date: 2016-05-11; Completion date: 2017-09-06
Enrollment: 142 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial is to compare the safety, tolerability, and efficacy of adding MK-1029 to montelukast in adults with persistent asthma that is uncontrolled while receiving montelukast alone. Participants will have a specific genetic marker for clinical efficacy of MK-1029. The primary hypothesis is that when added to montelukast, treatment with MK-1029 is superior to placebo, as demonstrated by an increase in forced expiratory volume in one second (FEV1), measured as the average change from baseline at the end of Week 4 and Week 6 of treatment.

Detailed description:

Arms: arm 1: Participants receive single-blind MK-1029 Matching-image Placebo + open-label Montelukast 10 mg for a 2 to 4 week run-in period while discontinuing or tapering off asthma controller medications. Participants receive double-blind MK-1029 150 mg + Montelukast 10 mg for 6 weeks in the treatment period. Participants can use rescue medication during both periods as needed. arm 2: Participants receive single-blind MK-1029 Matching-image Placebo + open-label Montelukast 10 mg for a 2 to 4 week run-in period while discontinuing or tapering off asthma controller medications. Participants receive double-blind MK-1029 Matching-image Placebo + Montelukast 10 mg for 6 weeks in the treatment period. Participants can use rescue medication during both periods as needed.
Interventions: intervention 1: MK-1029 150 mg intervention 2: MK-1029 Matching-image Placebo intervention 3: Montelukast 10 mg intervention 4: Albuterol/Salbutamol 90 mcg - 100 mcg per inhalation
Intervention descriptions: intervention 1: 150 mg tablet administered orally, once a day (QD), at bedtime intervention 2: Matching-image placebo tablet administered orally, QD, at bedtime intervention 3: 10 mg tablet administered orally, QD, at bedtime intervention 4: 1 or 2 inhalations 4 times a day (QID) as needed (PRN) as a Rescue Medication

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT02720081 
Document Date: 
03-Mar-2016
A Phase-II, Randomized, Placebo-Controlled, Parallel-Group 
Clinical Trial to Study the Efficacy and Safety of MK-1029 in Adult 
Subjects with Persistent Asthma That is Uncontrolled While 
Receiving Montelukast


Product:  MK-1029 
1
Protocol/Amendment No.: 015-01 
MK-1029-015-01 Final Protocol
3-Mar-2016
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase-II, Randomized, Placebo-Controlled, Parallel-Group Clinical Trial to Study the 
Efficacy and Safety of MK-1029 in Adult Subjects with Persistent Asthma That is 
Uncontrolled While Receiving Montelukast.
IND NUMBER: 111,055
EudraCT NUMBER:  2015-005054-36
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 22
2.0
TRIAL DESIGN........................................................................................................ 22
Trial Design ........................................................................................................... 22
2.1
Trial Diagram........................................................................................................ 24
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 24
Primary Objective(s) & Hypothesis(es) .............................................................. 24
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 24
3.2
Exploratory Objectives......................................................................................... 25
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 25
Background ........................................................................................................... 25
4.1
Pharmaceutical and Therapeutic Background .................................................... 25
4.1.1
Results from a Recently Completed Clinical Trial ............................................. 26
4.1.2
Background on Montelukast ............................................................................... 27
4.1.3
Rationale................................................................................................................ 28
4.2
Rationale for the Trial and Selected Subject Population .................................... 28
4.2.1
SNP+ Population.......................................................................................... 28
4.2.1.1
Age Range.................................................................................................... 29
4.2.1.2
Lung Function.............................................................................................. 29
4.2.1.3
Rationale for Dose Selection/Regimen............................................................... 29
4.2.2
Rationale for the use of Placebo .................................................................. 30
4.2.2.1
Rationale for Endpoints ...................................................................................... 30
4.2.3
Efficacy Endpoints....................................................................................... 30
4.2.3.1
Safety Endpoints .......................................................................................... 31
4.2.3.2
Planned Exploratory Biomarker Research................................................... 31
4.2.3.3
Future Biomedical Research........................................................................ 32
4.2.3.4
Benefit/Risk ........................................................................................................... 32
4.3
5.0
METHODOLOGY ................................................................................................... 33
 
 
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Entry Criteria........................................................................................................ 33
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 33
5.1.1
Subject Inclusion Criteria.................................................................................... 33
5.1.2
Subject Exclusion Criteria .................................................................................. 35
5.1.3
Trial Treatment(s) ................................................................................................ 38
5.2
Dose Selection .................................................................................................... 39
5.2.1
Dose Selection (Preparation) ....................................................................... 39
5.2.1.1
Timing of Dose Administration .......................................................................... 39
5.2.2
Trial Blinding...................................................................................................... 39
5.2.3
Randomization or Treatment Allocation............................................................ 39
5.3
Stratification.......................................................................................................... 40
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 40
5.5
Prior/Concomitant Beta-Agonist Bronchodilator Use ........................................ 40
5.5.1
Prior/Concomitant Inhaled Corticosteroid (ICS) Use ......................................... 40
5.5.2
Allowed Asthma Therapy ................................................................................... 41
5.5.3
Allowed Allergic Rhinitis and Immunotherapy Medications ............................. 41
5.5.4
Prohibited Medications ....................................................................................... 41
5.5.5
Rescue Medications & Supportive Care............................................................. 42
5.6
Diet/Activity/Other Considerations..................................................................... 43
5.7
Diet/Activity/Awake/Sleep Cycle....................................................................... 43
5.7.1
Caffeine............................................................................................................... 43
5.7.2
Contraception and Pregnancy Testing ................................................................ 43
5.7.3
Subject Withdrawal/Discontinuation Criteria................................................... 44
5.8
Subject Replacement Strategy............................................................................. 45
5.9
Beginning and End of the Trial ........................................................................... 45
5.10
Clinical Criteria for Early Trial Termination ................................................... 45
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 46
7.0
TRIAL PROCEDURES ........................................................................................... 50
Trial Procedures ................................................................................................... 50
7.1
Administrative Procedures.................................................................................. 50
7.1.1
Informed Consent......................................................................................... 50
7.1.1.1
General Informed Consent.................................................................... 50
7.1.1.1.1
 
 
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Consent and Collection of Specimens for Future Biomedical 
7.1.1.1.2
Research................................................................................................ 51
Inclusion/Exclusion Criteria ........................................................................ 51
7.1.1.2
Subject Identification Card .......................................................................... 51
7.1.1.3
Medical History ........................................................................................... 51
7.1.1.4
Asthma Baseline Profile ....................................................................... 51
7.1.1.4.1
Prior and Concomitant Medications Review ............................................... 51
7.1.1.5
Prior Medications.................................................................................. 51
7.1.1.5.1
Concomitant Medications..................................................................... 52
7.1.1.5.2
Assignment of Screening Number............................................................... 52
7.1.1.6
Assignment of Treatment/Randomization Number ..................................... 52
7.1.1.7
Trial Compliance ......................................................................................... 52
7.1.1.8
Study Procedures to be Reviewed with Subject .......................................... 52
7.1.1.9
e-Diary .................................................................................................. 52
7.1.1.9.1
Rescue Short-acting Beta-agonist (SABA) use .................................... 53
7.1.1.9.2
Short-Acting Beta-Agonist Supplies Assessed/Dispensed ............ 54
7.1.1.9.2.1
Calculate Overall Rescue Short-Acting Beta-Agonist Use............ 54
7.1.1.9.2.2
Asthma Symptoms................................................................................ 54
7.1.1.9.3
Additional Measures to Manage Deterioration of Asthma................... 55
7.1.1.9.4
Action Plan for Deterioration of Asthma..................................................... 56
7.1.1.10
Trial Medication........................................................................................... 56
7.1.1.11
Single-Blind Trial Medication + Montelukast Dispensed .................... 56
7.1.1.11.1
Witnessed Dosing ................................................................................. 56
7.1.1.11.2
Double Blind Trial Medication + Montelukast Dispensed................... 56
7.1.1.11.3
Trial Medication Compliance ............................................................... 56
7.1.1.11.4
Review of Adverse Experiences .................................................................. 57
7.1.1.12
Review of Subject Questionnaires............................................................... 57
7.1.1.13
Clinical Procedures/Assessments........................................................................ 57
7.1.2
Physical Exam.............................................................................................. 57
7.1.2.1
Vital Signs.................................................................................................... 57
7.1.2.2
Electrocardiogram (ECG) 12-lead ............................................................... 57
7.1.2.3
Asthma Control Questionnaire (ACQ-6) and Calculation of ACQ-6 
7.1.2.4
score............................................................................................................. 58
 
 
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Asthma Quality of Life Questionnaire (AQLQ(S)) ..................................... 59
7.1.2.5
Peak Flow Meter (PEF) ............................................................................... 59
7.1.2.6
PEF to Determine “Personal Best” and Alert Levels ........................... 60
7.1.2.6.1
Spirometry, also known as Pulmonary Function Testing (PFT).................. 60
7.1.2.7
Reversibility.......................................................................................... 61
7.1.2.7.1
Pre-Beta-Agonist Spirometry (FEV1, FVC) ......................................... 61
7.1.2.7.2
Post-Beta-Agonist Spirometry (FEV1, FVC)........................................ 61
7.1.2.7.3
Laboratory Procedures/Assessments .................................................................. 61
7.1.3
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 61
7.1.3.1
Blood for SNP testing .................................................................................. 62
7.1.3.2
Planned Genetic Analysis Sample Collection.............................................. 62
7.1.3.3
Future Biomedical Research Sample Collection ......................................... 62
7.1.3.4
Other Procedures................................................................................................. 63
7.1.4
Withdrawal/Discontinuation........................................................................ 63
7.1.4.1
Withdrawal From Future Biomedical Research ................................... 63
7.1.4.1.1
Blinding/Unblinding .................................................................................... 63
7.1.4.2
Domiciling ................................................................................................... 64
7.1.4.3
Calibration of Critical Equipment................................................................ 64
7.1.4.4
Visit Requirements.............................................................................................. 64
7.1.5
Rescreening.................................................................................................. 64
7.1.5.1
Post-treatment Visit ..................................................................................... 64
7.1.5.2
Assessing and Recording Adverse Events .......................................................... 65
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 65
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 66
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 66
7.2.3
Serious Adverse Events ............................................................................... 66
7.2.3.1
Events of Clinical Interest............................................................................ 67
7.2.3.2
Protocol-Specific Exceptions to Serious Adverse Event Reporting ............ 68
7.2.3.3
Evaluating Adverse Events ................................................................................. 68
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 71
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 71
 
 
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Statistical Analysis Plan Summary ..................................................................... 72
8.1
Responsibility for Analyses/in-house Blinding................................................... 73
8.2
Hypotheses/Estimation ......................................................................................... 73
8.3
Analysis Endpoints ............................................................................................... 73
8.4
Efficacy Endpoints.............................................................................................. 73
8.4.1
Safety Analysis ................................................................................................... 73
8.4.2
Derivations of Efficacy Endpoints...................................................................... 73
8.4.3
Derivations of Safety Endpoints ......................................................................... 74
8.4.4
Analysis Populations............................................................................................. 75
8.5
Efficacy Analysis Populations ............................................................................ 75
8.5.1
Safety Analysis Population ................................................................................. 75
8.5.2
Statistical Methods................................................................................................ 75
8.6
Statistical Methods for Efficacy Analysis........................................................... 75
8.6.1
Statistical Methods for Safety Analysis .............................................................. 78
8.6.2
Summaries of Baseline Characteristics, and Demographics............................... 80
8.6.3
Interim Analysis.................................................................................................... 81
8.7
Multiplicity ............................................................................................................ 81
8.8
Power and Sample Size......................................................................................... 81
8.9
Subgroup Analysis and Effect of Baseline Factors ............................................ 81
8.10
Compliance (Medication Adherence).................................................................. 82
8.11
Extent of Exposure................................................................................................ 82
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 83
Investigational Product ........................................................................................ 83
9.1
Packaging and Labeling Information ................................................................. 83
9.2
Clinical Supplies Disclosure................................................................................. 83
9.3
Storage and Handling Requirements.................................................................. 84
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 84
9.5
Standard Policies................................................................................................... 84
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 84
Confidentiality....................................................................................................... 84
10.1
Confidentiality of Data ....................................................................................... 84
10.1.1
 
 
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Confidentiality of Subject Records ..................................................................... 85
10.1.2
Confidentiality of Investigator Information........................................................ 85
10.1.3
Confidentiality of IRB/IEC Information............................................................. 85
10.1.4
Compliance with Financial Disclosure Requirements....................................... 86
10.2
Compliance with Law, Audit and Debarment ................................................... 86
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 88
10.4
Quality Management System............................................................................... 88
10.5
Data Management................................................................................................. 88
10.6
Publications ........................................................................................................... 88
10.7
11.0
LIST OF REFERENCES......................................................................................... 90
12.0
APPENDICES........................................................................................................... 92
Merck Code of Conduct for Clinical Trials........................................................ 92
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 94
Pharmacogenetics Information Brochure for IRB/IECs & Investigational 
12.3
Site Staff................................................................................................................. 98
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.4
by Sample Types ................................................................................................. 107
Body Mass Index................................................................................................. 108
12.5
List of Abbreviations .......................................................................................... 110
12.6
Method for Administering Short-Acting Beta-Agonist (SABA) during 
12.7
Postbronchodilator Testing................................................................................ 112
Method for Performing Peak Flow Measurements ......................................... 113
12.8
Action Plan for Deterioration of Asthma ......................................................... 114
12.9
Procedure for Tapering Controller Medications............................................. 115
12.10
13.0
SIGNATURES......................................................................................................... 117
Sponsor's Representative ................................................................................... 117
13.1
Investigator.......................................................................................................... 117
13.2
 
 
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LIST OF TABLES
Table 1
Abnormal Lab Results at Visit 1........................................................................... 37
Table 2
Prohibited Medications......................................................................................... 37
Table 3
Trial Treatment ..................................................................................................... 38
Table 4
OATP1B1/OATP1B3 Inhibitors/Substrates that are Permitted............................ 42
Table 5
Discontinuation Scenarios .................................................................................... 45
Table 6
Laboratory Tests ................................................................................................... 62
Table 7
Evaluating Adverse Events................................................................................... 69
Table 8
Analysis Strategy for Key Efficacy Variables...................................................... 77
Table 9
Analysis Strategy for Safety Parameters............................................................... 79
Table 10
Predefined Limits of Change ................................................................................ 80
Table 11
Product Descriptions............................................................................................. 83
 
 
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LIST OF FIGURES
          
Figure 1
Trial Diagram........................................................................................................ 24
Figure 2
MK-1029 Effect (when Added to Montelukast) in a Pre-Specified 
Pharmacogenetic Analysis.................................................................................... 27
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
Trial Summary
The duration of participation 
has 
been 
corrected 
to 
approximately 17 weeks as 
identified in the Trial Diagram 
and Trial Flow Chart. Clarified 
that subjects in either treatment 
group will take MK-1029 150 
mg or matching-image placebo 
and that both treatment groups 
will be taking
montelukast. 
Clarified that screening period 
is a total of up to 9 weeks.
Corrected error in summary.
2.1
Trial Design
Included text that this is a 
world-wide trial.
Clarified that patients who 
undergo the 2 week Run-in 
period need approximately 3 
weeks in “Pre-study” period to 
obey the “-5 weeks” rule from 
“Pre-study”
to 
“Treatment”
study period.
Added “approximately” prior to 
Run-in, Treatment and Post-
Treatment visit weeks to clarify 
that this time period will vary 
for subjects.
Clarified trial design study 
period, treatment groups and 
trial medication terminology.
 
 
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Clarified trial treatment during 
run-in and treatment periods. 
Clarified that “montelukast” and 
“montelukast sodium” may be used 
interchangeably.
2.2
Trial Diagram
The timing for scheduled visits 
has been clarified in Section 
2.2 Trial Diagram and Section 
6.0 Flow Chart.
Provided as a correction of 
study visit weeks. 
4.2.3.1
Efficacy Endpoints
Removed the description of 
Asthma Control Questionnaire 
(ACQ), Asthma Quality of Life 
Questionnaire 
(AQLQ), 
Asthma Disease Activity Score 
(ADAS)-6, and ADAS-4 from 
the endpoint discussion section.
Removed content description 
from the protocol.
5.1.2
Subject Inclusion Criteria
Inclusion Criteria #16 refers to 
Table 10 for investigators to 
check routine laboratory data. 
However, this should refer to 
Table 
6,
which 
correctly 
outlines the safety laboratory 
tests.
Corrected section reference.
5.1.3
Subject Exclusion Criteria 
Corrected 
visit 
numbers 
regarding 
blood 
pressure 
measurements 
in 
Exclusion 
#16.
Corrected typographical error 
in blood pressure visit time 
points.
 
 
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5.2.2, 
7.1.1.8,
6.0
and 
7.1.1.11.2
Trial 
Treatment, 
Trial 
Compliance
and 
Witnessed 
Dosing
Added language to respective 
sections 
that 
single-blind 
dosing of study medication 
may be witnessed at Visit 3 as 
per 
site 
SOPs 
or 
local 
requirements.
Clarified that witnessed dosing 
is required at Visit 4 to be 
consistent with Section 5.2.2, 
6.0 and 7.1.1.11.2.
Added due 
to 
single-blind 
study 
design 
to 
maintain 
subject 
blind 
at 
Visit 
3. 
Clarified 
double-blind 
trial 
medication witnessed dose at 
Visit 4.
6.0
Trial Flow Chart
Added study window for Visit 
2 and updated week ranges for 
Visit 1 and Visit 2.
Removed 
the 
study 
visit 
window for Visit 1 as this was 
an error. 
Corrected reference for Post-
beta-agonist spirometry (FEV1, 
FVC).
Clarified spirometry timing for 
pre-beta-agonist spirometry.
Corrected and clarified study 
procedures and time frames.  
7.1.2.2
Vital Signs
Corrected inconsistency with 
Section 6.0 flow chart to note 
that heart rate, sitting blood 
pressure and respiratory rate 
are to be collected as part of 
vitals. 
Corrected vitals procedures to 
improve 
readability 
across 
multiple protocol sections.
 
