Clinical trial NCT02741271
Conditions: Asthma
Sponsor: Organon and Co
Start date: 2016-05-11; Completion date: 2017-12-04
Enrollment: 181 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study compares the 12-week efficacy and 24-week safety of mometasone furoate/formoterol fumarate (MF/F) 100/10 mcg and mometasone furate (MF) 100 mcg, both administered twice daily (BID) via metered-dose inhaler (MDI) in children aged 5 to 11 years with persistent asthma.

Detailed description:

Arms: arm 1: Eligible participants will be assigned randomly to receive double-blinded MF/F MDI 100/10 mcg BID for 24 weeks. arm 2: Eligible participants will be assigned randomly to receive double-blinded MF MDI 100 mcg BID for 24 weeks.
Interventions: intervention 1: MF MDI 100 mcg BID (Open Label) intervention 2: MF/F MDI 100/10 mcg BID intervention 3: MF MDI 100 mcg BID intervention 4: Albuterol/Salbutamol PRN intervention 5: Prednisone/Prednisolone
Intervention descriptions: intervention 1: Eligible participants will receive open-label MF MDI 100 mcg BID during a 2-week run-in period. intervention 2: After a 2 week run-in on open-label MF MDI 100 mcg BID, eligible participants will receive double-blinded treatment with MF/F MDI 100/10 mcg BID. intervention 3: After a 2 week run-in on open-label MF MDI 100 mcg BID, eligible participants will receive double-blinded treatment with MF MDI 100 mcg BID. intervention 4: Participants may use study-provided short-acting beta agonist (SABA), albuterol/salbutamol, as needed (PRN) for the relief of asthma symptoms. intervention 5: Participants may use a systemic corticosteroid (prednisone/prednisolone) for acute asthma worsening per investigator discretion.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT02741271 
Document Date: 
04-OCT-2016
A Phase III, Randomized, Active-Controlled, Parallel-Group Clinical Trial to 
Study the Efficacy and Long-Term Safety of Mometasone Furoate / Formoterol 
Fumarate (MF/F, MK-0887A [SCH418131]), Compared with Mometasone 
Furoate (MF, MK-0887 [SCH032088]), in Children with Persistent Asthma


Product:  MK-0887A 
1
Protocol/Amendment No.: 087-01 
MK-0887A-087-01 Final Protocol
4-Oct-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, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Phase III, Randomized, Active-Controlled, Parallel-Group Clinical Trial to Study the 
Efficacy and Long-Term Safety of Mometasone Furoate / Formoterol Fumarate (MF/F, MK-
0887A [SCH418131]), Compared with Mometasone Furoate (MF, MK-0887 [SCH032088]), 
in Children with Persistent Asthma
IND NUMBER:  70,283 and IND 52,214 
EudraCT NUMBER:  2009–010110–30
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 20
2.0
TRIAL DESIGN........................................................................................................ 20
Trial Design ........................................................................................................... 20
2.1
Trial Diagram........................................................................................................ 23
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 23
Primary Objective(s) & Hypothesis(es) .............................................................. 23
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 24
3.2
4.0
BACKGROUND & RATIONALE.......................................................................... 25
Background ........................................................................................................... 25
4.1
Pharmaceutical and Therapeutic Background .................................................... 25
4.1.1
Rationale................................................................................................................ 27
4.2
Rationale for the Trial and Selected Subject Population .................................... 27
4.2.1
Rationale for Dose Selection/Regimen............................................................... 27
4.2.2
4.2.2.1
Rationale for the Use of Comparator........................................................... 29
Rationale for Endpoints ...................................................................................... 29
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 29
4.2.3.2
Pharmacokinetic Endpoints ......................................................................... 30
4.2.3.3
Future Biomedical Research........................................................................ 30
Benefit/Risk ........................................................................................................... 31
4.3
5.0
METHODOLOGY ................................................................................................... 32
Entry Criteria........................................................................................................ 32
5.1
 
 
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Diagnosis/Condition for Entry into the Trial ...................................................... 32
5.1.1
Subject Inclusion Criteria.................................................................................... 32
5.1.2
Subject Exclusion Criteria .................................................................................. 34
5.1.3
Trial Treatment(s) ................................................................................................ 35
5.2
Dose Selection .................................................................................................... 37
5.2.1
Timing of Dose Administration .......................................................................... 37
5.2.2
Trial Blinding/Masking....................................................................................... 39
5.2.3
Randomization or Treatment Allocation............................................................ 39
5.3
Stratification.......................................................................................................... 40
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 40
5.5
Rescue Medications & Supportive Care............................................................. 42
5.6
Diet/Activity/Other Considerations..................................................................... 43
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 43
5.8
Discontinuation of Treatment ............................................................................. 43
5.8.1
Withdrawal from the Trial .................................................................................. 44
5.8.2
Subject Replacement Strategy............................................................................. 44
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
7.1.1.1
Informed Consent......................................................................................... 50
General Informed Consent.................................................................... 50
7.1.1.1.1
Consent and Collection of Specimens for Future Biomedical 
7.1.1.1.2
 
 
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Research................................................................................................ 51
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 51
7.1.1.3
Subject Identification Card .......................................................................... 51
7.1.1.4
Medical History ........................................................................................... 51
7.1.1.5
Prior and Concomitant Medications Review ............................................... 51
Prior Medications.................................................................................. 51
7.1.1.5.1
Concomitant Medications..................................................................... 52
7.1.1.5.2
7.1.1.6
Assignment of Screening Number............................................................... 52
7.1.1.7
Assignment of Randomization Number....................................................... 52
7.1.1.8
Trial Compliance (Medication/Other) ......................................................... 52
Clinical Procedures/Assessments........................................................................ 54
7.1.2
7.1.2.1
Review Adverse Event................................................................................. 54
7.1.2.2
Physical Examination................................................................................... 54
7.1.2.3
Height and Weight ....................................................................................... 54
7.1.2.4
Oropharyngeal Examination ........................................................................ 54
7.1.2.5
Vital Signs.................................................................................................... 55
7.1.2.6
Spirometry, also known as Pulmonary Function Testing (PFT).................. 55
7.1.2.7
Airway Reversibility.................................................................................... 56
7.1.2.8
In-clinic witnessed dosing............................................................................ 57
7.1.2.9
Pre- and post-dose spirometry ..................................................................... 57
7.1.2.10 eDiary (IVRS/IWRS) and Peak Flow Meter: Instructions .......................... 57
7.1.2.11 Obtain/Review eDiary (IVRS/IWRS) Data with Subject and Caregiver .... 60
7.1.2.12 Asthma Action Plan ..................................................................................... 61
7.1.2.13 Asthma Baseline Pediatric Profile ............................................................... 62
7.1.2.14 Dispense/Collect Trial medication Inhalers................................................. 62
 
 
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7.1.2.15 Review Medication Compliance.................................................................. 64
7.1.2.16 Inhaler Use Training and Review ................................................................ 64
7.1.2.17 Rescue Medications ..................................................................................... 65
7.1.2.18 PK Sub-trial ................................................................................................. 65
Laboratory Procedures/Assessments .................................................................. 66
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 66
7.1.3.2
Pharmacokinetic/Pharmacodynamics Evaluations ...................................... 66
7.1.3.3
Blood Collection for Plasma MK-0887A .................................................... 67
7.1.3.4
Future Biomedical Research........................................................................ 67
Other Procedures................................................................................................. 67
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 67
Withdrawal From Future Biomedical Research ................................... 67
7.1.4.1.1
7.1.4.2
Lost to Follow-up......................................................................................... 68
7.1.4.3
Blinding/Unblinding .................................................................................... 68
7.1.4.4
Domiciling ................................................................................................... 69
7.1.4.5
Calibration of Critical Equipment................................................................ 69
Visit Requirements.............................................................................................. 69
7.1.5
7.1.5.1
Re- Screening............................................................................................... 69
7.1.5.2
Discontinued Subjects Continuing to be Monitored in the Trial ................. 70
7.1.5.3
Post-Trial...................................................................................................... 71
Assessing and Recording Adverse Events and Patient/Device Events............. 71
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 73
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 73
7.2.2
Immediate Reporting of Adverse Events and Incidents to the Sponsor ............. 74
7.2.3
 
 
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7.2.3.1
Serious Adverse Events and Incidents......................................................... 74
7.2.3.2
Events of Clinical Interest............................................................................ 75
Evaluating Adverse Events ................................................................................. 76
7.2.4
Sponsor Responsibility for Reporting Adverse Events and Patient/Device 
7.2.5
Events and Incidents ........................................................................................... 79
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 79
7.3
Scientific Advisory Committee........................................................................... 79
7.3.1
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 79
Statistical Analysis Plan Summary ..................................................................... 79
8.1
Statistical Analysis Plan ....................................................................................... 80
8.2
Hypothesis/Estimation ........................................................................................ 80
8.2.1
Analysis Endpoints ............................................................................................. 81
8.2.2
8.2.2.1
Derivations of Efficacy Endpoints............................................................... 81
8.2.2.2
Derivations of Safety Endpoints .................................................................. 81
Analysis Populations........................................................................................... 82
8.2.3
8.2.3.1
Efficacy Analysis Population....................................................................... 82
8.2.3.2
Safety Analysis Population.......................................................................... 82
Statistical Methods.............................................................................................. 82
8.2.4
8.2.4.1
Statistical Methods for Efficacy Analysis.................................................... 82
Applying a Control-based Multiple Imputation.................................... 83
8.2.4.1.1
Missing-Data Sensitivity Analyses....................................................... 84
8.2.4.1.2
8.2.4.2
Other Analysis ............................................................................................. 86
8.2.4.3
Statistical Methods for Safety Analyses ...................................................... 86
8.2.4.4
Summaries of Baseline Characteristics and Demographics......................... 87
Multiplicity ......................................................................................................... 88
8.2.5
 
 
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Justification of Sample Size................................................................................ 88
8.2.6
8.2.6.1
Sample-size Calculation for the Primary Analysis (using Multiple 
Imputation)................................................................................................... 88
Subgroup Analyses and Effect of Baseline Factors ............................................ 90
8.2.7
Interim Analyses ................................................................................................. 90
8.2.8
Compliance (Medication Adherence) ................................................................. 90
8.2.9
Extent of Exposure.............................................................................................. 91
8.2.10
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 91
Investigational Product ........................................................................................ 91
9.1
Packaging and Labeling Information ................................................................. 92
9.2
Clinical Supplies Disclosure................................................................................. 92
9.3
Storage and Handling Requirements.................................................................. 92
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 93
9.5
Standard Policies................................................................................................... 93
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 93
Confidentiality....................................................................................................... 93
10.1
Confidentiality of Data ....................................................................................... 93
10.1.1
Confidentiality of Subject Records ..................................................................... 93
10.1.2
Confidentiality of Investigator Information........................................................ 94
10.1.3
Confidentiality of IRB/IEC Information............................................................. 94
10.1.4
Compliance with Financial Disclosure Requirements....................................... 94
10.2
Compliance with Law, Audit and Debarment ................................................... 95
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 97
10.4
Quality Management System............................................................................... 97
10.5
 
 
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Data Management................................................................................................. 97
10.6
Publications ........................................................................................................... 97
10.7
11.0
LIST OF REFERENCES......................................................................................... 99
12.0
APPENDICES......................................................................................................... 100
Merck Code of Conduct for Clinical Trials...................................................... 100
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research............................................................................................................... 102
Pharmacogenetics 
Informational 
Brochure 
for 
IRBs/IECs 
& 
12.3
Investigational Site Staff .................................................................................... 109
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.4
by Sample Types ................................................................................................. 118
Pharmacokinetic Sub-Trial: MK-0887A Protocol 087.................................... 119
12.5
General Instructions for Use of the MDI.......................................................... 124
12.6
Stoughton-Cornell Scale..................................................................................... 126
12.7
Method for Administering Short-Acting Beta-Agonist (SABA) During 
12.8
Postbronchodilator testing for Airway Reversibility ...................................... 128
Standardization of Spirometry .......................................................................... 130
12.9
Asthma Action Plan............................................................................................ 131
12.10
Asthma eDiary (IVRS/IWRS) Questions.......................................................... 134
12.11
Statistical Methodology ...................................................................................... 136
12.12
List of Abbreviations .......................................................................................... 138
12.13
13.0
SIGNATURES......................................................................................................... 140
Sponsor's Representative ................................................................................... 140
13.1
Investigator.......................................................................................................... 140
13.2
 
 
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LIST OF TABLES
    
Table 1  Medications to be withheld prior to Spirometry Testing (All Visits with 
Spirometry) ................................................................................................................. 33
Table 2  Medications Excluded Prior to the Screening Visit (Visit 1) ................................... 35
Table 3  Trial Medication/Rescue Medication........................................................................ 36
Table 4  Double-Blind Treatment........................................................................................... 39
Table 5  Medications Prohibited After Screening and for the Duration of the Trial.............. 41
Table 6  Example Calculation of the Stability Limit for Peak Flow ...................................... 60
Table 7  Laboratory Tests ....................................................................................................... 66
Table 8  Evaluating Adverse Events....................................................................................... 77
Table 9  Summary of the Statistical Analysis Plan................................................................. 79
Table 10  Summary of Efficacy Analyses .............................................................................. 84
Table 11  Analysis Strategy for Safety Parameters ................................................................ 87
Table 12  Product Descriptions............................................................................................... 91
 
 
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LIST OF FIGURES
          
Figure 1  Trial design for Protocol MK-0887A-087............................................................... 23
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number
Section Title
Description of Change
Rationale
8.0
Statistical Analysis 
Plan
The control-based imputation of missing %-
predicted FEV1 data is now part of the 
primary analysis (it was originally proposed 
as a sensitivity analysis).  The original, 
primary method of imputation based on the 
Missing-At-Random assumption, has been 
moved to one of the supportive analyses.  
Note that the primary endpoint, %-predicted 
FEV1, remains the same.
FDA request to modify SAP 
on handling of missing data 
by reversing the roles of 
primary 
and 
sensitivity 
imputation methods.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
2.1
7.1.2.7
Trial Design
Airway Reversibility
Added reference to section on 
rescue medication.
Clarified visits and timeframe 
on when reversibility procedure 
can occur with related text:
“The reversibility testing prior 
to Visit 3 must be performed at 
least two days prior to the Visit 
3 due to the timeframe for the 
over-read of the spirometry 
report from the central vendor.”
Changes 
were 
made 
for 
reference 
and 
further 
clarification purposes on the 
reversibility procedure.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
Removed text with details of 
prior reversibility procedure 
and 
added 
reference 
to 
Appendix 12.8 for updated 
procedure.
4.2.1 
Rationale for the Trial and 
Selected Subject Population
Clarified 
timing 
of 
the 
reversibility procedure post-
bronchodilator 
administration 
to within “approximately” 30 
minutes instead of ‘within 30 
minutes’.
Changes were made based 
upon 
feedback 
from 
field 
operations as timing of updated 
reversibility 
procedure 
may 
vary and not be exactly within 
30 
minutes 
of 
SABA 
administration.
5.1.2
12.5
Subject Inclusion Criteria
Pharmacokinetic Sub-Trial: 
MK-0887A Protocol 087
Criteria #1:  Removed text in 
parenthesis related to age of 
assent: “(subjects ages 7 to 11 
years, would provide an assent, 
or 
provide 
consent 
in 
accordance 
with 
local 
regulations)”.
Per guidelines, age for assent 
would 
be 
determined 
by 
IRB/ERC.  Change does not 
impact ICF.
5.1.2
5.1.3
Subject Inclusion Criteria
Subject Exclusion Criteria
Table 1 (Medications to be 
withheld prior to Spirometry 
Testing), Table 2 (Medications 
Excluded Prior to the Screening 
Visit 
[Visit 
1]): 
Updated 
column header to ‘Minimum’ 
Excluded Timeframe instead of 
‘Excluded Timeframe”.
Provide 
clarification 
for
flexibility 
to 
washout 
timeframes.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.1.3
Subject Exclusion Criteria 
Criteria 
#4: 
Clarified 
compliance 
measurement 
is 
based off of MDI: “…and will 
be determined by comparing 
the change in dose counter 
readings relative to the duration 
of treatment as entered on the 
eCRF”.
To provide emphasis on use of 
MDI 
dose 
counter 
for 
compliance measure.
5.2 and throughout protocol
Trial Treatment
Other related sections
Changed Trial ‘Treatment’ to 
Trial ‘Medication’.
Updated 
wording 
for 
consistency 
in 
terminology 
throughout the protocol.
5.2
5.2.2
5.6
7.1.2.7
7.1.2.17
Trial Treatment(s)
Timing of Dose Administration
Rescue Medication & 
Supportive Care
Airway Reversibility
Rescue Medications
Clarified when use of spacers
are 
permitted 
and 
not 
permitted:
“Spacer 
devices 
are 
not 
permitted with the open-label 
and 
double-blinded 
trial 
medication as well as the 
training inhalers.”
“Spacers are only permitted for 
SABA 
used 
as 
rescue 
medication (as well as for 
SABA administered for the 
purposes 
of 
demonstrating 
reversibility [Section 7.1.2.7]).”  
To emphasize that use of spacer 
is 
not 
allowed 
with 
trial 
medication.  To clarify of 
spacers are only allowed for 
use with rescue SABA and 
during reversibility.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.8
Subject 
Withdrawal/Discontinuation 
Criteria
Organizational 
changes 
to 
reflect 
separate 
subsections 
beneath 
Section 
5.8 
for
discontinuation 
of 
treatment/vaccination 
(5.8.1) 
and 
withdrawal 
from 
trial 
(5.8.2).
Application 
of 
consistent 
terminology 
to 
refer 
to 
‘treatment/vaccination
discontinuation’ 
vs. 
‘withdrawal from trial’.
Brief 
rationale 
added 
to 
describe the importance of 
monitoring beyond treatment
discontinuation.
Template update as well as in 
alignment with FDA request to 
follow 
subjects 
who 
discontinue treatment during
the trial.
6.0
Trial Flowchart
Clarification to Footnotes k, m, 
and n:
k:  Referenced Section 7.1.2.7 
for 
details 
on 
reversibility 
procedure.
m & n: Clarified that females 
of child bearing potential need 
both dipstick and HCG urine 
testing.
Further clarify procedures for 
females 
of 
child-bearing 
potential.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.1.6
Assignment of Screening 
Number
Updated text to ‘Any subject 
who is rescreened….”
from 
“Any subject who is screened 
multiple times.”
In the protocol we do not allow 
for multiple re-screenings.
7.1.1.8
Trial Compliance
Added clarifying text on: 
A rescheduled visit should be 
“in 
accordance 
with 
the 
appropriate visit window.”
For 
the 
eDiary: 
“Daily 
assessment 
data 
must 
be 
reviewed by the investigator.”
To 
clarify 
guidance 
on 
rescheduled 
visit 
and 
emphasize review of diary data 
by investigators.
7.1.2.3
Height and Weight
Clarified that equipment used 
to measure height and weight 
does not need to have a 
separate calibration for the 
purposes of the trial. 
To clarify that not all devices 
need to be calibrated.
7.1.2.6
Spirometry, also known as 
Pulmonary Function Testing 
(PFT)
Provided information to sites 
that “if the site and the central 
vendor cannot agree on the data 
value(s), the sponsor should be 
consulted.”
Also, “In order to receive 
timely receipt of the vendor’s 
selected 
measurements, 
the 
PFT data should be transmitted, 
by the site, at the end of each 
Provided specific information 
to sites on vendor review of 
PFT data.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
testing 
day.” 
 
Note: 
The 
Investigator should consider the 
safety and well-being of the 
subject 
if 
reversibility 
is 
repeated more than once.  In
addition, 
the 
Investigator 
should have a clinical rationale 
for why reversibility should be 
repeated.  
7.1.2.10
eDiary (IVRS/IWRS) and Peak 
Flow Meter: Instructions 
Clarified 
that 
SABA 
as 
prevention for exercise-induced 
bronchospasm (EIB) is not 
considered rescue use; it should 
not be captured in the eDiary.  
This should be capture in the 
CM eCRF.
Clarify procedure of capturing 
SABA use for EIB.
7.1.2.13
Asthma Baseline Pediatric 
Profile
Added section on completing 
ABPP eCRF.
Provided specific information 
on completion of  standard 
respiratory eCRF.
7.1.2.17
Rescue Medications: 
Dispense/Retrieve Oral 
Prednisone/Prednisolone 
Medication (as needed):  All 
visits
Clarified for oral steroids that 
“The 
course 
of 
steroid 
treatment will be determined by 
the prescribing health care 
provider”.
Clarify 
the 
definition 
of 
‘course’.
7.1.3.1
Laboratory Safety Evaluations 
(Hematology, Chemistry and 
Female 
subjects
of 
child 
bearing 
potential 
will 
be 
required at all visits to perform 
Clarified 
urine 
collection 
procedure for females of child-
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
Urinalysis)
a urine pregnancy test with a 
dipstick as well as HCG urine 
testing.  Sites will submit HCG 
urine testing to the central lab 
regardless of the outcome from 
the site performed dipstick 
testing.
Table 7 Removed duplicate for 
Alanine 
aminotransferase 
(ALT).
bearing potential.
Removed duplicate test name.
7.1.4.1.2
Lost to Follow-up
Added section for procedures 
for Lost to Follow-up.
Added section per template as 
Section 5.8 was updated.
7.1.5.1
Re-Screening
Clarified 
definition 
of 
re-
screening to subjects who do 
not meet one or more criteria 
required for participation in a 
trial.
Clarified to be consistent with 
eCRF guidance.
7.1.5.2
Discontinued Subjects 
Continuing to be Monitored in 
the Trial
Updated section title from 
“Follow-up 
after 
Premature 
Discontinuation of Treatment” 
to match updated to template.
Updated title of section per 
template update.
8.2.4.1
Statistical Methods for Efficacy 
Analyses
Added description of 
how 
missing data will be imputed.
Changed 
primary 
efficacy 
analysis.
8.2.4.1.2
Missing-Data Sensitivity 
Analysis
Added leading statement for 
statistical sensitivity analyses.
Help better justify rationale for 
sensitivity analyses.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
8.2.6.1
Sample-size Calculation for the 
Primary Analysis (using 
Multiple Imputation)
Added leading statement for 
statistical sensitivity analyses.
Help 
better 
understand 
scenarios 
for 
sample 
size 
estimation.
8.2.6.1
Sample-size Calculation for the 
Primary Analysis (using 
Multiple Imputation)
Moved sample size statement 
from end to beginning of 
section.
Have sample size up front to 
help reader get the resulting 
sample size faster.
8.2.7
Subgroup Analyses and Effect 
of Baseline Factors
Added clarification statement 
for analysis of subgroups.
Alignment of statistical method 
for analysis of subgroups with 
primary efficacy analysis.
9.1
Investigational Product
Updated text to remove text on 
similarity of placebo trainer to 
trial medication. 
Updated/clarified 
to 
avoid 
confusion 
during 
CofA 
submissions.
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.
Updated protocol template.
12.8
7.1.2.7
Method for Administering 
Short-Acting Beta-Agonist 
(SABA) During Post 
bronchodilator testing for 
Airway Reversibility
Airway Reversibility
Clarification 
to 
reversibility 
procedure as per PCL (May 
2016).
Added text and listed procedure 
for using nebulization of SABA 
during reversibility.
Clarified procedure as it was 
not clear to sites.
Use of nebulization added 
based on site feedback.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
12.10
Asthma Action Plan
Updated calculation text.
Removed text on ‘comment 
card’ as these are not used in 
the trial.
Formatted text to improve 
readability of calculations for 
each range.
Updated text errors and other 
formatting changes for easier 
readability.
12.13
List of Abbreviations
Added abbreviation for ABPP: 
Asthma Baseline Pediatric 
Profile.
Added as this was added to the 
protocol.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
MK-0887A efficacy and long-term safety in children with persistent 
asthma
Trial Phase
III
Clinical Indication
Treatment of persistent asthma in children ages 5 to 11 years
Trial Type
Interventional
Type of control
Active control without placebo
Route of administration
Oral inhalation
Trial Blinding
Double-blind
Treatment Groups
Mometasone furoate / formoterol fumarate (MF/F) 100/10 mcg twice 
daily given via a metered dose inhaler (MDI)
MF 100 mcg twice daily given via a MDI
Number of trial subjects
Approximately 160 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 21
months from the time the first subject signs the informed consent 
until the last subject’s last visit.
Duration of Participation
Each subject participates in the trial for approximately 29 weeks, 
from the time the subject signs the Informed Consent Form (ICF) 
through the final contact. After a screening phase of ~1 week, each 
subject enters a ~2-week open-label run-in period, followed by a 
~24-week double-blind active treatment period.  After completion of 
the double-blind treatment period, each subject is followed for 
approximately 2 weeks.
A list of abbreviations used in this document is in Section 12.13.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a multi-center, randomized, double-blind, active-controlled, parallel-group trial of 
mometasone furoate / formoterol fumarate (MF/F) 100/10 mcg and mometasone furoate 
(MF) 100 mcg, each given via a metered-dose inhaler (MDI) twice daily, in children ages 5 
to 11 years with persistent asthma already receiving inhaled corticosteroid / long-acting beta-
agonist (ICS/LABA) combination therapy, to be conducted in conformance with Good 
Clinical Practices (GCP). The trial consists of a 1-week Screening Period, a 2-week Open-
label Run-in Period (during which all subjects receive MF), and a 24-week Double-blind 
Treatment Period (MF/F or MF, for assessment of efficacy and safety during the first 12 
weeks and assessment of safety during the last 12 weeks); 2 weeks after completing 
treatment, there is a follow-up assessment for safety.  
Randomization Ratio
1:1
 
