Clinical trial NCT02478398
Conditions: Rhinitis, Allergic, Seasonal
Sponsor: Merck Sharp & Dohme LLC
Start date: 2015-07-20; Completion date: 2018-11-19
Enrollment: 1025 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the efficacy and safety of short ragweed pollen allergen extract (MK-3641, SCH 039641, RAGWITEK™) sublingual immunotherapy tablets in children aged 5 to 17 years with ragweed-induced allergic rhinitis/rhinoconjunctivitis with or without asthma. The primary hypothesis of this study is that administration of short ragweed pollen allergen extract sublingual immunotherapy tablets to children 5 to 17 years of age, compared with placebo, will result in a significant reduction in the combination of rhinoconjunctivitis symptoms and medication use over the peak ragweed season (RS).

Detailed description:

Arms: arm 1: Participants receive one sublingual tablet containing 12 units of Ambrosia artemisiifolia major allergen number 1 (Amb a 1-U), once daily (QD) for up to 35 weeks. Participants may use study-provided rescue medication(s) as needed to treat rhinoconjunctivitis symptoms. arm 2: Participants receive one placebo sublingual tablet, QD for up to 35 weeks. Participants may use study-provided rescue medication(s) as needed to treat rhinoconjunctivitis symptoms.
Interventions: intervention 1: Short ragweed pollen allergen extract intervention 2: Placebo intervention 3: Self-injectable epinephrine intervention 4: Albuterol/Salbutamol intervention 5: Loratadine intervention 6: Olopatadine intervention 7: Mometasone furoate monohydrate
Intervention descriptions: intervention 1: One sublingual tablet containing 12 units of Amb a 1-U, once daily (QD) for up to 35 weeks. intervention 2: One placebo sublingual tablet, QD for up to 35 weeks. intervention 3: Intramuscular (IM) injection with suggested doses of 0.15 mg for participants weighing 15-30 kg (33-66 pounds) or 0.3 mg for participants weighing ≥30 kg (≥66 pounds), as needed for severe allergic reactions. Epinephrine was only provided in countries/study sites where it was a regulatory requirement. intervention 4: Inhalation of albuterol 90 mcg/puff or salbutamol 100 mcg/puff metered dose inhaler (MDI), as needed as asthma rescue medication for those participants with asthma intervention 5: 5 mg (1 mg/mL syrup or 5 mg tablet) for participants 5 years old or 10 mg (1 mg/mL syrup or 10 mg tablet) for participants 6 to 17 years old, as needed for rhinoconjunctivitis symptoms intervention 6: Opthalmic solution, 1 drop (0.1%) per affected eye twice daily (BID), as needed for rhinoconjunctivitis symptoms intervention 7: Intranasal spray, at doses of 1 spray (50 mcg/ spray) per nostril for participants 5 to 11 years old or 2 sprays (50 mcg/spray) per nostril for participants 12 to 17 years old, as needed for rhinoconjunctivitis symptoms

Protocol documents:
Prot_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT02478398 
Document Date: 
28-Jun-2018
A Phase III, Randomized, Placebo-Controlled Clinical Trial to Study 
the Efficacy and Safety of MK-3641, a Ragweed (Ambrosia 
artemisiifolia) Sublingual Immunotherapy Tablet, in Children With 
a History of Ragweed-Induced Rhinoconjunctivitis With or Without 
Asthma


Product:  MK-3641 
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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, Placebo-Controlled Clinical Trial to Study the Efficacy and Safety 
of MK-3641, a Ragweed (Ambrosia artemisiifolia) Sublingual Immunotherapy Tablet, in 
Children With a History of Ragweed-Induced Rhinoconjunctivitis With or Without Asthma
IND NUMBER:  12,970
EudraCT NUMBER:  2014-004341-27 
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 12
2.0
TRIAL DESIGN........................................................................................................ 12
Trial Design ........................................................................................................... 12
2.1
Trial Diagram........................................................................................................ 14
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 15
Primary Objective(s) & Hypothesis(es) .............................................................. 15
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 15
3.2
Other Objectives ................................................................................................... 16
3.3
Tertiary Objectives.............................................................................................. 16
3.3.1
Exploratory Objective......................................................................................... 16
3.3.2
4.0
BACKGROUND & RATIONALE.......................................................................... 16
Background ........................................................................................................... 16
4.1
Pharmaceutical and Therapeutic Background .................................................... 17
4.1.1
Rationale................................................................................................................ 17
4.2
Rationale for the Trial and Selected Subject Population .................................... 17
4.2.1
Rationale for Dose Selection/Regimen............................................................... 19
4.2.2
Rationale for the Use of Placebo ................................................................. 20
4.2.2.1
Rationale for Dose Interval and Trial Design .............................................. 20
4.2.2.2
Rationale for Endpoints ...................................................................................... 20
4.2.3
Efficacy Endpoints....................................................................................... 20
4.2.3.1
4.2.3.1.1
Rhinoconjunctivitis Endpoints.............................................................. 20
Total Combined Score (TCS)......................................................... 20
4.2.3.1.1.1
Rhinoconjunctivitis Daily Symptom Score (DSS)......................... 21
4.2.3.1.1.2
Rhinoconjunctivitis Daily Medication Score (DMS)..................... 21
4.2.3.1.1.3
4.2.3.1.2
Asthma Endpoints................................................................................. 22
Asthma Daily Symptom Score (aDSS) .......................................... 22
4.2.3.1.2.1
Beta2-agonist Use ........................................................................... 23
4.2.3.1.2.2
Nocturnal Awakenings................................................................... 23
4.2.3.1.2.3
Safety Endpoints .......................................................................................... 23
4.2.3.2
 
 
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Future Biomedical Research........................................................................ 23
4.2.3.3
Benefit/Risk ........................................................................................................... 24
4.3
5.0
METHODOLOGY ................................................................................................... 24
Entry Criteria........................................................................................................ 24
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 24
5.1.1
Subject Inclusion Criteria.................................................................................... 24
5.1.2
Subject Exclusion Criteria .................................................................................. 26
5.1.3
Trial Treatment(s) ................................................................................................ 29
5.2
Dose Selection .................................................................................................... 30
5.2.1
Dose Selection (Preparation) ....................................................................... 30
5.2.1.1
Timing of Dose Administration .......................................................................... 30
5.2.2
In-Clinic Dosing at Visit 2........................................................................... 30
5.2.2.1
At-home Dosing........................................................................................... 31
5.2.2.2
Temporary Study Drug Interruptions........................................................... 32
5.2.2.3
Trial Blinding/Masking....................................................................................... 32
5.2.3
Randomization or Treatment Allocation............................................................ 32
5.3
Stratification.......................................................................................................... 32
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 32
5.5
Rescue Medications & Supportive Care............................................................. 33
5.6
Allergy Rescue Medications for Rhinoconjunctivitis Symptoms....................... 33
5.6.1
Medications for Asthma Symptoms.................................................................... 34
5.6.2
Rescue Medication for Severe Allergic Reactions (Self-Injectable 
5.6.3
Epinephrine)........................................................................................................ 34
Diet/Activity/Other Considerations..................................................................... 35
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 35
5.8
Subject Replacement Strategy............................................................................. 36
5.9
Beginning and End of the Trial ........................................................................... 36
5.10
Clinical Criteria for Early Trial Termination ................................................... 36
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 37
7.0
TRIAL PROCEDURES ........................................................................................... 41
Trial Procedures ................................................................................................... 41
7.1
Administrative Procedures.................................................................................. 41
7.1.1
 
 
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Informed Consent......................................................................................... 41
7.1.1.1
7.1.1.1.1
General Informed Consent.................................................................... 41
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 42
Inclusion/Exclusion Criteria ........................................................................ 42
7.1.1.2
Interactive Voice Response System (IVRS) / Interactive Web Response 
7.1.1.3
System (IWRS)............................................................................................ 42
Subject Identification Card .......................................................................... 42
7.1.1.4
Medical History ........................................................................................... 42
7.1.1.5
Demography................................................................................................. 43
7.1.1.6
Prior and Concomitant Medications Review ............................................... 43
7.1.1.7
7.1.1.7.1
Prior Medications.................................................................................. 43
7.1.1.7.2
Concomitant Medications..................................................................... 43
Dispense Electronic Diary (e-diary) ............................................................ 43
7.1.1.8
Dispense Sublingual Immunotherapy (SLIT) Report Card ......................... 43
7.1.1.9
Dispense Comment Card ............................................................................. 44
7.1.1.10
Anaphylaxis Emergency Action Plan .......................................................... 44
7.1.1.11
Self-Injectable Epinephrine ......................................................................... 44
7.1.1.12
Assignment of Screening Number............................................................... 44
7.1.1.13
Assignment of Randomization Number....................................................... 45
7.1.1.14
Trial Compliance ......................................................................................... 45
7.1.1.15
Pollen Counts............................................................................................... 45
7.1.1.16
Clinical Procedures/Assessments........................................................................ 45
7.1.2
Vital Signs (Temperature, Blood Pressure, Pulse, Respiration) .................. 45
7.1.2.1
Body Height and Weight ............................................................................. 46
7.1.2.2
Physical Examination................................................................................... 46
7.1.2.3
Oropharyngeal Examination ........................................................................ 46
7.1.2.4
Pulmonary Function Tests ........................................................................... 46
7.1.2.5
Skin Prick Test............................................................................................. 47
7.1.2.6
Adverse Event Monitoring........................................................................... 47
7.1.2.7
7.1.2.7.1
Assess and Record Duration of Local Adverse Events of Interest ....... 47
7.1.2.7.2
Alternate Local Adverse Event Severity Grading ................................ 48
In-Clinic Dosing of Study Drug................................................................... 48
7.1.2.8
 
 
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Dispense/Review/Collect Study Medications (Study Drug, Self-
7.1.2.9
Injectable Epinephrine, Beta2-agonist and Allergy Rescue Medication) .... 48
Monitor Compliance with Study Medications ............................................. 48
7.1.2.10
Complete/Review Daily Symptoms in e-Diary ........................................... 49
7.1.2.11
Laboratory Procedures/Assessments .................................................................. 49
7.1.3
Serum-specific IgE....................................................................................... 50
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 50
7.1.3.2
Urine Pregnancy Test................................................................................... 51
7.1.3.3
Pharmacodynamic Evaluations.................................................................... 51
7.1.3.4
Future Biomedical Research........................................................................ 51
7.1.3.5
Other Procedures................................................................................................. 51
7.1.4
Withdrawal/Discontinuation........................................................................ 51
7.1.4.1
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 51
Blinding/Unblinding .................................................................................... 52
7.1.4.2
Calibration of Critical Equipment................................................................ 52
7.1.4.3
Visit Requirements.............................................................................................. 53
7.1.5
Assessing and Recording Adverse Events .......................................................... 53
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 54
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 54
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 55
7.2.3
Serious Adverse Events ............................................................................... 55
7.2.3.1
Events of Clinical Interest............................................................................ 56
7.2.3.2
Evaluating Adverse Events ................................................................................. 56
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 59
7.2.5
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 59
7.3
Scientific Advisory Committee........................................................................... 59
7.3.1
Executive Oversight Committee ......................................................................... 59
7.3.2
Data Monitoring Committee ............................................................................... 59
7.3.3
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 60
Statistical Analysis Plan Summary ..................................................................... 60
8.1
Efficacy Analyses ............................................................................................... 60
8.1.1
Safety Analyses................................................................................................... 61
8.1.2
 
 
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Power and Sample Size....................................................................................... 62
8.1.3
Interim Analyses ................................................................................................. 62
8.1.4
Statistical Analysis Plan ....................................................................................... 62
8.2
Responsibility for Analyses/In-House Blinding ................................................. 63
8.2.1
Hypotheses.......................................................................................................... 63
8.2.2
Analyses Endpoints............................................................................................. 63
8.2.3
Efficacy Endpoints....................................................................................... 63
8.2.3.1
Safety Endpoints .......................................................................................... 64
8.2.3.2
Derivations of Efficacy/Immunologic Endpoints ........................................ 65
8.2.3.3
Derivations of Safety Endpoints .................................................................. 65
8.2.3.4
Analysis Populations........................................................................................... 65
8.2.4
Efficacy Analysis Populations ..................................................................... 65
8.2.4.1
Safety Analysis Populations ........................................................................ 66
8.2.4.2
Statistical Methods.............................................................................................. 66
8.2.5
Statistical Methods for Efficacy/Immunologic Analyses ............................ 66
8.2.5.1
Statistical Methods for Safety Analyses ...................................................... 70
8.2.5.2
Summaries of Baseline Characteristics, Demographics, and Other 
8.2.5.3
Analyses....................................................................................................... 73
Multiplicity ......................................................................................................... 73
8.2.6
Sample Size and Power Calculations.................................................................. 73
8.2.7
Subgroup Analyses and Effect of Baseline Factors ............................................ 74
8.2.8
Interim Analyses ................................................................................................. 74
8.2.9
Compliance (Medication Adherence) ................................................................. 74
8.2.10
Extent of Exposure.............................................................................................. 75
8.2.11
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 75
Investigational Product ........................................................................................ 75
9.1
Packaging and Labeling Information ................................................................. 76
9.2
Clinical Supplies Disclosure................................................................................. 76
9.3
Storage and Handling Requirements.................................................................. 76
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 76
9.5
Standard Policies................................................................................................... 77
9.6
 
 
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10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 77
Confidentiality....................................................................................................... 77
10.1
Confidentiality of Data ....................................................................................... 77
10.1.1
Confidentiality of Subject Records ..................................................................... 77
10.1.2
Confidentiality of Investigator Information........................................................ 77
10.1.3
Confidentiality of IRB/IEC Information............................................................. 78
10.1.4
Compliance with Financial Disclosure Requirements....................................... 78
10.2
Compliance with Law, Audit and Debarment ................................................... 78
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 80
10.4
Quality Management System............................................................................... 80
10.5
Data Management................................................................................................. 81
10.6
Publications ........................................................................................................... 81
10.7
11.0
LIST OF REFERENCES......................................................................................... 83
12.0
APPENDICES........................................................................................................... 85
Merck Code of Conduct for Clinical Trials........................................................ 85
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 87
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff ...................................................................................... 93
Approximate Blood Volumes Drawn by Trial Visit and by Sample Types... 103
12.4
Algorithm for Assessing Out-of-Range Laboratory Values ........................... 104
12.5
Allergy Rescue Medications for Rhinoconjunctivitis Symptoms ................... 105
12.6
Instructions for Opening the Ragweed Sublingual Tablet (Oral 
12.7
Lyophilisate) from the Pack............................................................................... 106
Method for Performing Post-Bronchodilator Reversibility Testing.............. 110
12.9
List of Abbreviations .......................................................................................... 116
12.13
13.0
SIGNATURES......................................................................................................... 119
Sponsor's Representative ................................................................................... 119
13.1
 
 
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Investigator.......................................................................................................... 119
13.2
 
 
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LIST OF TABLES
Table 1
Low or Medium Daily Dose Corticosteroids as Defined by the NAEPP 
Guidelines............................................................................................................... 18
Table 2
Scoring of Symptomatic Rescue Medication Use .................................................. 22
Table 3
Prohibited Medications Prior to Randomization .................................................... 27
Table 4
Trial Treatments...................................................................................................... 29
Table 5
Prohibited Medications Beginning Prior to Pre-Season Visit 6 and for Duration 
of Trial.................................................................................................................... 33
Table 6
Laboratory Tests ..................................................................................................... 50
Table 7
Evaluating Adverse Events..................................................................................... 57
Table 8
Analysis Strategy for Key Efficacy Endpoints....................................................... 61
Table 9
Medication Score for Prednisone Usage................................................................. 67
Table 10 Analysis Strategy for the Efficacy/Immunologic Endpoints .................................. 69
Table 11 Analysis Strategy for Safety Parameters ................................................................ 72
Table 12 Product Descriptions............................................................................................... 75
Table 13 Kits Dispensed Per Visit......................................................................................... 76
 
 
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LIST OF FIGURES
Figure 1
Trial Diagram...................................................................................................... 14
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.8
Subject 
Withdrawal/
Discontinuation Criteria
Addition 
of 
“severe 
asthma 
exacerbation”
to 
the
list 
of
discontinuation criteria.
This change was made based on an 
update 
to 
the 
Reference 
Safety 
Information
in 
the 
Investigator’s 
Brochure (Edition 13).
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
6.0
Trial Flow Chart
Removed the “X” for IVRS/ IWRS at 
the Telephone/
Follow-up,
per the 
protocol 
clarification 
letter 
of 
08-NOV-2016.
Typographical error.
7.1.1.15
Trial Compliance
Added text to clarify that calculation of 
compliance with study drug is between 
study visits.
To clarify how to calculate compliance
with study drug.
7.1.2.10
Monitor Compliance with 
Study Medications
Revised text from “If not, the date(s) 
and reason for each deviation must be 
recorded.” to “If not, the date(s) and 
reason for each dose variation must be 
recorded on the study medication (SM) 
eCRF.”
To specify that dose variations must be 
recorded and where.
12.8
Anaphylaxis 
Emergency 
Action Plan
Added text stating that the Anaphylaxis 
Emergency Action Plan can also be 
modified in the United States, per the 
protocol 
clarification 
letter
of
20-FEB-2017.
To clarify that the plan in the United 
States can be modified if necessary.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
MK-3641 Ragweed Pediatric Allergic Rhinoconjunctivitis 
Efficacy/Safety Study
Trial Phase
Phase III
Clinical Indication
Ragweed pollen-induced rhinoconjunctivitis with or without 
asthma
Trial Type
Interventional
Type of control
Placebo
Route of administration
Sublingual
Trial Blinding
Double-blind
Treatment Groups
MK-3641 (12 Amb a 1-U);
Placebo
Number of trial subjects
Approximately 1000 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 
3.5 years from the time the first subject signs the informed 
consent until the last subject’s last visit. 
Duration of Participation
Each subject will participate in the trial for up
to 
approximately 20 months from the time the subject signs the 
Informed Consent Form (ICF) through the final contact.  
After a screening phase of up to 12 months, each subject will 
be receiving assigned treatment for up to 28 weeks.  After the 
end of treatment, each subject will be followed for 14 days.
A list of abbreviations used in this document can be found in Section 12.13.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a randomized, placebo-controlled, parallel-group, multi-site, double-blind trial of 
MK-3641 in children with ragweed pollen-induced allergic rhinitis/rhinoconjunctivitis, with 
or without asthma, to be conducted in conformance with Good Clinical Practices.  
Approximately 1000 children ages 5 to 17 years will be randomized in a 1:1 ratio to receive 
either MK-3641, at a dose of 12 Amb a 1-U, or placebo once daily for a total of 
approximately 20 to 28 weeks.  Subjects will be stratified by age to ensure an adequate 
number of subjects at younger ages are included.  Subjects will also be stratified by asthma 
status.  There may be multiple separate cohorts (approximately 2 to 3) recruited over 
consecutive ragweed seasons to complete the enrollment goal.  
The trial consists of a screening period and a treatment period, which includes pre-seasonal
and co-seasonal treatment. The screening period may last for up to approximately 12 months 
prior to randomization.  Once randomized, subjects are treated with a minimum of 
approximately 12 weeks (up to approximately 20 weeks) of pre-seasonal treatment and 
approximately 8 weeks of co-seasonal treatment.  There will be at least 7 clinic visits: 
Randomization Ratio
1:1
 
 
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screening (Visit 1), randomization (Visit 2), Off-season (Visit 3), Off-season (Visit 4), Pre-
season (Visit 6), In-season (Visit 7), and End-of-season (Visit 8 or Discontinuation Visit); 
Off-season (Visit 5) is only required if the time between Visit 4 and 6 is longer than 6-8 
weeks.  Subject compliance with study drug administration, rescue medication use, and daily 
e-dairy completion will be monitored. Compliance issues will prompt site retraining of 
subject/parent/guardian via telephone contacts as necessary.  The End-of-season visit will be 
scheduled approximately 1 week after the end of the ragweed season. A final telephone 
contact will occur approximately 14 days after the End-of-season (or discontinuation) visit 
for the safety follow-up.  Unscheduled visits are also permitted, if needed.  The trial diagram
is outlined in Section 2.2.
The first dose of MK-3641 must be administered in the clinic under the supervision of the 
investigator or qualified designee.  The subject must be monitored for 30 minutes to allow for 
direct observation of any adverse events (AEs) that occur soon after study drug 
administration.  Additionally, the supervised dose allows the investigator/qualified designee 
to ensure proper administration of study drug by the subject/parent/guardian.  Details for the 
in-clinic dosing are in Section 5.2.2 – Timing of Dose Administration.
The investigator/qualified designee will provide instructions on proper administration of the 
tablet, as well as discuss expected immediate application site reactions and potential severe 
AEs requiring medical evaluation and/or treatment, prior to dispensing the study drug to the 
subject/parent/guardian for at-home administration.  Doses of study drug subsequent to the 
first dose will be self-administered at home. 
Open-label rescue medications for rhinoconjunctivitis symptoms will be supplied at Visit 6 
for use throughout the ragweed season as required to treat allergic rhinoconjunctivitis 
symptoms. 
The subject/parent/guardian will record allergic rhinitis/conjunctivitis and asthma symptoms 
in an electronic diary (e-diary) each day beginning at Visit 4.  The study site and/or 
parent/guardian will determine whether the subject completes the e-diary him/herself or has
assistance from a parent/guardian (e.g., based on the individual subject’s abilities and
maturity level to complete the e-diary).  If the subject has assistance from a parent/guardian, 
the same parent/guardian should provide the assistance for the duration of the trial.
The subject/parent/guardian will also complete a side effect report card (called Sublingual 
Immunotherapy [SLIT] Report Card; Section 12.10) daily for the first ~28 days of study drug 
administration to record local side effects that occur within 60 minutes of study drug 
administration. The subject/parent/guardian will be provided a separate Comment Card to 
capture any AEs that occur and any medications used between scheduled clinic visits.  
During the first 28 days of study medication, local event occurring within the first 60 minutes 
of tablet administration should be collected on the SLIT Report Card and all other events 
should be collected on the Comment Card.  Following the first 28 days, any AEs will be 
captured on the Comment Card.
An external Data Monitoring Committee (eDMC) will monitor the interim safety data from 
this trial (Section 7.3.3).
 
 
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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 Diagram
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
Objective:  To evaluate the efficacy of MK-3641 sublingual immunotherapy tablet (12 Amb 
a 1-U) versus placebo in the treatment of children 5 to 17 years of age with ragweed-induced 
rhinoconjunctivitis, with or without asthma, based on the Total Combined Score (TCS) [sum 
of rhinoconjunctivitis daily symptom score (DSS) and rhinoconjunctivitis daily medication 
score (DMS)] averaged over the peak ragweed season (RS)
1.
Hypothesis:  Administration of MK-3641 sublingual immunotherapy tablet (12 Amb a 1-U) 
to children 5 to 17 years of age, compared with placebo, will result in a significant reduction 
in TCS averaged over the peak RS.
Secondary Objective(s) & Hypothesis(es)
3.2
1) Objective:  To compare the following between the MK-3641 (12 Amb a 1-U) and 
placebo groups:
1. Average TCS during the entire RS
2;
2. Average rhinoconjunctivitis DSS during the peak RS;
3. Average rhinoconjunctivitis DMS during the peak RS.
Hypotheses:  Administration of MK-3641 (12 Amb a 1-U) in children 5 to 17 years 
of age, compared with placebo, will result in a significant score reduction on the 
following endpoints:
1.
Average TCS during the entire RS;
2.
Average rhinoconjunctivitis DSS during the peak RS;
3.
Average rhinoconjunctivitis DMS during the peak RS.
2) Objective:  To assess the overall safety of MK-3641 (12 Amb a 1 U) in children 5 to 
17 years of age with ragweed-induced rhinoconjunctivitis, with or without asthma.
                                                
1  Peak ragweed season is defined as the 15 consecutive recorded days within the entire ragweed season with the highest 15-day moving 
average pollen count for each study site.
2  Entire ragweed season is defined as starting from the first day of 3 consecutive recorded days with pollen counts ≥10 grains/m3 through 
the last day of the last occurrence of 3 consecutive days with pollen counts ≥10 grains/m3.
 