 
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7.1.5.2
Post-treatment Visit
Corrected 
discrepancy 
with 
Trial Flow Chart in Section 6.0 
which had the correct window 
for the Post Treatment Visit of 
+4 days.
Removed text relating to the 
Post-treatment Visit procedures 
prior to 14 days because the 
protocol does not allow for this 
visit to occur earlier than 14 
days.
Corrected discrepancy in visit 
window for the Post Treatment 
Visit and aligned study window 
timeframe with Section 6.0 
Flow Chart.
9.3
Clinical Supplies Disclosure
Disclosure envelopes will not 
be used. This global study is
using 
the 
unblinding 
call 
center. Added a heading for 
blinded supplies to distinguish 
between open label and blinded 
clinical supplies disclosure. 
Corrected 
emergency 
unblinding 
procedures 
for 
global study and clarified open 
label 
and 
blinded 
clinical 
supplies.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
4.2.1.2
Age Range 
Included lower limit age range 
in this section.
Provided for clarity regarding 
age requirements.
4.2.2.1
Rationale for the use of Placebo
Re-arranged text to include 
rationale for placebo during
run-in period first followed by 
rationale for placebo during 
treatment period. No content 
changes were made.
Placed text in chronological 
order of study phases.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.1.2
Subject Inclusion Criteria
“ACQ” and “ACQ-6” refer to 
the same questionnaire, but the 
terminology 
was 
not 
used 
consistently 
in 
Inclusion 
Criteria #13 and throughout the
protocol. 
This 
has 
been 
corrected to 
use 
“ACQ-6” 
throughout the protocol. 
Provided 
to 
add 
clarity 
regarding terminology of ACQ-
6 questionnaire.
5.1.3
Subject Exclusion Criteria
Fixed error in Table 1 to note 
that creatinine is the specific 
lab test which will be drawn at 
Visit 1.
Edited table to be consistent 
with other table items. 
5.2
Trial Treatment
Re-formatted Table 3 to clarify 
run-in 
and 
treatment 
trial 
medications. 
Used 
terminology 
of 
“matching-image placebo” and 
clarified 
that
subjects 
will 
receive montelukast sodium 10 
mg and MK- 1029 150 mg or 
MK-1029
matching-image 
placebo 150 mg throughout the 
section.
Replaced 
“placebo-
comparator” terminology with 
“experimental” 
for 
trial 
treatment use. 
Clarified 
trial 
treatment 
medications during run-in and 
treatment periods, deleted text 
that was previously included in 
error
and added a footnote 
relating to locally sourced trial 
medication.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
Clarified that bottler order will 
not be labeled as such and thus 
removed “first” and “second” 
bottle text.
Removed suggested text which 
was previously included in 
error because Merck GCS 
provides is providing clinical 
supplies.
Included a footnote in the table 
that albuterol/salbutamol will 
be sourced locally.  
5.2.2, 5.2.3, 5.3, 8.1, 8.9, 8.11, 
12.10
Timing 
of 
Dose 
Administration,
Trial 
Blinding and
Randomization 
or 
Treatment 
Allocation, 
Statistical 
Analysis 
Plan 
Summary, Power and Sample 
Size, Compliance (Medication 
Adherence) and
Procedure 
for 
Tapering 
Controller 
Medications
Clarified treatment groups and 
included 
strength 
of 
montelukast.
Clarified 
that 
placebo 
is 
matching-image 150 mg to MK 
1029 150 mg.
Clarified treatment groups to 
increase 
readability 
across 
sections in the protocol.
5.5.2
Prior/Concomitant 
Inhaled 
Corticosteroid (ICS) Use
Clarified 
Visit 
1 
and 
medication criteria to progress 
to Visit 2 as well as the start 
point of Visit 3 ICS tapering. 
Clarified study criteria and 
procedures 
relating 
to 
medication use.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.5.5.
Prohibited Medications
Removed 
conflicting 
information 
regarding 
post-
treatment follow-up period.
Clarified discrepancy in text.
5.7.3
Contraception and Pregnancy 
Testing
Added 
language 
regarding 
pregnancy notification and trial 
medication discontinuation. 
Clarified study procedures in 
the event of pregnancy between 
study visits.
5.8
Subject 
Withdrawal/Discontinuation 
Criteria
Reference 
provided 
for 
pregnancy 
and 
persistent 
elevations in ALT or AST
discontinuation procedures.
Clarified 
discontinuation 
criteria. 
7.1.1.2
Inclusion/Exclusion Criteria
Included the Section reference
5.1 for Entry Criteria.
Provided to increase readability 
across 
multiple 
protocol
sections.
7.1.1.9.1
e-Diary
Moved e-Diary text which was 
previously incorrectly noted in 
section 
7.1.2.6,
which 
contained peak flow meter 
information. Clarified that e-
Diary data will be entered 
twice. 
Moved content to fall under the 
correct heading and clarified e-
Diary data entry.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.1.9.4
Administrative Procedures 
Section 
7.1.1.9.4 
regarding 
description 
of 
e-Diary 
questions and answer selections 
the protocol language indicates 
the e-Diary has a check box 
selection 
for 
“Call 
your 
doctor,” however this is not a 
selection on the e-Diary screen 
and has been removed. Also 
clarified wording and order of 
choices as stated in the e-Diary 
screen.
Removed the check box since it 
does not impact e-Diary data 
analysis.
7.1.1.11.3
Double Blind Trial Medication 
+ Montelukast Dispensed
Corrected error to reflect Trial 
Flow Chart in Section 6.0 
schedule for dispensing of trial 
medication. Also clarified that 
only visit 4 will be a witnessed 
dose. 
Corrected 
study 
medication 
dispensation discrepancy and 
clarified first witnessed dose 
visit in clinic.
7.1.1.11.4
Trial Medication Compliance
Moved 
paragraph 
regarding 
study staff instructions earlier 
in the section, there is no 
content change.
Increased 
readability 
of 
compliance check by site staff.
7.1.1.12
Review 
of 
Adverse 
Experiences
The protocol section reference 
regarding instructions on the 
reporting of SAEs to the 
sponsor is referred to Section 
7.2.3; however, the correct 
reference is 7.2.3.1.
Corrected section reference to 
improve 
readability 
across 
multiple protocol sections.  
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.2.4
Asthma Control Questionnaire 
(ACQ-6) and Calculation of 
ACQ-6 score
Included 
the 
reference 
for 
Inclusion Criterion #13 related 
to ACQ-6 score eligibility.
Included section reference to 
improve 
readability 
across 
multiple 
protocol 
sections
relating 
to 
ACQ-6 
score 
eligibility.  
7.1.2.5
Asthma 
Quality 
of 
Life 
Questionnaire (AQLQ(S))
Clarified that the questionnaire 
will be programmed in the e-
Diary and the order of the e-
Diary questionnaires which is 
also 
included 
in 
Section 
7.1.2.4. 
Clarified e-Diary questionnaire 
design.
7.1.2.6.1
PEF to Determine “Personal 
Best” and Alert Levels
The protocol section reference 
regarding 
deterioration 
of 
asthma is incorrectly referred to 
Appendix 12.7 and has been 
corrected to refer to Appendix 
12.9.
Corrected section reference.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.2.7
Spirometry, also known as 
Pulmonary Function Testing 
(PFT)
Re-arranged 
content 
within 
section to increase readability. 
New content additions included 
adding 
a 
“Calibration” 
subheading and clarifying the 
timing 
of 
spirometry 
procedures. 
Additionally, 
corrected 
that 
NHANESIII
and/or
The Journal of The 
Japanese Respiratory Society 
guidelines (as applicable per 
local 
guidelines)reference 
ranges are to be used to 
determine percent predicted of 
both FEV1 and FVC
Re-arranged 
structure
and 
added section subtitle. Included 
timing reminder to improve 
readability 
across 
multiple 
protocol 
sections,
corrected 
content of reference ranges and 
included new reference range.
7.1.2.7.1
Reversibility 
The protocol section reference 
regarding asthma medications 
is referred to as Section 3.2.1.4 
and has been corrected to refer 
to Section 5.5.1. Also added 
reference to Appendix 12.7 for 
reversibility testing.
Corrected wording of Visit 2 to 
“pre-study” phase to align with 
study diagram and flow chart.
Corrected section reference, 
added additional reference and 
corrected 
study 
visit 
terminology.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.2.7.3
Post Beta-Agonist Spirometry 
(FEV1, FVC)
The protocol section reference 
regarding 
post 
beta-agonist 
spirometry 
procedures 
is 
referred to as Appendix 12.8 
and has been corrected to refer 
to Appendix 12.7.
Corrected section reference.
7.1.3.1
Laboratory Safety Evaluations 
(Hematology, Chemistry and 
Urinalysis)
The 
laboratory 
evaluations 
incorrectly referred to Section 
12.4 
twice 
and 
has 
been 
corrected to refer to Table .1 
Corrected section reference.
7.1.4.4
Calibration 
of 
Critical 
Equipment
The reference to Section 7.1.2.6 
for detail on calibration of the 
spirometer is incorrect and has 
been corrected to refer to 
Section 7.1.2.7
Corrected section reference.
9.2
Packaging 
and 
Labeling 
Information
Clarified that supplies are for 
four weeks of dosing. 
Clarified 
clinical 
supplies 
dispensation. 
10.4
Compliance 
with 
Trial 
Registration 
and 
Results 
Posting Requirements
Updated 
language 
within 
section 10.4 includes reference 
to trial registration and results 
posting 
obligations 
to 
the 
EMA.
To include trial registration and 
results posting obligations to 
the EMA
11.0
List of References
Deleted reference #17, #18 and 
#19 as related content moved to 
the 
supplemental 
statistical 
analysis plan, and updated 
subsequent numbering in the 
section and throughout the 
protocol.
Content will not be included in 
the 
protocol 
therefore 
the 
references are deleted. 
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
12.3
Appendix 
Removed “Understanding the 
Intent, Scope and Public Health 
Benefits 
of 
Exploratory 
Biomarker Research: A Guide 
for 
IRBs/IECs 
and 
Investigational 
Site 
Staff  
Pharmacogenetics 
Informational 
Brochure 
for 
IRBs/IECs & Investigational 
Site Staff” and replaced with 
“Pharmacogenetics 
Informational 
Brochure 
for 
IRBs/IECs & Investigational 
Site Staff.”
Only the leftover extracted 
DNA would be stored for FBR 
therefore included the correct 
brochure. 
12.4
Approximate 
Blood/Tissue 
Volumes Drawn/Collected by 
Trial Visit and by Sample 
Types
Clarified that Serum β-Human 
Chorionic Gonadotropin will be 
drawn at Visit 1 and for 
subsequent study visits if urine 
pregnancy test is positive. 
Clarified parameter for testing 
to increase readability across 
protocol.
All
All 
Minor editorial changes as 
needed
To ensure consistency through 
the document. 
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase-II Study of MK-1029 added to Montelukast in Adults with 
Uncontrolled Asthma
Sponsor Product Identifiers
MK-1029
Montelukast
Trial Phase
Phase-II
Clinical Indication
Treatment of persistent asthma
Trial Type
Interventional
Type of control
Placebo
Route of administration
Oral
Trial Blinding
Double-blind
Treatment Groups

MK-1029 150 mg and montelukast 10 mg

MK-1029 150 mg matching-image placebo and montelukast 10 
mg
Number of trial subjects
Approximately 110 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 17
months from the time the first subject signs the informed consent until 
the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject participates in the trial for up to about 17 weeks from the 
time of signing the Informed Consent Form (ICF) through the final 
contact. After a pre-screen, pre-study and run-in phase (total of up to 9 
weeks), each subject receives assigned treatment for about 6 weeks. 
After the end of treatment, each subject is followed for 2 weeks.
A list of abbreviations used in this document can be found in Section 12.6.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a world-wide randomized, double-blind placebo-controlled, parallel-group trial of 
MK-1029 in subjects with persistent asthma who remain uncontrolled while being 
maintained on montelukast (may be referred to and/or used interchangeably with montelukast 
sodium), to be conducted in conformance with Good Clinical Practices. The purpose of this 
trial is to examine the effects of adding MK-1029 to montelukast therapy, versus maintaining 
montelukast alone, in adults with persistent asthma who have a specific genetic marker for a 
clinical efficacy response to MK-1029. In brief, subjects with persistent asthma are evaluated 
for eligibility (including the ability to taper off any pre-study asthma controller therapy other 
than montelukast). Eligible subjects whose asthma is uncontrolled during the run-in period 
(while receiving single-blind MK-1029 150 mg matching image placebo and montelukast
sodium 10 mg) enter a 6-week double-blind treatment period in which they are randomized 
to receive either MK-1029 150 mg and montelukast 10 mg or MK-1029 150 mg matching-
Randomization Ratio
1:1
 
 
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image placebo and montelukast 10 mg. Follow-up information is obtained approximately 2 
weeks after completing the double-blind treatment period. The study is summarized as 
follows: 

Pre-screening: At this visit, a blood sample is collected to assess for the presence of a 
specific genetic marker for a robust clinical efficacy response to MK-1029 (see Section 
4.2.1.1).

Pre-study (approximately 1 to 3 weeks): Any eligible subjects receiving Long-acting 
Beta-Agonist (LABA) therapy must discontinue the LABA at the start of this period.

Run-in (approximately 2 to 4 weeks): Subjects receive single-blind MK-1029 150 mg 
matching-image placebo and open-label montelukast 10 mg. Subjects taking asthma 
controller therapies prior to Visit 2 must discontinue or taper off these pre-study 
medications before randomization (according to a tightly specified approach) while 
receiving open-label montelukast 10 mg.

Treatment (approximately 6 weeks): Subjects receive double-blind treatment of MK-
1029 150 mg plus montelukast 10 mg; or MK-1029 150 mg matching-image placebo
plus montelukast 10 mg. 

Post-Treatment (approximately 2 weeks): Follow-up is scheduled to occur after the last 
dose of trial medication. All female subjects of child-bearing potential are to return to the 
clinic for a follow-up visit that includes a urine pregnancy test. All other subjects will 
receive a telephone contact for post-treatment evaluation.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
 
 
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Trial Diagram
2.2
The trial diagram is depicted in Figure 1
Figure 1
Trial Diagram
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
In adults who have persistent asthma that remains uncontrolled while receiving montelukast 
and who have a specific genetic marker for response to MK-1029:
Primary Objective: To demonstrate that MK-1029, compared with placebo, increases lung 
function when added to montelukast.
Hypothesis: When added to montelukast, treatment with MK-1029 is superior to placebo, as 
demonstrated by an increase in forced expiratory volume in one second (FEV1), measured as 
the average change from baseline at the end of Week 4 and Week 6 of treatment.
Secondary Objective(s) & Hypothesis(es)
3.2
1) Key Secondary Objective: To demonstrate that MK-1029, compared with placebo,
improves control of asthma when added to montelukast.
 
 
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Hypothesis: When added to montelukast, treatment with MK-1029 is superior to 
placebo, as demonstrated by a decrease in the percent of days with worsening asthma 
(%d-WA), measured daily during Week 3 to Week 6 of treatment (inclusive).
2) Objective: To characterize the safety and tolerability of MK-1029, when added to 
montelukast, during 6 weeks of treatment.
Exploratory Objectives
3.3
1) Objective: To explore the relationship between pre-specified single-nucleotide 
polymorphisms (SNPs) and response to the treatment administered. Genetic variation 
will be analyzed for association with clinical data collected in this study.
2) Objective: To explore the relationship between genetic variation and response to the 
treatment administered. Variation across the human genome will be analyzed for 
association with clinical data collected in this study.
4.0 BACKGROUND & RATIONALE
Background
4.1
MK-1029 is a potent and selective Chemoattractant Receptor-homologous molecule on Th2 
cells (CRTH2) receptor antagonist that is being developed as monotherapy and/or 
combination therapy with montelukast for chronic asthma. The availability of a novel, oral, 
potent antagonist of CRTH2, particularly in combination with montelukast, will offer 
asthmatic patients a treatment option that is both highly efficacious and convenient as an oral 
therapy, thus fostering better compliance and asthma control. 
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-1029.
Pharmaceutical and Therapeutic Background
4.1.1
MK-1029 is a specific inhibitor of CRTH2 (also known as DP2), a G protein-coupled 
receptor for the inflammatory mediator prostaglandin D2 (PGD2). The major cellular source 
of PGD2 in the human lung is the mast cell [1], which is recognized to be a major effector 
cell type in asthma. Cells that are known to express CRTH2 include eosinophils, T-helper 
cell type-2 (Th2) lymphocytes, basophils, and an innate lymphocyte thought to be the 
principal early producer of IL-13 [2]. In susceptible individuals, inhaled antigens interact 
with receptor-bound Immunoglobulin E (IgE) on the surface of mast cells, inducing 
clustering of IgE receptors. Clustered IgE receptors trigger the release of pro-inflammatory 
mediators including PGD2, which activates CRTH2 on eosinophils, basophils, and Th2 cells. 
Accumulating evidence indicates that agents that target CRTH2 may be beneficial in asthma. 
In an animal model, inhalation of PGD2 enhances eosinophilic and lymphocytic airway 
inflammation in a CRTH2-dependent fashion [3]. Additionally, over-expression of PGD 
synthase, an enzyme that catalyzes production of PGD2, leads to increased allergic airway 
inflammation and Th2 cytokines in transgenic mice [4]. In humans, PGD2 is found at high 
levels in bronchoalveolar lavage fluid of asthmatics [5]. Finally, recent clinical studies of 
other CRTH2 antagonists have suggested clinical efficacy in subjects with asthma [6]. In 
 
 
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contrast, clinical trials of compounds that antagonize the other recognized receptor of PGD 2, 
DP1, showed a lack of clinical efficacy, whether as a specific antagonist of DP1 [7], or as a 
dual antagonist of DP1 and CRTH2 [8]. Taken together, these findings are consistent with a 
potentially important role for PGD2 and for inhibition of one of its two receptors, CRTH2, in 
the treatment of asthma.
Based on studies designed to assess the potential for drug-drug interactions (DDI), early data 
have suggested that exposure of MK-1029 and its glucuronide metabolite may be increased 
by inhibitors of the OATP1B1 and OATP1B3 proteins. MK-1029 is not expected to be an 
OATP1B1 inhibitor at the proposed clinical dose. Based on in vitro data, MK-1029 is not 
expected to be a “victim” of an interaction with the major human CYP or UGT isoforms at 
the target concentrations expected in this trial. Montelukast, at the clinically recommended 
dose, is not expected to inhibit the hepatic uptake of MK-1029 based on both in vitro and in 
vivo drug interaction data. Refer to the Investigator’s Brochure (IB) for more detailed 
information.
Results from a Recently Completed Clinical Trial 
4.1.2
Refer to the Investigator’s Brochure (IB) for summaries of the primary results of all 
completed clinical trials data.
The primary efficacy results for Protocol 011 (P011), a 2-period crossover trial that assessed 
the addition of MK-1029 to montelukast in subjects with persistent asthma, are described in 
the IB: MK-1029 (versus placebo, when each was added to open-label montelukast) did not 
show significant efficacy in the primary analysis of lung function, measured as FEV 1, at the 
end of the 4-week treatment period, with an improvement of only 47mL (p=0.282).
Additional efficacy results have subsequently become available from P011, including from 
secondary pharmacogenetic analyses of the clinical efficacy data. The pharmacogenetic 
analyses assessed a set of approximately 70 SNPs that had been pre-specified for analysis in 
P011, based on available literature suggesting these SNPs could have a potential role in the 
biology of CRTH2 receptor antagonism for treatment of asthma. After P011 was unblinded, a 
closer examination of the data also revealed a baseline imbalance on efficacy measurements 
across treatment periods in one of the two crossover sequences in this study; therefore, a 
subsequent statistical adjustment for the baseline imbalance artifact was conducted. Finally, 
across the 70 pre-specified SNPs that were analyzed, a large treatment effect of MK-1029 
was discovered in association with the presence of 
at a SNP with the 
Reference SNP (rs) identifier number 
 In this 
pre-specified pharmacogenetic analysis, MK-1029 showed an improvement of 268mL in the 
29 subjects in P011 who had a genotype 
. 
This large treatment effect was significantly greater than the effect seen in the 74 subjects in 
P011 without this genotype, with a significant treatment-by-genotype interaction (including 
after Bonferroni adjustment), as shown in Figure 2.
 