 
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Screening Period (Visit 1 to Visit 2)
At the Screening Visit (Visit 1), after providing consent, subjects will undergo general 
screening procedures. Subjects will enter the trial having been adequately controlled on a 
stable dose of ICS/LABA fixed-dose combination (FDC) therapy, such as Advair®,1 for at 
least 4 weeks prior to Visit 1. During the Screening Period, subjects will remain on their 
pre-trial ICS/LABA combination therapy. At Visit 1, subjects will practice inhalation 
technique with a MDI training inhaler under supervision at the trial site, in order to 
demonstrate appropriate MDI inhalation technique. At Visit 1, the site will review, with the 
subjects/caregivers, the proper completion of an electronic diary (eDiary) that is based on an 
interactive voice-response system / integrated web-response system (IVRS/IWRS). The
eDiary (IVRS/IWRS) is to be used daily to capture the subject’s use of trial medication and 
use of rescue medication(s). Rescue medications (short-acting beta-agonist [SABA,
albuterol/salbutamol] and oral corticosteroid [prednisone or prednisolone]) will be made 
available for the subject at Visit 1 (Section 5.6). Rescue medication is to be used for 
worsening asthma per the Asthma Action Plan (AAP [Appendix 12.10]). An individualized 
written AAP is provided at Visit 1, by the investigator to the subject and the caregiver, to
provide guidance on effectively managing the subject’s asthma symptoms, as recommended 
by clinical practice guidelines. Subjects should have access to a peak expiratory flow (PEF) 
meter to use daily for the duration of the trial.  Subjects must perform PEF measurements 
every morning (AM) upon rising. Based on once-daily PEF measurements (AM only) 
reported during the Screening Period, a PEF “stability limit” will be calculated at Visit 2, 
prior to entering the Open-label Run-in Period.
Run-in Period (Visit 2 to Visit 3)
Beginning at Visit 2, there will be an approximately 2-week Open-label Run-in Period, 
during which subjects will receive MF 100 mcg given via a MDI twice daily. Subjects will 
have taken the last dose of their pre-trial ICS/LABA combination therapy the night before 
Visit 2. The morning of Visit 2, subjects will receive their first dose of MF 100 mcg in the 
clinic, as a witnessed dose.  
                                                
1 ADVAIR® is a registered trademark of the GlaxoSmithKline group of companies, Research Triangle Park, NC 27709 USA
 
 
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The purpose of the Run-in Period is to ascertain that the subject acceptably performs all 
necessary procedures and can be eligible for randomization. The rationale for treating with
MF MDI is to standardize treatment prior to randomization. This may also afford a greater 
opportunity to demonstrate airway reversibility (since subjects will likely demonstrate higher 
FEV1 and lower reversibility on FDC at Screening). If the subject does not meet reversibility 
criteria at Visit 1, repeat assessments can be performed at least two days prior to Visit 3.  
(Section 7.1.2.7)
Double-blind Treatment Period (Visit 3 to Visit 8)
At Visit 3, subjects meeting all the inclusion criteria and none of the exclusion criteria will be 
randomized to enter an approximately 24-week Double-blind Treatment Period, during 
which they will receive either MF/F 100/10 mcg or MF 100 mcg, given via a MDI twice 
daily. Approximately 160 subjects will be randomized to receive MF/F or MF in a 1:1 ratio, 
according to the Sponsor’s computer-generated randomization schedule. To ensure adequate 
and balanced representation of younger subjects, randomization is stratified by age (5-to-7
versus 8-to-11 years of age). Ongoing trial monitoring will be used to target approximately 
20% of randomized subjects in the 5- to 7-year-old age stratum. To ensure that treatment 
allocation is balanced across geographic regions of the world in this large multinational trial, 
randomization is also stratified by region. At each visit during this treatment period (Visit 3 
to Visit 7), blinded trial medication is administered as a witnessed dose, followed by one 
hour of serial spirometry measurements. Further, at Visit 3 and at Visit 7, spirometry will 
also be performed at two hours and four hours after the witnessed dose.
At Visit 3 (or any visit prior to Visit 7), subjects at selected sites (and after signing consent to 
participate in the main trial) will have the option to sign a separate informed consent to 
participate in a pharmacokinetic (PK) sub-trial. At Visit 7, blood samples will be collected 
from approximately 20 subjects, to characterize the plasma concentration-time profile of MF 
(AUC0-12h, AUC0-last, Cmax, and Tmax) following repeated twice-daily oral inhalations of MF/F 
or MF. Specific procedures and timing of the PK assessments are further described in 
Appendix 12.5.
After Visit 8 (which ends the approximately 24-week Double-blind Treatment Period), all
subjects will be followed for a post-treatment assessment approximately 2 weeks later. The 
post-treatment assessment captures any adverse events or other reportable events occurring
after the final dose of trial medication (Section 7.1.5.3).
Assessments during all periods
Throughout the trial, the site will evaluate the subject's asthma status (based on PEF 
measurement and rescue medication use) and medication usage (based on eDiary 
[IVRS/IWRS] data). During the trial, PEF measurements will be obtained once daily, AM 
only.  Subjects must perform PEF measurements every morning upon rising. The eDiary 
(IVRS/IWRS) will be utilized to alert the investigator to changes in PEF assessments that 
may indicate asthma worsening. The investigators should review and reach out to the subject 
for follow up.  
 
 
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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.
Trial Diagram
2.2
The trial design is depicted in Figure 1.  
Figure 1  Trial design for Protocol MK-0887A-087
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
Primary Efficacy Objective 
To demonstrate the efficacy of MF/F 100/10 mcg twice daily, compared with MF 100 mcg 
twice daily, by evaluating lung function during the first 12 weeks of double-blind treatment 
in children ages 5–11 years with persistent asthma.
 
 
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Primary Efficacy Hypothesis
MF/F 100/10 mcg twice daily is superior to MF 100 mcg twice daily on AM post-dose 
%-predicted FEV1 (measured during 60 minutes post-dose), and analyzed as the mean post-
dose change from baseline across Day 1, Week 1, Week 4, Week 8, and Week 12 in children 
ages 5 to 11 years with persistent asthma.
Trial success is defined by demonstrating a statistically significant improvement in the 
primary endpoint (AM post-dose change in %-predicted FEV1 after a witnessed dose) for 
MF/F compared with MF.  
Primary Safety Objective  
To characterize the safety and tolerability of MF/F 100/10 mcg twice daily and MF 100 mcg 
twice daily based on adverse events reported in association with up to 24 weeks of treatment 
in children ages 5 to 11 years with persistent asthma.
There is no hypothesis for the safety objective.
Secondary Objective(s) & Hypothesis(es)
3.2
Key Secondary Efficacy Objective
To determine the onset of action for the efficacy of MF/F 100/10 mcg twice daily, compared 
with MF 100 mcg twice daily, by evaluating %-predicted FEV1 in the AM of Day 1 of 
dosing, analyzed beginning at 4 hours post-dose and continuing to 2 hours, 60, 30, 15, and 5 
minutes post-dose, and measured as the change from baseline (AM pre-dose on Day 1).
Secondary Efficacy Hypothesis
MF/F 100/10 mcg has an onset of action more rapid than that of MF 100 mcg, evaluated as 
%-predicted FEV1 in the AM of Day 1 of dosing (analyzed beginning at 4 hours post-dose 
and continuing to 2 hours, 60, 30, 15, and 5 minutes post-dose) and measured as the change 
from baseline (AM pre-dose on Day 1), by comparing MF/F 100/10 mcg versus MF 100 mcg
in children ages 5 to 11 years with persistent asthma.
Secondary Objectives
(1)
To demonstrate the efficacy of MF/F 100/10 mcg twice daily, compared with MF 
100 mcg twice daily, on the change from baseline in AM post-dose %-predicted 
FEV1 as measured during 4 hours post-dose, at Day 1 and Week 12.
(2)
To demonstrate the efficacy of MF/F 100/10 mcg twice daily, compared with MF 
100 mcg twice daily, on the change from baseline in AM pre-dose %-predicted 
FEV1, averaged over weeks 4, 8, and 12 of treatment.
(3)
To demonstrate the efficacy of MF/F 100/10 mcg twice daily, compared with MF 
100 mcg twice daily, on the change from baseline in total daily short-acting 
beta-agonist (SABA) use across the first 12-weeks of double-blind treatment. 
 
 
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(4)
To characterize the plasma pharmacokinetics (PK) profile of MF and to determine 
the PK parameters (e.g., AUC0-12h, AUC0-last, Cmax, and Tmax) at steady state after 
multiple oral inhalations via MDI device in children ages 5-11 years old with 
persistent asthma.  
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB) and/or approved labeling for detailed background 
information on MK-0887A.
Pharmaceutical and Therapeutic Background
4.1.1
Asthma is the leading cause of chronic illness in many countries of the world, and there is 
concern that the prevalence of asthma is rising in developed countries, as well as in the 
developing world [1]. In the United States (US) in 2012, an estimated 18.7 million adults and 
6.8 million children were reported to have asthma, equivalent to 9.3% of children under age 
18 years in the US (National Health Interview Survey [NHIS], National Center for Health 
Statistics, Centers for Disease Control and Prevention, 2014 [NHIS 2014] [Available from: 
URL: http://www.cdc.gov/nchs/fastats/asthma.htm]). The economic impact of childhood 
asthma is reflected in hospitalization and medication costs, as well as the cost of parental 
work absences.  The impact of asthma on school-age children is immense; among persons 
with at least one asthma attack in the previous 12 months for 2008, there were 10.5 million 
school days missed due to asthma among children aged 5–17 years (Available from: URL: 
http://www.cdc.gov/nchs/data/series/sr_03/sr03_035.pdf). Inhaled corticosteroids (ICSs) are 
currently the most effective anti-inflammatory medications for the treatment of persistent 
childhood asthma and are recommended as the initial asthma therapy for children ages 5 
years and older by current asthma guidelines (Global Initiative for Asthma [GINA] 
Guidelines [Available from: http://www.ginasthma.org/]). Current asthma guidelines also 
recommend the use of long-acting β-agonist (LABAs) as add-on therapy in children ages 5 
years and older whose asthma is insufficiently controlled by ICS alone.
LABA monotherapy is not recommended as an asthma controller therapy since studies have 
suggested that LABAs increase the risk of asthma-related death and other serious asthma 
outcomes. In June 2010, the US Food and Drug Administration (FDA) announced labeling 
recommendations stating that use of a LABA alone without a long-term asthma controller 
medication, such as ICS, is contraindicated in the treatment of asthma. When subjects are 
treated concomitantly with ICS, the risk of LABAs is uncertain; however in this trial, the risk 
is manageable because the safety of all subjects is closely monitored.
Mometasone furoate (MF) is a synthetic glucocorticosteroid that binds to the glucocorticoid 
receptor (GR) with very high affinity. It is a potent corticosteroid with a low potential to 
cause systemic side effects. Controlled clinical trials in children with asthma have 
demonstrated that inhaled MF via dry powder inhaler (DPI) is efficacious in improving lung 
 
 
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function, reducing symptoms, and reducing frequency and severity of asthma exacerbations 
at doses of 100 to 200 mcg/day in children ages 4 to 11 years with no unusual or unexpected 
treatment-emergent adverse events (AEs) reported.  
Formoterol (F), a LABA, has been shown to quickly increase lung function within 5 minutes 
of administration and to maintain efficacy over 24 hours at a dose of 10 mcg twice daily
(BID). Results of Phase III clinical trials in children with asthma indicated that F at doses of 
10 or 20 mcg BID was effective in children ages 5 years and older [2].  
Co-administration (in a single inhaler) of an ICS and a long-acting bronchodilator in 
glucocorticosteroid-dependent asthma subjects is clinically superior to the same dose of ICS 
administered alone and clinically equivalent to the separate administration of the ICS and 
LABA, as acknowledged in GINA guidelines. For drugs providing rapid onset of relief from 
asthma symptoms, adherence to prescribed medication is likely to be higher than when there 
is no perceived effect on breathing. Thus, the addition of F to MF in a single inhaler may 
improve adherence to prescribed medication.  
Successful formulation of the combination of MF plus F (MF/F) in a single metered-dose 
inhaler (MDI) has made it possible to establish the twice-daily efficacy and safety profile of
this fixed-dose combination (FDC) in adults and adolescents ages 12 years and older. 
Collectively, results from Phase III clinical trials showed that in subjects who were 
inadequately controlled on ICS, MF/F delayed the time-to-first asthma exacerbation, 
compared with F alone and placebo [3]; [4]. In addition, MF/F provided rapid and sustained 
improvement in lung function, improved asthma control and quality of life, and reduced 
nocturnal awakenings requiring use of SABA when compared with placebo. Based on those 
trials, MF/F has been approved in the US (DULERA®2 MF/F MDI 100/5 mcg and 200/5 
mcg, two inhalations twice daily), Canada (ZENHALE®3 MF/F MDI 50/5 mcg, 100/5 mcg, 
and 200/5 mcg, two inhalations twice daily), and other countries for the treatment of asthma 
in adults and adolescents ages 12 years and older.
                                                
2 DULERA®, ASMANEX® HFA, and ASMANEX® TWISTHALER® are registered trademarks of Merck Sharp & Dohme Corp., 
Whitehouse Station, NJ 08889 USA
3 ZENHALE® is a trademark of MSD International Holdings Gmbh. Merck Canada Inc., a subsidiary of Merck & Co., Inc., Canada.
 
 
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The current Phase III trial evaluates MF/F MDI 100/10 mcg and MF MDI 100 mcg in 
children ages 5 to 11 years with persistent asthma. This trial builds on the documented safety 
and efficacy of MF DPI in children ages 5–11 years for ASMANEX® TWISTHALER®3 
and the documented efficacy of MF/F MDI versus MF MDI with acceptable safety that is 
well-established in adults and adolescents ages 12 years and older. The current trial is 
expected to generate data to support that MF/F MDI is superior to MF MDI for efficacy and 
to support that both MF/F MDI and MF MDI are safe for patients ages 5–11 years.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
Current asthma guidelines recommend the use of LABAs as add-on therapy in children ages 
5 years and older whose asthma is not adequately controlled on ICS alone. Based on this 
established clinical practice, there is a substantial pediatric patient population that has been 
determined by their physician to require an ICS/LABA combination to obtain adequate 
control of their asthma, and this trial will exclusively select subjects for enrollment from this 
population. This trial will include children, of any race and either sex, 5 to 11 years of age, 
with persistent asthma, who are receiving an ICS/LABA combination and whose asthma is 
adequately controlled, as defined by the Global Initiative for Asthma (GINA) guidelines (at 
http://www.ginasthma.org/). Subjects must have been diagnosed with asthma for at least 6 
months prior to Visit 1 and treated with a stable dose of ICS/LABA combination for at least 
4 weeks prior to Visit 1. Subjects are included in this trial based on an appropriate level of 
lung function at baseline, as well as demonstrating reversibility of airway obstruction within 
approximately 30 minutes of bronchodilator.
Rationale for Dose Selection/Regimen
4.2.2
Dose of Mometasone Furoate 
Controlled clinical trials have demonstrated that inhaled MF (MK-0887) via DPI is 
efficacious in improving lung function, reducing symptoms and reducing the frequency and 
severity of exacerbations at doses of 100 to 200 mcg/day in children 4 to 11 years of age. MF
DPI 100 mcg once daily (QD) in the evening (PM) is approved in the US for the maintenance 
treatment of asthma in patients 4 to 11 years of age. MF DPI 200 mcg QD is approved for 
use in patients 12 years of age and older in the US and European Union (EU). 
Previous clinical trials in children have demonstrated that a total daily dose of MF 100 mcg 
and MF 200 mcg – when given via DPI – significantly improved lung function. The 
incidence and nature of AEs reported were similar to those observed for other ICSs in 
children and were not notably different from those observed with MF DPI in adults and 
adolescents.
However, in trials C97-380 and C98-005, that assessed MF 100 mcg in the DPI formulation, 
MF DPI 100 mcg once daily in the morning or once daily in the evening did not achieve 
 
 
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statistical significance in improving lung function in children ages 4 to 11 years. In contrast, 
MF 100 mcg BID – both via DPI and via MDI – was significantly better than placebo in 
improving lung function. These results suggest that when MF is formulated as a MDI, a 
higher and/or BID dose may be necessary to achieve a comparable therapeutic effect to MF 
when given via DPI. 
A phase II dose-ranging trial (P086) was conducted to demonstrate dose-related efficacy of 
MF, by evaluating morning lung function at the end of the dosing interval (AM pre-dose 
%-predicted forced expiratory volume in one second [FEV1]) after 12 weeks of treatment. 
Three dose levels of MF MDI (50 mcg, 100 mcg, and 200 mcg) BID were each compared 
with placebo in children 5 to 11 years of age with persistent asthma. The trial demonstrated 
that each of the three doses of MF MDI was statistically superior to placebo.  Among the 3 
dose levels, however, 50 mcg BID showed sub-maximal efficacy, while both 100 mcg BID 
and 200 mcg BID showed statistically significant and clinically meaningful efficacy. The 
effects of 100 mcg BID and 200 mcg BID were similar (wherein the effect of 200 mcg BID 
was numerically slightly smaller than the effect of 100 mcg BID).  Finally, all 3 doses of MF 
MDI showed a numerically greater effect on FEV1 compared with MF DPI 100 mcg QD in 
the evening.
P086 also demonstrated that each of the 3 doses of MF MDI was well tolerated.  Across all 
the treatment arms in P086, there were no reports of the prespecified AEs of oropharyngeal 
candidiasis or dysphonia. Overall, the types and frequencies of AEs in P086 were generally 
similar across the treatment arms, with no dose-responsive pattern of reporting.  
The data from P086 support MF 100 mcg BID (via MDI) as the minimum dose providing 
clinically meaningful efficacy that is also expected to have an acceptable safety profile when 
combined with formoterol. Based on these results, this trial will evaluate MF 100 mcg BID
versus MF/F 100/10 mcg BID. 
Dose of Formoterol 
In the US, formoterol is currently approved for asthma maintenance in patients 5 years or
older, with a total daily dose not to exceed 24 mcg. Outside the US, the dosage in children is 
approved up to 40 mcg (ex-actuator) daily maximum dose. 
In a phase II trial (P06476), the bronchodilatory effect of a single administration of MF/F
MDI 100/10 mcg (with or without a spacer) was compared with F DPI 10 mcg, and with 
placebo MDI (with/without spacer) in children ages 5–11 years. The trial showed no 
difference in bronchodilation between a single administration of MF/F MDI 100/10 versus 
the approved formulation of F DPI, thus supporting the dose selection of F 10 mcg for this 
trial [4]; [5].
 
 
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4.2.2.1
Rationale for the Use of Comparator
To assess the efficacy of MF/F combination therapy, MF monotherapy is the comparator 
chosen, allowing the trial to demonstrate the contribution of the formoterol component to the 
clinical benefits of the fixed-dose combination of MF/F in children. The safety and 
effectiveness of MF monotherapy has already been assessed in controlled clinical trials in 
adults and adolescents, and most recently, in children 5-11 years of age (P086). The MF 
comparator product has the same formulation as the MF/F combination product, with the 
exception that the drug substance F has been removed and replaced with the equivalent 
amount of HFA-227 propellant, dehydrated alcohol and oleic acid. This trial will not include 
F monotherapy as a control arm because of general safety concerns associated with the use of 
a LABA as monotherapy in subjects with asthma.
Placebo is not a comparator in this trial because it is believed that a placebo control arm is 
not required to support the efficacy or safety assessments of MF/F or MF, particularly in this 
population of asthmatic children who all enter the trial being treated with ICS/LABA 
combination therapy. Furthermore, efficacy and safety of both MF/F and MF have already 
been well shown in previous studies. For MF/F in adults, 21 clinical studies (9 Phase-1 
studies, 4 Phase-2 studies, and 8 Phase-3 studies) assessing the safety, tolerability, clinical 
pharmacology, patient handling (of the MDI with an integrated dose counter), and clinical 
effectiveness of the MF/F MDI combination product have been completed. For MF in 
children, the efficacy and safety of MF have already been shown in placebo-controlled trials, 
both in studies of MF DPI in children ages 5–11 years and in P086, the recently completed 
MF MDI dose-ranging trial in children ages 5–11 years.  
Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
Primary
The primary efficacy endpoint is the AM post-dose %-predicted FEV1 (measured as the 
change from AM pre-dose %-predicted FEV1). The AM post-dose %-predicted FEV1 is 
calculated as the area under the curve from zero to 60 minutes (using the trapezoid rule) after 
a witnessed dose and divided by the time interval (to preserve the unit, %-predicted). This 
method of calculation provides an aggregate bronchodilatory effect during 1 hour post-dose. 
A separate AM post-dose %-predicted FEV1 measurement is calculated for each visit, and is 
evaluated as a change from baseline of the mean across Day 1, Week 1, Week 4, Week 8 and 
Week 12. 
Based on previous clinical studies (in adults and in children), the maximal bronchodilator 
effect of formoterol is achieved at 1 hour after dosing and is sustained for 12 hours (see also 
Section 8.2.6.)  Therefore, a series of measurements up to 60 minutes post-dose will 
adequately capture the effect of the addition of F to MF for the efficacy evaluation of MF/F 
compared with MF. 
 