 
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Other Objectives 
3.3
Tertiary Objectives
3.3.1
1) Objective:  To compare the average rhinoconjunctivitis DSS during the entire RS 
between the MK-3641 (12 Amb a 1-U) and placebo groups.
2) Objective: To assess and compare the following immunologic parameters between 
the MK-3641 and placebo groups at specified time points before and during 
treatment:
1. Immunoglobulin E (IgE) level against Ambrosia artemisiifolia;
2. Immunoglobulin G4 (IgG4) level against Ambrosia artemisiifolia.
Exploratory Objective
3.3.2
Objective:  To explore the effect of MK-3641 versus placebo on asthma endpoints in those 
subjects with asthma and those without asthma. 
4.0 BACKGROUND & RATIONALE
Background
4.1
Allergic rhinitis/rhinoconjunctivitis (AR/ARC) affects between 10% to 30% of adults and up 
to 40% of children in the US [1].  Ragweed pollen is one of the most common inhalant 
allergens in North America, and for many patients ragweed pollen is a cause of their 
rhinoconjunctivitis symptoms [2]. Until recently, ragweed was predominantly a problem in 
North America, however, higher rates of ragweed allergy prevalence and sensitization are 
now seen in some European countries [3].  
Allergen-specific immunotherapy consists of administering allergens to an allergic patient in 
order to induce immunological tolerance to the natural allergen.  Subcutaneous 
immunotherapy (SCIT) has been the main approach for the application of this type of therapy
[4]. However, these treatments are associated with risk of severe systemic reactions and 
must be administered by trained health care personnel at the physician’s office. The 
administration of an oral allergen formulation, such as sublingual immunotherapy tablets, 
also reduces immediate reactivity to specific IgE antibody and is associated with a favorable 
safety profile that, in contrast to SCIT, permits self-administration by the patient after the 
first dose has been shown to be tolerable under physician observation.  The predominant 
adverse reactions when administering allergen sublingually include local allergic events such 
as oral pruritus, itching of the throat, or swelling under the tongue, which will generally 
resolve with continuous treatment over the following weeks.  
 
 
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MK-3641 (RAGWITEK®3) is a sublingual immunotherapy (SLIT) tablet approved for use in 
the United States (US) and Canada for the treatment of short ragweed pollen-induced allergic 
rhinitis, with or without conjunctivitis, in adults 18 through 65 years of age.  It is self-
administered at home after the first dose is administered under supervision by a health care 
professional.  To date, MK-3641 has not been studied in children.  However, a similar tablet 
formulation containing Timothy grass (MK-7243) has been shown to be efficacious and safe 
for children down to 5 years of age.  MK-7243 is approved in North America and Europe 
under the trade names of GRASTEK®4 and GRAZAX®5, respectively, for the treatment of 
allergic rhinitis and conjunctivitis in patients 5 to 65 years of age.
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3641.
Pharmaceutical and Therapeutic Background
4.1.1
MK-3641 is a freeze-dried, rapidly (within seconds) dissolving SLIT tablet containing 
Ambrosia artemisiifolia (short ragweed) extract, specifically 12 Amb a 1-U of the major 
short ragweed allergen Amb a 1.  The effect of MK-3641 on alleviating the symptoms of 
ragweed pollen-induced allergic
rhinoconjunctivitis is thought to be mediated via 
immunization of oral Langerhans cells inducing immunologic responses within the oral 
mucosa or local lymph nodes after sublingual allergen exposure and potential uptake into 
local tissues [5].
The placebo tablet is indistinguishable from the active tablet in appearance but contains no 
ragweed allergen.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
MK-3641 has been demonstrated to be efficacious for ragweed-allergic adults in reducing the 
symptoms of rhinoconjunctivitis and has an acceptable tolerability profile with few reported 
serious AEs (SAEs), of which none were assessed as related to the SLIT tablet.  MK-3641 
has yet to be studied in subjects <18 years old.  
The prevalence rate of ragweed allergy in children ages 5 to 11 years and 12 to 17 years in 
the general population is not yet established. However, in one survey of children with 
asthma seen in an allergy specialty clinic, sensitization to short ragweed was 14% in young 
children (ages 3 to 11 years) and 25% in adolescents (ages 12 to 18 years) [6].  This study 
                                                
3 RAGWITEK® (MK-3641) is a registered trademark of Merck & Co., Inc., Whitehouse Station, New Jersey, U.S.A.
4 GRASTEK® (MK-7243) is a registered trademark of Merck & Co., Inc., Whitehouse Station, New Jersey, U.S.A.
5 GRAZAX® is a registered trademark of ALK-Abelló A/S, Hørsholm, Denmark.
 
 
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will be the first trial to evaluate the efficacy and safety of MK-3641 in children 5 to 17 years 
of age (inclusive).  
There is no reason to first perform dose-escalation safety and tolerability studies of MK-3641 
in the pediatric population when a safety and tolerable dose has been established for adults as 
the general dosing principal of immunotherapy treatment is the same regardless of age.  This 
is in accordance with current allergen immunotherapy practice guidelines that recommend
initiating the same dose across ages and do not recommend specific dose adjustments for 
children [7].  This is supported by data from similar SLIT tablet formulations (MK-7243 
Timothy grass tablet and MK-8237 house dust mite tablet) that have been studied in dose-
escalation and Phase 3 studies in adults and children 5 years of age and older, and the data 
show a similar safety profile of the same maintenance dose across age ranges [8].  The study
will be stratified by age and will endeavor to enroll approximately 35% of subjects 5 to 11 
years of age; this distribution is to ensure an adequate number of subjects in the younger age 
group are included in the study.  
As subjects with severe or uncontrolled asthma could be considered at higher risk of a 
potential systemic allergic reaction becoming severe, only those subjects with controlled 
asthma may be eligible for participation in this study.  Those subjects on long-acting inhaled 
beta2-agonists (LABAs) are not eligible for the study.  Provided that their asthma is 
controlled on the regimen, subjects with asthma may use short-acting beta2-agonists 
(SABAs) and/or low or medium daily doses of inhaled corticosteroids (ICS) as defined by 
the National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3: 
Guidelines for the Diagnosis and Management of Asthma (Table 1) [9].  If a subject with 
asthma is controlled on an ICS that is delivered by a method or modality other than those 
specified in the NAEPP Guidelines [10], the dose that the subject is receiving should be 
clinically equivalent to those noted in Table 1 in order to be allowed entry into this study.  
The assessment of asthma control will be determined per individual physician judgment at 
the time of screening and randomization, and at each clinic visit. This study will also be 
stratified by subject asthma status (yes/no).
Table 1
Low or Medium Daily Dose Corticosteroids as Defined by the NAEPP 
Guidelines
Inhaled Corticosteroid Medication
Low or Medium Daily Dose
5 to 11 Years of Age
≥12 Years of Age
Beclomethasone HFA
≤320 mcg
≤480 mcg
Budesonide DPI
≤800 mcg
≤1200 mcg
Flunisolide
≤1250 mcg
≤2000 mcg
Flunisolide HFA
≤320 mcg
≤640 mcg
Fluticasone DPI
≤400 mcg
≤500 mcg
Fluticasone HFA/MDI
≤352 mcg
≤440 mcg
Mometasone furoate 
<440 mcga
≤440 mcga
Triamcinolone acetonide
≤900 mcg
≤1500 mcg
Ciclesonide HFA
≤160 mcga
≤320 mcga
DPI = dry-powder inhaler; GINA = Global Initiative for Asthma; HFA = hydrofluoroalkane; MDI = metered-dose 
inhaler; NAEPP = National Asthma Education and Prevention Program.
Dose delivery by method or modality other than those noted above should be clinically equivalent.
a Per GINA guidelines [11].
 
 
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Potential trial subjects will be recruited from clinics with experience in the diagnosis and 
treatment of allergy and endemic areas with high ragweed pollen exposure such as the US, 
Canada, and Eastern Europe, where there is minimal overlap from other pollen/mold/dust 
mite seasons.
The primary endpoint of this study, the Total Combined Score (TCS), is a combination of
(sum of) the rhinoconjunctivitis daily symptom score (DSS) and the rhinoconjunctivitis daily 
medication score (DMS) averaged over the peak ragweed season. The effectiveness of the 
treatment will depend on how well the rhinoconjunctivitis symptoms are relieved. A lower
symptom score on active treatment indicates effectiveness compared with placebo.  
However, the use of rescue medications by a subject will result in a lower symptom score 
and will, therefore, be a confounding variable. As a result, basing the efficacy of the 
treatment on the symptom score alone may not reflect the treatment's true efficacy potential.
Additionally, more subjects on the placebo group are likely to use rescue medications than 
those in the active treatment group, indicating the need to account for the use of rescue 
medications. 
The combined symptom and medication score, which reflects the use of rescue medications, 
is an appropriate indicator of the efficacy potential of the treatment.  This is consistent with 
current global regulatory positions on appropriate reporting of results from specific 
immunotherapy trials.  The European Medicines Agency (EMA) has stated in their guidance 
on specific immunotherapy that the primary endpoint for trials should be reflective of both 
severity of symptoms and the intake of rescue medications [12].  In addition, the World 
Allergy Organization (WAO) has stated that symptoms and rescue medication utilization are 
interdependent variables.  Therefore, in assessing the effect of allergen immunotherapy, a 
single predefined combined daily symptom and medication score more accurately reflects the 
clinical benefit experienced by the subject [13].  The TCS during the peak ragweed season is 
the same endpoint that has been used in the adult studies and was the basis for health 
authority approval.  By focusing on the peak season, the treatment effect of MK-3641 will be 
evaluated during the time when pollen exposure is highest, least variable, and when 
symptoms are more likely to be most severe.
Rationale for Dose Selection/Regimen
4.2.2
The basic principle for allergen immunotherapy dose selection is to use the highest tolerable 
and safe dose. The highest tolerable/safe and effective dose of MK-3641 has been shown to 
be 12 Amb a 1-U in adults. The safety and efficacy profile of the same dose of sublingual 
tablet immunotherapy has been shown to be similar in adults and children [7] [14] [15] [16].
Also, the practice guidelines do not recommend dose adjustment in children as allergens act 
on the immune system, and are neither systemically absorbed nor metabolized by the liver 
and kidneys.  Therefore, the MK-3641 dose of 12 Amb a 1-U approved for use in adults will 
also be used in children in this study, in line with the clinical practice of using the same 
dosage of immunotherapy in adults and children.  This approach was utilized for a similar 
tablet-based SLIT product, MK-7243 (GRASTEK®/ GRAZAX®), approved for treatment of 
allergic rhinitis and conjunctivitis in patients 5 to 65 years of age.  A comparable efficacy 
and safety profile in the adult and pediatric grass allergic subjects was demonstrated with the 
same 2800 BAU/75,000 SQ-U dose of the Timothy grass tablet (MK-7243).
 
 
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Rationale for the Use of Placebo
4.2.2.1
A placebo arm will be used as a comparator to MK-3641.  A placebo arm is considered 
ethically justifiable since subjects will be allowed to use rescue medications to treat their 
allergic rhinoconjunctivitis symptoms during the ragweed season.  In addition, subjects will 
be medically monitored during the study and be provided appropriate treatment as needed.  
Subjects can also discontinue from the study at any time if they find the treatment intolerable.
Rationale for Dose Interval and Trial Design
4.2.2.2
Continuous exposure to the allergen is essential to induce allergen-specific tolerance and 
disease-modifying treatment effects from immunotherapy.
Results from previous adult/pediatric (ages 5 to 65 years) grass SLIT trials (MK-7243) and 
adult ragweed SLIT trials (MK-3641) have indicated that subjects receiving at least 12 weeks 
of pre-seasonal treatment demonstrate a higher treatment effect compared to subjects with 
shorter pre-seasonal treatment periods.  In addition, the RAGWITEK label (approved for use 
in adults) indicates that treatment should be initiated at least 12 weeks before the expected 
onset of ragweed pollen season and continued throughout the season.  Thus, subjects in the 
current study will receive approximately 12 weeks (and up to approximately 20 weeks) of 
pre-seasonal treatment with MK-3641 and continue through the ragweed season with 
approximately 8 weeks of co-seasonal treatment.  
Rationale for Endpoints
4.2.3
Efficacy Endpoints
4.2.3.1
4.2.3.1.1 Rhinoconjunctivitis Endpoints
The components that contribute to the 
rhinoconjunctivitis endpoints 
of TCS, 
rhinoconjunctivitis DSS, and rhinoconjunctivitis DMS are collected in an e-diary completed 
by the subject/parent/guardian.  These rhinoconjunctivitis endpoints were agreed to by 
regulatory authorities (e.g., US Food and Drug Administration [FDA]) and were used as 
primary or key secondary endpoints in the adult RAGWITEK (ages 18 to 65 years) and 
adult/pediatric GRASTEK® (ages 5 to 65 years) programs.  One change is that prednisone is 
not included in the rhinoconjunctivitis DMS for this pediatric ragweed trial.  Few subjects in 
the previous studies used prednisone, with no difference in the efficacy analyses between the 
full analysis set (included subjects who used prednisone) and a sensitivity analysis that 
excluded subjects who used prednisone.  It is anticipated that even fewer children will use 
prednisone than was seen with the previous studies in which the majority of subjects were 
adults.  
Total Combined Score (TCS)
4.2.3.1.1.1
The TCS is the sum of the rhinoconjunctivitis daily symptom score (DSS) and the 
rhinoconjunctivitis daily medication score (DMS).  
 
 
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Rhinoconjunctivitis Daily Symptom Score (DSS)
4.2.3.1.1.2
The rhinoconjunctivitis DSS consists of a total of 6 allergic symptoms: 4 rhinitis symptoms 
and 2 conjunctivitis symptoms, and will be measured on a scale from 0 to 3 as follows:
0: No symptoms; (i.e., no sign/symptom evident);
1: Mild symptoms (i.e., sign/symptom clearly present, but minimal awareness; 
easily tolerated);
2: Moderate symptoms (i.e., definite awareness of sign/symptom that is bothersome 
but tolerable);
3: Severe symptoms (i.e., sign/symptom that is hard to tolerate; may cause 
interference with activities of daily living and/or sleeping).
The 6 allergic symptoms are classified in 2 groups as follows:

Rhinitis:
–
Runny nose;
–
Stuffy nose;
–
Sneezing;
–
Itchy nose.

Conjunctivitis:
–
Itchy eyes;
–
Watery eyes.
The maximum daily symptoms score is 18 points if a subject experiences all six symptoms 
with an intensity of 3 for each symptom.
Rhinoconjunctivitis Daily Medication Score (DMS)
4.2.3.1.1.3
The rhinoconjunctivitis DMS consists of rhinoconjunctivitis symptomatic rescue medication 
scores.  To transform the amount of symptomatic medications used into medication scores, 
the scoring principles detailed in Table 2 are applied.
 
 
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Table 2
Scoring of Symptomatic Rescue Medication Use
RHINOCONJUNCTIVITIS
Step
Rescue Medicationa
Subject Dosing 
Instructions
Score/
Dose Unit
Maximum 
Daily Score
1
Loratadine syrup, 1 mg/mL
5 years old:
5 mL once daily
6 
per 5 mL
6
or
6 to 17 years old:
10 mL once daily
6
per 10 mL
Loratadine oral tablet, 5 mg or
10 mg
5 years old:
5 mg tablet (1 tablet) 
once daily
6 to 17 years old:
10 mg tablet (1 tablet) 
once daily
6
per tablet
1b
Olopatadine hydrochloride 
ophthalmic solution, 0.1%
1 drop in each affected eye 
twice daily
1.5
per drop
6
2
Mometasone furoate 
monohydrate nasal spray, 
50 mcg
5 to 11 years old:
1 spray in each nostril 
once daily
4
per spray
8
12 to 17 years old:
2 sprays in each nostril 
once daily
2
per spray
Maximum rhinoconjunctivitis daily medication score (DMS)
20
a
In countries where a rescue medication is not available, a similar medication will be dispensed in a clinically 
equivalent dosage.
4.2.3.1.2 Asthma Endpoints
All of the asthma endpoints will be collected in the e-diary completed by the 
subject/parent/guardian.  The asthma daily symptom score (aDSS) has been used in the 
previous adult RAGWITEK program (ages 18 to 65 years), as well as the adult/pediatric 
GRASTEK® program (ages 5 to 65 years).  The beta2-agonist use and nocturnal awakenings 
endpoints have been used extensively in previous adult and pediatric asthma studies as key 
secondary and other endpoints, respectively.
Asthma Daily Symptom Score (aDSS)
4.2.3.1.2.1
The aDSS consists of a total of 3 asthma symptoms: cough, wheeze, and chest 
tightness/dyspnea.  Each symptom is measured on the same scale as the rhinoconjunctivitis 
DSS.  The aDSS will be completed daily beginning with Visit 4 by all subjects in the study.  
 
 
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Beta2-agonist Use 
4.2.3.1.2.2
Only those subjects with asthma will record on the e-diary the number of puffs of as-needed 
SABA (albuterol/salbutamol) used each day for asthma symptoms.  Any use of SABA for 
prophylaxis, such as for exercise-induced asthma, will not be included.
Nocturnal Awakenings 
4.2.3.1.2.3
Only those subjects with asthma will record on the e-diary whether they woke up at night due 
to asthma symptoms requiring SABA (albuterol/salbutamol) use (yes/no).
Safety Endpoints
4.2.3.2
The safety endpoints for this trial have been selected based on previous studies in subjects 
with grass (adult/pediatric subjects 5 to 65 years of age), ragweed (adult subjects), and/or 
house-dust mite (adult/pediatric subjects 5 years of age and older) allergies treated with grass 
(MK-7243), ragweed (MK-3641), or house-dust mite (MK-8237) SLIT tablets, respectively.  
By assessing the severity and frequency of commonly occurring local AEs, in addition to 
overall AEs and drug-related AEs, safety and tolerability can be assessed.  
In addition, the SLIT
Report Card (Section 12.10) will be completed by the 
subject/parent/guardian, daily for the first ~28 days of dosing, to collect information on local 
side effects of SLIT that occur within the first 60 minutes after each daily study drug intake.  
An exploratory review of severity grading will be conducted for identified local AEs as
graded programmatically and as assessed by the investigator.
Future Biomedical Research
4.2.3.3
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial. This research may include genetic analyses (DNA), 
gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or the 
measurement of other analytes.
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 
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.
 
 
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Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from 
treatment/vaccination during participation, as clinical trials are designed
to provide 
information about the safety and effectiveness of an investigational medicine.
MK-3641 provides an alternative formulation and mode of administration of immunotherapy 
that expands the treatment options for children suffering from ragweed-induced allergic 
rhinoconjunctivitis.  MK-3641 is an effective treatment for adult patients for whom 
immunotherapy is indicated and has an acceptable safety profile in this population.  In 
contrast to subcutaneous immunotherapy treatments, MK-3641 allows for a short induction 
period with a simple dosing form that does not require up- or down-titration and allows for 
at-home dosing after administration of the first dose in a health care setting under the 
supervision of a physician with experience in the diagnosis and treatment of allergic diseases.  
Based on the efficacy/safety studies of MK-3641 in adults and those of a grass SLIT tablet 
(MK-7243) in both adults and children (ages 5 to 65 years), the benefit/risk assessment for 
conducting this pediatric trial of MK-3641 is favorable.  Risks in this trial are manageable 
when the first tablet is administered under physician supervision and with appropriate 
education of the subject and parent/guardian about symptoms and signs of severe allergic 
reactions.  There is no expectation of an increased safety risk for children enrolled in this trial
compared with that observed in the adult ragweed trials and adult/pediatric grass trials.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with a history of ragweed pollen-induced allergic rhinoconjunctivitis, 
with or without asthma, between the ages of 4 and 17 years (inclusive) 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. Have a legal representative who provides written informed consent for the trial on the 
subject’s behalf after understanding the study procedures, alternative treatments 
available, risks involved with the study, and voluntarily agreeing to allow the subject 
to participate.  The legal representative may also provide consent for Future 
Biomedical Research on the subject’s behalf.  However, the subject may participate in 
the main trial without participating in Future Biomedical Research.  The subject, 
depending on their age and ability to understand the nature and intent of the study, 
must also assent to participate in the study main trial and to Future Biomedical 
Research.
 
 
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2. Be ≥4 to ≤17 years of age on the day informed consent is obtained from the legal 
representative, however, the subject must be ≥5 years old at the Randomization Visit.  
The subject may be of either gender and any race/ethnicity.
3. Have 
a 
clinical 
history 
of 
significant 
ragweed 
pollen-induced 
allergic 
rhinitis/rhinoconjunctivitis of ≥1 year (at least 1 season for ages 4 to 6 years) or ≥2 
years (at least 2 seasons for ages 7 to 17 years) duration diagnosed by a physician 
(with or without asthma) and have received treatment for the condition during the 
previous ragweed season.
Note:  If medical records are not available, verbal history from subject/parent/legal 
guardian may be elicited at the Screening Visit and can be used to fulfill this criterion 
if documented in the subject study file by the investigator.
4. Have a positive skin prick test response (average wheal diameter ≥5 mm larger than 
the saline control after 15 to 20 minutes) to Ambrosia artemisiifolia at the Screening 
Visit.
Note:  The test can have been performed up to 1 year before the Screening Visit if the 
skin prick test reagents and prick devices used are the same as provided for this trial.
5. Have a specific IgE against Ambrosia artemisiifolia ≥IgE Class 2 (0.7 kU/L) at the 
Screening Visit.
6. Have a forced expiratory volume in 1 second (FEV1) ≥80% of predicted value at the 
Screening and Randomization Visits (following at least a 6-hour washout of short-
acting beta2-agonists, 12-hour washout of twice daily long-acting beta2-agonists, or 
24-hour washout of once daily long-acting beta2-agonists).  
Note: Long-acting inhaled beta2-agonists are prohibited within 30 days prior to 
randomization and for the duration of the study.  
Note: A subject who is ≤7 years old and cannot perform reproducible FEV1
maneuvers, despite coaching, does not need to meet this criterion.
7. Have safety laboratory tests and vital signs conducted at the Screening Visit be within 
normal limits or are clinically acceptable to the investigator/Sponsor.
8. Be able to adhere to dose and visit schedules.
9. Be able to read, understand, and complete the questionnaires and diaries (or can have 
help from the parent/guardian).  
10. Have a negative urine pregnancy test at the Screening and Randomization Visits (if 
female of reproductive potential). A female subject who is not of reproductive 
potential is defined as: one who 1) has not reached menarche, 2) is 6 weeks post-
surgical documented total hysterectomy and/or bilateral salpingo-oophorectomy, or 
3) has had bilateral tubal ligation.
 
