Conditions: Cough
Keywords: cough, acute cough, pediatric, Dextromethorphan Hydrobromide, antitussive, ambulatory cough recording device
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 131
Healthy volunteers: no

Brief summary:
This is a placebo-controlled, double-blind, randomized, parallel group pilot study in approximately 150 subjects to evaluate the efficacy of dextromethorphan hydrobromide (DXM) on acute cough in a pediatric population. Subjects will be otherwise healthy males and females aged 6-11 inclusive who are experiencing acute cough as a symptom of common cold or upper respiratory tract infection. Subjects must have had onset of symptoms within 3 days of screening and qualify based on physical exam and symptom questionnaire. Eligible subjects will be given a single-blind placebo, and fitted with a cough counting device for a 2 hour run-in period. Qualifying subjects will be stratified by age and then randomized to either DXM or placebo in a 1:1 ratio and fitted with the cough recording device for the first 24 hours of treatment. Subjects will receive approximately 9 doses of investigational product over the course of the 4 day study and will complete patient reported outcome questions before the morning and afternoon doses. Subjects will return to the study site on Day 2 to remove the cough recorder and on Day 4 (+ 2 days) to complete the final visit. A review of any reported adverse events will also be completed.

Detailed description:
This is a placebo-controlled, double-blind, randomized, parallel group pilot study in approximately 150 subjects to evaluate the efficacy of dextromethorphan hydrobromide DXM) on acute cough in a pediatric population. Subjects will be otherwise healthy males and females aged 6-11 inclusive who are experiencing acute cough as a symptom of common cold or upper respiratory tract infection. Subjects must have had onset of symptoms within 3 days of screening and qualify based on physical exam and symptom questionnaire. Eligible subjects will be given a single-blind placebo, and fitted with a cough counting device for a 2 hour run-in period. Qualifying subjects will be stratified by age and then randomized to either DXM or placebo in a 1:1 ratio and fitted with the cough recording device for the first 24 hours of treatment. Subjects will receive approximately 9 doses of investigational product over the course of the 4 day study and will complete patient reported outcome questions before the morning and afternoon doses. Subjects will return to the study site on Day 2 to remove the cough recorder and Day 4 (+2 days) to complete the final visit. A review of any reported adverse events will also be completed. Validated Patient Reported Outcomes (PRO) used in the study include morning cough assessment, afternoon cough assessment, Child Global Question, and Child Cold Symptom Checklist

Arms:
arm 1: 15 mg/ 10 mL: 10 mL of Dextromethorphan Hydrobromide arm 2: 10 mL of Placebo

Interventions: intervention 1: Dextromethorphan Hydrobromide intervention 2: Placebo intervention 3: Cough recording device
Intervention descriptions: intervention 1: 15 mg/ 10 mL: 10 mL of Dextromethorphan Hydrobromide intervention 2: 10 mL Placebo intervention 3: FDA approved device validated for use in adults and children

Protocol document:
Prot_000.pdf: 
PF-02450388, Dextromethorphan Hydrobromide
A6531002
Final Protocol Amendment 4 - 18 July 2018 
PFIZER CONFIDENTIAL
Page 1
A PLACEBO-CONTROLLED, DOUBLE-BLIND, RANDOMIZED, PARALLEL 
GROUP PILOT STUDY TO EVALUATE THE EFFICACY OF 
DEXTROMETHORPHAN HYDROBROMIDE ON ACUTE COUGH IN A 
PEDIATRIC POPULATION
Compound:
PF-02450388
Compound Name:
Dextromethorphan Hydrobromide
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
Not applicable
Protocol Number:
A6531002
Phase:
4
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  
In the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
CCI


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Document History
Document
Version Date
Summary of Changes and Rationale
Original protocol
18 Nov 2015
Not applicable (N/A)
Amendment #1
04 Feb 2016
The following changes were made based on comments 
and recommendations during and after the Investigator’s 
Meeting (15-16 Jan 2016):

Typos and other minor errors were corrected.

Modified the time of dosing of the single-blind 
liquid oral confection from before approximately 
11:30 am to ‘recommended to be before 11:30 am’.

Modified the time of first dose of investigational 
product from before approximately 3:00 pm to 
‘recommended to be before 3:30 pm’.

A clarification was made that, although not 
encouraged, to allow the parent/legally acceptable 
representative some flexibility regarding the timing 
of the second dose, the second dose may be taken as 
early as 4 hours post-Dose 1, but not earlier.

A clarification was made that height and weight will 
only be assessed at Screening, and not at Visit 4; the 
superscripted footnote text in Table 2 was reordered 
accordingly.

Procedures and instructions were added for an Early 
Termination Visit for subjects who discontinue early 
from the study.

Lifestyle Assessments were deleted from the Post 
Study Follow-Up Visit (Day 18).

A clarification was made that subjects vomiting 
after the administration of Dose 1 at the clinic will 
not be re-dosed.  In addition, it was clarified that all 
the subsequent clinical procedures and subsequent 
dosings should be continued and performed as 
described in the protocol.

Modified the time of first dose of investigational 
product from before approximately 3:00 pm to 
before 3:30 pm.


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Version Date
Summary of Changes and Rationale

Inclusion Criterion #6, regarding excluded 
medications, was clarified as follows:

Ear drop antibiotics will not be allowed; ocular 
antibiotics and local cream/ointment antibiotics will 
be allowed.

Inhaled glucocorticosteroids will not be allowed.

Intranasal saline sprays, inhalations or washes will 
be allowed.

Bronchial hyperresponsiveness was added to the 
various exclusion criteria regarding common clinical 
characteristics/conditions to be excluded:

Exclusion Criterion #1;

Exclusion Criterion #3;

Exclusion Criterion #5.

Exclusion Criterion #6 was modified to specify 
fever greater than 39ºC (102ºF oral temperature) at 
the time of screening.

Exclusion Criterion #10 was clarified regarding 
initial and repeat blood pressure readings.

Exclusion Criterion #15 was modified regarding 
washout periods of excluded medications:

Added a new Bullet #2, excluding ear drop 
antibiotics with a 5-day washout;

Added a new Bullet #4, excluding inhaled 
glucocorticosteroids as ever used, and with no 
elimination half-life;

Bullet #10 was deleted, already covered in 
previous Bullet #5;

Bullet #21 was rewritten to only include nasal 
glucocorticosteroids, since inhaled 
glucocorticosteroids are already covered in 
previous Bullet #4.

Exclusion Criterion #17 was revised by deleting the 
word “significant” from “…or been exposed to 
significant secondhand smoke…”.


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Version Date
Summary of Changes and Rationale

Exclusion Criterion #18 regarding consumption of 
alcohol was deleted. 

A new Exclusion Criterion #19 was added to 
exclude siblings from participating in the study 
contemporaneously.

The randomization criteria were numbered, as 
opposed to a bulleted list.

Section 5.3 Subject compliance, simplified the 
language regarding the assessment subject’s 
compliance with investigational product.

Deleted all references to ‘oz’ and ‘teaspoons’ 
throughout the protocol, using mL instead:

Section 5.7 Investigational Product Accountability 
was modified:

Clarified that subject diary dosing entries will also 
be reviewed as part of subject compliance.

Added simplified language regarding the assessment 
investigational product accountability.

The following modifications were made to 
Section 8.4, Medication Errors:

Bullet describing mediation errors was modified 
to include acetaminophen (APAP) provided by 
the sponsor as a permitted concomitant 
medication if required for headache, fever and/or 
body aches and pains associated with the 
common cold.

Non-templated language describing overdoses 
was deleted.

Changed “parent/legal guardian” to “parent/legally 
acceptable representative” throughout the 
document.

Added pictures to Appendix 4 and 5.


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Version Date
Summary of Changes and Rationale
Amendment #2
23 Mar 2016
The following changes were made to the protocol based 
on FDA recommendation, and additional revisions were 
requested from investigative sites for increased study 
flexibility without affecting the integrity of the study.  
In addition, the dosing time windows for evening and 
morning dosing are shortened from 2 hours to 
30 minutes before bedtime or after waking, respectively. 

The primary endpoint is 24-hour cough count, 
and the key secondary endpoint is cough count 
during the first dosing interval on Day 1.

A justification was added to support the safety of 
DXM should the 15 mg dosage be administered 
with a 4-hour interval between doses 1 and 2 on 
Day 1. 

The Day 18 phone call to assess for subject 
safety was extended to Day 18 + up to 3 days.

Subject bronchodilator or inhaled glucocorticoid 
use is prohibited for a 6-month period prior to 
screening.

Bronchial hyperresponsiveness was removed as 
an exclusion criterion for this protocol.  
Prohibited bronchodilator and inhaled 
glucocorticoid use serves as a surrogate for the 
measurement of bronchial hyperresponsiveness. 
The following change was made to the dose time 
windows:

The allowed dosing time window for the 
evening of Day 1 and the morning of Day 2 was 
shortened from 2 hours to 30 minutes before 
bedtime or after waking, respectively, because 
the dose times are being used as a surrogate for 
sleep and wake times.  These dose times, with 
the shortened time windows from actual sleep 
and wake times, will more closely reflect sleep 
time for cough counting calculations, necessary 
information for determining and evaluating 
nighttime and daytime cough counts (secondary 
endpoints).  To maintain consistency for 
subject-reported endpoints on Days 2 through 
4, the allowed time windows for dosing on 


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Version Date
Summary of Changes and Rationale
Days 3 and 4 are also shortened from 2 hours to 
30 minutes before bedtime for the evening 
doses, and from 2 hours to 30 minutes after 
waking for the morning doses. 
Additional changes were made to inclusion/exclusion 
criteria:
• Ocular antibiotics were added as an exclusion.
• Oral glucocorticoid use was added as an 
exclusion (along with inhaled glucocorticoid 
use). 
• The inactive ingredient list for acetaminophen 
(APAP) was added to the exclusion criterion 
concerning hypersensitivity or allergy. 
• Inclusion #4 (regarding the subject having a 
URTI, and the URTI being within 3 days of 
onset of symptoms at the screening visit) was 
segmented into 2 bullets for database 
categorization purposes.
The procedures conducted at an early termination visit 
were made consistent or corrected as appropriate. 
Subject enrollment will be actively monitored with the 
goal of attaining at least 40% population in the younger 
group (6-8 years).
Requirements for investigational product compliance 
and accountability checks were clarified.
The procedures conducted at an early termination visit 
were made consistent across the protocol. 
The regulatory status and reference for the VitaloJAK 
device were corrected.
 safety 
analysis was added.
In addition, minor grammatical changes or clarifications 
were made throughout the protocol. 
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Version Date
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Amendment #3
07 Nov 2016
Under Protocol Summary/Study Design and 
Section 3.0 Study Design, the bullet outlining what is 
collected on the subject diary will include mention of 
the time and date of APAP dosing if applicable, for 
completeness.
Exclusion criterion #5 (Protocol Section 4.2) will be 
edited to read as follows:
5.  Pneumonia (active or with a symptom-free period of 
<30 days), asthma (active or with a symptom-free 
period of <1 year) or other significant pulmonary 
diseases.
Principal investigators/physicians for this study have 
reported that in some instances, children in the past may 
have had a wheezing episode and had a diagnosis of 
asthma applied to their patient chart/record, but these 
children are neither currently asthmatic nor receiving 
corticosteroids or bronchodilators.  Such children would 
be appropriate for enrollment in this study.
Section 6.6 Subject Discontinuation:
Fever greater than 39°C (102°F) oral temperature will 
be removed as a reason for subject discontinuation. 
Principal investigators/physicians for this study have 
reported that in some instances, children may report 
with a fever greater than 39°C (102°F), and still have an 
uncomplicated common cold/upper respiratory tract 
infection.  Removing this discontinuation criterion is not 
a safety concern, as acetaminophen is allowed (and 
provided) as part of the study.
Table 5.  Concomitant Medication, Acetaminophen, has 
product numbers WH-0001-0568-001 (originally 
provided at study start) and 
WH-0001-0568-002 (provided as re-supply during 
study conduct).
Section 15.1, all references to subjects should be 
changed to patients. 
Spelling error(s) as noted were corrected.


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Summary of Changes and Rationale
Amendment #4
July 18, 2018
The following changes were made primarily to support 
the interim analysis planned after at least 50% of 
subjects have completed or discontinued early:

Language was added documenting and supporting a 
planned interim analysis.

Language was modified for the analysis of primary 
endpoint and an additional analysis was added for 
the primary endpoint:    

The treatment effect for dextromethorphan 
hydrobromide vs placebo from the primary 
negative binomial model was rephrased using a 
ratio of rates instead of an odds ratio. 

A linear model will be used based on the log-
transformed primary endpoint, including 
treatment, study site, log-transformed baseline 
average cough count per hour (based on the 
Baseline Run-in Period), and age group terms in 
the model.

Clarification was made for the primary endpoint 
analysis and the main effect model is defined as 
primary.

Additional secondary endpoint variables were 
added:  

Total cough count collected by the cough 
recording device over the first dosing interval on 
Day 1 (Dose 1 to Dose 2) and the first dosing 
interval on Day 2 (Dose 3 to Dose 4). 

Time accumulated over a 24-hour period when 
cough events occurred. 

The analysis model for the other endpoint variables 
was revised.  

The inclusion criterion (#4) was revised slightly for 
clarity as follows: An onset of symptoms within 
3 days of Visit 1, as determined by the subject or 
parent/legally acceptable representative (ie, Visit 1 
should not occur later than on Day 3 of symptoms). 


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
WH numbers were described more generically to 
account for multiple lots of investigational product 
supplied throughout the study.  

APAP will no longer be included in the study kit, 
but supplied separately from the study kit.   

A correction was made to the protocol for 
consistency, that subjects will be stratified by age 
group (6-8 years and 9-11 years).  

Several statements from the US. Pharmacopeia 
(USP) were added to the 5.6 Investigational Product 
Storage section.  

The safety section of the protocol was updated to 
reflect current standardized safety language.   

Updated information about the planned interim 
analysis and the Internal Review Committee (IRC) 
for reviewing the unblinded data has been added to 
this amendment.  

Several minor formatting inconsistencies or other 
corrections were made across the document.

Several references were added to the References 
section of the protocol.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc.


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................13
LIST OF FIGURES .................................................................................................................13
APPENDICES .........................................................................................................................14
PROTOCOL SUMMARY.......................................................................................................15
SCHEDULE OF ACTIVITIES................................................................................................22
1. INTRODUCTION ...............................................................................................................26
1.1. Mechanism of Action/Indication.............................................................................26
1.2. Background and Rationale ......................................................................................26
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................27
2.1. Objectives................................................................................................................27
2.2. Endpoints.................................................................................................................27
3. STUDY DESIGN.................................................................................................................28
4. SUBJECT SELECTION......................................................................................................32
4.1. Inclusion Criteria.....................................................................................................32
4.2. Exclusion Criteria....................................................................................................34
4.3. Randomization Criteria ...........................................................................................37
4.4. Lifestyle Guidelines ................................................................................................38
4.4.1. Contraception..............................................................................................38
4.5. Sponsor’s Qualified Medical Personnel..................................................................38
5. STUDY TREATMENTS.....................................................................................................38
5.1. Allocation to Treatment ..........................................................................................40
5.2. Breaking the Blind (If Applicable)..........................................................................40
5.3. Subject Compliance.................................................................................................41
5.4. Investigational Product Supplies.............................................................................41
5.4.1. Dosage Form(s) and Packaging..................................................................41
5.4.2. Preparation and Dispensing........................................................................41
5.5. Administration.........................................................................................................42
5.6. Investigational Product Storage ..............................................................................44
5.7. Investigational Product Accountability...................................................................45
5.7.1. Destruction of Investigational Product Supplies ........................................45
5.8. Concomitant Treatment(s).......................................................................................45


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5.9. Rescue Medication ..................................................................................................46
6. STUDY PROCEDURES .....................................................................................................46
6.1. Screening and Baseline ...........................................................................................46
6.1.1. Pre-Screening..............................................................................................46
6.1.2. Screening/Morning Baseline (Day 1).........................................................46
6.1.3. Afternoon Baseline/Run-in Period: Visit 1 (Day 1) ...................................47
6.1.4. Randomization/First Dose: Visit 2 (Day 1)................................................48
6.2. Treatment Period (Day 1 Evening – Day 4 Morning).............................................50
6.3. Visit 4 (End of Study Visit; Day 4 Afternoon or Day 5 or 6).................................51
6.4. Early Termination Visit...........................................................................................51
6.5. Post-Study Follow-up..............................................................................................52
6.6. Subject Discontinuation ..........................................................................................52
6.7. Subject Withdrawal.................................................................................................52
7. ASSESSMENTS..................................................................................................................54
7.1. Efficacy ...................................................................................................................54
7.1.1. Cough Counts .............................................................................................54
7.1.2. Subjective Assessments..............................................................................55
7.1.2.1. Subjective Cough Assessments (Screening/Mornings).............55
7.1.2.2. Subjective Cough Assessments (Baseline/Afternoons) ............55
7.1.2.3. Child Global Question...............................................................55
7.1.2.4. Global Satisfaction by Subject ..................................................56
7.1.2.5. Global Satisfaction by Parent/Legally Acceptable 
Representative ...................................................................................56
7.2. Screening Assessments ...........................................................................................56
7.2.1. Pregnancy Testing ......................................................................................56
7.2.2. Physical Examination .................................................................................57
7.2.3. Vital Signs ..................................................................................................57
7.2.4. Height and Weight Measurements..............................................................57
7.3. Assessment of Suicidal Ideation and Behavior.......................................................57
7.4. Child Cold Symptom Checklist...............................................................................57
8. ADVERSE EVENT REPORTING......................................................................................58
8.1. Adverse Events........................................................................................................58


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8.1.1. Additional Details on Recording Adverse Events on the CRF...................59
8.1.2. Eliciting Adverse Event Information..........................................................59
8.1.3. Withdrawal From the Study Due to Adverse Events (see Also the 
Subject Withdrawal Section) ...........................................................................59
8.1.4. Time Period for Collecting AE/SAE Information......................................60
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................60
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................60
8.1.5. Causality Assessment .................................................................................60
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................61
8.2. Definitions...............................................................................................................61
8.2.1. Adverse Events ...........................................................................................61
8.2.2. Abnormal Test Findings .............................................................................62
8.2.3. Serious Adverse Events ..............................................................................62
8.2.4. Hospitalization............................................................................................63
8.3. Severity....................................................................................................................64
8.4. Special Situations ....................................................................................................64
8.4.1. Protocol-Specified Serious Adverse Events...............................................64
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................64
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................66
8.4.3.1. Exposure During Pregnancy......................................................66
8.4.3.2. Exposure During Breastfeeding ................................................67
8.4.3.3. Occupational Exposure .............................................................68
8.4.4. Medication Errors .......................................................................................68
8.4.4.1. Medication Errors......................................................................68
8.5. Medical Device Complaint Reporting Requirements .............................................69
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................69
9.1. Sample Size Determination.....................................................................................69
9.2. Efficacy Analysis ....................................................................................................69
9.2.1. Analysis of Primary Endpoint ....................................................................70
9.2.2. Analysis of Secondary Endpoints...............................................................70
9.2.3. Analysis of Other Endpoints.......................................................................71
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9.3. Safety Analysis........................................................................................................73
9.4. Interim Analysis ......................................................................................................73
9.5. Data Monitoring Committee ...................................................................................74
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................74
11. DATA HANDLING AND RECORD KEEPING .............................................................74
11.1. Case Report Forms/Electronic Data Record .........................................................74
11.2. Record Retention...................................................................................................75
12. ETHICS..............................................................................................................................76
12.1. Institutional Review Board/Ethics Committee......................................................76
12.2. Ethical Conduct of the Study ................................................................................76
12.2.1. Subject Information and Consent/Assent .................................................76
12.3. Subject Recruitment ..............................................................................................77
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
Good Clinical Practice...............................................................................................77
13. DEFINITION OF END OF TRIAL...................................................................................77
13.1. End of Trial in Participating Countries .................................................................77
14. SPONSOR DISCONTINUATION CRITERIA ................................................................78
15. PUBLICATION OF STUDY RESULTS..........................................................................78
15.1. Communication of Results by Pfizer ....................................................................78
15.2. Publications by Investigators ................................................................................79
16. REFERENCES ..................................................................................................................80
LIST OF TABLES
Table 1.
Dosing Schedule...................................................................................................19
Table 2.
Schedule of Activities...........................................................................................23
Table 3.
Investigational Product for Baseline Run-In Period.............................................39
Table 4.
Investigational Product for Treatment Period.......................................................39
Table 5.
Concomitant Medication ......................................................................................40
LIST OF FIGURES
Figure 1.
Study Design Schematic.......................................................................................18