 
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Secondary
Formoterol is characterized by a rapid bronchodilator effect, which may be observed within 
5 minutes of administration [4]. The key secondary endpoint of AM %-predicted FEV1 at 
each of the 5-, 15-, 30-, and 60-minute, 2- and 4 hour post-dose evaluations on Day 1 of 
dosing will assess the onset of action of MF/F. 
To further examine the overall contribution of F to the MF/F combination, an additional 
secondary endpoint, the AM post-dose %-predicted FEV1 measured during 4 hours post-dose
will be analyzed on Day 1 and Week 12 (see also Section 8.2.2.1). The secondary endpoint of 
AM pre-dose FEV1 (as averaged over weeks 4, 8, and 12 of treatment) specifically supports 
the primary endpoint evaluation by assessing the effect of the bronchodilator at the end of the 
12-hour dosing interval. Finally, the secondary endpoint of SABA use across the initial 12-
weeks of double-blind treatment provides a clinically relevant measure of asthma control 
during treatment.  
4.2.3.2
Pharmacokinetic Endpoints
Blood samples from a subgroup of subjects will be collected to characterize the plasma 
concentration-time profile of MF following multiple oral inhalations of MF/F or MF via MDI 
device administered to approximately steady state in children ages 5–11 years old with 
persistent asthma.  Plasma MF concentrations, obtained after approximately 12 weeks of 
twice-daily dosing of MF/F MDI or MF MDI, will be used to characterize PK parameters 
including steady-state Area Under the concentration-time Curve from 0 to 12 hours (AUC0-
12h), area under the curve from 0 to last concentration observed (AUC0-last), maximum 
concentration (Cmax), and time to Cmax (Tmax) of MF in children with persistent asthma. 
The PK sampling times were optimized based on the one-compartment nature of the PK 
profile of MF. Evaluation suggests that the reduced sampling scheme being used in this sub-
trial, when compared to the dense samplings used in historic clinical PK studies in adults, 
will provide adequate assessment of the non-compartmental PK parameters (Cmax and AUC0-
12h) of MF with minimum bias (<5%).
Please refer to the PK Sub-trial details in Appendix 12.5.
4.2.3.3
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on buccal swab DNA specimens 
collected 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. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
 
 
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Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. 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.
As acknowledged in Section 4.1.1, there are general safety concerns associated with the use 
of LABA. In the US, the product labeling for all ICS/LABA combination therapies includes a 
boxed warning regarding the risk of asthma-related death and other serious asthma outcomes 
in association with use of LABAs for asthma. All subjects eligible for this trial have been 
determined by their physician to have needed ICS/LABA combination therapy for adequate 
control of their asthma. Asthma treatment guidelines (both from GINA and from US National 
Institutes 
of 
Health, 
National 
Heart 
Lung 
and 
Blood 
Institute 
http://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines) 
recommend to 
step down therapy as tolerated in patients whose asthma is controlled. The design of this trial 
allows assessment of the need for ICS/LABA while ensuring that subjects’ safety is 
monitored closely, during both the 2-week Run-in Period with ICS alone and during the 
Double-blind Treatment Period. The level of clinical monitoring during this trial (as 
described in the next paragraph) may be even greater than is generally available in standard 
clinical practice. If a subject is randomized to receive ICS alone and remains well controlled, 
this supports the opportunity to maintain treatment with ICS and without LABA. If a subject 
does not do well on ICS alone during the trial, this may confirm a clinical need to maintain 
treatment with ICS/LABA. Alternatively, if a subject is randomized to receive ICS/LABA, 
this remains consistent with the clinical decision of his/her physician to place the child on 
ICS/LABA combination therapy. 
Some subjects in the trial may show a modest asthma worsening 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 a supply of 
bronchodilator rescue medication to be used on an as-needed basis. In addition, each subject 
will be given a supply of oral prednisone/prednisolone in case of an asthma exacerbation; any 
subject requiring the use of systemic steroid treatment more than once for worsening asthma
will be discontinued from trial medication immediately (and should continue to be monitored 
 
 
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through the end of the trial). Explicit instructions on when to use these additional 
medications will be provided to the subject. Trial subjects will use their PEF meter (a lung 
function measurement device) as a self-monitoring tool, as guided by a written Asthma 
Action Plan (AAP Appendix 12.10), 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 AAP containing very specific instructions on actions to take 
when symptoms increase and/or PEF reductions are recorded or perceived. 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 
around-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
Subjects ages 5–11 years with a diagnosis of persistent asthma on ICS/LABA combination 
therapy 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 willing to give written informed consent/assent (in accordance with local 
regulations) prior to Screening; and the subject’s legal representative must also give 
written informed consent for the subject to participate in the trial. The subject’s legal 
representative may also provide written informed consent and the subject provide 
assent for Future Biomedical Research. However, the subject may participate in the 
main trial without participating in Future Biomedical Research.
For the PK Sub-trial: subject and the subject’s legal representative must be willing to 
actively participate in the main trial and indicate understanding and willingness to 
participate in the sub-trial by signing the sub-trial specific informed consent/assent.
2. Be between 5 and 11 years of age (inclusive) at Visit 1, of either sex, and of any race.
3. Have a diagnosis of asthma according to the international guidelines of at least 6 
months prior to Visit 1 (Global Initiative for Asthma [GINA] Guidelines Available 
from: http://www.ginasthma.org/).
 
 
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4. Have asthma that is adequately controlled on a stable dose of ICS/LABA combination 
therapy for at least 4 weeks prior to Visit 1 according to the clinical judgment of the 
investigator.
5. Demonstrate at Visit 1, an FEV1 >60% and ≤90% predicted when all restricted 
medications have been withheld for the appropriate intervals (Table 1).
Table 1  Medications to be withheld prior to Spirometry Testing (All Visits with Spirometry)
Medication
Minimum Excluded 
Timeframes
Beta-adrenergic bronchodilators, sustained-release tablets
48 hours
Beta-adrenergic bronchodilators, syrups and tablets
24 hours
Beta-adrenergic bronchodilators, long-acting, inhaled
12 hours
Ipratropium bromide inhaled, aerosol or nebulized  or 
combination with albuterol/salbutamol
12 hours
Beta-adrenergic bronchodilators, short-acting, inhaled, or 
nebulized
6 hours
6. Demonstrate at Visit 1, an increase in absolute FEV1 of at least 12% within 30 minutes 
after administration of albuterol/salbutamol (must be demonstrated according to the 
procedure specifically defined in Appendix 12.8). If the 12% reversibility criterion is 
not met at Visit 1, reversibility must be demonstrated prior to the randomization visit 
(Visit 3).
7. Demonstrate the ability to: use an MDI (without spacer) correctly according to 
protocol-defined procedures at Visit 1 (Screening Visit) and Visit 2 (Run-in Visit); use 
a peak flow meter correctly and perform spirometry correctly before Visit 2 (Run-in 
Visit).
8. Be willing (with consent of their parent(s)/guardian [i.e., caregiver]) to discontinue 
his/her prescribed asthma medication before beginning the Run-in Period, if based 
upon the medical judgment of the investigator, there is no inherent harm in changing 
the subject’s current asthma therapy.
9. Demonstrate an ability to follow trial procedures (including use of MDI training 
inhaler, use of open-label run-in medication, use of PEF meter, and use of eDiary 
[IVRS/IWRS]) to the satisfaction of the investigator/qualified designee prior to 
randomization.
Note: Subjects may be rescreened once if they do not meet inclusion/exclusion 
criteria at Visit 1 or Visit 2. A subject may not be rescreened once they have entered 
the open-label Run-in Period in the trial.
 
 
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10. Have clinical laboratory tests (complete blood count [CBC], blood chemistries, 
including urine pregnancy for female subjects of child-bearing potential [i.e., who 
have started menstruating], and urinalysis) conducted at Visit 1 documented to be 
clinically acceptable to the investigator before beginning the Run-in Period. A female 
subject of childbearing potential (i.e., who has started menstruating) must have a 
negative urine pregnancy test at Visit 1 to be considered eligible for the trial.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Requires the use of >8 inhalations per day of albuterol, 100 mcg per actuation (or its 
equivalent), and/or >2 nebulized treatments per day of 2.5 mg albuterol (or its 
equivalent), on any 2 consecutive days between the Screening Visit (Visit 1) and the 
Randomization Visit (Visit 3). If a subject uses both MDI and nebulized formulations 
of SABA in the same day, then one nebulized treatment is considered equivalent to 4 
inhalations of the MDI in order to calculate if the subject has exceeded the equivalent 
of 8 inhalations in total SABA use for that day.  
2. Experiences a clinical worsening of asthma between the Screening Visit (Visit 1) and 
the Randomization Visit (Visit 3), that results in emergency room visit (for an asthma 
exacerbation), hospitalization due to asthma, or treatment with additional, excluded 
asthma medication (other than SABA).
3. Has experienced an upper or lower respiratory tract infection within the 4 weeks prior 
to Visit 1. If there is evidence of an upper or lower respiratory tract infection at Visit 1 
or at Visit 2 (prior to the subject entering the Run-in Period), the subject may be 
treated as appropriate, and Visit 1 or Visit 2 can be rescheduled to be at least 4 weeks 
after resolution.
4. Demonstrates <80% compliance with use of trial medication during the 2 week Run-in 
Period. Compliance will be determined prior to randomization at Visit 3 and will be 
determined by comparing the change in dose counter readings relative to the duration 
of treatment as entered on the eCRF.
5. Is considered to have unstable asthma at the end-of the Run-in Period, based on the 
clinical judgment of the investigator.
6. Has had greater than 4 asthma exacerbations (defined as a worsening of asthma 
requiring systemic corticosteroid use and/or a 24-hour or longer stay in an emergency 
department, urgent care center, and/or hospital) within the 52 weeks prior to Visit 1.
7. Has had a history of life-threatening asthma, including an asthma episode that required 
intubation and/or was associated with hypercapnia requiring non-invasive ventilatory 
support.
8. Has been taking any restricted medications (listed in Table 2) prior to the Screening 
Visit (Visit 1) without meeting the required washout timeframes.  
 
 
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Table 2  Medications Excluded Prior to the Screening Visit (Visit 1)
Medication
Minimum Excluded 
Timeframes
Investigational antibodies for asthma or rhinitis
6 months
Monoclonal antibodies (for example, Xolair®/Omalizumab)
6 months
Methotrexate, cyclosporine, gold, and other cytotoxic agents
3 months
Investigational drugs or vaccines
1 month
Any systemic glucocorticosteroids (intravenous, intra-articular, or 
intramuscular)
12 weeks
Any oral glucocorticosteroid (eg, prednisone/prednisolone)
4 weeks
Glucocorticosteroids, high potency dermatologicals, plain and/or 
combination classifications of mid-strength, or potent or super potent by 
Stoughton-Cornell Scale (Appendix 12.7)
1 month
Theophylline
2 weeks
Cromolyn sodium, nedocromil, inhaled
2 weeks
Leukotriene modifiers (e.g., montelukast, zafirlukast, zileuton)
2 weeks
Beta-adrenergic bronchodilators, sustained-release tablets
48  hours
Beta-adrenergic bronchodilators, syrups and tablets
24 hours
Ipratropium bromide inhaled, aerosol or nebulized or combination with 
albuterol/salbutamol
12 hours
Beta-adrenergic bronchodilators, short-acting, inhaled or nebulized
6 hours
9. Has a clinically significant condition or situation, other than the condition being 
studied which, in the opinion of the investigator, may interfere with trial evaluations, 
subject safety or optimal participation in the trial (e.g. hypoxic seizures).
10. Has a known or suspected hypersensitivity to ICS, beta2 agonists, or any components 
of the trial medications.
11. 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. Rescue Medication is 
also described in this table, but is expected to be locally sourced (i.e., generally not provided
directly by the Sponsor).
 
 
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Table 3  Trial Medication/Rescue Medication
Trial Medication
Drug
Total Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/    
Treatment Period
Use
MF/F via MDI
100/10 mcg 
Twice daily 
Orally inhaled 
24-week 
double-blind period 
Experimental
MF via MDI 
100 mcg 
Twice daily 
Orally inhaled 
24-week 
double-blind period 
Experimental
MF via MDI 
100 mcg 
Twice daily 
Orally inhaled 
2-week 
open-label period
Run In 
MDI Training    
Inhaler
0 mcg
Twice daily 
Orally inhaled 
All Visits
Training
Rescue Medication†
Drug
Total Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/   
Treatment Period
Use
SABA [albuterol/
salbutamol]
NA
PRN (when 
necessary)
Orally inhaled
(with or without a 
spacer)
NA
Rescue
oral corticosteroid 
[prednisone/
prednisolone])
NA
PRN
Oral
NA
Rescue
†Rescue Medication is expected to be locally sourced by the site, with cost re-imbursement by the Sponsor.
At Visit 1 and Visit 2, subjects will practice taking “inhaled trial medication” with a MDI 
training inhaler, perform AM PEF measurements, and complete the eDiary (IVRS/IWRS).  
Subjects will continue to use their current ICS/LABA combination therapy between Visit 1 
and Visit 2. Subjects will also be provided with SABA and oral prednisone/prednisolone, 
which are for potential use as rescue medications during the Screening, Run-in and Double-
blind Treatment periods (Appendix 12.10- Asthma Action Plan). 
Note: Spacers are only permitted for SABA used as rescue medication as well as SABA 
administered for the purposes of demonstrating reversibility (Section 7.1.2.7).  Spacers are 
not permitted for use with trial medication.
Open-label MF MDI will be provided at Visit 2 for use during the Run-in Period. Trial 
medication during the Run-in Period should be taken twice daily (2 puffs in the morning 
upon awakening and 2 puffs in the evening), approximately 12 hours apart. 
Blinded trial medication will begin at the Randomization Visit (Visit 3). Trial medication
during the approximately 24-week Double-blind Treatment Period should be taken twice 
daily (2 puffs in the morning upon awakening and 2 puffs in the evening), approximately 12 
hours apart.  
 
 
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In general, the morning dose of trial medication should be taken after the subject completes 
the AM PEF measurements and prior to the eDiary (IVRS/IWRS) entries. But, on the day of 
an in-clinic visit, the morning dose should not be taken at home and instead will be given as a 
witnessed dose in the clinic (this includes the open-label trial medication at Visit 2, as well as 
the first dose of blinded trial medication after randomization at Visit 3), after observing the 
subject using the MDI training inhaler.
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
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
Screening Visit (Visit 1)
At Visit 1, the subject will be trained on the proper inhalation technique using an MDI 
training inhaler without a spacer. The caregiver will also be trained to ensure the subject 
performs proper inhalation techniques. Spacer devices are not permitted with the open-label 
and double-blinded trial medication as well as the training inhalers.
These training inhalers should not be dispensed to the subject and should be retained by the 
investigational site personnel.  The investigator or qualified designee should be satisfied that 
the subject is properly trained on how to inhale the medication through the MDI training 
inhaler. A training inhaler should be used at every visit as appropriate in order to check and 
reinforce proper dosing technique. The investigator or qualified designee should observe the 
subject’s dosing technique with the MDI training inhaler and should make adjustments to 
their technique, if necessary. Verbal and written instructions for proper use of the MDI will 
be provided to the subject.
At Visit 1, subjects will receive supplies of rescue medications (SABA [albuterol/salbutamol] 
and oral corticosteroid [prednisone/prednisolone]) to be used, with investigator instructions,
for worsening asthma per the Asthma Action Plan (Appendix 12.10). Subjects will be
reminded to contact the investigator if they notice any worsening of their asthma symptoms. 
Rescue medication supplies will be assessed at every visit throughout the Screening, Run-in 
and Double-blind Treatment periods.
At Visit 1, subjects will also be instructed to bring their previous asthma medication(s) at the 
next visit (Visit 2) for verification. Subjects will be reminded that they will discontinue their 
prior medication (pre-trial ICS/LABA combination therapy) before starting the Open-label 
Run-in medication; the last dose of pre-trial medication should be taken the night before Visit 
2.
 
 
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Throughout this protocol, the caregiver is expected to be an active participant and oversee 
and assist with, as appropriate, compliance with the subject’s dosing/visit schedule and 
proper use of the inhaler, PEF meter, and eDiary (IVRS/IWRS).
Open-Label Run-in (Between Visit 2 and Randomization Visit [Visit 3])
At Visit 2, if the investigator determines that laboratory results, including urine pregnancy 
results for female subjects of child-bearing potential, are clinically acceptable, a subject may 
enter the Run-in Period.    The subject will then be instructed to start taking the first dose of 
their Run-in open-label MF MDI medication, as a witnessed dose in the clinic.
Trial medication should be taken twice a day (two puffs in the morning upon awakening and 
2 puffs in the evening, approximately 12 hours apart), after the subject completes the PEF 
measurement (AM only) and prior to the eDiary (IVRS/IWRS) entries.  
Run-in treatment is as follows: 

MF MDI 50 mcg: 2 puffs twice daily, approximately 12 hours apart, for a total daily dose 
of 200 mcg (100 mcg twice daily).
At in-clinic visits, the morning dose of trial medication will be given as a witnessed dose. 
During the Run-in Period (Visit 2 to Visit 3), investigator must evaluate if the subject has a 
decrease in AM PEF below the stability limit on any 2 consecutive days prior to 
randomization.  If yes, the investigator must determine if the subject can continue based on 
his/her clinical judgment; the decision should be clearly documented in the subject’s trial 
files. 
Note: The AM Run-in Period stability limit is calculated by the eDiary (IVRS/IWRS) based 
on the reported PEF data. The best PEF value (i.e., the highest of 3 efforts) will be entered by 
the subject/caregiver in the eDiary [IVRS/IWRS]), in the morning on each day when the 
assessment was completed (Section 7.1.2.10). The calculation for the PEF stability limit is as 
follows: the AM PEF values from each of the 7 days prior to the Run-in Period are added, 
divided by the number of non-missing values, and multiplied by 0.70.
Double-Blind Treatment Period
At the Randomization Visit (Visit 3), a subject meeting all inclusion criteria and none of the 
exclusion criteria will be randomly allocated to treatment with MF/F 100/10 mcg or MF 100
mcg for approximately 24 weeks.  
At in-clinic visits, the morning dose of trial medication will be given as a witnessed dose.
At home between visits, trial medication should be taken twice a day (two puffs in the 
morning upon awakening and 2 puffs in the evening, approximately 12 hours apart), after the 
subject completes the PEF measurement (AM only) and prior to the eDiary (IVRS/IWRS) 
entries, as outlined in Section 5.2.
 
 
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During the Double-blind Treatment Period, if the subject has a decrease in AM PEF below 
the stability limit on any 2 consecutive days, the investigator must determine if the subject 
can continue based on his/her clinical judgment; the decision should be clearly documented 
in the subject’s trial files.
Subjects will be reminded to bring their blinded inhalers and all other trial medication to the 
clinic (whether used or not).  
Double-blind treatments are listed in Table 4.
Table 4  Double-Blind Treatment
Trial Blinding/Masking
5.2.3
A double-blind/masking technique will be used during the Double-Blind Treatment Period.  
MF/F 100/10 mcg and MF 100 mcg will be packaged identically so that blind/masking 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.
The Run-in Period is open-label therefore; the Sponsor, investigator, and subject will know 
the treatment administered.
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
Randomization will occur centrally using an interactive voice response system / integrated 
web response system (IVRS/IWRS).
There are 2 treatment arms in the Double-blind 
Treatment Period.  Subjects will be assigned randomly in a 1:1 ratio to MF/F 100/10 mcg and 
MF 100 mcg, respectively. Note that the IVRS/IWRS system functionality used by site 
personnel for randomization is distinct from the eDiary functionality used by 
subjects/caregivers.  
MF/F MDI 50/5 mcg (per actuation [“puff”])

2 puffs (100/10 mcg) twice daily, approximately 12 hours apart, for a total daily dose of 200/20 mcg
MF MDI 50 mcg (per actuation [“puff”])

2 puffs (100 mcg) twice daily, approximately 12 hours apart, for a total daily dose of 200 mcg
 
 
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Stratification
5.4
Randomization will be stratified according to the following factors:

Age: Age stratification (5-to-7 versus 8-to-11 years of age) will be performed in 
order to ensure an adequate number of younger subjects balanced between each 
treatment group. The randomization IVRS/IWRS will be used to monitor the 
simultaneous enrollment of both age groups. Ongoing trial monitoring will be used to 
target approximately 20% of randomized subjects in the 5- to 7-year-old age group.  

Region:  Region stratification will ensure that treatment allocation is balanced across 
geographic regions of the world in this large multinational trial. Details of the regions 
will be provided in a separate supplemental Statistical Analysis Plan (sSAP).
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Over the counter (OTC) pain relief medications may be used for minor ailments without prior 
consultation with the Sponsor Clinical Monitor.
In addition, the following concomitant medications are also permitted without prior 
consultation with the Sponsor Clinical Monitor:

Topical antimicrobials and systemic antibiotics.

Albuterol 90 mcg/salbutamol 100 mcg HFA MDI (ex-actuator) (SABA) treatment to 
be used as rescue medication during the Run-in Period and during the Double-blind 
Treatment Period (with at least an 6-hour washout period before trial visits [which
also includes 6- hour washout prior to spirometry testing). 

Nebulizations of 2.5 mg albuterol/salbutamol per treatment to be used as rescue 
medication during the Run-in Period and during the Double-blind Treatment Period
(with at least an 6- hour washout period before trial visits which also includes 6- hour 
washout prior to spirometry testing]). For the purposes of this protocol, one 
nebulization treatment will be regarded as equivalent to four inhalations from an 
MDI.

Oral prednisone/prednisolone, to be used per investigator’s instructions and the 
subject’s Asthma Action Plan (Appendix 12.10), for an asthma exacerbation.  

Oral antihistamines for subjects with allergy symptoms.

Ocular or nasal antihistamines.

Oral, ocular, or nasal decongestant for subjects with allergy symptoms.
 
 
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
Immunotherapy treatments if the subject is on a stable maintenance schedule for at 
least 4 weeks prior to Visit 1. However, doses should not be given within 24 hours 
prior to a trial visit. A subject can receive their immunotherapy dose while in the 
office for a trial visit after all protocol-specified procedures have been completed. 
Oral immunotherapy or short-course (rush) immunotherapy using escalating doses are 
prohibited. The Sponsor should be notified if rush venom immunotherapy is being 
considered for the subject.

Vaccines (e.g., influenza, hepatitis, etc.) with a 1-week washout before a visit.

Mild potency (Stoughton-Cornell Scale Appendix 12.7) topical glucocorticoids for 
dermatologic use only, for use in controlling eczema, etc. are allowed.

Ocular, intra-nasal, and otic glucocorticosteroids.

Thyroid replacement hormone if on a stable dose.
Listed below are some specific restrictions for concomitant therapy use during the course of 
the trial.  If there is a clinical indication for any medication specifically prohibited during the 
trial, discontinuation from trial therapy may be required.  The investigator should discuss any 
questions regarding this with the Sponsor.  The final decision on any supportive therapy rests 
with the investigator and/or the subject's primary physician.  However, the decision to 
continue the subject on trial therapy requires the mutual agreement of the investigator, the 
Sponsor and the subject.
The following concomitant medications are prohibited:
Table 5  Medications Prohibited After Screening and for the Duration of the Trial
Leukotriene modifiers.
Oral immunotherapy or short-course rush immunotherapy or the initiation of immunotherapy 
treatment.
Medication linked with clinically significant incidence of hepatotoxicity (e.g., methotrexate, 
17-alkylsteroids) or which may cause significant liver enzyme induction (e.g., barbiturates).
Beta blockers regardless of route of administration.
Theophylline.
Oral (permitted as outlined in section 5.5), intramuscular, intra-articular, intravenous, and inhaled  
glucocorticosteroids (not including trial medication).
Glucocorticosteroids, high potency dermatologicals, plain and/or combination classifications of 
mid-strength, potent or superpotent by Stoughton-Cornell Scale (Appendix 12.7).
Any therapeutic antibody treatment, including but not limited to omalizumab (Xolair®), or 
investigational antibodies.
Oral or inhaled bronchodilators e.g., salmeterol, formoterol, theophylline, and ipratropium bromide 
Inhaled ipratropium bromide alone or in combination with albuterol/salbutamol (Combivent®), 
tiotropium.
Inhaled cromolyn sodium and nedocromil.
Amphetamines, methylphenidates and dextroamphetamines and lisdexamfetamine or similar 
stimulants with potential bronchodilatory effects used to treat ADHD/ADD (e.g., Ritalin, Concerta, 
Adderall, Dexedrine, Vyvanse).
Other investigational drugs and vaccines.
 