 
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Figure 2
MK-1029 
Effect 
(when 
Added 
to 
Montelukast) 
in 
a 
Pre-Specified 
Pharmacogenetic Analysis.
Background on Montelukast 
4.1.3
Cysteinyl leukotrienes have been correlated with the pathophysiology of asthma and allergic 
rhinitis. Montelukast sodium is an antagonist of the cysteinyl leukotriene receptor type-1 
(CysLT1) receptor. It binds with high affinity and selectivity to the CysLT 1 receptor (in 
preference to other pharmacologically important airway receptors, such as the prostanoid, 
cholinergic, or beta-adrenergic receptor). Montelukast inhibits physiologic actions of 
cysteinyl leukotrienes at the CysLT1 receptor without agonist activity. In adults, oral 
montelukast 10 mg once daily in the evening is approved for prophylaxis and treatment of 
chronic asthma. 
Montelukast has been evaluated in randomized controlled clinical studies for treatment of 
asthma in approximately 2600 adult patients 15 years of age and older. In two similarly 
designed, 12-week placebo-controlled clinical studies, the only adverse experiences reported 
as drug related in 1% of patients treated with Montelukast and at a greater incidence than in 
patients treated with placebo were abdominal pain and headache. The incidences of these 
events were not significantly different in the two treatment groups. With prolonged 
treatment, the adverse experience profile did not change.
 
 
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Co-administration of MK-1029+Montelukast
In a bioavailability study assessing the combination of MK-1029 and montelukast (this 
combination is referred to as MK-1029A), two probe fixed-dose combination (FDC) 
formulations were compared with co-administration of the individual components. In 
Protocol 013, 24 healthy adult subjects received 3 treatments in a crossover design: a single 
MK-1029A FDC tablet (MK-1029 150 mg with montelukast sodium 10 mg) as a monolithic-
blend formulation, a single MK-1029A FDC tablet (MK-1029 150 mg with montelukast 
sodium 10 mg) as a bi-layer formulation, and co-administration of a single MK-1029 150 mg 
tablet with a montelukast sodium 10 mg tablet. The pharmacokinetic characteristics of each 
analyte (MK-1029 and montelukast) were very similar between the two test formulations. 
For MK-1029 and montelukast, the median Tmax of the monolithic tablet, the bi-layer tablet, 
and co-administration was 2.00 hours. Also, montelukast and MK-1029 exposures observed 
in this study when co-administered were similar to exposures observed in a previous drug-
drug interaction study. All treatments were deemed generally safe and were well tolerated by 
the subjects. There were no serious adverse experiences (SAEs) reported during this study 
and all adverse experiences (AEs) reported were mild and resolved prior to completion of the 
study. No subject was discontinued during the study due to adverse events. For all panels, 
there were no clinically important abnormalities in laboratory parameters, vital signs, and 
electrocardiogram (ECG) parameters. Refer to the Investigator’s Brochure (IB) for more 
detailed information.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
Asthma is a highly prevalent disease associated with significant morbidity and mortality, and 
accounting for high direct and indirect healthcare expenditures. World Health Organization 
(WHO) data currently estimate the prevalence of asthma to be 300 million individuals 
worldwide, with this number expected to increase to 400 million by 2025 [9]. This high 
disease burden is in part due to patients who are not well controlled on standard therapy [10].
In addition, compliance with standard inhaler therapy is relatively low. It is estimated that 
44.2% and 51.5% of patients who begin a combination and concurrent inhalational therapy, 
respectively, do not renew their initial prescription during the first year [11]. Alternative 
options to inhalers include oral agents, such as montelukast and zileuton, as well as 
methylxanthines such as theophylline; however, these agents are recognized to be less potent 
than inhaled agents. Therefore, there is a need for a new, well-tolerated oral agent that 
effectively treats asthma, either alone or in combination with available therapies, such as oral 
montelukast.
SNP+ Population 
4.2.1.1
Based on the presence of an identified genetic marker for the efficacy response to MK-1029 
(when added to montelukast), the efficacy data in this trial may demonstrate the utility of a 
highly specific predictor of a robust clinical response to treatment with MK-1029 for asthma, 
an approach using genotypic data for patient selection that is sometimes referred to as 
“personalized medicine” or “precision medicine”. 
 
 
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This trial will enroll subjects with a specific genetic marker for response to MK-1029, herein 
referred to as the SNP+ (“SNP positive”) population. As defined for this trial (see also 
Section 4.1.2) SNP+
SNP. Pre-screening in 
this trial uses pharmacogenetic testing to identify SNP+ patients. Only subjects who are 
SNP+ are eligible to continue into the pre-study period. Additionally, randomized allocation
to treatment is stratified 
 (i.e., having 
 copies
of the 
 SNP (see also Section 5.4). 
Age Range
4.2.1.2
The age range (18 to 65 years, inclusive) for this study is consistent with many clinical trials 
of similar design. Analysis of a large cohort of asthmatics [12] suggests that late-onset 
asthmatics are more likely to demonstrate sputum neutrophilia and are likely to be 
phenotypically distinct from asthmatics whose onset of asthma is <45 yr [13]; therefore, we 
have established 65 years of age as the upper limit age range for recruited subjects in this 
trial.
Lung Function
4.2.1.3
The inclusion criterion specifying ranges of lung function (e.g., FEV1 ≥55%-predicted and 
≤85%-predicted for subjects not
receiving controllers and 
≥60%-predicted and 
≤90%-predicted for subjects receiving controllers) is based on the following considerations: 
International treatment guidelines for asthma, including from the Global Initiative for 
Asthma (GINA), generally divide asthma treatments into one of two categories [9]: “Non-
controllers” are asthma medications that provide bronchodilation without treating the 
underlying inflammation of asthma; these medications include beta2-adrenergic agonists, 
both short-acting beta-agonists
(SABAs) and long-acting beta-agonists (LABAs). 
“Controllers” are asthma medications that can treat the underlying inflammation of asthma; 
these medications include corticosteroids (inhaled, oral or injected), anti-leukotrienes, 
methylxanthines, anti-IgE and/or other biologic therapies. The lower FEV1 limits in both 
controller and non-controller subjects were chosen to include subjects who are likeliest to 
conform to the target patient population for MK-1029. A slightly higher FEV1 criterion for 
subjects on controllers was chosen, under the presumption that patients receiving controllers 
as pre-study therapy may have underlying asthma that is more difficult to manage.
Rationale for Dose Selection/Regimen
4.2.2
A sheep model was used, initially, to determine MK-1029 exposures that reduce
inflammatory lung dysfunction after inhaled allergen challenge. Plasma levels of MK-1029 
that inhibit a pharmacodynamic (PD) marker for MK-1029 activity (surface expression of 
cluster of differentiation molecule 11b [CD11b], as an activation marker on eosinophils, in 
an ex-vivo PGD2 stimulation assay) were determined first. The degree of inhibition of the PD 
marker after exposure to MK-1029 was then examined versus the level of lung dysfunction 
induced by allergen challenge in sheep after exposure to MK-1029. This same approach was 
then applied in Phase-1 human data; first, establishing the relationship between plasma levels
of MK-1029 and the inhibition of ex-vivo expression of CD11b on eosinophils; and then,
examining lung function and sputum eosinophil counts in response to inhaled allergen 
 
 
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challenge in a Phase-1b study of subjects with allergic asthma. In Protocol 03 (P003, as fully 
described in the IB), a lung allergen challenge model was used to assess the effects of MK-
1029 60 mg and 500 mg. Both doses significantly inhibited the late bronchoconstrictive and 
inflammatory responses following inhaled allergen challenge. Maximal effects were seen at 
the 60 mg dose; i.e., no greater effects were seen with the 500 mg dose in this allergen 
challenge model. These clinical results were also examined versus the results for detailed 
pharmacokinetics (PK) assessment and for the CD11b PD marker. The available Phase-I data 
suggest that the 150 mg dose is at (or near) the plateau of the dose-response curve for 
efficacy, which supported selection of the 150 mg dose for use in P011 and Protocol 012 
(P012, as fully described in the IB). The margin of safety established in Phase-I trials (with 
doses up to 1000 mg) and in Phase-II trials further supports use of the 150 mg dose.
Specifically, no safety issues were identified with MK-1029 at doses of 150 mg (and lower)
administered once daily in P011 and P012, as fully described in the IB. Therefore, 150 mg 
once daily was chosen as the dose of MK-1029 for this trial. 
Rationale for the use of Placebo
4.2.2.1
Placebo during the Run-in Period
This study targets a population of subjects who have asthma that is inadequately controlled 
while receiving montelukast. Both to ensure that this population is correctly identified and to 
maintain blinding of randomized therapy during the treatment period, the trial medication 
administered during the run-in period is (single-blind) placebo for MK-1029 added to open-
label montelukast. As stated above, the risks of placebo treatment (during the run-in) are 
minimized by allowing subjects to continue their use of “as-needed” inhaled 
albuterol/salbutamol in addition to open-label treatment with montelukast and by providing 
subjects an action plan for deteriorating asthma (Appendix 12.9).
Placebo during the treatment period
To date, efficacy of MK-1029 has not been definitively established in asthmatics; therefore, a 
placebo comparison is necessary to ensure the validity of this study. The risks of placebo 
treatment are minimized by allowing all subjects to continue their use of “as-needed” inhaled 
albuterol/salbutamol in addition to open-label treatment with the asthma controller 
montelukast and by providing subjects an action plan for deteriorating asthma (Appendix 
12.9). In addition, should subjects demonstrate evidence of deterioration in their level of 
asthma such that they require more than one oral steroid rescue during the treatment period, 
they will be discontinued from the trial medication. 
Rationale for Endpoints
4.2.3
Efficacy Endpoints
4.2.3.1
The primary efficacy endpoint in this trial is a measure of lung function that is considered 
standard in asthma clinical trials, FEV1, which is known to have excellent measurement 
characteristics in various lung diseases and has been used as the basis for the product 
registrations of almost all asthma treatments now in wide clinical use. The key secondary 
efficacy endpoint, %d-WA, is a composite measure that combines subjective components 
 
 
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(e.g., symptoms scores reported by subjects in a daily e-Diary) and objective components
(e.g., lung function measured daily as peak expiratory flow) into a single endpoint that 
provides a daily quantitative assessment of asthma control. The definition of %d-WA used in 
this trial has been used in a number of asthma studies previously performed by Merck and 
published in the peer-reviewed literature (Note: in these older publications, this endpoint was 
referred to as “percent of days with asthma exacerbations”) [12,14,15,16]. 
The primary time period for evaluation of efficacy is during the final 4 weeks of the 6-week 
double-blind treatment period. Prior experience in P011 suggests that subjects begin to 
benefit from MK-1029 as early as 2 weeks from initiation of treatment. But, it is not expected 
that the treatment effect will plateau at the end of Week 2. Therefore, the primary efficacy 
assessment period for this trial begins at the start of Week 3 (i.e., after subjects have been
exposed to treatment for a full 2 weeks) and proceeds through the end of Week 6. In this 
way, the primary and secondary objectives both evaluate the effect of the final 4 weeks of 
treatment. 

Primary – FEV1: Spirometry is performed at visits scheduled every 2 weeks during the 
6-week treatment period.  Therefore, FEV1 data obtained at the last 2 visits during this 
period (i.e., at the end of Week 4 and Week 6, respectively) measure the cumulative 
effect over the last 4 weeks of treatment, and the endpoint is calculated based on the 
measurements at Week 4 and Week 6.

Key Secondary – %d-WA: This measure of asthma control is obtained daily. Therefore, 
this key secondary endpoint is calculated based on daily measurements obtained from the 
start of Week 3 through the end of Week 6, to measure the effect over the final 4 weeks 
of treatment. 
Safety Endpoints
4.2.3.2

Clinical and laboratory adverse experiences reported during each period of the trial. 

Change from baseline in vital signs parameters and change or percent change (as 
appropriate) from baseline in laboratory safety parameters at the end of treatment.
Planned Exploratory Biomarker Research
4.2.3.3
As described in Section 4.2.1.1, analysis of the SNP 
 SNP will be used as a key 
factor to define the groups being studied, in order to understand if this SNP is associated with 
efficacy of MK-1029 in this trial.  SNP 
 was initially selected for pre-specified analysis 
in P011 
 
The 
 SNP was determined to be an expression SNP 
(eSNP), meaning that it was shown to associate with gene expression levels, in multiple 
different data sets. Published eSNP data 
 
 Also, this SNP is located in a 
Deoxyribonucleic acid (DNA) loop that is highly transcribed in mast cells. Like basophils, 
mast cells are inflammatory cells that are known to be associated with asthma and to generate 
large amounts of inflammatory mediators in asthma, such as Prostaglandin D2 (which is 
 
 
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blocked by MK-1029) and Leukotriene D4 (which is blocked by montelukast). Based on all 
of these available data, 
 defines “SNP+” status. 
 
, is associated with 
long-term decline over time in the ratio of FEV1/ forced vital capacity (FVC) in asthmatic 
patients, but not in non-asthmatic patients; this result 
 was both genome-wide 
significant and replicated. Of interest, 
 Additional fine-mapping analyses in the region of the 
 SNP have 
been performed, using data from P011. From these post-hoc analyses, two other SNPs have 
been identified that are in linkage disequilibrium 
and are associated with a large 
FEV1 effect in P011, similar to that seen 
(Section 4.1.2, Figure 2); these SNPs 
are identified as 
 
Because these three SNPs 
 are considered secondary to 
 
they are not part of the definition of “SNP+” status in this trial.
Planned Genetic Analysis
Understanding genetic determinants of drug response is an important endeavor during 
medical research. This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation. If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
In addition to evaluating variation across the human genome, SNPs 
 
 also of specific interest and so have been pre-specified for planned genetic 
analysis in this trial. 
Future Biomedical Research
4.2.3.4
The Sponsor will conduct Future Biomedical Research on DNA specimens collected for future 
biomedical research during this clinical trial.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of this Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
 
 
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Some subjects in the trial may show a modest deterioration of asthma during the trial period. 
The trial design ensures that subjects’ safety will be carefully monitored during the Run-in 
Period and the double-blind Treatment Period. Each subject will have access to 
bronchodilator rescue medication to be used as-needed. Instructions on when to use rescue 
medications will be provided to the subject. Trial subjects will use their peak expiratory flow 
(PEF) meter (a lung function measurement device) as a self-monitoring tool, as guided by the 
Action Plan for Deterioration of Asthma (Appendix 12.9), to increase awareness of asthma 
control and to alert the subjects to changes in lung function that might require medical 
intervention. Subjects will be given an individualized written action plan containing very 
specific instructions on actions to take if symptoms are increased and/or PEF is decreased. 
The protocol also stipulates rules for calculating stability limits based on PEF measurements, 
which the investigator will use during the course of the trial to help ascertain if there is a 
need for asthma rescue medication and/or additional medical management. Finally, subjects 
will be provided with contact information for physician/medical support at all times and will 
have round-the-clock access to physicians.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with persistent asthma between the ages of 18 and 65 will be enrolled 
in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Be able to provide written informed consent for the trial and may also provide consent for 
Future Biomedical Research. However, the subject may participate in the trial without 
participating in Future Biomedical Research.
2. Be female or male between 18 and 65 years of age, inclusive.
3. Have a consistent clinical history, for at least one year, of symptoms of persistent asthma 
that may include, but are not limited to, dyspnea, wheezing, chest tightness, cough, 
and/or sputum production.
4. Must be willing to provide blood sample for SNP testing at Visit 1.
5. Must have documented SNP+ test result prior to Visit 2.
 
 
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Contraception 
6. Not be pregnant (as evidenced by negative serum pregnancy test for subjects of 
childbearing potential) or breastfeeding and does not plan to become pregnant for the 
duration of the trial and post-treatment follow-up period.
7. If of reproductive potential:  Agree to remain abstinent or to use (and/or have their 
partner use) 2 acceptable methods of birth control within the projected duration of the 
trial. Accepted methods of birth control are: intrauterine device (IUD), diaphragm with 
spermicide, contraceptive sponge, condom, vasectomy, hormonal contraceptives. 
A female subject who is not of reproductive potential is eligible without requiring the use 
of contraception. A female subject who is not of reproductive potential is defined as one 
who has either 1) reached natural menopause (defined as 6 months of spontaneous 
amenorrhea with serum follicle stimulating hormone (FSH) levels in the postmenopausal 
range as determined by the laboratory, or 12 months of spontaneous amenorrhea), 2) 6 
weeks post-surgical bilateral oophorectomy with or without hysterectomy, or 3) bilateral 
tubal ligation.
A male subject who is not of reproductive potential is eligible without requiring the use 
of contraception. A male subject who is not of reproductive potential is defined as: one 
who has undergone a successful vasectomy. A successful vasectomy is defined as: (1) 
microscopic documentation of azoospermia, or (2) a vasectomy more than 2 years ago 
with no resultant pregnancy despite sexual activity post-vasectomy.
Note: If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
Pulmonary function test (PFT)
8. Have acceptable lung function at Visit 2 and Visit 4: 
8.1 FEV1 ≥55% and ≤85% of the predicted value (or, ≥60% and ≤90% of the predicted 
value if subject is receiving controllers) at Visit 2, after withholding inhaled beta-
agonist 
bronchodilators 
prior 
to 
spirometry 
(see 
section 
5.5.1); 
AND
8.2 FEV1 ≥50% and ≤85% of the predicted value at Visit 4, after withholding inhaled 
beta-agonist bronchodilators prior to spirometry (see section 5.5.1).
9. Have evidence of reversibility of airway obstruction, defined as an increase in FEV1 of at 
least 12% and at least 200mL when measured 10 to 30 minutes following short-acting
beta-agonist 
(SABA) 
administration, 
after 
withholding 
inhaled 
beta-agonist 
bronchodilators prior to spirometry (see section 5.5.1).  
NOTE: For subjects who are not on controllers at Visit 2, reversibility is documented 
once during Visit 2 or Visit 3; for subjects who are on controllers at Visit 2, reversibility 
is documented once during Visit 2 or Visit 4.
 