 
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11. If female, agree to remain abstinent or use (or have their partner use) an acceptable 
method of birth control within the projected duration of the study.  Abstinence is 
defined as true abstinence, when this is in line with the usual lifestyle of the subject.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.  Acceptable 
methods of birth control are intrauterine device (IUD), hormonal contraception, 
diaphragm with spermicide, contraceptive sponge, condom, vasectomy, as per local 
regulations or guidelines.  A female subject who is not of reproductive potential is 
eligible without requiring the use of contraception.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Has a clinical history of symptomatic seasonal allergic rhinitis (and/or asthma) due to 
another allergen, which has required regular medication during, or potentially 
overlapping, the ragweed season.
2. Has a clinical history of significant symptomatic perennial allergic rhinitis and/or 
asthma due to an allergen to which the subject is regularly exposed during the 
ragweed season which would interfere with assessment of the treatment effect.
3. Has any nasal condition that could confound the efficacy or safety assessments (e.g., 
nasal polyposis).
4. Has asthma requiring high daily doses of inhaled corticosteroids within the 6 months 
prior to the Screening Visit.
5. Is one of the following:

>7 years old and cannot perform reproducible FEV1 maneuvers despite coaching;

≤7 years old who cannot perform reproducible FEV1 maneuvers despite coaching
and has current symptoms of asthma characterized by recurrent episodes of 
wheezing, or episodes of cough, wheeze, difficulty in breathing, or chest tightness 
[17].
6. Has severe, unstable, or uncontrolled asthma, as judged by the clinical investigator, or 
has experienced a life-threatening asthma attack or an occurrence of any clinical 
deterioration of asthma that resulted in emergency treatment, hospitalization due to 
asthma, or treatment with systemic corticosteroids (but allowing short-acting beta-
agonists) at any time within the last 3 months prior to the Screening
or 
Randomization Visits.
7. Has a history of anaphylaxis with cardiorespiratory symptoms
with prior 
immunotherapy, unknown cause, or inhalant allergen.
8. Has a diagnosis of eosinophilic esophagitis.
9. Has a history of chronic urticaria and/or chronic angioedema.
10. Has a clinical history of chronic sinusitis during the 2 years prior to the Screening or 
Randomization Visits.
 
 
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11. Has current severe atopic dermatitis.
12. Has a history of allergy, hypersensitivity, or intolerance to the ingredients of the 
investigational medicinal products (except for Ambrosia artemisiifolia), rescue 
medications, or self-injectable epinephrine.
13. Has any clinically significant condition or situation, other than the condition being 
studied that, in the opinion of the investigator, would interfere with the study 
evaluations or optimal participation in the study.  Specific examples include, but are 
not limited to, hypertension being treated with beta blockers, arrhythmia, ocular 
conditions requiring topical beta blockers, any condition requiring the use of beta 
blockers, and systemic disease affecting the immune system, i.e., autoimmune 
diseases, immune complex diseases, or immune deficiency diseases.
14. Is female and is breast-feeding at randomization, pregnant, or intending to become 
pregnant within the projected duration of the study.
15. Has previously received MK-3641.
16. Is unable to meet medication washout requirements as listed in Table 3.
Table 3
Prohibited Medications Prior to Randomization
Prohibited Medication(s)a
Washout Period 
Prior to Randomization
Anti-IgE treatment (e.g., Xolair)
At any time
Maintenance doses of ragweed immunotherapyb
5 years
High daily doses of inhaled corticosteroidsc
6 months
Immunosuppressive therapy (except steroids for allergic and 
asthma symptoms)
90 days
Investigational drugs
30 days
Long-acting inhaled beta2-agonists
30 days
Tricyclic antidepressant medications with antihistaminic effects 
(e.g., doxepin, mianserin)
14 days
Monoamine oxidase inhibitors
14 days
Beta blockers, regardless of route of administration
7 days
Antipsychotic medications with antihistaminic effects 
(e.g., chlorpromazine, levomepromazine, clozapine, olanzapine, 
thioridazine)
7 days
ICS = inhaled corticosteroid.
a
Although medications in Table 5 (Section 5.5) are not specifically prohibited prior to randomization, 
please consider whether a subject is able to wash out of the listed medications prior to Visit 6 (e.g., 
leukotriene antagonist use for allergic rhinitis could be washed out; however, subjects using a leukotriene 
antagonist for asthma should not be enrolled in this trial unless it is used as short-term treatment outside of 
the ragweed season (e.g., during winter season, tree pollen season).
b
Allowed within the last 5 years if duration of ragweed immunotherapy from initiation <1 month.
c
Subjects maintained on a low- or medium-dose ICS will be allowed to continue on his/ her medication 
during the trial. A subject must have been using a low or medium daily dose of ICS for at least 12 weeks
before screening and/or randomization and must have been on a stable regimen (daily dose unchanged) 
for at least 2 weeks before Screening (Visit 1) and/or 4 weeks before Randomization (Visit 2). Low or 
medium daily doses of ICS can be found in Section 4.2.1 Table 1; Note: Dose delivery by method or 
modality other than described in Table 1 should be clinically equivalent.
 
 
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17. Is unable to or will not comply with the use of self-injectable epinephrine 
administration (in countries where epinephrine is a regulatory requirement).
18. May be at greater risk of developing adverse reactions after epinephrine 
administration.
19. Has a clinically significant abnormal vital sign or laboratory value that, in the opinion 
of the investigator, would preclude participation in the study, or has a laboratory 
value that does not meet the Algorithm for Assessing Out-of-Range Laboratory 
Values (see Section 12.5).  
Note: A maximum of one re-draw is permitted for re-evaluation of out-of-range 
safety laboratory values.  The investigator is encouraged to ensure prompt follow-up 
of all subjects with a potentially life threatening laboratory abnormality, as per 
investigator’s clinical judgment.
20. Is unlikely to be able to complete the trial, for any reason, or likely to travel for 
extended periods of time during the ragweed season, which in the opinion of the 
investigator will compromise the data.
21. Has previously been randomized into this study.
22. Is participating in the study at another investigational site.
23. Is participating in any other clinical study or plans to participate in another clinical 
study during the duration of this study.
24. Has a history or current evidence of any condition, therapy, lab abnormality or other 
circumstance that might expose the subject to risk by participating in the trial, 
confound the results of the trial, or interfere with the subject’s participation for the 
full duration of the trial.
25. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
 
 
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Trial Treatment(s)
5.2
The treatments to be used in this trial are outlined below in Table 4.
Table 4
Trial Treatments
Drug
Dose/ Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Period
Use
MK-3641
12 Amb a 1-U
Once daily
Sublingual
Up to
~28 weeks
Experimental
Placebo
Not applicable
Once daily
Sublingual
Up to
~28 weeks
Placebo 
comparator
Self-injectable 
epinephrinea, b
Suggested doses =
15-30 kg 
(33-66 pounds): 
0.15 mg 
≥30 kg 
(≥66 pounds):
0.3 mg
As needed
Intramuscular
-
Rescue 
medication 
dispensed 
at 
Randomization 
(Visit 2), when 
applicable
Albuterol/
Salbutamolc
90 mcg/puffd
As needed 
Inhalation
-
Rescue 
medication 
dispensed 
at 
Randomization 
(Visit 2)
Loratadineb, e
5 years old:
5 mg (1 mg/mL 
syrup or 5 mg 
tablet)
6 to 17 years old: 
10 mg (1 mg/mL 
syrup or 10 mg 
tablet)
-
Oral
-
Rescue 
medication 
dispensed 
at 
Pre-Season 
Visit (Visit 6)
Olopatadine 
hydrochlorideb, e
1 drop (0.1%) per 
affected eye
-
Ophthalmic 
-
Rescue 
medication 
dispensed 
at 
Pre-Season 
Visit (Visit 6)
Mometasone 
furoate 
monohydrateb, e
5 to 11 years old:
1 spray (50 mcg/ 
spray) per nostril
12 to 17 years old: 
2 sprays (50 
mcg/spray) per 
nostril
-
Intranasal
-
Rescue 
medication 
dispensed 
at 
Pre-Season 
Visit (Visit 6)
a
Provided in countries where epinephrine is a regulatory requirement.
b
In countries where a rescue medication is not available, a similar medication will be dispensed in a clinically equivalent 
dosage.
c
Provided to those subjects with asthma. 
d
Albuterol metered-dose inhaler (MDI) 90 mcg/puff; salbutamol MDI 100 mcg/puff.
e
See Table 2 for dosing instructions. 
 
 
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The first dose of trial treatment will be administered at the trial site at Visit 2.  Subsequent 
dosing will be performed once daily by the subject (i.e., unsupervised at his/her home) at 
approximately the same time each day.
All supplies indicated in Table 4 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.
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.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, usage and disposal of 
trial treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection
5.2.1
Dose Selection (Preparation)
5.2.1.1
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
Timing of Dose Administration
5.2.2
The first dose of study drug will be administered under supervision at the study site at Visit 
2.  Subsequent dosing will be performed once daily at home by the subject/parent/guardian at 
approximately the same time each day for up to approximately 28 weeks and should occur at 
a time of the day that would allow the parent/guardian to keep the subject under observation 
for AEs for approximately 30 minutes after administration.
In-Clinic Dosing at Visit 2
5.2.2.1
At Visit 2, the first dose of study drug will be administered under supervision at the study 
site, and then the subject will be required to stay at the study site for an observation period of 
approximately 30 minutes to assess any AEs.  Prior to administration of the first dose of 
study drug, the investigator should discuss well-known immediate application site reactions 
and severe AEs requiring medical evaluation and/or the use of rescue emergency medications 
(such as antihistamines, epinephrine, etc.) with the subject/parent/guardian.  The site should 
record the duration of AEs (in minutes) following the first administration of the study drug at 
the randomization visit.  If any significant AE such as wheezing, dyspnea, severe oral 
swelling, or signs of generalized anaphylactic reaction is observed or reported, the 
investigator or medically qualified sub-investigator must evaluate the subject to determine 
whether treatment of the adverse reaction should be initiated.  In such cases, the observation 
period should be extended for at least an additional 30 minutes.  When the 
subject/parent/guardian leave the study site, instructions should be given to contact the study 
site immediately if the reaction reoccurs or a new reaction appears.  If the investigator 
determines that a subject cannot leave the study site but needs further attention not otherwise 
 
 
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available at the study site, the subject will be transferred to an appropriate facility such as an 
emergency room.
Subjects not experiencing clinically significant reactions may leave the study site 
approximately 30 minutes after the first dose of study drug has been given.  The 
subject/parent/guardian should be instructed to contact the study site immediately if any 
reaction occurs after leaving the study site.
At-home Dosing
5.2.2.2
Following the first supervised dose of study drug, the subject/parent/guardian will be 
dispensed the study drug for at-home administration for subsequent dosing.  The 
subject/parent/guardian will be instructed on how to open the blister pack and administer the 
tablet.  In addition, the subject/parent/guardian will be provided with a written description of 
the procedure (Section 12.7). The tablet is to be placed under the tongue and allowed to 
remain there for a few seconds until it has dissolved.  The subject should be advised not to 
swallow during the first minute.  The subject also should be advised not to eat or drink for 
approximately 5 minutes after tablet administration.  The subject/parent/guardian will be 
instructed to contact the study site for any AEs that the subject/parent/guardian considers 
significant or if the subject/parent/guardian considers treatment for the AE necessary. The 
subject/parent/guardian will be instructed on and provided with an Anaphylaxis Emergency 
Action Plan6 (Section 7.1.1.10; Section 12.8) for any potential anaphylactic reactions.  In 
addition, those subjects in countries where self-injectable epinephrine is a regulatory 
requirement will be provided with self-injectable epinephrine (Section 5.6.3; Section 
7.1.1.11). The subject should only take 1 tablet of study drug each day.  If the subject misses 
a dose of study drug, they should resume taking study drug the following day.  At each clinic 
visit, any missed doses should be reported.
Study drug administration should occur at approximately the same time each day and should 
occur at a time of the day that would allow the parent/guardian to keep the subject under 
observation for AEs for approximately 30 minutes after administration.
                                                
6 The Anaphylaxis Emergency Action Plan can be modified outside the US to meet local standards for the use (or type) of epinephrine 
dispensed, and for calls to 911 or alternative local emergency services.
 
 
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Temporary Study Drug Interruptions
5.2.2.3
Treatment with study drug should be temporarily stopped for up to 7 days under the 
following conditions:
1. In case of oral surgery (including dental extraction), oral injury or other oral 
conditions affecting the integrity of the oral mucosa to allow healing of the oral cavity
(not including loss of deciduous teeth);
2. Other reasons as deemed necessary by the investigator or designee.
If a subject has a treatment interruption due to a worsening AE related to the study drug, then 
the subject should be re-evaluated by the investigator, or designee, prior to reinitiating the 
study drug.
Trial Blinding/Masking
5.2.3
A double-blind/masking technique will be used. MK-3641 and placebo will be packaged 
identically so that blind/masking is maintained. The subject/parent/guardian, the investigator 
and Sponsor personnel or delegate(s) who are involved in the treatment administration or 
clinical evaluation of the subjects are unaware of the group assignments.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization or Treatment Allocation
5.3
Randomization will occur centrally using an interactive voice response system / integrated 
web response system (IVRS/IWRS). There are 2 treatment arms.  Subjects will be assigned 
randomly in a 1:1 ratio to MK-3641 and placebo, respectively.
Stratification
5.4
Randomization will be stratified according to the following factors:
1. Age (5 to 11 years, 12 to 17 years);
2. Asthma status (asthma, non-asthma) of the subjects.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
 
 
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Restrictions for concomitant therapy beginning prior to the start of the ragweed season (with 
the listed washout requirements) and continuing for the duration of the study (with the 
exception of study-provided rescue medications) are listed in Table 5.  Those medications 
listed in Table 3 are prohibited beginning with the washout periods prior to randomization 
and continuing for the duration of the study.  
Table 5
Prohibited Medications Beginning Prior to Pre-Season Visit 6 and for 
Duration of Trial
Prohibited Medication(s)
Washout Period
Prior to Pre-Season 
Visit 6 
Long-acting parenteral (intramuscular, intra-articular) 
corticosteroids
90 days
Oral corticosteroids
60 days
Nasal corticosteroids
30 days
Short-acting parenteral corticosteroids
30 days
Leukotriene antagonists/synthase inhibitors
30 days
Corticosteroid eye drops
30 days
Inhaled, topical, or oral nedocromil or cromolyn sodium
14 days
Oral or topical antihistaminesa
7 days
Nasal or ocular decongestants
7 days
a
Pre-treatment with medications (e.g., antihistamines) to treat potential AEs will not be permitted; this is to avoid 
masking or delayed reactions.  
Medications or vaccines that are not restricted by the protocol (Table 3 and Table 5) and that 
would not be expected to interfere with the conduct of the study are allowed.  Chronic 
medications should be dosed on a stable regimen.  All concomitant medications must be 
appropriately documented on the electronic case report form (eCRF).  The use of any 
concomitant medication must relate to the documented medical history, prophylaxis, or an 
AE of the subject.
Rescue Medications & Supportive Care
5.6
Allergy Rescue Medications for Rhinoconjunctivitis Symptoms
5.6.1
Subjects may experience allergy symptoms that require additional treatment.  Thus, rescue 
medications for rhinitis/conjunctivitis symptoms will be provided (beginning at Visit 6) 
according to the following steps (for dosage instructions, see Table 2; for subject 
instructions, see Section 12.6):
1. Step 1:  Loratadine syrup, 1 mg/mL or loratadine oral tablet, 5 mg (5 years old) or 10 
mg (≥6 years old)
2. Step 1b:  Olopatadine hydrochloride ophthalmic solution, 0.1%
3. Step 2:  Mometasone furoate monohydrate nasal spray, 50 mcg.
 
 
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Medications for Asthma Symptoms
5.6.2
Short-acting inhaled beta2-agonist (i.e., albuterol/salbutamol metered-dose inhaler) will be 
provided to those subjects with asthma.  Other medications for asthma will not be provided.  
Subjects who are taking low or medium daily dose inhaled corticosteroids for asthma 
management will be allowed to continue with the same medications during the study.  A 
subject must have been using a low or medium daily dose of ICS for at least 12 weeks before 
screening and/or randomization and must have been on a stable regimen (daily dose 
unchanged) for at least 2 weeks before Screening (Visit 1) and/or 4 weeks before 
Randomization (Visit 2).  Low and medium daily doses of inhaled corticosteroids are defined 
in Table 1 (Section 4.2.1).
If a subject requires additional asthma medications, the subject should follow 
recommendations regarding medication adjustments provided by his/her physician.  
Medication use should be recorded on the eCRF.  
Rescue Medication for Severe Allergic Reactions (Self-Injectable Epinephrine)
5.6.3
Self-injectable epinephrine will be provided to each subject/parent/guardian at the 
randomization visit (Visit 2) in countries where it is a regulatory requirement, and should be 
available around the time that the tablets are administered at home.  
Self-injectable epinephrine is intended for immediate self-administration for an anaphylactic 
reaction, including symptoms/signs of upper airway obstruction.  Anaphylaxis is likely when 
multiple organ systems are adversely affected following exposure to an allergen.  A list of 
symptoms that may be present during anaphylaxis include flushing, apprehension, syncope, 
tachycardia, thread or unobtainable pulse associated with a fall in blood pressure, vomiting, 
diarrhea and abdominal cramps, wheezing, dyspnea due to laryngeal spasm, lower airway 
obstruction, pruritus, rashes (such as urticaria), or angioedema.  Self-injectable epinephrine 
should be administered promptly (in countries where it is part of usual care) when significant 
respiratory and/or cardiovascular symptoms accompany an allergic reaction.  
If eligible for enrollment after completing all of the screening procedures, the 
subject/parent/guardian in countries where epinephrine is a regulatory requirement will be 
provided with self-injectable epinephrine at the Randomization Visit (Visit 2).  The 
investigator or designee will instruct the subject/parent/guardian on how to administer the 
self-injectable epinephrine and have it available when tablet(s) are administered.  The 
investigator or designee will provide and explain to the subject/parent/guardian written 
instructions, and will review when to administer the self-injectable epinephrine.  The 
investigator/designee will complete an Anaphylaxis Emergency Action Plan7 for each 
                                                
7 The Anaphylaxis Emergency Action Plan can be modified outside the US to meet local standards for the use (or type) of epinephrine 
dispensed, and for calls to 911 or alternative local emergency services.
 
 
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subject, provide a copy to the subject/parent/guardian, and keep a copy for the site’s records 
(Section 12.8).
In the event that self-injectable epinephrine is used, the subject/parent/guardian must 
immediately call the local emergency number and the 24-hour investigational site emergency 
number indicated in the informed consent and on the subject identification card.  An 
unscheduled visit will be arranged to further evaluate the subject.  The investigator or 
designee must notify the Sponsor within 1 working day of first becoming aware of the use of 
self-injectable epinephrine.  The symptoms and/or circumstances that triggered the use of 
self-injectable epinephrine must be clearly recorded on the eCRF.
Diet/Activity/Other Considerations
5.7
Subjects will be allowed to consume their usual diet and engage in their usual level of 
exercise throughout the trial.
Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
Discontinuation from treatment is “permanent”.  Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

The subject experiences an SAE (not including those only associated with an
overdose) which is considered treatment related, OR a causal association cannot be 
ruled out, OR the cause of the SAE is unknown.

The subject experiences persistent and escalating adverse reactions in the mouth or 
throat. 

The subject experiences severe or persistent symptoms of esophagitis. 

The subject experiences an anaphylactic reaction with severe symptoms associated 
with the investigational treatment.

The
subject
experiences
a severe asthma exacerbation
(such as
requiring 
hospitalization or oral corticosteroid use) or the subject’s asthma becomes difficult to 
control.

The subject experiences other persistent, intolerable AEs considered to be due to the 
study treatment, as determined by the investigator or the subject/parent/guardian.
 
 
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
The subject has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the subject at unnecessary risk through 
continued participation in the trial or does not allow the subject to adhere to the 
requirements of the protocol.

The subject is unable to tolerate the study medication, as perceived by the investigator 
or subject. 

The subject fails to comply with the dosing (see Sec 7.1.1.15), evaluations, or 
requirements of the study, despite documentation at the site of repeated efforts to 
reinforce compliance. 

The subject has a confirmed positive serum pregnancy test.

The subject becomes pregnant.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone call or visit, 
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.11
Early trial termination will be the result of the criteria specified below:
1. Treatment-related death of an individual;
2. Treatment-related anaphylactic shock in at least 2 subjects*.
* The criterion for 2 events is based on prior trial experience where it has been observed 
that events of severe anaphylactic reactions unrelated to investigational medicinal 
product (IMP) may occur in allergic trial subjects even with a temporal relationship to 
tablet administration.
Study drug intake may only be resumed after the information has been presented to health
authorities, and health authorities concur with continued drug intake. In case of complete 
premature termination of the trial, participating investigators/subjects/parent/guardian, the 
IRB/ERC, and the relevant health authorities must be promptly informed of the termination.
 