 
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Rescue Medications & Supportive Care
5.6
Short-acting beta-agonist (SABA) (albuterol 90 mcg or salbutamol 100 mcg HFA MDI) and 
oral corticosteroid (prednisone or prednisolone) will be provided at the Screening Visit by 
sites to subjects for potential use at home as rescue medications. Throughout the trial, each 
subject will have access to a supply of bronchodilator rescue medication to be used on an as-
needed basis. Nebulizations of albuterol/salbutamol 2.5 mg are also allowed for treatment of 
asthma symptoms, but are not provided by sites to subjects for potential use at home. 
A SABA MDI (to be purchased locally by the site) will be provided to the subject for use as 
rescue medication. The SABA is to be used in accordance with the product labeling. 
Note: Spacers are permitted for SABA used as rescue medication as well as SABA 
administered for the purposes of demonstrating reversibility (Section 7.1.2.7).

The subject should be advised not to take SABA (via MDI or nebulizer) regularly or in 
anticipation 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 Screening Visit. Because the use of 
SABA as prevention for EIB is not considered rescue use, it should not be captured in the 
IVRS/IWRS for the purpose of assessing 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 Screening (Visit 1), 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. 

Nebulizations of 2.5 mg albuterol/salbutamol per treatment are permitted during the trial 
as directed by the protocol. If a subject uses both MDI and nebulized formulations of 
SABA in the same day, then one nebulized treatment is considered equivalent to 
4 inhalations of the MDI in order to calculate if the subject has exceeded the equivalent 
of 8 inhalations in total SABA use for that day.  

Use of SABA in powder form (in lieu of the MDI provided) is prohibited. 
Oral prednisone/prednisolone (to be purchased locally by the site) will also be provided to 
the subject. The subject should be advised not to take oral prednisone/prednisolone regularly 
or in anticipation of asthma symptoms. In case of an exacerbation of the subject's asthma, 
oral prednisone/prednisolone should be used as needed, in accordance with the prescribed 
dose and regimen as rescue medication. The oral prednisone/prednisolone should be taken 
only after the subject (or caregiver) calls the office and after investigator approval, if 
possible.
 
 
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Diet/Activity/Other Considerations
5.7
At all visits with pre-dose measurement of FEV1, visits should be scheduled so that lung 
function testing is performed in the morning between 6 am to 10 am, prior to the morning 
dose of trial medication (see Section 7.1.2.6). 
Subjects will be allowed to consume their usual diet throughout the trial and engage in their 
usual level of exercise throughout the trial.
For the subjects who have signed consent to participate in the PK sub-trial, water may be 
administered ad libitum during the PK collection Visit (Visit 7). ). Subjects may be provided 
meals (breakfast, lunch, and/or dinner) and snacks while at the trial site for the PK sub-trial. 
Food may be administered up to 1 hour prior to and as soon as 1 hour after trial drug 
administration. Grapefruit and grapefruit juice should be avoided.  There are no other 
specific food restrictions prior to or after dosing, with the exception of ensuring a reasonable 
degree of consistency of any meals/snacks (with respect to content) and ensuring that 
meals/snacks do not interfere with clinical procedures during the trial.
Subject Withdrawal/Discontinuation Criteria
5.8
Discontinuation of Treatment
5.8.1
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment period will still continue to participate in the trial as 
specified in Section 6.0 - Trial Flow Chart and Section 7.1.5.2 – Discontinued Subjects 
Continuing to be Monitored in the Trial.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:

The subject or subject’s legally acceptable representative requests to discontinue 
treatment.

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 treatment in the trial or does not allow the subject to adhere to the 
requirements to receive treatment in the trial.
 
 
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
Any drug-related serious AE (SAE) or any SAE (including serious asthma 
exacerbation) which, in the opinion of the investigator and/or Sponsor, might affect 
the ability of the subject to safely continue to receive treatment.

Chronic failure to comply with the dosing, evaluations, or other requirements of the 
trial, despite documentation at the site of repeated efforts to reinforce compliance.

Any drug-related AE.

The subject (menstruating female) has a confirmed positive serum pregnancy test.  
The pregnancy will be followed to resolution.

Use of more than 1 course of oral prednisone/prednisolone for worsening asthma.  
The course of steroid treatment will be determined by the prescribing health care 
provider. 

If a subject is being treated (according to the Asthma Action Plan, Appendix 12.10) 
for worsening of asthma symptoms and is not stabilized within 14 days of initial
treatment, based on the judgment of the Investigator.
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
see Section 7.1.5.2 – Discontinued Subjects Continuing to be Monitored in the Trial for those 
procedures to be completed at each specified visit.
Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
Withdrawal from the Trial
5.8.2
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.4 
– Other Procedures.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
 
 
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Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit, 
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.11
There are no pre-specified criteria for terminating the trial early.
 
 
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6.0 TRIAL FLOW CHART
Trial Period:
Screening
Run-In
Double-Blind Treatment
Post-Treatment
Visit Number:
Title:
1
2
3
Randomization
4
5
6
7
8
9
Follow-up 
(Phone)
Discon-
tinuationa
Pre
Post
Scheduled Week:
Day:
-3
(Day-21)
-2
(Day-14)
0
(Day 1)
1
(Day 8)
4
(Day 29)
8
(Day 57)
12
(Day 85)
24
(Day 169)
Post 
14 days
(Day 183)
At time of 
Discon-
tinuation
Scheduling Windowb:
NA
± 3 Days
± 3 Days
± 3 Days
± 3 Days
±3 Days
±3  Days
± 5 Days
±3 Days
Administrative Procedures
Informed Consent/Assentc
X
Informed Consent for Future 
Biomedical Researchd
X
Inclusion/Exclusion Criteria
X
X
X
Informed consent for PK 
sub-trial (at a subset of sites)e
X
Subject Identification Card
X
Medical History
X
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
Screening number assigned
X
Treatment Allocation/
Randomization
X
Telephone contact to remind 
subject of clinic visit (day before 
specified visit)f
X
X
X
X
X
X
X
Xn
Follow-up telephone contact: 
subjects who discontinue trial 
medication earlyg
X
X
X
X
X
Clinical Procedures/Assessments
Inhaler Training/Review with 
practice MDI training inhaler h
X
X
X
X
X
X
X
Assess subject understanding of 
trial procedures
X
X
X
X
X
X
X
X
 
 
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Trial Period:
Screening
Run-In
Double-Blind Treatment
Post-Treatment
Visit Number:
Title:
1
2
3
Randomization
4
5
6
7
8
9
Follow-up 
(Phone)
Discon-
tinuationa
Pre
Post
Scheduled Week:
Day:
-3
(Day-21)
-2
(Day-14)
0
(Day 1)
1
(Day 8)
4
(Day 29)
8
(Day 57)
12
(Day 85)
24
(Day 169)
Post 
14 days
(Day 183)
At time of 
Discon-
tinuation
Scheduling Windowb:
NA
± 3 Days
± 3 Days
± 3 Days
± 3 Days
±3 Days
±3  Days
± 5 Days
±3 Days
Run-in Period Medication 
(open-label MF): 
Dispensing/Collectionb
X
X
Double-blind Medication (MF/F 
or MF): Dispensing/Collection as 
requiredb
X
X
X
X
X
X
Compliance Measure Review
X
X
X
X
X
X
X
Dispense/Retrieve 
Rescue Medication as Neededb
X
X
X
X
X
X
X
X
X
Train eDiary (IVRS/IWRS)/
Peak Flow meter: Obtain/Review 
Data with Subject and Caregiveri
X
X
X
X
X
X
X
X
X
Dispense/Review 
Asthma Action Plan
X
X
X
X
X
X
X
X
Full Physical Examination
X
Directed Physical Examinationj
X
X
Height and Weight
X
Xe
Oropharyngeal Examination
X
X
X
X
X
X
X
X
X
Vital Signs (heart rate, blood 
pressure, respiratory rate, 
oral/tympanic temperature) prior 
to spirometry, when applicable
X
X
X
X
X
X
X
X
Reversibility testk
X
X (if needed)
Spirometry 
(Pulmonary Function Test)
X
Serial Spirometry: 
Predose (-30 and 0 minutes);     
Postdose (5, 15, 30, 60 minutes)
X
X
X
X
X
 
 
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Trial Period:
Screening
Run-In
Double-Blind Treatment
Post-Treatment
Visit Number:
Title:
1
2
3
Randomization
4
5
6
7
8
9
Follow-up 
(Phone)
Discon-
tinuationa
Pre
Post
Scheduled Week:
Day:
-3
(Day-21)
-2
(Day-14)
0
(Day 1)
1
(Day 8)
4
(Day 29)
8
(Day 57)
12
(Day 85)
24
(Day 169)
Post 
14 days
(Day 183)
At time of 
Discon-
tinuation
Scheduling Windowb:
NA
± 3 Days
± 3 Days
± 3 Days
± 3 Days
±3 Days
±3  Days
± 5 Days
±3 Days
Serial Spirometry: 
Postdose (2 and 4 hours)
X
X
In-Clinic Witnessed Dosing
X
X
X
X
X
X
Adverse Events Monitoring
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures / Assessmentsl
Hematology/Chemistry/Urinalysism
X
Review
Urine Pregnancy Testm
X
X
X
X
X
X
X
X
Xn
X
Blood Collection (PK sub-trial)e
X
Buccal swab samples for Future 
Biomedical Researchd
X
All references to “subject(s)” in this pediatric trial imply that a caregiver/guardian will oversee, or be directly involved in, all procedures.
Note: If a subject is not able to visit the investigational site on the day or week as stipulated in the protocol, the visit may be re-scheduled at another time with prior agreement of 
the sponsor. Every attempt should be made to re-schedule as close as possible to the original visit date.  Throughout the trial, the site must ensure that the subject has 
sufficient trial drug to last until the next visit.
a.
Criteria for discontinuation from participation in the trial are in Section 5.8, and details regarding discontinuation procedures are in Section 7.1.4;  criteria to consider 
discontinuation from treatment while continuing to monitor in the trial (i.e., not requiring a Discontinuation Visit) are also in Section 5.8.  All subjects should be followed 
through trial completion regardless of premature discontinuation of treatment, unless the subject’s caregiver withdraws consent.
b.
The investigator will be responsible for providing and ensuring all subjects have adequate supplies of trial medication and rescue medication (inhaled SABA 
[albuterol/salbutamol], oral prednisone/prednisolone). Subjects who discontinue trial medication early will have access to a supply of bronchodilator rescue medication to be 
used on an as-needed basis. At Visit 8/Discontinuation Visit, supplies will only be collected and no further supplies will be dispensed.  
c.
Informed consent/assent forms MUST be obtained prior to the Visit 1 procedures including trial-specific medication washouts for spirometry. (Note: two separate calls to 
IVRS would need to be made [one to obtain the screening number at Visit 1, and one to obtain the allocation number for randomized subjects at Visit 3]).
d.
Informed consent for future biomedical research must be obtained before buccal swab samples are collected. The buccal swab DNA samples should be obtained at Visit 3, as 
the last sample drawn, on randomized subjects only, or at a later date as soon as the informed consent is obtained. Specimens should only be collected at a scheduled visit.
e.
A pharmacokinetic (PK) sub-trial will only be conducted at a subset of sites and only in subjects who consent to this sub-trial (see Appendix 12.5 for details). If consent for 
the sub-trial is not obtained at Visit 1, it is acceptable to obtain consent prior to the sub-trial Visit (Visit 7).  For subjects participating in the PK sub-trial, height and weight 
must be performed at this PK Visit 7.
 
 
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f.
The site must contact the subject (caregiver) the day before each visit to remind them of the visit. Additionally, the telephone contact should serve as a reminder for ensuring 
restricted medication washout times will need to be observed. The appointment time for all visits should be established in advance to ensure that the subject is able to be at the 
site and begin spirometry assessments 12 hours after the prior evening’s dose of trial medication.  
g.
All subjects should be followed through trial completion regardless of premature discontinuation of treatment, unless the subject’s caregiver withdraws consent.   Subjects
who discontinue trial medication early  will be contacted via telephone through the end of the trial for assessments of Adverse Events and concomitant medications as well 
assessments of daily eDiary (IVRS/IWRS) entries, if applicable.
h.
The subject must demonstrate proper use of the MDI prior to entering the Run-in Period.
i.
After receiving training on both electronic diary systems (i.e., IVRS and IWRS) at Screening (Visit 1), subjects will select to use either the IVRS or the IWRS to collect daily 
trial assessments. The daily eDiary (IVRS/IWRS) assessments will begin the morning of the Screening Visit and continue throughout the last in-clinic visit (Visit 8).  Daily 
assessment data must be reviewed by the investigator.  Subjects who discontinue trial medication early should be encouraged to continue to complete the daily eDiary 
(IVRS/IWRS) assessments through the end of the trial.
j.
Directed (Focused) examination will be performed at Visit 8 and at Discontinuation Visit based on reason for discontinuation. (See Section 7.1.2.2)
k.
Post β-agonist spirometry will be determined by administering 4 to 8 puffs of albuterol/salbutamol (Appendix 12.8).  Subjects who meet pre-defined reversibility criteria at 
Visit 1 need not repeat reversibility testing at Visit 2. Subjects must meet pre-defined reversibility criteria prior to Visit 3 to be randomized at Visit 3. (See Section 7.1.2.7)
l.
Once the laboratory results are received at the site, they should be promptly reviewed by the investigator and found to be clinically acceptable by the investigator in order to 
evaluate eligibility to begin run-in treatment at Visit 2. A single repeat test is permitted and must be reviewed and found to be clinically acceptable prior to Visit 2. Additional 
laboratory tests for drug-induced liver injury (DILI, see also Section 7.2.3.2) may be conducted if needed, based on investigator concern on initial DILI results.
m.
Female subjects (or their Caregiver) must be asked at each visit if the subject has begun menses. Responses should be recorded in the eCRF.  If a female subject reaches 
menarche (menstruates for the first time) during the trial, a urine pregnancy test (dipstick and HCG urine testing) must be done at that visit and every visit thereafter.  
Pregnancy tests will then be done at each visit.  Post-menarche female subjects must have a negative urine pregnancy test at Screening.  If urine test result is positive at any 
time during the trial, it would need to be confirmed with a serum β-hCG test. 
n.
Female subjects of child-bearing potential must return for a urine pregnancy test (dipstick and HCG urine testing) at the post-trial visit. All other subjects will receive a 
telephone contact for post-trial evaluation.
 
 
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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
7.1.1.1
Informed Consent
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.  
 
 
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The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
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.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified 
designee, at Visits 1-3, to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
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.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
7.1.1.5
Prior and Concomitant Medications Review
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 30 days or longer as appropriate prior to Visit 1. Any prior medications are to be 
recorded on the electronic Case Report Form (eCRF).  The identity of the therapy, the dose, 
route of administration, and regimen, the dates started and stopped (or notation of 
“continuing” if that is the case), and the reason for use must be recorded. 
Section 5.1.3 provides a list of medications prohibited prior to the Screening Visit.
 
 
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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.  The identity of the therapy, the dose, route of 
administration, the dates and times started and stopped (or notation of “continuing” if that is 
the case), and the reason for use must be recorded.
Section 5.5 outlines concomitant medications allowed and prohibited during the ongoing 
trial.
7.1.1.6
Assignment of Screening Number
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 allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.
Any subject who is rescreened 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
7.1.1.7
Assignment of Randomization Number
All eligible subjects will be randomly allocated and will receive a randomization number.  
The randomization number identifies the subject for all procedures occurring after 
randomization.  Once a 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 randomization number.
7.1.1.8
Trial Compliance (Medication/Other)
Interruptions from the protocol specified treatment plan for a total interruption of 5 
consecutive days require consultation between the investigator and the Sponsor and written 
documentation of the collaborative decision on subject management.
Subjects and caregivers should be reminded of all appropriate medication washout times 
during telephone contact before any visits requiring spirometry testing.
 
 
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If the subject uses the following medications:

SABA rescue medication within 6 hours, or

ICS/ LABA within 12 hours, 
of a scheduled spirometry assessment at Visit 1, (Visit 2 or an unscheduled visit, if 
reversibility is being assessed) and Visit 3 through Visit 7; then, if necessary, the entire visit 
should be delayed or rescheduled (in accordance with the appropriate visit windows) until the 
appropriate washout is met. If the subject requires the use of the medications indicated above 
before a subsequent visit, he/she should be instructed to take the medication and call the 
office to reschedule the visit.  
Verbal and written instruction for proper use of the MDI (Appendix 12.6) should be given to 
the subject and caregiver. As appropriate, the investigator or qualified designee should 
observe the subject at every visit as he/she doses themselves using the practice MDI training 
inhaler. Adjustment to their technique should be made, if necessary, until the subject is 
properly trained on how to use the inhaler. The MDI training inhaler will remain at the trial
site and is not to be dispensed to the subject to take home.
At the Screening Visit (Visit 1) each subject will be instructed on an electronic diary
(IVRS/IWRS) to use (the subject will use the eDiary with the assistance of their caregiver) 
for the duration of the trial (see Section 7.1.2.10 for details and Appendix 12.11). The 
caregiver designated for assistance of completion of the eDiary (IVRS/IWRS) must remain 
the same throughout the trial. At the Screening Visit and at all subsequent visits (except the 
subject’s Final Visit), the subject and their caregiver should be instructed on how to properly 
use the eDiary (IVRS/IWRS) system to capture daily peak flow, trial medication use, and 
rescue medication use while in the trial. The subject and their caregiver should be instructed 
to ensure completeness of all required electronic data entries when returning for all 
subsequent visits.  Daily assessment data must be reviewed by the investigator.
The subject’s eDiary (IVRS/IWRS) data and PEF should be reviewed by the investigator or 
designee at each visit after Visit 1. The investigator’s review should include an assessment 
by direct and open questions to the subject and caregiver. Overall completeness and accuracy 
of all recorded entries should be reviewed. Deficiencies should be immediately discussed 
with the subject and caregiver in order to improve the quality of information subsequently 
entered on the eDiary (IVRS/IWRS). The investigator and qualified designee should ensure 
that any relevant comments that refer to possible adverse events are discussed or clarified 
with the subject and caregiver, and are captured on the electronic Case Report Form (eCRF)
for adverse events.  
Compliance with eDiary (IVRS/IWRS) completion, trial medication use, and rescue 
medication usage or oral prednisone/prednisolone emergency use is essential, and any non-
compliance noted by the investigator or designee should result in consultation with the 
subject and caregiver on corrective measures needed to ensure compliance.
 
 
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Clinical Procedures/Assessments
7.1.2
7.1.2.1
Review Adverse Event
See Section 7.2 Assessing and Recording Adverse Events and Patient/ Device Events. 
7.1.2.2
Physical Examination
A complete physical examination will be performed at Visit 1, and a directed/focused 
physical examination will be performed at Visit 8 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 directed/focused 
physical examination as part of the discontinuation procedures.  
A directed/focused physical exam will include the following: assessment of appearance, 
throat and nasal examination, and auscultation of heart and lungs. Other body systems may 
be examined as clinically indicated. Any abnormal physical findings (from visits other than 
at screening) should be recorded in the adverse event section of the eCRF. 
7.1.2.3
Height and Weight
Height (cm) and weight (kg) will be measured prior to performing spirometry at Visit 1 as 
indicated in the Trial Flow Chart (Section 6.0). Height and weight will also be measured at
Visit 7 only for the subjects participating in the PK Sub-trial; for all of these subjects, height 
and weight will be updated, but on the eCRF only. To avoid a difference in spirometry 
predicted values, height and weight collected at Visit 7 should not be updated in the 
spirometry equipment.
Note: Equipment used to measure height and weight does not need to have a separate 
calibration for the purposes of the trial.
7.1.2.4
Oropharyngeal Examination
An oropharyngeal examination will be performed at all in-clinic visits. Oropharyngeal 
candidiasis present (upon visual inspection, laboratory culture is not required) at the 
Screening Visit (Visit 1) or at the Randomization Visit (Visit 3) should be treated and the 
subject rescheduled when the candidiasis is resolved. During the treatment period, if there is 
suspected infection, therapy should be initiated as appropriate, and the occurrence should be 
captured as an adverse event on the eCRF. A subject with candidiasis may continue in the 
trial on appropriate treatment with approval of the investigator.
 
 
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7.1.2.5
Vital Signs
Systolic and diastolic blood pressure (mm Hg), temperature (°C), pulse (beats/minute), and 
respiratory rate (breaths/minute) will be measured, (just before spirometry measurements
at Visit 1 [Visit 2 or an unscheduled visit, if reversibility is being assessed], Visits 3-7), with 
the subject in the sitting position. Vitals signs are to be performed at all in-clinic visits as 
specified in the Trial flowchart (Section 6.0). Any clinically significant abnormalities in vital 
signs noted after Visit 1 will be recorded as adverse events on the eCRF.
7.1.2.6
Spirometry, also known as Pulmonary Function Testing (PFT)
The subject and caregiver must be contacted (e.g. by phone) the day before each visit through
to the subject's final visit [including discontinuation visit, if possible]. The primary purpose 
of this contact is to remind the subject and caregiver of the appointment time for the next 
day’s visit and spirometry testing schedule (if applicable); and post-screening, to coordinate 
the timing of that evening's asthma medication dose to a specified time relative to his/her 
testing schedule the following day. Additionally, the phone contact should serve as a
reminder for ensuring that restricted asthma medication washout times are observed. The 
appointment time for all visits should be established in advance to ensure that the subject is 
able to be at the investigational site and begin spirometry assessments 12 hours after the prior 
evening's dose of trial medication.
At all visits with pre-dose PFTs, PFTs should be performed in the morning, between 6 am to 
10 am prior to the morning dose of trial medication. After restricted asthma medications have 
been withheld for the appropriate interval (Section 5.1.2), tests will be performed to measure 
FEV1, and forced vital capacity (FVC). The subject will be given their dose of trial 
medication in the clinic following completion of the pre-dose spirometry testing at these 
visits. Post-dose spirometry measurements should be performed at the visits and times 
designated in the trial flow chart.
All PFTs will be captured and reported using centralized data services for diagnostic 
spirometry. Sites will be equipped with a trial-specific spirometer to perform spirometry at 
the specified visits. Every attempt must be made to use one spirometer consistently on each 
subject.    
In this trial, Polgar reference ranges are to be used to determine percent predicted. If the 
subject self-reports his/her race as Black, appropriate adjustments will automatically be made 
for race by programming the spirometer using the formula:
FEV1 predicted x 0.88 = FEV1 predicted adjusted for race
Spirometry should be performed in accordance with guidelines established by the American 
Thoracic 
Society/European 
Respiratory 
Society 
(ATS/ERS) 
(Available 
from: 
http://www.thoracic.org/statements/). Additional details regarding spirometry procedures will 
be provided by the centralized spirometry vendor. 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 
 
 
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be noted on the spirometry report. For any subject, the position should be consistent 
throughout the trial.  
Three measurements fulfilling the ATS/ERS acceptability and repeatability criteria should be 
obtained during every test session. The acceptability criteria must be applied before the 
repeatability criteria (Available from: http://www.thoracic.org/statements/). Unacceptable 
maneuvers must be discarded before applying the repeatability criteria. If a subject fails to 
provide repeatable maneuvers, an explanation should be recorded on the appropriate eCRF.  
At least two acceptable curves must be obtained.  
The highest FEV1 and the highest FVC values will be recorded after examining the data from 
all the acceptable curves, even if the values are not derived from the same curve. If two (or 
all three) spirometry efforts have identical FEV1, the FEV1 from the effort with the highest 
FVC will be recorded. The centralized spirometry vendor will perform readings of the PFTs 
from all sites to determine the selected measurements fulfill the ATS/ERS acceptability and 
repeatability criteria. These data values will be automatically reported from the central 
vendor’s database once acceptability/repeatability criteria have been applied and agreed upon 
between the site and the central vendor.  If the site and the central vendor cannot agree on the 
data value(s), the sponsor should be consulted.
In order to ensure timely receipt of the vendor’s selected measurements, the PFT data should 
be transmitted, by the site, at the end of each testing day.  
The spirometer must be calibrated according to ATS/ERS guidelines (i.e., with a 3-liter 
syringe), every day that a trial subject is seen and spirometry carried out, or at least weekly, 
that a trial subject is seen and spirometry carried out. The calibration records should be 
printed and kept in a reviewable log. It is preferred that the calibration syringe used to 
calibrate the spirometer also be subjected to a validated calibration according to the 
manufacturer’s specifications.
Additional details regarding spirometry procedures and spirometer calibrations will be 
provided by the centralized spirometry vendor.  
7.1.2.7
Airway Reversibility
At Visit 1 (Screening Visit), a test of airway reversibility will be administered following 
pulmonary function testing after asthma medications have been withheld for the appropriate 
intervals (Section 5.1.2 and Section 7.1.1.8). Reversibility (maximal post-bronchodilator 
spirometry) is defined as an increase in absolute FEV1 of greater than or equal to 12% larger 
than the baseline value. Maximal post-bronchodilator spirometry must be performed as 
outlined in Appendix 12.8. 
Note: Spacers are permitted for SABA administered for the purposes of demonstrating 
reversibility.
 