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APPENDICES
Appendix 1. Abbreviations......................................................................................................82
Appendix 2. Child Cold Symptom Checklist ..........................................................................84
Appendix 3. Child Global Question.........................................................................................86
Appendix 4. Subjective Cough Assessments (Screening/Morning Baseline/Mornings) ........87
Appendix 5. Subjective Cough Assessments (Afternoon Baseline/Afternoons).....................88
Appendix 6. Global Satisfaction..............................................................................................89
Appendix 7. Blood Pressure Levels for Boys and Girls..........................................................90
Appendix 8. Cough Counting Process and Timing .................................................................95


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PROTOCOL SUMMARY
Background and Rationale
Dextromethorphan (DXM) is the most commonly used oral antitussive ingredient in both 
adult and pediatric non-prescription medications (Dicpinigaitis, 2004),3 and is “Generally 
Recognized as Safe and Effective” (GRASE) under the over-the-counter (OTC) Monograph 
system (21 US Code of Federal Regulations (CFR) 341.14).  The product is intended for use 
in adults and children 2 years of age and over, with the indication:  
Temporarily relieves cough due to minor throat and bronchial irritation as may occur with a 
cold (21 CFR 341.74(b)(1)).  Under 21 CFR 341.74(d)(iii), DXM can be formulated as 
syrups and as solid oral dosage forms, with age-dependent dosing as follows:

Adults and children 12 years of age and older: 10 to 20 mg every 4 hours up to 
6 doses/day or 30 mg every 6-8 hours up to 4 doses/day, not to exceed 120 mg/day;

Children 6 to under 12 years of age: 5 to 10 mg every 4 hours up to 6 doses/day or 
15 mg every 6-8 hours up to 4 doses/day, not to exceed 60 mg/day;

Children 2 to under 6 years of age: 2.5 to 5 mg every 4 hours or 7.5 mg every 6 to 
8 hours; not to exceed 30 mg/day.
The safety and efficacy of DXM in adults at the United States monograph-approved dose of 
30 mg has been established in a variety of studies (Pavesi et al., 2001).13 Efficacy in children 
is less well established and results have been equivocal (Shadkam et al, 2010; Paul, 2004a; 
Paul, 2004b; Yoder, 2006).14,11,12,19 The difficulty in establishing efficacy in children is at 
least partially due to the lack of a standardized methodology and a validated device to 
evaluate objective antitussive effects (ie, a reduction in cough count), in the natural 
environment. 
The leading pharmaceutical manufacturers of over-the-counter (OTC) pediatric cough and 
cold products, via the Consumer Healthcare Products Association (CHPA), and in 
consultation with the Food and Drug Administration (FDA), announced in 2008 that they are 
transitioning product labeling as it relates to children aged less than 4 years of age.  The 
product labeling now states "Do not use in children under four years of age."  The safety of 
the ingredients in these products was not in question; it was found that dosing errors and 
accidental ingestions were the leading cause of rare adverse events in children (CHPA, 
2008).2
This pilot study is being conducted to identify the appropriate endpoints and sample size for 
a subsequent definitive pediatric cough study that will evaluate the efficacy of 
dextromethorphan hydrobromide (DXM HBr) at the approved monograph dose in children 
aged 6 to 11 years.  This current pilot study will utilize -the 510(k) status cough recording 
device (VitaloJAKTM, Vitalograph Ltd, Ennis, Ireland), which has been validated for use in 
adults (McGuiness, 2012) 7 and has recently been validated in children (Elghamoudi, 2015).5
A subject-completed patient-reported outcome (PRO) self-assessment of cough symptoms 
will also be included as a secondary endpoint, to provide another endpoint for evaluation.


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Objective
The objective of this pilot study is to evaluate the endpoints and analyses that may be most 
appropriate to evaluate the efficacy of dextromethorphan hydrobromide (DXM HBr) 
15 mg/10 mL versus placebo in children ages 6 to 11 years in a future study.
Endpoints
The primary endpoint of this study is the total cough count collected by the cough recording 
device in an ambulatory setting over a 24-hour period post-first dose on Day 1 after 
randomization to DXM HBr or placebo.
Secondary endpoints are the total cough count collected in the dosing intervals of interest 
during the 24-hour interval:

Total cough count collected by the cough recording device during the first dosing 
interval (Dose 1 to Dose 2) on Day 1;

Total cough count collected by the cough recording device over the dosing interval 
from evening dose (Dose 2) on Day 1 to morning dose (Dose 3) on Day 2 (ie, night 
time cough count);

Total cough count collected by the cough recording device over the first dosing 
interval on Day 2 (interval between morning dose and afternoon dose on Day 2, ie, 
Dose 3 to Dose 4);

Total cough count collected by the cough recording device over the first dosing 
interval on Day 1 (Dose 1 to Dose 2) and the first dosing interval on Day 2 (Dose 3 to 
Dose 4).  These 2 dose intervals approximately represent the daytime cough count.  
Time accumulated over a 24-hour period when cough events occurred.  Other endpoints as 
assessed by patient reported outcomes (PROs) include:

Change from screening evaluation (assessed in the morning) in morning cough 
frequency (“from when you woke up this morning until now, how much have you 
been coughing”), cough severity (“how bad is your cough this morning”), and impact 
on sleep (“last night in bed, how much did your cough keep you awake”), assessed by 
subject; 

Change from baseline evaluation (assessed at afternoon) in afternoon cough 
frequency (“how much have you been coughing this afternoon”) and severity (“how 
bad is your cough this afternoon”) in the afternoon of Days 2-4, assessed by subject; 

Change from baseline evaluation (assessed at afternoon) in daily assessment of the 
cold in the Child Global Question (“how bad is your cold today”), assessed by 
subject;


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•
Subject and parent/legally acceptable representative global assessment of satisfaction 
with study medication at the end of the study.
  Protocol Amendment #4 introduced an 
interim analysis to assess whether or not the study would be continued. The rationale is 
based upon the vulnerable subject population (pediatrics) being studied and in association 
with the extended recruitment period and challenging enrollment for the trial.  The main 
focus of this interim analysis is the primary endpoint and the first secondary endpoint (cough 
count during the first dosing interval), but other secondary 
 endpoints may also be 
considered by the independent committee established to review the information as detailed in 
the committee charter and described in Section 9.4. The interim analysis will be conducted 
after at least 50% subjects complete the study or discontinue early.    
Adverse Events (AEs) will be collected to assess the safety of DXM HBr and placebo during 
the study period. 
Study Design
This is a randomized, stratified by age group (6-8 years and 9-11 years), parallel, 
double-blind, placebo-controlled, multicenter, pilot study in approximately 150 males and 
females aged 6 to 11 years, inclusive, who exhibit cough associated with a common cold or 
acute upper respiratory tract infection (URTI) but are otherwise healthy.  Prior to performing 
any study-related activities and after having been informed of the study by the investigator or 
authorized designee, the parent/legally acceptable representative will provide informed 
consent, and the subject will provide informed assent to participate.  The study design is 
shown in Figure 1 below.  The dosing schedule is shown in Table 1 below.  The schedule of 
activities is shown in Table 2 below.
CCI
CCI


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Figure 1.
Study Design Schematic


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Table 1.
Dosing Schedule
DAY
TIME OF ADMINISTRATION
MORNING
AFTERNOON
EVENING
1
Single-Blind, Liquid Oral 
Confection
(In the morning, recommended 
to be before 11:30 am, at the 
study site)
Dose 1a,b
(Recommended to be before
3:30 pm, at the study site)
Dose 2a,c
(Prior to bedtime [within 
30 minutes], 6-8 hours after Dose 
1)
2
Dose 3a
(In the morning, within 
30 minutes of waking up)
Dose 4a
(6-8 hours after morning dose and 
at least 24 hours after Dose 1; 
administered at the study site)
Dose 5a
(Prior to bedtime [within 
30 minutes], 6-8 hours after 
afternoon dose)
3
Dose 6a
(In the morning, within 
30 minutes of waking up)
Dose 7a
(6-8 hours after morning dose)
Dose 8a
(Prior to bedtime [within 
30 minutes], 6-8 hours after 
afternoon dose)
4
Dose 9a
(In the morning, within 
30 minutes of waking up)
a Double-blind randomized investigational product.
b Subjects vomiting after the administration of Dose 1 at the clinic will not be re-dosed. In addition, all the subsequent 
clinical procedures and dosings should be continued and performed as described in the protocol.
c Although not encouraged, but to ensure there is a second dose administered on Day 1, and to allow the parent/legally 
acceptable representative some flexibility regarding the timing of that second dose, the second dose may be taken as 
early as 4 hours post-Dose 1, but not earlier.
Subjects who meet screening criteria, including sufficient cough and acute URTI or common 
cold symptoms, will be enrolled in a 2-hour Baseline Run-in Period and follow the 
procedures below: 

The subject will be fitted with the VitaloJAKTM device at the study site for at least 
2 hours of ambulatory cough count monitoring;

The parent/legally acceptable representative will be advised that the VitaloJAKTM is a 
sound recording device, and therefore may inadvertently capture confidential 
information from casual speech within its range; and that Vitalograph has standard 
operation procedures and measures in place to ensure that any such information is 
kept confidential, including removing such speech to a certain extent.  While wearing 
the device, the subject should also avoid overly noisy locations;

The subject will be given a single-blind (to the parent/legally acceptable 
representative and subject), inactive (non-medicinal) liquid oral confection at the 
study site, recommended to be before 11:30 am.  The 2-hour recording will begin 
immediately (+5 minutes) after the confection is administered;

The subject and parent/legally acceptable representative will be released from the 
study site during the 2-hour ambulatory cough count monitoring and instructed to 
engage in normal activities.  Alternatively, they may stay at the study site, if 
convenient.  The study site staff will capture in the case report form (CRF) whether or 
not the subject leaves the study site;


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
The subject and parent/legally acceptable representative will return to the study site 
after at least 2 hours and preferably before 2:30 pm.  The VitaloJAKTM device will be 
removed.  The subject will complete the afternoon subjective cough assessments and
Child Global Question, and if qualified, will be enrolled in the 4-day Treatment 
Period.
Activities for the Treatment Period are as follows: 

The study site staff will set-up the VitaloJAKTM device for 24 hours of ambulatory 
cough count recording;

The subject will be stratified based on the subject’s age (6-8 years or 9-11 years) and 
randomized to investigational product;

The subject will receive the first dose of investigational product at the study site, 
recommended to be before 3:30 pm. Subjects vomiting after the administration of 
Dose 1 at the clinic will not be re-dosed, and all the subsequent clinical procedures 
and dosings should be continued and performed as described in the protocol;

The subject and parent/legally acceptable representative will receive investigational 
product, permitted acetaminophen (APAP) as concomitant medication, and subject 
diary.  In addition, the subject will be wearing the VitaloJAKTM device and will 
receive instructions regarding its use;  

After receiving instructions for diary completion and investigational product 
administration for the remaining days, the subject and parent/legally acceptable 
representative will be allowed to leave the study site during the 24-hour ambulatory 
cough count monitoring to engage in normal activities;

The subject will receive investigational product in the evenings of Days 1-3 prior to 
bedtime, on the mornings of Days 2-4, and in the afternoons of Days 2-3 (Table 1);

The subject will complete subjective cough assessments in the mornings and
afternoons of Days 2-4, immediately prior to the morning and afternoon dosing with 
the investigational product (as applicable);

The subject will complete the Child Global Question in the afternoons of Days 2-4;

A subject diary will be used to record the time and date of investigational product
dosing; the time and date of APAP dosing if applicable; and the time, date, and 
entries for the subjective cough assessments/Child Global Question.  The subject 
diary will be used from the afternoon of Day 1 through the afternoon of Day 4.  The 
parent/legally acceptable representative may assist or complete diary entries for dates 
and times, but the subject must choose the responses for the subjective cough 
assessments and child global question without assistance;


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
The subject and parent/legally acceptable representative will return to the study site in 
the afternoon of Day 2 for Visit 3, at least 24 hours after recording began on Day 1, 
for removal of the VitaloJAKTM device, for assessment of compliance with the 
investigational product and diary completion, and evaluation of concomitant 
treatments and adverse events;

The subject and parent/legally acceptable representative will return to the study site
for an End of Study visit on Day 4 (+1 to 2 days for scheduling flexibility).  A global 
assessment of product satisfaction should be completed by the subject, and 
subsequently by the parent/legally acceptable representative, at this visit.  The 
afternoon subjective cough assessments and Child Global Question should be 
completed on the afternoon of Day 4 even if the End of Study visit occurs on 
Day 5 or 6. Compliance with the investigational product and diary completion, and 
evaluation of concomitant treatments and adverse events, will be assessed at this visit.  
All study materials should be returned at this visit;

A post-study follow-up phone visit will occur 14 (+ up to 3 days for scheduling 
flexibility) days after the last dose of investigational product (ie, Day 18).  The study 
site staff will call the subject and parent/legally acceptable representative to inquire 
about any serious adverse events (SAEs) that may have occurred.
Study Treatments
The double-blind investigational product assessed for efficacy and safety in this pediatric 
population are:

DXM HBr 15 mg/10 mL, administered as 10 mL per dose;

Placebo, administered as 10 mL per dose.
Subjects will be randomized to treatment in a 1:1 ratio.
A single-blind (to the parent/legally acceptable representative and subject), inactive
(non-medicinal), liquid oral confection will be given to all subjects during the Baseline 
Run-in Period.
During the Treatment Period, APAP will be provided by the sponsor as a permitted 
concomitant medication if required for headache, fever and/or body aches and pains 
associated with the common cold.  Dosing will be as directed per the product label, based on 
weight or age. If requested by parent/legally acceptable representative, use of ibuprofen 
(IBU) will be permitted after consultation with the investigator or designee.  IBU will not be 
supplied by the sponsor.


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Statistical Methods
Statistically significant treatment differences will be declared if the probability of random 
occurrence among or between the treatment groups (p) is 0.05.  Treatment differences will 
be declared marginally significant if 0.05<p≤0.10.  All tests will be 2-sided.
No formal sample size determination was performed, as information on cough count using 
the VitaloJAKTM device in children in an ambulatory setting is limited.  The sample size of 
approximately 150 subjects to be enrolled in the study was based on clinical judgment. The 
primary efficacy parameter (total cough count collected in an ambulatory setting over the 
24-hour period post-first dose on Day 1) will be analyzed with a negative binomial regression 
model (SAS Proc GENMOD) with effects for treatment, study site, baseline cough count 
(average per hour, based on the Baseline Run-in Period), and age group terms in the model, 
with logarithm of the time over which the cough count is evaluated as the offset parameter.
AEs will be summarized by severity, and relationship to study treatment.
SCHEDULE OF ACTIVITIES
The schedule of activities (Table 2) provides an overview of the protocol visits and 
procedures.  Refer to the Study Procedures and Assessments sections of the protocol for 
detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities, in order to conduct evaluations or assessments required to protect the 
well-being of the subject.


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Table 2.
Schedule of Activities
Visit Identifier
Screening
/Run-In
Period
Randomization/ 
First Dose 
Active Treatment Period
End Study
Post 
Study 
Follow-up
Day 1
Visit 1
Day 1
Visit 2
Day 1
Day 2
Visit 3
Day 3
Day 4
Days 4-6
Day 18
+3 days
Protocol Activity
AM
Afternoon
PM
AM
Afternoonh
PM
AM
Afternoon 
PM
AM
Visit 4
(afternoon) or
Early 
Termination
Phone call
Informed consent/assenta
X
Demographics
X
Inclusion/Exclusion 
Criteria
X
Medical historyb
X
Physical examination 
X
X
Vital signs (height, 
weight, respirations, 
temperature, sitting BP, 
pulse rate)c
X
Xc
Urine pregnancy testd
X
X
Lifestyle Assessmente
X
Morning subjective cough 
assessments
X
X
X
X
Afternoon subjective 
cough assessmentsf
X
X
X
Xf
Child Cold Symptom 
Checklist
X
Child Global Questionf
X
X
X
Xf
Single-blind, liquid oral 
confection administrationg
X
Ambulatory 2-hour cough 
recordingi
X
Stratification and 
randomization
X
Diary/investigational 
product/APAP 
dispensed/retrieved
X
X
X
Study Medication 
administrationj
X 
X
X
X
X
X
X
X
X


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Visit Identifier
Screening
/Run-In
Period
Randomization/ 
First Dose 
Active Treatment Period
End Study
Post 
Study 
Follow-up
Day 1
Visit 1
Day 1
Visit 2
Day 1
Day 2
Visit 3
Day 3
Day 4
Days 4-6
Day 18
+3 days
Protocol Activity
AM
Afternoon
PM
AM
Afternoonh
PM
AM
Afternoon 
PM
AM
Visit 4
(afternoon) or
Early 
Termination
Phone call
Ambulatory 24-hour 
cough recordingk
X
X
Ambulatory cough 
recorder removal/retrieval
X
X
Assessment of compliance 
with study medication
X
X
Prior/concomitant 
treatments
X
Global Satisfaction by 
subject and parent/legally 
acceptable representative
X
Adverse eventsl,m
SAE
Xl
Non-SAE 
Visit 1 and Visit 2 (Screening/Morning Baseline, Afternoon Baseline Run-In Period, and Randomization/First Dose) occur on Day 1 of the study.  Visit 4 (End of Study) may 
occur on the afternoon of Day 4, or on Days 5 or 6.  Early termination visit is not restricted to an afternoon timeframe.
Abbreviations: APAP = acetaminophen; BP = blood pressure; SAE = serious adverse event.
a.
Parent/legally acceptable representative will provide informed consent, and child will provide assent.
b.
Subject must be symptomatic with a common cold or acute URTI, with onset of symptoms within 3 days of Visit 1, as determined by the subject or parent/legally acceptable 
representative (ie, Visit 1 should not occur later than on Day 3 of symptoms).
c.
Height and weight will only be collected at screening, but not at Visit 4 or Early Termination Visit.
d.
Pregnancy test for post-menarchal females. 
e.
The Lifestyle Assessment (Section 4.4) is the opportunity to assess reproductive/childbearing status, communicate the protocol requirement for complete sexual abstinence 
and document the discussion.
f.
Afternoon subjective cough assessments and Child Global Question should be completed before afternoon dosing on Days 1, 2 and 3 and in the afternoon on Day 4 (even if 
the End of Study visit occurs on Day 5 or 6).  In the event of early termination, the subject-assessed afternoon cough assessment and the Child Global Question will not be 
performed. 
g.
The baseline, single-blind (to the parent/legally acceptable representative and subject), liquid oral confection will be administered at Visit 1 (Day 1), recommended to be 
before 11:30 am.
h.
Visit 3 (Day 2 afternoon) will occur at the study site at least 24 hours after the start cough recording that began on Day 1.


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i.
Ambulatory 2-hour cough recording should be set up before the baseline, single-blind confection is administered, with cough recording beginning immediately (+5 minutes) 
after dosing.  The parent/legally acceptable representative will be advised regarding VitaloJAKTM use as specified in Section 6 Study Procedures.
j.
Dose 1 of double-blind investigational product will be administered at Visit 2 (Day 1) at the study site after at least 2 hours of baseline cough recording. At Visit 3 (Day 2), 
the afternoon dose (Dose 4) will also be administered at the study site.  All other doses (Doses 5-9) of investigational product will be administered to the subject by the 
parent/legally acceptable representative. Subjects vomiting after the administration of Dose 1 at the clinic will not be re-dosed, and all the subsequent clinical procedures and 
dosings should be continued and performed as described in the protocol.
k.
Ambulatory 24-hour cough recording should be set up before the first investigational product dose (Dose 1) is administered at Visit 2 (Day 1), with cough recording 
beginning immediately (+5 minutes) after dosing.  The parent/legally acceptable representative will be advised regarding VitaloJAKTM use as specified in Section 6 Study 
Procedures.
l.
Serious adverse event (SAE) collection begins from the time of informed consent and non-serious AE collection begins from the time that the subject receives the first dose of 
investigational product.
m.
Post study follow-up visit will occur by phone 14 (+ up to 3 days for scheduling flexibility) days after the last dose of investigational product.  The study site staff should 
inquire about any SAEs that may have occurred.