 
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Asthma Medications Use
10. Have a history of asthma treatment, prior to Visit 1, that is in one of two categories (see 
section 4.2.1.3):
10.1
Controllers: Receiving stable doses of low- or medium-dose ICS, combination 
ICS/LABA, and/or other asthma controller medications; and (based on 
investigator’s judgment) can tolerate tapering of these controllers (e.g., ICS) or 
discontinuing these controllers (i.e., non-ICS) while receiving montelukast 10mg 
once daily (QD) starting at Visit 3; OR
10.2  Non-controllers:  Not receiving asthma controller medications, and using only 
“as-needed” inhaled SABAs, for ≥4 weeks prior to Visit 1.
11. Agree at Visit 3 to discontinue controllers (e.g., leukotriene antagonists other than 
montelukast), or taper them (e.g., ICS) over 2-4 weeks (as described in Appendix 12.10). 
Also, agree at Visit 3 to begin montelukast 10 mg QD.
12. Have a daytime and nocturnal SABA administration average ≥1 puff per day, as recorded 
on the subject’s e-Diary for the last 7 days prior to Visit 4.
13. Have an ACQ-6 score meeting the following requirements. 
13.1 Non-controllers:  At Visit 2, must have an ACQ-6 score ≥1.5 and a score between 1 
and 6 for Question #6. At Visit 4, must have an ACQ-6 score ≥1.5.
13.2 Controllers: Visit 4 must have an ACQ-6 score ≥1.5.
Trial-specific criteria
14. Be a non-smoker or is a non-smoker for at least 1 year, with a smoking history of no 
more than 10 pack-years (i.e., 1 pack [20 cigarettes] per day for 10 years) as evaluated at 
Visit 2.
15. Have a Body Mass Index (BMI) between 15 and 40 kg/m2 inclusive (BMI =weight in 
kg/[height in meters]2) (Appendix 12.5).
16. Be judged to be in stable health (except for his/her asthma) on the basis of medical 
history, physical examination, and routine laboratory data (see Table 6), and appears able 
to successfully complete this trial.
17. Demonstrate at least 80% compliance with self-administration of trial medication and at 
least 80% compliance with completion of the e-Diary (to record symptoms, SABA use, 
and PEF) between Visit 3 and Visit 4.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Is, in the opinion of the investigator, mentally or legally incapacitated preventing 
informed consent from being obtained, unable to read or comprehend written material, or 
unable to comply with the study procedures or protocol.
2. Intends to move or anticipates missing any clinic visit days.
 
 
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3. Has participated in a clinical trial involving an investigational drug within the 4 weeks 
prior to Visit 1.
Spirometry, also known as Pulmonary function test (PFT)
4. Is unable to perform acceptable, repeatable spirometry.
5. Has evidence of another clinically significant, active pulmonary disorder, such as 
bronchiectasis or COPD, documented by history, physical examination, or chest x-ray.
6. Has been treated in an emergency room for asthma within 4 weeks of Visit 1 or has been 
hospitalized for asthma or respiratory condition within 2 months prior to Visit 1.
7. Has had an upper respiratory tract infection (viral or bacterial) within 1 month prior to 
Visit 1.
8. Has evidence of active, clinically significant sinus disease within 2 weeks prior to Visit 1.
9. Experiences a clinically significant deterioration of asthma between Visit 2 and Visit 4. A
significant deterioration of asthma is defined as one or more of the following:
9.1 Decrease in absolute FEV1 (in L) by 20% or more from the FEV1 at Visit 2;
9.2
Decrease in %-predicted FEV1 to less than 50% of the predicted value; 
9.3
Clinical asthma exacerbation requiring emergency treatment, hospital admission 
(serious AE), or treatment with additional asthma medication (other than SABAs).
General Medical
10. Has a recent history (within 3 months of Visit 1) of myocardial infarction, congestive 
heart failure, or uncontrolled cardiac arrhythmia; or of a clinically significant psychiatric 
disorder, other than stable depression.
11. Is currently a regular user or a recent past abuser (within the past 5 years) of alcohol 
(>14 drinks/week) or illicit drugs, as evaluated at Visit 2.
12. Has undergone any major surgical procedure within 4 weeks prior to Visit 1.
13. Has donated a unit of blood within 2 weeks prior to Visit 1 or intends to donate a unit of 
blood at any time during the course of this study.
14. Has a history of HIV.
15. Is hypersensitive or intolerant to inhaled beta-agonists, leukotriene antagonists, 
leukotriene synthesis inhibitors, or any of their formulation components, including 
lactose and its metabolite, galactose.
16. Has evidence of uncontrolled hypertension, defined as systolic >160 mmHg and/or 
diastolic >100 mmHg, during at least 2 of the 3 study visits (Visit 2, Visit 3, and Visit 4).
17. Has a clinically unstable disease of the ophthalmologic, neurological, hepatic, renal, 
connective tissue, genitourinary, gastrointestinal, cardiovascular or hematologic systems.
18. Has a history of any illness that would require treatment with an excluded medication, 
could be immediately life threatening (e.g., ventricular arrhythmia, neoplasia, 
incompletely cured or treated in the last 3 months], poorly-controlled diabetes mellitus), 
 
 
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would pose a restriction on participation or successful completion of the trial, or would 
pose an additional risk to the subject on administration of trial medication.
19. Has a history of malignancy ≤5 years prior to signing informed consent except for 
adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
20. Has any of the following abnormalities on Visit 1 laboratory studies:
Table 1
Abnormal Lab Results at Visit 1
Lab Result
Exclusion Value
Creatinine 
≥1.5 mg/dL
Hemoglobin
<11 g/dL
WBC count
<3000/mm3
Platelet count
<100,000/mm3
Alanine aminotransferase (ALT) †
>1.5 times the upper limits of normal (ULN)
Aspartate aminotransferase (AST) †
>1.5 times the upper limits of normal (ULN)
†Note: For the ALT and/or AST parameters, one retest will be allowed for subjects at Visit 1, if values 
are >1.5 x ULN and ≤2 x ULN.
21. Has had an electrocardiogram (ECG), obtained at screening or at any point prior to 
randomization at Visit 4, which demonstrates a clinically significant or unexplained 
abnormality that requires further diagnostic evaluation or intervention (e.g., new 
clinically significant arrhythmia or a conduction disturbance).
22. Has taken or is taking any of the below prohibited medications:
Table 2
Prohibited Medications 
Medication
Timing of Last Dose
SABAs other than albuterol/salbutamol
Throughout the study
Initiation of immunotherapy (“allergy shots” or sublingual 
immunotherapy)
At least 6 months prior to Visit 2
ICS high dose
At least 6 months prior to Visit 2
Omalizumab or other biological agents
At least 4 weeks prior to Visit 2
Systemic corticosteroids (e.g., oral, intravenous, intramuscular, 
intra-articular or rectal)
At least 4 weeks prior to Visit 2
Digoxin, digitoxin
At least 2 weeks prior to Visit 2
Inhibitors or substrates of OATP1B1 and OATP1B3: atazanavir, 
bosentan, clarithromycin, cyclosporine, gemfibrozil, lopinavir, 
methotrexate, paclitaxel, rifampin
(Please see Table 4:  OATP1B1/OATP1B3 inhibitors/substrates 
that are permitted)
At least 2 weeks prior to Visit 2
Inhaled long- or short-acting anticholinergic agents
At least 2 weeks prior to Visit 2
LABA (see also Section 5.5.1)
At least 12 hours prior to Visit 2
Oral controllers (e.g., theophylline)
After Visit 3
ICS low/medium dose
Between Visit 3 and Visit 4 
(following controller tapering)
 
 
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Specific medications, although not listed individually, are excluded if they are used to 
treat conditions that are excluded by the protocol. However, if a patient received an 
excluded therapy after being randomized that is not explicitly excluded in the protocol, 
the investigator will determine based on his/her clinical judgment if the patient may 
continue in the study.
23. Is known to be sensitive to or has not had previous exposure to aspirin or non-steroidal 
anti-inflammatory drugs.
24. Has previously been randomized in a study and received MK-1029.
25. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
Trial Treatment(s)
5.2
The treatments to be used in this trial are outlined below in Table 3.
Table 3
Trial Treatment
Trial Medication
Dose/Potency
Dose 
Frequency
Route of 
Administration
Treatment 
Period
Use
MK-1029
Matching-image 
Placebo 
Placebo for 150 
mg 
QD
Oral
Run-in
Experimental
Montelukast
sodium
10 mg
QD
Oral
Run-in
Standard of 
care
MK-1029     
150 mg  
QD
Oral
Treatment  
Experimental  
MK-1029 
Matching-image 
Placebo
Placebo for 150 
mg
QD
Oral
Treatment
Experimental
Montelukast
sodium
10 mg
QD
Oral
Treatment
Standard of 
care
Albuterol/ 
Salbutamol†
90 μg – 100 μg
per inhalation
1 or 2 
inhalations 
QID PRN
Inhaled
Run-in & 
Treatment
Rescue 
medication
† Will be sourced locally, all other supplies will be provided by Sponsor.
A subject who meets all eligibility criteria enters the placebo run-in period to receive MK-
1029 150 mg matching-image placebo (in a single-blind fashion) and open-label montelukast
10 mg. Although the investigator is aware that the study drug during this period is placebo, 
“single-blind” requires that the subject is NOT told that the content of the study drug during 
this period is placebo.
The first dose of double-blind trial treatment is administered at the trial site at Visit 4.  
Trial medication supplies are packaged in 2 bottles.  One bottle contains open-label 
montelukast sodium 10 mg. The other bottle contains MK-1029 150 mg or matching-image
placebo tablets.
 
 
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection
5.2.1
Dose Selection (Preparation)
5.2.1.1
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
Timing of Dose Administration
5.2.2
Subjects will be instructed to take 1 tablet from each bottle once daily in the evening at 
bedtime with or without food, throughout the duration of the run-in and treatment period of 
the study, with the exception of Visit 3 and Visit 4.
At Visit 3, dosing of trial medication may be witnessed as per site standard operating 
procedures (SOPs) or local requirements in the morning at the clinic. No evening dose will 
be administered on the day of Visit 3.
At Visit 4, dosing of trial medication will be administered as a witnessed dose in the morning 
at the clinic. No evening dose will be administered on the day of Visit 4.
All subsequent trial medication doses by the subject (i.e. unsupervised at home) will be 
administered once daily in the evening at bedtime with or without food
Trial Blinding 
5.2.3
Prior to randomization, patients will receive MK-1029 150 mg matching-image placebo. A 
single-blinding technique will be used. The single-blind technique is specific to the period 
between Visit 3 and Visit 4. MK-1029 150 mg matching-image placebo will be packaged so 
that blinding is maintained. The subject will not know the treatment they are administered;
however, the investigator and Sponsor personnel or delegate(s) who are involved in the 
treatment or clinical evaluation of the subjects will be aware of the group assignments.
A double-blinding technique with in-house blinding will be used.  MK-1029 150 mg and the 
MK-1029 150 mg matching-image placebo will be packaged identically so that blinding is 
maintained.
The subject, the investigator and Sponsor personnel or delegate(s) who are 
involved in the treatment or clinical evaluation of the subjects are unaware of the group 
assignments.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization or Treatment Allocation
5.3
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 2 treatment arms.  
Subjects will be assigned randomly in a 1:1 ratio to either MK-1029 150 mg plus
 
 
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montelukast sodium 10 mg or MK-1029 150 mg matching-image placebo plus montelukast 
sodium 10 mg.
Stratification
5.4
Treatment allocation/randomization will be stratified according to the number 
 
, yielding two strata:
1.
2.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Prior/Concomitant Beta-Agonist Bronchodilator Use
5.5.1
Inhaled bronchodilator medications must be restricted prior to clinic visits, as follows:
1. Inhaled SABA, such as albuterol/salbutamol, for at least 6 hours before any clinic visit;
2. Inhaled LABA administered twice daily, such as salmeterol or formoterol, for at least 
12 hours before Visit 2;
3. Inhaled LABA administered once daily, such as vilanterol or indacaterol, for at least 
24 hours before Visit 2.
If any of the above inhaled beta-agonist medications are required within the specified time 
prior to a visit, the subject should notify the investigator and the visit should be rescheduled. 
Compliance with respect to the withholding of medications will be noted on the case report 
form or electronic case report form.  
Use of any inhaled SABA other than albuterol/salbutamol is prohibited during this study. Use 
of any beta-agonist bronchodilator other than by the inhaled route is also prohibited. It is 
expected that after Visit 2, subjects will no longer be using any LABA therapies.  
Prior/Concomitant Inhaled Corticosteroid (ICS) Use
5.5.2
A subject, who has successfully met the criteria for Visit 1 and has been on a stable dose of 
low or medium ICS or combination ICS/LABA (any dose) for at least 4 weeks prior to Visit 
2 can be screened to determine eligibility. For subjects taking combination ICS/LABA prior 
to Visit 2, they will be required to discontinue the LABA component at Visit 2 while 
continuing to receive an ICS component (until ICS tapering begins at Visit 3). If eligible at 
 
 
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Visit 3, these subjects must be able to tolerate tapering off ICS while taking montelukast 10 
mg QD. 
Maximal permitted daily doses* of ICS at screening are as follows:  
•
1000 μg beclomethasone CFC
•
500 μg beclomethasone HFA
•
800 μg budesonide
•
2000 μg flunisolide
•
500 μg fluticasone propionate
•
100 μg fluticasone furoate
•
<800 μg mometasone furoate
•
2000 μg triamcinolone acetonide
•
320 μg ciclesonide
*Note: These doses correspond to the approximate doses delivered to the lung, rather 
than the actuated doses.
Study subjects may not use ICS or combination ICS/LABA, at any dose, after they are 
randomized into the study at Visit 4. 
Allowed Asthma Therapy
5.5.3
Subjects are permitted to use inhaled albuterol/salbutamol throughout the study on an “as-
needed” basis for relief of asthma symptoms. Subjects are encouraged to decrease their use 
of albuterol/salbutamol if their asthma has improved.
In the event of significant deterioration of asthma, an action plan for treatment and 
continuation of subjects in the study is outlined in Appendix 12.9.
Allowed Allergic Rhinitis and Immunotherapy Medications
5.5.4
Intranasal corticosteroids will be allowed, if the patient has been on a stable dose for at least 
4 weeks prior to Visit 2. The dose must remain constant throughout the study. Intranasal 
cromolyn or nedocromil will be permitted as needed during the study.
Non-sedating systemic antihistamines with low anticholinergic effects will be allowed 
throughout the study, as will oral or nasal decongestants.
Immunotherapy (e.g., allergy shots or sublingual immunotherapy), will be allowed if the 
subject has been on a stable dose of immunotherapy for at least 6 months prior to Visit 2. 
Prohibited Medications
5.5.5
Specific medications, although not listed individually, are excluded if they are used to 
treat conditions that are excluded by the protocol. However, if a patient received an 
excluded therapy after being randomized that is not explicitly excluded in the protocol, 
the investigator will determine based on his/her clinical judgment if the patient may 
continue in the study. 
 
 
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1. The following inhibitors or substrates of OATP1B1 and OATP1B3 are prohibited at 
any dose: atazanavir, bosentan, clarithromycin, cyclosporine, gemfibrozil, lopinavir, 
methotrexate, paclitaxel, rifampin.
2. The following OATP1B1/OATP1B3 inhibitors or substrates are permitted, provided 
that the daily dose (alone, or as part of a fixed-dose combination) is less than or equal 
to the indicated dose. Because this list is not comprehensive, the investigator should 
use his/her medical judgment when a subject presents with an OATP1B1/OATP1B3 
inhibitor or substrate not described in Table 4, or call the Sponsor Clinical Monitor 
for clarification:
Table 4
OATP1B1/OATP1B3 Inhibitors/Substrates that are Permitted
Drug
Maximum Allowed Daily Dose
atorvastatin
40 mg
cefoperazone
2 g
enalapril
20 mg
erythromycin
1 g
olmesartan
20 mg
pitavastatin
2 mg
pravastatin
20 mg
rosuvastatin
20 mg
simvastatin
20 mg
telmisartan
40 mg
valsartan
160 mg
caspofungin
70 mg by mouth
glyburide
20 mg
repaglinide
16 mg
torasemide
200 mg
3. Beta-adrenergic receptor blocking agents in individuals known to be sensitive to these 
compounds or who have not had previous exposure.
4. Aspirin and nonsteroidal anti-inflammatory medication in subjects known to be 
sensitive or subjects who have not had previous exposure to these compounds.
Subjects who, in the assessment by the investigator and after consultation with the Sponsor, 
require the use of any of the aforementioned treatments for clinical management should be 
removed from the trial. 
There are no prohibited therapies during the post-treatment follow-up period.  
Rescue Medications & Supportive Care
5.6
Throughout the trial, each subject will have access to a supply of bronchodilator rescue 
medication (to be purchased locally by the site) for use on an as-needed basis. Short-Acting 
Beta-Agonist (SABA) via metered-dose inhaler (MDI), as albuterol/salbutamol 90 or 100 μg
 
 
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per inhalation, will be provided by sites to subjects for potential use at home as a rescue 
medication. The SABA is to be used in accordance with the product labeling.

The subject should be advised to take SABA on a rescue/as-needed basis only, and not on 
a regular basis in absence of asthma symptoms. However, use of SABA as a prevention 
for exercise-induced bronchospasm (EIB) is permitted, only if previously taken in this 
manner, and should be discussed with the investigator at the Pre-study visit. Because the 
use of SABA when taken as prevention for EIB is not considered rescue use, it should not
be captured/recorded by subjects in the e-Diary for the purpose of assessing daily asthma 
control.

Once the subject consents to trial participation, the use of the SABA should be withheld 
at least 6 hours before each subsequent visit. If the subject used any SABA within 
6 hours of the scheduled spirometry assessment at the Pre-study visit (Visit 2), the 
assessment should be delayed (or rescheduled) until the appropriate washout is met. If the 
subject requires the use of SABA within 6 hours prior to a subsequent visit, they should 
be instructed to take the SABA and call the office to reschedule the visit.

If the subject requires more than 8 inhalations per day on any 2 consecutive days, the 
subject/caregiver should be advised to contact the investigator.