 
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6.0 TRIAL FLOW CHART
Trial Period:
Screening
Treatment
Post-
treatment
Visit Number:
1
2
3
4/5 a
6
7
8
--
Visit Title:
Screening
Randomization
Off-Season
Off-Season
Pre-Season
In-Season
End-of-Season/ 
Discontinuation
Telephone/
Follow-up
Scheduled Day/Week:
Weeks
-52 to -1b
Day 1
Week 4c
Midway 
between 
Visits 3 & 6
~2 weeks 
before start 
of RS
~3 weeks 
after start of
RSd
~1 week after 
end of RS
Post 14 days
Scheduling Window (Days):
-
-
+7 days
+ 7 days
+ 7 days
+ 5 days
Administrative Procedures
Informed Consente
X
Informed Consent for Future 
BiomedicalResearchf
X
IVRS/IWRS
X
X
X
X
X
X
X
Inclusion/Exclusion Criteria
X
X
Demography
X
Medical History
X
X
Allergic Rhinitis Baseline Profile and Family 
History of Atopy
X
X
Prior/Concomitant Medication Review
X
X
X
X
X
X
X
X
Issue/Update Subject Identification Card
X
Xg
Issue/Instruct in the use of e-diary
X
Review e-diary data and instructions for use 
X
X
Activate Medication section of e-diary
X
Discontinue/Collect e-diaries
X
Dispense/Review Anaphylaxis Emergency 
Action Planh
X
X
X
X
X
Provide Self-Injectable Epinephrine and 
Educational Information, Instruct in its usei
X
 
 
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Trial Period:
Screening
Treatment
Post-
treatment
Visit Number:
1
2
3
4/5 a
6
7
8
--
Visit Title:
Screening
Randomization
Off-Season
Off-Season
Pre-Season
In-Season
End-of-Season/ 
Discontinuation
Telephone/
Follow-up
Scheduled Day/Week:
Weeks
-52 to -1b
Day 1
Week 4c
Midway 
between 
Visits 3 & 6
~2 weeks 
before start 
of RS
~3 weeks 
after start of
RSd
~1 week after 
end of RS
Post 14 days
Scheduling Window (Days):
-
-
+7 days
+ 7 days
+ 7 days
+ 5 days
Provide albuterol/salbutamol to subjects with 
asthmaj
X
Xj
Xj
Xj
Xj
Issue/Instruct in the use of SLIT Report Card
X
Collect/Review SLIT Report Card
X
Issue/Instruct in the use of Comment Card
X
X
X
X
X
Collect/Review Comment Card
X
X
X
X
X
Clinical Procedures/Assessments
Vital Signs (Temperature, Blood Pressure, 
Pulse, Respiration Rate) k
X
X
X
X
X
X
X
Body Height and Weightk
X
X
Physical Examination
X
Xk
Oropharyngeal Examinationl
X
Xl
X
X
X
X
X
Pulmonary Function Testsm
X
X
X
X
X
Beta2-agonist reversibilityn
X
Skin Prick Test
X
Adverse Events Monitoring
X
X
X
X
X
X
X
On-site Dosing of Study Medication
X
Dispense Study Medication
X
X
X
X
X
Verify Subject has Self-Injectable Epinephrine 
and Review Instructions for use
X
X
X
X
Verify subjects with history of asthma have 
albuterol/salbutamol 
X
X
X
X
Check/Collect Study Medication
X
X
X
X
X
 
 
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Confidential
Trial Period:
Screening
Treatment
Post-
treatment
Visit Number:
1
2
3
4/5 a
6
7
8
--
Visit Title:
Screening
Randomization
Off-Season
Off-Season
Pre-Season
In-Season
End-of-Season/ 
Discontinuation
Telephone/
Follow-up
Scheduled Day/Week:
Weeks
-52 to -1b
Day 1
Week 4c
Midway 
between 
Visits 3 & 6
~2 weeks 
before start 
of RS
~3 weeks 
after start of
RSd
~1 week after 
end of RS
Post 14 days
Scheduling Window (Days):
-
-
+7 days
+ 7 days
+ 7 days
+ 5 days
Dispense/Review Need for Allergy Rescue 
Medication 
X
X
Record Use of Allergy Rescue Medication (e-
diary)
X
X
X
Collect Rescue Medication/Self-Injectable 
Epinephrine
X
Monitor compliance with Study Medication
X
X
X
X
X
Monitor Compliance with e-dairy completion
X
X
X
X
Laboratory Procedures/Assessments
Serum specific IgE to a panel of allergens
X
Hematology, Chemistry, Urinalysis
X
Urine Pregnancy Test – if applicableo
X
X
X
X
X
X
X
Immunologic sample (IgE, IgG4)p
X
X
X
Saliva (DNA) for Future Biomedical Researchq
X
DNA = deoxyribonucleic acid; e-diary = electronic diary; FBR = future biomedical research; FEV1 = forced expiratory volume in 1 second; IgE = immunoglobulin E; IgG4 = immunoglobulin G4; 
IVRS/IWRS = Interactive Voice/Web Response System; PFT = pulmonary function test; RS = ragweed season; SLIT= sublingual immunotherapy; US = United States.
a.
All subjects are to complete Visit 4 midway between Visit 3 and Visit 6, but not more than 6 to 8 weeks after Visit 3. If time between Visits 4 & 6 is > 6 to 8 weeks, then subject should be 
scheduled to return for Visit 5 approximately midway between Visits 4 and 6; study drug is not dispensed at Visit 5 (see Section 9.2 for the visits when study drug is dispensed).   
b.
During the first season of screening, subjects may be in screening up to approximately 9 months (-39 to -1 week).  During subsequent season(s) of screening, subjects may be in screening up to 
approximately 12 months (-52 to -1 week).
c.
Visit 3 should be scheduled on Day 28 (+7 days) to allow the subject to complete the SLIT Report Card for ~28 days.
d.
It is preferable that Visit 7 be scheduled approximately 3 weeks after the start of the ragweed season.
e.
Informed consent/assent must be obtained before any trial-related procedures are performed.
f.
Informed consent for future biomedical research samples (optional) must be obtained before the saliva for DNA sample.
g.
Update Subject Identification Card with randomization number.
h.
The Anaphylaxis Emergency Action Plan can be modified outside the US to meet local standards for the use (or type) of epinephrine dispensed, and for calls to 911 or alternative local emergency 
services.
 
 
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Product:  MK-3641 
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Protocol/Amendment No.: 008-02 
MK-3641-008-02 Final Protocol
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Confidential
Trial Period:
Screening
Treatment
Post-
treatment
Visit Number:
1
2
3
4/5 a
6
7
8
--
Visit Title:
Screening
Randomization
Off-Season
Off-Season
Pre-Season
In-Season
End-of-Season/ 
Discontinuation
Telephone/
Follow-up
Scheduled Day/Week:
Weeks
-52 to -1b
Day 1
Week 4c
Midway 
between 
Visits 3 & 6
~2 weeks 
before start 
of RS
~3 weeks 
after start of
RSd
~1 week after 
end of RS
Post 14 days
Scheduling Window (Days):
-
-
+7 days
+ 7 days
+ 7 days
+ 5 days
i.
Self-injectable epinephrine is provided only in those countries where it is a regulatory requirement.
j.
Albuterol/salbutamol should also be dispensed to subjects diagnosed with asthma during the trial as needed.
k.
Vital Signs (axillary temperature, blood pressure, pulse, respiration rate) in a seated position, height, and weight should be performed prior to performing pulmonary function tests. At the End-of-
season/Discontinuation visit a limited physical exam will be performed.
l.
Oropharyngeal examinations will be performed before and after study drug administration at Visit 2.  Targeted physical examinations may be conducted at visits that do not already include a 
physical exam, if deemed necessary by the investigator, due to signs/symptoms.
m. FEV1 results should be available and reviewed by investigator or designee prior to administration of first dose of study medication to ensure results meet inclusion criteria. Following 
randomization, PFTs are required only for subjects with asthma at the subsequent visits identified in the trial flow chart, unless the investigator feels a PFT is warranted for a subject without 
asthma. Note: PFTs are not required for those subjects ≤7 years of age who cannot perform reproducible FEV1 maneuvers despite coaching; those subjects ≤7 years of age who can perform 
reproducible FEV1 maneuvers, including those who initially could not at the Screening Visit, must complete the PFTs.
n.
Beta2-agonist reversibility (Section 12.9) will be performed at Visit 2 for all subjects performing PFTs (i.e., all subjects >7 years of age and all subjects ≤7 years of age who can perform 
reproducible FEV1 maneuvers).
o.
If a urine test result is positive, confirm with a serum β-hCG test.
p.
Immunologic samples will only be collected at selected sites.  The Visit 2 sample should be collected prior to administration of the first dose of study drug.  Leftover main study serum samples will 
be stored for future biomedical research if the subject consents to future biomedical research.
q.
Saliva (DNA) for FBR should be the last procedure performed at Visit 2.  If not obtained at Visit 2, can be obtained at a subsequent visit once the informed consent for FBR is obtained.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
Informed Consent
7.1.1.1
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
Inclusion/Exclusion Criteria
7.1.1.2
All inclusion and exclusion criteria will be reviewed at Visits 1 and 2 by the investigator or 
qualified designee to ensure that the subject qualifies for the trial.
Interactive Voice Response System (IVRS) / Interactive Web Response System 
7.1.1.3
(IWRS)
The investigator or designee will call into IVRS/IWRS following each subject’s Screening 
Visit. Upon confirmation of a subject’s eligibility at Visit 2, the investigator or designee will 
call back into IVRS/IWRS to randomize the subject. Subjects who do not continue to meet 
the eligibility criteria at Visit 2 will be screen-failed via IVRS/IWRS. For all randomized 
subjects, the investigator or designee will continue to call into IVRS/IWRS as per the Trial 
Flow Chart (Section 6.0). The investigator or designee will make the final call into 
IVRS/IWRS following completion of each randomized subject’s final visit at the end of the 
study.
Subject Identification Card
7.1.1.4
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.  At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
7.1.1.5
A medical history will be obtained by the investigator or qualified designee.  This will 
include a full medical history for the 5 years prior to Visit 1.  Subjects will be asked to 
provide information on allergic rhinitis history and related conditions, as well as family 
history of atopy.  
Those subjects suspected of having asthma must meet at least one of the following 3
minimum criteria to be considered as having a diagnosis of asthma (and documented as such 
in the appropriate eCRF):

At least one episode of wheeze, cough, shortness of breath or chest tightness and a 
change in FEV1 ≥12% after beta2-agonist administration;
 
 
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
Recurrent wheeze with or without prolonged phase of forced exhalation observed at 
physical examination and an intake of asthma medication which resulted in a 
clinically relevant effect;

Wheezing with or without prolonged phase of forced exhalation observed at physical 
examination and a change in FEV1 ≥12% after beta2-agonist administration.
Subjects who do not have asthma at randomization (Visit 2) and are subsequently diagnosed 
with asthma during the study should have asthma listed on the AE eCRF; also, the Asthma 
Diagnosis (ASDX) eCRF should be completed.
As the screening period can be up to 1 year in duration, medical history, including allergic 
rhinitis history and family history, should be reviewed at Visit 2 for any new information, 
with the appropriate eCRF(s) updated accordingly.
Demography
7.1.1.6
All subjects will have their demographic information collected.
Prior and Concomitant Medications Review
7.1.1.7
7.1.1.7.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days (or longer if appropriate) before starting the trial.  Medications will be 
recorded on the eCRF as per data entry guidelines.
7.1.1.7.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
Dispense Electronic Diary (e-diary)
7.1.1.8
Electronic diaries will be dispensed and instructions reviewed for use.  
Dispense Sublingual Immunotherapy (SLIT) Report Card
7.1.1.9
The investigator or designee will train the subject/parent/guardian on the use of the SLIT
Report Card (Section 12.10) prior to dispensing study medication to the subject at 
randomization (Visit 2). The SLIT Report Card will be completed daily for the first ~28 
days of study drug administration.  The SLIT Report Card will be reviewed at the next 
scheduled clinic visit (Visit 3) and stored in the subject’s source document file. Any AE data 
from the SLIT Report Card will be entered into the eCRF with appropriate assessments made 
by the investigator.
 
 
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Dispense Comment Card
7.1.1.10
The investigator or designee will train the subject/parent/guardian on the use of the Comment
Card prior to dispensing study medication to the subject at randomization (Visit 2).  The 
Comment Card will be dispensed at Visits 2 through 7, reviewed at the next scheduled clinic 
visit (Visits 3 through 8), and stored in the subject’s source document file.  Any AE data 
from the Comment Card will be entered into the eCRF with appropriate assessments made by 
the investigator.  Any concomitant therapy data from the Comment Card will be entered as 
appropriate into the eCRF.
Anaphylaxis Emergency Action Plan
7.1.1.11
The subject/parent/guardian will be provided with educational information regarding 
symptoms of anaphylaxis and treatment, including a written Anaphylaxis Emergency Action 
Plan (Section 12.8) at Visit 2. The Anaphylaxis Emergency Action Plan can be modified 
outside the US to meet local standards for the type of epinephrine dispensed (or local 
standard of care if it does not include the use of epinephrine) and for calls to 911 or 
alternative local emergency services.
Self-Injectable Epinephrine
7.1.1.12
In countries where self-injectable epinephrine is a regulatory requirement, the investigator or 
designee will dispense self-injectable epinephrine, instruct in its use, and provide the 
subject/parent/guardian with educational information, including a written Anaphylaxis 
Emergency Action Plan8 (Section 12.8) at Visit 2. At each subsequent visit following the 
dispensing, the investigator or designee will verify the subject has self-injectable epinephrine 
and will review instructions for use. Unused rescue self-injectable epinephrine will be 
collected at Visit 8.
Assignment of Screening Number
7.1.1.13
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.
Given the long screening period (up to one year), re-screening may be permitted up to 1 time,
but only if prior to randomization and upon Sponsor consultation.  Any subject who is re-
screened will retain the original screening number assigned at the initial screening visit.  
                                                
8 The Anaphylaxis Emergency Action Plan can be modified outside the US to meet local standards for the use (or type) of epinephrine 
dispensed, and for calls to 911 or alternative local emergency services.
 
 
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Assignment of Randomization Number
7.1.1.14
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.
Trial Compliance
7.1.1.15
The subject will be asked whether he/she has taken study medication as instructed at each 
visit, during telephone contacts, and at unscheduled visits.
Interruptions from the protocol specified treatment plan (compliance ≤75% between study 
visits) require consultation between the investigator and the Sponsor and written 
documentation of the collaborative decision on subject management.
Administration of the first dose of study drug will be witnessed by the investigator and/or 
trial staff (see Section 7.1.2.8—In-Clinic Dosing of Study Drug for further details).
Pollen Counts
7.1.1.16
Each study site will obtain pollen count data an average of 5 days per week.
Each study site will obtain daily pollen count data locally, regionally, or through a 
professional provider (e.g., National Allergy Bureau) for ragweed and other pollen, including 
tree, grass, and other weeds, as appropriate.  Daily pollen counts will be recorded on a pollen 
count log for approximately 2-4 weeks prior to the expected ragweed season and 2-4 weeks 
after the end of the expected ragweed season, which will reflect the pollen present in the area 
of the study site.  The counts for ragweed, expressed as counts per meter cubed air, will be 
tabulated for each site and used to determine the ragweed pollen season for the efficacy 
analyses.  All other counts will be expressed as absent, low, medium, high, or very high.  
Rain days should be noted on the pollen count logs. 
Clinical Procedures/Assessments
7.1.2
Vital Signs (Temperature, Blood Pressure, Pulse, Respiration)
7.1.2.1
Vital signs will be recorded as noted on the Trial Flow Chart (Section 6.0). For in-clinic 
dosing visits, vital signs will be performed prior to the administration of study drug. Vital 
signs will include axillary temperature, blood pressure (mmHg), pulse rate (beats/minute), 
and respiratory rate (breaths/minute), measured while in a seated position after ≥3 minutes of 
seated inactivity.
 
 
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Body Height and Weight
7.1.2.2
The subject’s body height and weight will be recorded as noted on the Trial Flow Chart 
(Section 6.0).
Physical Examination
7.1.2.3
All subjects will undergo a full physical examination at Screening. A targeted physical exam 
may be performed at any clinic visit that does not already include a physical exam if deemed 
necessary by the investigator due to signs/symptoms.  A physical exam (full or limited, based 
on investigator judgment) can be performed at any unscheduled visit if deemed necessary by 
the investigator.
Physical findings at Screening will be recorded on the medical history page of the eCRF. 
Abnormal findings from other visits will be recorded on the AE section of the eCRF.
The full examination should be based on the following body systems: general appearance, 
head (oral inspection, ears, eyes, nose, and throat), respiratory (auscultation/stethoscopy 
examination of the lungs), heart (auscultation/stethoscopy examination of the heart), 
abdomen, musculoskeletal, neurological, lymph nodes, and skin. Subjects with evidence of 
current, clinically significant, intercurrent illness (e.g., significant cold or flu) may be 
rescheduled for rescreening on resolution of their illness.
For the following body systems, questioning regarding symptoms may be sufficient: 
abdomen, urogenital, musculoskeletal, and neurological. If deemed necessary by the 
investigator, a physical examination of these body systems will be performed.
At the End-of-Season/ Discontinuation visit, a limited physical exam will be performed. The 
exam will be directed based on investigator judgment.
Oropharyngeal Examination
7.1.2.4
The oral cavity will be inspected for signs of mouth irritation, edema, and any other 
abnormalities according to the schedule noted on the Trial Flow Chart (Section 6.0). 
Abnormal findings at Visit 1 should be recorded on the medical history.  Abnormal findings 
after Visit 1 considered AEs must be recorded on the AE module of the eCRF.  
Oropharyngeal examinations preformed at Visit 2 will take place before and after 
investigational study drug administration.
Pulmonary Function Tests
7.1.2.5
Pulmonary function tests (PFTs) will include measurements of FEV1, FEV1 percent 
predicted, forced vital capacity (FVC), and FVC percent predicted for all subjects at Visits 1 
and 2 (exception: those subjects ≤7 years of age who cannot perform reproducible PFT 
maneuvers despite coaching). PFTs will continue to be performed as noted on the Trial Flow 
Chart (Section 6.0) for those subjects with asthma (exception: those subjects ≤7 years of age 
who cannot perform reproducible PFT maneuvers despite coaching). For those subjects ≤7 
years of age who could not perform reproducible PFT maneuvers at Visit 1, it is expected 
that sites will try to obtain reproducible PFT maneuvers at subsequent visits (Visit 2 for all 
subjects and subsequent visits for those with asthma).  PFTs may also be performed at a 
 
 
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subsequent visit for those subjects without asthma at baseline if the investigator or designee 
considers a PFT is warranted.
Beta2-agonist reversibility (Section 12.9) will be performed at Visit 2 for all subjects 
performing PFTs (i.e., all subjects >7 years of age and all subjects ≤7 years of age who can 
perform reproducible FEV1 maneuvers); beta2-agonist reversibility is not an entry criterion 
for this study.
Skin Prick Test
7.1.2.6
Skin prick testing will be performed to confirm hypersensitivity to the ragweed allergen 
extract (Ambrosia artemisiifolia) (2 tests).
Investigators/designees should follow standard 
office procedures with respect to wash-out requirements of antihistamines prior to skin 
testing. Skin test solutions will be applied to the inner forearm in duplicate. A histamine 
positive control (1 test) and saline negative control (1 test) will also be applied to the inner 
forearm. For each of the two wheals produced by the ragweed allergen extract (Ambrosia 
artemisiifolia), the wheal size will be determined by averaging the horizontal and vertical 
diameters 15 to 20 minutes after application. To record the skin testing, each wheal should 
be outlined on the skin with a ball point pen.  Tape should be adhered to the skin and then 
removed.  The pen outlines of the wheal should have transferred to the tape, and this record 
of the wheal size should then be adhered to the source documents and measured.  Additional 
detailed information regarding skin prick testing will be provided separately.
Subjects should wait an appropriate amount of time before departing from the study site 
following the test and should be counseled to call the study site if any untoward symptoms 
occur.
Skin prick test reagents and prick test devices will be provided by the Sponsor or designee. 
Adverse Event Monitoring
7.1.2.7
The investigator or designee will question the subject about AEs and intercurrent illnesses as 
well as review the Comment Card since the last visit (as applicable), and will record the 
pertinent information on the eCRF.
If a subject has a treatment interruption due to a worsening AE related to the study drug, then 
the subject should be re-evaluated by the investigator, or designee, prior to reinitiating the 
study drug.
See Section 7.2.3 for instructions on the reporting of SAEs to the sponsor and Section 7.2.4 
for instructions on the assessment of SAEs.
7.1.2.7.1 Assess and Record Duration of Local Adverse Events of Interest
Pre-specified local AEs that occur on Day 1, including the date, time, and duration (in 
minutes) will be monitored by site personnel, recorded in source documents, and entered into 
the eCRF based on the data entry guidelines, which will be provided to the sites by the 
Sponsor.  
During all in-clinic visits, the site will also collect information regarding pre-specified local 
AEs [date(s) and duration (if less than 24 hours)] by questioning the subject (including 
 
 
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review of the SLIT Report Card at Visit 3), and this will be recorded in the source documents 
and entered into the eCRF.
7.1.2.7.2 Alternate Local Adverse Event Severity Grading
The SLIT Report Card (Section 12.10) will be employed as an alternate method to capture 
adverse experience information in real time on a daily basis from the subject.  The SLIT 
Report Card is to be completed by the subject/parent/guardian to collect information on AEs 
identified as local effects of sublingual immunotherapy that occur within the first 60 minutes 
after study drug intake.  
Subjects will be trained on the proper method to complete the SLIT Report Card by 
completing a practice SLIT Report Card (paper format) at Visit 2.  The subject will be 
provided the SLIT Report Card at Visit 2 to complete daily for approximately 28 days of 
treatment and document the presence of any pre-specified local side effects of SLIT during 
the first 60 minutes after dosing on the SLIT Report Card. The SLIT Report Card data will 
be reviewed at the next scheduled clinic visit (Visit 3) and any AEs will be recorded on the 
eCRF. If Visit 3 is less than 28 days after Visit 2, then the subject should take the SLIT 
Report Card back and continue completing the SLIT Report Card until Day 28 of study 
medication administration.
In-Clinic Dosing of Study Drug
7.1.2.8
A subject who meets the eligibility criteria will have the first dose of study medication taken 
at the study site at Visit 2.  The subject will remain at the site for approximately 30 minutes 
following the first dose of study medication.  The duration in minutes of the pre-specified 
local adverse events will be recorded during the first supervised dose of study medication.
Dispense/Review/Collect
Study Medications (Study
Drug, Self-Injectable 
7.1.2.9
Epinephrine, Beta2-agonist and Allergy Rescue Medication)
Study drug will be dispensed for ‘at home administration’ at Visit 2, following the first on-
site administration of study medication and the subsequent observation period. All doses are 
to be taken at approximately the same time of day. Unused study medication will be collected 
at each study visit during the treatment period.
Self-injectable epinephrine (in countries where it is a regulatory requirement) and beta2-
agonist (for subjects with asthma) will be dispensed at Visit 2 and subsequent visits 
(including unscheduled visits) as necessary.  Allergy rescue medications will be dispensed at 
Visit 6. The investigator or designee will provide instructions (see Table 2 and Section 12.6) 
and demonstrate proper technique in the use of each medication.
The subject’s use and 
requirement for rescue medications should be reviewed by the investigator or designee at 
each visit during the ragweed season. Unused rescue medications will be collected at Visit 8.
Monitor Compliance with Study Medications
7.1.2.10
The subject must take the first dose of study drug at the study site under the supervision of 
the investigator or designee.  At all protocol-specified visits, the investigator or qualified 
designee is to note in the appropriate section of the eCRF whether study drug had been taken 
 
 
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per protocol in the preceding interval.  If not, the date(s) and reason for each dose variation 
must be recorded on the study medication (SM) eCRF. 
Study staff will instruct each subject to bring all study drug and rescue medications to each 
visit. The study drug and rescue medications (empty, partially used, and unused) will be 
inspected at all protocol-specified visits.
Compliance with the e-diary and rescue medication usage is essential.  The subject should 
record daily the intake of any rescue medications (beta2-agonist from Visit 4 to Visit 8 and 
allergy rescue medication from Visit 6 to Visit 8) in the e-diary.  Any rescue medication 
taken prior to dispensing of the e-diary should be reported on the Concomitant Medications 
eCRF. Any noncompliance noted upon review will result in documented consultation with 
the subject on corrective measures needed to ensure compliance.
Complete/Review Daily Symptoms in e-Diary
7.1.2.11
The subject/parent/guardian will be required to record allergy and asthma symptoms in an 
e-diary once daily, preferably in the evening before bedtime, from Visit 4 to Visit 8. 
Subjects should be instructed to record the worst severity rating for each symptom during the 
24-hour recall period.  For example, if the subject experienced severe itchy eyes for only 10 
minutes during the past 24 hours and mild itchy eyes for the rest of the past 24-hour period, 
the subject should record ‘Severe Symptoms’ on the e-diary for the day.  In the rare case that 
the subject/parent/guardian cannot complete the e-diary at their regular time, they will be 
allowed to complete the daily e-diary up to 9 am the following morning.  An e-diary will be 
issued at Visit 4 and collected at Visit 8. Instructions on how to complete entries and e-diary 
findings will be reviewed with the subject/parent/guardian at all visits.  
A total of nine symptoms, six rhinoconjunctivitis symptoms (runny nose, stuffy nose, 
sneezing, itchy nose, itchy eyes, and watery eyes) and three asthma symptoms (cough, 
wheeze, chest tightness/shortness of breath [dyspnea]) will be measured on a scale of 0 to 3 
as follows:
0 = no symptoms 
No sign/symptom evident
1 = mild symptoms 
Sign/symptom is clearly present but minimal
awareness; easily tolerated
2 = moderate symptoms 
Definite awareness of sign/symptom, which is
bothersome but tolerable
3 = severe symptoms 
Sign/symptom is hard to tolerate; may cause
interference with activities of daily living and/or sleeping
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 to be drawn over the course of the trial (from pre-
trial to post-trial visits), including approximate blood volumes drawn by visit and by sample 
type per subject can be found in Section 12.4.
 