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Dextromethorphan (DXM) is a cough suppressant used to temporarily relieve cough due to 
minor throat and bronchial irritation as may occur with a cold.
1.2. Background and Rationale
DXM is the most commonly used oral antitussive ingredient in both adult and pediatric 
non-prescription medications (Dicpinigaitis, 2004)3, and is “Generally Recognized as Safe 
and Effective” (GRASE) under the over-the-counter (OTC) Monograph system (21 CFR 
341.14).  The product is intended for use in adults and children 2 years of age and over, with 
the indication:  

Temporarily relieves cough due to minor throat and bronchial irritation as may occur 
with a cold (21 CFR 341.74(b)(1)).  Under 21 CFR 341.74(d)(iii), DXM can be 
formulated as syrups and as solid oral dosage forms, with age-dependent dosing as 
follows:

Adults and children 12 years of age and older: 10 to 20 mg every 4 hours up 
to 6 doses/day or 30 mg every 6-8 hours up to 4 doses/day, not to exceed 
120 mg/day;

Children 6 to under 12 years of age: 5 to 10 mg every 4 hours up to 
6 doses/day or 15 mg every 6-8 hours up to 4 doses/day, not to exceed 
60 mg/day;

Children 2 to under 6 years of age: 2.5 to 5 mg every 4 hours or 7.5 mg every 
6 to 8 hours; not to exceed 30 mg/day.
The safety and efficacy of DXM in adults at the United States monograph-approved dose of 
30 mg has been established in a variety of studies (Pavesi et al., 2001).13 Efficacy in children 
is less well established and results have been equivocal (Shadkam et al, 2010; Paul, 2004a; 
Paul, 2004b; Yoder, 2006).14,11,12,19 The difficulty in establishing efficacy in children is at 
least partially due to the lack of a standardized methodology and a validated device to 
evaluate objective antitussive effects, ie, a reduction in cough count, in the natural 
environment. 
The leading pharmaceutical manufacturers of over-the-counter (OTC) pediatric cough and 
cold products, via the Consumer Healthcare Products Association (CHPA), and in 
consultation with the Food and Drug Administration (FDA), announced in 2008 that they are 
transitioning product labeling as it relates to children aged less than 4 years of age.  The 
product labeling now states "Do not use in children under four years of age."  The safety of 
the ingredients in these products was not in question; it was found that dosing errors and 
accidental ingestions were the leading cause of rare adverse events in children
(CHPA, 2008).2


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This pilot study is being conducted to identify the appropriate endpoints and sample size for 
a subsequent definitive pediatric cough study that will evaluate the efficacy of 
dextromethorphan hydrobromide (DXM HBr) at the approved monograph dose in children 
aged 6 to 11 years.  This current pilot study will utilize the 510(k) status- cough recording 
device (VitaloJAKTM, Vitalograph Ltd, Ennis, Ireland), which has been validated for use in 
adults (McGuiness, 2012)7 and has recently been validated in children (Elghamoudi, 2015).5
A subject completed patient-reported outcome (PRO) self-assessment of cough symptoms 
will also be included as a secondary endpoint, to provide another endpoint for evaluation.
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigator’s Brochure (IB).  The product 
labeling (monograph) for APAP is also considered a SRSD.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
The objective of this pilot study is to evaluate the endpoints and analyses that may be most 
appropriate to evaluate the efficacy of DXM HBr 15 mg/10 mL versus placebo in children 
ages 6 to 11 years in a future study. 
2.2. Endpoints
The primary endpoint of this study is the total cough count collected by the cough recording 
device in an ambulatory setting over a 24-hour period post-first dose on Day 1 after 
randomization to DXM HBr or placebo. 
Secondary endpoints are the total cough count collected in the dosing intervals of interest 
during the 24-hour interval:

Total cough count collected by the cough recording device during the first dosing 
interval (Dose 1 to Dose 2) on Day 1;

Total cough count collected by the cough recording device over the dosing interval 
from evening dose (Dose 2) on Day 1 to morning dose (Dose 3) on Day 2 (ie, night 
time cough count);

Total cough count collected by the cough recording device over the first dosing 
interval on Day 2 (interval between morning dose and afternoon dose on Day 2, ie, 
Dose 3 to Dose 4);

Total cough count collected by the cough recording device over the first dosing 
interval on Day 1 (Dose 1 to Dose 2) and the first dosing interval on Day 2 (Dose 3 to 
Dose 4).  These 2 dose intervals approximately represent the daytime cough count;

Time accumulated over a 24-hour period when cough events occurred.


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Other endpoints as assessed by PRO include:
•
Change from screening evaluation (assessed in the morning) in morning cough 
frequency (“from when you woke up this morning until now, how much have you 
been coughing”), cough severity (“how bad is your cough this morning”) and impact 
on sleep (“last night in bed, how much did your cough keep you awake”), assessed by 
subject;
•
Change from baseline evaluation (assessed at afternoon) in afternoon cough 
frequency (“how much have you been coughing this afternoon”) and severity (“how 
bad is your cough this afternoon”) in the afternoon of Days 2-4, assessed by subject; 
•
Change from baseline evaluation (assessed at afternoon) in daily assessment of the 
cold in the Child Global Question (“how bad is your cold today”), assessed by 
subject; 
•
Subject and parent/legally acceptable representative global assessment of satisfaction 
with study medication at the end of the study.
Protocol Amendment #4 introduced an interim analysis to assess whether or not the study 
would be continued. The rationale is based upon the vulnerable subject population 
(pediatrics) being studied and in association with the extended recruitment period and 
challenging enrollment for the trial.  The main focus of this interim analysis is the primary 
endpoint and the first secondary endpoint (cough count during the first dosing interval), but 
other secondary 
 endpoints may also be considered by the independent committee 
established to review the information as detailed in the committee charter and described in
Section 9.4.  The interim analysis will be conducted after at least 50% subjects complete the 
study or discontinue early.  AEs will be collected to assess the safety of DXM HBr and 
placebo during the study period. 
3. STUDY DESIGN
This is a randomized, stratified by age group (6-8 years and 9-11 years), parallel, 
double-blind, placebo-controlled, multicenter pilot study in approximately 150 males and 
females aged 6 to 11 years, inclusive, who exhibit cough associated with common cold or 
acute upper respiratory tract infection (URTI) but are otherwise healthy.  Prior to performing 
any study-related activities and after having been informed of the study by the investigator or 
authorized designee, the parent/legally acceptable representative will provide informed 
consent, and the subject will provide assent to participate.  The study design is shown 
in below.  The dosing schedule is shown in Figure 1 below.
CCI
CCI


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Figure 1.
Study Design Schematic
Table 1.
Dosing Schedule
DAY
TIME OF ADMINISTRATION
MORNING
AFTERNOON
EVENING
1
Single-Blind, Liquid Oral 
Confection
(In the morning, recommended 
to be before 11:30 am, at the 
study site)
Dose 1a,b
(Recommended to before 
3:30 pm, at the study site)
Dose 2a,c
(Prior to bedtime [within 
30 minutes], 6-8 hours after Dose 
1)
2
Dose 3a
(In the morning, within 
30 minutes of waking up)
Dose 4a
(6-8 hours after morning dose and 
at least 24 hours after Dose 1; 
administered at the study site)
Dose 5a
(Prior to bedtime [within 
30 minutes], 6-8 hours after 
afternoon dose)
3
Dose 6a
(In the morning, within 
30 minutes of waking up)
Dose 7a
(6-8 hours after morning dose)
Dose 8a
(Prior to bedtime [within 
30 minutes], 6-8 hours after 
afternoon dose)
4
Dose 9a
(In the morning, within 
30 minutes of waking up)
a Double blind randomized investigational product.
b Subjects vomiting after the administration of Dose 1 at the clinic will not be re-dosed. In addition, all the subsequent 
clinical procedures and dosings should be continued and performed as described in the protocol.
c Although not encouraged, to allow the parent/legally acceptable representative some flexibility regarding the timing of 
the second dose, the second dose may be taken as early as 4 hours post-Dose 1, but not earlier.


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Subjects who meet screening criteria, including sufficient cough and acute URTI or common 
cold symptoms, will be enrolled in a 2-hour Baseline Run-in Period and follow the 
procedures below: 

The subject will be fitted with the VitaloJAKTM device at the study site for at least 
2 hours of ambulatory cough count monitoring.

The parent/legal representative will be advised that the VitaloJAKTM is a sound 
recording device, and therefore may inadvertently capture confidential information 
from casual speech within its range; and that Vitalograph has standard operation 
procedures and measures in place to ensure that any such information is kept 
confidential, including removing such speech to a certain extent.  While wearing the 
device, the subject should also avoid overly noisy locations.

The subject will be given a single-blind (to the parent/legally acceptable 
representative and subject), inactive (non-medicinal), liquid oral confection at the 
study site, recommended to be before 11:30 am. The 2-hour recording will begin 
immediately (+5 minutes) after the confection is administered.  The time and date of 
administration and recording start date and time will be recorded in the CRF by the 
study site staff.

The subject and parent/legally acceptable representative will be released from the 
study site during the 2-hour ambulatory cough count monitoring and instructed to 
engage in normal activities.  Alternatively, they may stay at the study site, if 
convenient.  The study site staff will capture in the CRF whether or not the subject
leaves the study site.

The subject and parent/legally acceptable representative will return to the study site
after at least 2 hours and preferably before 2:30 pm, the device will be removed, and 
the time and date when the recording stops will be recorded in the CRF by the study 
site staff.  The subject will complete subjective cough assessments and the Child 
Global Question, and then be enrolled in the 24-hour Treatment Period if all 
eligibility requirements are met. 
Activities for the Treatment Period are as follows: 

The study site staff will set up the VitaloJAKTM device for 24 hours of ambulatory 
cough count recording and re-fit the subject with the device.

The subject will be stratified based on the subject’s age (6-8 years or 9-11 years) and 
randomized to receive investigational product.  The time and date of the first 
administration will be recorded in CRF by the study site staff.


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
The subject will receive the first dose of double blind investigational product at the 
study site, recommended to be before 3:30 pm.  Subjects vomiting after the 
administration of Dose 1 at the clinic will not be re-dosed, and all the subsequent 
clinical procedures and dosings should be continued and performed as described in 
the protocol.  The 24-hour recording will begin immediately (+5 minutes) after the 
dose is administered.  The date and time of the first dose and the recording start date 
and time will be recorded in the CRF by the study site staff.

The subject and parent/legally acceptable representative will receive investigational 
product, permitted APAP as concomitant medication, and subject diary.  In addition, 
the subject will be wearing the VitaloJAKTM device and will receive instructions 
regarding its use. 

After receiving instructions for diary completion and investigational product
administration for the remaining days, the subject and parent/legally acceptable 
representative will be allowed to leave the study site to engage in normal activities.

The subject will receive investigational product in the evenings of Days 1-3 prior to 
bedtime, the mornings of Days 2-4, and the afternoons of Days 2-3.

The subject will complete subjective cough assessments in the mornings and 
afternoons of Days 2-4, immediately prior to morning and afternoon dosing with the 
investigational product (as applicable).

The subject will complete the Child Global Question in the afternoons of Days 2-4.

A subject diary will be used to record the time and date of investigational product
dosing; the time and date of APAP dosing if applicable; and the time, date, and 
entries for the subjective cough assessments/Child Global Question.  The subject 
diary will be used from the afternoon of Day 1 through the afternoon of Day 4.  The 
parent/legally acceptable representative may assist or complete diary entries for dates 
and times, but the subject should choose the responses for the subjective cough 
assessments and the Child Global Question without assistance.

The subject and parent/legally acceptable representative will return to the study site
on Day 2 in the afternoon, at least 24 hours after the cough recording began on Day 1, 
for removal of the VitaloJAKTM device, for assessment of compliance with the 
investigational product and diary completion, and evaluation of concomitant 
treatments and adverse events.  The date and stop time of the 24-hour ambulatory 
cough count recording will be recorded in the CRF by the study site staff. If the 
device was taken off before 24 hours, the parent/legally acceptable representative will 
be asked to report the time and date when the device was taken off at Visit 3 (when 
they return the device).


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
The subject and parent/legally acceptable representative will return to the study site
for the End of Study visit on Day 4 (+1 to 2 days for scheduling flexibility).  A global 
assessment of product satisfaction will be completed by the subject and parent/legally 
acceptable representative at this visit.  The afternoon subjective cough assessments
and Child Global Question should be completed on the afternoon of Day 4, even if 
the End of Study visit occurs on Day 5 or 6. Compliance with the investigational 
product and diary completion, and evaluation of concomitant treatments and adverse 
events, will be assessed at this visit.  All study materials should be returned at this 
visit.

A post-study follow-up phone visit will occur 14 (+ up to 3 days for scheduling 
flexibility) days after the last dose of investigational product (ie, Day 18).  The study 
site staff will call the subject and parent/legally acceptable representative to inquire 
about any SAEs that may have occurred 
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular subject is suitable for this protocol. 
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of a personally signed and dated informed consent document indicating the 
parent/legally acceptable representative has been informed of all pertinent aspects of 
the study.
2. Evidence of a personally signed or printed and dated assent document or verbal 
assent, indicating the subject is willing to participate in the study.
3. Generally healthy male or female children/adolescents ages 6 to 11 years, inclusive.
4. Subject has: 
a.
An acute cough and other symptoms consistent with a common cold/acute URTI
diagnosis as deemed by the investigator or qualified designee based on findings 
from medical history review, full physical examination, and vital signs.
b. An onset of symptoms within 3 days of Visit 1, as determined by the subject or 
parent/legally acceptable representative (ie, Visit 1 should not occur later than on 
Day 3 of symptoms). 


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5. The subject self-reports on the Child Cold Symptom Checklist (Appendix 2):

At least “Some” on the 5-point scale for the cough and sore throat questions and;

At least ‘Some’ for at least 1 other symptom of sneezing, runny nose, stuffy nose, 
or difficulty breathing deeply.
The remaining symptoms (hurting head, hurting face, and aching arms and legs) 
are additional non-qualifying symptoms assessed as part of the checklist.
6. Parent/legally acceptable representative, and subject agrees the subject will not use 
any other cough or cold treatments during the study, such as:

Systemic antibiotics;

Ear or eye drop antibiotics (local cream/ointment antibiotics are allowed);

Bronchodilators (inhaled and oral);

Inhaled or oral glucocorticosteroids;

Intranasal sprays containing antihistamines, decongestants, glucocorticosteroids, 
or chromones;

Antitussives;

Expectorants;

Mucolytics;

Decongestants (oral or nasal);

Antihistamine-containing products (solid forms and syrups);

Cough/throat lozenges;

Any cough/cold medications;

Hard candies;

Honey, chocolate or cocoa-containing products;

Any herbal/dietary supplemental cold/flu preparation (eg, Echinacea, zinc, 
vitamin C in doses above the recommended daily allowance, etc.);

Aspirin;


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
Vaporizers and steam inhalation treatments;

Menthol containing products (including topical ointments and patches).
7. Subject and parent/legally acceptable representative are considered reliable, 
cooperative and of adequate intelligence to comprehend the study procedures in the 
opinion of the investigator.
8. Subject and parent/legally acceptable representative are willing and able to comply 
with scheduled visits, treatment plan, study procedures and laboratory tests (if
required).
4.2. Exclusion Criteria
Subjects with any of the following clinical characteristics/conditions will not be included in 
the study:
1. A subchronic, or chronic cough due to any condition other than an URTI or common 
cold as established by the investigator, nurse practitioner, or physician’s assistant, in 
accordance with the American College of Chest Physicians’ (ACCP) Guidelines for 
Diagnosis and Management of Cough (Irwin, 2006).6 Special attention should be 
paid to highly prevalent conditions commonly presenting with cough such as asthma,
rhinitis, or gastroesophageal reflux disease (GERD).
2. Symptoms of runny nose, stuffy nose, sore throat, or sneezing due to any condition 
other than URTI or common cold (eg, seasonal or perennial allergic rhinitis, sinusitis, 
strep throat, vasomotor rhinitis, etc.) as established by the investigator.
3. An acute cough that occurs with excessive phlegm (mucus) or is chronic such as 
occurs with smoking, asthma, bronchitis, allergies, or a gastroesophageal condition 
(eg, acid reflux and GERD) or history of such a cough.
4. Clinical features of a complication of the common cold during the physical 
examination at screening (eg, otitis media, sinusitis, or pneumonia) with or without 
the need for systematic antibiotics.
5. Pneumonia (active or with a symptom-free period of <30 days), asthma (active or 
with a symptom-free period of <1 year), or other significant pulmonary diseases.
6. Fever greater than 39ºC (102ºF oral temperature) at the time of screening if, in the 
judgment of the investigator, the individual is too ill to participate in the study or the 
fever is due to reasons other than URTI.
7. Signs of dehydration (as may be due to vomiting, diarrhea, or lack of fluid intake) 
during the physical examination at screening.
8. Diabetes or hypoglycemic disorders.


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9. Known contraindications to the investigational product or APAP.
10. Sitting blood pressure reading at or above the limits as documented in Appendix 7.  If 
the initial blood pressure reading is at or above the limits as documented in 
Appendix 7, the subject will be allowed to rest for 15 minutes and the blood pressure 
measurement repeated 2 additional times consecutively approximately 5 minutes
apart. These three readings will be averaged.  Subjects who have an average systolic 
and/or diastolic blood pressure reading at or above the established limit will be 
excluded from the study.
11. Other severe acute or chronic medical or psychiatric condition that may increase the 
risk associated with study participation or investigational product administration or 
may interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the subject inappropriate for entry into this study.
12. Obstructive sleep apnea caused by enlarged tonsils and adenoids, low muscle tone, or 
allergies (Mukherjee, 2015).9
13. History of known or suspected allergy or hypersensitivity to DXM or APAP, or any 
of the non-medicinal ingredients contained in the single-blind confection, 
double-blind investigational products, or APAP:
a.
Investigational products (DXM HBr; Placebo): benzoic acid; citric acid; dibasic 
sodium phosphate; edetate disodium; artificial and natural flavors; propylene 
glycol, red dye #40, purified water, sorbitol or sucrose.
b. Grenadine: high fructose sugar; citric acid; natural and artificial flavors; sodium 
citrate; sodium benzoate; Red 40; Blue 1.
c.
APAP: anhydrous citric acid, butylparaben, calcium sulfate, carrageenan, FD&C 
red #40, flavor, glycerin, high fructose corn syrup, hydroxyethyl cellulose, 
microcrystalline cellulose and carboxymethylcellulose sodium, propylene glycol, 
purified water, sodium benzoate, sorbitol solution, tribasic sodium phosphate.
14. Pregnant female subjects; breastfeeding female subjects; male subjects able to father 
children and female subjects of childbearing potential who are unwilling or unable to 
agree to sexual abstinence as outlined in this protocol for the duration of the study 
and for 28 days after the last dose of investigational product (Section 4.4.1).
15. History of taking any of the following prohibited medications or products within the 
corresponding washout periods, if applicable, prior to taking the first dose of 
investigational product:

Systemic antibiotics: 5 times the elimination half-life;

Ear or eye drop antibiotics: 5 days;

Bronchodilators (inhaled and oral): subject should not have used within the 
6 months prior to screening;


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
Inhaled or oral glucocorticosteroids: subject should not have used inhaled or oral 
glucocorticosteroids within the 6 months prior to screening;

Intranasal sprays containing antihistamines, decongestants, glucocorticosteroids, 
or chromones: 5 times the elimination half-life;

Monoamine oxidase inhibitors: 2 weeks;

First or second generation antihistamines (certirizine, fexofenadine, loratadine, 
brompheniramine, diphenhydramine, hydroxyzine, chlorpheniramine): 5 times the 
elimination half-life;

Oral decongestants: phenylephrine and short-acting pseudoephedrine, 12 hours; 
long-acting pseudoephedrine, 24 hours;

Expectorants/mucolytics (guaifenesin, N-acetylcysteine): 12 hours;

DXM: 20 hours;

Opioids (eg, codeine): 5 times the elimination half-life;

Other cough suppressants: 24 hours;

Long-acting analgesics and cyclooxygenase -2 (COX-2) inhibitors: 5 times the 
elimination half-life;

Honey: 12 hours;

Cough lozenges: 12 hours;

Cough/cold herbal medications, dietary supplements, beta-agonists: 24 hours;

Mentholated topical ointments or patches: 12 hours;

Any other cough/cold medication, saline rinses or washes, herbal remedy, 
homeopathic remedy, steam inhalation (humidifier): 12 hours;

Potent CYP3A inhibitors: (eg, ritonavir, ketoconazole, clarithromycin): 5 times 
the elimination half-life;

Selective serotonin uptake inhibitors: 5 times the elimination half-life;

Angiotensin-converting enzyme inhibitors such as captopril (Capoten) or 
enalapril (Vasotec): 5 times the elimination half-life;

Products with grapefruit, grapefruit juice, papaya or pomegranate: 72 hours
(DiMarco, 2002).4


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16. History of taking a medication that is sedating within the past 24 hours prior to 
screening (eg, sedatives, hypnotics, tranquilizers, anticonvulsants, benzodiazepines, 
and clonidine).
17. Current smoker or has smoked tobacco/nicotine-containing products, or been exposed 
to secondhand smoke (eg, living in the same household with a family member who 
smokes routinely in the home) within 6 months of entry into the study (Note: smoking 
or exposure to secondhand smoke is defined as 3 or more cigarettes per week).
18. History of substance abuse within 1 year prior to screening.
19. Subject has a sibling contemporaneously participating in this study.
20. Participation in other studies involving investigational drug(s) within 30 days prior to 
study entry and/or during study participation.
21. Previous participation in this study.
22. Investigational site staff members directly involved in the conduct of the study and 
their family members, study site staff members otherwise supervised by the 
investigator, or subjects who are Pfizer employees directly involved in the conduct of 
the study.  However, children related to hospital/clinical unit staff members not 
directly involved with the study may be enrolled.
4.3. Randomization Criteria
Subjects must meet all of the following criteria to be eligible for randomization:
1. Subjects must complete the 2-hour ambulatory cough counting baseline run-in 
recording period and must return to the study site for randomization at least 2 hours 
(+1 hour) after the recording started. 
2. Subjects whose equipment failed, preventing collection of cough count data for at 
least 2 hours during the Baseline Run-in Period, or those who took off the device 
during this period will be excluded from further study participation. 
3. Subjects who do not return to the study site (before 3:30 pm) in time for the afternoon 
dose will not be randomized.
4. The Child Global Question will be completed (Appendix 3).  Subjects will rate the 
severity of their cold on a 5-point categorical scale in response to the question, “How 
bad is your cold today?”  Subjects must have a response of at least ‘bad’ to be 
randomized into the study.  The study site staff or parent/legally acceptable 
representative may assist the child with reading the words of the questions or 
responses, but may not assist in choosing the responses.
5. In addition, to qualify for the study, subjects must agree to follow the study 
requirements outlined in this protocol.