 
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If the subject does not meet reversibility criteria at Visit 1, repeat assessments can be 
performed.  At Visits where reversibility is performed, only a single series of (up to) 
8 inhalations of SABA or 2 nebulizations of SABA is permitted to test for reversibility at that 
visit. If the subject meets reversibility at Visit 1, reversibility testing is not needed after Visit 
1. 
The subject must meet reversibility before Visit 3.  The reversibility testing prior to Visit 3 
must be performed at least two days prior to the Visit 3 due to the timeframe for the over-
read of the spirometry report from the central vendor. (In order to have the final result in 
time to make a decision for subject inclusion in the trial, the latest timeframe reversibility 
should performed is 2 days prior to the randomization visit [V3].)
Note: The Investigator should consider the safety and well-being of the subject if 
reversibility is repeated more than once.  In addition, the Investigator should have a clinical 
rationale for why reversibility should be repeated.  
7.1.2.8
In-clinic witnessed dosing
At all in-clinic visits, the morning dose of trial medication will be given as a witnessed dose 
in the clinic (this includes the first dose of open-label trial medication and the first dose of 
double-blind trial medication). During Visits that include spirometry (Visit 1, [Visit 2 or an 
unscheduled visit, if reversibility is being assessed] and Visit 3 to Visit 7), the morning dose 
of trial medication will be given as a witnessed dose after pre-dose spirometry measurements 
are completed.
7.1.2.9
Pre- and post-dose spirometry
At Visits 3, 4, 5, 6, and 7 (as indicated in the Trial Flow Chart Section 6.0), serial spirometry 
measurements will be performed prior to administration of trial medication: at -30 minutes
(before trial medication), then at 0 minutes (immediately prior to trial medication), and then 
during one hour following administration of trial medication (at 5, 15, 30, and 60 minutes
after trial medication). At Visits 3 and 7 only, spirometry measurements also will be 
conducted at 2 hours and at 4 hours after trial medication. All post-dose evaluations will be 
performed after a witnessed dose in the clinic. The subject should refrain from using rescue 
medication for 1 hour after trial medication (and for 4 hours, at Visits 3 and 7). However, if a 
subject requires rescue medication during this time, he/she is allowed to receive SABA 
rescue medication, but then should not continue performing spirometry after receiving the 
rescue SABA.
7.1.2.10 eDiary (IVRS/IWRS) and Peak Flow Meter: Instructions 
At the Screening Visit (Visit 1), each subject will be instructed on the use of an eDiary
(IVRS/IWRS) and a PEF meter to use (with the assistance of a caregiver) for the duration of 
the trial.  
 
 
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The eDiary (IVRS/IWRS) records use of rescue medication and whether the subject took the 
trial medication. The Peak Expiratory Flow [PEF] measurements from the peak flow meter 
device used in this trial will also be recorded on the eDiary (IVRS/IWRS). Additional details 
(including setup/programming of the eDiary [IVRS/IWRS] and peak flow meter [if 
applicable]) will be provided by the central vendor(s).
After receiving training on both electronic diary systems (i.e., IVRS and IWRS) at Screening 
(Visit 1), subjects will select to use either the IVRS or the IWRS to collect daily trial
assessments. The daily IVRS/IWRS assessments will begin the morning of the Screening 
Visit and continue through to the last in-clinic Visit (Visit 8).  Daily assessment data must be 
reviewed by the investigator. Subjects who discontinue trial medication early should be 
encouraged to continue to complete the daily eDiary (IVRS/IWRS) assessments through the 
end of the trial.  
The subject and the caregiver will be instructed in the proper collection of PEF and 
completion of the eDiary (IVRS/IWRS) at Visit 1. The subject and the caregiver should also 
be instructed to bring the peak flow meter to all visits to confirm that they are using it 
correctly and that it is working properly.  Subjects must be able to demonstrate eDiary
(IVRS/IWRS)/PEF meter use and must be able to perform spirometry maneuvers before 
beginning the Run-in Period (Visit 2).
The subject, with the assistance of their caregiver, should record diary entries twice daily.
With the assistance of their caregiver, the subject will measure PEF first (once daily in the 
morning). After the subject has completed their PEF measurements, he/she will take the trial
medication and record the trial medication administration in the eDiary (IVRS/IWRS). Then, 
he/she will complete the additional questions in the eDiary (IVRS/IWRS), which record any 
use of rescue medications (SABA, oral corticosteroids) since the last diary entry.  Because 
the use of SABA as prevention for exercise-induced bronchospasm (EIB) is not considered 
rescue use, it should not be captured in the IVRS/IWRS system for the purpose of assessing 
asthma control. Use of SABA for prevention of EIB will be recorded in the concomitant 
medication module of the electronic case report form (eCRF).
Note: If SABA is used in response to asthma symptoms after exercise, this would be 
considered rescue use.
Specifically, regarding PEF: 

The subject should make 3 attempts to generate his/her best PEF on the peak flow 
meter. The best (i.e., highest) value of the 3 PEF attempts will be entered by the 
subject/caregiver in the eDiary (IVRS/IWRS).  

The subject should be asked to refrain from using their SABA 6 hours prior to 
performing the AM PEF measurements. If rescue medication is required within the 6 
hours before measuring AM PEF, the subject will indicate this on the eDiary 
(IVRS/IWRS).  
 
 
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
Throughout the trial, the subject should be instructed to perform triplicate PEF 
measurements once daily, immediately before trial medication administration and/or 
rescue medication use (which is in the morning upon awakening).  
The eDiary data will be downloaded/reviewed by the investigator or qualified designee. The 
review should include an assessment of:

Peak Flow

Daily rescue medication use

Daily trial medication use

Overall completeness and accuracy of all recorded entries  
Deficiencies should be immediately discussed with the subject (and caregiver, as appropriate) 
in order to improve the quality of information subsequently recorded on the diaries.
Compliance with diary completion is essential. Any non-compliance noted by the 
Investigator or designee should result in documented consultation with the subject on 
corrective measures needed to ensure compliance.
Calculating the Stability Limits for Peak Flow to be Used for the Run-in and Double-
blind Treatment Periods
The stability limits are calculated by the eDiary (IVRS/IWRS) based on the reported PEF 
data. (The best [i.e., highest of the three efforts] PEF value each day will be entered by the 
subject/caregiver in the eDiary [IVRS/IWRS]), in the morning when the assessment was 
completed.) The equation used to calculate a stability limit is as follows:  the AM PEF values 
from the 7 days preceding Visit 2 are added, divided by the number of non-missing values, 
and multiplied by 0.70.  Note: a minimum of 4 days of PEF data is required for the stability 
limit to be calculated.  
See Table 6 for an example calculation of a stability limit. 
 
 
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Table 6  Example Calculation of the Stability Limit for Peak Flow
Trial Visit
Date
Trial Day
AM PEF
Pre Run-in (V2)
09-JUL
-14
-
08- JUL
-15
280
07- JUL
-16
290
06- JUL
-17
270
05- JUL
-18
290
04- JUL
-19
280
03- JUL
-20
270
02- JUL
-21
280
Total
1960
Divide by 7
280
Multiply by 0.70
196
During the Run-in Period and Double-blind Treatment period, the investigator must evaluate 
if the subject has a decrease in AM PEF below the stability limit on any 2 consecutive days.  
If yes, the investigator must determine if the subject can continue in the trial based on his/her 
clinical judgment; the decision should be clearly documented in the subject’s trial files. Note 
that the subject/caregiver will also be monitoring daily PEF values according to their 
Personal Best PEF as recorded in the AAP (Section 7.1.2.12).
7.1.2.11 Obtain/Review eDiary (IVRS/IWRS) Data with Subject and Caregiver
At all trial visits from Visit 2 through the Final Visit (including follow-up telephone calls for 
subjects who have discontinued trial medication early), eDiary (IVRS/IWRS) data will be 
downloaded and reviewed with each subject and each caregiver by trial site personnel. The 
eDiary (IVRS/IWRS) data will be reviewed for missing or inconsistent information and 
missing doses of trial medication, and subjects and caregivers will be re-trained on the 
importance of complete diary information and diary procedures if there is missing data. The 
eDiary (IVRS/IWRS) data are available in a central database where the information should 
be reviewed by the investigator/designee.  
Review/Record Short-Acting Beta-Agonist (SABA) Use 
Twice daily, the subject, with the assistance of the caregiver, will document the number of 
SABA inhalations used for rescue (and will not include any SABA used specifically for 
prevention of EIB) during the time period since the last IVRS/IWRS session. The subject 
will also document (yes/no) whether SABA was used within the 6 hours prior to measuring 
their PEF in the morning.
 
 
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The electronic record of SABA use will be used by the Investigator for assessments of 
asthma worsening/exacerbation. Daily IVRS/IWRS records of SABA use will also be used 
for determination of the secondary efficacy endpoint (total SABA use across the first 12 
weeks of double-blind treatment).  
NOTE:  All use of SABA that is not provided to the subject by this trial (e.g., at an acute visit 
to the ER, hospital or other urgent-care facility) must be recorded at site visits and telephone 
contacts by the investigator/qualified designee. The reason for the use of this non-trial-
provided SABA and the dose, route, start and stop dates should be recorded in the 
appropriate section of the eCRF. Chronic use of non-trial-provided SABA during the trial is 
not permitted and should be discontinued by the investigator upon notification by the 
subject/caregiver.
Review/Record Oral Corticosteroid (Prednisone/Prednisolone) Use
Twice daily, the subject, with the assistance of the caregiver, will document if oral 
prednisone/prednisolone was used as a rescue medication during the time period since the 
last evaluation. If the answer is “yes”, oral prednisone/prednisolone use must be documented 
as a concomitant medication in the eCRF. If oral prednisone/prednisolone is used more than 
once for worsening asthma during the trial, the subject will be discontinued.
Subjects dispensed oral prednisone/prednisolone should be trained to use it only after the 
subject (or parent/legal guardian) calls the investigational site and after investigator approval, 
if possible. The subject will be advised not to take oral prednisone/prednisolone regularly or 
in anticipation of symptoms. Oral prednisone/prednisolone should only be used as emergency 
rescue medication at the discretion of the investigator in accordance with the subject's 
individualized written Asthma Action Plan (Appendix 12.10).  
Review/Record Nebulized Treatment Usage
Twice daily, the subject, with the assistance of the caregiver, will document the number of 
nebulized albuterol/salbutamol treatments used during the time period since the last 
evaluation (one nebulized treatment is defined as 2.5 mg of albuterol/salbutamol).
Review/Record PEF Measurements
Once daily, the subject, with the assistance of the caregiver, will perform three PEF 
maneuvers in the AM upon rising.  The best of the three efforts (i.e., the highest) will be 
recorded in the eDiary (IVRS/IWRS) in the morning when the assessment was completed.
7.1.2.12 Asthma Action Plan
At Visit 1, an individualized written Asthma Action Plan (see sample in Appendix 12.10) 
will be provided by the investigator to the subject and the caregiver to provide guidance on 
effectively managing the subject’s asthma, as recommended by clinical practice guidelines.  
Additionally, the AAP will include a reminder for subjects to contact the investigational site 
immediately if they have experienced worsening asthma resulting in an ER/urgent-care visit 
 
 
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or hospitalization.  (Note that in addition to the use of the AAP to help manage a subject’s 
asthma, the IVRS/IWRS will be programmed to alert the investigators to contact the 
subject/caregiver if the subject has reported more than 8 inhalations of SABA for rescue on 
two consecutive days [one nebulized treatment is considered equivalent to 4 inhalations of 
the MDI in order to calculate if the subject has exceeded the equivalent of 8 inhalations in 
total SABA use for that day]).  
For the AAP, three measurements of AM PEF, using the peak flow meter, will be obtained 
during Visit 1.  The investigator will record the highest AM PEF (greatest value in 3 
attempts) value and enter it as the “personal best” level on the Asthma Action Plan.  This 
value will be used to determine the PEF range, along with changes in symptoms, which will 
guide the subject/caregiver in effectively managing the subject’s symptoms as per the AAP.  
(Note that in addition, PEF measurements will be monitored by the Investigator according to 
the established stability limit, as described in Section 7.1.2.10).  
The AAP will be reviewed with the subject/caregiver at all visits and should be updated by 
the investigator/qualified designee during the course of the trial, as needed.  The AAP will be 
collected at the Final Visit and/or upon trial Discontinuation along with all trial-provided 
supplies.
7.1.2.13 Asthma Baseline Pediatric Profile
Subjects will also be asked to provide information on their asthma history and related
conditions for completion of an Asthma Baseline Pediatric Profile (ABPP). The investigator 
or qualified designee will obtain medical history information about asthma to allow 
completion of an ABPP at Visit 1.
7.1.2.14 Dispense/Collect Trial medication Inhalers
Priming
All new inhalers dispensed should be primed (which means performing 4 actuations of the 
inhaler that are not to be inhaled by the subject) prior to first use. When inhalers for the trial 
medications are used as directed (i.e., two puffs taken in the morning and two puffs taken in 
the evening), each inhaler will be adequate to provide for the four actuations required for 
priming when the inhaler is dispensed, as well as 30 days of twice-daily dosing. Re-priming 
is required only if the inhaler is not used for more than 3 consecutive days. If a subject stops 
dosing for 3 days during the trial, the subject should be advised to contact the site for 
instruction on how to proceed with dosing.  
 
 
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Dispensing a backup inhaler
During the Double-blind Treatment period, a backup (i.e., second) MDI will be provided to 
the subject. For tracking purposes, the investigator or designee should fill in the “Do not use 
after ____” field on the inhaler used in the office at the dispensing visit. The date should 
correspond with 30 days of dosing for the MDI. Subjects should be advised that the second 
MDI will serve as a backup for prolonged visit schedules. If the backup needs to be used, 
subjects should be advised of the appropriate priming requirements of the MDI. At 
subsequent visits, additional new MDIs should be dispensed and the date field should be 
completed accordingly. From Visit 3 to Visit 8 of the Double-blind Treatment Period, 
subjects will be provided sufficient inhalers to cover the length of time between the visits as 
well as 1 additional inhaler as a backup.
Instructions for Dispensing
The subject and caregiver should be instructed to keep the inhaler in a secure, dry location at 
all times. Each inhaler will have enough medication for 30 days of dosing.  

At the Run-in Visit (Visit 2), the subject will be dispensed open-label MF MDI. 
Subjects will be switched from their previous asthma therapy to open-label MF MDI 
once laboratory 
results 
are found to 
be clinically 
acceptable by the 
investigator/sponsor, provided subjects continue to meet all inclusion criteria and 
none of the exclusion criteria.  After appropriate priming, the first dose of open-label 
MF MDI will be administered to the subject in the office under the supervision of the 
investigator or qualified designee. This administration will be documented in the 
eDiary (IVRS/IWRS) and the source document.

At Visit 2 and thereafter, subjects will be instructed to take 2 inhalations of trial 
medication upon rising and 2 at bedtime for the duration of the trial. After trial 
medication administration has been completed, the subject should also be advised to 
rinse their mouth with water or a suitable mouthwash and then spit it out. The subject 
should receive additional instruction on the proper completion of the eDiary
(IVRS/IWRS) to reinforce the importance of accurately recording the date and time 
of trial medication dosing.

At the Randomization Visit (Visit 3), the subject with the assistance of their caregiver 
should be initially dispensed one treatment kit as well as a back-up treatment kit. 
After appropriate priming, the first dose of blinded trial medication will be 
administered to the subject in the office under the supervision of the investigator or 
qualified designee. This administration will be documented in the eDiary
(IVRS/IWRS) and the source document.  
 
 
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
At subsequent visits, IVRS will manage dispensing a variable number of inhalers 
depending on the time between visits, the need for additional backup inhalers and 
expiration of the product. The same process should be followed for site notations on 
the primary and backup inhalers. This will help ensure that the subjects use the 
correct inhalers, in the correct order, and have sufficient supply until their next visit.
Trial supplies are to be brought to each visit for inspection and evaluation. A new inhaler(s)
will be dispensed when applicable. If a dispensed inhaler is found to be defective or non-
operational, a replacement inhaler will be dispensed and primed at the discretion of the 
investigator or qualified designee.
All used and unused trial medication will be returned to the investigator or designee.  All 
supplies should be accounted for, by the investigator or designee, at each visit and at the end 
of the trial.
7.1.2.15 Review Medication Compliance
The investigator or qualified designee will review trial medication usage with the subject 
from Visit 3 through the subject's Final Visit. To promote daily medication usage, the subject 
will be asked twice daily in their eDiary (IVRS/IWRS) whether they have taken their trial
medication. The investigator or designee will train each subject, with the assistance of the 
caregiver, on the diary content and proper completion procedures. Any problems with 
medication usage should be addressed with the subject and their caregiver as soon as the 
investigator or designee becomes aware.
Subject must demonstrate at least 80% compliance with use of their trial medication during 
the 2-week Run-in Period to be eligible for randomization.
Throughout the trial, compliance will be determined by comparing the change in dose 
counter readings relative to the duration of treatment as entered on the eCRF.  
7.1.2.16 Inhaler Use Training and Review 
At Visit 1 the subject with the assistance of their caregiver will be instructed in the proper 
use of the MDI inhaler (Appendix 12.6). If the subject does not demonstrate proper use prior 
to the administration of Run-in medication, the subject should be excluded from the trial.
The investigator or qualified designee should observe the subject using the demonstration 
inhaler at every visit (throughout the Run-in and Double-blind Treatment period), as 
appropriate, in order to reinforce proper dosing technique. The investigator or qualified 
designee should make adjustments to the technique if necessary. These training supplies will 
remain at the site and are not to be dispensed to the subject to take home. Supplemental 
training should be provided, as needed, at all visits (with the exception of the final visit).  
 
 
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7.1.2.17 Rescue Medications
Dispense/Retrieve SABA Medication (as needed):  All visits
SABA will be made available (as needed): Visit 1 until the end of the trial.
Albuterol 90 mcg/salbutamol 100 mcg HFA MDI (ex-actuator) (SABA) will be available to 
all sites as rescue medication for the acute relief of asthma symptoms.

Spacers are only permitted for SABA used as rescue medication (as well as for SABA 
administered for the purposes of demonstrating reversibility [Section 7.1.2.7]).  

The subject will be instructed to return all used and unused SABA at each visit.

Use of SABA as a prevention for exercise-induced bronchospasm (EIB) is permitted 
if previously taken in this manner and should be discussed with the investigator at the 
Screening Visit. Use of SABA for prevention of EIB will be recorded in the 
concomitant medication module of the eCRFs and not on the eDiary.

Subjects who discontinue trial medication early will have the option to continue to 
receive SABA, to be used on an as-needed basis.
Dispense/Retrieve Oral Prednisone/Prednisolone Medication (as needed):  All visits
Prednisone/prednisolone tablets/syrup will also be made available as rescue medication, 
which will be administered according to the Asthma Action Plan (Appendix 12.10).  
Prednisolone will be provided in countries where prednisone is not available. Per GINA 2012 
guidelines, the recommended dose for an acute asthma exacerbation, for self-administration 
at home, is 1-2 mg/kg/day (maximum dose 60 mg), but the dosage prescribed (the course of 
steroid treatment will be determined by the prescribing health care provider) is at the 
investigator’s discretion. The subject should be instructed to contact the investigator urgently 
(immediately) for instructions before initiating treatment, and if the investigator is not 
immediately available, the subject should start oral prednisone/prednisolone as indicated on 
the subject’s individualized Asthma Action Plan. Any subject with PEF <60% of personal 
best, or as defined by the subject’s Asthma Action Plan, must proceed to the emergency 
room immediately after taking the prescribed prednisone/prednisolone.
7.1.2.18 PK Sub-trial
At a subset of trial sites, subjects who have signed a specific consent form to participate in 
the main trial will also have the option to sign a separate informed consent to participate in 
the Pharmacokinetic (PK) sub-trial. See Appendix 12.5 for details of the PK sub-trial, 
including objective, design, procedures etc.  
 
 
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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.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 7.
Female subjects of child bearing potential will be required at all visits to perform a urine 
pregnancy test with a dipstick as well as HCG urine testing.  Sites will submit HCG urine 
testing to the central lab regardless of the outcome from the site performed dipstick testing.
Table 7  Laboratory Tests
Hematology
Chemistry
Urinalysis
Red blood cells 
(RBCs)
Hematocrit
Hemoglobin
Platelet count
WBC (total and 
differential)
Eosinophils
Neutrophils
Lymphocytes
Monocytes
Basophils
Albumin
Alkaline phosphatase
Aspartate aminotransferase (AST; SGOT)
Alanine aminotransferase (ALT; SGPT)
Bicarbonate 
Lactate dehydrogenase
Calcium
Chloride
Creatinine
Glucose
Inorganic Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total bilirubin is elevated 
above the upper limit of normal
Total protein
Blood Urea Nitrogen (BUN)
Cholesterol
Serum β-Human Chorionic
Gonadotropin (β-hCG [if needed to confirm 
a positive urine pregnancy test])
pH
Specific Gravity
Protein
Glucose
Ketones
Blood
Microscopic exam
Urine pregnancy test (beta hCG) (for girls 
of childbearing potential)
7.1.3.2
Pharmacokinetic/Pharmacodynamics Evaluations
See detail of PK Sub-trial in Appendix 12.5 for PK evaluations.  No PK/PD evaluations are 
planned.
 
 
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7.1.3.3
Blood Collection for Plasma MK-0887A
Sample collection, storage and shipment instructions for plasma samples for MF are provided 
in Appendix 12.5 for the PK Sub-trial.  
7.1.3.4
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Buccal swabs for genomics use.
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment
prior to completion of the treatment 
regimen should continue to be monitored in the trial.
When a subject discontinues and withdraws consent from participation in the trial, all 
applicable activities scheduled for the final trial 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. Thus, if a subject 
discontinues from participation in the trial (i.e., withdraws consent) after being given trial
medication, a Discontinuation Visit will be performed, if possible, as soon as feasible and 
any related worksheets will be completed. These worksheets will be completed whether the 
discontinuation occurs during a regularly scheduled visit, shortly before, or shortly after such 
a visit. Every attempt should be made to schedule a Discontinuation Visit as soon as possible 
once a decision to discontinue participation in the trial has been made. A clear evaluation of 
the patient’s condition must be made.
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 
(clinical.specimen.management@merck.com), 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.
 
 
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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.
7.1.4.2
Lost to Follow-up
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit.  If the 
subject is contacted, the subject should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the 
subject at each missed visit (e.g. phone calls and/or a certified letter to the 
subject’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the subject’s medical record.