Use of SABA in powder form (in lieu of the MDI provided) is prohibited.
Diet/Activity/Other Considerations
5.7
Diet/Activity/Awake/Sleep Cycle
5.7.1
Subjects will be allowed to consume their usual diet throughout the study and engage in their 
usual level of exercise throughout the study. However, it is recommended that subjects 
refrain from strenuous exercise for at least 72 hours prior to clinic visits during which blood 
samples will be collected (Appendix 12.4).
It is recommended that subjects maintain a constant day/night, awake/sleep cycle in order to 
reduce the diurnal variation that can be seen in pulmonary function testing.
Caffeine
5.7.2
Subjects are asked not to change their usual consumption of caffeine once enrolled in the 
study. It is recommended that subjects refrain from the use of caffeinated beverages or food 
for at least 8 hours prior to each clinic visit in order to reduce a potential confounding effect 
on pulmonary function testing.
Contraception and Pregnancy Testing
5.7.3
A subject who is of reproductive potential agrees to remain abstinent or use (and/or have 
their partner use) 2 acceptable methods of birth control within the projected duration of the 
study. Acceptable methods of birth control are: intrauterine device (IUD), diaphragm with 
spermicide, contraceptive sponge, condom, vasectomy, hormonal contraceptives.
A female subject who is not of reproductive potential is eligible without requiring the use of 
contraception. A female subject who is not of reproductive potential is defined as: one who 
 
 
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has either 1) reached natural menopause (defined as 6 months of spontaneous amenorrhea 
with serum FSH levels in the postmenopausal range as determined by the laboratory, or 12 
months of spontaneous amenorrhea), 2) 6 weeks post-surgical bilateral oophorectomy with or 
without hysterectomy, or 3) bilateral tubal ligation.
A male subject who is not of reproductive potential is eligible without requiring the use of 
contraception. A male subject who is not of reproductive potential is defined as: one who has 
undergone a successful vasectomy. A successful vasectomy is defined as: (1) microscopic 
documentation of azoospermia, or (2) a vasectomy more than 2 years ago with no resultant 
pregnancy despite sexual activity post-vasectomy.
If there is any question that a subject will not be reliable in the use of these 
contraceptive methods, he/she should not be entered into the study.
Subjects must be completely informed of the unknown risks of pregnancy and agree not to 
become pregnant during the time they are participating in this study. In the case of a positive 
pregnancy test, study drug will be stopped immediately, and the patient will be discontinued. 
The site will contact the subject at least monthly and document the patient’s status until the 
pregnancy has been terminated or completed. The outcome of the pregnancy will be reported 
to the Merck Clinical Monitor without delay.
All females participating in the study will have a serum beta-human chorionic gonadotropin 
(β-hCG) or urine pregnancy test at each study visit as indicated in the Study Flow Chart, 
beginning at entry with Visit 1 and ending with the Post-treatment Visit (Visit8). All females 
who discontinue before completion of the Treatment period will return 14 days after the 
Discontinuation Visit for a urine pregnancy test. Subjects who become aware they are 
pregnant between study visits should contact the site immediately and stop trial medication.
Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
Table 5 provides reasons why a subject must be discontinued from treatment but may 
continue to be monitored in the trial, as well as reasons why a subject must be discontinued 
from treatment and the trial.
 
 
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Table 5
Discontinuation Scenarios 
Reason for Discontinuation Scenario
Action
The subject or legal representative (such as a parent or legal 
guardian) withdraws consent.
Discontinue from Treatment and Trial
The subject’s treatment assignment has been unblinded by 
the investigator, Merck subsidiary or through the emergency 
unblinding call center.
Discontinue from Treatment and Trial
The subject has a medical condition or personal 
circumstance which, in the opinion of the investigator and/or 
Sponsor, places the subject at unnecessary risk through 
continued participation in the trial or does not allow the 
subject to adhere to the requirements of the protocol.
Discontinue from Treatment and Trial
The subject has a confirmed positive serum pregnancy test
(Refer to Section 7.2.2 for procedures).
Discontinue from Treatment 
(may continue to monitor in the trial)
The subject develops persistent elevations in ALT or AST (2 
consecutive measurements) ≥3 times ULN (Refer to Section 
7.2.3.2). 
Discontinue from Treatment 
(may continue to monitor in the trial)
Significant deterioration of asthma that requires
discontinuation from trial medication based on one or more 
of the following:
•
decrease in %-predicted FEV1 to less than 50% of 
predicted normal;
•
decrease in absolute FEV1 (L) of ≥20% from baseline (at 
randomization, Visit 4). 
Discontinue from Treatment 
(may continue to monitor in the trial)
The subject requires therapy with any excluded medication 
(including parenteral corticosteroids).
Discontinue from Treatment 
(may continue to monitor in the trial)
The subject has received any rescue therapy other than that 
outlined in Appendix 12.9.
Discontinue from Treatment 
(may continue to monitor in the trial)
Discontinuation due to asthma exacerbation that does not 
respond to the Action Plan for Deterioration of Asthma.
Discontinue from Treatment 
(may continue to monitor in the trial)
Discontinuation from trial medication is permanent. Once a subject is discontinued, he/she 
shall not be allowed to restart trial medication.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.11
There are no pre-specified criteria for terminating the trial early.
 
 
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1 Discontinuation Visit is for subjects who are discontinued after randomization, but prior to completion of Visit 7.
2 Female subjects of child-bearing potential must come to the clinic for a urine pregnancy test.  All other subjects are expected to complete the post-treatment 
follow-up visit via telephone.
3
Informed consent must be obtained prior to any Visit 1 procedures.
4
The investigator will be responsible for providing and ensuring subjects have adequate supplies of inhaled SABA (albuterol/salbutamol).
5
Trial medication will be witnessed in the clinic the morning of Visit 4 and may be witnessed in the clinic per site SOPs or local requirements the morning of 
Visit 3; no evening dose will be administered on these visit days. Subjects will be instructed to administer all subsequent doses, outside of the clinic, in the 
evening at bedtime with or without food.
6
Height should only be measured once (at Visit 2 only).
7
Vital signs and ECG should be obtained prior to administration of albuterol/salbutamol (reversibility).
8
Only performed on non-controller subjects at Visit 2.
9
Only to be performed at Visit 3 for subjects who discontinued LABA at Visit 2
10 Spirometry testing should be initiated between 6 AM and 10 AM. Spirometry measurements for a given subject should occur at about the same time during 
each visit
11 Spirometry measurements for a given subject should occur at about the same time during each visit. Post beta-agonist spirometry will be determined by 
administering 4 puffs of albuterol/salbutamol through a spacer device, then measuring spirometry 10 to 30 minutes after albuterol/salbutamol administration 
(Appendix12.7).  Subjects who meet pre-defined reversibility criteria at one visit need not repeat reversibility testing at a later visit.
12 Laboratory safety blood test samples should be collected between 6 AM and 10 AM at each visit. Safety blood test samples for a given subject should occur 
about the same time during each visit.
13 A negative pregnancy test (serum β-hCG) at Visit 1 (and prior to Visit 4) must be confirmed for all female subjects of child-bearing potential.  
14 If urine pregnancy test is positive at any point during the trial, a serum β-hCG test is required for confirmation.
15 The blood sample is drawn for genotyping 
. 
16 This sample will be drawn for 
 genotyping and for planned analysis of the association between genetic variants in DNA and drug 
response. Data analysis will be limited to 
 genotyping if the IRB/IEC does not approve of, or if there is a documented law or 
regulation prohibiting, the planned analysis of the association between DNA variations and drug response. Leftover extracted DNA will be stored for future 
biomedical research if the subject signs the FBR consent.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
Informed Consent
7.1.1.1
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
General Informed Consent
7.1.1.1.1
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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Consent and Collection of Specimens for Future Biomedical Research
7.1.1.1.2
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
Inclusion/Exclusion Criteria
7.1.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial (Section 5.1).
Subject Identification Card
7.1.1.3
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
7.1.1.4
A medical history will be obtained by the investigator or qualified designee. This will include 
a full medical history for the 5 years prior to Visit 1. 
Asthma Baseline Profile 
7.1.1.4.1
Subjects will also be asked to provide information on their asthma history and related 
conditions for completion of an Asthma Baseline Profile. The investigator or qualified 
designee will obtain medical history information about asthma to allow completion of an 
Asthma Baseline Profile at Visit 2.
Prior and Concomitant Medications Review
7.1.1.5
Prior Medications
7.1.1.5.1
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject
within 4 weeks or longer as appropriate prior to Visit 2. Any prior medications are to be
recorded on the electronic Case Report Form (eCRF). 
Section 5.1.3 provides a list of medications prohibited prior to Visit 2.
 
 
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Concomitant Medications
7.1.1.5.2
The investigator or qualified designee will review and record concomitant medications, if 
any, taken by the subject during the trial. Any concomitant therapy taken by the subject 
during the trial is to be recorded on the eCRF. 
Section 5.5 outlines concomitant medications allowed and prohibited during the ongoing 
trial.
Assignment of Screening Number
7.1.1.6
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened more than once will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening visit requirements 
(screening/rescreening) are provided in Section 7.1.5.1.
Assignment of Treatment/Randomization Number
7.1.1.7
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Trial Compliance
7.1.1.8
Interruptions from the protocol specified study medication for compliance ≤80% require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on subject management.
Administration of trial medication may be witnessed by the investigator and/or trial staff at
Visit 3 per site SOPs or local requirements for single-blind trial medication and will be 
witnessed at the Treatment Visit 4 for double-blind trial medication.  
Study Procedures to be Reviewed with Subject
7.1.1.9
In the performance of this trial, there are a number of procedures that must be discussed with 
subjects, to ensure correct performance of procedures and appropriate collection of trial data. 
These include e-Diary use (for collection of data on SABA use, PEF, asthma symptoms, 
additional measures to manage deterioration of asthma , as well as triggering of alerts), 
appropriate use of medications during the trial, and collection of data regarding adverse 
experiences and other patient-reported outcomes.
e-Diary
7.1.1.9.1
The e-Diary will be used to collect asthma symptoms (daytime and nighttime), inhaled 
SABA (albuterol/salbutamol) use (daytime and nighttime), AM and PM PEF, and additional 
 
 
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measures to manage deterioration of asthma (i.e., oral steroids, unscheduled physician visits, 
emergency department visits or hospitalizations) throughout the study. The subject will 
complete all data fields in the electronic diary every morning and evening. The subject 
should be instructed to bring the e-Diary to all visits to confirm that the devices are used 
correctly and are working properly. The importance of maintaining a current and accurate e-
Diary will be reinforced by the study staff.
All subjects must demonstrate proper use of the e-Diary, including adequate compliance. At 
Visit 2, the subject will be given an e-Diary to be completed twice daily and returned at the 
next visit. Before giving the e-Diary to the subject, the study coordinator is responsible for 
explaining to the subject the e-Diary questions and the proper method for entering data into 
the e-Diary twice daily. Subjects should be instructed to bring the e-Diary to the clinic at 
each visit. At each visit (Visit 3 through Visit 7 and/or discontinuation), the study coordinator 
must carefully review the e-Diary entries with the subject to ensure there is adequate 
comprehension of the questions/responses and adequate compliance with data entry.
Competence with the e-Diary will be assessed. The subject should demonstrate competence, 
including at least 80% compliance with recording e-Diary data between Visit 3 and Visit 4, 
in the opinion of the investigator and/or study site staff.
To ensure ongoing subject compliance with e-Diary reporting throughout the study, sites are 
requested to carefully monitor e-Diary data at least weekly using the study internet site. Sites 
should retrain subjects who are not compliant and should ascertain problems with non-
compliance to ensure that subjects experiencing difficulties are re-trained. 
The e-Diary data, including PEF readings, will be obtained and reviewed for each subject. 
The e-Diary will record information to a central database and/or a printed version of all e-
Diary information will be provided to the investigator or qualified designee. The e-Diary 
information should be reviewed for completeness of entries and subjects should be re-
educated in their correct use, if deemed necessary.
Rescue Short-acting Beta-agonist (SABA) use
7.1.1.9.2
Subjects should be carefully instructed to use inhaled SABAs on an “as-needed” basis only. 
Routine (habitual) use of inhaled SABAs in the absence of symptoms should be discouraged. 
Investigators will provide all subjects with inhaled SABAs (as albuterol/salbutamol only).
Twice daily (upon arising and before going to sleep), the subject will record in the e-Diary 
the total number of inhalations (“puffs”) of SABA used. The number of SABA puffs to be 
recorded is the number of actuations of the canister. For example, when SABA use is 
required and 3 actuations are inhaled, this should be recorded as 3. 
If the subject administered salbutamol immediately before going to bed these puffs must be 
recorded under total salbutamol puffs since arising. The puffs recorded under total 
albuterol/salbutamol puffs since bedtime must reflect the amount of salbutamol used since 
getting into bed and before arising at the normal time in the morning.
Subjects will also record the number of nebulizer treatments used, if any. If the subject 
should require short-acting beta-agonist by nebulization during the study, by convention one 
administration should be recorded as three puffs on the e-Diary.
 
 
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Although habitual use of inhaled SABAs in the absence of symptoms should be discouraged, 
the use of SABA as a prevention for exercise-induced bronchospasm (EIB) is permitted, only 
if previously taken in this manner, and should be discussed with the investigator at the Pre-
study visit. Because use of SABA when taken as prevention for EIB is not considered “as 
needed” rescue use; it should not be captured/recorded by subjects in the e-Diary.
The puffs of salbutamol used during a clinical visit to assess airway reversibility also are not 
considered “as needed” use, and will not be recorded on the e-Diary.
For trial eligibility:  The subject must have a daytime and nocturnal beta-agonist 
administration average ≥1 puff per day, as recorded on the subject’s e-Diary between Visits 3
and 4. This value will be calculated by the e-Diary at Visit 4. The average number of SABA 
puffs is the sum of puffs recorded in the morning e-Diary for the 7 days prior to Visit 4
(including the morning of the study visit) and in the evening e-Diary for the 7 days prior to 
Visit 4, divided by 7. If the patient did not record SABA puffs in any e-Diary for those 7 
days, a value of 0 should be used for the estimated number of puffs. 
Short-Acting Beta-Agonist Supplies Assessed/Dispensed
7.1.1.9.2.1
Albuterol/salbutamol, will be supplied by the investigative site as needed. The investigator or 
designee will record the lot number, expiration date, and drug dispensed.
Calculate Overall Rescue Short-Acting Beta-Agonist Use
7.1.1.9.2.2
This will be collected in the e-Diary and is the sum of daytime and nighttime number of puffs 
of SABA use for each day.
Asthma Symptoms
7.1.1.9.3
In the evening just before going to bed, the subject scores his/her symptoms for the period 
since arising. Symptoms to be considered by the subject in determining the daily symptom 
score are symptoms of asthma that might include, but are not limited to, chest discomfort 
(tightness), wheezing, shortness of breath (breathlessness), and cough.
 
 
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Each of 4 questions is evaluated using a 7-point scale, as follows:
1) How often did you experience asthma symptoms today?
0
1
2
3
4
5
6
None 
of the time
All 
of the time
2) How much did your asthma symptoms bother you?
0
1
2
3
4
5
6
Not at all 
bothered
Severely 
bothered
3) How much activity could you do today?
0
1
2
3
4
5
6
More than usual 
activity
Less than usual 
activity
4) How often did your asthma affect your activities today?
0
1
2
3
4
5
6
None 
of the time
All 
of the time
Additional Measures to Manage Deterioration of Asthma
7.1.1.9.4
On the e-Diary, subjects will answer the following question regarding healthcare resource 
utilization and management of a deterioration of their asthma:
In the past 24 hours, did worsening asthma symptoms cause you to?
If yes, check all that apply:

None

Take oral steroids (e.g., prednisone)

Make an unplanned visit to a physician’s office or urgent care clinic

Go to the emergency room 

Stay in the hospital overnight
If the subject answers “yes” to this question, the study coordinator should verify that any new 
medication or medication change is listed in the corresponding Concomitant Medication 
(CM) electronic case report form, that any procedures that occurred during a doctor’s visit, 
hospitalization, or emergency room visit are listed in the Procedure (PROC) electronic case 
report form (only if related to the adverse experience), and that “asthma exacerbation” should 
be listed in the corresponding Adverse Events electronic case report form. Note that some of 
these events may require either consideration for, or mandatory, discontinuation, as outlined 
in Section 5.8.
 
 
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Action Plan for Deterioration of Asthma
7.1.1.10
Subjects will be instructed to monitor their asthma symptoms and PEF levels and to 
telephone the study site in the event of deterioration of asthma. The investigator will review 
with each subject the procedures to be followed in the event of deterioration of asthma 
(Appendix 12.9). Note that any deterioration of asthma documented by the investigator 
should be considered an AE and should be evaluated and reported according to the 
procedures outlined in Section 7.2.
Note: Subjects who require rescue therapy (with prednisone) will be asked to return to the 
clinic (for an unscheduled visit) to perform spirometry measurements before prednisone 
therapy is initiated, whenever possible. The spirometry measurements obtained at these 
unscheduled visits will be used in the efficacy analysis for this study.
Trial Medication
7.1.1.11
Single-Blind Trial Medication + Montelukast Dispensed
7.1.1.11.1
Study medication will be dispensed at Visit 3 for ‘at home administration’ during the run-in 
period. All doses are to be taken in the evening, at approximately the same time of day.
Witnessed Dosing
7.1.1.11.2
During Visit 3, the first dose of trial medication may be witnessed in the presence of site staff 
as per site SOPs or local requirements. During Visit 4, the first dose of trial medication will 
be given as a witnessed dose in the clinic. 
Double Blind Trial Medication + Montelukast Dispensed
7.1.1.11.3
Study medication will be dispensed for ‘at home administration’ at Visits 4 and 6. The first 
dose, at Visit 4 will be administrated at the site as a witnessed dose in the presence of site 
staff after all Visit 4 study procedures have been completed. All doses (except Visit 4 
witnessed dose) are to be taken in the evening, at approximately the same time of day.
Unused study medication will be collected at specific study visits during the treatment 
period, as outlined in Section 6.0.
Trial Medication Compliance
7.1.1.11.4
The investigator or designee will review trial medication compliance with the subject. Any 
problems with medication usage should be addressed with the subject as soon as the 
investigator or designee becomes aware. 
Study staff will instruct each subject to bring all study drug and rescue medications to each 
visit. The study drug and rescue medications (empty, partially used, and unused) will be 
inspected at all protocol-specified visits.
Subject must demonstrate at least 80% compliance with use of their trial medication between 
Visits 3 and 4 to be eligible for randomization. Throughout the trial, sites will determine 
 
 
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compliance by assessing if subjects have any missed doses or any overdoses of trial 
medication (which will be entered in the eCRF).
Review of Adverse Experiences
7.1.1.12
The investigator or designee will question the subject about all AEs and intercurrent illnesses 
since the last visit (as applicable) and will record the pertinent information on the eCRF.
See Section 7.2.3.1, for instructions on the reporting of SAEs to the sponsor and Section 
7.2.4 for instructions on the assessment of AEs.
Review of Subject Questionnaires
7.1.1.13
The following questionnaires will be reviewed with the patient as indicated in the study flow 
chart (Section 6.0):

Asthma Control Questionnaire  (ACQ-6)