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4.4. Lifestyle Guidelines
4.4.1. Contraception
All male subjects who are able to father children and female subjects who, are of 
childbearing potential and in the opinion of the investigator, are sexually active and at risk 
for pregnancy, must agree that it is their preferred and usual lifestyle to abstain from sexual 
activity and must agree to continue to do so for the duration of the active treatment period 
and for 28 days after the last dose of investigational product.  Abstinence is defined as 
refraining from all heterosexual intercourse; periodic abstinence (eg, calendar, ovulation, 
symptothermal or postovulation methods) and withdrawal are not acceptable for this study.  
The investigator or his/her designee will discuss with the subject and his/her parent/legally 
acceptable representative the need to remain abstinent according to the schedule of activities
and document such conversation in the subject’s chart.  In addition, the investigator or his or 
her designee will instruct the subject to call immediately if he/she is unable/unwilling to 
comply or if pregnancy is known or suspected in the subject or the subject’s partner. 
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation 
and team SharePoint site. 
To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, subjects or parents/legally acceptable representatives are provided 
with a contact card.  The contact card contains, at a minimum, protocol and investigational 
compound identifiers, subject study number, contact information for the investigational site 
and contact details for a contact center in the event that the investigational site staff cannot be 
reached to provide advice on a medical question or problem originating from another 
healthcare professional not involved in the subject’s participation in the study.  The contact
number can also be used by investigational staff if they are seeking advice on medical 
questions or problems; however, it should only be used in the event that the established 
communication pathways between the investigational site and the study team are not 
available.  It is therefore intended to augment, but not replace the established communication 
pathways between the investigational site and study team for advice on medical questions or 
problems that may arise during the study.  The contact number is not intended for use by the 
subject or parent/legally acceptable representative directly and if a subject calls that number 
they will be directed back to the investigational site.
5. STUDY TREATMENTS 
At the beginning of the Baseline Run-in Period, and in order to preserve the blinding due to 
potential taste differences between the double-blind active and placebo investigational 
products in this study, all subjects will be given a single-blind (to the parent/legally 
acceptable representative and subject), inactive (non-medicinal), liquid oral confection 
(Table 3) by a qualified member of the study site staff.  The sponsor will supply bottles of 
Rose’s Grenadine syrup for this purpose along with dosing cups.


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Table 3.
Investigational Product for Baseline Run-In Period
Treatment Group 
Per Unit
Per Dose/Route
Inactive (non-medicinal) Liquid
Oral Confection - Rose’s Grenadine 
Syrup
WH-0001-0569-(XXX) where XXX 
identifies the Investigational Product 
manufacturing supply lot
----
10 mL, orally
The sponsor will supply the following investigational product in double-blind fashion for 
administration during the Treatment Period (Table 4).
Subjects will be stratified by age group (6-8 years and 9-11 years) and randomized in a 
1:1 ratio to receive investigational product during the 4 days of study participation.  Subject 
enrollment will be actively monitored with the goal of attaining at least 40% population in 
the younger group (6-8 years).
Dosing is 10 mL orally administered 3 times daily except on Day 1 (when the subjects will 
receive 2 doses), and Day 4 (when the subjects will receive 1 dose in the morning).
Table 4.
Investigational Product for Treatment Period
Treatment Group
Per Unit
Per Dose/Route
DXM HBr Cough Syrup 
(118 mL/bottle) –
Children’s Robitussin 
Cough Long-Acting
WH-0508-0006-(XXX) 
where XXX identifies the 
Investigational Product 
manufacturing supply lot
Dextromethorphan HBr 
15 mg/10 mL
15 mg (10 mL, orally)
Placebo Oral Syrup
(118 mL/bottle)
WH-1285-0009-(XXX) 
where XXX identifies the 
Investigational Product 
manufacturing supply lot
----
10 mL orally
During the Treatment Period, APAP will be provided by the sponsor as a permitted 
concomitant medication if required for headache, fever and/or body aches and pains 
associated with the common cold.  The product will be provided as described in Table 5, and 
dosing will be as directed per the product label, based on weight or age. 


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Table 5.
Concomitant Medication
Concomitant Medication
Per Unit
Per Dose/Route
Acetaminophen 160 mg/5 mL oral 
suspension – Good Neighbor 
Pharmacy Children’s Pain and 
Fever Suspension (Cherry)
(118 mL bottle)
WH-0001-0568-(XXX) where 
XXX identifies the concomitant 
medication supply lot
160 mg/5 mL
Based on weight or 
age per product label 
directions, 
administered orally 
For the purposes of this study, and per International Conference on Harmonization (ICH)
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).
5.1. Allocation to Treatment
Treatment assignments will be determined by a computer-generated randomization schedule
created and maintained by Pfizer. 
Subjects completing the Baseline Run-in Period as required will be randomized to 1 of
2 treatments, DXM HBr or placebo, in a 1:1 ratio, and stratified according to their age group,
6-8 and 9-11 years.  Subjects 6-8 years will be assigned numbers in sequential order from 
; subjects 9-11 years will be assigned numbers in sequential order from 
.
The randomization list will be provided to Pfizer Consumer Health (PCH) Consumer Study 
Supplies for packaging and labeling. 
5.2. Breaking the Blind (If Applicable)
In the event of a medical emergency that necessitates breaking the code, the sealed disclosure
on the label containing emergency identification of the package contents may be opened.  
The blind will only be broken by the investigator in the event of an emergency for which 
knowledge of the subject’s double-blind investigational product will have a direct impact on 
treatment decisions.  Every effort will be made to discuss the decision to break the blind with 
the PCH monitor in advance.
When the blind is broken, the investigator will notify the sponsor’s Clinical/Medical Monitor 
within 24 hours after determining that it is necessary to unblind the treatment assignment and 
document the reason and date of the unblinding.  The event will also be recorded on the case 
report form (CRF) and in the source document.  Any AE or serious adverse event (SAE)
associated with breaking the blind must be recorded and reported as specified in this 
protocol.
PPD
PPD


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5.3. Subject Compliance

At Visit 2 (Day 2) and Visit 4 (Day 4, 5, or 6), study staff will assess compliance by 
visually evaluating remaining product quantities and subject diary information.  Study 
staff will query the parent/legally acceptable representative if product quantity and 
subject diary information appears discrepant. 
At the end of study completion, the subject and parent/legally acceptable representative will 
return all used and unused bottles of investigational product (ie, blinded investigational 
product), the outer study kit package, and the APAP concomitant medication. 
Subject accountability will be assessed by verifying the number of doses recorded in the CRF 
(91 doses required, per protocol), as described in Section 5.7.
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
All study products will be code-labeled by the sponsor (PCH) or an appropriate designee. 
Double-blinded investigational product will be packaged in identical 118 mL bottles, with a 
three-part tear-off label.  Each bottle of investigational product will include a dose cup for 
product dispensing.  The double-blind investigational products will be similar in flavor, 
scent, color and viscosity. 
The inactive liquid oral confection for administration during the Baseline Run-In Period will 
be supplied in bulk bottles and will be labeled for investigational use.  Dosing cups to 
dispense the oral confection will be provided.
Each subject will receive 1 bottle of APAP (liquid suspension 160 mg/5 mL, provided as a 
118 mL commercially-labeled bottle) as unblinded permitted concomitant medication.  The
bottles of commercially marketed APAP will receive study labels.
Investigational product will be packaged in a numbered study kit containing the bottle of 
blinded investigational product, such that subjects randomized to DXM HBr will receive 
1 bottle of DXM HBr oral syrup, and subjects randomized to placebo will receive 1 bottle of 
placebo oral syrup.  
APAP oral suspension will also be provided to subjects for this study, allowed as a permitted 
concomitant medication if required for headache, fever and/or body aches and pains 
associated with the common cold.  Prior to July, 2018, the APAP was provided as part of the 
investigational study kit.  After Amendment #4, July 2018 (inclusive), APAP will be 
provided separate from the study kit.
5.4.2. Preparation and Dispensing
After completing the screening activities and confirming eligibility, all qualifying subjects 
will be given a single-blind (to the parent/legally acceptable representative and subject),
inactive (non-medicinal) liquid oral confection at the beginning of the Baseline Run-in 


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Period.  The liquid oral confection will be prepared at the study site in a room separate from 
other subject screening and baseline activities, by measuring the liquid oral confection into a 
dose cup (provided by the sponsor) prior to dispensing to the subject. 
Upon return of the study subject after the 2-hour Baseline Run-in Period is completed, the 
investigator or qualified member of the study site staff will determine the appropriate 
stratification for the subject based on the subject’s age, and randomize the subject by 
assigning the next available randomization number within the appropriate randomization 
block.  The investigator or qualified member of the study site staff will remove the tear-off 
portion of the 3-part study label from the blinded investigational product bottle included in 
the study kit, prior to dispensing.  The tear-off portion will be placed on a dispensing record, 
and the assigned subject number and kit number will be recorded on the dispensing log.
The investigator or qualified member of the study site staff will dispense the 10 mL dose of 
the appropriate investigational product, using the dose cup provided with the bottle. 
The dispensing of the:

single-blind liquid oral confection at the Baseline Run-in Period, 

first dose of double-blind investigational product at the clinical study site, 

the study kit with remaining investigational product, and

the bottle of APAP.
will be documented on dispensing logs.
5.5. Administration
A dose cup will be provided to measure and dispense all double-blind investigational product
doses. The dates and times for all doses administered by the parent/legally acceptable 
representative while away from the study site will be recorded in the subject’s diary.
The dosing schedule is shown in Table 1.  Recommended to be before 11:30 am, the 
investigator or qualified member of the study site staff will administer the single-blind (to the 
parent/legally acceptable representative and subject), inactive, liquid oral confection to 
subjects who qualify for the Baseline Run-in Period.  If desired, the subject may have a drink 
of water.  The time of administration will be recorded in the CRF. 
Subsequent to the subject’s return to the study site after the 2-hour Baseline Run-in Period is 
completed, each qualifying subject will be randomized to double-blind investigational 
product. The investigator or qualified member of the study site staff will administer the first 
dose of double-blind investigational product of DXM HBr 15mg/10mL or 10 mL of placebo
to the subject, recommended to be before 3:30 pm, and record the time of dosing in the CRF.  
If desired, the subject may have a drink of water.


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Subjects vomiting after the administration of Dose 1 at the clinic will not be re-dosed, and all 
the subsequent clinical procedures and dosings should be continued and performed as 
described in the protocol.
After the first dose of investigational product is administered, the subject will begin the 
24-hour recording period using the VitaloJAKTM ambulatory cough count recording device. 
The investigator or qualified member of the study site staff will explain the dosing 
instructions for the subsequent doses to the parent/legally acceptable representative and then 
dispense the study kit (including the opened bottle of investigational product and dose cup) to 
the parent/legally acceptable representative. Prior to July 2018, the bottle of APAP was 
provided with the study kit; after Amendment #4, July 2018 (inclusive), APAP will be 
provided separate from the study kit.
On Day 1, the parent/legally acceptable representative will administer the second dose of 
double-blind investigational product to the subject within 30 minutes before bedtime, 
6-8 hours from the previous dose (Dose 1).  Although not encouraged, to allow the 
parent/legally acceptable representative some flexibility regarding the timing of the second 
dose, the second dose may be taken as early as 4 hours post-Dose 1, but not earlier.
The justification for the safety of a one-time 4-hour dosing window between Doses 1 and 
2 for DXM 15 mg in children ages 6 to 11 years is based on summary safety data and 
overdose information in this age range.  At exposures similar to the monograph dose or 
slightly above, the adverse event reporting rate for DXM is very low.  Most reports of 
toxicity occur at high dosages because of misuse, ingestion with suicidal intent, or drug 
abuse.  DXM is considered to have a wide margin of safety; in addition, pharmacokinetic 
polymorphism known to be a factor with DXM does not pose a clinically significant safety 
risk when therapeutic doses of DXM are used for short-term cough suppression, such as its 
use in this study (Bem, 1992).1 In addition, on Day 1 of this study, 2 doses will be 
administered, for a total daily dose of 30 mg (half of the allowed maximum dose per 
monograph of 60 mg/day). 
On Day 2 after completion of the morning subjective cough assessments, the parent/legally 
acceptable representative will administer the third dose of double-blind investigational 
product to the subject within 30 minutes of waking.  In the afternoon, at least 24 hours after
the first dose of the double-blind treatment and start of the cough recording, a study site visit 
will occur, during which time the VitaloJAKTM device will be removed, and the subject will
complete the afternoon subjective cough assessment and the Child Global Question.  If 
subjects and parent/legally acceptable representative return to the clinic in less than 24 hours, 
they will be asked to wait until the 24-hour recording period is complete for the device 
removal.  The Day 2 afternoon dose will be administered by the parent/legally acceptable
representative at the study site under supervision of study site staff.
The Day 2 evening dose, the Day 3 morning, afternoon, and evening doses, and the 
Day 4 morning dose will be administered by the parent/legally acceptable representative.  
The Day 4 morning dose is the final dose of study product to be administered during the 
study even if the End of Study visit (Visit 4) occurs on Day 5 or Day 6.


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5.6. Investigational Product Storage
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products including the inactive (non-medicinal) liquid oral confection and 
APAP are stored in a secured area with controlled access under required storage conditions 
and in accordance with applicable regulatory requirements.
Investigational product should be stored in its original container and in accordance with the 
label.  Storage conditions stated in the single reference safety document (SRSD) (eg, IB for 
DXM HBr and product labeling [monograph] for APAP) will be superseded by the storage 
conditions stated in the labeling.
The liquid oral confection (Rose’s Grenadine Syrup) should be stored in accordance with the 
bottle label.
Study site systems must be capable of measuring and documenting (for example, via a log), 
at a minimum, daily minimum and maximum temperatures for all study site storage locations 
(as applicable, including frozen, refrigerated and/or room temperature products).  This 
information should be captured from the time of investigational product receipt throughout 
the study.  Even for continuous monitoring systems, a log or study site procedure that ensures 
active daily evaluation for excursions should be available.  The operation of the temperature 
monitoring device and storage unit (for example, refrigerator), as applicable, should be 
regularly inspected to ensure it is maintained in working order. 
Controlled room temperature is defined as the temperature maintained thermostatically that 
encompasses at the usual and customary working environment of 20°-25°C (68°-77 °F). 
Excursions between 15° and 30°C (59° and 86 °F) that are experienced in pharmacies, 
hospitals, and warehouses, and during shipping, are allowed. Transient spikes up to 40° are 
permitted as long as these increases do not exceed 24 h in duration.  Any excursions from the 
product label storage conditions should be reported upon discovery.  The study site should 
actively pursue options for returning the product to the storage conditions as described in the 
labeling, as soon as possible.  Deviations from the storage requirements, including any 
actions taken, must be documented and reported to the sponsor.  Once an excursion is 
identified, the investigational product must be quarantined and not used until the sponsor 
provides documentation of permission to use the investigational product.  It will not be 
considered a protocol deviation if the sponsor approves the use of the investigational product 
after the temperature excursion. Use of the investigational product prior to sponsor approval 
will be considered a protocol deviation.
Specific details regarding information the study site should report for each excursion will be 
provided to the study site.
Study site staff will instruct the subject’s parent or legally acceptable representative on the 
proper storage requirements for take-home investigational products, and the need to return all 
unused products to the study site at Visit 3 and the End of Study visit. 


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5.7. Investigational Product Accountability
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.
At the end of study completion, the subject and parent/legally acceptable representative will 
return all used and unused bottles of investigational product and the outer study kit package, 
as well as the APAP concomitant medication.  Investigational product accountability will be 
assessed by the study monitor, who will measure the volume of the investigational product 
remaining in the returned bottle (ie, approximately 28±10 mL should remain in each bottle).
In addition, the monitor will inspect the storage facility at appropriate time intervals 
throughout the clinical investigation, depending on the length of the study.  The principal 
investigator must account for any significant discrepancy and/or deficiency.
5.7.1. Destruction of Investigational Product Supplies
At the end of the study, all used investigational study product (empty containers), as well as 
all unused study product will then be returned to:
Pfizer Consumer Healthcare Consumer Study Supplies
Attention: Consumer Study Supplies
Protocol No. A6531002
Phone: 
5.8. Concomitant Treatment(s)
Subjects who require medication on a continuing basis may be entered into the study 
provided none of the medications or the conditions which the medications are treating are 
excluded by the inclusion/exclusion criteria.  All concomitant medication used during the 
study will be reported to the investigator or his/her staff and recorded on the subject’s CRF.
During the Treatment Period, APAP will be permitted as a concomitant relief medication if 
required for headache, fever and/or body aches and pains associated with the common cold.  
If requested by parent/legally acceptable representative, use of ibuprofen (IBU) will be 
permitted after consultation with the investigator or designee. However, IBU will not be 
supplied by the sponsor. Dosing will be as directed per the product label, based on weight or 
age and must not exceed recommended dosage.  The dates and times for all APAP doses will 
be recorded in the subject diary and IBU use will be recorded as a concomitant medication on 
the CRF. 
No other medications expected to confound the evaluation of the investigational product will 
be allowed during the course of the study. 
PPD
PPD


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5.9. Rescue Medication
No rescue medication will be permitted during the study, in accordance with the prohibited 
treatments as outlined in Inclusion Criterion 6 and Exclusion Criterion 15.
6. STUDY PROCEDURES 
6.1. Screening and Baseline
6.1.1. Pre-Screening
Study personnel will pre-screen potential subjects by parental/legally acceptable 
representative interview.  Those who meet all inclusion/exclusion criteria that can be 
assessed during pre-screening will be scheduled for Visit 1.  In addition, a parent /legally 
acceptable representative must verbally confirm the availability to report to the study site at 
the scheduled time.
On the day of the observation period (Day 1), subjects will be asked to wear a comfortable 
T-shirt from home that can be worn through the completion of the 24-hour ambulatory cough 
recording period on Day 2.
6.1.2. Screening/Morning Baseline (Day 1)
After the parent/legally acceptable representative has provided informed consent (See
Section 12.2.1) and the subject has provided assent, subjects will then undergo eligibility 
screening, including:

Review of demographics;

Medical history;

Medication history (including a discussion of all current medications and all 
medications, including vitamins and herbal supplements, taken up to 14 days prior to 
Visit 1);

Vital signs assessment (sitting blood pressure, pulse rate, respiratory rate and
temperature) as specified in Section 7.2.3;

Height and weight measurements as detailed in Section 7.2.4;

Lifestyle Assessments for boys and girls of child bearing potential will be reviewed 
as detailed in Section 4.4.  A subject is of childbearing potential if, in the opinion of 
the investigator, he/she is biologically capable of having children (ie, 
post-menarchal);

Urine pregnancy test for females of childbearing potential will be collected.  A 
subject is of childbearing potential if, in the opinion of the investigator, he/she is 
biologically capable of having children (ie, post-menarchal);


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
Inclusion/exclusion criteria review.  Subjects who do not initially meet screening 
inclusion and exclusion criteria, may be re-screened for study participation if 
re-screening occurs at least 30 days after the initial screening period.  Any subject 
re-screened will undergo all screening and baseline assessments.  A subject may be 
re-screened only once;

A full physical examination (including oropharyngeal examination) performed by a 
physician, physician’s assistant or nurse practitioner as specified in Section 7.2.2.  
Examination findings must be consistent with signs of a cold or acute URTI;

Subjects will provide responses to the subjective cough assessments at screening 
(Appendix 4).  The study site staff or parent/ legally acceptable representative may 
assist the child with reading the words of the questions or responses, but may not 
assist in choosing the responses;

Subjects will complete the Child Cold Symptom Checklist (Appendix 2). The study 
site staff or parent/ legally acceptable representative may assist the subject with 
reading the words of the questions or responses, but may not assist in choosing the 
responses. 
6.1.3. Afternoon Baseline/Run-in Period: Visit 1 (Day 1)
Subjects who qualify for study participation, based on the inclusion and exclusion criteria 
described in Section 4.1 and Section 4.2, will be eligible for the Baseline Run-in Period.  
Scheduling of the Baseline Run-in Period must allow for administration of the baseline 
confection, recommended to be before 11:30 am. 
Subjects will be assigned a VitaloJAKTM device.  The study site staff will program the
VitaloJAKTM and insert a new data card and batteries into the device, per Vitalograph 
instructions.  The VitaloJAKTM lapel microphone will be clipped to the subject’s clothing at 
the neck or upper chest level, and the chest wall sensor will be attached to the subject’s chest 
at the top of the sternum for audio recording.
The parent/legally acceptable representative will be advised that the VitaloJAKTM is a sound 
recording device, and therefore may inadvertently capture confidential information from 
casual speech within its range; and that Vitalograph has standard operation procedures and 
measures in place to ensure that any such information is kept confidential, including 
removing such speech to a certain extent.  While wearing the device the subject should also 
avoid overly noisy locations.
After the VitaloJAKTM device is checked for correct operation, the subject will be given a
single-blind (to the parent/legally acceptable representative and subject), inactive
(non-medicinal), liquid oral confection in a dose cup by a qualified member of the study site 
staff.  -If desired by the subject, water will be provided.  The recording will begin 
immediately (+5 minutes) after administration of the single-blind oral confection and the date 
and start time of the 2-hour run-in recording will be recorded in the CRF. 