Note:  A subject is not considered lost to follow up until the last scheduled visit 
for the individual subject.  The amount of missing data for the subject will be 
managed via the pre-specified data handling and analysis guidelines.
7.1.4.3
Blinding/Unblinding
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, but should continue to be monitored in the trial.
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) 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.
 
 
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7.1.4.4
Domiciling
The trial will be conducted in an outpatient clinic setting. Subjects will report to the clinic on 
the morning of the scheduled visit days, during which trial drug is administered. Following 
trial drug administration, subjects will continue with additional testing. At the discretion of 
the investigator, subject may be requested to remain in the clinic longer.  See Appendix 12.5 
for domiciling requirements for subjects participating in the PK Sub- trial.
7.1.4.5
Calibration of Critical Equipment
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 with the study 
documentation as source documentation at the trial site.
Critical Equipment for this trial includes:

Spirometer
Please refer to Section 7.1.2.6 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.
7.1.5.1
Re- Screening
Approximately 1 week prior to the Run-in Visit, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. Screening 
procedures may be repeated after consultation with the Sponsor.
 
 
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A subject who has at least one trial procedure performed in addition to signing an informed 
consent form and is assigned a subject identifier but does not meet one or more criteria 
required for participation in the trial is classified as a “screen failure”. The Interactive 
Voice/Web Response System (IVRS/IWRS) system used to track trial enrollment must be 
notified. At a minimum, the following information on subjects who are not randomized must 
be collected in the eCRF:

Date screened 

Subject screening number

Demography (race, age, and gender)

Reason subject failed screening

Any Serious Adverse Event (SAE) related to trial procedures or concomitant 
medications that occurred after signing the informed consent/assent
Per the judgment of the investigator, a subject who is classified as a screen failure may be re-
screened once if they do not meet inclusion/exclusion criteria at Visit 1 or Visit 2. A subject 
may not be rescreened after they have entered the open-label Run-in Period in the trial. 
To be dispensed Run-in trial medication, subjects must meet all the relevant entry criteria as 
of Visit 2. The Sponsor must be notified when subjects who do not meet the entry criteria are 
incorrectly started on Run-in treatment.
7.1.5.2
Discontinued Subjects Continuing to be Monitored in the Trial
It is intended that all subjects should be followed through completion of the trial, regardless 
of premature discontinuation of treatment, unless the subject’s caregiver withdraws consent. 
Thus, subjects who discontinue from trial medication prior to completion of the trial should
continue to be monitored through the end of the trial, by use of follow-up phone calls, to 
obtain relevant information.  Follow-up phone calls should be made in a timeframe that 
corresponds to each remaining clinic visit. Such telephone contacts will allow collection of 
follow-up information, including if any adverse events have occurred, any concomitant 
medication have been used, and will allow assessment of daily eDiary (IVRS/IWRS) entries, 
as applicable. 
For these subjects who have discontinued trial medication early, sites will be instructed to 
exert diligent efforts to continue to contact these subjects (and their caregivers). To enable 
sites to reach subjects/caregivers, the caregivers should provide primary and secondary 
contact information (e.g., home phone, work phone, mobile phone). Sites must document the 
outcome of the telephone contact(s), to demonstrate diligent efforts have been made.  If a 
subject/caregiver does not agree to be contacted by phone for follow-up for each of the 
remaining visits, the subject/caregiver should be encouraged to accept a telephone contact at 
least at the final visit date (Week 24). 
 
 
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Subjects/caregivers should be asked (and sites must document) the preferred method of 
follow-up:

No on-site trial visits, but agree to be contacted by telephone, for each remaining clinic 
visit, through Week 24: Investigators may continue to collect trial-related information 
from available sources, such as medical records.

No on-site trial visits and no telephone contacts for each remaining clinic visit, but 
agree to be contacted at Week 24 only: Investigators may continue to collect trial-related 
information from available sources, such as medical records.

No on-site trial visits and no longer wishes to be contacted: No further trial-related 
contacts will occur. No further data collection will occur. (This final choice should only 
pertain when the subject’s caregiver withdraws consent for further trial participation.) 
Additionally, the informed consent form will explain the importance of continued data 
collection from subjects, including the use of continued contact by phone. 
7.1.5.3
Post-Trial 
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-
trial visit (Visit 9) and will return to the clinic in 14 (±3) days. All male subjects and those 
female subjects who are not of child-bearing potential will receive a telephone contact for 
post-trial evaluation.
If the post-trial visit occurs less than 14 days after the last dose of trial drug, a subsequent 
follow-up phone call should be made at 14 days after the last dose of trial drug to determine 
if any adverse events have occurred since the post-trial clinic visit.
Assessing and Recording Adverse Events and Patient/Device Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
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.
 
 
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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 EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Device and/or patient events include all untoward events related to the use of the device or 
device-like features of a drug delivery system. Device events include any malfunction or 
deterioration in the characteristics and/or performance of the device, as well as any 
inadequacy in the labeling or the instructions for use, that led to or could have led to an 
untoward event for the user or any person. Patient events are adverse events experienced by 
the subject caused by or suspected to be caused by the device or device-like features of a 
drug delivery system.
All device or patient events that occur after the consent form is signed but before 
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 allocation/randomization through 14 days following cessation of 
treatment, all device or patient events must be reported by the investigator. Such events will 
be recorded at each examination on the Adverse Event case report forms/worksheets. The 
reporting timeframe for events meeting any serious criteria is described in section 7.2.3.1. 
The investigator will make every attempt to follow all non-serious device or subject events 
for outcome.  
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose is any dose higher than the dose specified in Section 5.2 of this 
protocol.
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.
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).
 
 
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Immediate Reporting of Adverse Events and Incidents to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events and Incidents
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.
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 8 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.
 
 
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An incident is any malfunction or deterioration in the characteristics and/or performance of 
the device, as well as any inadequacy in the labeling or the instructions for use that, directly 
or indirectly, led to or could have led to, the death of a subject or user, or of other persons, or 
to a serious deterioration in their state of health.
A serious deterioration in the state of health can include:
1. Life-threatening illness;
2. Permanent impairment of a body function or permanent damage to a body structure;
3. A condition necessitating medical or surgical intervention to prevent 1 or 2;
4. A condition that requires hospitalization or significant prolongation of existing 
hospitalization; or
5. Fetal distress, fetal death or any congenital abnormalities or birth defects.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any incident, including follow up to an incident, including death 
due to any cause, that occurs to any subject must be reported within 24 hours to the Sponsor 
if it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any incident, or follow-up to an incident, whether or not 
related to the device, must be reported within 24 hours to the Sponsor either by electronic 
media or paper.   Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any incident considered by an investigator who is a qualified physician to be 
related to the Sponsor's product that is brought to the attention of the investigator at any time 
outside of the time period specified above also must be reported immediately to the Sponsor.
All subjects involved with incidents must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
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.
 
 
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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 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).
3. an asthma exacerbation that results in emergency care (an emergency room visit or 
hospitalization due to asthma) or treatment with oral corticosteroid use.
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 8. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 8 for instructions in evaluating adverse events.
 
 
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Table 8  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 and Patient/Device Events 
7.2.5
and Incidents
All Adverse Events and Patient/Device Events and Incidents will be reported to regulatory 
authorities, IRB/IECs and investigators in accordance with all applicable global laws and 
regulations, i.e., per ICH Topic E6 (R1) Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Scientific Advisory Committee
7.3.1
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the trial. If, after the 
trial has begun, but prior to any unblinding, changes made to primary and/or key secondary 
hypotheses, or the statistical methods related to those hypotheses, then the protocol will be 
amended (consistent with ICH Guideline E-9). Changes to exploratory or other non-
confirmatory analyses made after the protocol has been finalized, but prior to unblinding, 
will be documented in a supplemental SAP (sSAP) and referenced in the Clinical Study 
Report (CSR) for the trial. Post hoc exploratory analyses will be clearly identified in the 
CSR.   
Statistical Analysis Plan Summary
8.1
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
Table 9  Summary of the Statistical Analysis Plan
Study Design Overview
A phase III, randomized, active-controlled, parallel-group clinical trial 
to study the efficacy and long-term safety of mometasone furoate / 
formoterol fumarate (MF/F, MK-0887A [SCH418131]), compared with 
mometasone furoate (MF, MK-0887 [SCH032088]), in children with 
persistent asthma
Treatment Assignment
Subjects will be randomized, in a 1:1 ratio, to MF/F 100/10 mcg twice 
daily or MF 100 mcg twice daily.  Randomization will be stratified 
according to the following factors: Age and Region.
 
 
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Analysis Populations
Efficacy: Full Analysis Set (FAS)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint
AM Post-dose %-predicted FEV1 (measured during 60 minutes post-
dose) averaged across Day 1, Week 1, Week 4, Week 8 and Week 12 
of treatment.  
Key Secondary Endpoint
Change from baseline (pre-dose on Day 1) in AM post-dose 
%predicted FEV1 at 4 and 2 hours, 60, 30, 15, and 5 minutes on Day 1
Statistical Methods for Key 
Efficacy Analyses
The Primary Hypothesis will be evaluated by comparing MF/F 100/10
mcg twice daily to MF 100 mcg twice daily using a constrained LDA
method proposed by Liang and Zeger [6], adjusting for
treatment, time, treatment-by-time interaction, age strata (5-to-7 or 8-
to-11 years of age, inclusive) and region, after applying a control-
based multiple imputation proposed by Ratitch and O’Kelly [7]. MF/F
100/10 mcg twice daily will be considered superior to MF 100 mcg
twice daily if the MF/F 100/10 treatment is superior to MF 100 with 
an observed two-sided p-value ≤ 0.050, which will determine the 
success of the trial.
Statistical Methods for Key 
Safety Analyses
Pre-specified Tier-1 AEs include headache, tremor, and tachycardia.  
Tier-2 AEs include any Asthma Exacerbations; Treatment-Emergent 
AE, any SAE, any Drug-Related AE, any Serious and Drug-Related 
AE, any Discontinuations due to AE; and any Specific AEs with 
incidence ≥4 subjects in one of the treatment groups.  Tier-1 AEs will 
be evaluated with p-values and 95% confidence intervals (CI) for 
between-treatment differences in the percentage of subjects with 
events using the Miettinen and Nurminen method [8]. Tier-2 AEs will 
also be evaluated using the Miettinen and Nurminen method, but will 
only be evaluated with 95% confidence intervals for between-
treatment differences in the percentage of subjects.  
Interim Analyses
No interim analysis will be performed in this trial.  
Multiplicity
The Type-I error rate over the primary and key secondary endpoints 
will be controlled by a sequential testing procedure.  
Sample Size and Power 
The planned sample size is 160 subjects for the primary endpoint.  The 
trial has between 77% and 82% power to demonstrate that MF/F 
100/10 mcg twice daily is superior to MF 100 mcg twice daily at an 
overall two-sided 5% alpha-level, if the underlying treatment 
difference is 4.2 percentage-points. The range of power is a reflection 
of the potential impact of a control-based imputation applied to the 
analysis dataset prior to analysis.
Statistical Analysis Plan
8.2
The statistical analysis of the data obtained from this trial will be the responsibility of the 
designee/ Clinical Biostatistics department of the SPONSOR.
This trial will be conducted as a double-blind trial under in-house blinding procedures.  
Hypothesis/Estimation
8.2.1
Objectives and hypotheses of the trial are stated in Section 3.0.
 
 
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Analysis Endpoints
8.2.2
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are summarized in Section 8.1.
8.2.2.1
Derivations of Efficacy Endpoints
Evaluations of the primary endpoint, AM post-dose %-predicted FEV1 as measured during
60 minutes post-dose, are scheduled at Day 1, Week 1, Week 4, Week 8 and Week 12.  
Assignment of scheduled evaluations will use visit windows as: Week 1 evaluation, ± 3 days; 
Week 4, ± 1 week; and Week 8 and 12 evaluations, ± 2 weeks.
The primary endpoint will be derived at each visit by first calculating an AUC using the
trapezoid rule. Trapezoids will be derived and summed across 0-5, 5-15, 15-30, and 30-60
minute time intervals. To preserve the units for analysis, the AUC will be divided by the total
time interval: 60 minutes for subjects with a complete 60-minute evaluation, and less than 60
minutes for those who discontinue the evaluation series early. This will ensure the post-dose 
%-predicted FEV1 is standardized to the same percentage units as the baseline pre-dose 
evaluation. Interim missing serial evaluations will be imputed using linear interpolation prior 
to the calculation of the AUC. Derivation of the post-dose %-predicted FEV1 when measured 
during 4 hours post-dose at Day 1 and Week 12 will be performed in a similar manner.
For the calculation of baseline for the primary endpoint, the mean of two pre-dose measures 
of %-predicted FEV1 (at -30 minutes and 0 minutes pre-dose) will be calculated. If one of 
the two evaluations is missing, baseline will consist of the remaining non-missing evaluation.  
For visit endpoints, if a subject discontinues early and the final visit evaluation is performed
outside of a visit window, that evaluation will be carried forward into the next scheduled visit
window.
Total daily short-acting beta-agonist (SABA) usage (as needed by the subject) will be 
collected across the 24-week Double-blind Treatment Period. Data collected during the first 
12 weeks will be analyzed as a secondary efficacy endpoint, while data collected during the 
second 12 weeks are to be used by the investigator to help assess safety. There are two 
sources of SABA inhalation: 1) a handheld MDI and 2) a nebulizer. For computing the daily 
totals, one nebulizer administration is equivalent to 4 inhalations (“puffs”) of a handheld 
MDI. 
8.2.2.2
Derivations of Safety Endpoints
For vital sign parameters, changes are based on subtracting the most recent pre-treatment 
value from the on-treatment value.  
 
 
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Analysis Populations
8.2.3
8.2.3.1
Efficacy Analysis Population
The Full Analysis Set (FAS) will be used for the efficacy analysis. This population includes 
all subjects that are as close as possible to the ideal implied by the intention-to-treat principle.  
This set is derived from the set of all subjects that received randomized treatment assignment 
by minimal and justified exclusion of subjects. For this trial, the FAS includes subjects who 
have received at least one dose of randomized trial medication with at least one primary 
efficacy evaluation across the 12-week efficacy period.
8.2.3.2
Safety Analysis Population
All Subjects as Treated (ASaT) population will be used for assessments of safety and 
tolerability.  The ASaT population consists of all randomized subjects who receive at least 
one dose of trial medication. For the analysis of safety data using the ASaT population,
subjects will be included in the treatment group corresponding to the trial medication they 
actually received. For most subjects, this will be the treatment group to which they are
randomized. Subjects who take incorrect trial medication for the entire treatment period will 
be included in the treatment group corresponding to the trial medication actually received.
Statistical Methods
8.2.4
Statistical methods for the analysis of efficacy endpoints are provided in Section 8.2.4.1.
Statistical testing and inference for safety analyses are described in Section 8.2.4.3. Efficacy 
results that will be considered to be statistically significant after consideration of the strategy 
for controlling the Type I error are described in Section 8.2.5. Nominal p-values will be 
computed for other efficacy analyses as a measure of strength of association between the 
endpoint and the treatment effect, rather than as formal tests of hypotheses (i.e., these 
nominal p-values are not controlled for multiplicity). Unless otherwise stated, all statistical 
tests will be conducted at the overall two-sided 5% alpha-level.
8.2.4.1
Statistical Methods for Efficacy Analysis
The primary efficacy variable is the AM post-dose %-predicted FEV1 as measured during 60 
minutes post-dose, analyzed as the change from AM pre-dose %-predicted FEV1, and 
averaged across Day 1, Week 1, Week 4, Week 8 and Week 12 of treatment for the 
comparison of the MF/F 100/10 twice daily with MF 100 twice daily.  For subjects in the 
MF/F group who are missing the %-predicted FEV1 data, the missing data will be imputed 
based on the MF group data.  For subjects in the MF group, missing data will be imputed 
using the MAR assumption.  See below for details of imputations.   
 
 
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Applying a Control-based Multiple Imputation
8.2.4.1.1
Prior to analysis, a control-based multiple-imputation will be applied to the analysis dataset 
of the primary efficacy variable. This imputation method includes implementation of a 
pattern mixture model approach using PROC MI in SAS® with a control-based pattern 
multiple imputation proposed by Ratitch and O’Kelly [7]. Given the visit schedule, the 
analysis dataset is expected to have a non-monotone missing-data pattern. Some subjects will 
have missing FEV1 evaluations at intermediate visits with data available at subsequent visits, 
other subjects will have all data missing subsequent to dropout (a monotone missing-data 
pattern), and still other subjects will have a combination of these two missing-data patterns. 
Therefore, missing-data imputation will be performed in two steps. 

First, interim visits will be imputed using the Monte Carlo Markov Chain (MCMC) 
method assuming a multivariate normal distribution, under the assumption of missing 
at random (MAR). This method is justified by the fact that those subjects with 
missing data who return to the clinic for subsequent FEV1 evaluations are most likely 
not missing data due to lack of efficacy, so their interim missing data are independent 
of the unobserved values, after accounting for the observed values in the imputation. 
Multiple monotone missing datasets are generated under this first step. 

Next, each of the monotone missing datasets will be imputed step-wise by missing 
visit. Imputation will only consider all subjects in the MF (control) arm, and those 
subjects in the MF/F treatment arm who have missing observations in that visit. This 
approach assumes all subjects who drop out follow a pattern of treatment response 
similar to MF, as such subjects are assumed to not respond to the additive effect of F 
in the MF/F treatment arm, supporting a zero treatment difference assumption 
between MF and MF/F. To assign the subjects included in each step, MF/F treatment 
subjects will be partitioned into cohorts based on the timing of their dropout, and 
combined with all the subjects in the MF treatment at each step. Therefore, 
imputations will be performed in five steps; one step for each missing data visit: Day 
1, Week 1, Week 4, Week 8, and Week 12. At each step, after the MF/F treatment 
subject missing data is imputed, those MF/F subjects excluded from the imputation 
step are added to the imputed subjects for a complete subject dataset. This complete 
subject dataset is considered for the next step. 
Once all visits are imputed, each completely imputed dataset will be analyzed using a
constrained longitudinal data analysis (cLDA) method proposed by Liang and Zeger [6].
This method assumes a common mean across treatment groups at baseline and a different
mean for each treatment at each of the post-baseline time points. Time is treated as a
categorical variable so that no restriction is imposed on the trajectory of the means over
time. In the model, the response vector consists of baseline and the values observed at each
post-baseline time point. The analysis model will adjust for treatment, time, treatment-by-
time interaction, age stratum (5- to-7 or 8-to-11 years of age, inclusive) and region (US,
ex-US). An unstructured covariance matrix will be used to model the correlation among
repeated measurements. Although the baseline measurement is included in the response
 
 
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vector, it is independent of treatment, and hence, the baseline means are constrained to be
the same for different treatment groups.  
The results of the cLDA for each completely imputed dataset will be combined into an 
overall result by applying the MIANALYZE procedure.
The same method of analysis, using the cLDA with control-based multiple-imputation, will
be applied to the key secondary endpoint (i.e., serial FEV1 data on Day 1). Analyses
of other efficacy endpoints will be based on the cLDA approach without imputation. Table 9 
summarizes the efficacy analyses.
Table 10  Summary of Efficacy Analyses
Endpoint/Variable
(Description, Time Point)
Statistical
Method
Analysis
Population
Missing Data
Approach
Primary Endpoint
Change from baseline AM post-dose %-predicted FEV1as measured
during 60 minutes post-dose, averaged across Day 1, Week 1,
Week 4, Week 8 and Week 12 of treatment
cLDA†  with
Multiple
Imputation
FAS
Control-based
Imputation‡
Key Secondary Endpoint
Change from baseline AM post-dose %-predicted FEV1 at 4 and 2
hours, 60, 30, 15 and 5 minutes post-dose on Day 1 of treatment
cLDA†  with
Multiple
Imputation
FAS
Control-based
Imputation‡
Other Secondary Endpoints
Change from baseline AM post-dose %-predicted FEV1 as measured
during 4 hour post-dose, at Day 1 and Week 12 of treatment
cLDA†
FAS
Model-based
(MAR)
Change from baseline in AM pre-dose %-predicted FEV1 averaged
across Week 4, Week 8 and Week 12 of treatment
cLDA†
FAS
Model-based
(MAR)
Change from baseline in total daily SABA use across the first
12-weeks of treatment
cLDA†
FAS
Model-based
(MAR)
Characterize the plasma PK profile of MF
cLDA†
FAS
Model-based
(MAR)
† Constrained Longitudinal Data Analysis model with terms for treatment, time, treatment-by-time interaction, age stratum
(5-to-7 or 8-to-11 years of age, inclusive) and region
‡Pattern Mixture Model proposed by Ratitch and O’Kelly
Missing-Data Sensitivity Analyses
8.2.4.1.2
The primary analysis incorporates imputations of missing data.  Additional, sensitivity 
analyses will be performed to further examine the impact of missing data on study results 
using imputation methods other than that used in primary analysis. The description of these 
sensitivity analyses is as follows:
 
 
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Constrained Longitudinal Data Analysis without Multiple Imputation
This analysis will be performed using a constrained longitudinal data analysis (cLDA)
method proposed by Liang and Zeger [6] without multiple imputation, and thus will rely
on the
model for handling of missing data. The cLDA model will adjust for the same
covariates as those applied to the control-based imputation datasets in the primary analysis.
Given this model relies on the missing-at-random assumption (MAR), the results of this
sensitivity analysis can be compared to the control-based imputation primary and key
secondary analyses
to
assess
the
impact of early
dropouts. Details of the
model
specification, assumptions, and SAS implementation codes are given in Appendix 12.12.
Tipping-point Multiple-imputation Analysis
Sensitivity analysis using a pattern-mixture model, and based on the tipping-point approach,
will be used to assess the robustness of the control-based imputation primary approach.
For a given constant, c, the tipping-point analysis is conducted in a fashion similar to that
used in standard
multiple imputation, whereby m complete datasets are randomly
generated using the original observed dataset [9]; [10]; [11]. These m complete datasets
are subsequently analyzed using the primary model, and the results of those analyses
are then combined. This procedure will be repeated (using the same m imputed datasets)
until the smallest
c is found such that the significant result turns non-significant (i.e., p
≥0.050). This tipping-point
value c provides a measure of robustness of the primary
result. A relatively large value of c implies better robustness of the primary analysis
against the impact of missing data in the trial. It is noted that when c=0, the tipping-point
analysis described above corresponds to an analysis conducted under the assumption that
the missing data are MAR. For values of c larger than 0, the tipping point analyses do not
assume that the missing values follow a MAR mechanism. In fact, the analysis is based on
a special MNAR mechanism in which all missing data in the MF/F treatment arm are
assumed to have a worse response by a constant amount of c than the values would have
had under MAR, while the missing data in the MF control arm are assumed to be the same
as that obtained under MAR. The search for tipping point will be performed separately
over a grid of varying shift values in the MF control arm. Note that this grid will
include negative and positive values in order to allow both worsenings and improvements
in the control arm. Note also that the search for tipping point will include cases where
dropouts in the MF/F treatment arm have worse outcomes than those in the MF control arm.
Additional Imputation Analyses
To further evaluate the robustness of the primary results, additional sensitivity analyses
will be
performed
to
reflect
different
reasons
for
discontinuation,
and
possibly
treatment groups, as factors in the imputation steps, ensuring that lack of efficacy is not
imputed as treatment success in these algorithms.
Additional computational details of sensitivity analyses to address missing data will be
provided in the supplemental SAP (sSAP).
 