Asthma Quality of Life Questionnaire (AQLQ(S))
Clinical Procedures/Assessments
7.1.2
Physical Exam
7.1.2.1
A complete physical examination will be performed at Visit 3, and a focused physical 
examination will be performed at Visit 2 and Visit 7 or the Discontinuation Visit as indicated 
in the Trial Flow Chart (Section 6.0). If the subject is discontinued for any reason during the 
Double-blind Treatment Period, every attempt should be made to perform a focused physical 
examination as part of the discontinuation procedures.
A focused physical exam will include the following: assessment of appearance, throat and 
nasal examination, and auscultation of heart and lungs, height and weight measures. Other 
body systems may be examined as clinically indicated. Any abnormal physical findings 
(from visits other than Visit 2) should be recorded in the adverse event section of the eCRF.
Vital Signs 
7.1.2.2
Vital signs including heart rate, sitting blood pressure, and respiratory rate should be assessed 
as indicated in the study flow chart (Section 6.0). Subjects should be resting in a semi-
recumbent position for at least 10 minutes prior to having vital sign measurements obtained.
Vital signs should be obtained prior to administration of albuterol/salbutamol (e.g., for 
reversibility testing).
Electrocardiogram (ECG) 12-lead
7.1.2.3
A local 12-Lead ECG should also be performed at Visit 3, as indicated in the study flow 
chart (Section 6.0), and any abnormalities should be documented.  Results must be available 
prior to the subject receiving study medication.  Subjects should be resting in a semi-
recumbent position for at least 10 minutes prior to having ECG readings obtained. Clinically 
 
 
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significant findings from the Visit 3 ECG must be documented in the subject's chart and 
captured on the medical history eCRF.
If an ECG is performed for any medical reason while the patient is on the study treatment or 
during the follow-up period, any clinically significant changes compared with the Visit 3
ECG must be captured as AEs on the eCRF and documented in the subject’s chart.
The ECG should be obtained prior to administration of albuterol/salbutamol (e.g., for 
reversibility testing).
Asthma Control Questionnaire (ACQ-6) and Calculation of ACQ-6 score
7.1.2.4
The investigator or qualified designee will administer the 6 patient-reported items of the 
ACQ-6 to the subject at the visits indicated in the Study Flow Chart and upon study 
discontinuation. The ACQ-6 is a validated 6-item measure of asthma control that was 
developed for use in clinical trials to evaluate asthma control both at a single point in time 
and to assess change in asthma control over time in response to therapy.
The individual responsible for administering the questionnaire must review the standards for 
administration of the ACQ-6 and follow the procedures described below. The subject must 
complete the ACQ-6 independently. In order to mitigate any potential bias, every effort 
should be made to have the same individual administer the questionnaire at approximately 
the same time at each visit. The ACQ-6 administrator should explain to the subject that the 
ACQ-6 assesses how well their asthma is controlled. Ensure that the subject has a private, 
quiet place in which to complete the questionnaire. The subject should be reminded that all 
questions should be answered, that responses should be focused on asthma and not on other 
problems. Remind the subject of the recall period of the “last week.” The ACQ-6
administrator will review the completed questionnaire with the subject (and the subject’s 
legal representative, as appropriate) to ensure that all questions have been completed, and ask 
the subject to complete missing items. Completion of the ACQ-6 is estimated to take 
approximately 5 minutes. The ACQ-6 should be completed immediately after the AQLQ(S) 
is completed.
The ACQ-6 is scored as the mean of the responses to the 6 items. The score, therefore, is 
between 0 (totally controlled) and 6 (extremely poorly controlled). The developer does not 
have a specific standard for missing data but generally recommends no more than 10% 
missing data in a single questionnaire. Therefore, if more than one item is missing, then the 
score will not be calculated. Please note, at Visit 2 for subjects not receiving controllers, and 
at Visit 4 for all subjects, subjects will be required to respond to all 6 ACQ questions to 
determine eligibility in the study. The ACQ-6 administrator will confirm that complete 
responses are provided at these visits as needed, and that the subject meets the inclusion 
criteria (see Section 5.1.2 inclusion criterion #13) before a subject is randomized.
The ACQ-6 will be programmed into the e-Diary unit and will be completed at the visits 
specified in the Study Flow Chart. Instructions on the administration of the ACQ-6
questionnaire using the e-Diary unit will be provided by the vendor developing and
supplying the e-Diary.  SABA inhalation data reflecting rescue use, collected for the ACQ-6, 
will not be reconciled with the total SABA usage recorded in the e-Diary. In addition, no 
effort will be made to reconcile other individual components of the ACQ-6 (symptoms, 
activity limitation, or awakenings) with e-Diary data.
 
 
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Asthma Quality of Life Questionnaire (AQLQ(S))
7.1.2.5
This is a self-administered validated questionnaire that will be programmed in the e-Diary . 
The AQLQ(S) will be performed as indicated in the Study Flow Chart. The subject should 
complete the AQLQ(S) independently. The AQLQ(S) is to be completed before the ACQ-6.
Instructions on the administration of the AQLQ(S) using the e-Diary unit will be provided by 
the vendor developing and supplying the e-Diary.
Peak Flow Meter (PEF)
7.1.2.6
The peak flow meter will be provided to all study subjects for measurement of PEF at home
(Appendix 12.8). The peak flow meter device used in this study measures and saves all 
relevant expiratory parameters, (i.e., PEF). Additional details (including setup/programming 
of the peak flow meter) will be provided by the vendor. 
At the Pre-study (Visit 2), the subject will be provided with verbal and written instructions on 
the proper use of the e-Diary and the PEF meter. These instructions will be reviewed at each 
subsequent visit. In addition, the user will be guided through the entire process by clear and 
easy-to-read instructions on a screen. Visual indicators allow for an immediate assessment of 
the measurement. The Flow-Volume sensor complies with current American Thoracic 
Society / European Respiratory Society (ATS/ERS) standards and produces repeatable and 
accurate measurement results. The date and time will automatically be recorded.
The subject should be instructed to bring the peak flow meters to all visits to confirm that the 
devices are used correctly and are working properly. The subject should be instructed to 
perform triplicate PEF measurements twice daily (BID), in the AM upon rising and in the 
PM, immediately before study drug administration, at bedtime. All three values will be 
recorded and the best measurement will be determined through the e-Diary. The subject 
should be asked to refrain from using SABA within the 6 hours prior to performing the PEF 
measurements. If the subject should use SABA within 6 hours of his/her regular bedtime, the 
subject should measure the PEF before using the SABA. If it is more than 6 hours until 
bedtime, the subject will use SABA and wait until the regular bedtime to measure PEF. After 
the subject has completed their PEF measurements, he/she will be instructed to complete 
their e-Diary questions every morning and evening.
An alarm will be triggered if the subject hasn't made any measurements that AM or PM. It is 
very important that the subject use the peak flow meter and e-Diary twice a day.
At each study visit, after Visit 2, the investigator or qualified designee will review the PEF 
readings and any findings will be discussed with the subject and clinical relevance 
determined. The e-Diary data, including PEF readings, will be obtained (downloaded) and 
reviewed for each subject. The e-Diary will download all recorded information to a central 
database and/or a printed version of all e-Diary information will be provided to the 
investigator or qualified designee. The e-Diary information should be reviewed for 
completeness of entries and subjects should be re-educated in their correct use, if deemed 
necessary.
 
 
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PEF to Determine “Personal Best” and Alert Levels
7.1.2.6.1
Three measurements of PEF will be obtained during the clinic visits and the “personal best” 
level (greatest value in 3 attempts) determined for the subject. An alert level at 60% of the 
personal best is calculated and programmed in the subject e-Diary as a reference level. The 
subject should be instructed to measure their PEF immediately upon rising in the morning 
and immediately before going to bed in the evening (prior to taking study drug, and before 
using any SABA [albuterol/salbutamol]), and to call the study site if their PEF level falls 
below the 60% alert range. In this situation, the subject’s asthma status will be assessed by 
the site and an action plan for deterioration of asthma will be instituted, if appropriate 
(Appendix12.9).
Competence with the PEF meter will be assessed. The subject should demonstrate 
competence, including at least 80% compliance with recording PEF completion, in the 
opinion of the investigator and/or study site staff.
Spirometry, also known as Pulmonary Function Testing (PFT)
7.1.2.7
A standard spirometer will be provided for this study. 
Spirometry should be performed in accordance with guidelines established by the American 
Thoracic Society/European Respiratory Society (ATS/ERS) Standardization of Lung 
Function Testing: Standardization of Spirometry; 2005.
At all visits, PFTs should be performed in the morning, between 6 AM to 10 AM. Spirometry 
measurements for a given subject should occur at about the same time during each visit.
Every attempt must be made to use one spirometer consistently on each subject. For safety 
reasons, spirometry should be performed with the subject sitting using a chair with arms and 
without wheels; however, if necessary to undertake the testing with the subject standing or in 
another position, this should be noted on the spirometry report. For any subject, the position 
should be consistent throughout the study.
The subject should refrain from using SABA 6 hours prior to PFT initiation unless the PEF 
falls below the stability limit. 
After albuterol/salbutamol has been withheld for the 
appropriate interval, tests will be performed to measure FEV1 and FVC. Reference ranges 
are to be used to determine percent predicted include NHANESIII and/or The Journal of The 
Japanese Respiratory Society guidelines, whichever is applicable per local requirements.
Three measurements will be performed at each visit. The largest FEV 1 and the largest FVC 
should be recorded after the data are examined from all of the acceptable curves, even if they 
do not come from the same curve. Automated best efforts, which combine FEV1 and FVC, 
are not acceptable.
Calibration
The spirometer must be calibrated following the principles of the ATS/ERS Guidelines (i.e., 
with a 3-liter syringe) every day that a study subject is seen and spirometry is performed. The 
calibration records should be kept in a reviewable log. It is preferred that the calibration 
equipment (i.e., a 3-liter syringe) that is used to calibrate the spirometer be subjected to a 
validated calibration according to the manufacturer’s specifications.
 
 
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Additional details regarding spirometry procedures will be provided by the centralized 
spirometry vendor.
Reversibility
7.1.2.7.1
At Visit 2, a reversibility test will be administered following pulmonary function testing after 
asthma medications have been withheld for the appropriate intervals (Section 5.5.1). Subjects 
will receive four puffs of albuterol/salbutamol from a primed MDI (Appendix 12.7). 
Reversibility, which is defined as an increase in absolute FEV1 of greater than or equal to 
12%, and at least 200 mL, over the Baseline value, should be demonstrated within 30 
minutes of bronchodilator administration.
If the subject meets reversibility criteria at Visit 2, post SABA PFTs are not needed after
Visit 2.
If the subject does not meet the reversibility criterion at Visit 2, and the subject is not
receiving controllers, reversibility testing will be performed at Visit 3. A subject who is not 
receiving controllers at Visit 2, must demonstrate reversibility once during Visit 2 or Visit 3.
For subjects who were receiving controllers during the pre-study period between Visits 2 and 
3 and did not demonstrate reversibility at Visit 2, as defined above, reversibility testing can 
be repeated at Visit 4. Reversibility must be documented once during Visit 2 or Visit 4.
Pre-Beta-Agonist Spirometry (FEV1, FVC)
7.1.2.7.2
Spirometry testing should be initiated between 6 AM and 10 AM, and measurements should 
occur at about the same time during each visit for each subject.
Post-Beta-Agonist Spirometry (FEV1, FVC)
7.1.2.7.3
Post beta-agonist spirometry will be determined by administering 4 puffs of 
albuterol/salbutamol through a spacer device and then measuring spirometry 10 to 30 
minutes after albuterol/salbutamol administration (Appendix 12.7).
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in Section 12.4.
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
7.1.3.1
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 6.
Laboratory evaluations will be performed at a central laboratory chosen by the Sponsor. If all 
of the laboratory values are within the normal reference range at Pre-Screening Visit 1, the 
subject may continue to be evaluated for study entry. If one or more values fall outside of the 
normal range, the investigator may either exclude the subject from the study or investigate 
further to determine clinical relevance (Table 1). The investigation will include a careful 
evaluation of the potential subject’s complete medical history and current physical 
examination in the context of the abnormal laboratory value(s). If the investigator does not 
 
 
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identify any medical condition or disease that could result in the observed laborator y 
abnormality, the abnormal laboratory value may be considered not clinically relevant by the 
investigator and will be documented as such on the laboratory results form. Any questionable 
laboratory results should be reviewed with the Sponsor prior to randomization (Table 1). 
Repeat laboratory testing, at the discretion of the investigator and/or Sponsor, is permitted 
and should be indicated as such. If there is any clinical uncertainty regarding the significance 
of an abnormal value(s), the subject will be excluded from the study. 
All laboratory results must be found clinically acceptable to the investigator, and Sponsor, 
where appropriate, prior to study medication administration.
Table 6
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Hemoglobin
WBCa
Platelets
Albumin
BUN
Creatinine
Total bilirubin
AST
ALT
Alkaline phosphate
Glucose
Sodium
Potassium
Chloride
Bicarbonate
Calcium
Cholesterol
Uric acid
Glucose
pH
Protein
Microscopic: WBCs, 
RBCs 
Urine pregnancy testc
Blood for SNP testing
Blood for Genetic Analysis 
Follicle Stimulating Hormone 
(FSH)b
Serum Beta-human chorionic 
gonadotropin (β-hCG)
a. Total and differential (neutrophil, lymphocyte, atypical lymphocyte, monocyte, eosinophil, basophil)
b. For postmenopausal women at screening only 
c. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
Blood for SNP testing
7.1.3.2
This sample will be drawn for genotyping SNP 
. The result of this testing is required in 
order to proceed to Visit 2 of the study. 
Planned Genetic Analysis Sample Collection
7.1.3.3
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the operations/laboratory manual.
Future Biomedical Research Sample Collection
7.1.3.4
The following specimens are to be obtained as part of Future Biomedical Research:
-- DNA for future research.
 
 
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Other Procedures
7.1.4
Withdrawal/Discontinuation
7.1.4.1
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the Discontinuation Visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
Withdrawal From Future Biomedical Research
7.1.4.1.1
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
 and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Blinding/Unblinding
7.1.4.2
When the investigator or sub-investigator needs to identify the drug used by a subject and the 
dosage administered in case of emergency e.g., the occurrence of serious adverse 
experiences, he/she will contact the emergency unblinding call center by telephone and make 
a request for emergency unblinding.  As requested by the investigator or sub-investigator the 
emergency unblinding call center will provide the information to him/her promptly and 
report unblinding to the sponsor.  The emergency unblinding call center will make a record 
promptly however, the investigator or sub-investigator must enter the intensity  of the 
adverse experiences observed,   their relation to study drug, the reason thereof, etc., in the 
medical chart etc., before unblinding is performed. Subjects whose treatment assignment has 
been unblinded must be discontinued from study drug.
Section 5.8 outlines the criteria for allowing subjects who are discontinued from treatment to 
continue to be monitored in the trial.
 
 
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Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. Only the principal investigator or 
delegate and the respective subject’s code should be unblinded. Trial site personnel and 
Sponsor personnel directly associated with the conduct of the trial should not be unblinded.
Subjects whose treatment assignment has been unblinded (by the investigator, Merck 
subsidiary, or through the emergency unblinding call center) must be discontinued from 
study drug.
Domiciling
7.1.4.3
Not applicable 
Calibration of Critical Equipment
7.1.4.4
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Spirometer
Please refer to Section 7.1.2.7 for detail on calibration of the spirometer.
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Rescreening
7.1.5.1
Per the judgment of the investigator, a subject who is classified as a screen failure may be re-
screened once due to not meeting all inclusion/exclusion criteria at either Visit 1 or Visit 2. A 
subject may not be re-screened after entering the open-label Run-in Period of the trial.
Post-treatment Visit
7.1.5.2
Approximately 14 days after the last regularly scheduled dose of blinded trial therapy or trial 
end/discontinuation, female subjects of child-bearing potential will be scheduled for a Post 
Treatment Visit and will return to the clinic in 14 (+4) days. All male subjects and those 
female subjects who are not of child-bearing potential will receive a telephone contact for 
post-trial evaluation.
 
 
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Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose for MK-1029 is any dose higher than 1 tablet a day.  An overdose 
for montelukast is a dose more than 10 mg a day, consistent with its approved use. An 
overdose of as-needed SABA (albuterol/salbutamol) is administration of greater than 16 
puffs per day on two consecutive days.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
 
 
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If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
Serious Adverse Events
7.2.3.1
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
 
 
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●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 7 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
7.2.3.2
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
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 
 
 
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than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
Protocol-Specific Exceptions to Serious Adverse Event Reporting
7.2.3.3
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 7 . The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 7 for instructions in evaluating adverse events.
 
 
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Table 7
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.   (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event?   The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor's 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any final database lock, changes made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9).  Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to final 
database lock, will be documented in a supplemental SAP (sSAP) and referenced in the 
Clinical Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly 
identified in the CSR.  Separate analysis plans (i.e., separate documents from the sSAP) will 
be developed to detail other planned analyses (i.e., those specific to the analysis of future 
biomedical research).
 
 
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Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan (SAP) are summarized below; the 
comprehensive plan is provided in Sections 8.2-8.12.
Study Design Overview
A randomized, double-blind placebo-controlled, parallel-group trial of 
MK-1029 in subjects with persistent asthma who remain uncontrolled 
while being maintained on montelukast.
Treatment Assignment
Subjects will be randomized in 1:1 ratio to either MK-1029 150 mg 
plus montelukast 10 mg or MK-1029 150 mg matching-image placebo
plus montelukast 10 mg, stratified by the number 
 
  Double-blind assignment with in-house 
blinding will be implemented. 
Analysis Populations
Efficacy: Full Analysis Set (FAS).
The FAS approach includes all 
randomized subjects who receive at least one dose of trial treatment.  
Subjects will be included in the treatment group to which they are 
randomized.
Safety: All Subjects as Treated (ASaT). The ASaT population consists 
of all randomized subjects who received at least one dose of trial 
treatment. 
Subjects will be included in the treatment group 
corresponding to the trial treatment they actually received.
Primary Endpoint
Average change from baseline in forced expiratory volume in 1 second 
(FEV1) measured at the end of Week 4 and Week 6 of treatment
Key Secondary Endpoint
Percent of days with worsening asthma measured daily during Week 3 
to Week 6 of treatment (inclusive)
Statistical Methods for 
Key Efficacy Analyses
The primary hypothesis will be evaluated by comparing MK-1029 to 
placebo, when added to montelukast, on the average change from 
baseline in FEV1 using a constrained longitudinal data analysis model. 
The key secondary hypothesis will be evaluated by comparing 
MK-1029 to placebo, when added to montelukast, on the %d-WA using 
an analysis of variance model.
Statistical Methods for 
Key Safety Analyses
No Tier 1 safety endpoint is specified for this trial. For Tier 2 
endpoints, between-group comparisons will be assessed via point 
estimates with 95% confidence intervals provided using the stratified 
Miettinen and Nurminen method.
Interim Analyses
No interim analysis is planned in this trial.
Multiplicity
The primary and key secondary endpoints will be tested in a stepwise 
procedure, where statistical conclusions will be made on the key 
secondary efficacy endpoint only if statistical significance is 
demonstrated in the primary efficacy endpoint. 
Sample Size and Power 
The planned sample size is 110 subjects in total. 
For the average change from baseline in FEV1 measured at the end of 
Week 4 and Week 6 of treatment, the trial has approximately 92% 
power to demonstrate that MK-1029 is superior to placebo at an overall 
two-sided 5% alpha-level, if the underlying treatment difference in 
mean changes from baseline in FEV1 is 180ml.  For the %d-WA
measured during Week 3 to Week 6 of treatment, the trial has 
approximately 80% power to demonstrate that MK-1029 is superior to 
placebo at an overall two-sided 10% alpha-level, if the underlying 
treatment difference in %d-WA is -10.0%.
 