 
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Serum-specific IgE
7.1.3.1
Blood samples will be collected at screening (Visit 1) for determination of serum-specific 
IgE against ragweed (Ambrosia artemisiifolia), other weeds (dependent upon region), grasses 
(dependent upon region), oak and other trees (dependent upon region), cat, dog, alternaira, 
cladosporium, dust mites, mugwort, and other allergens considered clinically relevant for a 
particular locale. 
A subject must have a specific IgE against Ambrosia artemisiifolia of ≥0.7 kU/L at screening 
to be included in the trial.
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
7.1.3.2
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 6.  
Laboratory evaluations will be performed at a central laboratory chosen by the Sponsor. If all 
of the laboratory values are within the normal reference range at Screening Visit 1, the 
subject may continue to be evaluated for study entry. If one or more values fall outside of the 
normal range, the investigator may either exclude the subject from the study or investigate 
further to determine clinical relevance (Section 12.5). The investigation will include a careful
evaluation of the potential subject’s complete medical history and current physical 
examination in the context of the abnormal laboratory value(s). If the investigator does not 
identify any medical condition or disease that could results in the observed laboratory 
abnormality, the abnormal laboratory value may be considered not clinically relevant by the 
investigator and will be documented as such on the laboratory results form. Any questionable 
laboratory results should be reviewed with the Sponsor prior to randomization (Section 12.5). 
Repeat laboratory testing, at the discretion of the investigator and/or Sponsor, is permitted 
and should be indicated as such. If there is any clinical uncertainty regarding the significance 
of an abnormal value(s), the subject will be excluded from the study.
All laboratory results must be found clinically acceptable to the investigator, and Sponsor, 
where appropriate, prior to study medication administration. 
Table 6
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Hemoglobin
Alkaline phosphatase
Glucose
Serum β-human 
chorionic gonadotropin 
(β-hCG)a
Platelet count
Alanine aminotransferase 
(ALT)
Protein
WBC (total and 
differential)
Aspartate aminotransferase 
(AST)
Specific gravity 
Bicarbonate
Microscopic exam, if 
abnormal results are 
noted
Blood Urea Nitrogen
Calcium
Chloride
 
 
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Hematology
Chemistry
Urinalysis
Other
Creatinine
Glucose
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total 
bilirubin is elevated above 
the upper limit of normal
Total protein
a Only performed if urine pregnancy test is positive.
Urine Pregnancy Test 
7.1.3.3
A female subject of childbearing potential must have a negative urine pregnancy test at Visits
1 and 2 to be eligible to participate in the study. A positive urine pregnancy test should be 
followed up with a serum pregnancy test (β-hCG).  Pregnancy tests should be repeated as per 
the Trial Flow Chart (Section 6.0).
Pharmacodynamic Evaluations
7.1.3.4
Blood samples for the immunologic assessment will be collected for a subset of subjects at 
selected sites per the study flow chart (Section 6.0). The serum samples for analyses of 
specific IgE and IgG4 will be submitted to ALK-Abelló for measurement.
Future Biomedical Research
7.1.3.5
The following specimens are to be obtained as part of Future Biomedical Research:

Saliva for future research,

Leftover main study serum from immunologic samples (IgE, IgG4) stored for future 
research.
Other Procedures
7.1.4
Withdrawal/Discontinuation
7.1.4.1
When a subject discontinues/withdraws 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.
7.1.4.1.1 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 
 
 
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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.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Blinding/Unblinding
7.1.4.2
When the investigator or sub-investigator needs to identify the drug used by a subject and the 
dosage administered in case of emergency e.g., the occurrence of serious adverse 
experiences, he/she will contact the emergency unblinding call center by telephone and make 
a request for emergency unblinding.  As requested by the investigator or sub-investigator the 
emergency unblinding call center will provide the information to him/her promptly and 
report unblinding to the sponsor.  The emergency unblinding call center will make a record 
promptly however, the investigator or sub-investigator must enter the intensity of the adverse 
experiences observed, their relation to study drug, the reason thereof, etc., in the medical 
chart etc., before unblinding is performed.  
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.
Calibration of Critical Equipment
7.1.4.3
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
 
 
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Critical Equipment for this trial includes:

Spirometer
The spirometer must be calibrated according to American Thoracic Society
guidelines. Calibration checks should be performed (i.e., with a 3-liter syringe) at a 
minimum of each day that a trial subject performs a spirometry assessment.  The 
calibration check records should be printed and kept in a reviewable log.  It is 
preferred that the calibration syringe used to check calibration of the spirometer also 
be subjected to a validated calibration according to the manufacturer’s specifications.
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.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before 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 
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.
 
 
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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).
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 
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 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 to the Sponsor
7.2.3
Serious Adverse Events
7.2.3.1
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 7 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until 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 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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Events of Clinical Interest
7.2.3.2
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until randomization, any ECI, 
or follow up to an ECI, that occurs to any subject must be reported within 24 hours to the 
Sponsor if it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure.
For the time period beginning at 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. Anaphylactic reactions, anaphylaxis and/or systemic allergic reactions.
4. Events treated with epinephrine.
5. Severe local swelling or edema of the mouth and/or throat. 
6. Severe drug-related asthma exacerbations.
7. Eosinophilic esophagitis.
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 7. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 7 for instructions in evaluating adverse events.
 
 
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Table 7
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.   (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event?   The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor's 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
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.
Executive Oversight Committee
7.3.2
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the
Data Monitoring Committee (DMC) regarding the trial.
Data Monitoring Committee
7.3.3
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.1.4 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the DMC.  The DMC will monitor the trial at an appropriate 
frequency, as described in the detailed DMC charter.  The DMC will also make 
recommendations to the Sponsor protocol team regarding steps to ensure both subject safety 
and the continued ethical integrity of the trial.
 
 
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8.0 STATISTICAL ANALYSIS PLAN
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).
Efficacy Analyses
8.1.1
Primary Efficacy Analysis
The primary analysis will be conducted on the Full Analysis Set (FAS) population.  The FAS 
population includes all subjects who receive at least one dose of study treatment. Subjects 
will be analyzed according to the treatment group to which they are randomized. 
The primary efficacy endpoint for the current trial is the average TCS during the peak 
ragweed season.  It will be analyzed using the analysis of variance (ANOVA) model, which 
includes fixed effects of treatment, baseline asthma status (yes, no), age group (5 to 11 years, 
12 to 17 years), pollen season, and pollen region nested within pollen season. Pollen region 
will be defined based on pollen station, and may include several sites within an acceptable 
distance between the pollen counters and corresponding sites.
Two-sided 95% confidence interval (CI) of the treatment difference in adjusted means will 
be presented. Also, the treatment difference in adjusted means relative to the adjusted mean 
of the placebo group will be presented as a percentage with corresponding 2-sided 95% CI 
derived using the bootstrap method. No missing data will be imputed.
The normality assumption of the ANOVA model will be checked using the Shapiro-Wilk test 
and inspection of the Q-Q plot. If a severe violation is observed, the primary analysis will be 
based on Wilcoxon Rank Sum test; the p-value will be reported together with the associated 
Hodges-Lehmann estimate of the treatment difference and its 2-sided 95% CI. Also, the 
difference in the treatment group medians relative to the median of the placebo group will be 
presented as a percentage with the corresponding 2-sided 95% CI derived using the bootstrap 
method. 
A Per Protocol (PP) analysis will be conducted for the primary efficacy endpoint, where the 
same ANOVA model and missing data approach will be used. See Section 8.2.5.1 for further 
sensitivity analyses of the primary efficacy endpoint. 
Key Secondary Efficacy Analyses
The key secondary efficacy endpoints for the current trial include:

Average TCS during the entire RS;

Average rhinoconjunctivitis DSS during the peak RS;

Average rhinoconjunctivitis DMS during the peak RS.
These endpoints will be analyzed based on the FAS population using the same ANOVA 
model as the primary efficacy endpoint. A fixed sequence procedure will be applied to 
 
 
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control multiplicity, where the primary efficacy endpoint will be tested first, and then the key 
secondary efficacy endpoints will be tested in the order stated above.
In a situation when there are more than 30% of the daily rhinoconjunctivitis DMS equal to 
zero, the zero-inflated lognormal model [18] will be used as the primary analysis method for 
rhinoconjunctivitis DMS as appropriate; this model takes the average rhinoconjunctivitis
DMS during the peak RS as response and adjusts for the same terms as in the ANOVA 
model.
Table 8 summarizes the key analysis strategy for the primary and key secondary efficacy 
endpoints.
Table 8
Analysis Strategy for Key Efficacy Endpoints
Endpoint
Statistical Methoda
Analysis 
Population
Missing Data 
Approach
Primary Efficacy Endpoint
Average TCS during the 
peak RS
ANOVA 
FAS
Observed data only
LOCF
Multiple Imputationb
PP
Observed data only
Wilcoxon Rank Sum Test; 
Hodges-Lehmann estimate of 
treatment differencec
FAS
Observed data only
Longitudinal Data Analysis
FAS
Model based
Key Secondary Efficacy Endpoints
Average TCS during the 
entire RS
ANOVA
FAS
Observed data only
Average rhinoconjunctivitis 
DSS during the peak RS
ANOVA
FAS
Average rhinoconjunctivitis 
DMS during the peak RS
ANOVA
FAS
Zero-inflated log-normalc
TCS = Total Combined Score; DSS = Daily Symptom Score; DMS = Daily Medication Score; RS = Ragweed Season.
ANOVA = Analysis of Variance; LOCF = Last non-missing observation carried forward.
FAS = Full Analysis set; PP = Per Protocol.
a Details of the statistical models are described in Section 8.2.5.
b Missing data from both treatment groups will be imputed using the sample distribution of TCS observed from the 
placebo group.
c This method will be applied if excessive zeros are observed in the data.
Safety Analyses
8.1.2
An All-Subjects-as-Treated (ASaT) population will be used for safety analyses. The ASaT 
population includes all subjects who receive at least one dose of study treatment. Subjects 
will be included in the treatment group corresponding to the study treatment they actually 
receive during the trial. 
 
 
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The analysis of safety endpoints will follow a tiered approach. For this study, Tier 1 safety 
endpoints include:

Proportion of subjects reporting pre-specified local application site reactions 
(including adverse events related to lip swelling/edema, mouth swelling/edema,
palatal swelling/edema,
swollen tongue/edema,
oropharyngeal swelling/edema, 
pharyngeal edema/throat tightness, oral pruritus, throat irritation, tongue pruritus, and 
ear pruritus);

Proportion of subjects reporting anaphylaxis and/or systemic allergic reactions;

Proportion of subjects treated with epinephrine.
Tier 1 safety endpoints will be subject to inferential testing for statistical significance with 
p-values and 95% confidence intervals provided for between-group comparisons. They will 
be analyzed using the stratified Miettinen and Nurminen method [1985] with baseline asthma 
status and age group as stratification factors.
Power and Sample Size
8.1.3
A total of approximately 1000 subjects will be randomized in a 1:1 ratio to either MK-3641
or placebo.  Assuming a 15% dropout rate, this gives approximately 425 evaluable subjects 
per treatment group. 
With 425 subjects per arm, the study will have:

approximately 90% power (2-sided, α = 0.05) to have the upper bound of the 95% CI 
for relative difference below -10%, and

more than 90% power (2-sided, α = 0.05) to have an estimated relative difference 
below -15%.
See Section 8.2.7 for further details of sample size calculation.
Interim Analyses
8.1.4
No efficacy interim analysis is planned for this trial. Safety data will be reviewed by an 
external Data Monitoring Committee (eDMC) (see Section 7.3.3).
Statistical Analysis Plan
8.2
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9).  Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to final 
database lock, will be documented in a supplemental SAP (sSAP) and referenced in the 
Clinical Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly 
identified in the CSR.  
 
 
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Responsibility for Analyses/In-House Blinding
8.2.1
The statistical analysis of the data obtained from this study will be the responsibility of the 
designee of the sponsor. 
This study will be conducted as a double-blind study under in-house blinding procedures.  
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol violators have been identified, and data have been declared final and 
complete.
The randomized allocation schedule will be generated by the sponsor, and implemented by 
the vendor of the study interactive voice response system (IVRS).
Safety will be monitored by the external Data Monitoring Committee (eDMC) on an ongoing 
basis and the eDMC will make recommendations to the sponsor as appropriate.
Hypotheses
8.2.2
Objectives and hypotheses of the study are stated in Section 3.0.
Analyses Endpoints
8.2.3
Efficacy and safety endpoints that will be evaluated for within- and between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected 
endpoints.
Efficacy Endpoints
8.2.3.1
Primary Efficacy Endpoint

Average TCS during the peak RS.
Key Secondary Efficacy Endpoints

Average TCS during the entire RS;

Average rhinoconjunctivitis DSS during the peak RS;

Average rhinoconjunctivitis DMS during the peak RS.
Tertiary Efficacy/Immunologic Endpoints

Average rhinoconjunctivitis DSS during the entire RS

Change from baseline in IgE level against Ambrosia artemisiifolia at Visit 6 and at 
Visit 8;

Change from baseline in IgG4 level against Ambrosia artemisiifolia at Visit 6 and at 
Visit 8.
Exploratory Efficacy Endpoints

Average Asthma DSS during the peak RS and the entire RS;Average daily number of 
puffs of as-needed SABA used during the peak RS and the entire RS;
 
 
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
Average weekly number of nights with nocturnal awakening due to asthma symptoms 
requiring SABA use during the peak RS and the entire RS.
Safety Endpoints
8.2.3.2
Tier 1 Safety Endpoints

Proportion of subjects reporting pre-specified local application site reactions 
(including adverse events related to lip swelling/edema, mouth swelling/edema,
palatal swelling/edema,
swollen tongue/edema,
oropharyngeal swelling/edema, 
pharyngeal edema/throat tightness, oral pruritus, throat irritation, tongue pruritus, and 
ear pruritus);

Proportion of subjects reporting anaphylaxis and/or systemic allergic reactions;

Proportion of subjects treated with epinephrine.
Tier 2 Safety Endpoints

Proportion of subjects with any AE;

Proportion of subjects with any serious AE;

Proportion of subjects with any drug-related AE;

Proportion of subjects with any serious and drug-related AE;

Proportion of subjects who discontinue due to an AE;

Proportion of subjects with specific AEs or SOCs (incidence ≥1% subjects in one or 
more of the treatment groups).
Tier 3 Safety Endpoints

Change from baseline in laboratory test parameters at each post-baseline visit;

Change from baseline in vital sign parameters at each post-baseline visit;

Summaries by system organ class (SOC) for general AEs, serious AEs, drug-related 
AEs, and AEs resulting in discontinuation;

Average duration of pre-specified local application site reactions in minutes on Day 
1;

Average duration of pre-specified local application site reactions in days over Day 2 
to Day 14;

Average duration of pre-specified local application site reactions in days over Day 15 
to Day 28.
 
 
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Derivations of Efficacy/Immunologic Endpoints 
8.2.3.3
Ragweed Season
Entire Ragweed Season: the start of the entire ragweed season is the first day of 3 
consecutive recorded days with a pollen count of ≥10 grains/m3; the end of the entire 
ragweed season is the last day of 3 consecutive recorded days with a pollen count of ≥10 
grains/m3. This is specific for each study site.
Peak ragweed season: the 15 consecutive recorded days within the entire ragweed season 
with the highest 15-day moving average pollen count. This is specific for each study site.
TCS, Rhinoconjunctivitis DSS, Rhinoconjunctivitis DMS, Asthma DSS
These are defined in Section 4.2.3.1.
Derivations of Safety Endpoints
8.2.3.4
For laboratory tests and vital sign parameters, the baseline value is defined as the last 
measurement taken prior to randomization. Change from baseline in laboratory and vital 
signs parameters is calculated by on-treatment value minus the baseline value.
Analysis Populations
8.2.4
Efficacy Analysis Populations
8.2.4.1
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study. The FAS population consists of all randomized subjects who 
receive at least one dose of study treatment. Subjects will be analyzed according to the 
treatment group to which they are randomized. 
A supportive analysis using the Per-Protocol (PP) population will be performed for the
primary efficacy endpoint. The PP population excludes subjects due to important deviations 
from the protocol that may substantially affect the results of the primary efficacy endpoints.
The major protocol violations that would lead to exclusion of a subject or a data point are 
described below:

Subjects with asthma requiring prescribed high daily doses of inhaled corticosteroids 
(as defined in the protocol);

Subjects with chronic sinusitis during the previous 2 years;

Subjects treated with immunotherapy within 5 years prior to screening;

Subjects unable to meet medication washout requirements;

Subjects randomized in the study more than once; 

Subjects who participated in the same study at another site;

Subjects with pre-seasonal duration of treatment exposure < 56 Days;

Subjects with a negative skin prick test response to ragweed;

Subjects with specific IgE to ragweed < 0.7 kU/L;
 
 
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
Subjects with overall treatment compliance < 75% between Visit 2 and Visit 8;

Subjects who took prohibited medications as defined in the protocol, with the exception 
of antihistamines. Subjects who have taken antihistamines (other than sponsor provided 
rescue medications) will be considered protocol violators if they have taken the 
medication for 2 or more consecutive days between Visit 6 and Visit 8;

Subjects who had their blinded treatment randomization code broken. 
Analyses related to SABA use and nocturnal awakening will be based on subjects with 
asthma in the FAS population.
Safety Analysis Populations
8.2.4.2
The All-Subjects-as-Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be grouped by the study treatment actually 
received. 
Statistical Methods
8.2.5
Statistical testing and inference for efficacy and safety analyses are described in Sections 
8.2.5.1 and 8.2.5.2. Controlling of family-wise Type I error rate is described in Section 8.2.6, 
Multiplicity. Nominal p-values will be computed for tertiary and exploratory efficacy 
analyses as a measure of strength of association between the endpoint and the treatment 
effect rather than formal tests of hypotheses. Unless otherwise stated, all statistical tests will 
be conducted at α=0.05 (2-sided) level.
Statistical Methods for Efficacy/Immunologic Analyses
8.2.5.1
Primary Efficacy Analysis
The primary efficacy endpoint for the current trial is the average TCS during the peak 
ragweed season. It will be analyzed using the ANOVA model, which includes fixed effects 
of treatment, baseline asthma status (yes, no), age group (5 to 11 years, 12 to 17 years), 
pollen season, and pollen region nested within pollen season. Pollen region will be defined 
based on pollen station, and may include several sites within an acceptable distance between 
the pollen counters and corresponding sites.
Two-sided 95% CI of the treatment difference in adjusted means will be presented. Also, the 
treatment difference in adjusted means relative to the adjusted mean of the placebo group 
will be presented as a percentage with corresponding 2-sided 95% CI derived using the 
bootstrap method. No missing data will be imputed.
The normality assumption of the ANOVA model will be checked using the Shapiro-Wilk test 
and inspection of the Q-Q plot. If a severe violation is observed, the primary analysis will be 
based on Wilcoxon Rank Sum test; the p-value will be reported together with the associated 
Hodges-Lehmann estimate of the treatment difference and its 2-sided 95% CI. Also, the 
difference in the treatment group medians relative to the median of the placebo group will be 
 
 
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presented as a percentage with the corresponding 2-sided 95% CI derived using the bootstrap 
method. 
Sensitivity Analysis
The PP analysis will be conducted for the primary efficacy endpoint, where the same 
ANOVA model and missing data approach will be used. In addition, the following sensitivity
analyses will be performed for the primary efficacy endpoint.

The same ANOVA model based on the FAS population will be used. Missing data 
will be imputed by the LOCF approach. For each subject, only the observations 
within the pollen season are eligible to be carried forward. 

The same ANOVA model based on the FAS population will be used. Missing data 
will be handled by the multiple imputation method. Missing data from both treatment 
groups will be imputed using the sample distribution of TCS observed from the 
placebo group, which is considered to be a conservative approach for imputations. 

Longitudinal Data Analysis model based on the FAS population will be used. Daily 
TCS during the peak season will be the response variable and covariates will include 
treatment, time, the interaction of treatment by time, baseline asthma status, age 
group, pollen season, and pollen region nested within pollen season. The Toeplitz 
structure will be used to model the covariance of the repeated TCS measurements 
over time within subjects.  Additional covariance structures, such as unstructured 
covariance, may be considered if convergence issues are encountered with the 
analysis model.
Furthermore, if there are more than 2% of subjects taking prednisone during any one 
ragweed season in the course of the study, a sensitivity analysis will be conducted for the 
primary efficacy endpoint, where the usage of prednisone is included in the definition of the 
rhinoconjunctivitis DMS. The medication scores for prednisone usage are defined in Table 
9.
Table 9
Medication Score for Prednisone Usage
Rescue Medication
Subject Dosing Instructions
Score/Dose Unit
Maximum Daily 
Score
Prednisone tablet
5 mg
Day 1: 1 mg/kg/day, Max 50 mg/day
1.6 (per tablet)
16
Day 2+: 0.5 mg/kg/day, Max 25 mg/day
1.6 x 2 (per tablet)
16
In addition, in order to minimize missing data, subjects will be allowed to complete the daily 
e-diary up to 9 am the following morning (in case the subject cannot complete it at their 
regular time that day). A sensitivity analysis will be conducted for the FAS population, where 
only the data entered on the same day (instead of next morning) are included. The same 
ANOVA model and missing data approach will be used. 
 