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During the Baseline Run-in Period, continuous digital audio recordings will be obtained 
through the VitaloJAKTM device, clipped to the subject using a belt or fanny pack.
The subject and parent/legally acceptable representative will be released from the study site 
and instructed to engage in normal activities during the 2-hour ambulatory cough count 
monitoring.  Alternatively, they may stay at the study site, if convenient.  The study site staff 
will capture in the CRF whether or not the subject leaves the study site.
Subjects and their parent/legally acceptable representative will be instructed to return to the 
study site after at least 2 hours (+1 hour) after beginning the VitaloJAKTM cough count 
recording begins, and in time for a first dose recommended to be before 3:30 pm.
6.1.4. Randomization/First Dose: Visit 2 (Day 1)
Upon return to the study site after the 2-hour Baseline Run-in Period is completed, the 
VitaloJAKTM device will be removed and re-set with a new data card and batteries in 
accordance with the device instructions, in preparation for monitoring during the 24-hour 
Treatment Period.  The date and stop time for the run-in recording will be recorded in the 
CRF.
Subjects must meet all of the following criteria to be eligible for randomization:

Subjects must complete the 2-hour ambulatory cough counting period and return to 
the study site for randomization at least 2 hours (+1 hour) after the baseline cough 
count recording start. 

Subjects whose equipment failed, preventing collection of cough count data 
for at least 2 hours during the Baseline Run-in Period, or those who took off 
the device during this period, will be excluded from further study
participation. 

Subjects who do not return to the study site in time for the afternoon dose
(recommended to be before 3:30 pm) will not be randomized.

The Child Global Question will be completed (Appendix 3).  Subjects will rate the 
severity of their cold on a 5-point categorical scale in response to the question, “How 
bad is your cold today?”  Subjects must have a response of at least ‘bad’ to qualify for 
the study.  The study site staff or parent/ legally acceptable representative may assist 
the subject with reading the words of the questions or responses, but may not assist in 
choosing the responses.

In addition, subjects must agree to follow the study requirements outlined in this 
protocol. 


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Subjects who continue to qualify for the study and meet the randomization criteria will be:

Stratified according to the subject’s age, and randomized to receive DXM HBr 
(15 mg/10 mL) or placebo (10 mL) treatment;

Instructed to complete the afternoon subjective cough assessments (Appendix 5) prior 
to dosing.  The study site staff or parent/ legally acceptable representative may assist 
the subject with reading the words of the questions or responses, but may not assist in 
choosing the responses;

Administered the first dose of double-blind investigational product, using the 
provided dose cup to measure the correct dose.  The date and time of the first dose 
will be recorded in the CRF.  Subjects vomiting after the administration of Dose 1 at 
the clinic will not be re-dosed, and all the subsequent clinical procedures and dosings 
should be continued and performed as described in the protocol;

Set up with the VitaloJAKTM device, programmed for monitoring during the 24-hour 
Treatment Period. It will be placed on the subject as described for the Baseline 
Run-in Period (Section 6.1.3).  At the time of administration of the assigned 
double-blind investigational product, the 24-hour ambulatory cough count recording
period will begin (+5 minutes for scheduling purposes).  The date and the start time of
the 24-hour recording will be recorded in the CRF.
Prior to being dismissed from the study site the study site staff will provide the subject and 
the parent/legally acceptable representative:

A diary for collection of assessments and doses administered while not at the study 
site.  The study site staff will instruct the subject and parent/representative on how the 
diary should be completed, the times when each assessment should be completed 
each day, and what to do if an assessment is missed (ie, to leave it blank);

Instructions for the ambulatory cough count recorder;

Study medication (1 bottle of blinded investigational product with dose cup; and 
1 bottle of open-label APAP with dose cup), along with dosing instructions for the 
remainder of Day 1 and Day 2 (ie, within 30 minutes of bedtime on Day 1, and the 
morning of Day 2 within 30 minutes of waking);

Instructions to return for the next study visit on the afternoon of Day 2 with the cough 
recorder and accessories, the diary, and the investigational product and APAP bottles.  
The parent/legally acceptable representative will be instructed to not administer the 
afternoon dose of investigational product on Day 2 until returning to the study site;

Instructions to not administer any of the prohibited treatments as outlined in inclusion 
criterion 6 and exclusion criterion 15.
Study site staff will assess any SAEs that may have occurred since signing consent/assent.


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6.2. Treatment Period (Day 1 Evening – Day 4 Morning)

Day 1 evening;
Within 30 minutes of the subject’s bedtime and ideally, approximately 6-8 hours after 
the afternoon dose, the parent/legally acceptable representative will administer the 
evening dose of double-blind investigational product to the subject, following the 
instructions provided by the study site staff. Although not encouraged, to allow the 
parent/legally acceptable representative some flexibility regarding the timing of the 
second dose, the second dose may be taken as early as 4 hours post-Dose 1, but not 
earlier.

Day 2 morning;
Within 30 minutes of waking, the subject will complete the Day 2 morning subjective
cough assessments and receive the morning dose of double-blind investigational 
product. Any doses of APAP taken should be recorded in the diary.

Day 2 afternoon (at study site);
After the 24-hour ambulatory cough count recording is completed, the subject and 
parent/legally acceptable representative will return to the study site for removal and 
retrieval of the ambulatory cough count recorder and auxiliary equipment (device, 
microphone, sensor, instructions, etc.).  The date and stop time for cough recording 
will be recorded by the study site staff on the CRF.  Study site personnel will also 
assess compliance with the diary and dosing instructions to-date, and inquire about 
concomitant medication use and adverse events or SAEs. 

Prior to double-blind investigational product dosing, the subject will complete the 
Day 2 afternoon subjective cough assessments (Appendix 5), and then complete the 
Child Global Question found in Appendix 3;

The parent/legally acceptable representative will administer the fourth dose of
double-blind investigational product, following the instructions provided in 
Section 5.5.  The date and time of dosing will be recorded in the CRF;

The subject and parent/legally acceptable representative will be dismissed from the 
study site, with instructions for completing the study through Day 4, and an 
appointment to return on either the afternoon of Day 4 (or on Day 5 or 6 for 
scheduling flexibility) for the end of study visit.  The subject and parent/legally 
acceptable representative will be instructed to return all study-related medications and 
the subject diary at the end of study visit. 
Data collection required by subject and parent/legally acceptable representative from
Day 1 evening through the afternoon of Day 4 of the study is indicated below:

Times and dates of evening, morning, and afternoon dosing through morning of 
Day 4 for doses not taken at the study site (collected via diary);


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
Subjective cough assessments by the subject in the morning and afternoon on 
Days 2 through 4 (collected via diary);

The Child Global Question on the afternoons of Days 2-4 (collected via diary);

The use of APAP (collected via diary).
6.3. Visit 4 (End of Study Visit; Day 4 Afternoon or Day 5 or 6)
An end of study visit will be scheduled in the afternoon of Day 4 (or Day 5 or 6 for 
scheduling flexibility), and will include the following activities:

Collect bottles of double-blind investigational product and APAP, and assess 
compliance by visually evaluating remaining product quantities and subject diary 
information;

Conduct full physical exam as outlined in Section 7.2.2;

Conduct vital signs assessment (sitting blood pressure, pulse rate, respiratory rate and
temperature);

Collect and review subject diary;

Review AE/SAE and concomitant treatment information during the study period 
(collected via CRF);

Collect urine pregnancy test for females of childbearing potential.  A subject is of 
childbearing potential if, in the opinion of the investigator, she is biologically capable 
of having children (ie, post-menarchal);

Collect separate evaluations of subject and parent/legally acceptable representative
global assessment of product satisfaction (collected via CRF).
6.4. Early Termination Visit
If an early termination occurs on Day 1, 2 or 3, the Early Termination Visit could be on those 
days.  If not, an early termination visit should be scheduled to occur as soon as possible. 
(The early termination visit is not restricted to an afternoon timeframe.  In the event of early 
termination, the subject-assessed afternoon cough assessment and the Child Global Question 
will not be performed). The Early Termination Visit will include the following activities:  

Collect bottles of double-blind investigational product and APAP, and assess 
compliance by visually evaluating remaining product quantities and subject diary 
information;

Conduct full physical exam as outlined in Section 7.2.2;


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
Conduct vital signs assessment (sitting blood pressure, pulse rate, respiratory rate and
temperature;

Collect and review subject diary;

Review AE/SAE and concomitant treatment information during the study period 
(collected via CRF);

Collect urine pregnancy test for females of childbearing potential.  A subject is of 
childbearing potential if, in the opinion of the investigator, she is biologically capable 
of having children (ie, post- menarchal);

Collect separate evaluations of subject and parent/legally acceptable representative 
global assessment of product satisfaction (collected via CRF).
6.5. Post-Study Follow-up
Fourteen days after the last dose of investigational product (ie, Day 18 + up to 3 days for 
scheduling flexibility), the study site staff will call the subject and parent/legally acceptable 
representative to inquire about any SAEs that may have occurred. This call should be 
documented in the source documentation and any SAE should be reported as specified in
Section 8.1.4.
6.6. Subject Discontinuation
Changes in the subject’s medical condition or diagnosis may require discontinuation from the 
study.  Subjects who develop a complication of the common cold (eg, otitis media, sinusitis, 
or pneumonia) with or without the need for systemic antibiotics, become too ill to continue 
participation in the judgment of the investigator, show signs of dehydration (as may be due to 
vomiting, diarrhea, or lack of fluid intake), or develop a cough that occurs with excessive 
phlegm (mucus) should be discontinued.  In addition, if the subject develops any condition 
that requires the use of any prohibited treatment as outlined in Inclusion Criterion 6 or
Exclusion Criterion 15, the subject should be discontinued.  If a parent/legally acceptable 
representative inadvertently administers any of these treatments the subject does not need to 
be discontinued, but the treatment must be recorded in the CRF.  Attempts should be made to 
complete the study procedures outlined for the Early Termination Visit.
6.7. Subject Withdrawal
Withdrawal of consent: Subjects or their parent/legally acceptable representative who request 
to discontinue study treatment will remain in the study and must continue to be followed for 
protocol specified follow-up procedures.  The only exception to this is when a subject or their 
parent/legally acceptable representative specifically withdraws consent for any further 
contact with him or her or persons previously authorized by the subject or their parent/legally 
acceptable representative to provide this information.  Subjects or their parent/legally 
acceptable representative should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible.  The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the withdrawal is 


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only from further receipt of investigational product or also from study procedures and/or post 
treatment study follow-up, and entered on the appropriate CRF page.  In the event that vital 
status (whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Lost to follow-up: All reasonable efforts must be made to locate subjects or their 
parent/legally acceptable representative to determine and report their ongoing status.  This 
includes follow-up with persons authorized by the subject or their parent/legally acceptable 
representative as noted above.  Lost to follow-up is defined by the inability to reach the 
subject or parent/legally acceptable representative after a minimum of 2 documented phone 
calls, faxes, or e-mails as well as lack of response by the subject or their parent/legally 
acceptable representative to one (1) registered mail letter.  All attempts should be 
documented in the subject’s medical records.  If it is determined that the subject has died, the 
site will use permissible local methods to obtain the date and cause of death.  If the 
investigator’s use of a third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed assent or their parent/legally acceptable 
representative informed consent, then the investigator may use a sponsor-retained third-party 
representative to assist site staff with obtaining the subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study.  The site 
staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.  If, after all attempts, 
the subject or their parent/legally acceptable representative remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the subject’s medical records.
Subjects or their parent/legally acceptable representative may withdraw from the study at any 
time at their own request, or they may be withdrawn at any time at the discretion of the 
investigator or sponsor for safety or behavioral reasons, or the inability of the subject to 
comply with the protocol-required schedule of study visits or procedures at a given study 
site. 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject or their parent/legally acceptable representative.  All attempts to contact the subject
or their parent/legally acceptable representative and information received during contact 
attempts must be documented in the subject’s medical record.  In any circumstance, every 
effort should be made to document subject outcome, if possible.  The investigator should 
inquire about the reason for withdrawal, request that the subject return all unused 
investigational product(s) and study-related equipment, request that the subject return for a 
final visit, if applicable, and follow up with the subject regarding any unresolved adverse 
events (AEs).
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.


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7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases, the investigator will take all steps necessary to ensure the 
safety and well-being of the subject.  When a protocol required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he or she has taken to ensure that normal processes are adhered to as soon as possible.  
The study team will be informed of these incidents in a timely fashion.
7.1. Efficacy
7.1.1. Cough Counts
The primary efficacy assessment is based on objective cough counts, obtained from an 
ambulatory cough recording device (VitaloJAKTM) that records cough sounds for a 24-hour 
period.  The 24-hour cough recording period will begin after the 2-hour Baseline Run-in 
Period cough recording period is completed, at the time (+5 minutes) of the first dose of 
double-blind investigational product administration.  The VitaloJAKTM device records 
continuous digital audio obtained through both a lapel microphone clipped to the subject’s 
clothing at the neck or upper chest level, and a chest wall sensor attached to the subject’s 
chest at the top of the sternum.  Additional information regarding set-up and use of the 
VitaloJAKTM device and data retrieval/storage requirements are provided in the
study-specific site manual prepared by Vitalograph, and supporting materials 
(eg, VitaloJAKTM Model 7100 User Manual) on file for this study. 
The parent/legally acceptable representative will be advised that the VitaloJAKTM is a sound 
recording device, and therefore may inadvertently capture confidential information from 
casual speech within its range; and that Vitalograph has standard operation procedures and 
measures in place to ensure that any such information is kept confidential, including 
removing such speech to a certain extent.  While wearing the device the subject should also 
avoid overly noisy locations.
Cough data will be retrieved from the VitaloJAKTM device, as available from the data cards 
(1 card from the Baseline Run-in Period and 1 card from the double-blind Treatment Period).  
Cough data will be downloaded by study site staff via a secure Vitalograph web portal, to a 
secure server with daily data back-up and firewall protection. 
Vitalograph Cough Analysts, trained at the University of Manchester Respiratory Research 
Group, Manchester, United Kingdom, will follow standard operating procedures in obtaining 
objective counts of individual coughs from the audio recordings.  These analysts will follow 
the standard cough counting procedures of the University of Manchester Respiratory 
Research Group.  The counting process is described in Appendix 8.


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The number of individual coughs will be quantified by counting the number of explosive 
sounds.  An explosive sound is always present in a cough and is the characteristic sound 
recognized as cough (Smith, 2006a; Smith, 2008).15,17 In a series of individual coughs, each
expiration will be counted as 1 cough.  Cough counts will be reported out in consecutive 
1-hour segments over the entire 2-hour Baseline Run-in and 24-hour Treatment Periods.
7.1.2. Subjective Assessments
Subjective subject assessments of cough frequency, severity and impact on sleep will be 
obtained during this study, as described below.  The self-assessment of cough symptoms will 
be completed using a validated PRO. 
7.1.2.1. Subjective Cough Assessments (Screening/Mornings)
Subjects will complete the following 3 questions at the Screening Visit on Day 1 morning as 
part of the screening evaluations (Appendix 4). Study site staff or parent/legally acceptable 
representative may assist the subject with reading the words of the questions or responses, 
but may not assist in choosing the responses. 
Randomized subjects will complete the same questions on the mornings of Days 2-4 of the 
Treatment Period (within 30 minutes of waking and before their morning dose).

Last night in bed, how much did your cough keep you awake?

How bad is your cough this morning?

From when you woke this morning until now, how much have you been coughing?
7.1.2.2. Subjective Cough Assessments (Baseline/Afternoons)
Subjects will complete the following 2 questions at the Baseline Visit on Day 1 afternoon as 
part of the baseline evaluations before the first dose of double-blind investigational product
(Appendix 5). Study site staff or parent/legally acceptable representative may assist the 
subject with reading the words of the questions or responses, but may not assist in choosing 
the responses.
Randomized subjects will complete the same questions on the afternoons of Days 2-4 of the 
Treatment Period (before the afternoon dose on Days 2 and 3).  The assessment should be 
completed in the afternoon of Day 4 even if the End of Study visit occurs on Day 5 or 6.

How bad is your cough this afternoon?

How much have you been coughing this afternoon?
7.1.2.3. Child Global Question
The Child Global Question below will be completed on Day 1 afternoon at Baseline (Visit 2)
and on the afternoons of Days 2 through 4 (Appendix 3).  The Child Global Question should 
be completed after afternoon subjective cough assessments, but before dosing. On Day 4, the 


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question should be completed in the afternoon even if the End of Study visit occurs on 
Day 5 or 6.  The study site staff or parent/ legally acceptable representative may assist the 
child with reading the words of the question or responses, but may not assist the child in 
choosing the response
To be randomized into the treatment phase of the study on Day 1 (Visit 2), subjects must 
have a response of at least ‘bad’ to the Child Global Question.

How bad is your cold today?
7.1.2.4. Global Satisfaction by Subject

Global satisfaction with the study medication will be self-assessed by the subject at the 
end of study site visit, scheduled on the afternoon of Day 4, or on Days 5 or 
6 (Appendix 6). The study site staff or parent/legally acceptable representative may 
assist the subject with reading the words of the questions or responses, but may not assist 
in choosing the responses.

How would you rate the study medication for taking away your cough?
7.1.2.5. Global Satisfaction by Parent/Legally Acceptable Representative
Global satisfaction with the study medication will be assessed by the parent/legally 
acceptable representative (after the subject assessment is completed) at the end of study 
office visit, scheduled on the afternoon of Day 4, or on Days 5 or 6 (Appendix 6).  The 
parent/legally acceptable representative should complete this assessment (within 
+ 20 minutes) after the subject has completed the global satisfaction assessment.

How would you rate the study medication for taking away your child’s cough?
7.2. Screening Assessments
7.2.1. Pregnancy Testing
For female subjects of childbearing potential, a urine pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed before investigational product administration at the 
screening visit and at the end of treatment visit. A negative pregnancy result is required 
before the subject may receive the investigational product.  A subject is of childbearing 
potential if, in the opinion of the investigator, she is biologically capable of having children
(ie, post-menarchal). Pregnancy tests will also be done whenever 1 menstrual cycle is missed 
during the active treatment period (or when potential pregnancy is otherwise suspected), 
and/or at the end of the study to confirm the subject has not become pregnant during the 
study.  In the case of a positive confirmed pregnancy test, the subject will be withdrawn from 
administration of investigational product but may remain in the study.  Pregnancy tests may 
also be repeated as per request of Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC) or if required by local regulations.