 
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8.2.4.2
Other Analysis
Analysis of the PK Sub-trial is provided in Appendix 12.5.
8.2.4.3
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters
including AEs, Asthma Exacerbations and vital signs measurements. Tier 1 and Tier 2
safety summaries will be provided, in addition, the number and percentage of subjects
will be reported for AEs, SAEs, drug-related AEs, and discontinuations due to AEs.
Continuous measures such as changes from baseline (or percent change from baseline as
appropriate) in vital signs will be summarized in table format by treatment group/arm, and
as a pooled group for measurements upon completion of the trial or early discontinuation of
the trial. For subjects who discontinue trial medication early, their off-treatment safety
data will be summarized separately. Baseline for vital signs will be defined based on
the last available measurement prior to randomization.
The analysis of safety results will follow a tiered approach (Table 10). 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 vital signs that are not pre-specified as Tier-1 endpoints will be classified
as belonging
to either "Tier 2" or "Tier 3", based on the number of events observed.
Membership in Tier 2 requires that at least 4 subjects in any treatment group exhibit the
event; all other AEs and predefined limits of change (PDLC) 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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Continuous measures, such as changes from baseline in vital signs that are not pre-
specified as Tier-1 endpoints, will be considered Tier 3 safety parameters. Summary
statistics for baseline, on-treatment, and change from baseline values will be provided
by treatment group in table format.
P-values (Tier 1 only) and 95% confidence intervals (Tier 1 and Tier 2) will be provided
for between-treatment differences in the percentage of subjects with events; these analyses
will be
performed
using
the
Miettinen
and
Nurminen
method
(1985)
[ 8 ] ,
an
unconditional, asymptotic method. If events do not meet minimum frequency criteria, as
determined by the
commonly occurring event definition, only point estimates will be
provided. The analysis strategy for safety parameters is provided in Table 10
Table 11  Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
p-Value
95% CI for
Treatment
Comparison
Descriptive
Statistics
Tier 1
Headache
Tremor
Tachycardia
X
X
X
X
X
X
X
X
X
Tier 2
Any Treatment Emergent AE
Any SAE
Any Drug-Related AE
Any Serious and Drug-Related AE
Discontinuation due to AE
Specific AEs‡ (incidence ≥4 subjects in one of
the treatment groups)
Asthma Exacerbations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tier 3
Specific AEs‡ (incidence <4 subjects in all of
the treatment groups)
Change from Baseline Results (Vital Signs)
X
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.
SOC=System Organ Class; X = results will be provided.
8.2.4.4
Summaries of Baseline Characteristics and Demographics
Demographic variables (sex, race, age, weight, height, etc., and other baseline characteristics 
such as asthma, previous asthma therapy, reversibility, and %-predicted FEV1) will be 
summarized by treatment group.  No inferential analysis of these data is planned.
 
 
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Multiplicity
8.2.5
The step-down approach for multiplicity will be applied to the primary and key
secondary endpoint. If success of the primary endpoint is met (i.e., MF/F 100/10 mcg twice
daily is superior to MF 100 mcg twice daily with an observed two-sided p-value ≤0.050),
then the success of the key secondary endpoint will be tested. The key secondary endpoint
will be assessed sequentially for the comparison of MF/F 100/10 mcg twice daily to MF
100 mcg twice daily in the following order: 4 hours, 2 hours, followed by 60, 30, 15, and 5
minutes. Using this sequential approach, the onset of action of MF/F will be determined as 
the earliest time point with a two-sided p-value ≤0.050..
Other
secondary
endpoints
are
supportive
in
nature
and
are
not
controlled
for
multiplicity. Therefore, observed p-values are nominal, as discussed in Section 8.2.4.
Justification of Sample Size
8.2.6
8.2.6.1
Sample-size Calculation for the Primary Analysis (using Multiple Imputation)
Power/sample size was calculated under two scenarios: the primary analysis (using control-
based imputation), and the sensitivity analysis (under the MAR assumption).  
The resulting power for the primary analysis was estimated to be approximately 77% under
the worst-case 5% reduction in the mean treatment difference, given a sample size of 160,
with 80 subjects in each arm. Therefore, depending on the impact of missing data in this
trial, power is expected to range from 82% down to 77% under the control-based multiple
imputation primary analysis method.  Details of power calculation are provided below.
To estimate the sample size and power for this trial, the following process was adopted:

First, in order to assess the magnitude of reduction in the mean treatment difference
from a missing-at-random based cLDA approach (without multiple imputation, see
Section 8.2.6.2)
to the control-based imputation cLDA approach, the primary
analysis method using control- based multiple imputation was applied to each of
four previous MF/F adult studies. The four
studies
included
asthma
studies
(P04073 and P04334), and COPD studies (P04229 and
P04230), which were
selected for this estimation exercise based on similarities to this trial in
visit 
scheduling and FEV1 endpoints, as well as the available comparison of MF/F versus 
MF at the same dose of MF. Two endpoints were considered in the evaluation
across a multiple-
evaluation visit schedule: FEV1 AUC and pre-dose FEV1.
Across the four studies and the
two endpoints, the reduction in treatment
difference did not exceed ~5% of the missing-at-
random cLDA treatment
difference.
 
 
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
Next, the sample size for this trial was calculated under the missing-at-random
cLDA analysis (without multiple-imputation) assuming, among other parameters,
the effect size of
4.2% of predicted FEV1, resulting in ~82% power at the two-
sided 5% level of significance (discussed in Section 8.2.6.2 below).

Finally, taking into consideration a reduction of treatment difference in this trial
similar to that noted in the four adult trials, the power was recalculated under the 
same assumptions for all other parameters. Sample-size Calculation for the cLDA 
Analysis (without Multiple Imputation)
Approximately 355 subjects will be screened (assuming a screen-failure rate of 55%) in
order to randomize 80 subjects into the MF/F arm and 80 subjects into the MF arm. With
at least 160 total randomized subjects in the analysis, assuming a pooled standard deviation
of 9.0% derived from an unstructured covariance matrix for the efficacy evaluations
repeated across the visit schedule, a true mean treatment difference of 4.2 percentage-
point difference (MF/F compared
with MF) in AM post-dose %-predicted FEV1
measured during 60 minutes post-dose will be detectable with a power of ~82% and two-
sided 5% level of significance. The following pattern of discontinuation was assumed in
the calculation of the total sample size for estimating the power: 0, 2%, 10%, 15%, and
20% for each of the two treatment arms at Day 1, Week 1, Week 4, Week 8 and Week 12, 
respectively.
The target effect size of 4.2 percentage-point difference is supported by the results of a
previous pediatric trial P06476 (a Phase II single-dose trial to evaluate spacer use), in which
MF/F 100/10 mcg, F 10 mcg, and placebo were evaluated over 12 hours on Day 1 of
dosing. An average across the first hour of this evaluation in P06476 was derived to match
the primary endpoint in this current trial. An effect size of 4.5 percentage points for the AM 
%-predicted FEV1 measured during 60 minutes post-dose was observed for the comparison
of MF/F 100/10 mcg to placebo (in change from baseline) in P06476. This effect size can
be used to estimate the comparison of MF/F to MF on Day 1 because the effect of MF is
expected to be none to minimal after only one day of dosing, and the current trial includes
a run-in on MF prior to randomization. Given the pediatric trial was only 1 day in
duration and used a cross-over design, data from a similarly designed adolescent and
adult 12-week trial (P04073) was used to generate an adjusted covariance matrix to match
the estimate of 9.0% for the pooled standard deviation across a 12-
week evaluation
period. This pooled standard deviation was observed in a previous 12-week pediatric
trial (C98005) comparing MF 100 mcg to placebo in AM pre-dose %-predicted FEV1, and
is expected to be similar to the pooled standard deviation of the AM %-predicted FEV1
measured during 60 minutes post-dose to be evaluated in this current trial, based on
comparing pooled standard deviations between these two FEV1 endpoints in P04073 (i.e.,
comparing MF/F 100/10 mcg to MF). Assumptions for the pattern of discontinuations
over time are based on examining the drop-out patterns observed in the two 12-week
trials; C98005 in the pediatric subjects and P04073 in the adolescent and adult subjects.
Finally, the magnitude of the effect size is expected to be similar across visits, given the
bronchodilator effect of F is expected to reach maximal efficacy after 1 hour with a
 
 
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sustained effect throughout the 12-week treatment period.
Due to the inherent variability of FEV1 evaluations across asthma populations, there is
no universally accepted clinically meaningful difference. However, effect sizes of ~5
percentage-
point difference have been accepted as evidence of efficacy in regulatory
submissions, and have been observed in both pediatric trials P06476 (as a 12-hour
evaluation comparing MF/F to placebo on Day 1 for the bronchodilator effect), and in
C98005 (as AM pre-dose evaluation comparing MF to placebo at Week 12 for the steroid
effect). Therefore, a target effect size of 4.2
percentage points is reasonable since the
comparison of MF/F is to MF (not placebo), and since the one hour duration for the primary 
endpoint does not include later evaluations (2 and 4 hours) which have larger formoterol
effects than the effects prior to 1 hour evaluation.
Subgroup Analyses and Effect of Baseline Factors
8.2.7
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 the following classification 
variables.  (The primary method of analysis, control-based imputation, will be used for 
calculating the treatment effects and CI’s across subgroups.)   : 

Age category (5 to 7 years vs. 8 to 11 years)

Sex (female, male)

Race (white, non-white)

Region 
Subgroup plots may exclude categories which accrue <15% of the FAS subjects (i.e. < 24 out 
of 160 subjects) as the exploration of such small sample sizes are considered to be non-
informative in nature. 
Interim Analyses
8.2.8
No interim analyses are planned for this trial.
Compliance (Medication Adherence)
8.2.9
In this trial, as part of the routine recording of the amount of trial treatment taken by
each subject, the number of inhalations (“puffs”) of trial medication will be reviewed and
recorded at regular intervals. These results will be used to calculate subject compliance.
 
 
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A subject will be considered 100% compliant only if usage of exactly 4 puffs of trial
medication per day is recorded on the eCRF. Therefore, the rate of compliance will be a
function of the total number of puffs while on therapy, to be calculated using the following
formula:
Percent Compliance = 100 x the recorded number of puffs of trial medication
while on therapy, divided by the expected number of puffs while on therapy.
The days on therapy includes the interval of days from randomization to the last day of
dose of trial medication, whether the subject completes the full scheduled trial regimen or
discontinues
early. Days of follow-up after discontinuation of trial treatment are not
included in the compliance calculation (e.g., follow-up on pregnancy).
Summary statistics will be provided on percent-compliance by treatment group for the
FAS population.
Extent of Exposure
8.2.10
Duration of subject exposure to randomized treatment will be summarized, by treatment 
group, across intervals of time through the last observed exposure weekly interval; In 
addition, summary statistics (n, median, minimum and maximum) for duration (in days) will 
be provided.
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 12.
Table 12  Product Descriptions
Product Name & Potency
Dosage Form
Mometasone furoate 50 mcg
Metered Dose Inhaler (MDI)
Mometasone furoate / formoterol fumarate 
50/5 mcg
Metered Dose Inhaler (MDI)
MDI Placebo (Trainer) 
Metered Dose Inhaler (MDI)
All other supplies not indicated in Table 12 above will be provided centrally by the Sponsor 
or locally by the trial site, subsidiary or designee, depending on local country operational or 
regulatory requirements.
 
 
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For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product.
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Supplies will be packaged as kits where each kit will contain 1 inhaler. At the Run-in visit, 
each patient will be dispensed an open label kit of mometasone furoate 50 mcg MDI. 
Blinded, monthly kits will be provided to all randomized subjects during the treatment 
period. Subjects will be dispensed sufficient kits to support their visit interval plus back-up 
inhalers as required. 
Clinical Supplies Disclosure
9.3
The emergency unblinding call center will use the randomization schedule for the trial to 
unblind subjects and to unmask treatment. In the event that the emergency unblinding call 
center is not available for a given site in this trial, the central electronic 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 to the emergency unblinding call center.
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 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded to treatment assignment. Subjects whose
treatment assignment has been unblinded (by the investigator, Merck subsidiary, or through the 
emergency unblinding call center) must be discontinued from study drug, but should continue to 
be monitored in the trial.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
 
 
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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 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 
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.
 
 
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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 member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
 
 
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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, 
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 
 
 
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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 
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.
 
 
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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 
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 
 
 
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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]
Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med. 2006 Nov 
23;355(21):2226-35.
[2]
U.S. Prescribing Information: FORADIL AEROLIZER (formoterol fumarate 
inhalation powder) for oral inhalation only: 2012.
[3]
Nathan RA, Nolte H, Pearlman DS; P04334 Study Investigators. Twenty-six-
week efficacy and safety study of mometasone furoate/formoterol 200/10 microg 
combination treatment in patients with persistent asthma previously receiving 
medium-dose inhaled corticosteroids. Allergy Asthma Proc. 2010 Jul-
Aug;31(4):269-79.
[4]
Meltzer EO, Kuna P, Nolte H, Nayak AS, LaForce C. Mometasone 
furoate/formoterol reduces asthma deteriorations and improves lung function. Eur 
Respir J 2012;39(2):279-89.
[5]
Berger WE, Bensch GW, Weinstein SF, Skoner DP, Prenner BM, Shekar T, et al. 
Bronchodilation with mometasone furoate/formoterol fumarate administered by 
metered-dose inhaler with and without a spacer in children with persistent 
asthma. Pediatr Pulmonol. 2014 May;49(5):441-50.
[6]
Liang K-Y, Zeger SL. Longitudinal data analysis using generalized linear 
models. Biometrika 1986;73(1):13-22.
[7]
Ratitch B, Michael O'kelly. Implementation of pattern-mixture models using 
standard SAS/STAT procedures. Proceedings of the PharmaSUG2011 on 
Statistics and Pharmacokinetics - Paper SP04; 2011 May 7-11; Nashville, TN.
[8]
Miettinen O, Nurminen M. Comparative analysis of two rates*. Statist Med 
1985;4:213-26.
[9]
SAS Institute Inc. SAS/STAT 9.3 User’s Guide: the mianalyze procedure 
(chapter). Cary (NC): SAS Institute Inc; c2011. Chapter 57 The mianalyze 
procedure; p. 4668-715.
[10]
Rubin DB. Multiple Imputation for Nonresponse in Surveys.  Toronto: John 
Wiley & Sons, Inc.; c1987. Front Matter, Preface and Contents; p. iii-xxix.
[11]
Ratitch B, O'Kelly M, Tosiello R. Missing data in clinical trials: from clinical 
assumptions to statistical analysis using pattern mixture models. Pharm Stat. 2013 
Nov-Dec;12(6):337-47.
[12]
Wang Y, Jadhav PR, Lala M, Gobburu JV. Clarification on precision criteria to 
derive sample size when designing pediatric pharmacokinetic studies. J Clin 
Pharmacol. 2012 Oct;52(10):1601-6.
 
 
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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 DNA specimen(s) collected in the current trial will be used to study various causes 
for how subjects may respond to a drug/vaccine.  The DNA  specimen(s) will be stored 
to provide a resource for future trials conducted by Merck 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 Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
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.
 
 
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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.  Information contained on the consent form alone cannot be traced 
to any specimens, test results, or medical information once the specimens have been 
rendered de-identified.
Subjects are not required to participate in the Future Biomedical Research sub-trial in 
order to participate in the main trial. Subjects who decline to sign the Future 
Biomedical Research informed consent will not have the specimen collected nor will 
they be discontinued from the main trial.
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.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Buccal swab specimens for DNA isolation will be obtained at a time when the subject 
is having other trial procedures conducted. Specimens like tissue and bone marrow 
will usually be obtained at a time when the subject is having such a procedure for 
clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
 
 
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If specimens are collected for a specific genotype or expression analysis as an 
objective to the main trial, this analysis is detailed in the main body of this protocol 
(Section 8.0 – Statistical Analysis Plan).  These specimens will be processed, 
analyzed, and the remainder of the specimen will be destroyed.  The results of these 
analyses will be reported along with the other trial results.  A separate specimen will 
be obtained from properly-consented subjects in this protocol for storage in the 
biorepository for Future Biomedical Research.
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, Merck has developed secure policies and procedures.  All 
specimens will be de-identified 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.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
 
 
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The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  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 the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
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 Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck 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 Merck 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.
 
 
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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 acquisition.  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 Merck 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 Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor 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 in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
 
 
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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 as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Buccal swab 
specimens will be collected inside the cheek with no associated venipuncture to obtain 
the specimen. Therefore, there will not be an additional risk for the subject.
Merck 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.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
 
 
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13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. 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 Informational Brochure for IRBs/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
Trial Visit/Cycle/etc.
Screening
Visit 1
Treatment 
Visit 3
Treatment
Visit 4
Treatment 
Visits 5-7
Post-
Treatment
Blood Parameter†
Approximate Blood Volume (mL)
Hematology
2 mL
NA
NA
NA
NA
Serum/Plasma Chemistry
6 mL
NA
NA
NA
NA
Expected Total (mL)
8.5 mL
NA 
NA
† Refer to Appendix 12.5 for PK collection blood volumes
 
 
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Pharmacokinetic Sub-Trial: MK-0887A Protocol 087
12.5
A. BACKGROUND AND RATIONALE
This pharmacokinetic (PK) sub-trial is intended to characterize the plasma concentration-
time profile and the key PK parameters for mometasone furoate (MF) following multiple oral 
inhalations of MF/F or MF from a metered-dose inhaler, when administered to approximately 
steady-state in children ages 5–11 years old with persistent asthma.  
To minimize discomfort and avoid multiple venipunctures, subjects may be housed overnight
for trial-related activities during the PK Visit. Blood samples collected at the time points 
specified in the protocol may be obtained via an indwelling catheter.  The total amount of 
blood collected during the 12-hour period will be within the limitation of most guidelines 
suggested; i.e., no more than 5% of Total Blood Volume (TBV).
B. OBJECTIVE

To characterize the plasma pharmacokinetics (PK) profile of MF and to determine the PK 
parameters (e.g., AUC0-12h, AUC0-last, Cmax, and Tmax) at steady state after multiple oral 
inhalations via MDI device in children ages 5-11 years old with persistent asthma.

Estimation: The plasma PK parameters of MF (e.g., AUC0-12h, AUC0-last, Cmax, and Tmax) 
at steady state after multiple oral inhalations in children ages 5-11 years old with 
persistent asthma.
C. SUBJECT DEFINITION
1. Inclusion Criteria
1. Subject is actively participating in the main trial (Protocol 087).
2. Subject is willing to give written informed assent, in accordance with local 
regulations, and the subject’s legal representative to give written informed consent for 
the trial.
3. Subject has a body weight ≥18 kg.
4. Subject has both normal hemoglobin and normal hematocrit at the Visit 1 laboratory 
safety measurements.
2. Exclusion Criteria 
1. In the opinion of the investigator, the subject suffers from any physical, psychological 
or other condition(s) that might prevent participation in the pharmacokinetic sub-trial.
2. On the day of the PK Visit (Visit 7), the subject has a body weight <18 kg.
 
 
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D. TRIAL DESIGN
1. Summary of Sub-Trial Design/Procedures
At a prespecified subset of trial sites, subjects who have been randomized to the main trial 
for Protocol 087 will have the option to participate in a PK sub-trial.  There will be specific 
consent/assent forms for the PK sub-trial (i.e., the consent/assent
forms for the 
pharmacokinetic sub-trial will be distinct from the consent/assent forms for the main trial).  
Participation in the PK sub-trial will require the subject’s legal representative to give written 
informed consent for the sub-trial and subjects to give written informed assent, in accordance 
with local regulations, on or before Visit 7.  
Approximately 20 subjects (from either the MF/F arm or the MF arm) who have consented to 
participate in the sub-trial, and have met the criteria for both the main trial and sub-trial, will
participate in the PK sub-trial. Attempts will be made to ensure that subjects who complete 
the PK sub-trial adequately represent the targeted population (ages 5 to 11 years). Because
the inter-subject coefficient of variation (CV) ranged from approximately 35 to 70% for Cmax
and AUC values following multiple-dose administration of MF/F MDI to asthmatic adults 
(Refer to Investigator’s Brochure for details), it is anticipated that approximately 20 subjects 
is appropriate to characterize the pharmacokinetics of MF with adequate precision in the 
targeted pediatric population [12].  On the other hand, to respect the special needs of 
children, a higher number of participants in this PK sub-trial, as well as a higher number of 
venipunctures, is not desirable. 
In addition to the procedures outlined in the main trial, at Visit 7 (Week 12 of treatment), 
subjects who agree to participate in this sub-trial will have pharmacokinetic samples obtained 
at specified time points shown in the table.  
Dosing and Pharmacokinetic Sampling Time Points
Procedure
Times Obtained (Hours)
Dosing
0 (8 AM ± 1 hour)
Blood samples for 
pharmacokinetics†
0 hour (predose), 0.75, 1.5, 3, 8, 12 hours 
postdose
†Samples (3-mL each) will be collected into tubes containing pre-chilled K3-EDTA.  
PK samples should be taken as close to the nominal time as possible.  PK blood collection 
is to take precedence over all other trial procedures (including those in the main trial) with 
the exception of spirometry measurements.  Record the actual time the PK sample was 
obtained in the electronic case report form.
 
 
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Procedures for the sub-trial are detailed below.
At Visit 7, subjects participating in the sub-trial will report to the trial site at 8 am ± 1 hour.  
At the investigator’s discretion, subjects may be admitted to the trial site on the evening prior 
to Visit 7. Peripheral intravenous access may be established for the purpose of obtaining 
pharmacokinetic samples. Blood sampling may also be accomplished by repeated 
venipuncture at the discretion of the investigator. Topical anesthetics are permitted for the 
purposes of establishing peripheral venous access and/or venipuncture. Blood samples will 
be collected at specified time points.  
Pharmacokinetic samples for the sub-trial should be obtained as close to the scheduled time 
as possible. Pharmacokinetic blood collections take precedence over all other procedures 
(including those of the main trial) at any given time point with the exception of spirometry 
measurements.  The exact time at which the in-clinic witnessed dosing takes place and the 
time at which a pharmacokinetic sample is obtained must be recorded on the electronic case 
report forms.
The total volume of blood required from each patient will not be of physiological 
significance in these non-anemic subjects. Since subjects are required to have a body weight 
of ≥18 kg, the total amount of blood collected (18 mL) for pharmacokinetic samples over the 
12-hour collection period will be well below the limitation of most guidelines suggested; i.e., 
no more than 5% of Total Blood Volume. 
Throughout the PK sub-trial, water may be administered ad libitum. Subjects may be 
provided meals (breakfast, lunch, and/or dinner) and snacks while at the trial site for the PK 
sub-trial. Food may be administered up to 1 hour prior to and as soon as 1 hour after trial 
drug administration. Grapefruit and grapefruit juice should be avoided. There are no other 
specific food restrictions prior to or after dosing, with the exception of ensuring a reasonable 
degree of consistency of any meals/snacks (with respect to content) and ensuring that 
meals/snacks do not interfere with clinical procedures during the trial.  
Subjects will be discharged from the trial site after completion of the 12-hour post-dose 
blood sample and removal of the venous access (as applicable).  At the investigator’s 
discretion, subjects may be remain overnight at the trial center on the evening prior to Visit 7 
and be discharged from the clinic after completing serial spirometry and the 12 hours PK 
procedure at Visit 7.  
Sample processing and shipping is described below.
2. Treatment
Except as directly related to the sub-trial, subjects enrolled in the sub-trial will follow the 
same 
treatment 
plan, 
special 
handling 
requirements, 
prior 
and 
concomitant 
medications/treatments, and diet/activity/other described in the main trial (Protocol 087). 
Please refer to the main trial protocol for details.
 
 
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E. TRIAL PROCEDURES
1. Allocation Scheme
Subjects enrolled in the sub-trial will use the same allocation number assigned in the main 
trial.
2. Protocol Outline
Subjects enrolled in the sub-trial will complete procedures as listed in the main trial (Protocol 
087). Please refer to the main trial protocol for details.
3. General Sub-trial Procedures
General protocol procedures listed in the main trial apply for the sub-trial. Please refer to the 
main trial protocol for details. Additional procedures unique to the sub-trial are listed below.
F. PROCESSING OF PHARMACOKINETIC SAMPLES
1. Blood Samples for Plasma Mometasone Furoate Determination

Careful attention to collection, handling and storage is essential to reduce 
pharmacokinetic variability.