 
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Key Secondary Efficacy Analyses
The key secondary efficacy endpoints for the current trial include:

Average TCS during the entire RS;

Average rhinoconjunctivitis DSS during the peak RS;

Average rhinoconjunctivitis DMS during the peak RS.
These endpoints will be analyzed based on the FAS population using the same ANOVA 
model as the primary efficacy endpoint. 
Based on the rescue medication usage from previous AIT trials, many subjects used little 
rescue medication during the trial, which resulted in large amounts of rhinoconjunctivitis
DMS records equal to zero. Data with excessive zeroes may not conform to the normality 
assumption for the ANOVA model and may also prevent the proper application of non-
parametric method. In a situation when there are more than 30% of the daily 
rhinoconjunctivitis DMS equal to zero, the zero-inflated lognormal model [18] will be used 
as the primary analysis method for rhinoconjunctivitis DMS as appropriate; this model takes 
the average rhinoconjunctivitis DMS during the peak RS as response and adjusts for the same 
terms as in the ANOVA model.
Tertiary Efficacy/Immunologic Analyses
The tertiary efficacy/immunologic endpoints for the current trial include:

Average rhinoconjunctivitis DSS during the entire RS;

Change from baseline in IgE level against Ambrosia artemisiifolia at Visit 6;

Change from baseline in IgE level against Ambrosia artemisiifolia at Visit 8;

Change from baseline in IgG4 level against Ambrosia artemisiifolia at Visit 6;

Change from baseline in IgG4 level against Ambrosia artemisiifolia at Visit 8.
Average rhinoconjunctivitis DSS during the entire RS will be analyzed based on the FAS 
population using the same ANOVA model as the primary efficacy endpoint.
IgE and IgG4 related endpoints will be analyzed separately using the constrained LDA 
(cLDA) model. The cLDA model assumes a common mean across treatment groups at 
baseline and different means for different treatments at each post-baseline time point. In this 
model, the response vector consists of the baseline value and the values observed at each 
post-baseline time point. The model will adjust for time, the interaction of treatment by time, 
baseline asthma status, age group, pollen season, and pollen region nested within pollen 
season. Time is treated as a categorical variable so that no restriction is imposed on the 
trajectory of the means over time. A Toeplitz covariance matrix will be used to model the 
correlation among repeated measurements. Further details of the model specification, 
assumptions, and SAS implementation codes will be provided in the sSAP.
 
 
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Exploratory Efficacy Analyses
The exploratory efficacy endpoints for the current trial include:

Average Asthma DSS during the peak RS;

Average Asthma DSS during the entire RS;

Average daily number of puffs of as-needed SABA used during the peak RS;

Average daily number of puffs of as-needed SABA used during the entire RS;

Average weekly number of nights with nocturnal awakening due to asthma symptoms 
requiring SABA use during the peak RS;

Average weekly number of nights with nocturnal awakening due to asthma symptoms 
requiring SABA use during the entire RS.
These endpoints will be analyzed using the same ANOVA model as the primary efficacy 
endpoint. Asthma DSS related endpoints will be analyzed based on the FAS population,
while SABA use and nocturnal awakening related endpoints will be analyzed based on 
subjects with asthma in the FAS population.
In addition, components of the rhinoconjunctivitis DSS (ocular symptoms and nasal 
symptoms) will be summarized for the peak RS and the entire RS.
Table 10 summarizes the key analysis strategy for the efficacy/immunologic endpoints.
Table 10
Analysis Strategy for the Efficacy/Immunologic Endpoints
Endpoint
Statistical Methoda
Analysis 
Population
Missing Data 
Approach
Primary Efficacy Endpoint
Average TCS during the peak RS
ANOVA 
FAS
Observed data only
LOCF
Multiple Imputationb
PP
Observed data only
Wilcoxon Rank Sum Test; 
Hodges-Lehmann estimate of 
treatment differencec
FAS
Observed data only
Longitudinal Data Analysis 
FAS
Model based
Key Secondary Efficacy Endpoints
Average TCS during the entire RS
ANOVA
FAS
Observed data only
Average rhinoconjunctivitis DSS 
during the peak RS
ANOVA
FAS
Average rhinoconjunctivitis DMS 
during the peak RS
ANOVA
FAS
Zero-inflated log-normalc
Tertiary Efficacy/Immunologic Analyses 
Average rhinoconjunctivitis DSS 
during the entire RS
ANOVA 
FAS
Observed data only
Change from baseline in IgE level 
against Ambrosia artemisiifolia at 
Visit 6 and Visit 8
constrained Longitudinal Data 
Analysis
FAS
Model based
 
 
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Endpoint
Statistical Methoda
Analysis 
Population
Missing Data 
Approach
Change from baseline in IgG4 level 
against Ambrosia artemisiifolia at 
Visit 6 and Visit 8
constrained Longitudinal Data 
Analysis
FAS
Model based
Exploratory Efficacy Analyses 
Average Asthma DSS during the 
peak RS and the entire RS
ANOVA 
FAS
Observed data only
Average daily number of puffs of 
as-needed SABA used during the 
peak RS and the entire RS
ANOVA 
FAS 
(asthma only)
Observed data only
Average weekly number of nights 
with nocturnal awakening due to 
asthma symptoms requiring SABA 
use during the peak RS and the 
entire RS
ANOVA 
FAS 
(asthma only)
Observed data only
ANOVA = Analysis of Variance; DSS = Daily Symptom Score; DMS = Daily Medication Score; FAS = Full Analysis set; IgE = 
immunoglobulin E; IgG4 = immunoglobulin G4; LOCF = Last non-missing observation carried forward; PP = Per Protocol; RS = 
Ragweed Season; SABA = short-acting beta2-agonist; TCS = Total Combined Score.
a Details of the statistical models are described in Section 8.2.5.
b Missing data from both treatment groups will be imputed using the sample distribution of TCS observed from the placebo 
group.
c This method will be applied if excessive zeros are observed in the data.
Handling of Missing Data
The missing data approaches are specified for the primary efficacy endpoint sensitivity 
analyses (including multiple imputation, LOCF, and model based) and immunologic
endpoints (model based). All other analyses will be conducted based on the observed data 
only. Proportion of subjects with missing data will be summarized for each 
efficacy/immunologic endpoint.
Statistical Methods for Safety Analyses
8.2.5.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, and vital sign measurements.
The analysis of safety results will follow a tiered approach (Table 11). The tiers differ with 
respect to the analyses that will be performed. Tier 1 safety endpoints will be subject to 
inferential testing for statistical significance with p-values and 95% CIs provided for 
between-group comparisons.  Tier 2 safety endpoints will be evaluated via point estimates 
and 95% CIs for between-group comparisons. Tier 3 safety endpoints will be evaluated via 
point estimates only.
For this trial, Tier 1 safety endpoints include:

Proportion of subjects reporting pre-specified local application site reactions 
(including adverse events related to lip swelling/edema, mouth swelling/edema,
palatal swelling/edema,
swollen tongue/edema,
oropharyngeal swelling/edema, 
pharyngeal edema/throat tightness, oral pruritus, throat irritation, tongue pruritus, and 
ear pruritus);

Proportion of subjects reporting anaphylaxis and/or systemic allergic reactions;
 
 
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
Proportion of subjects treated with epinephrine.
For the analysis of “Proportion of subjects treated with epinephrine”, the denominator will 
include all subjects in the ASaT population, regardless of whether self-injectable epinephrine 
was provided or not. Meanwhile, a sensitivity analysis will be conducted where the 
denominator will include subjects in the ASaT population who were provided with self-
injectable epinephrine, and the numerator will be subjects from the denominator subjects 
who were treated with epinephrine. 
Tier 2 safety endpoints for this trial include:

Proportion of subjects with any AE;

Proportion of subjects with any serious AE;

Proportion of subjects with any drug-related AE;

Proportion of subjects with any serious and drug-related AE;

Proportion of subjects who discontinue due to an AE;

Proportion of subjects with specific AEs or SOCs (incidence ≥1% subjects in one or 
more of the treatment groups).
The Tier 1 and Tier 2 safety endpoints will be analyzed using the stratified Miettinen and 
Nurminen method [1985] with baseline asthma status and age group as stratification factors. 
Tier 3 safety endpoints for this trial include:

Change from baseline in laboratory test parameters at each post-baseline visit;

Change from baseline in vital sign parameters at each post-baseline visit;

Change from baseline in pulmonary function test parameters at each post-baseline 
visit;

Summaries by SOC for general AEs, serious AEs, drug-related AEs, serious and 
drug-related AEs, and AEs resulting in discontinuation;

Average duration of pre-specified local application site reactions in minutes on Day 
1;

Average duration of pre-specified local application site reactions in days over Day 2 
to Day 14;

Average duration of pre-specified local application site reactions in days over Day 15 
to Day 28.
Point estimates will be provided for the Tier 3 safety endpoints. In addition, AE summaries 
(general AEs, serious AEs, drug-related AEs, serious and drug-related AEs, and AEs 
resulting in discontinuation) by asthma status will also be provided. For pulmonary function 
test parameters, a cLDA model based analysis will also be conducted (see Section 8.2.5.1 for 
more details about the cLDA model). 
Table 11 summarizes the safety tier and level of analysis for the safety endpoints.
 
 
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Table 11
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpointa
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Proportion of subjects reporting pre-specified local 
application site reactions (including adverse events related 
to lip swelling/edema, mouth swelling/edema, palatal 
swelling/edema, swollen tongue/edema, oropharyngeal 
swelling/edema, pharyngeal edema/throat tightness, oral 
pruritus, throat irritation, tongue pruritus, and ear pruritus);
Proportion of subjects reporting anaphylaxis and/or 
systemic allergic reactions;
Proportion of subjects treated with epinephrine.
X
X
X
Tier 2
Any AE;
X
X
Any Serious AE;
Any Drug-Related AE;
Any Serious and Drug-Related AE;
Discontinuation due to AE;
Specific AEs or SOCsb (incidence ≥1% of subjects in one 
or more of the treatment groups)
Tier 3
Change from baseline in laboratory test parameters at each 
post-baseline visit;
Change from baseline in vital sign parameters at each post-
baseline visit;
Change from baseline in pulmonary function test 
parameters at each post-baseline visit;
Summaries by SOC for general AEs, serious AEs, drug-
related AEs, serious and drug-related AEs, and AEs 
resulting in discontinuation;
AE summaries by asthma status;
Average duration of pre-specified local application site 
reactions in minutes on Day 1;
Average duration of pre-specified local application site 
reactions in days over Day 2 to Day 14;
Average duration of pre-specified local application site 
reactions in days over Day 15 to Day 28.
X
AE = adverse event; CI = confidence interval; SOC = System Organ Class; X = results will be provided.
a
Adverse Experience references refer to both Clinical and Laboratory AEs.
b
Includes only those endpoints not pre-specified as Tier 1 or Tier 2 endpoints.
In addition, the SLIT
Report Card (Section 4.2.3.2) will be completed by the 
subject/parent/guardian, daily for the first ~28 days of dosing, to collect information on local 
side effects of SLIT that occur within the first 60 minutes after each daily study drug intake. 
Identified local AEs will be graded via a programmatic approach and clinical review as mild, 
moderate, or severe. An exploratory review of the severity grading via the programmatic 
 
 
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approach and that as determined by the investigator’s review of the AEs with their
subjects/parents/guardians will be conducted. 
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.2.5.3
Demographic and Baseline Characteristics
The number and percentage of subjects screened, randomized, the primary reasons for 
screening failure, and the primary reason for discontinuation will be displayed. 
Demographic variables (including age, gender, race, weight, height, and body mass index),
baseline characteristics (including baseline asthma status, inhaled corticosteroid use, duration 
of allergic rhinitis, sensitization type, ragweed specific IgE, wheal size from skin prick test, 
and number of puffs of bronchodilator used for FEV1 reversibility), primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables. The comparability of the treatment groups for each 
relevant characteristic will be assessed by the summary tables. No statistical hypothesis tests 
will be performed on these characteristics.
Skin Prick Test (SPT) Analysis
Descriptive statistics (mean, standard deviation, etc.) of the wheal size determined from the 
SPT will be provided for all randomized subjects.
Multiplicity
8.2.6
A fixed sequence procedure will be applied to control multiplicity. The primary and key 
secondary efficacy endpoints will be tested in the following order:

Average TCS during the peak RS;

Average TCS during the entire RS;

Average rhinoconjunctivitis DSS during the peak RS;

Average rhinoconjunctivitis DMS during the peak RS.
A lower order endpoint will be tested only if all higher order endpoints have been tested and 
claimed statistically significant.
Sample Size and Power Calculations
8.2.7
A total of approximately 1000 subjects will be randomized in a 1:1 ratio to either MK-3641 
or placebo.  Assuming a 15% dropout rate, this gives approximately 425 evaluable subjects 
per treatment group. 
With 425 subjects per arm, the study will have:

approximately 90% power (2-sided, α = 0.05) to have the upper bound of the 95% CI 
for relative difference below -10%, and

more than 90% power (2-sided, α = 0.05) to have an estimated relative difference 
below -15%.
 
 
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The calculations are based on the assumptions that the true difference between treatment 
arms in average TCS during peak RS is -2.12, that the average TCS during peak RS from the 
placebo group is 8.9, and that the standard deviation is 5.60. These assumptions, as well as 
the assumption on dropout rate, are based on the two MK-3641 (AIT ragweed) adult studies, 
P05233 and P05234, and the pediatric trial P05239 for MK-7243 (AIT grass).
Subgroup Analyses and Effect of Baseline Factors
8.2.8
Analysis for the primary efficacy endpoint will be provided for the following subgroups of 
baseline factors:

Baseline asthma status (yes, no);

Age group (5 to 11 years, 12 to 17 years);

Gender (male, female);

Race (Caucasians, non-Caucasians);

ICS use for subjects with asthma (yes, no);

Allergen sensitization type (ragweed only, ragweed + others);

Geographic region (e.g., US, Canada, Europe). Region classification for each study site 
will be determined before database lock.
In addition, subgroup analysis on the primary efficacy endpoint will be provided for:

Pollen counts (low, high): The subgroups will be defined based on the median of the 
subject level accumulated pollen counts during the first 21 days of the pollen season;

Local application site reaction (had local application site reactions, did not have local 
application site reactions).
The same ANOVA model as in the primary efficacy analysis will be applied for the subgroup 
analyses.
Interim Analyses
8.2.9
No efficacy interim analysis is planned for this trial. Safety data will be reviewed by an 
eDMC.
Compliance (Medication Adherence)
8.2.10
For each subject, percent compliance will be calculated using the following formula:
%
100
Therapy
on 
Be
Should
Days
of
Number 
Therapy
on 
Days
of
Number 
Compliance
Percent 


A day within the study will be considered an “On-Therapy” day if the subject takes all 
required medication as instructed in Section 5.2. When a subject takes less than or more than 
the required medication on a day, that day is not considered an On-Therapy day.
 
 
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For subjects who are followed for the entire study period, the “Number of Days Should be on 
Therapy” is the number of days from the first scheduled treatment day to the last scheduled 
treatment day.  For subjects who discontinue from the study, the “Number of Days Should 
Be on Therapy” is the number of days from the first scheduled treatment day to the last dose 
day.
Summary statistics will be provided on percent compliance for the ASaT population.
Extent of Exposure
8.2.11
The duration of treatment for each subject will be evaluated by calculating the number of 
days on therapy. The range and mean for days on therapy will be calculated for the ASaT 
population. 
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.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 12
Product Descriptions
Product Name & Potency
Dosage Form
MK-3641 12 Amb a 1-U
Sublingual Rapid Dissolving Tablet
MK-3641 placebo
Sublingual Rapid Dissolving Tablet
All placebos were created by the Sponsor to match the active product.
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.
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.
 
 
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Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive blinded monthly kits. Each kit will contain 4 blister cards (Table 13).
Table 13
Kits Dispensed Per Visit
Visit Number
Number of Kits to be dispensed
2 (Randomization)
1
3, 4, 6, and 7
2
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 identity. 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.
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.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
 
 
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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.
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
 
 
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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 
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.
 
 
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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 
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.
 
 
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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.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  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 FDAMA/FDAAA 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 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
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 
 
 
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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 
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 
 
 
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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]
Wallace DV, Dykewicz MS, Bernstein DI, Blessing-Moore J, Cox L, Khan DA, 
et al. The diagnosis and management of rhinitis: an updated practice parameter. J 
Allergy Clin Immunol. 2008 Aug;122(2 Suppl):S1-84.
[2]
Arbes SJ, Gergen PJ, Elliott L, Zeldin DC. Prevalences of positive skin test 
responses to 10 common allergens in the US population: results from the Third 
National Health and Nutrition Examination Survey. J Allergy Clin Immunol 
2005;116(2):377-83.
[3]
Burbach GJ, Heinzerling LM, Röhnelt C, Bergmann KC, Behrendt H, Zuberbier 
T. Ragweed sensitization in Europe - GA2LEN study suggests increasing 
prevalence. Allergy 2009;64:664-5.
[4]
Frew AJ, Powell RJ, Corrigan CJ, Durham SR. Efficacy and safety of specific 
immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic 
rhinoconjunctivitis. J Allergy Clin Immunol 2006;117(2):319-25.
[5]
Scadding G, Durham S. Mechanisms of sublingual immunotherapy. J Asthma 
2009;46:322-34.
[6]
Ogershok PR, Warner DJ, Hogan MB, Wilson NW. Prevalence of pollen 
sensitization in younger children who have asthma. Allergy Asthma Proc 
2007;28(6):654-8.
[7]
Cox L, Nelson H, Lockey R. Allergen immunotherapy: A practice parameter 
third update. J Allergy Clin Immunol 2011;127(1):S1-S55.
[8]
Corzo JL, Carrillo T, Pedemonte C, Plaza Martin AM, Martin Hurtado S, Dige 
E, et al. Tolerability during double-blind randomized phase I trials with the 
house dust mite allergy immunotherapy tablet in adults and children. J Investig 
Allergol Clin Immunol. 2014;24(3):154-61.
[9]
US Department of Health and Human Services (National Heart, Lung, and
Blood Institute). National Asthma Education and Prevention Program: expert 
panel report 3: guidelines for the diagnosis and management of asthma (NIH 
publication 07-4051). Bethesda, MD: National Institutes of Health; 2007.
[10]
U.S.Department of Health and Human Services.  Expert Panel Report 3: 
Guidelines for the diagnosis and management of asthma, full report 2007.
[11]
Global Initiative for Asthma. Pocket guide for asthma management and 
prevention (for adults and children older than 5 Years). Geneva: Global 
Initiative for Asthma; 2016. 28 p.
 
 
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[12]
European Medicines Agency. Guideline on the clinical development of products 
for 
specific 
immunotherapy 
for 
the 
treatment 
of 
allergic 
diseases 
(CHMP/EWP/18504/2006), 20-Nov-2008.
[13]
Canonica GW, Bousquet J, Casale T, Lockey RF, Baena-Cagnani CE, Pawankar 
R, et al. Sub-lingual Immunotherapy: World Allergy Organization Position 
Paper 2009. Allergy 2009;64(Suppl 91):1-59.
[14]
Radulovic S, Calderon MA, Wilson D, Durham S. Sublingual immunotherapy 
for allergic rhinitis. Cochrane Database Syst Rev 2011(12):1-135.
[15]
Nelson HS, Nolte H, Creticos P, Maloney J, Wu J, Bernstein DI. Efficacy and 
safety of timothy grass allergy immunotherapy tablet treatment in North 
American adults. J Allergy Clin Immunol 2011;127(1):72-80.
[16]
Blaiss M, Maloney J, Nolte H, Gawchic S, Yao R, Skoner DP. Efficacy and 
safety of timothy grass allergy immunotherapy tablets in North American 
children and adolescents. J Allergy Clin Immunol 2011;127:64-71.
[17]
Papadopoulos NG, Arakawa H, Carlsen KH, Custovic A, Gern J, Lemanske R, 
et al. International consensus on (ICON) pediatric asthma. Allergy. 2012 
Aug;67(8):976-97.
[18]
Tooze JA, Grunwald GK, Jones RH. Analysis of repeated measures data with 
clumping at zero. Stat Methods Med Res 2002;11(4):341-55.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing. In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.5 – Future Biomedical 
Research will be used to study various causes for how subjects may respond to a 
drug/vaccine.  Future biomedical research specimen(s) will be stored to provide a 
resource for future trials conducted by 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.
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 
 
 
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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified
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
Saliva 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.
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 
 
 
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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.
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 
 
 
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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.
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, 
 
 
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concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
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. Saliva
specimens will be collected from the mouth 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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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff
 
 
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Approximate Blood Volumes Drawn by Trial Visit and by Sample Types
12.4
Trial Visit:
Screening
Visit 1
Randomization
Visit 2
Treatment
Visit 6
Treatment
Visit 8
Blood Parameter 
Approximate Blood Volume (mL)
Hematology
2.0
Serum Chemistry
2.5
Serum-specific IgE
5.0
Immunologic Sample (IgE, IgG4)
10a
10a
10a
Expected Total (mL)
9.5
10a
10a
10a
a Samples will only be collected at selected sites. Leftover main study serum samples will be 
stored at the end of the study for future biomedical research if the subject/parent/guardian 
consents to future biomedical research. 
 
 
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Algorithm for Assessing Out-of-Range Laboratory Values
12.5
For all safety laboratory values obtained at prestudy evaluation (see Table 6 in Section 
7.1.3.2):
A.
If all values are normal, the subject may enter the study.
B.
If ≥1 value is outside the normal range, the following choices are available:
1. The subject may be excluded from the study;
2. The subject may be included in the study if the investigator agrees that the 
abnormal value(s) is not clinically relevant.  The sponsor may be consulted if 
uncertainty exists.
3. The subject may be included in the study if the abnormality is anticipated because 
of the disease state; e.g., an elevated eosinophils count in a subject with asthma 
(this should be noted in the “comments” section of the appropriate case report 
form); or 
4. The abnormal test may be repeated (go to item C).
C.
If the repeat test value is within the normal range, the subject may enter the study.
D.
If the repeat test value is still abnormal, the investigator will evaluate the potential 
subject with a complete history and physical examination, looking especially for 
diseases that could result in an abnormality in the laboratory value in question.  If 
such diseases can be excluded, and if the investigator feels that the abnormal 
laboratory value is not clinically relevant, then the subject may enter the study.  The 
Sponsor may be consulted in the decision of whether or not to enroll the subject in the 
study, if uncertainty exists.
E.
If there is any clinical uncertainty regarding the significance of an abnormal value, 
the subject will be excluded from the study.
F.
For the purposes of this protocol, if the following tests are within 10% of the upper or 
lower limits of normal value they will not be considered clinically abnormal and 
subjects can be enrolled in the study: bilirubin, BUN, creatinine, glucose, alkaline 
phosphatase, total white blood cell count, and platelets.  Subjects outside this range 
must be evaluated according to protocol.  
G.
The subject cannot proceed to Visit 2 until all abnormalities have been resolved 
according to this protocol.
 
 
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Allergy Rescue Medications for Rhinoconjunctivitis Symptoms
12.6
Use of any rescue medications for rhinitis/conjunctivitis symptoms must be approved by the 
investigator or designee.  The use of rescue medication is subject to the following step-wise 
requirements:
Step 1
Loratadine syrup, 1 mg/mL or Loratadine oral tablet, 5 mg (for 5 years old) or 10 mg (for 6 
to 17 years old), will be dispensed to the subject at Visit 6 but must not be used before the 
investigator has confirmed that in his/her opinion the RS has started and the subject has an 
adequate level of symptoms as evaluated in accordance with the following procedure:
The subject must be instructed to contact the investigator in case of rhinitis/conjunctivitis 
symptoms and the need for rescue medication.  The investigator will then ask the subject to 
score his/her nose and eye symptoms (i.e., runny nose, blocked nose, sneezing, itchy nose, 
gritty feeling/itchy/red eyes, and watery eyes) using a scale from 0 to 3 (0 = no symptoms, 1 
= mild symptoms, 2 = moderate symptoms and 3 = severe symptoms).
Once the investigator has confirmed a total symptom score of ≥4 and the RS has started, the 
subject may be authorized to start using Step 1 medication.  The total symptom score and the 
date of this authorization must be recorded in the source documents as required by the 
sponsor.
Once symptoms are improved, the subject should reduce or stop use of rescue medication.
Step 1b
Olopatadine hydrochloride 0.1% ophthalmic solution will be dispensed to the subject at Visit 
6 but should only be used in addition to Step 1 Loratadine syrup or oral tablet if eye 
symptoms persist in spite of Step 1 treatment.
Once symptoms are improved, the subject should reduce or stop use of this rescue 
medication.
Step 2
Mometasone furoate monohydrate nasal spray 50 mcg will be dispensed to the subject at 
Visit 6 but should only be used if symptoms are not satisfactorily controlled by Step 1 
medication as evidenced by a persisting minimum total symptom score of ≥4.  The subject 
should again call the investigator for authorization to use mometasone furoate monohydrate 
nasal spray to be taken in addition to Step 1 medication.
Once symptoms are improved, the subject should reduce or stop use of this rescue 
medication.
 