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7.2.2. Physical Examination
Physical examinations (including oropharyngeal examination) may be conducted by a 
physician, trained physician's assistant, or nurse practitioner as acceptable according to local 
regulation.  A full physical examination will include head, ears, eyes, nose, mouth, skin,
neck, throat, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, 
and neurological systems.  Examinations will be performed at screening and Visit 4 (or end 
of study) and findings should be consistent with signs of a cold or acute URTI.
7.2.3. Vital Signs
Vital signs (sitting blood pressure, pulse rate, respiratory rate, and temperature) will be 
assessed at screening and Visit 4 (or end of study). 
If a subject with no history of hypertension has a blood pressure reading at or above the 
limits specified in Appendix 7, the subject will be allowed to rest for 15 minutes and the 
blood pressure measurement repeated 2 additional times consecutively approximately 
5 minutes apart.  These three readings will be averaged.  Subjects who have an average
systolic and/or diastolic blood pressure reading at or above the established limit will be 
excluded from the study.  The same arm (preferably the dominant arm) should be used 
throughout the study whenever possible. 
Supine/sitting pulse rate will be between the ranges of 40 - 120 beats per minute (bpm), and 
respiration rates will be between 14 – 22 respirations/minute.  If values are not within these 
set guidelines, a medically qualified study site staff member will determine if the subject is 
appropriate to continue in the study and will document in the CRF. 
Temperature should be obtained orally.
7.2.4. Height and Weight Measurements
Height and weight measurements will only be collected at screening.  Subject height should 
be obtained after removal of shoes, on a flat surface, with the heels touching the wall.  If 
available, a stadiometer should be used.  Height will be measured in inches, and weight will 
be measured in pounds. 
7.3. Assessment of Suicidal Ideation and Behavior 
A suicidality assessment evaluation is not a required assessment for DXM HBr for this study, 
given that this product is being dosed within product labeling, and given the product’s use 
profile over at least 50 years with no documented signal for suicidality relative to the general 
population (Bem, 1992).1
7.4. Child Cold Symptom Checklist
The Child Cold Symptom Checklist (Appendix 2), a validated questionnaire that includes 
9 questions intended to assess the severity of the subject’s cold symptoms on a 5-point 
categorical scale, will be completed by the subject.  For study qualification, subjects must 
have a self-reported: 1) rating of at least “Some” for cough and sore throat [questions 2 and 


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7, respectively], and 2) a rating of at least ‘Some’ for at least 1 other symptom of sneezing, 
runny nose, stuffy nose, and difficulty breathing deeply (hurting head, hurting face and
aching arms and legs are additional non-qualifying symptoms assessed as part of the 
checklist).  The study site staff or parent/ legal representative may assist the subject with 
reading the words of the questions or responses, but may not assist in choosing the responses.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; (2) non-
serious adverse events (AEs); and (3) exposure to the investigational product under study 
during pregnancy or breastfeeding, and occupational exposure.  
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs. 
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
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For each event, the investigator must pursue and obtain information adequate both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
As noted in the Protocol-Specified Serious Adverse Events section, should an investigator 
judge one of the identified protocol-specified SAEs to have a causal relationship with the 
investigational product, the investigator must report the SAE to Pfizer Safety within 24 hours 
of investigator awareness.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject/parent(s)/legal guardian/legally acceptable representative.  In 
addition, each study subject/parent(s)/legal guardian/legally acceptable representative will be
questioned about the occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see Also the Subject 
Withdrawal Section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF.  


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When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any study-
related procedure and/or receiving investigational product), through and including a 
minimum of 14 calendar days after the last administration of the investigational product.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious); the investigator must record the causal relationship on the CRF, and report such an 
assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
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In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse;

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;


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
Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms and/or

Test result requires additional diagnostic testing or medical/surgical intervention 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.


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Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).

Hospitalization or prolongation of hospitalization in the absence of a precipitating, 
clinical AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, 
for work-up of persistent pre-treatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the 
study protocol);

Optional admission not associated with a precipitating clinical AE (eg, for 
elective cosmetic surgery);

Hospitalization for observation without a medical AE;


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
Pre-planned treatments or surgical procedures.  These should be noted in the 
baseline documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity 
If required on the AE case report forms, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function
MODERATE
Interferes to some extent with subject's usual function
SEVERE
Interferes significantly with subject's usual function
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to assess LFTs because a subject 
presents with clinical signs/symptoms, such LFT results should be managed and followed as 
described below.


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In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value
<2 × ULN or not available.

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT values 
>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 


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analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.  
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been
exposed (eg, due to treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product.
2. An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
3. A male has been exposed (eg, due to treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer Drug Safety Unit on the CT SAE report form and an EDP
supplemental form, regardless of whether an SAE has occurred.  In addition, the investigator
must submit information regarding environmental exposure to a Pfizer product in a pregnant 


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woman (eg, a subject reports that she is pregnant and has been exposed to a cytotoxic product 
by inhalation or spillage) to Pfizer Safety using the EDP supplemental form.  This must be 
done irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product;

Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, 
the investigator will provide the study subject with the Pregnant Partner Release of 
Information Form to deliver to his partner.  The investigator must document in the 
source documents that the subject was given the Pregnant Partner Release of 
Information Form to provide to his partner.
8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.


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8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the CT SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.4.4. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
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Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.5. Medical Device Complaint Reporting Requirements 
All medical device complaints, regardless of whether the medical device complaint is 
associated with an AE, will be recorded on the applicable pages within the CRF.  This 
includes potential incidents or malfunctions associated with the use of a medical device 
product.  An incident or malfunction is an event that might have led to death or serious 
deterioration in health, or if it occurred again might lead to death or serious deterioration in 
health.
Pfizer is to be notified of all medical device complaints within 24 hours of the investigator’s 
awareness of the event. 
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan, which will be maintained by the sponsor.  
This document may modify the plans outlined in this protocol; however, any major 
modifications to the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Sample Size Determination
As there is limited information on cough count data for acute cough in pediatric population 
using this device in an ambulatory setting, a formal sample size determination cannot be 
performed.  The sample size of approximately 150 subjects to be enrolled in the study was 
based on clinical judgment. 
9.2. Efficacy Analysis
All computations will be performed using the SAS version 9.3 or later.  Statistically 
significant treatment differences will be declared if the probability of random occurrence 
among or between the treatment groups (p) is 0.05.  Treatment differences will be declared 
marginally significant if 0.05<p0.10.  All tests will be 2-sided. 
Primary efficacy population (Full Analysis Set) will be the intent-to-treat population, defined 
as all subjects who are randomized, take Dose 1, have a valid baseline cough count 
assessment, and provide any post-dosing efficacy data.  Subjects will be classified according 
to randomized treatment.  This analysis set will be used for all efficacy analyses. 
The per-protocol (PP) analysis set will be a subset of the FAS (Full Analysis Set) excluding 
data from subjects with important protocol deviations.  The following deviations are 
considered to be important deviations leading to the exclusion from PP analysis set:

Subjects who missed Dose 2 or Dose 3, or both 

Time of Dose 2 is missing.


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
Subjects have less than one hour of cough count recording (ie, the post randomization 
recording period is shorter than one hour) in the first dosing interval.
Per Protocol analysis will only be performed for the primary and secondary endpoints.
9.2.1. Analysis of Primary Endpoint 
The primary efficacy variable will be the total cough count collected by the cough recording 
device during the 24-hour interval post-first dose on Day 1.
The cough count during the 24-hour interval will be analyzed via a negative binomial 
regression model (SAS Proc GENMOD) with treatment, study site, baseline average cough 
count per hour (based on the Baseline Run-in Period), and age group terms in the model, with 
logarithm of the time over which the cough count is evaluated as the offset parameter.  The 
ratio of rates and corresponding 95% confidence limit for DXM HBr vs placebo will be 
obtained from the primary model.
Further assessment will be conducted on the primary endpoint by adding the interaction term 
for 1) treatment by baseline average cough count, and 2) treatment by age group, separately, 
into the initial model.  
If the treatment by age group interaction is significant (p≤0.10), the primary and the 
secondary end points may be analyzed by the levels of this stratifying factor.
In addition, the total 24-hour cough count will be log-transformed and analyzed using a 
linear model with treatment, study site, log-transformed baseline average cough count per 
hour (based on the Baseline Run-in Period), and age group terms in the model.
9.2.2. Analysis of Secondary Endpoints

Total cough count collected by the cough recording device during the first dosing 
interval on Day 1 (interval between Dose 1 and Dose 2);

Total cough count collected by the cough recording device over the dosing interval 
from Dose 2 on Day 1 to Dose 3 on Day 2 (ie, night time cough count);

Total cough count collected by the cough recording device over the first dosing
interval on Day 2 (interval between Dose 3 and Dose 4);

Total cough count collected by the cough recording device over the first dosing 
interval on Day 1 (Dose 1 to Dose 2) and the first dosing interval on Day 2 (Dose 3 to 
Dose 4).  These 2 dose intervals approximately represent the daytime cough count;  

Time accumulated over a 24-hour period when cough events occurred.
These first four endpoints (cough counts) will be analyzed via a similar negative binomial 
regression model as used for the primary parameter.


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The cough time accumulated over a 24-hour period will be log transformed and analyzed 
with analysis of covariance (ANCOVA) model with treatment, study site, the log-
transformed baseline cough time, and age group included in the model. 
9.2.3. Analysis of Other Endpoints

Change from screening evaluation (assessed in the morning) in morning cough 
frequency (“from when you woke up this morning until now, how much have you 
been coughing”), cough severity (“how bad is your cough this morning”) and impact 
on sleep (“last night in bed, how much did your cough keep you awake”), assessed by 
subject.
These parameters collected from the PRO assessment will be analyzed using an ANOVA 
model with treatment, study site, the corresponding screening assessment by subject, and age 
group included in the model.  The 95% confidence limit for the treatment difference will be 
based on the least squares means and their standard errors obtained from the final model.

Change from baseline evaluation (assessed at afternoon) in afternoon cough 
frequency (“how much have you been coughing this afternoon”) and severity (“how 
bad is your cough this afternoon”) in the afternoon of Days 2-4, assessed by subject.
These parameters collected from the PRO assessment will be analyzed using an ANOVA 
model with treatment, study site, the corresponding baseline assessment by subject, and age 
group included in the model.  The 95% confidence limit for the treatment difference will be 
based on the least squares means and their standard errors obtained from the final model.

Change from baseline evaluation (assessed at afternoon) in daily assessment of the 
cold in the Child Global Question (“how bad is your cold today”), assessed by 
subject.
This parameter collected from the PRO assessment will be analyzed using an ANOVA model 
with treatment, study site, the baseline assessment in Child Global Question cold assessment 
by subject and age group included in the model.  The 95% confidence limit for the treatment 
difference will be based on the least squares means and their standard errors obtained from 
the final model.

Subject and parent/legally acceptable representative global assessments of satisfaction 
with investigational product at the end of the study.
The global satisfaction assessments collected from the PRO assessment (completed by 
subjects and parents) will also be analyzed by an ANOVA model with treatment, study site, 
and age group included in the model.  The 95% confidence limit for the treatment difference
will be based on the least squares means and their standard errors obtained from the final
model.
Additionally, the interaction of treatment by stratification factor may be assessed by adding 
the interaction term to the initial model. 


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9.3. Safety Analysis
The safety population will consist of all subjects who take at least one dose of investigational 
product (DXM HBr or placebo). 
AEs will be summarized by the Medical Dictionary for Regulatory Activities (MedDRA)
system organ class (SOC) and preferred term and classified according to their severity (mild, 
moderate, or severe) and relationship (related, or not related) to study product.  For the 
summary by severity, subjects who have multiple occurrences of the same AE will be 
classified according to the worst reported severity of the AE.  Similarly, for the summary by 
relationship to the study product, the AE will be classified according to the closest 
relationship.
Specifically, AEs occurred on Day 1 following the first dose will be summarized by 
treatment and by various intervals: 0- ≤4 hours, 4- ≤6 hours, 6- ≤8 hours, and >8 hours till 
midnight after first dose, separately for subjects who take their 2nd dose in (1) Hour 4 - ≤6;
(2) Hour 6 - ≤8; and (3) later than Hour 8 on Day 1. 
In addition, screening vital signs (blood pressure, pulse rate, rate of respiration, and
temperature) will be summarized.
9.4. Interim Analysis
Due to the slow recruitment in children aged 6 to 11 years, an interim analysis is planned to 
assess the futility of the study at interim after at least 50% subjects have either completed or 
discontinued from the study. The interim analysis will be performed by an Internal Review 
Committee (IRC). The interim analysis details including decision criteria will be pre-
specified and documented in the IRC charter and the interim statistical analysis plan. The 
results of the interim analysis will not be distributed to anyone directly involved in the 
management of all or part of the study or data collection including investigators and subjects. 
After reviewing the tabular data, the IRC members will make one of the following 
recommendations: 
1. Continue the study unaltered; or 
2. Terminate the study early.
Only one interim analysis will be performed in this study. This interim analysis does not 
consider the control of type-1 error, and sample size will not be re-estimated in this interim 
analysis. 
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The methodology used in the interim analysis is based on the calculation of conditional 
power using the weighted z-score test method20-22 for the primary endpoint and one 
secondary endpoint. No efficacy claim will be made at the interim analysis.
9.5. Data Monitoring Committee 
This study will use an IRC. 
The IRC will evaluate the study data for the planned interim analysis according to and as pre-
specified and documented in an IRC charter and an interim statistical analysis plan.  The 
recommendations made by the IRC to continue or stop the study will be forwarded to Pfizer 
for final decision.  Pfizer will forward such decisions, which may include summaries of 
aggregate analyses of endpoint events and of safety data that are not endpoints, to regulatory 
authorities, as appropriate.  
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practice (GCP) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.


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A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital or the physician's subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent and assent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to ICH guidelines, according to local regulations, or as 
specified in the Clinical Study Agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.


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12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent/assent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.2.1. Subject Information and Consent/Assent
All parties will ensure protection of subject personal data and will not include subject names
or other identifiable data in any reports, publications, or in any other disclosures, except 
where required by laws.
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, address and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify the study subjects.  The study 
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent and assent document must be in compliance with ICH GCP, local 
regulatory requirements, and legal requirements, including applicable privacy laws.
The informed consent and assent document(s) used during the informed consent process must 
be reviewed by the sponsor, approved by the IRB/IEC before use, and available for 
inspection. 
The investigator must ensure that each study subject or his or her parent/legally acceptable 
representative is fully informed about the nature and objectives of the study and possible 
risks associated with participation. 


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Whenever consent is obtained from a subject’s parent/legally acceptable representative, the 
subject’s assent (affirmative agreement) must subsequently be obtained when the subject has 
the capacity to provide assent, as determined by the IRB/EC.  If the investigator determines 
that a subject’s decisional capacity is so limited he/she cannot reasonably be consulted, then,
as permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
subject’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study subject does not provide his or her own consent, the source documents 
must record why the subject did not provide consent (eg, minor, decisionally impaired adult), 
how the investigator determined that the person signing the consent was the subject’s legally 
acceptable representative, the consent signer’s relationship to the study subject (eg, parent, 
spouse), and that the subject’s assent was obtained, or waived.  If assent is obtained verbally 
it must be documented in the source documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each parent/legally acceptable representative before any study-specific activity 
is performed.  In addition, assent will be obtained from the subject, except in instances where 
they cannot provide assent.  The investigator will retain the original of each subject's signed 
consent and assent documents.
12.3. Subject Recruitment
Advertisements approved by IRBs/EC and investigator databases may be used as recruitment 
procedures.  Advertisements may mention that compensation may be offered, but will not 
indicate the amount of compensation to which the subject or parent/legally acceptable 
representative may be entitled subsequent to study participation. 
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used. 
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH Good 
Clinical Practice
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP of that the investigator becomes aware
of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in Participating Countries 
End of Trial is defined as last subject last visit (LSLV). 


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14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of DXM 
HBr at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 3 days.  As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the prespecified protocol or was 
terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the primary completion date for studies in adult populations or 
within 6 months of the primary completion date for studies in pediatric populations.


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www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed.  If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication.  However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating study sites, the investigator is free to publish separately, subject to
the other requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
1.
Bem JL, Peck R.  Dextromethorphan:  an overview of safety issues.  Drug Safety 1992; 
(3):190-9.
2.
Statement from CHPA on the Voluntary Label Updates to Oral OTC Children’s Cough 
and Cold Medicines, 2008) 
http://www.chpa.org/10_07_08labelupdatecoughmedicine.aspx
3.
Dicpinigaitis PV, Potential new cough therapies.  Pulm Pharmacol Ther 2004; 17; 
459-62.
4.
DiMarco MP, Edwards DJ, Wainer IW, et al.  The effect of grapefruit juice and Seville 
orange juice on the pharmacokinetics of dextromethorphan: The role of gut CYP3A and
P-glycoprotein.  Life Sci 2002; 71(10):1149-60.
5.
Elghamoudi DD, Sumner H, McGuiness K et al.  The feasibility and validity of 
objective cough monitoring in children using an adult cough detection system.  Poster 
session presented at:  British Thoracic Society Meeting; 2015 Dec 02-04; London, UK.  
6.
Irwin RS.  Assessing cough severity and efficacy of therapy in clinical research:  
ACCP evidence-based clinical practice guidelines.  Chest 2006; 129: 232S-7S.
7.
McGuiness K, Holdt K, Dockry R, Smith, J. Validation of the VitaloJAK™ 24 hour 
ambulatory cough monitor.  Thorax 2012; 67:A131. Doi: 
10.1136/thoraxjnl-2012-202678.220.
8.
Mitchell CK, Theriot JA, Sayat JG, et al.  A simplified table improves the recognition of 
pediatric hypertension.  J Ped Child Health 2011; 47:22-26.  
9.
Mukherjee S, Patel SR, Kales SN, et al.  An Official American Thoracic Society 
Statement: The Importance of Healthy Sleep. Recommendations and Future Priorities. 
AJRCCM 2015: 191(12): 1450-1458. 
10.
National High Blood Pressure Education Program Working Group (NHBPEPWG) on 
High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, 
evaluation, and treatment of high blood pressure in children and adolescents. 
Pediatrics.2004;114 (2 suppl 4th report):555– 576.
11.
Paul IM, Shaffer ML, Yoder KE, et al.  Dose-response relationship with increasing 
doses of dextromethorphan for children with cough.  Clin Ther 2004a: 26(9): 
1508-1514.
12.
Paul IM, Yoder KE, Crowell KR, et al.  Effect of dextromethorphan, diphenhydramine, 
and placebo on nocturnal cough and sleep quality for coughing children and their 
parents.  Pediatrics 2004b; 114(1): 85-90.


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13.
Pavesi L, Subburaj S, Porter-Shaw K.  Application and validation of a computerized 
cough acquisition system for objective monitoring of acute cough: A meta-analysis.  
Chest 2001; 120: 1121-1128.
14.
Shadkam MN, Mozaffari-Khosravi H, Mozayan MR.  A comparison of the effect of 
honey, dextromethorphan, and diphenhydramine on nightly cough and sleep quality in 
children and their parents.  J Altern Complement Med. 2010;16(7):787-93.
15.
Smith JA, Ashurst HL, Jack S, Woodcock AA, et al.  The description of cough sounds 
by healthcare professionals.  Cough 2006a; Jan 25; 2: 1.
16.
Smith JA, Earis JE, Woodcock AA.  Establishing a gold standard for manual cough 
counting:  video versus digital audio recordings.  Cough 2006b; 2:2-6.  
17.
Smith JA, Woodcock A.  New developments in the objective assessment of cough.  
Lung 2008; 186 (Suppl 1): S48-54.  
18.
Sumner H, Kelsall A, Woodcock AA, et al.  A semiautomatic method to reduce the time 
taken for manual cough counting.  American Thoracic Society.  Am J Respir Crit Care 
Med 181; 2010: A5555.  
19.
Yoder KE, Shaffer ML, La Tournous SJ, et al.  Child assessment of dextromethorphan, 
diphenhydramine, and placebo for nocturnal cough due to upper respiratory infection.  
Clin Pediatr 2006; 45:633-640.  
20.
Lan, K. K. G. and Zucker, M., Sequential monitoring of clinical trials: the role of 
information and Brownian motion. Statistics in Medicine 1993; 12: 753–765.
21.
Fisher, LD. Self-designing clinical trials. Statistics in Medicine 1998; 17:1551-1562.
22.
Cui, L, Huang, HMJ, Wang, SJ. Modification of sample size in group sequential clinical 
trials. Biometrics 1999; 55:853-857.