 
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Responsibility for Analyses/in-house Blinding
8.2
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This study will be conducted as a double-blind study under in-house blinding procedures.  
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.  Randomization will be implemented in an interactive voice 
response system (IVRS).
Hypotheses/Estimation
8.3
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
8.4
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected 
endpoints.
Efficacy Endpoints
8.4.1
The descriptions of the efficacy measurements and time points at which they are measured 
are described in Section 4.2.3.1.
Primary Efficacy Endpoint

Average change from baseline in FEV1 as measured at the end of Week 4 and Week 6 
of treatment
Key Secondary Efficacy Endpoint

Percent of days with worsening asthma (%d-WA) as measured daily during Week 3 
to Week 6 (inclusive) of treatment
Safety Analysis 
8.4.2

Percentage of subjects with adverse experience

Clinical and laboratory adverse experiences reported during the treatment period

Change from baseline in vital signs parameters and change or percent change (as 
appropriate) from baseline in laboratory safety parameters at the end of the trial
Derivations of Efficacy Endpoints
8.4.3
This section provides the descriptions of the primary and key secondary efficacy endpoints.  
Descriptions of the exploratory endpoints are provided in the sSAP.
 
 
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FEV1
For FEV1, baseline value (Visit 4) and measurements at the end of Weeks 2, 4, and 6 will be 
included in the analysis model. Assignment of an FEV1 measurement to a specific week will 
be based on the relative day at which the measurement is obtained. If more than 1 FEV1
measurement is obtained within or assigned to a week, the FEV1 associated with the last 
relative day within that specific week is kept for the analysis. An FEV1 measurement 
obtained up to 1 week from the last day of an asthma (systemic corticosteroid) rescue-therapy 
episode will not be used in any analysis.  The start of an asthma rescue episode is defined as 
the first day the subject’s asthma symptoms require treatment with steroids as indicated on 
the subject diary and/or concomitant medication case report form. The episode ends on the 
last day of a period with steroid use.
Day with Worsening Asthma
For this trial, a day with worsening asthma (d-WA) is defined based on e-Diary entries, as 
any day during which any of the following occurs: 

a decrease from baseline in AM PEF of more than 20%

AM PEF less than 180 L/min

an increase in beta-agonist use of more than 70% (and a minimum increase of at least 
2 puffs)

an increase from baseline in daytime asthma symptom score of more than 50%

overnight asthma symptom of: Awake “all night”

an asthma attack, as defined by any day when one or more of the following events 
due to asthma has occurred: corticosteroid use (systemic); unscheduled visit to the 
doctor or urgent care clinic; unscheduled visit to the emergency department; and/or 
hospitalization.
The percentage days with worsening asthma, as well as other diary-derived endpoints, will be 
calculated using the e-Diary values collected from the beginning of Week 3 to the end of 
Week 6 (or discontinuation).  No e-Diary measurement obtained up to 1 week from the last 
day of an asthma rescue-therapy episode will be included for the endpoint derivation.  It is 
required that at least 80% of the expected diary data from the beginning of Week 3 to the end 
of Week 6 (or discontinuation) should be available to compute the diary-derived endpoints.
Baseline
For the primary efficacy endpoint of FEV1, the pre-dose baseline value is defined as the last 
measurement obtained on or before Visit 4 prior to randomization.
Derivations of Safety Endpoints
8.4.4
For laboratory, and vital sign parameters, baseline is defined as the last measurement taken 
prior to the first dose of double-blind trial treatment, which is typically taken at the day of 
randomization. Change from baseline in laboratory, and vital signs parameters is calculated 
as on-treatment value minus the baseline value.
 
 
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Analysis Populations
8.5
Efficacy Analysis Populations
8.5.1
A full analysis set (FAS) approach will be used for efficacy analyses. The FAS approach 
includes all randomized subjects who receive at least one dose of trial treatment. 
A supportive analysis using the Per-Protocol (PP) population will be performed for the 
primary efficacy endpoint if the number of protocol violators is more than 10% of the FAS 
population in either treatment group. The PP population excludes subjects due to important 
deviations from the protocol based on a set of pre-specified criteria (e.g., dropouts, 
noncompliant of trial procedure, etc.). The final determination on major protocol deviations, 
and thereby the composition of the Per-Protocol population, will be made prior to the final 
unblinding of the database and will be documented in a separate memo.
Subjects will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using both the FAS and PP populations.  If an endpoint analysis 
involves baseline, a baseline measurements is required for the subject to be included in that 
analysis.  Details on the approach to handling missing data are provided in Section 8.6 –
Statistical Methods.
Safety Analysis Population
8.5.2
The All Subjects as Treated (ASaT) population will be used for the analysis of safety d ata in 
this trial.  The ASaT population consists of all randomized subjects who received at least one 
dose of trial treatment. Subjects will be included in the treatment group corresponding to the 
trial treatment they actually received for the analysis of safety data using the ASaT 
population.  If a subject takes incorrect trial treatment for the entire treatment period, the 
subject will be included in the treatment group corresponding to the trial treatment actually 
received.  Otherwise, subjects will be included in the treatment group to which they are 
randomized.
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
trial treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in 
Section 8.6 – Statistical Methods.
Statistical Methods
8.6
Statistical testing and inference for safety analyses are described in 8.6.2. Efficacy results 
that will be deemed to be statistically significant after consideration of the Type I error 
control strategy are described in Section 8.8, Multiplicity.  Nominal p-values may be 
computed for other efficacy analyses, but should be interpreted with caution due to potential 
issues of multiplicity, sample size, etc.  Unless otherwise stated, all statistical tests will be 
conducted at the α=0.05 (2-sided) level.
Statistical Methods for Efficacy Analysis
8.6.1
This section describes the statistical methods that address the primary and key secondary 
objectives.  Methods related to exploratory objectives will be described in the sSAP.  
 
 
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Primary Endpoint
For the analysis of the average change from baseline in FEV1 at the end of Week 4 and 
Week 6, a constrained longitudinal data (cLDA) method proposed by Liang and Zeger [20] 
will be used.  This model assumes a common mean across treatment groups at baseline and a 
different mean for each treatment at each post-baseline time points.  In this model, the 
response vector consists of the baseline FEV1 and the FEV1 observed at each post-baseline 
time points (up to Week 6).  Time is treated as categorical variable so no restriction is 
imposed on the trajectory of the means over time.  The analysis model will adjust for 
treatment, visit, the treatment-by-visit interaction, number of C alleles at the rs’961 SNP (1
copy / 2 copies), and prior inhaled corticosteroids (ICS) use (Yes/No).  An unstructured 
covariance matrix will be used to model the correlation among repeated measurement. The 
Kenward-Roger adjustment will be used with residual maximum likelihood (REML) to make 
proper statistical inference.  The treatment difference in terms of the average change from 
baseline in FEV1 at the end of Week 4 and Week 6 will be estimated and tested from the 
cLDA model. 
Although the baseline measurement is included in the response vector, it is independent of 
treatment, and hence, the baseline means are constrained to be the same for different 
treatment groups. Of note, in the event that there are no missing data, the estimated 
treatment difference from the above cLDA model will be identical to that from a traditional 
longitudinal Analysis of covariance (ANCOVA) model which uses the baseline value as a 
covariate. However, unlike longitudinal ANCOVA, the cLDA model accounts for variability 
in the baseline values, thus providing more accurate standard errors and confidence intervals 
for individual treatment effects. Moreover, this model allows the inclusion of subjects who 
are missing either the baseline or post-baseline measurements, thereby increasing efficiency. 
Details of the model specification, assumptions, and SAS implementation codes will be 
provided in the sSAP.
The cLDA method assumes that data are missing at random (MAR).  Based on the 
experience in previous Phase-II trials for MK-1029, typical reasons for discontinuation from 
the trial include clinical or laboratory adverse experiences, protocol deviations/non-
compliance, physician decision, and/or lack of efficacy.  It is expected that in this trial,
Missing at Random and Missing Completely at Random (MAR/MCAR) mechanisms will 
underlie most of the missingness, combined with the assumed dropout rate of 10%, the 
proportion of data missing not at random (MNAR), driven solely by unobserved values of the 
study endpoints, will be small.
Supportive Analysis for the Primary Endpoint
Supportive analyses based on the Per Protocol (PP) population will be conducted using the 
same cLDA model described above.  The PP population contains all subjects in the FAS who 
do not meet the protocol violation criteria.
In addition, the Jump-to-Reference (J2R) multiple-imputation and the tipping-point analysis
will be performed, as supportive analyses for the primary endpoint, to evaluate the 
MAR/MCAR assumptions and the impact of missing data.  

The J2R approach assumes that subjects who dropout during the trial have the same
response profile as those in the control group at time points after discontinuation, had 
they remained in the trial. Under the J2R approach, missing data from all subjects after 
 
 
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dropout will be imputed using the profile from the control group (i.e., placebo plus 
montelukast).  

In the tipping-point analysis, missing data are first imputed for all time points under the 
MAR assumption, and then the worsening/shift is applied.  This procedure is repeated 
with increasing the delta-shift (worsening) until the result is no longer statistically 
significant.  
Further details of these two analyses are provided in the sSAP.
Key Secondary Endpoint
The key secondary endpoint of %d-WA will be analyzed using an analysis of variance 
(ANOVA) model with fixed effects of treatment, 
 and prior ICS use (Yes/No).  The ANOVA model will be based on the FAS 
and subjects will be evaluable for this analysis if they have non-missing endpoint value.
The primary analysis approach for the %d-WA will be based on non-missing values only, 
that is, the percentage will be calculated as:
The supportive analysis approach for the %d-WA will be based on a worse-neighbor 
imputation approach.  That is, for each component of d-WA, missing value on any given day 
(consecutive days) will be imputed by the worse of the non-missing value immediately 
before and after the missing one(s).  Worsening of asthma will then be evaluated based on 
the imputed value(s).  The percentage of days with worsening asthma based on the worse-
neighbor approach is calculated as:
Table 8 summarizes the primary and key secondary efficacy analyses. 
Table 8
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary 
vs. 
Supportive 
Approach†
Statistical 
Method‡
Analysis 
Population
Missing Data Approach
Primary Endpoint
Average change from baseline in 
FEV1 at the end of Week 4 and 
Week 6
P
cLDA§
FAS
Model-based
S
PP
Model-based
S
ANCOVA#
FAS
Jump-to-Reference multiple 
imputation
S
Tipping-point analysis
Secondary Endpoints/Hypotheses
Key Secondary Endpoint
Percent of days with worsening 
asthma during Week 3 to Week 6 
of treatment
P
ANOVA
FAS
Average of non-missing 
values, no missing data will 
be imputed
S
Worse-neighbor imputation
 † P=Primary approach; S=Supportive approach.
  ‡ Statistical models are described in further detail below:
  § constrained longitudinal data analysis model with terms for treatment, time, and the interaction of time by treatment, 
 
and prior inhaled corticosteroids use (Yes/No).
  #ANCOVA model with terms for treatment, 
 and prior inhaled corticosteroids 
use (Yes/No) as fixed effects and baseline as a covariate.
ANOVA model with terms for treatment, 
 and prior inhaled corticosteroids 
use (Yes/No). 
FEV1 = Forced expiratory volume in 1 second; FAS=Full analysis set; PP=per-protocol analysis
 
 
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Statistical Methods for Safety Analysis 
8.6.2
Safety and tolerability will be assessed by a clinical review of all relevant parameters,
including adverse experiences (AEs), laboratory safety parameters, and vital signs. 
The analysis of safety results will follow a tiered approach (Table 9). The tiers differ with 
respect to the analyses that will be performed. Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p-values and 95% confidence 
intervals provided for between-group comparisons.  Other safety parameters will be 
considered Tier 2 or Tier 3.  Tier 2 parameters will be assessed via point estimates with 95% 
confidence intervals provided for between-group comparisons; only point estimates by 
treatment group are provided for Tier 3 safety parameters.
Adverse experiences (specific terms as well as system organ class terms) and predefined 
limits of change in laboratory, vital signs, and ECG parameters that are not pre-specified as 
Tier-1 endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on the number 
of events observed.  Membership in Tier 2 requires that at least 4 subjects in any treatment 
group exhibit the event; all other adverse experiences and predefined limits of change will 
belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences.  Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences 
and predefined limits of change.
 
 
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Table 9
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint†
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
(none)
Tier 2
Any AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs, or PDLCs‡ (incidence ≥4 of 
subjects in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <4 of subjects 
in all of the treatment groups)
X
Change from Baseline Results (Labs, Vital Signs)
X
† Adverse Experience references refer to both Clinical and Laboratory AEs.
‡ Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier 2 endpoints.
Note: 
(1)
CI = Confidence Interval; SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X = results will be 
provided.
(2)
PDLC criteria for laboratory parameters are provided in Table 10.
For this trial, no adverse experiences have been identified as Tier 1 events. The broad clinical 
and laboratory AE categories consisting of the percentage of subjects with any AE, a drug 
related AE, a serious AE, an AE which is both drug-related and serious, and who 
discontinued due to an AE will be considered Tier 2 endpoints. For Tier 2 events, point 
estimates with 95% confidence intervals will be provided for between-treatment differences 
in the percentage of subjects with events, using the Miettinen and Nurminen method
stratified 
Continuous measures such as changes from baseline in laboratory, and vital signs parameters 
that are not pre-specified as Tier 1 endpoints will be considered as Tier 3 safety parameters.  
Summary statistics for baseline, on-treatment, and change from baseline values will be 
provided by treatment group in table format.  Table 10 summarizes the predefined limits of 
change for laboratory parameters:
 
 
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Table 10
Predefined Limits of Change
Laboratory Test
Predefined Limit of Change
Hematocrit (%)
Decrease 20% and <LLN
Increase 20% and >ULN
WBC count (1000/mm3)
Decrease 20% and <LLN
Increase 20% and >ULN
Platelet count (1000/mm3)
Decrease 25% and <LLN
Increase 50% and >ULN
Bilirubin (mg/dL)
Increase 100% and >ULN
≥ 50% increase and >1.5X ULN
≥ 50% increase and >2X ULN
>3X ULN
>5X ULN
AST (IU/L)
Increase 100% and >ULN
≥ 50% increase and >1.5X ULN
≥ 50% increase and >2X ULN
>3X ULN
>5X ULN
ALT (IU/L)
Increase 100% and >ULN
≥ 50% increase and >1.5X ULN
≥ 50% increase and >2X ULN
>3X ULN
>5X ULN
ALP (IU/L)
Increase 100% and >ULN
≥ 50% increase and >1.5X ULN
≥ 50% increase and >2X ULN
>3X ULN
>5X ULN
Neutrophil (1000/mm3)
Decrease 20% and <LLN
Increase 20% and >ULN
BUN(mg/dL)
Increase ≥ 50%
Increase ≥ 20% and BLN>ULN
Serum creatinine(mg/dL)
Increase ≥ 50%
Increase ≥ 20% and BLN>ULN
WBC = White Blood Cell; AST = Aspartate transaminase; 
ALT = Alanine transaminase; ALP = Alkaline phosphatase; 
LLN = Lower limit of normal range; ULN = Upper limit of normal range.
Summaries of Baseline Characteristics, and Demographics
8.6.3
The comparability of the treatment group for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed. 
Demographic variables (including age, gender, race, weight, height, and body mass index), 
baseline characteristics (including duration of asthma, age diagnosed of asthma, asthma 
controller pre-trial, ICS use, blood eosinophil count, baseline ACQ-6, and smoking history), 
primary and secondary diagnoses, prior and concomitant therapies, 
 
 
 
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will be summarized by treatment either by descriptive statistics or 
categorical tables.
Interim Analysis
8.7
No formal efficacy interim analysis is planned for this trial. Safety data will be continuously 
monitored in a blinded fashion by the study team.
Multiplicity 
8.8
The primary and key secondary endpoints will be tested in a stepwise procedure, where
statistical conclusion will be made on the key secondary efficacy endpoint only if statistical
significance is demonstrated in the primary efficacy endpoint. No multiplicity adjustment 
will be implemented among the exploratory endpoints.
Power and Sample Size
8.9
Subjects will be randomized in a 1:1 ratio to either MK-1029 150 mg plus montelukast 10 
mg or MK 1029 150 mg matching-image placebo montelukast 10 mg.  Assuming a 10% drop 
out rate, a total of 55 subjects per treatment group will be randomized. 
With approximately 55 randomized subjects per group, the study has about 92% power to 
demonstrate the superiority of MK-1029 over placebo, when added to montelukast at an 
overall two-sided 5% alpha-level, if the underlying treatment difference in average change 
from baseline FEV1 is 180mL.  The sample size is based on the following assumptions: 1) an 
approximately 10% cumulative overall dropout rate over the 6-week treatment, 2) an 
unconditional correlation matrix of compound symmetry structure with correlation 
coefficient of 0.9, and 3) an unconditional standard deviation of 705ml on FEV1 at each time 
point. The calculation is based on Inverse Probability Weighted Complete Cases Approach 
by Lu, Mehrotra and Liu (2008) [21] with 55 subjects in each treatment group expected to be 
included in the analysis and is carried out using SAS v9.3.  In addition, there is 
approximately 80% power to detect (at 2-sided α=0.10) a difference of -10.0 percentage 
points in %d-WA between MK-1029 and placebo, assuming a standard deviation (SD) of 
19.6 percentage points. The assumptions for treatment difference and SD for the primary and 
key secondary endpoints, and the dropout rate are based on Phase-II trials already conducted 
for MK-1029. 
Subgroup Analysis and Effect of Baseline Factors
8.10
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoint will be estimated and plotted within each category of each subgroup.  The following 
are examples of classification variables:

Age groups (≤/> median)

Gender (female, male)

Race (Asian, White, Black or African American, and Other)
 
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
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Region (Americas, Europe/Africa, Asia/Pacific)

FEV1 %-predicted at baseline (≤/> median)

Baseline ACQ-6 (≤/> median)

Age Diagnosed of Asthma (≤/> 12 yrs.)