 
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Instructions for Opening the Ragweed Sublingual Tablet (Oral Lyophilisate) 
12.7
from the Pack 
1. Tear off the blank perforated strip at the end of the oral tablet pack, opposite the 
labeled end.
2. Tear a square off the oral tablet pack along the perforated lines.
3. Do not force the oral tablet through the foil.  It may damage the oral tablet as it 
easily breaks.  Instead, fold back the marked corner of the foil and then pull it off.
 
 
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4. Make sure that the tablet is free of all lidding foil before removal.  Remove the oral 
tablet carefully from the foil and take the oral tablet immediately.
5. Place the oral tablet under the tongue.  Allow it to remain there for a few seconds 
until it has dissolved.  Do not swallow during the first minute.  Do not eat or drink 
for at least 5 minutes.
 
 
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This plan can be modified within and outside the US to meet local standards for the use (or 
type) of epinephrine dispensed, and for calls to 911 or alternative local emergency services.
 
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Method for Performing Post-Bronchodilator Reversibility Testing
12.9
In assessing short-acting β-agonist (SABA) response in the clinic, 2 to 8 puffs of SABA 
(albuterol/salbutamol) will be administered via a metered-dose inhaler (MDI).  Investigator 
and/or subject/parent/guardian can choose to end procedure after Step 9 for any reason.
Procedure
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 puff and repeat the same sequence 3 additional times.
9. After either 2 or 4 inhalations of SABA (per investigator discretion), wait 
approximately 10 minutes and then perform spirometry.  Compare results with 
baseline spirometry.

If there is a < 5% change or ≥12% change in absolute FEV1, then end procedure
and record results in appropriate eCRF.

If there is a ≥ 5% to < 12% change in FEV1, continue to Step 10. 
10. Repeat steps 2-7 to administer an additional 2 inhalations of SABA with 
approximately 30 seconds between inhalations.
11. Wait approximately 10 minutes, perform spirometry, and compare with baseline 
FEV1.

If there is a < 10% change or ≥12% change in absolute FEV1, then end procedure
and record results in appropriate eCRF.

If there is a ≥ 10% to < 12% change in FEV1, continue to Step 12.
12. Repeat steps 2-7 to administer an additional 2 inhalations of SABA with 
approximately 30 seconds between inhalations.
13. Wait approximately 10 minutes, perform spirometry, compare with baseline FEV 1, 
and record results in appropriate eCRF.
 
 
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List of Abbreviations
12.13
Abbreviation
Definition
aDSS
Asthma Daytime Symptom Score
AE(s) 
Adverse event(s)
AIT
Allergy immunotherapy
ALT
Alanine aminotransferase
AMA
American Medical Association
ANOVA
Analysis of variance
AR
Allergic rhinitis
ARC
Allergic rhinoconjunctivitis
ASaT
All subjects as treated
AST
Aspartate aminotransferase
BAU
Bioequivalent allergy unit
β-hCG
Beta-human chorionic gonadotropin
BUN
Blood urea nitrogen
CFR
Code of Federal Regulations
CI
Confidence interval
cLDA
Constrained longitudinal data analysis
CSR
Clinical study report
DMC
Data Monitoring Committee
DMS
Daytime Medication Score
DNA
Deoxyribonucleic acid
DPI
Dry-powder inhaler
DSS
Daytime Symptom Score
ECI
Event of clinical interest
eCRF
Electronic case report form
e-diary
Electronic diary
eDMC
External Data Monitoring Committee
EMA/EMEA
European Medicines Agency
EOC
Executive Oversight Committee
ERC
Ethical Review Committee
EU
European Union
FAS
Full analysis set
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
 
 
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Abbreviation
Definition
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
HFA
Hydrofluoroalkane
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICS
Inhaled corticosteroid
IEC
Independent Ethics Committee
IgE
Immunoglobulin E
IgG4
Immunoglobulin G4
IMP
Investigational medicinal product
IRB
Institutional Review Board
IUD
Intrauterine device
IVRS
Interactive voice response system
IWRS
Interactive web response system
LABA
Long-acting beta2-agonist
LOCF
last observation carried forward
MDI
Metered-dose inhaler
NAEPP
National Asthma Education and Prevention Program
OTC
Over-the-counter
PFT
Pulmonary function test
PGt
Pharmacogenetic
PIN
Personal identification number
PK/PD
Pharmacokinetic/Pharmacodynamic
PP
Per protocol
Protocol CI
Protocol coordinating investigator
RNA
Ribonucleic acid
RS
Ragweed season
SABA
Short-acting beta2-agonist
SAC
Scientific Advisory Committee
SAE(s)
Serious adverse event(s)
SAP
Statistical Analysis Plan
SCIT
Subcutaneous immunotherapy
 
 
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Abbreviation
Definition
SLIT
Sublingual immunotherapy
SM
Study medication
SOC
System organ class
SOP
Standard operating procedure
SPT
Skin prick test
SQ-U
Standardized quality unit
TCS
Total Combined Score
US
United States
WAO
World Allergy Organization
WBC
White blood cell
 
 
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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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SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
NCT02478398 
Document Date: 
30-Nov-2018
A Phase III, Randomized, Placebo-Controlled Clinical Trial to Study 
the Efficacy and Safety of MK-3641, a Ragweed (Ambrosia 
artemisiifolia) Sublingual Immunotherapy Tablet, in Children With 
a History of Ragweed-Induced Rhinoconjunctivitis With or Without 
Asthma


MK-3641
PAGE 1
PROTOCOL NO. 008-02
SUPPLEMENTAL SAP
30NOV2018 – AMENDMENT #2
Supplemental Statistical Analysis Plan (sSAP)
1
INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to
the information presented in the protocol SAP which provides the principal features of
confirmatory analyses for this trial, this supplemental SAP provides additional statistical
analysis details/data derivations and documents modifications or additions to the analysis
plan that are not “principal” in nature and result from information that was not available at the
time of protocol finalization.
2
SUMMARY OF CHANGES
Date
Page
Changes
Oct-21-2015
9
Added the sensitivity analysis for rescue medications not supplied
by the Sponsor
Dec-1-2016
10
Added the sensitivity analysis for rescue medications not supplied
by the Sponsor, for the two exploratory endpoints related to
asthma medication.
Nov-30-2018
2
Added further definition of pollen regions.
Nov-30-2018
9
Added sensitivity analysis to include non-study provided allergy 
rescue medications for the DMS.
Nov-30-2018
10
Deleted sensitivity analysis for the nocturnal awakenings 
exploratory endpoints as related data was not collected.  These 
analysis   were originally added inadvertently.
Nov-30-2018
15
Added the adverse events identified by the WAO as local side 
effects of SLIT, the WAO method of grading AE intensity, and 
definition of the modified WAO intensity grading.
Nov-30-2018
18
Added the data analysis conventions for cross-treated subjects.
3
ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
STATISTICAL ANALYSIS PLAN SUMMARY
This section contains a brief summary of the statistical analyses for this trial. Full detail is in
the Statistical Analysis Plan (SAP) Section 3.2.
3.1.1
Efficacy Analyses
Primary Efficacy Analysis
The primary analysis will be conducted on the Full Analysis Set (FAS) population. The
FAS population includes all subjects who receive at least one dose of study treatment.
Subjects will be analyzed according to the treatment group to which theyare randomized.
 
 
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30NOV2018 – AMENDMENT #2
The primary efficacy endpoint for the current trial is the average TCS during the peak
ragweed season. It will be analyzed using the analysis of variance (ANOVA) model,
which includes fixed effects of treatment, baseline asthma status (yes, no), age group (5 to
11 years, 12 to 17 years), pollen season, and pollen region nested within pollen season.
Pollen region will be defined based on pollen station and may include several sites
within an acceptable distance between the pollen counters and corresponding sites. To avoid 
failure in model convergence, observed in model testing on the blinded data, pollen region 
will be defined by participating countries, except for the United States, which will be split 
into 2 pollen regions.
Two-sided 95% confidence interval (CI) of the treatment difference in adjusted means will
be presented. Also, the treatment difference in adjusted means relative to the adjusted mean
of the placebo group will be presented as a percentage with corresponding 2-sided 95%
CI derived using the bootstrap method. No missing data will be imputed.
The normality assumption of the ANOVA model will be checked using the Shapiro-Wilk
test and inspection of the Q-Q plot. If a severe violation is observed, the primary analysis
will be based on Wilcoxon Rank Sum test; the p-value will be reported together with the
associated Hodges-Lehmann estimate of the treatment difference and its 2-sided 95% CI.
Also, the difference in the treatment group medians relative to the median of the placebo
group will be presented as a percentage with the corresponding 2-sided 95% CI derived
using the bootstrap method.
A Per Protocol (PP) analysis will be conducted for the primary efficacy endpoint, where
the same ANOVA model and missing data approach will be used. See Section 3.2.5.1 for
further sensitivityanalyses of the primary efficacy endpoint.
Key Secondary Efficacy Analyses
The key secondary efficacy endpoints for the current trial include:

Average TCS during the entire RS;

Average rhinoconjunctivitis DSS during the peak RS;

Average rhinoconjunctivitis DMS during the peak RS.
These endpoints will be analyzed based on the FAS population using the same ANOVA
model as the primary efficacy endpoint. A fixed sequence procedure will be applied to
control multiplicity, where the primary efficacy endpoint will be tested first, and then the key
secondary efficacy endpoints will be tested in the order stated above.
In a situation when there are more than 30% of the daily rhinoconjunctivitis DMS equal to
zero, the zero-inflated lognormal model will be used as the primary analysis method for
rhinoconjunctivitis DMS as appropriate; this model takes the average rhinoconjunctivitis
DMS during the peak RS as response and adjusts for the same terms as in the ANOVA
model.
 
 
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SUPPLEMENTAL SAP
30NOV2018 – AMENDMENT #2
[Table 1] summarizes the key analysis strategy for the primary and key secondary
efficacy endpoints.
Table 1 Analysis Strategy for Key Efficacy Endpoints
Endpoint
Statistical Methoda
Analysis
Population
Missing Data
Approach
Primary Efficacy Endpoint
Average TCS during the
peak RS
ANOVA
FAS
Observed data only
LOCF
Multiple Imputationb
PP
Observed data only
Wilcoxon Rank Sum Test;
FAS
Observed data only
Hodges-Lehmann estimate of
treatment differencec
Longitudinal Data Analysis
FAS
Model based
Key Secondary Efficacy Endpoints
Average TCS during the
entire RS
ANOVA
FAS
Observed data only
Averagerhinoconjunctivitis
DSS during the peak RS
ANOVA
FAS
Averagerhinoconjunctivitis
DMS during the peak RS
ANOVA
FAS
Zero-inflated log-normalc
TCS = Total Combined Score; DSS = Daily Symptom Score; DMS = Daily Medication Score; RS = Ragweed Season.
ANOVA = Analysis of Variance; LOCF = Last non-missing observation carried forward.
FAS = Full Analysis set; PP = Per Protocol.
a   Details of the statistical models are described in Section 3.2.5.
b  Missing data from both treatment groups will be imputed using the sample distribution of TCS observed from 
the placebo group.
c   This method will be applied if excessive zeros are observed in the data.
3.1.2
Safety Analyses
An All-Subjects-as-Treated (ASaT) population will be used for safety analyses. The
ASaT population includes all subjects who receive at least one dose of study treatment.
Subjects will be included in the treatment group corresponding to the study treatment they
actually receive during the trial.
The analysis of safety endpoints will follow a tiered approach. For this study, Tier 1
safety endpoints include:

Proportion of subjects reporting pre-specified local application site reactions
(including adverse events related to lip swelling/edema, mouth swelling/edema,
palatal swelling/edema, swollen tongue/edema, oropharyngeal swelling/edema,
pharyngeal edema/throat tightness, oral pruritus, throat irritation, tongue pruritus, and
ear pruritus);
 
 
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SUPPLEMENTAL SAP
30NOV2018 – AMENDMENT #2

Proportion of subjects reporting anaphylaxis and/or systemic allergic reactions;

Proportion of subjects treated with epinephrine.
Tier 1 safety endpoints will be subject to inferential testing for statistical significance
with p-values and 95% confidence intervals provided for between-group comparisons.
They will be analyzed using the stratified Miettinen and Nurminen method [1985] with
baseline asthma status and age group as stratification factors.
3.1.3
Power and Sample Size
A total of approximately 1000 subjects will be randomized in a 1:1 ratio to either MK-
3641 or placebo. Assuming a 15% dropout rate, this gives approximately 425 evaluable
subjects per treatment group.
With 425 subjects per arm, the study will have:

approximately 90% power (2-sided, α = 0.05) to have the upper bound of the 95% CI
for relative difference below -10%, and

more than 90% power (2-sided, α = 0.05) to have an estimated relative
difference below -15%.
See Section 3.2.7 for further details of sample size calculation.
3.1.4
Interim Analyses
No efficacy interim analysis is planned for this trial. Safety data will be reviewed by an
external Data Monitoring Committee (eDMC) (see Section 7.3.3 of the protocol).
3.2
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after
the study has begun, but prior to any unblinding, changes are made to primary and/or key
secondary hypotheses, or the statistical methods related to those hypotheses, then the
protocol will be amended (consistent with ICH Guideline E-9). Changes to exploratory or
other non- confirmatory analyses made after the protocol has been finalized, but prior to final
database lock, will be documented in a supplemental SAP (sSAP) and referenced in the
Clinical Study Report (CSR) for the study. Post hoc exploratory analyses will be clearly
identified in the CSR.
3.2.1
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of
the designee of the sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures.
The official, final database will not be unblinded until medical/scientific review has been
 
 
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SUPPLEMENTAL SAP
30NOV2018 – AMENDMENT #2
performed, protocol violators have been identified, and data have been declared final and
complete.
The randomized allocation schedule will be generated by the sponsor and implemented by
the vendor of the study interactive voice response system (IVRS).
Safety will be monitored by the external Data Monitoring Committee (eDMC) on an
ongoing basis and the eDMC will make recommendations to the sponsor as appropriate.
3.2.2
Hypotheses
Objectives and hypotheses of the study are stated in Section 3 of the protocol.
3.2.3
Analyses Endpoints
Efficacy and safety endpoints that will be evaluated for within- and between-treatment
differences are listed below, followed by the descriptions of the derivations of selected
endpoints.
3.2.3.1
Efficacy Endpoints

Average TCS during the peak RS.
Key Secondary Efficacy Endpoints

Average TCS during the entire RS;

Average rhinoconjunctivitis DSS during the peak RS;

Average rhinoconjunctivitis DMS during the peak RS.
Tertiary Efficacy/Immunologic Endpoints

Average rhinoconjunctivitis DSS during the entire RS

Change from baseline in IgE level against Ambrosia artemisiifolia at Visit 6 and at
Visit 8;

Change from baseline in IgG4 level against Ambrosia artemisiifolia at Visit 6 and at
Visit 8.
Exploratory Efficacy Endpoints

Average Asthma DSS during the peak RS, the entire RS, and the whole treatment
period;

Average daily number of puffs of as-needed SABA used during the peak RS and
the entire RS;
 
 
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30NOV2018 – AMENDMENT #2

Average weekly number of nights with nocturnal awakening due to asthma
symptoms requiring SABA use during the peak RS and the entire RS.
3.2.3.2
Safety Endpoints
Tier 1 Safety Endpoints

Proportion of subjects reporting pre-specified local application site reactions
(including adverse events related to lip swelling/edema, mouth swelling/edema,
palatal swelling/edema, swollen tongue/edema, oropharyngeal swelling/edema,
pharyngeal edema/throat tightness, oral pruritus, throat irritation, tongue pruritus, and
ear pruritus);

Proportion of subjects reporting anaphylaxis and/or systemic allergic reactions;

Proportion of subjects treated with epinephrine.
Tier 2 Safety Endpoints

Proportion of subjects with any AE;

Proportion of subjects with any serious AE;

Proportion of subjects with any drug-related AE;

Proportion of subjects with any serious and drug-related AE;

Proportion of subjects who discontinue due to an AE;

Proportion of subjects with specific AEs or SOCs (incidence ≥1% subjects in one
or more of the treatment groups).
Tier 3 Safety Endpoints

Change from baseline in laboratory test parameters at each post-baseline visit;

Change from baseline in vital sign parameters at each post-baseline visit;

Summaries by system organ class (SOC) for general AEs, serious AEs, drug-related
AEs, and AEs resulting in discontinuation;

Average duration of AEs in minutes on Day 1;

Average duration of AEs in days over Day 2 to Day 14;

Average duration of AEs in days over Day 15 to Day 28.
 
 
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3.2.3.3
Derivations of Efficacy/Immunologic Endpoints
Ragweed Season
Entire Ragweed Season: the start of the entire ragweed season is the first day of 3
consecutive recorded days with a pollen count of ≥10 grains/m3; the end of the entire
ragweed season is the last day of 3 consecutive recorded days with a pollen count of ≥10
grains/m3. This is specific for each study site.
Peak ragweed season: the 15 consecutive recorded days within the entire ragweed season
with the highest 15-day moving average pollen count. This is specific for each study site.
TCS, Rhinoconjunctivitis DSS, Rhinoconjunctivitis DMS, Asthma DSS
These are defined in Section 4.2.3.1 of the protocol.
3.2.3.4
Derivations of Safety Endpoints
For laboratory tests and vital sign parameters, the baseline value is defined as the last
measurement taken prior to randomization. Change from baseline in laboratory and vital
signs parameters is calculated by on-treatment value minus the baseline value.
3.2.4
Analysis Populations
3.2.4.1
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis
of efficacy data in this study. The FAS population consists of all randomized subjects who
receive at least one dose of study treatment. Subjects will be analyzed according to the
treatment group to which they are randomized.
A supportive analysis using the Per-Protocol (PP) population will be performed for the
primary efficacy endpoint. The PP population excludes subjects due to important
deviations from the protocol that may substantially affect the results of the primary
efficacy endpoints. The major protocol violations that would lead to exclusion of a subject or
a data point are described below:

Subjects with asthma requiring prescribed high daily doses of inhaled corticosteroids
(as defined in the protocol);

Subjects with chronic sinusitis during the previous 2 years;

Subjects treated with immunotherapy within 5 years prior to screening;

Subjects unable to meet medication washout requirements;

Subjects randomized in the study more than once;
 
 
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
Subjects who participated in the same study at another site;

Subjects with pre-seasonal duration of treatment exposure < 56 Days;

Subjects with a negative skin prick test response to ragweed;

Subjects with specific IgE to ragweed < 0.7 kU/L;

Subjects with overall treatment compliance < 75% between Visit 2 and Visit 8;

Subjects who took prohibited medications as defined in the protocol, with the
exception of antihistamines. Subjects who have taken antihistamines (other than
sponsor provided rescue medications) will be considered protocol violators if they
have taken the medication for 2 or more consecutive days between Visit 6 and Visit
8;

Subjects who had their blinded treatment randomization code broken.
Analyses related to SABA use and nocturnal awakening will be based on subjects with
asthma in the FAS population.
3.2.4.2
Safety Analysis Populations
The All-Subjects-as-Treated (ASaT) population will be used for the analysis of safety data in
this study. The ASaT population consists of all randomized subjects who received at least
one dose of study treatment. Subjects will be grouped by the study treatment actually
received.
3.2.5
Statistical Methods
Statistical testing and inference for efficacy and safety analyses are described in Sections
3.2.5.1 and 3.2.5.2. Controlling of family-wise Type I error rate is described in Section
3.2.6, Multiplicity. Nominal p-values will be computed for tertiary and exploratory efficacy
analyses as a measure of strength of association between the endpoint and the treatment
effect rather than formal tests of hypotheses. Unless otherwise stated, all statistical tests
will be conducted at α=0.05 (2-sided) level.
3.2.5.1
Statistical Methods for Efficacy/Immunologic Analyses
Primary Efficacy Analysis
The primary efficacy endpoint for the current trial is the average TCS during the peak
ragweed season. It will be analyzed using the ANOVA model, which includes fixed effects
of treatment, baseline asthma status (yes, no), age group (5 to 11 years, 12 to 17 years),
pollen season, and pollen region nested within pollen season. Pollen region will be defined
based on pollen station and may include several sites within an acceptable distance
between the pollen counters and corresponding sites.
 
 
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Two-sided 95% CI of the treatment difference in adjusted means will be presented. Also,
the treatment difference in adjusted means relative to the adjusted mean of the placebo group
will be presented as a percentage with corresponding 2-sided 95% CI derived using the
bootstrap method. No missing data will be imputed.
The normality assumption of the ANOVA model will be checked using the Shapiro-Wilk
test and inspection of the Q-Q plot. If a severe violation is observed, the primary analysis
will be based on Wilcoxon Rank Sum test; the p-value will be reported together with the
associated Hodges-Lehmann estimate of the treatment difference and its 2-sided 95% CI.
Also, the difference in the treatment group medians relative to the median of the placebo
group will be presented as a percentage with the corresponding 2-sided 95% CI derived
using the bootstrap method.
Sensitivity Analysis
The PP analysis will be conducted for the primary efficacy endpoint, where the same
ANOVA model and missing data approach will be used. In addition, the following sensitivity
analyses will be performed for the primary efficacy endpoint.

The same ANOVA model based on the FAS population will be used. Missing data
will be imputed by the LOCF approach. For each subject, only the observations
within the pollen season are eligible to be carried forward.

The same ANOVA model based on the FAS population will be used. Missing data
will be handled by the multiple imputation method. Missing data from both
treatment groups will be imputed using the sample distribution of TCS observed
from the placebo group, which is considered to be a conservative approach for
imputations.

Longitudinal Data Analysis model based on the FAS population will be used. Daily
TCS during the peak season will be the response variable and covariates will
include treatment, time, the interaction of treatment by time, baseline asthma status,
age group, pollen season, and pollen region nested within pollen season. The
Toeplitz structure will be used to model the covariance of the repeated TCS
measurements over time within subjects. Additional covariance structures, such as
unstructured covariance, may be considered if convergence issues are encountered
with the analysis model.
Furthermore, if there are more than 2% of subjects taking prednisone during any one
ragweed season in the course of the study, a sensitivity analysis will be conducted for the
primary efficacy endpoint, where the usage of prednisone is included in the definition of
the rhinoconjunctivitis DMS. The medication scores for prednisone usage are defined in
[Table 2].
 