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Appendix 1. Abbreviations
This is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
ACCP
American College of Chest Physicians
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APAP
Acetaminophen
AST
aspartate aminotransferase
BP
blood pressure
bpm
beats per minute
CFR
Code of Federal Regulations
CHPA
Consumer Healthcare Products Association
COX-2
cyclooxygenase-2
CRF
case report form
CSA
clinical study agreement
CT
clinical trial
CYP3A
cytochrome P450, family 3, subfamily A
DXM
Dextromethorphan
DXM HBr
dextromethorphan hydrobromide
EC
ethics committee
EDP
exposure during pregnancy
EMEA
European Medicines Agency
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration (United States)
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GERD
gastroesophageal reflux disease
GRASE
Generally Considered as Safe and Effective
IB
investigator’s brochure
IBU
Ibuprofen
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
IRC
internal review committee
IND
Investigational New Drug
INR
international normalized ratio
IUD
intrauterine device
LFT
liver function test
LSLV
last subject last visit 
MedDRA
Medical Dictionary for Regulatory Activities


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Abbreviation
Term
N/A
not applicable
OTC
over-the-counter
PCH
Pfizer Consumer Healthcare
PE
physical examination
PRO
patient-reported outcome
PT
prothrombin time
SAE
serious adverse event
SOC
System Organ Class
SRSD
single reference safety document
TEAEs
treatment-emergent adverse events
ULN
upper limit of normal
UPT
urine pregnancy test
URTI
upper respiratory tract infection
UK
United Kingdom
US
United States


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Appendix 6. Global Satisfaction
The global satisfaction question will be self-assessed by the subject at the end of study visit 
after all other activities have been completed.  The corresponding question for the 
parent/legally acceptable representative should be completed after the subject’s assessment 
(within +20 minutes).
GLOBAL SATISFACTION BY SUBJECT
Circle one answer
“How would you rate the study medication for taking away your cough?”
GLOBAL SATISFACTION BY PARENT/LEGALLY ACCEPTABLE 
REPRESENTATIVE
Circle one answer
“How would you rate the study medication for taking away your child’s cough?”
      0                   1                  2                   3                  4                  5                   6 
Excellent     Very good       Good             Fair             Poor         Very poor       Terrible
    0                   1                  2                   3                  4                  5                   6 
Excellent     Very good       Good             Fair             Poor         Very poor       Terrible


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Appendix 7. Blood Pressure Levels for Boys and Girls
A simplified blood pressure table is provided below, which indicates when the provider 
should consult reference standards for identifying pediatric hypertension (extracted from 
Mitchell, 2011).8
Look up blood pressure value if…
Age in years
Systolic BP (mmHg)
Diastolic BP (mmHg)
6 to <9
≥105
>70
9 to <12
≥110
>75
If BP must be assessed further to determine study eligibility, systolic or diastolic blood 
pressure level at or above the 95th percentile by gender, age, and height (NHBPEPWG, 
2004)10 should be excluded. Reference tables are provided below.


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Appendix 8. Cough Counting Process and Timing
Cough Recordings during Baseline Run-in and Treatment Periods 
Subjects will receive a single-blind (to the parent/legally acceptable representative and 
subject), inactive (non-medicinal), liquid oral confection at the onset of the Baseline Run-in 
Period, and will wear an ambulatory cough recording device during the 2-hour period.  
During the initial Treatment Period, subjects will receive the first dose of double-blind study 
medicine (DXM HBr or placebo) and then wear the ambulatory cough recording device for 
approximately 24 hours.  The second and third doses (Day 1 evening and Day 2 morning) of 
medication will be given while the subject is undergoing monitoring. Of importance, 
subjects will be instructed to not take their fourth dose (Day 2 afternoon) of double-blind 
investigational product (DXM HBr or placebo) until they are at the study site and the 
VitaloJAKTM device has been removed.
VitaloJAKTM and Cough Counting Process
The VitaloJAKTM system uses a contact microphone placed on the chest wall and a 
custom-made digital recording device to detect cough from sound.  A lapel microphone is 
also attached to make simultaneous free-field recordings for validation purposes (manual 
cough counting).  Data are captured on a data card, and downloaded to a secure server.  The 
Vitalograph analysts’ count the data files by accessing the secure server, and runs a 
compression algorithm on each file.
As subjects cough, acoustic parameters from these voluntary coughs can be used to develop a 
24-hour sound recording and identify spontaneous cough sounds.  Initial evaluation in 
10 subjects (5 with chronic cough, 5 with asthma) suggested that the equipment and process 
have a sensitivity and specificity of approximately 98% (Smith, 2008).17
For the purpose of this study, coughs will be counted by explosive first phases (Smith, 
2008).17 The following definitions are provided below:
Cough: Inspiration, followed by glottis closure, contraction of the expiratory muscles 
against the closed glottis, and followed by the sudden glottis opening with rapid 
expulsion of air accompanied by a characteristic cough sound.  Cough sounds can 
occur as individual events or as a long series of explosive cough sounds often known 
as cough bouts, epochs, peals, or attacks. 
Individual cough: A typical cough is characterized by an early, loud, explosive phase, 
followed by an intermediate phase, and in about half of coughs, a subsequent voiced 
phase. 
Cough bouts: These cough sounds may vary enormously in length and have voiced 
phases interspersed.  It is possible for a cough bout to include more than 1 explosive 
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Digital cough counting has been shown to have excellent agreement with simultaneous video 
recordings in a research environment (Smith, 2006b).16 In addition, cough counts obtained 
from cut-down files are comparable to those obtained from full recordings, with agreement 
comparable to that seen between 2 trained observers (Sumner, 2010).18
Data Transfer
PCH will receive completed cough count data for individual subjects by hourly segments for 
analysis.  The cough count specifications will minimally include the date/time of each cough, 
number of coughs per segment, and total coughs for the full recording periods (2 or 24 hour).  
The data will be provided in a secure fashion.

SAP_001.pdf: 
Protocol A6531002 (CompoundNumber- PF-02450388) Statistical Analysis Plan
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TMF Doc ID: 98.03
Protocol A6531002
A Placebo Controlled, Double Blind, Randomized, Parallel Group Pilot Study to Evaluate the 
Efficacy of Dextromethorphan Hydrobromide on Acute Cough in a Pediatric Population
Statistical Analysis Plan 
(SAP)
Version:
2
Date:
23-Aug-2018


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TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives .......................................................................................................6
2.2. Study Design .............................................................................................................6
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................14
3.1. Primary Endpoint(s) ................................................................................................14
3.2. Secondary Endpoint(s) ............................................................................................14
3.3. Other Endpoints.......................................................................................................15
3.4. Baseline Variables...................................................................................................16
3.4.1. Stratification Variables...............................................................................17
3.4.2. Covariates ...................................................................................................17
3.5. Safety Endpoints .....................................................................................................17
3.5.1. Adverse Events...........................................................................................17
3.5.2. Vital Signs ..................................................................................................18
3.5.3. Physical Examination .................................................................................18
3.5.4. Other Safety Endpoints...............................................................................18
4. ANALYSIS SETS ...............................................................................................................18
4.1. Full Analysis Set .....................................................................................................19
4.2. Per Protocol Analysis Set........................................................................................19
4.3. Safety Analysis Set..................................................................................................19
4.4. Other Analysis Sets .................................................................................................19
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................19
5.1. Hypotheses and Decision Rules ..............................................................................19
5.2. General Methods .....................................................................................................20
5.2.1. Analyses for Count Data.............................................................................20
5.2.2. Analyses for Continuous Data....................................................................20
5.2.3. Analyses for Patient-Reported Outcome Data............................................21
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5.3. Methods to Manage Missing Data ..........................................................................21
6. ANALYSES AND SUMMARIES ......................................................................................22
6.1. Primary Endpoint ....................................................................................................22
6.1.1. Primary Analysis ........................................................................................22
6.1.1.1. Additional Analyses ..................................................................22
6.2. Secondary Endpoint(s) ............................................................................................23
6.2.1. Secondary Cough Count Endpoints............................................................23
6.2.2. Secondary Cough Time Endpoint...............................................................24
6.3. Other Endpoint(s)....................................................................................................25
6.3.1. Subjective Cough Assessments ..................................................................25
6.3.2. Child Global Question................................................................................26
6.3.3. Global Assessments of Satisfaction............................................................26
6.5. Baseline and Other Summaries and Analyses.........................................................27
6.5.1. Baseline Summaries....................................................................................27
6.5.1.1. Demographic Data.....................................................................27
6.5.1.2. Background Information ...........................................................27
6.5.1.3. Baseline Run-in Cough Counts.................................................28
6.5.1.4. Child Cold Symptom Checklist.................................................28
6.5.1.5. Child Global Question...............................................................28
6.5.1.6. Subjective Cough Assessment ..................................................29
6.5.2. Study Conduct and Subject Disposition .....................................................29
6.5.3. Concomitant Medications and Non-Drug Treatments................................29
6.6. Safety Summaries and Analyses .............................................................................29
6.6.1. Adverse Events...........................................................................................29
6.6.2. Vital Signs ..................................................................................................30
6.6.3. Physical Examination .................................................................................30
6.6.4. Laboratory Data..........................................................................................30
7. INTERIM ANALYSES.......................................................................................................30
7.1. Introduction .............................................................................................................30
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7.2. Interim Analyses and Summaries............................................................................31
8. REFERENCES ....................................................................................................................31
9. APPENDICES .....................................................................................................................32
LIST OF TABLES
Table 1. Summary of Major Changes in SAP Amendments .....................................................5
Table 2. Dosing Schedule ..........................................................................................................7
Table 3. Schedule of Activities..................................................................................................9
LIST OF FIGURES
Figure 1.
Study Design Schematic.........................................................................................7
APPENDICES
Appendix 1. Child Cold Symptom Checklist ..........................................................................32
Appendix 2. Child Global Question.........................................................................................34
Appendix 3. Subjective Cough Assessments (Screening/Morning Baseline/Mornings) ........35
Appendix 4. Subjective Cough Assessments (Afternoon Baseline/Afternoons).....................36
Appendix 5. Global Satisfaction..............................................................................................37
Appendix 6. Statistical Methodology Details..........................................................................37
Appendix 7. Target Medical Event (TME) List.......................................................................38


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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study A6531002 is based on the protocol dated 
18JUL2018.  
Table 1. Summary of Major Changes in SAP Amendments
SAP 
Version
Change
Rationale
1
Not Applicable
Not Applicable
2
The baseline covariate average cough 
count per hour based on the Baseline 
Run-in Period will be included in the 
negative binomial model after a log-
transformation.
In the negative binomial regression 
using SAS GENMOD procedure, 
log link function is used for 
modeling event rates, thus the 
predictor baseline average cough 
count per hour will be log-
transformed to be included in the 
model.
Note: In this document any text taken directly from the protocol is italicized.
2. INTRODUCTION
Dextromethorphan (DXM) is a cough suppressant used to temporarily relieve cough due to 
minor throat and bronchial irritation as may occur with a cold.
DXM is the most commonly used oral antitussive ingredient in both adult and pediatric 
non-prescription medications (Dicpinigaitis, 2004), and is “Generally Recognized as Safe 
and Effective” (GRASE) under the over-the-counter (OTC) Monograph system (21 CFR 
341.14).  The product is intended for use in adults and children 2 years of age and over, with 
the indication:  
Temporarily relieves cough due to minor throat and bronchial irritation as may occur with a 
cold (21 CFR 341.74(b)(1)).  Under 21 CFR 341.74(d)(iii), DXM can be formulated as 
syrups and as solid oral dosage forms, with age-dependent dosing as follows:

Adults and children 12 years of age and older: 10 to 20 mg every 4 hours up to 
6 doses/day or 30 mg every 6-8 hours up to 4 doses/day, not to exceed 120 mg/day;

Children 6 to under 12 years of age: 5 to 10 mg every 4 hours up to 6 doses/day or 
15 mg every 6-8 hours up to 4 doses/day, not to exceed 60 mg/day;


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
Children 2 to under 6 years of age: 2.5 to 5 mg every 4 hours or 7.5 mg every 6 to 
8 hours; not to exceed 30 mg/day.
The safety and efficacy of DXM in adults at the United States monograph-approved dose of 
30 mg has been established in a variety of studies (Pavesi et al., 2001). Efficacy in children is 
less well established and results have been equivocal (Shadkam et al, 2010; Paul, 2004a; 
Paul, 2004b; Yoder, 2006). The difficulty in establishing efficacy in children is at least 
partially due to the lack of a standardized methodology and a validated device to evaluate 
objective antitussive effects, ie, a reduction in cough count, in the natural environment. 
The leading pharmaceutical manufacturers of over-the-counter (OTC) pediatric cough and 
cold products, via the Consumer Healthcare Products Association (CHPA), and in 
consultation with the Food and Drug Administration (FDA), announced in 2008 that they are 
transitioning product labeling as it relates to children aged less than 4 years of age.  The 
product labeling now states "Do not use in children under four years of age."  The safety of 
the ingredients in these products was not in question; it was found that dosing errors and 
accidental ingestions were the leading cause of rare adverse events in children.
This pilot study is being conducted to identify the appropriate endpoints and sample size for 
a subsequent definitive pediatric cough study that will evaluate the efficacy of 
dextromethorphan hydrobromide (DXM HBr) at the approved monograph dose in children 
aged 6 to 11 years.  This current pilot study will utilize the 510(k) status- cough recording 
device (VitaloJAKTM, Vitalograph Ltd, Ennis, Ireland), which has been validated for use in 
adults (McGuiness, 2012) and has recently been validated in children (Elghamoudi, 
2015). A subject completed patient-reported outcome (PRO) self-assessment of cough 
symptoms will also be included as a secondary endpoint, to provide another endpoint for 
evaluation.
The cough recording device VitaloJAKTM provides the means to sense voice and cough 
activity from a subject, record this information and store it to a Compact Flash™ memory 
card for later analysis. The data is uncompressed so that no information is lost due to data 
compression methods. The VitaloJAK is capable of recording 24hrs worth of information 
continuously, uninterrupted without the need to replace batteries. The VitaloJAK also 
contains a Real Time Clock in order to provide time information for the data recorded. All 
the cough count endpoints will be derived using the VitaloJAKTM.
2.1. Study Objectives
The objective of this pilot study is to evaluate the endpoints and analyses that may be most 
appropriate to evaluate the efficacy of DXM HBr 15 mg/10 mL versus placebo in children 
ages 6 to 11 years in a future study. 
2.2. Study Design
This is a randomized, stratified by age group (6-8 years and 9-11 years), parallel, 
double-blind, placebo-controlled, multicenter pilot study in approximately 150 males and 


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females aged 6 to 11 years, inclusive, who exhibit cough associated with common cold or 
acute upper respiratory tract infection (URTI) but are otherwise healthy. Prior to performing 
any study-related activities and after having been informed of the study by the investigator or 
authorized designee, the parent/legally acceptable representative will provide informed 
consent, and the subject will provide assent to participate.  
The study design is shown in Figure 1 and the dosing schedule in shown in Table 2. The 
schedule of activities (Table 3) provided an overview of the protocol visits and procedures.
Figure 1.
Study Design Schematic
Table 2. Dosing Schedule
DAY
TIME OF ADMINISTRATION
MORNING
AFTERNOON
EVENING
1
Single-Blind, Liquid Oral 
Confection
(In the morning, recommended 
to be before 11:30 am, at the 
study site)
Dose 1 a, b
(Recommended to before 
3:30 pm, at the study site)
Dose 2 a c
(Prior to bedtime [within 30 
minutes], 6-8 hours after Dose 1)
2
Dose 3 a
(In the morning, within 30 
minutes of waking up)
Dose 4 a
(6-8 hours after morning dose and 
at least 24 hours after Dose 1; 
administered at the study site)
Dose 5 a
(Prior to bedtime [within 30 
minutes], 6-8 hours after 
afternoon dose)


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Table 2. Dosing Schedule
DAY
TIME OF ADMINISTRATION
MORNING
AFTERNOON
EVENING
3
Dose 6 a
(In the morning, within 30 
minutes of waking up)
Dose 7 a
(6-8 hours after morning dose)
Dose 8 a
(Prior to bedtime [within 30 
minutes], 6-8 hours after 
afternoon dose)
4
Dose 9 a
(In the morning, within 30 
minutes of waking up)
a Double blind randomized investigational product.
b Subjects vomiting after the administration of Dose 1 at the clinic will not be re-dosed. In addition, all the subsequent 
clinical procedures and dosings should be continued and performed as described in the protocol.
c Although not encouraged, to allow the parent/legally acceptable representative some flexibility regarding the timing of 
the second dose, the second dose may be taken as early as 4 hours post-Dose 1, but not earlier.


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Table 3. Schedule of Activities
Visit Identifier
Screening 
/ Run-In
Period
Randomization/ 
First Dose 
Active Treatment Period
End Study
Post 
Study 
Follow-up
Day 1
Visit 1
Day 1
Visit 2
Day 1
Day 2
Visit 3
Day 3
Day 4
Days 4-6
Day 18
+ 3 days
Protocol Activity
AM
Afternoon
PM
AM
Afternoonh
PM
AM
Afternoon 
PM
AM
Visit 
4 (afternoon) 
or
Early 
Termination
Phone call
Informed consent/assenta
X
Demographics
X
Inclusion/Exclusion 
Criteria
X
Medical historyb
X
Physical examination 
X
X
Vital signs (height, 
weight, respirations, 
temperature, sitting BP, 
pulse rate)c
X
Xc
Urine pregnancy testd
X
X
Lifestyle Assessmente
X
Morning subjective cough 
assessments
X
X
X
X
Afternoon subjective 
cough assessmentsf
X
X
X
Xf
Child Cold Symptom 
Checklist
X
Child Global Questionf
X
X
X
Xf
Single-blind, liquid oral 
confection administrationg
X
Ambulatory 2-hour cough 
recordingi
X
Stratification and 
randomization
X


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Visit Identifier
Screening 
/ Run-In
Period
Randomization/ 
First Dose 
Active Treatment Period
End Study
Post 
Study 
Follow-up
Day 1
Visit 1
Day 1
Visit 2
Day 1
Day 2
Visit 3
Day 3
Day 4
Days 4-6
Day 18
+ 3 days
Protocol Activity
AM
Afternoon
PM
AM
Afternoonh
PM
AM
Afternoon 
PM
AM
Visit 
4 (afternoon) 
or
Early 
Termination
Phone call
Diary/investigational 
product/APAP 
dispensed/retrieved
X
X
X
Study Medication 
administrationj
X 
X
X
X
X
X
X
X
X
Ambulatory 24-hour 
cough recordingk
X
X
Ambulatory cough 
recorder removal/retrieval
X
X
Assessment of compliance 
with study medication
X
X
Prior/concomitant 
treatments
X
Global Satisfaction by 
subject and parent/legally 
acceptable representative
X
Adverse eventsl, m
SAE 
Xl
Non-SAE 
Visit 1 and Visit 2 (Screening/Morning Baseline, Afternoon Baseline Run-In Period, and Randomization/First Dose) occur on Day 1 of the study.  Visit 4 (End of 
Study) may occur on the afternoon of Day 4, or on Days 5 or 6.  Early termination visit is not restricted to an afternoon timeframe. 
Abbreviations: APAP = acetaminophen; BP = blood pressure; SAE = serious adverse event.
a.
Parent/legally acceptable representative will provide informed consent, and child will provide assent.
b.
Subject must be symptomatic with a common cold or acute URTI, with onset of symptoms no more than 3 days prior to Visit 1.


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c.
Height and weight will only be collected at screening, but not at Visit 4 or Early Termination Visit.
d.
Pregnancy test for post-menarchal females. 
e.
The Lifestyle Assessment is the opportunity to assess reproductive/childbearing status, communicate the protocol requirement for complete sexual abstinence and document 
the discussion.
f.
Afternoon subjective cough assessments and Child Global Question should be completed before afternoon dosing on Days 1, 2 and 3 and in the afternoon on Day 4 (even if 
the End of Study visit occurs on Day 5 or 6).  In the event of early termination, the subject-assessed afternoon cough assessment and the Child Global Question will not be 
performed. 
g.
The baseline, single-blind (to the parent/legally acceptable representative and subject), liquid oral confection will be administered at Visit 1 (Day 1), recommended to be 
before 11:30 am.
h.
Visit 3 (Day 2 afternoon) will occur at the study site at least 24 hours after the start cough recording that began on Day 1.
i.
Ambulatory 2-hour cough recording should be set up before the baseline, single-blind confection is administered, with cough recording beginning immediately (+5 minutes) 
after dosing.  The parent/legally acceptable representative will be advised regarding VitaloJAKTM use.
j.
Dose 1 of double-blind investigational product will be administered at Visit 2 (Day 1) at the study site after at least 2 hours of baseline cough recording.  At Visit 3 (Day 2), 
the afternoon dose (Dose 4) will also be administered at the study site.  All other doses (Doses 5-9) of investigational product will be administered to the subject by the 
parent/legally acceptable representative. Subjects vomiting after the administration of Dose 1 at the clinic will not be re-dosed, and all the subsequent clinical procedures and 
dosings should be continued and performed as described in the protocol.
k.
Ambulatory 24-hour cough recording should be set up before the first investigational product dose (Dose 1) is administered at Visit 2 (Day 1), with cough recording 
beginning immediately (+5 minutes) after dosing.  The parent/legally acceptable representative will be advised regarding VitaloJAKTM use. 
l.
Serious adverse event (SAE) collection begins from the time of informed consent and non-serious AE collection begins from the time that the subject receives the first dose of 
investigational product.
m.
Post study follow-up visit will occur by phone 14 (+ up to 3 days for scheduling flexibility) days after the last dose of investigational product.  The study site staff should 
inquire about any SAEs that may have occurred.