Collect 3 mL of whole blood at each specified time point into pre-chilled tubes 
containing K3-EDTA for determination of drug concentrations.

Keep samples on wet ice until centrifuged, then frozen.

Place blood sample into a centrifuge, and centrifuge 15 minutes at 1,500g.

Collect plasma and dispense into Corning 2 mL polypropylene cryotubes (Corning 
Part No. 430659; self-standing, externally threaded, orange-capped vials).

Samples must be stored frozen at -20 °C (or colder) until transferred to the analytical 
site on dry ice.

Samples must be transferred to the analytical site on dry ice.
The assay will be conducted at a contract laboratory.  
2. Packaging Samples for Shipment
It is the responsibility of the primary investigator to ensure that all staff personnel who will 
be handling, packaging, and/or shipping clinical specimens act in conformance with 
International Air Transport Association (IATA) regulations relating to the handling and 
shipping of hazardous goods.
1. All shipments will be made in freezer boxes containing adequate amount of DRY ICE to 
keep samples frozen for at least 72 hours.
2. Please include a sample inventory with each shipment.
 
 
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3. Samples should be sent at intervals to be determined by the SPONSOR and the 
investigator.  Shipments should be sent on MONDAY or TUESDAY to assure receipt by 
Friday.
3. Shipment Information
Shipment information is provided separately in the laboratory procedures manual.
G. CRITERIA FOR SUBJECT DISCONTINUATION FROM PK SUB-TRIAL
The subject must be discontinued from further participation in the sub-trial if any of the 
discontinuation criteria for the main trial are met or if the subject and legal guardian 
withdraw consent/assent.
Note: Discontinuation from the PK sub-trial does not mean that the subject must be 
discontinued from the main trial; see Section 5.8 for criteria for discontinuation from the 
main trial.
H. PHARMACOKINETIC MEASUREMENTS
Blood samples will be collected for the determination of PK parameters for MF at steady 
state such as area under the concentration-time curve from 0 to 12 hours (AUC0-12h), area 
under the curve from 0 to last concentration observed (AUC0-last), maximum plasma 
concentration (Cmax), and time to Cmax (Tmax). 
PK parameters for formoterol will not be determined in this trial.
Samples will be assayed by a LC-MS/MS (Liquid Chromatography–Mass Spectrometry / 
Mass Spectrometry) assay method.  
I.
SAFETY MEASUREMENTS
Safety measurements for subjects participating in the PK sub-trial will be presented within 
the main trial report (Protocol 087); safety data from the sub-trial will not be reported
separately.
J. DATA ANALYSIS
Main efficacy data for subjects participating in the PK sub-trial will be analyzed within the 
main trial report (Protocol 087) and will not be reported separately. Additional data analyses 
unique to the sub-trial are presented below.
Individual values will be listed for plasma concentrations and each derived pharmacokinetic 
parameters (AUC0-12h, AUC0-last, Cmax, and Tmax) for mometasone furoate and summarized by 
treatment groups and combined across treatments and the following descriptive statistics will 
be provided by treatments as well as combined across treatment groups: N (number of 
subjects with non-missing data), arithmetic mean, standard deviation, arithmetic coefficient 
of variation (calculated as 100x standard deviation/arithmetic mean), geometric mean, 
geometric coefficient of variation (calculated as 100 x sqrt( exp(s2) - 1), where s2 is the 
observed variance on the natural log-scale), minimum, median and maximum.
 
 
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General Instructions for Use of the MDI
12.6
1.
REMOVE THE CAP FROM THE MOUTHPIECE (Figure 1).  Check mouthpiece for 
foreign objects prior to use.  Make sure the canister is fully inserted into the actuator.
Figure 1
2.
SHAKE THE INHALER WELL immediately before each use.
3.
BREATHE OUT FULLY THROUGH THE MOUTH expelling as much air from 
your lungs as possible.  Place the mouthpiece fully into the mouth holding the inhaler 
in its upright position (Figure 1) and closing the lips around it.
4.
WHILE BREATHING IN DEEPLY AND SLOWLY THROUGH THE MOUTH, 
FULLY DEPRESS THE TOP OF THE METAL CANISTER with your index finger 
(Figure 2).  Release your finger from the canister.
Figure 2
5.
HOLD YOUR BREATH AS LONG AS POSSIBLE, up to 10 seconds.  Then remove 
the inhaler from your mouth and breathe out through your nose, while keeping the 
lips closed.
6.
For administration of the second puff, wait at least half a minute, shake the inhaler 
again and repeat Steps 2 through 5.
7.
Replace the cap immediately after use.
Upright
Position
Mouthpiece
Cap
Actuator
Canister
FOR ORAL
INHALATION
ONLY
 
 
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For best results, MDIs should always be used at room temperature.  The product should not 
be exposed to extreme heat or cold.
After you have finished taking your dose, rinse your mouth with water or a mouthwash 
solution and then spit this out.  This will help you prevent thrush.
Cleaning Instructions:  
Keeping the plastic mouthpiece clean is extremely important to prevent medication build-up.  
The mouthpiece should be cleaned using a dry wipe after every 7 days of use.
For cleaning do not remove the unit from the actuator.  Wipe the internal and external 
surfaces of the actuator mouthpiece with a clean, dry tissue.  Do not wash or put any part of 
the inhaler in water.
Never immerse the metal canister in water.
 
 
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Stoughton-Cornell Scale
12.7
POTENCY RANKING OF SOME COMMONLY USED BRAND NAME CORTICOSTEROIDa
Potency
Group
Preparation
Super Potent
1
Temovate cream
0.05%
(a)
Temovate ointment
0.05%
(a)
Diprolene cream
0.05%
(b)
Diprolene ointment
0.05%
(b)
Psorcon ointment
0.05%
(c)
Potent
2
Cyclocort ointment
0.1%
(d)
Diprolene cream AF
0.05%
(b)
Diprosone ointment
0.05%
(e)
Elocon ointment
0.1%
(f)
Florone ointment
0.05%
(g)
Halog cream
0.1%
(h)
Lidex cream
0.05%
(I)
Lidex gel
0.05%
(I)
Lidex ointment
0.05%
(I)
Maxiflor ointment
0.05%
(g)
Topicort cream
0.25%
(j)
Topicort gel
0.05%
(j)
Topicort ointment
0.25%
(j)
3
Aristocort A ointment
0.1%
(k)
Cyclocort cream
0.1%
(d)
Cyclocort lotion
0.1%
(d)
Diprosone cream
0.05%
(e)
Florone cream
0.05%
(g)
Lidex E cream
0.05%
(I)
Halog ointment
0.1%
(h)
Maxiflor cream
0.05%
(g)
Valisone ointment
0.1%
(l)
Mid-Strength
4
Cordran ointment
0.05%
(m)
Elocon cream
0.1%
(f)
Kenalog cream
0.1%
(k)
Synalar ointment
0.025%
(n)
Westcort ointment
0.2%
(o)
5
Cordran cream
0.05%
(m)
Diprosone lotion
0.05%
(e)
Kenalog lotion
0.1%
(k)
Locoid cream
0.1%
(p)
Synalar cream
0.025%
(n)
Valisone cream
0.1%
(l)
 
 
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POTENCY RANKING OF SOME COMMONLY USED BRAND NAME CORTICOSTEROIDa
Potency
Group
Preparation
Westcort cream
0.2%
(o)
Mild
6
Alclovate cream
0.05%
(q)
Alclovate ointment
0.05%
(q)
Aristocort cream
0.1%
(k)
DesOwen cream
0.05%
(r)
Synalar solution
0.01%
(n)
Tridesilone cream
0.05%
(r)
Valisone lotion
0.05%
(l)
7
Topicals 
w/hydrocortisone, 
dexamethasone, 
flumethalone, 
prednisolone and methylprednisone
a:
Group 1 is the super-potent category; potency descends with each group to Group 7, which is least 
potent (2, 3 -- potent steroids; 4, 5 -- mid-strength steroids; 6, 7 -- mild steroids).  There is no 
significant difference between agents within Groups 2 through 7; the compounds are simply 
arranged alphabetically.  However, within Group 1, Temovate cream or ointment is more potent 
than Diprolene cream or ointment and Psorcon ointment.
(a)
Clobetasol propionate
(b)
Betamethasone dipropionate (optimized vehicle)
(c)
Diflorasone diacetate (optimized vehicle)
(d)
Amcinonide
(e)
Betamethasone dipropionate
(f)
Mometasone furoate
(g)
Diflorasone diacetate
(h)
Halcinonide
(I)
Fluocinonide
(j)
Desoximetasone
(k)
Triamcinolone acetonide
(l)
Betamethasone valerate
(m) Flurandrenolide
(n)
Fluocinolone acetonide
(o)
Hydrocortisone valerate
(p)
Hydrocortisone dipropionate
(q)
Alclometasone dipropionate
(r)
Desonide
 
 
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Method 
for 
Administering 
Short-Acting 
Beta-Agonist 
(SABA) 
During 
12.8
Postbronchodilator testing for Airway Reversibility
In assessing β-agonist response in the clinic, four to eight inhalations (“puffs”) of SABA 
(albuterol/salbutamol) or one to two nebulizations of SABA will be administered.
If nebulizations of SABA will be used during the reversibility procedure, please refer to 
guidance directly after the procedure for ‘puffs’ of SABA.
Note: Spacers are permitted for SABA administered for the purposes of demonstrating 
reversibility.
Procedure - ‘Puffs’ of SABA
1. Perform Pre-Bronchodilator spirometry (baseline FEV1)
2. Shake the metered-dose inhaler
3. Tilt the head back slightly and breathe out
4. Place device in mouth
5. Press down on inhaler to release medication
6. Breathe in slowly (3 to 5 seconds) to total lung capacity
7. Hold breath for 10 seconds
8. Wait 30 seconds between each inhalation (“puff”) and repeat the same sequence 3 
additional times
9. After 4 inhalations of SABA, wait approximately 10 minutes and then perform spirometry. 
Compare results with baseline spirometry

If there is a < 12% change in FEV1, continue to Step 10

If there is a ≥ 12% change in absolute FEV1, then end procedure – patient has met 
inclusion criteria
10. Repeat steps to administer an additional 2 inhalations of SABA with approximately 30 
seconds between inhalations
 
 
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11. Wait approximately 10 minutes, perform spirometry, and compare with baseline FEV1

If there is a < 12% change in FEV1, continue to Step 12

If there is a ≥ 12% change in absolute FEV1, then end procedure – patient has met 
inclusion criteria
12. Repeat steps to administer an additional 2 inhalations of SABA with approximately 30 
seconds between inhalations
13. Wait approximately 10 minutes, perform spirometry, compare with baseline FEV1

If there is a < 12 % change in absolute FEV1, the subject has not met the inclusion 
criterion for reversibility

If there is a ≥ 12 % change in absolute FEV1, the subject has met the inclusion 
criterion for reversibility
Procedure - ‘Nebulization’ of SABA
Nebulization treatments of 2.5 mg albuterol/salbutamol per treatment can be used to 
demonstrate reversibility.  The reversibility procedure for using nebulized treatments is 
described below:
1. Perform Pre-Bronchodilator spirometry (baseline FEV1)
2.  After 1 nebulized treatment, wait approximately 10 minutes and then perform spirometry. 
Compare results with baseline spirometry

If there is a < 12% change in FEV1, continue to the next step

If there is a ≥ 12% change in absolute FEV1, then end procedure – patient has met 
inclusion criteria
3. Repeat step to administer 1 additional nebulized treatment
4. Wait approximately 10 minutes, perform spirometry, and compare with baseline FEV1

If there is a < 12% change in FEV1, continue to the next step

If there is a ≥ 12% change in absolute FEV1, then end procedure – patient has met 
inclusion criteria
5. You may wait an additional 10 minutes (approximately) and attempt only spirometry again
(without any further use of nebulization of SABA)
 
 
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Standardization of Spirometry 
12.9
American Thoracic Society. ATS Documents: Statements, Guidelines & Reports: ATS/ERS 
standardisation of lung functioning testing: Standardisation of spirometry, 2005. 
http://www.thoracic.org/statements/
Also refer to the detailed instructions provided by the Central Vendor.
 
 
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Asthma Action Plan
12.10
MK-0887A Protocol 087
GUIDE TO PERCENTAGE CALCULATIONS (ASTHMA ACTION PLAN)
(This guide is to be completed and included for the subject’s study files.
Please remove this guide prior to providing the Asthma Action Plan to the 
subject and Parent/Caregiver)
The Asthma Action Plan must first be completed with the subject’s peak expiratory flow (PEF) ranges. 
However, for some subjects the PEF is of limited value and change of symptoms may be of greater 
importance. This should be explained to the subject and Parent/Caregiver. The Investigator will indicate on 
the form below, the adequate rescue medication to use, depending on the PEF range and symptoms. The 
Asthma Action Plan will help the subject and their parent/caregiver to effectively manage his/her/the 
subject’s symptoms.
Measure the subject’s highest peak expiratory flow (PEF).
This should be the highest PEF from three attempts.
Enter the subject’s highest PEF onto the Asthma Action Plan.
Calculate the percentage ranges as follows:
CALCULATE ONE PERCENT OF THE SUBJECT’S BEST PEF:
1% = PEF ÷ 100
THEN USE THE FOLLOWING TO CALCULATE THE RANGES:
100% = 1% x 100 (this is equal to PEF)
80% = 1% x 80
79% = 1% x 79
70% = 1% x 70
60% = 1% x 60  
Enter these ranges (80-100%, 60-79%, <60%) onto the asthma action plan.
.
 
 
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EXAMPLE
A subject has three attempts at PEF and records 325, 270, 300. The subject’s highest PEF is 325.
CALCULATE 1% of 325:
325 ÷ 100 = 3.25
CALCULATE THE RANGES:
80% TO 100%
= 3.25 x 80
to
3.25 x 100
= 260
to
325
Range (80% to 100%) =  260 to 325
60% TO 79%
= 3.25 x 60
to
3.25 x 79
= 195
to
256.75
Range (60% to 79%) = 195 to 256.75
<60%
See 60% calculation above
Range (less than 60%) = calculation above.
 
 
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  Asthma eDiary (IVRS/IWRS) Questions
12.11
The eDiary (IVRS/IWRS) is to be used daily to capture the subject's use of trial medication 
and use of rescue medication(s). Because the use of SABA as prevention for exercise-
induced bronchospasm (EIB) is not considered rescue use, it should not be captured in the 
IVRS/IWRS system for the purpose of assessing asthma control. Use of SABA for 
prevention of EIB will be recorded in the concomitant medication module of the electronic 
case report form (eCRF).
A sample listing of the asthma eDiary (IVRS/IWRS) questions is provided below.  
Additional details (including set-up/programming of the eDiary) will be provided by the 
central vendor. At the Screening Visit, the subject and parent/legal guardian will be provided 
with verbal and written instructions on the proper use of the eDiary (IVRS/IWRS) and PEF 
meter.  In addition, the user will be guided by clear and easy-to-read instructions on the 
eDiary (IVRS/IWRS).  
Morning Questionnaire:
The subject, with the assistance of the parent/legal guardian, will answer the following 
questions in the morning upon rising and after completing their PEF measurements, and 
taking their trial medication and/or SABA (albuterol/salbutamol) (Section 5.2). SABA taken 
as pre-treatment for prevention of exercise-induced bronchospasm (EIB) is not
considered as rescue use and should not be recorded on the asthma eDiary 
(IVRS/IWRS).  
During the Screening Period (between Visit 1 and Visit 2), “trial medication” in Question 1 
refers to the subjects pre-trial ICS/LABA combination therapy. Also, as Visit 1 will be the 
first trial visit, Questions 2 through 7 of the Morning Questionnaire will not apply for that 
visit.
For subjects who discontinue/withdraw from trial medication prior to completion of the trial, 
Question 1 will not apply.
Question
Response(s)
1.
Have you taken your trial medication this morning? 
Yes/No 
2.
Did you take any puffs of albuterol/salbutamol 
since your last eDiary session?
Yes/No
3.
How many puffs of albuterol/salbutamol have you taken 
since your last eDiary session?
0 – X puff(s) 
4.
Did you take any albuterol/salbutamol nebulizations 
since your last eDiary session?
Yes/No
5.
How many nebulizations of albuterol/salbutamol have you taken 
since your last eDiary session?
0 – X neb(s)
6.
Did you take albuterol/salbutamol (puffs or nebulizations) 
within last 6 hrs. of this morning PEF Reading?  
Yes/No
7.
Did you take oral prednisone/prednisolone 
since your last eDiary session?
Yes/No
 
 
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Evening Questionnaire:
The subject, with the assistance of the parent/legal guardian, will answer the following 
questions in the evening at bedtime and after taking their trial medication and/or SABA 
(albuterol/salbutamol) (Section 5.2). SABA taken as pre-treatment for prevention of exercise-
induced bronchospasm (EIB) is not considered as rescue use and should not be recorded on 
the asthma eDiary (IVRS/IWRS).  
During the Screening Period (between Visit 1 and Visit 2), “trial medication” in Question 1 
refers to the subjects pre-trial ICS/LABA combination therapy.  
For subjects who discontinue/withdraw from trial medication prior to completion of the trial, 
Question 1 will not apply.
Question
Response(s)
1. Have you taken your trial medication this evening?
Yes/No
2. Did you take any puffs of albuterol/salbutamol 
since your last eDiary session?
Yes/No
3. How many puffs of albuterol/salbutamol have you taken 
since your last eDiary session?
0 – X puff(s) 
4. Did you take any albuterol/salbutamol nebulizations 
since your last eDiary session?
Yes/No
5. How many nebulizations of albuterol/salbutamol have you taken 
since your last eDiary session?
0 – X neb(s)
6. Have you taken oral prednisone/prednisolone 
since your last eDiary session?
Yes/No
 
 
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Statistical Methodology
12.12
Constrained Longitudinal Data Analysis (cLDA) Method (with Adjustment for Baseline 
Values) –
Technical Details for Model Specification, Assumptions, and SAS 
Implementation Codes
Model
Let Y ijt be the response for subject i, with treatment assignment j, at time t. The marginal 
mean responses of the cLDA model can be formulated as 
and 
The mean response γ0 at t =0 is constrained to be the same for all treatment groups due to 
randomization. The effect γ jt denotes the change from baseline for treatment j at time t. The 
cLDA model assumes that baseline and post-baseline values have a joint multivariate normal 
distribution. An unstructured covariance matrix can be specified in the mixed model to 
account for within subject correlation at times t ≥0 (including baseline). 
The treatment difference for the mean change from baseline at time point t, 
          
is defined as:
At each time point t, 
, the mean change from baseline (LSMEANS) for test drug 
and control are 
and
, respectively, as defined in the cLDA model above.
This longitudinal model provides valid statistical inference in the presence of possible 
missing data if the missing data mechanism is ignorable (or more specifically, missing at 
random [MAR] or missing completely at random [MCAR]). This missing data mechanism 
requires that the probability of a data point being missing does not depend on the missing 
data after adjusting for the observed data. For reasons discussed in Section 8.2 of the 
protocol, it is expected that MAR/MCAR mechanisms will underlie most of the missingness 
and the proportion of data missing not at random [MNAR], driven solely by unobserved 
values of the trial endpoints, will be small.
Model Convergence 
If the unstructured covariance model fails to converge with the default algorithm, then Fisher 
scoring algorithm or other appropriate methods can be used to provide initial values of the 
covariance parameters. In the rare event that none of the above methods yield convergence, a 
structured covariance such as Toeplitz can be used to model the correlation among repeated 
measurements. In this case, the empirical option will be used because the sandwich variance 
estimator is asymptotically unbiased.
 
 
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SAS Codes
SAS codes for fitting the full likelihood cLDA model are provided below. 
*--- SAS Coding assumes the dataset is already structured for analysis ---;
*--- Model effects decodes and explanation of options ---
            age=age strata (5<=age<=7 ,8<=age<=11)
region=geographical region
trt=treatment (MF/F 100/10 mcg twice daily, MF 100 mcg )
time=week of scheduled visit (0, 1,4, 8,12 weeks)
kr=the kenwardroger option performing degrees of freedom calculations based on 
                  Kenward and Roger (1997).
om=assures weighing of categorical covariates but requires an equal number of
                   records per subject (i.e. include a records of missing evaluations in database)
          
*---- Constrain the Baseline as a single estimate across treatments ---;
data a; set a; if time=0 then trt='x';  
*---- Estimate statements are provided for the Day1 post dose treatment difference, 
                and the Day 1 post dose, Weeks 1,4,8,12 average treatment difference (MF/F 
versus MF) ----;
proc sort data=a;  by time;
proc mixed data=a;
class subjnbr time trt age region;
model y = age region trt*time/noint ddfm=kr; 
repeated time/subject=subjnbr type=un;
lsmeans trt*time/cl pdiff om; 
estimate ‘Day 1 diff ' trt*time 0  -1   1  0  0  0  0  0  0  0  0  / cl;
estimate ‘Weeks diff ' trt*time 0  -1/5   1/5  -1/5  1/5  -1/5  1/5  -1/5  1/5  -1/5  1/5  / cl;
output will be programmed to extract those estimates relevant for the remaining pre-specified 
analyses in the protocol, such as treatment differences at each time point.
 
 
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List of Abbreviations
12.13
AAP
Asthma Action Plan
ABPP
Asthma Baseline Pediatric Profile
AE
Adverse experience
ANCOVA
Analysis of covariance
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATS/ERS
American Thoracic Society/European Respiratory Society
AUC0-12h
Area under the concentration-time curve from 0 to 12 hours
AUC0-last
Area under the curve from 0 to last concentration observed
β-hCG
β-Human Chorionic Gonadotropin
BID
Twice daily
CI
Confidence interval
CI (Protocol)
Principal Coordinator / Coordinating Investigator
cLDA
Constrained longitudinal data analysis
Cmax
Maximum concentration
CSR
CV
Clinical Study Report
Coefficient of Variation
DILI
Drug-induced liver injury
DPI
Dry-powder inhaler
ECI
Event of clinical interest
eCRF
Electronic Case Report Form
EIB
Exercise-induced bronchospasm
ERC
EU
Ethics Review Committee
European Union
F
Formoterol Fumarate
FAS
Full analysis set
FDC
Fixed Dose Combination
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
GINA
Global Initiative for Asthma
GCP
Good Clinical Practice
Ht
Height
IB
Investigator's Brochure
ICF
Informed consent form
ICS
Inhaled corticosteroids
 
 
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IEC
Institutional ethics committee
IRB
Institutional Review Board
IVRS
Interactive voice-response system
IWRS
Integrated web-response system
Kg
Kilograms
LABA
LC-MS/MS 
Long-acting beta-agonist
Liquid Chromatography–Mass Spectrometry / Mass Spectrometry
LDA
Longitudinal data analysis
MAR
Missing at Random
MCAR
Missing Completely at Random
mcg
Micrograms
MDI
Metered-dose inhaler
Mg
Milligrams
MF
NHIS
Mometasone Furoate
National Center for Health Statistics
NSAE
Non-serious adverse experience
OTC
Over the counter
PD
Pharmacodynamics
PDLC
Predefined limits of change
PEF
Peak expiratory flow 
PFT
Pulmonary Function Test
PGt
Pharmacogenetic
PK
PRN
QD
Pharmacokinetics
When necessary
Once daily
SABA
Short-acting beta-agonist
SAE
Serious adverse experience
SAP
Statistical analysis plan
SD
Standard deviation
Tmax
Time to Cmax 
US
United States
Wt
Weight
 
 
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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 – 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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