Blood eosinophilia (yes/no), with eosinophilia defined based on blood eosinophil 
count 0.30 × 106/L at Visit 4 

The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above.
Compliance (Medication Adherence)
8.11
In this trial, as part of the routine recording of the amount of trial treatment taken by each 
subject, the number of tablets remaining in trial packaging will be counted, reviewed, and 
recorded at regular intervals.  These results will be used to calculate subject compliance.
A day within the trial will be considered an “On-Therapy” day if the subject takes all the 
required number of tablets of each type (MK-1029 150 mg or matching-image placebo and
montelukast 10 mg) as noted in Section 5.2.
For a subject who is followed for the entire treatment period, the “Number of Days Should be 
on Therapy” is the total number of days from randomization to the last scheduled day for 
treatment administration for that subject.  For a subject who discontinued from the trial 
permanently, the “Number of Days Should be on Therapy” is the total number of days from 
randomization to the earlier of 

the date of the last dose of trial medication.

the date the subject discontinued from the trial.
For each subject, percent compliance will then be calculated using the following formula:
    
Summary statistics will be provided on percent compliance by treatment group for the FAS 
population.
Extent of Exposure
8.12
The Extent of Exposure to study treatment will be evaluated by summary statistics (N, mean, 
median, and standard deviation) and frequencies (< 2 weeks, 2 to < 4 weeks, 4 to 6 weeks, 
and > 6 weeks) for the “Number of Days on Therapy” by treatment group.
 
 
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9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 11.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 11
Product Descriptions
Product Name & Potency
Dosage Form
Montelukast sodium 10 mg 
Tablet 
MK-1029 150 mg or matching-image placebo  
Tablet 
All placebos were created by the Sponsor to match the active product.
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive per dispensing visit, one open label bottle of montelukast sodium 10 mg 
and one blinded bottle of either MK-1029 150 mg or MK-1029 150mg matching-image
placebo to support four weeks of dosing. 
No kitting is required.  
Clinical Supplies Disclosure
9.3
Open label montelukast sodium: The montelukast sodium in this trial is open-label; 
therefore, the subject, the trial site personnel, the Sponsor and/or designee are not blinded. 
Montelukast sodium 10 mg  (name, strength or potency) is included in the label text; random 
code/disclosure envelopes or lists are not provided.
Blinded Supplies: MK 1029 150 mg or matching-image placebo  
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind subjects and to unmask treatment identity. In the event that the emergency 
unblinding call center is not available for a given site in this trial, the central electronic 
treatment allocation/randomization system (IVRS/IWRS) should be used in order to unblind 
subjects and to unmask treatment/vaccine identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
 
 
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Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.  Only the principal investigator or 
delegate and the respective subject’s code should be unblinded.  Trial site personnel and 
Sponsor personnel directly associated with the conduct of the trial should not be unblinded to 
treatment assignment. Subjects whose treatment assignment has been unblinded (by the 
investigator, Merck subsidiary, or through the emergency unblinding call center) must be 
discontinued from study drug.
Section 5.8 outlines the criteria for allowing subjects who are discontinued from treatment to 
continue to be monitored in the trial.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
9.6
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
 
 
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be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
 
 
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and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
 
 
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copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
 
 
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knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
 
 
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authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
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11.0 LIST OF REFERENCES
1. Holgate ST, Burns GB, Robinson C, Church MK. Anaphylactic- and calcium-dependent 
generation of prostaglandin D2 (PGD2), thromboxane B2, and other cyclooxygenase 
products of arachidonic acid by dispersed human lung cells and relationship to histamine 
release. J Immunol 1984;133(4):2138-44. 
2. Mjosberg JM, Trifari S, Crellin NK, Peters CP, van Drunen CM, Piet B, et al. Human IL-
25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of 
CRTH2 and CD161. Nat Immun 2011;1-9.
3. Shiraishi Y, Asano K, Nakajima T, Oguma T, Suzuki Y, Shiomi T, et al. Prostaglandin 
D2-induced eosinophilic airway inflammation is mediated by CRTH2 receptor. J 
Pharmacol Exp Ther 2005;312(3):954-60. 
4. Fujitani Y, Kanaoka Y, Aritake K, Uodome N, Okazaki-Hatake K, Urade Y. Pronounced 
eosinophilic lung inflammation and Th2 cytokine release in human lipocalin-type 
prostaglandin D synthase transgenic mice. J Immunol 2002;168:443-9. 
5. Liu MC, Bleecker ER, Lichtenstein LM, Kagey-Sobotka A, Niv Y, McLemore TL, et al. 
Evidence 
for 
elevated 
levels 
of 
histamine, 
prostaglandin 
D2, 
and 
other 
bronchoconstricting prostaglandins in the airways of subjects with mild asthma. Am Rev 
Respir Dis 1990;142:126-32. 
6. Barnes N, Pavord I, Chuchalin A, Bell J, Hunter M, Lewis T, et al. A randomized, 
double-blind, placebo-controlled study of the CRTH2 antagonist OC000349 in moderate 
persistent asthma. Clin Exp Allergy. 2011;42:38-48.
7. Philip G, van Adelsberg J, Loeys T, Liu N, Wong P, Lai E, et al. Clinical studies of the 
DP1 antagonist laropiprant in asthma and allergic rhinitis. J Allergy Clin Immunol 
2009;124:942-8. 
8. Busse WW, Wenzel SE, Meltzer EO, Kerwin EM, Liu MC, Zhang N et al.. Safety and 
efficacy of the prostaglandin D2 receptor antagonist AMG 853 in asthmatic patients. J 
Allergy Clin Immunol 2013;131:339-345.
9. Masoli M, Fabian D, Holt S, Beasley R, for the Global Initiative for Asthma (GINA) 
Program. The global burden of asthma: executive summary of the GINA Dissemination 
Committee Report. Allergy 2004;59:469-78. 
10. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJH, Pauwels RA, et al. Can 
guideline-defined asthma control be achieved?: the gaining optimal asthma control study. 
Am J Respir Crit Care Med 2004;170:836-44.
11. Marceau C, Lemiere C, Berbiche D, Perreault S, Blais L. Persistence, adherence, and 
effectiveness of combination therapy among adult patients with asthma. J Allergy Clin 
Immunol 2006;118:574-81. 
12. Wasfi YS, Villarán C, Le Bailly de Tilleghem C, Smugar SS, Hanley WD, Reiss TF, et 
al. The efficacy and tolerability of MK-0633, a 5-lipoxygenase inhibitor, in chronic 
asthma. Resp Med 2012;106:34-46. 
 
 
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13. Rossall M, Cadden P, Kolsum U, Singh D. A comparison of the clinical and induced 
sputum characteristics of early- and late-onset asthma. Lung 2012;190:459-62.
14. Philip G, Villarán C, Shah SR, Vandormael K, Smugar SS, Reiss TF. The efficacy and 
tolerability of inhaled montelukast plus inhaled mometasone compared with mometasone 
alone in patients with chronic asthma. J Asthma. 2011;48(5):495–502. 
15. Malmstrom K, Rodriguez-Gomez G, Guerra J, Villaran C, Piñeiro A, Wei LX, et al. Oral 
montelukast, inhaled beclomethasone, and placebo for chronic asthma: a randomized, 
controlled trial. Ann Intern Med 1999;130(6):487-95. 
16. Reiss TF, Chervinsky P, Dockhorn RJ, Shingo S, Seidenberg B, Edwards TB. 
Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic 
asthma: a multicenter, randomized, double-blind trial. Arch Intern Med 1998;158:1213-
20. 
17. Okada Y, Hirota TKY, Takahashi A, Ohmiya H, Kumasaka N, Higasa K, et al. 
Identification of nine novel loci associated with white blood cell subtypes in a Japanese 
population. PLoS Genet 2011;7(6):1-10. 
18. Westra HJ, Peters MJ, Esko T, et al. Systematic identification of trans eQTLs as putative 
drivers of known disease associations. Nature Genetics 2013;45:1238-1245.
19. Imboden M, Bouzigon E, Curjuric I, et al. Genome-wide association study of lung 
function decline in adults with and without asthma. J Allergy Clin Immunol
2012;129:1218–1228. 
20. Liang K-Y, Zeger SL. Longitudinal data analysis of continuous and discrete responses for 
pre-post designs. Sankhya: the Indian Journal of Statistics 2000;62:134-48. 
21. Lu K, Mehrotra DV, Liu G. Sample size determination for constrained longitudinal data 
analysis. Stat Med 2009;28(4):679-699.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.4 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease. The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
 
 
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
 
 
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mailbox 
 and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
 
 
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through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects 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 subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained). 
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Pharmacogenetics Information Brochure for IRB/IECs & Investigational Site Staff
12.3
 
 
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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
12.4
Sample Types
Pre-
screening
Visit 1
Treatment 
Visit 4
Treatment
Visit 5-6
Treatment 
Visit 7
Post-
Treatment
Blood Parameter 
Approximate Blood Volume (mL)
Hematology
2 mL
2 mL
2 mL
Serum/Plasma Chemistry
2 mL
2 mL
2 mL
Serum β-Human Chorionic 
Gonadotropin (β-hCG)a
1 mL
Serum Follicle Stimulating 
Hormone (FSH)b
1 mL
Blood for Planned Genetic 
Analysis c
8.5 mL
Blood for SNP testing
4 mL
Expected Total (mL)
10 mL
12.5 mL
4 mL
a. For female subjects of child bearing potential only drawn at visit 1. If the urine pregnancy test is positive at 
subsequent visits, β-hCG sample will be drawn to confirm.
b. If applicable 
c. No additional specimens are being collected for Future Biomedical Research (i.e., only leftover samples 
from the blood for planned genomic analyses are being retained for future biomedical research)
 
 
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List of Abbreviations
12.6
ACQ-6
Asthma Control questionnaire- 6 items
AE
Adverse experience
ALP
Alkaline Phosphatase
ALT
Alanine aminotransferase
AN
Allocation number
ANCOVA
Analysis of covariance
AQLQ
Asthma Quality of Life Questionnaire
AQLQ(S)
Asthma Quality of Life Questionnaire (Standardised Activities)
AST
Aspartate aminotransferase
ATS/ERS
American Thoracic Society/European Respiratory Society
BMI
Body Mass Index
CD11b
Cluster of differentiation molecule 11b
CFC
Chlorofluorocarbon
cLDA
Constrained longitudinal data
CI
Confidence interval
Cmax
Maximum concentration
CRTH2
Chemoattractactant Receptor-homologous molecule on Th2 cells 
CSR
Clinical study report
CysLT1
Cysteinyl leukotriene receptor type-1
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECI
Event of clinical interest
eCRF
Electronic case report form
eSNP
Expression SNP
FAS
Full Analysis Set
FEV1
Forced expiratory volume in 1 second
FSH
Follicle stimulating hormone
FVC
Forced vital capacity
GINA
Global Initiative for Asthma
hCG
Human chorionic gonadotropin
HFA
Hydrofluoroalkane
HIV
Human immunodeficiency virus
IB
Investigator's brochure
ICS
Inhaled corticosteroids
IEC
Institutional ethics committee
IgE
Immunoglobulin E
IRB
Institutional Review Board
IUD
Intrauterine device
IVRS
Interactive voice response system
LABA
Long-acting (inhaled) β2-adrenergic agonist
LLN
Lower limits of normal
 
 
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MDI
Metered-dose inhaler
mg
Milligrams
mL
Milliliter
mRNA
Messenger ribonucleic acid
PD
Pharmacodynamic
PDLC
Predefined limits of change
PEF
Peak expiratory flow
PFT
Pulmonary Function Test
PGD2
Prostaglandin D2
PK
Pharmacokinetics
QD
Once daily
rs
Reference SNP (identifier)
SABA
Short-acting β2-adrenergic agonist
SAE
Serious adverse experience
SAP
Statistical analysis plan
SD
Standard deviation
SNP
Single nucleotide polymorphism
sSAP
Supplemental statistical analysis plan
Th2
T-helper cell type 2
ULN
Upper limit of normal
μg
Microgram
 
 
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Method 
for 
Administering 
Short-Acting 
Beta-Agonist 
(SABA) 
during 
12.7
Postbronchodilator Testing 
In assessing -agonist response in the clinic, spacer devices will be used to administer 
medication. Four puffs of SABA (albuterol/salbutamol) will be administered.
Procedure
1.
Shake the metered-dose inhaler and insert into spacer device.
2.
Tilt the head back slightly and breathe out.
3.
Place spacer device in mouth.
4.
Press down on inhaler to release medication into spacer device.
5.
Breathe in slowly (3 to 5 seconds) to total lung capacity.
6.
Hold breath for 10 seconds.
7.
Wait 1 minute between each puff and repeat the same sequence 3 additional times. 
 
 
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Method for Performing Peak Flow Measurements
12.8
A peak flow meter will be provided to each patient and should be used throughout the study 
by all patients. Patients should demonstrate adequate performance of the peak flow 
procedure.
Procedure
1.
Place the indicator at the base of the numbered scale.
2.
Stand up.
3.
Take a deep breath to total lung capacity.
4.
Place the meter in the mouth and close lips around the mouthpiece. Hold the meter such 
that fingers will not interfere with the movement of the indicator.
5.
Blow out as hard and fast as possible. A prolonged expiration is necessary when 
performing spirometry, but not in PEF.
6.
Write down the achieved measurement or value.
7.
Repeat the process 2 more times.
8.
Record the highest of the 3 numbers achieved.
The peak flow measurement is to be obtained in the early morning, upon rising, and at 
bedtime prior to taking study drug. All peak flow measurements should be obtained at least 6
hours after the last SABA (albuterol/salbutamol) dose. If SABA is needed within the 6 hours 
before going to bed in the evening, then the peak flow should be done before the 
administration of SABA.
Otherwise, AM peak flow should be performed immediately upon arising out of bed. PM 
peak flow should be performed immediately before going to bed in the evening prior to 
taking study drug, and before using any SABA.
 
 
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Action Plan for Deterioration of Asthma
12.9
A. If the PEF decreases below the predefined alert level (60%) compared to baseline
OR
If the subject believes that there is significant worsening of asthma symptoms 
necessitating an increase in usual medications:
1. The subject should call the investigator immediately.
2. The investigator will make a clinical evaluation of the patient.
3. If additional treatment is required, the use of nebulized -adrenergic agents should be 
the first treatment and the patient should be brought in for an unscheduled visit as 
soon as possible.
4. If other therapy is deemed necessary:

Perform spirometry as soon as possible after subject notes worsening of asthma 
symptoms.

Begin oral corticosteroid therapy (equivalent of prednisone) 20 to 60 mg daily.
5. If the subject is stabilized within 5 days (return to clinical state before exacerbation), 
the subject can be continued in the study.
Note: Whenever possible, the patient will be asked to return to the clinic for 
interim spirometry measurements before rescue therapy is initiated.
B.
If stabilization does not occur within 5 days with the above action plan, the subject will 
be discontinued from further study after consultation with the clinical monitor.
C.
A subject should be discontinued from further study if any corticosteroid therapy other 
than the single oral corticosteroid rescue therapy is required (e.g., inhaled corticosteroid 
therapy is initiated), or if theophylline (oral or intravenous) is required for an asthma 
attack. 
D.
Once stable, every attempt should be made to taper the oral corticosteroid dose to zero 
within 14 days. If the subject must be maintained on oral corticosteroid therapy for 
greater than 14 days in order to achieve stability, then the subject should be considered 
to be discontinued from the study.
E.
If the subject receives more than one rescue after randomization, then the patient should 
be discontinued from the study.
F.
If the subject receives one rescue between Visits 2 and 4, then the subject should be 
discontinued from the study.
 
 
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Procedure for Tapering Controller Medications
12.10
Any subject receiving asthma controller medication(s) prior to Visit 2 is required to undergo 
controller reduction, using a tightly specified approach, between Visit 2 and Visit 4. Short-
acting Beta-Agonist (SABA), for rescue use as needed, will be provided to all subjects.
While tapering off controllers, the subject completes the e-Diary for twice-daily monitoring 
of symptoms and PEF, which helps ensure subject safety. 
1. Pre-study Period from Visit 2 to Visit 3 (about 1 week in duration): 
1.1
Subjects receiving LABA discontinue it at Visit 2. Subjects continue to receive 
their usual dose of ICS.*
*Note: In some cases, substitution of the subject’s ICS with a different but comparable 
ICS is permissible if local regulations or reimbursement policies make it difficult for the 
subject to continue a specific ICS.
1.2
Subjects not receiving LABA continue their pre-study controller regimen. 
2. Single-blind Run-in Period from Visit 3 to Visit 4 (about 2 to 4 weeks in duration): 

During this period, all subjects receive open-label montelukast (supplied by this 
study), plus MK-1029 150 mg matching-image placebo, which are taken together
once daily in the evening (QD PM). Subjects should not be told that placebo is 
administered specifically during this period.
Tapering:  Patients receiving asthma controller therapy will taper off that therapy during 
this period. 
2.1
Subjects receiving leukotriene antagonists, xanthines (e.g., theophylline), or other 
oral controllers will discontinue them. 
If the subject does not meet Tapering Exclusion Criteria (defined below) during
≥14 days of receiving only open-label montelukast plus MK-1029 150 mg 
matching-image placebo, then the subject returns to the site for Visit 4. 
2.2
Subjects receiving ICS will reduce the total daily ICS dose by approximately 50%. 
This could be accomplished by decreasing the number of puffs/day (e.g., 2 puffs 
BID decreases to 1 puff BID; or, 1 puff [of the lowest strength of ICS] BID 
decreases to 1 puff QD PM) or by decreasing the ICS strength (e.g., fluticasone 
propionate 250 μg BID decreases to 100 μg BID).
If the subject does not meet Tapering Exclusion Criteria (defined below) during 
≥14 days of reduced ICS therapy, then the ICS is discontinued. THEN…
If the subject does not meet Tapering Exclusion Criteria (defined below) during 
≥14 days of receiving only open-label montelukast 10 mg plus MK-1029 150 mg 
matching-image placebo, then the subject returns to the site for Visit 4.
 
 
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Tapering Exclusion Criteria
At the discretion of the Investigator, subjects may be excluded from the study if one or more
of the following occur:
1. use of >12 puffs of SABA and/or >2 treatments with nebulized SABA on any two 
consecutive days;
2. a decrease in AM or PM peak flow below the “60% PEF alert” value (established at 
Visit 2) on two consecutive days;
3
the investigator believes the subject cannot tolerate tapering of asthma controller therapy.
A subject who experiences a clinically significant deterioration of asthma between Visit 2
and Visit 4 must be excluded from the study. The criteria for a significant deterioration of 
asthma that requires exclusion are one or more of the following, if observed:
1. a decrease in FEV1 to less than 50% of predicted normal;
2. an absolute decrease in FEV1 of 20% or greater from baseline at Visit 2;
3. a clinical asthma exacerbation requiring emergency treatment, hospital admission 
(serious AE) or treatment with additional asthma medication (other than SABA).
Summary of Procedure for Tapering Controller Medications
Visit 2:

In subjects receiving LABA/ICS, discontinue the LABA and maintain the 
ICS (at equivalent strength/dose) for about 1 week .
Visit 3:

In subjects receiving oral controllers, discontinue them for ≥14 days.

In subjects receiving ICS, reduce the dose by 50% for ≥14 days; 
About 2 weeks following Visit 3:

In subjects receiving reduced-dose ICS, discontinue ICS for ≥14 days.
 
 
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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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