 
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Table 2 Medication Score for Prednisone Usage
Rescue Medication
Subject Dosing Instructions
Score/Dose Unit
Maximum Daily Score
Prednisone tablet
5 mg
Day 1: 1 mg/kg/day, Max 50 mg/day
1.6 (per tablet)
16
Day 2+: 0.5 mg/kg/day, Max 25 mg/day
1.6 x 2 (per tablet)
16
In addition, in order to minimize missing data, subjects will be allowed to complete the daily
e-diary up to 9 am the following morning (in case the subject cannot complete it at their
regular time that day). A sensitivity analysis will be conducted for the FAS population,
where only the data entered on the same day (instead of next morning) are included. The
same ANOVA model and missing data approach will be used.
Moreover, the primary analysis will only consider the rescue medications provided by
the study (i.e., reported in the e-diary). Some subjects may take rescue medications that are
not provided by the study. A sensitivity analysis will be conducted for the DMS by
including these rescue medications if a medication score was pre-specified in the protocol.
Key Secondary Efficacy Analyses
The key secondary efficacy endpoints for the current trial include:

Average TCS during the entire RS;

Average rhinoconjunctivitis DSS during the peak RS;

Average rhinoconjunctivitis DMS during the peak RS.
These endpoints will be analyzed based on the FAS population using the same ANOVA
model as the primary efficacy endpoint.
Based on the rescue medication usage from previous AIT trials, many subjects used little
rescue medication during the trial, which resulted in large amounts of rhinoconjunctivitis
DMS records equal to zero. Data with excessive zeroes may not conform to the normality
assumption for the ANOVA model and may also prevent the proper application of non-
parametric method. In a situation when there are more than 30% of the daily
rhinoconjunctivitis DMS equal to zero, the zero-inflated lognormal model [16] will be
used as the primary analysis method for rhinoconjunctivitis DMS as appropriate; this
model takes the average rhinoconjunctivitis DMS during the peak RS as response and
adjusts for the same terms as in the ANOVA model.
 
 
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Tertiary Efficacy/Immunologic Analyses
The tertiary efficacy/immunologic endpoints for the current trial include:

Average rhinoconjunctivitis DSS during the entire RS;

Change from baseline in IgE level against Ambrosia artemisiifolia at Visit 6;

Change from baseline in IgE level against Ambrosia artemisiifolia at Visit 8;

Change from baseline in IgG4 level against Ambrosia artemisiifolia at Visit 6;

Change from baseline in IgG4 level against Ambrosia artemisiifolia at Visit 8.
Average rhinoconjunctivitis DSS during the entire RS will be analyzed based on the
FAS population using the same ANOVA model as the primaryefficacy endpoint.
IgE and IgG4 related endpoints will be analyzed separately using the constrained LDA
(cLDA) model. The cLDA model assumes a common mean across treatment groups at
baseline and different means for different treatments at each post-baseline time point. In
this model, the response vector consists of the baseline value and the values observed at
each post-baseline time point. The model will adjust for time, the interaction of
treatment by time, baseline asthma status, age group, pollen season, and pollen region
nested within pollen season. Time is treated as a categorical variable so that no restriction
is imposed on the trajectory of the means over time. A Toeplitz covariance matrix will
be used to model the correlation among repeated measurements. Further details of the
model specification, assumptions, and SAS implementation codes are provided in the
Appendix.
Exploratory Efficacy Analyses
The exploratory efficacy endpoints for the current trial include:

Average Asthma DSS during the peak RS;

Average Asthma DSS during the entire RS;

Average Asthma DSS during the whole treatment period;

Average daily number of puffs of as-needed SABA used during the peak RS;

Average daily number of puffs of as-needed SABA used during the entire RS;

Average weekly number of nights with nocturnal awakening due to asthma
symptoms requiring SABA use during the peak RS;

Average weekly number of nights with nocturnal awakening due to asthma
symptoms requiring SABA use during the entire RS.
 
 
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These endpoints will be analyzed using the same ANOVA model as the primary
efficacy endpoint. Asthma DSS related endpoints will be analyzed based on the FAS
population, while SABA use and nocturnal awakening related endpoints will be analyzed
based on subjects with asthma in the FAS population.
In addition, components of the rhinoconjunctivitis DSS (ocular symptoms and nasal
symptoms) will be summarized for the peak RS and the entire RS.
Moreover, the exploratory efficacy analyses will only consider the rescue medications
provided by the study (i.e., reported in the e-diary). Some subjects may take rescue
medications that are not provided by the study. A sensitivity analysis will be conducted
for the following endpoints by including these rescue medications:

Average daily number of puffs of as-needed SABA used during the peak RS;

Average daily number of puffs of as-needed SABA used during the entire RS.
[Table 3] summarizes the key analysis strategy for the efficacy/immunologic endpoints.
 
 
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Table 3 Efficacy/Immunologic Endpoints
Endpoint
Statistical Methoda
Analysis
Population
Missing
Data
Primary Efficacy Endpoint
Average TCS during the peak RS
ANOVA
FAS
Observed data only
LOCF
Multiple Imputationb
PP
Observed data only
Wilcoxon Rank Sum Test;
Hodges-Lehmann estimate
of treatment differencec
FAS
Observed data only
Longitudinal Data Analysis
FAS
Model based
Key Secondary Efficacy Endpoints
Average TCS during the entire RS
ANOVA
FAS
Observed data only
Average rhinoconjunctivitis DSS 
during the peak RS
ANOVA
FAS
Average rhinoconjunctivitis DMS 
during the peak RS
ANOVA
FAS
Zero-inflated log-normalc
Tertiary Efficacy/Immunologic Analyses
Average rhinoconjunctivitis DSS during
the entire RS
ANOVA
FAS
Observed data only
Change from baseline in IgE level against
Ambrosia artemisiifolia at Visit 6 and Visit 
8
constrained 
Longitudinal 
D
A
l
i
FAS
Model based
Change from baseline in IgG4 level against
Ambrosia artemisiifolia at Visit 6 and Visit 
8
constrained
Longitudinal 
D
A
l
i
FAS
Model based
Exploratory Efficacy Analyses
Average Asthma DSS during the peak 
RS, the entire RS, and the whole treatment
ANOVA
FAS
Observed data only
Average daily number of puffs of as-
needed SABA used during the peak RS
and the entire RS
ANOVA
FAS
(asthma only)
Observed data only
Average weekly number of nights with 
nocturnal awakening due to asthma
symptoms requiring SABA use during the
peak RS and the entire RS
ANOVA
FAS
(asthma only)
Observed data only
ANOVA = Analysis of Variance; DSS = Daily Symptom Score; DMS = Daily Medication Score; FAS = Full Analysis set; IgE = 
immunoglobulin E; IgG4 = immunoglobulin G4; LOCF = Last non-missing observation carried forward; PP = Per Protocol; RS =
Ragweed Season; SABA = short- acting beta2-agonist; TCS = Total Combined Score.
a  Details of the statistical models are described in Section 3.2.5.
b  Missing data from both treatment groups will be imputed using the sample distribution of TCS observed from the placebo group.
c This method will be applied if excessive zeros are observed in the data.
Handling of Missing Data
The missing data approaches are specified for the primary efficacy endpoint sensitivity
analyses (including multiple imputation, LOCF, and model based) and immunologic
endpoints (model based). All other analyses will be conducted based on the observed
data only. Proportion of subjects with missing data will be summarized for each
efficacy/immunologic endpoint.
 
 
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3.2.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters
including adverse experiences (AEs), laboratorytests, and vital sign measurements.
The analysis of safety results will follow a tiered approach [Table 4]. The tiers differ
with respect to the analyses that will be performed. Tier 1 safety endpoints will be
subject to inferential testing for statistical significance with p-values and 95% CIs
provided for between- group comparisons. Tier 2 safety endpoints will be evaluated via
point estimates and 95% CIs for between-group comparisons. Tier 3 safety endpoints will
be evaluated via point estimates only.
For this trial, Tier 1 safety endpoints include:

Proportion of subjects reporting pre-specified local application site reactions
(including adverse events related to lip swelling/edema, mouth swelling/edema,
palatal swelling/edema, swollen tongue/edema, oropharyngeal swelling/edema,
pharyngeal edema/throat tightness, oral pruritus, throat irritation, tongue pruritus, and
ear pruritus);

Proportion of subjects reporting anaphylaxis and/or systemic allergic reactions;

Proportion of subjects treated with epinephrine.
For the analysis of “Proportion of subjects treated with epinephrine”, the denominator
will include all subjects in the ASaT population, regardless of whether self-injectable
epinephrine was provided or not. Meanwhile, a sensitivity analysis will be conducted where
the denominator will include subjects in the ASaT population who were provided with self-
injectable epinephrine, and the numerator will be subjects from the denominator subjects
who were treated with epinephrine.
Tier 2 safety endpoints for this trial include:

Proportion of subjects with any AE;

Proportion of subjects with any serious AE;

Proportion of subjects with any drug-related AE;

Proportion of subjects with any serious and drug-related AE;

Proportion of subjects who discontinue due to an AE;

Proportion of subjects with specific AEs or SOCs (incidence ≥1% subjects in one
or more of the treatment groups).
The Tier 1 and Tier 2 safety endpoints will be analyzed using the stratified Miettinen
and Nurminen method [1985] with baseline asthma status and age group as stratification
 
 
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factors.
Tier 3 safety endpoints for this trial include:

Change from baseline in laboratory test parameters at each post-baseline visit;

Change from baseline in vital sign parameters at each post-baseline visit;

Change from baseline in pulmonary function test parameters at each post-baseline
visit;

Summaries by SOC for general AEs, serious AEs, drug-related AEs, serious and
drug- related AEs, and AEs resulting in discontinuation;

Average duration of AEs in minutes on Day 1;

Average duration of AEs in days over Day 2 to Day 14;

Average duration of AEs in days over Day 15 to Day 28.
Point estimates will be provided for the Tier 3 safety endpoints. In addition, AE
summaries (general AEs, serious AEs, drug-related AEs, serious and drug-related AEs, and
AEs resulting in discontinuation) by asthma status will also be provided. For pulmonary
function test parameters, a cLDA model-based analysis will also be conducted (see Section
3.2.5.1 for more details about the cLDA model).
[Table 4] summarizes the safety tier and level of analysis for the safety endpoints.
 
 
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Table 4 Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpointa
p-Value
95% CI for
Treatment
Comparison
Descriptive
Statistics
Tier 1
Proportion of subjects reporting pre-specified local
application site reactions (including adverse events
related to lip swelling/edema, mouth swelling/edema,
palatal swelling/edema, swollen tongue/edema,
oropharyngeal swelling/edema, pharyngeal
edema/throat tightness, oral pruritus, throat irritation,
tongue pruritus, and ear pruritus);
Proportion of subjects reporting anaphylaxis
and/or systemic allergic reactions;
Proportion of subjects treated with epinephrine.
X
X
X
Tier 2
Any AE;
Any Serious AE;
Any Drug-Related AE;
Any Serious and Drug-Related
AE; Discontinuation due to
AE;
Specific AEs or SOCsb (incidence ≥1% of subjects in
X
X
Tier 3
Change from baseline in laboratory test
parameters at each post-baseline visit;
Change from baseline in vital sign parameters at
each post-baseline visit;
Change from baseline in pulmonary function
test parameters at each post-baseline visit;
Summaries by SOC for general AEs, serious AEs,
drug- related AEs, serious and drug-related AEs,
and AEs resulting in discontinuation;
AE summaries by asthma status;
Average duration of AEs in minutes on Day 1;
Average duration of AEs in days over Day 2 to Day
14; Average duration of AEs in days over Day 15 to
X
AE = adverse event; CI = confidence interval; SOC = System Organ Class; X = results will be provided.
a
Adverse Experience references refer to both Clinical and Laboratory AEs.
b
Includes only those endpoints not pre-specified as Tier 1 or Tier 2 endpoints.
In addition, the SLIT Report Card (Section 4.2.3.2 of the protocol) will be completed by
the subject/parent/guardian, daily for the first ~28 days of dosing, to collect information on
local side effects of SLIT that occur within the first 60 minutes after each daily study
drug intake. Adverse events identified by the WAO as local side effects of SLIT include the 
following: dysgeusia, oral pruritus, swelling of lips, mucosal edema, ear pruritus, swollen 
tongue, glossodynia, mouth ulceration, tongue ulceration, throat irritation, pharyngeal edema, 
nausea, abdominal pain upper/abdominal pain, vomiting, and diarrhea.
 
 
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Identified local AEs will be graded via a programmatic approach and clinical review as
mild, moderate, or severe. An exploratory review of the intensity grading via 2 different 
methods, the programmatic approach using the WAO grading system and grading as
determined by the investigator’s review of the AEs with their subjects/parents/guardians,
will be conducted. 
The WAO grading system for SLIT local adverse events defines intensity as follows:
Mild (Grade 1)
Not troublesome and no symptomatic treatment required and 
no discontinuation of SLIT because of local side effects
Moderate (Grade 2)
Troublesome or requires symptomatic treatment and no 
discontinuation of SLIT because of local side effects
Severe (Grade 3)
Grade 2 and SLIT discontinued because of local side effects
The WAO local AE intensity grading was modified in that subjects collect the information on 
the presence of the AEs on the SLIT Report Card but do not indicate if they consider the AE 
“troublesome” or “not troublesome.” Subjects also indicate if a medication is utilized to treat 
the AE and information regarding discontinuation due to the AE is also collected. The WAO 
intensity grading for local AEs will be determined programmatically. Essentially, mild 
intensity (Grade 1) will be assigned to events that do not result in symptomatic use of a 
medication. If an AE results in use of a symptomatic medication to treat the AE, it is 
assigned an intensity of moderate (Grade 2) and considered troublesome; if an AE results in 
the use of a symptomatic medication and in discontinuation from treatment, it is assigned an 
intensity of severe (Grade 3).
3.2.6
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
The number and percentage of subjects screened, randomized, the primary reasons for
screening failure, and the primary reason for discontinuation will be displayed.
Demographic variables (including age, gender, race, weight, height, and body mass
index), baseline characteristics (including baseline asthma status, inhaled corticosteroid use,
duration of allergic rhinitis, sensitization type, ragweed specific IgE, wheal size from skin
prick test, and number of puffs of bronchodilator used for FEV1 reversibility), primary and
secondary diagnoses, and prior and concomitant therapies will be summarized by
treatment either by descriptive statistics or categorical tables. The comparability of the
treatment groups for each relevant characteristic will be assessed by the summary
tables. No statistical hypothesis tests will be performed on these characteristics.
Skin Prick Test (SPT) Analysis
Descriptive statistics (mean, standard deviation, etc.) of the wheal size determined from the
SPT will be provided for all randomized subjects.
 
 
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3.2.7
Multiplicity
A fixed sequence procedure will be applied to control multiplicity. The primary and key
secondary efficacy endpoints will be tested in the following order:

Average TCS during the peak RS;

Average TCS during the entire RS;

Average rhinoconjunctivitis DSS during the peak RS;

Average rhinoconjunctivitis DMS during the peak RS.
A lower order endpoint will be tested only if all higher order endpoints have been tested
and claimed statisticallysignificant.
3.2.8
Sample Size and Power Calculations
A total of approximately 1000 subjects will be randomized in a 1:1 ratio to either MK-
3641 or placebo. Assuming a 15% dropout rate, this gives approximately 425 evaluable
subjects per treatment group.
With 425 subjects per arm, the study will have:

approximately 90% power (2-sided, α = 0.05) to have the upper bound of the 95% CI
for relative difference below -10%, and

more than 90% power (2-sided, α = 0.05) to have an estimated relative
difference below -15%.
The calculations are based on the assumptions that the true difference between treatment arms
in average TCS during peak RS is -2.12, that the average TCS during peak RS from the
placebo group is 8.9, and that the standard deviation is 5.60. These assumptions, as well as
the assumption on dropout rate, are based on the two MK-3641 (AIT ragweed) adult studies,
P05233 and P05234, and the pediatric trial P05239 for MK-7243 (AIT grass).
3.2.9
Subgroup Analyses and Effect of Baseline Factors
Analysis for the primary efficacy endpoint will be provided for the following subgroups 
of baseline factors:

Baseline asthma status (yes, no);

Age group (5 to 11 years, 12 to 17 years);

Gender (male, female);

Race (Caucasians, non-Caucasians);
 
 
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
ICS use for subjects with asthma (yes, no);

Allergen sensitization type (ragweed only, ragweed + others);

Geographic region (e.g., US, Canada, Europe). Region classification for each study
site will be determined before database lock.
In addition, subgroup analysis on the primary efficacy endpoint will be provided for:

Pollen counts (low, high): The subgroups will be defined based on the median of the
subject level accumulated pollen counts during the first 21 days of the pollen season;

Local application site reaction (had local application site reactions, did not have
local application site reactions).
The same ANOVA model as in the primary efficacy analysis will be applied for the
subgroup analyses.
3.2.10 Interim Analyses
No efficacy interim analysis is planned for this trial. Safety data will be reviewed by an
eDMC.
3.2.11 Compliance (Medication Adherence)
For each subject, percent compliance will be calculated using the following formula:
Percent Compliance =
Number of Days on Therapy
100%
Number of Days Should Be on Therapy
A day within the study will be considered an “On-Therapy” day if the subject takes all
required medication as instructed in Section 5.2 of the protocol. When a subject takes less
than or more than the required medication on a day, that day is not considered an On-Therapy
day.
For subjects who are followed for the entire study period, the “Number of Days Should be
on Therapy” is the number of days from the first scheduled treatment day to the last
scheduled treatment day. For subjects who discontinue from the study, the “Number of Days
Should Be on Therapy” is the number of days from the first scheduled treatment day to the
last dose day.
Summary statistics will be provided on percent compliance for the ASaT population.
 
 
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3.2.12 Extent of Exposure
The duration of treatment for each subject will be evaluated by calculating the number of days
on therapy. The range and mean for days on therapy will be calculated for the ASaT
population.
3.2.13 Cross Treated Subjects
The following data analysis conventions will be used for cross treated subjects:
Safety Analysis:

Scenario 1: if the incorrect kit corresponded to the assigned treatment arm then the 
subject will be analyzed to the group randomized (no issue).

Scenario 2: If the subject incorrectly switched from active to placebo then the 
subject will be analyzed in the active treatment arm (conservative approach).

Scenario 3: If the subject incorrectly switched from placebo to active then the
subject will be analyzed in the active treatment arm (conservative approach).
For subjects that incorrectly switched from placebo to active, they will be excluded from the 
by-time-adverse event analyses.
For any adverse experiences (AE) occurring during the period that the incorrect study 
medications were taken, the cross-treatment information will be provided in the by-subject-
listing of AEs and the narratives if the subject had a serious AE or discontinued from the 
study due to an AE. 
Subject Compliance / Extent of Exposure:
The cross-treated information will be included in the clinical study report (CSR). The actual 
study drug exposure information within the clinical database for these subjects will be used 
to calculate the subject compliance and the duration of treatment presented in the relevant 
CSR tables (eg, Extent of Exposure), with the days exposed to the incorrect study drug being 
treated as days not exposed / non-compliant to the randomized treatment.
Efficacy Analysis:
No impact for the FAS analysis. As pre-specified in the protocol, subjects will be included in 
the Full Analysis Set (FAS) population and will be analyzed according to the treatment group 
to which he/she was randomized.
 
 
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APPENDIX: Technical Details for supplemental SAP
APPENDIX A
CONSTRAINED LONGITUDINAL DATA ANALYSIS (CLDA) METHOD (WITH ADJUSTMENT FOR BASELINE
VALUES) – TECHNICAL DETAILS FOR MODEL SPECIFICATION, ASSUMPTIONS, AND SAS IMPLEMENTATION
CODES
Model
Let Yijt 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
EሺYijOሻൌyO,       j ൌ0, 1.
and
EሺYijtሻ ൌyO ൅yjt,      j ൌ0, 1; t ൌ1,2, 3,4.
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. A Toeplitz covariance matrix can be specified in the mixed model to account for within
subject correlation at times t ≥0 (including baseline).
At each time point t, t ൌ1, 2, 3, 4, the mean change from baseline (LSMEANS) for jth dose of test drug and control are γ jt and γ 0t ,
respectively, as defined in the cLDA model above.
The treatment difference for jth treatment group vs. control for the mean change from baseline at time point t, t ൌ1, 2, 3, 4 is defined
as:
ηjt ൌ yjt െyOt.


.


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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.
Reasons for discontinuation from the trial may include lack of efficacy, clinical or laboratory adverse experiences, relocation,
withdrawal of consent, protocol violations, and/or data processing issues. Missing data caused by relocation and data processing
issues, are likely to be MCAR. On the other hand, missing data caused by discontinuation due to lack of efficacy may belong to
MAR because the discontinuation maydepend on the observed efficacy outcomes. The
MAR or MNAR mechanisms might each underlie the other reasons to some extent. If treatment in large part determines the loss of
data for these other reasons (such as clinical or laboratory adverse experiences), the mechanism may be close to MAR since
treatment assignment is an observed variable and included in the analysis model. Based on the prior trial results, missing data due
to other reasons is relatively infrequent.
Model Convergence
If the Toeplitz covariance model fails to converge with the default algorithm, then the AR(1) structure can be used to provide
initial values of the covariance parameters.
Example SAS Codes
********************************************************************;
** data step necessary prior to running SAS PROC MIXED;
********************************************************************; DATA long; SET long;
ARRAY T{5} t0-t4; * time indicator variables; ARRAY TT1{5} tt10-tt14;
** define week times treatment 1 indicator variables; DO i = 1 TO 5;
t{i} = (time=(i-1));
tt1{i} = t{i}*(trt=1);
tt2{i} = t{i}*(trt=2);
END; DROP i; RUN;
 
 
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********************************************************************;
** fitting the cLDA model using SAS PROC MIXED;
********************************************************************; PROC MIXED DATA=long;
CLASS subj time stratum; ** subj is the subject id number **; MODEL y=time tt11 tt12 tt13 tt14 tt21 tt22 tt23 tt24 stratum;
REPEATED time / SUBJECT=subj TYPE=TOEP;
ESTIMATE 'T1 Diff (MK - Placebo)' tt11 1; ESTIMATE 'T2 Diff (MK - Placebo)' tt12 1; ESTIMATE 'T3 Diff (MK - Placebo)' tt13 1;
ESTIMATE 'T4 Diff (MK - Placebo)' tt14 1;
ESTIMATE 'T1 Placebo LSM' time -1 1 0 0 0;
ESTIMATE 'T2 Placebo LSM' time -1 0 1 0 0;
ESTIMATE 'T3 Placebo LSM' time -1 0 0 1 0;
ESTIMATE 'T4 Placebo LSM' time -1 0 0 0 1;
ESTIMATE 'T1 MK LSM' time -1 1 0 0 0 tt11 1;
ESTIMATE 'T2 MK LSM' time -1 0 1 0 0 tt12 1;
ESTIMATE 'T3 MK LSM' time -1 0 0 1 0 tt13 1;
ESTIMATE 'T4 MK LSM' time -1 0 0 0 1 tt14 1;
ODS OUTPUT Estimates=outm1; RUN;
 
 
05423K
 
 
056NHQ