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Subjects who meet screening criteria, including sufficient cough and acute URTI or common 
cold symptoms, will be enrolled in a 2 hour Baseline Run in Period and follow the 
procedures below: 

The subject will be fitted with the VitaloJAKTM device at the study site for at least 2 
hours of ambulatory cough count monitoring. 

The parent/legal representative will be advised that the VitaloJAKTM is a sound 
recording device, and therefore may inadvertently capture confidential information 
from casual speech within its range; and that Vitalograph has standard operation 
procedures and measures in place to ensure that any such information is kept 
confidential, including removing such speech to a certain extent.  While wearing the 
device, the subject should also avoid overly noisy locations.

The subject will be given a single blind (to the parent/legally acceptable 
representative and subject), inactive (non medicinal), liquid oral confection at the 
study site, recommended to be before 11:30 am.  The 2 hour recording will begin 
immediately (+ 5 minutes) after the confection is administered.  The time and date of 
administration and recording start date and time will be recorded in the CRF by the 
study site staff.

The subject and parent/legally acceptable representative will be released from the 
study site during the 2-hour ambulatory cough count monitoring and instructed to 
engage in normal activities.  Alternatively, they may stay at the study site, if 
convenient.  The study site staff will capture in the CRF whether or not the subject 
leaves the study site.

The subject and parent/legally acceptable representative will return to the study site 
after at least 2 hours and preferably before 2:30 pm, the device will be removed, and 
the time and date when the recording stops will be recorded in the CRF by the study 
site staff.  The subject will complete subjective cough assessments and the Child 
Global Question, and then be enrolled in the 24 hour Treatment Period if all 
eligibility requirements are met. 
Activities for the Treatment Period are as follows: 

The study site staff will set up the VitaloJAKTM device for 24 hours of ambulatory 
cough count recording and re fit the subject with the device.

The subject will be stratified based on the subject’s age (6-8 years or 9-11 years) and 
randomized to receive investigational product.  The time and date of the first 
administration will be recorded in CRF by the study site staff.


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
The subject will receive the first dose of double blind investigational product at the 
study site, recommended to be before 3:30 pm.  Subjects vomiting after the 
administration of Dose 1 at the clinic will not be re dosed, and all the subsequent 
clinical procedures and dosings should be continued and performed as described in 
the protocol.  The 24 hour recording will begin immediately (+5 minutes) after the 
dose is administered.  The date and time of the first dose and the recording start date 
and time will be recorded in the CRF by the study site staff.

The subject and parent/legally acceptable representative will receive investigational 
product, permitted APAP as concomitant medication, and subject diary.  In addition, 
the subject will be wearing the VitaloJAKTM device and will receive instructions 
regarding its use. 

After receiving instructions for diary completion and investigational product 
administration for the remaining days, the subject and parent/legally acceptable 
representative will be allowed to leave the study site to engage in normal activities.

The subject will receive investigational product in the evenings of Days 1-3 prior to 
bedtime, the mornings of Days 2-4, and the afternoons of Days 2-3.

The subject will complete subjective cough assessments in the mornings and 
afternoons of Days 2-4, immediately prior to morning and afternoon dosing with the 
investigational product (as applicable).

The subject will complete the Child Global Question in the afternoons of Days 2-4.

A subject diary will be used to record the time and date of investigational product 
dosing; the time and date of APAP dosing if applicable; and the time, date, and 
entries for the subjective cough assessments/Child Global Question.  The subject 
diary will be used from the afternoon of Day 1 through the afternoon of Day 4.  The 
parent/legally acceptable representative may assist or complete diary entries for 
dates and times, but the subject should choose the responses for the subjective cough 
assessments and the Child Global Question without assistance.

The subject and parent/legally acceptable representative will return to the study site 
on Day 2 in the afternoon, at least 24 hours after the cough recording began on Day 
1, for removal of the VitaloJAKTM device, for assessment of compliance with the 
investigational product and diary completion, and evaluation of concomitant 
treatments and adverse events.  The date and stop time of the 24 hour ambulatory 
cough count recording will be recorded in the CRF by the study site staff.  If the 
device was taken off before 24 hours, the parent/legally acceptable representative 
will be asked to report the time and date when the device was taken off at Visit 3 
(when they return the device).


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
The subject and parent/legally acceptable representative will return to the study site 
for the End of Study visit on Day 4 (+1 to 2 days for scheduling flexibility).  A global 
assessment of product satisfaction will be completed by the subject and parent/legally 
acceptable representative at this visit.  The afternoon subjective cough assessments 
and Child Global Question should be completed on the afternoon of Day 4, even if the 
End of Study visit occurs on Day 5 or 6.  Compliance with the investigational product 
and diary completion, and evaluation of concomitant treatments and adverse events, 
will be assessed at this visit.  All study materials should be returned at this visit.

A post study follow up phone visit will occur 14 (+ up to 3 days for scheduling 
flexibility) days after the last dose of investigational product (ie, Day 18). The study 
site staff will call the subject and parent/legally acceptable representative to inquire 
about any SAEs that may have occurred.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
The primary endpoint of this study is the total cough count collected by the cough recording 
device in an ambulatory setting over a 24-hour period post-first dose on Day 1 after 
randomization to DXM HBr or placebo.
Cough events were recorded using the device VitaloJak. When a cough event occurred, date 
and time were recorded, with the date recorded in the format of YYYYMMDD, and time in 
the format of HHMMSS.
As described in the Vitalograph Cough Analysis Plan, cough events could be flagged as 
“poor quality” or “early removal”, and multiple cough events could occur within one second.
As this is a pilot study to evaluate the endpoints, the primary endpoint will be derived 
including all cough events regardless of the flags during the entire recording period.
The entire recording period, or the exposure time, will be derived as: exposure = end time –
first dosing time + 1. Specifically, the end time will be chosen from the following, whichever 
occurred first: 

Session stop date and time recoded by the VitaloJAK internal time clock, 
analyzed by Vitalograph staff (available in the transferred data); 

Time subjects discontinued.
3.2. Secondary Endpoint(s)
1. Total cough count collected by the cough recording device during the first dosing 
interval on Day 1 (interval between Dose 1 and Dose 2);


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2. Total cough count collected by the cough recording device over the dosing interval 
from Dose 2 on Day 1 to Dose 3 on Day 2 (i.e., night time cough count);
3. Total cough count collected by the cough recording device over the first dosing
interval on Day 2 (interval between Dose 3 and Dose 4);
4. Total cough count collected by the cough recording device over the first dosing 
interval on Day 1 (Dose 1 to Dose 2) and the first dosing interval on Day 2 (Dose 3 
to Dose 4).  These 2 dose intervals approximately represent the daytime cough count;  
5. Time accumulated over a 24-hour period when cough events occurred.
Secondary endpoints 1st - 4th listed above will be derived similarly to the primary endpoint. 
All the cough events collected during the recording period will be included in the cough 
count endpoints. 
In the event that either the start time or the end time is missing (i.e., Dose 2, and/or Dose 3,
and/or Dose 4 time), the corresponding endpoint will be considered as missing. No 
imputation will be applied.
3.3. Other Endpoints
Other endpoints as assessed by PRO include:

Change from screening evaluation (assessed in the morning) in morning cough 
frequency (“from when you woke up this morning until now, how much have you been 
coughing”), cough severity (“how bad is your cough this morning”) and impact on 
sleep (“last night in bed, how much did your cough keep you awake”), assessed by 
subject; 
The morning subjective cough assessments will be completed at Screening/Morning Baseline
(Visit 1, Day 1), and before the morning dose on Days 2-4 (Appendix 3). For each 
assessment with respect to cough frequency/cough severity/impact on sleep, change from 
screening evaluation is calculated as the assessment collected in the morning of each day 
(Days 2-4) minus the assessment collected at Screening Visit on Day 1, respectively.

Change from baseline evaluation (assessed at afternoon) in afternoon cough 
frequency (“how much have you been coughing this afternoon”) and severity (“how 
bad is your cough this afternoon”) in the afternoon of Days 2-4, assessed by subject; 
The afternoon subjective cough assessments will be completed at the Afternoon Baseline 
visit (Visit 2, Day 1), and in the afternoon of Days 2-4 of the Treatment Period
(Appendix 4). For each assessment with respect to cough frequency/cough severity, change 
from baseline evaluation is calculated as the assessment collected in the afternoon of each 
day (Days 2-4) minus the assessment collected at Baseline Visit on Day 1, respectively.


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
Change from baseline evaluation (assessed at afternoon) in daily assessment of the 
cold in the Child Global Question (“how bad is your cold today”), assessed by 
subject; 
The Child Global Question will be completed at the Baseline (Visit 2, Day 1), and in the 
afternoon of Days 2-4 (Appendix 2). The change from baseline evaluation is calculated as the 
assessment collected in the afternoon of each day (Days 2-4) minus the assessment collected 
at Baseline, respectively.

Subject and parent/legally acceptable representative global assessment of satisfaction 
with study medication at the end of the study.
Global satisfaction with the study medication will be assessed by the subjects and 
parent/legally acceptable representative (after the subject assessment is completed) at the end 
of study office visit, scheduled on the afternoon of Day 4, or Day 5 or 6 (Appendix 5).
3.4. Baseline Variables
Baseline variables are those collected prior to dosing and can occur at pre-screening, 
screening, or run-in period prior to Dose 1 during the study period (see Figure 1).
Demographic Data: Sex, race, ethnicity, age, height and weight will be collected at 
screening. These variables will be summarized and listed.
Background Information: Past and current medical history (non-drug allergies) will be 
collected at screening and will be summarized by treatment and total in a similar manner as 
adverse events (AEs) using the MedDRA system organ class (SOC) and preferred term.  The 
corresponding listing will be also produced. Drug allergies will be also collected at this time 
but will only be listed.
Baseline Run-in Cough Counts: Subjects who met the inclusion and exclusion criteria will 
be eligible to enter the Baseline Run-in Period. During this period, subjects will be assigned a 
VitaloJAKTM device; after the device is checked for correct operation, the subjects will be 
given a single-blind, inactive, liquid oral confection. The recording will begin immediately 
(+5 minutes) after administration of the single-blind oral confection and the date and start 
time of the 2-hour run-in recording will be recorded in the CRF. 
Subjects and their parent/legally acceptable representative will be instructed to return to the 
study site after at least 2 hours (+1 hour) after the VitaloJAKTM cough count recording 
begins, and the cough counts recorded during the 2-3 hour period will be considered as 
baseline run-in cough counts (or baseline cough counts).
The baseline average cough count per hour will be derived as the total cough counts collected 
during the Baseline Run-in Period divided by the duration of this period (in hours). 


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Child Cold Symptom Checklist: This checklist will be collected at screening and used for
checking subject eligiblily for enrollment, which includes 9 questions intended to assess the 
severity of the subject’s cold symptoms on a 5 point categorical scale. See Appendix 1 for 
details.
Child Global Question: At Visit 2 on Day 1, subjects will rate the severity of their cold on a 
5 point categorical scale in response to the question, “How bad is your cold today?”  Subjects 
must have a response of at least ‘bad’ to qualify for the study.  
Subjective Cough Assessments: The subjective cough assessments collected at Screening
visit and Baseline visit (Visit 1 and 2 on Day 1) will be considered as morning baseline and 
afternoon baseline assessments, respectively. See Appendix 3 and Appendix 4 for details.
3.4.1. Stratification Variables
Subjects were stratified by age group (6-8 years and 9-11 years), and randomized to receive 
investigational product. The term age group will be used as a stratification variable in the 
statistical analysis.
3.4.2. Covariates
For the analysis of the primary endpoint, the corresponding log-transformed baseline average 
cough count per hour will be used as a covariate, and the logarithm of the time over which 
the cough count is evaluated will be used as the offset variable in fitting the negative 
binomial model. The statistical specifications for these variables or related analysis are 
described in Section 5.2.1.
Due to difficulty in recruitment, the number of subjects to be enrolled is not limited at each 
study site. In a model-based analysis using Site as a term, investigator sites may be pooled to 
alleviate issues such as model convergence due to data sparseness. The pooling rules will be 
determined prior to final database lock and release.
3.5. Safety Endpoints
Adverse event analyses will include all events which initially occurred, or worsened
following treatment.
3.5.1. Adverse Events
An adverse event is considered treatment emergent relative to a given treatment (called
treatment emergent adverse events [TEAE]) if:
the event occurs for the first time during the treatment and was not seen prior to the 
start of treatment (i.e., receiving investigational product), or
the event was seen prior to the start of treatment but increased in severity during 
treatment.


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The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any study-
related procedure and/or receiving investigational product), through and including a 
minimum of 14 calendar days after the last administration of the investigational product.
No tier-1 events (pre-specified events of clinical importance) have been identified in the 
Safety Review Plan (SRP) for the product. However, for this study, AEs included in the 
Targeted Medical Event (TME) list of the SRP (See Appendix 7) will be summarized in a 
similar manner as Tier-1 events if any are identified . Therefore, a 3-tier approach will be 
used to summarize these type of AEs. Under this approach, AEs are classified into 1 of 3 
tiers. 
Tier-1 events: These are pre-specified events of clinical importance and are maintained in a 
list in the product’s TME of the SRP. For this study TME in the SRP are considered as Tier-1 
events.
Tier-2 events: These are events that are not tier-1 but are “common”. A MedDRA preferred
(PT) is defined as a tier-2 event if its frequency is at least 2% in any treatment group.
Tier-3 events: These are events that are neither tier-1 nor tier-2 events.
3.5.2. Vital Signs
Each subject’s vital signs (including sitting blood pressure, pulse rate, respiratory rate, and 
temperature) will be measured and recorded at Screening and Visit 4 (or end of study). They 
will be summarized/listed as described in Section 6.6.2.
3.5.3. Physical Examination
Physical examinations will be performed at Screening and Visit 4 (or end of study). A full 
physical examination will include head, ears, eyes, nose, mouth, skin, neck, throat, heart and 
lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. 
They will be summarized/listed as described in Section 6.6.3.
3.5.4. Other Safety Endpoints
The medication use data such as prior medication, and concomitant medication will be 
inquired and collected at each visit (See Table 3). They will be summarized/listed as 
described in Section 6.5.3.
4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in
each analysis population prior to releasing the database and unblinding. The classifications
will be documented per standard operating procedures.


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4.1. Full Analysis Set
The Full Analysis Set (FAS) is the intent-to-treat (ITT) subject population, defined as all 
subjects who are randomized, take Dose 1, have a valid baseline cough count assessment,
and provide any post-dosing efficacy data. Subjects will be assigned to the randomized 
treatment group regardless of the treatment received. This analysis set will be used for all 
efficacy analyses. 
4.2. Per Protocol Analysis Set 
The per-protocol (PP) analysis set will be a subset of the FAS excluding data from subjects 
with important protocol deviations. The following deviations are considered to be important 
deviations leading to the exclusion from PP analysis set:  

Subjects who missed Dose 2 or Dose 3, or both 

Time of Dose 2 is missing

Subjects have less than one hour of cough count recording (ie, the post randomization 
recording period is shorter than one hour) in the first dosing interval.
Per Protocol analysis will only be performed for the primary and secondary endpoints.
4.3. Safety Analysis Set
The safety analysis set will include all subjects who received the study product. Subjects will 
be analyzed according to the treatment they actually receive regardless of which treatment 
group they are randomized. A randomized but not treated subject will be excluded from the 
safety analyses. A treated but not randomized subject will be reported under the treatment 
actually received.
4.4. Other Analysis Sets
Not applicable.   
5. GENERAL METHODOLOGY AND CONVENTIONS
The final analysis of data will be performed after unblinding of the treatment codes.
5.1. Hypotheses and Decision Rules
The statistical alternative hypothesis tested will be that DXM HBr will be better than placebo 
with respect to a parameter evaluated.
Statistically significant treatment differences will be declared if the probability of random 
occurrence between the two treatment groups (p) is ≤0.05. Treatment differences will be 
declared marginally significant if 0.05<p≤0.10. All tests will be 2-sided.


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5.2. General Methods 
For all the efficacy endpoints, descriptive statistics including sample size, mean, standard 
deviation, median, minimum, and maximum will be provided by treatment group. 
5.2.1. Analyses for Count Data
Negative Binomial Regression
Analyses of count data endpoints (primary endpoint and 1st -4th secondary endpoints) will use 
the negative binomial regression model (SAS Proc GENMOD). The model will contain 
treatment, study site (pooled), log-transformed baseline average cough count per hour (based 
on the Baseline Run-in Period), and age group as factors, with logarithm of the time over 
which the cough count is evaluated as the offset parameter. The rate ratio and corresponding 
95% confidence limit for DXM HBr vs placebo will be obtained and presented. See 
Appendix 6 for an example.
Additional assessment will be conducted on the primary endpoint by adding the interaction 
term for 1) treatment by log-transformed baseline average cough count, and 2) treatment by 
age group, separately, into the negative binomial regression model.
5.2.2. Analyses for Continuous Data
The primary endpoint, total cough count collected over a 24-hour period, will be log-
transformed and analyzed using ANCOVA model with treatment, study site (pooled), log-
transformed baseline average cough count per hour (based on the Baseline Run-in Period), 
and age group terms in the model.
The hourly cough count collected during the first dosing interval, will be log-transformed and 
analyzed using a similar ANCOVA model with treatment, study site (pooled), log-
transformed baseline average cough count per hour, and age group terms in the model.
The 5th secondary endpoint, cough time accumulated over a 24-hour period, will be log 
transformed and analyzed using a similar ANCOVA model with treatment, study site
(pooled), the log-transformed baseline cough time, and age group included in the model.
For the analyses of subjective cough assessments (including change from baseline in cough 
frequency, cough severity, impact on sleep), and the analysis of Child Global Question cold 
assessment, an analysis of variance (ANOVA) model will be applied. The model will contain 
treatment, study site (pooled), the corresponding screening/baseline assessment by subject, 
and age group as factors. 
For the global assessments of satisfaction, an ANOVA model with treatment, study site
(pooled), and age group will be included in the model. 


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Additionally, the interaction of treatment by age group may be assessed by adding the
interaction term to the initial model for each of the PRO assessments, respectively.   
For each pairwise comparison of interest, the treatment difference based on the least-squares 
means (LSM), its standard error (SE), the p-value and the associated 95% confidence interval
(CI) will be presented. 
5.2.3. Analyses for Patient-Reported Outcome Data
For each of the Other endpoints as assessed by PRO in Section 3.3, the answers at each visit 
will be descriptively summarized with count and proportion by treatment.   
Additional psychometric evaluation of PRO measures will be performed by external vendor 
(Adelphi Values) for validation purpose only; those results will be independently presented 
and reported.
 
 
 
 
 
 
 
 
 
5.3. Methods to Manage Missing Data
No imputation will be applied for missing data in the cough count endpoints or the dosing 
time.
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For subjects who had missing data in the PRO assessments, no imputation will be used. 
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint
6.1.1. Primary Analysis
o
Endpoint: The total cough count collected during 24 hour post first dose;
o
Analysis population: Full Analysis Set;
o
Analysis methodology: The negative binomial regression model will contain 
treatment, study site (pooled), log-transformed baseline average cough count per 
hour (based on the Baseline Run-in Period), and age group as factors, with 
logarithm of the time over which the cough count is evaluated as the offset 
parameter (specified in Section 5.2.1).
o
Supporting objective: Primary Objective.
Reporting results:
o
Raw data: the total cough count will be summarized with sample size, mean, 
standard deviation, median, minimum and maximum for each treatment arm. 
o
The rate ratio, p-value, and corresponding 95% confidence limit for DXM HBr vs 
placebo will be obtained and presented.
Figures
o
Line chart showing the mean cough counts on the y-axis over the time (by hour) 
on the x-axis by treatment showing the change over the 24-hour based on the raw
mean cough count.
6.1.1.1. Additional Analyses
To support the primary analysis, the primary endpoint will be log-transformed and analyzed 
using an ANCOVA model.
o
Analysis population: Full Analysis Set;
o
Analysis methodology: The ANCOVA model will contain treatment, study site 
(pooled), log-transformed baseline average cough count per hour (based on the 
Baseline Run-in Period), and age group terms in the model.
Reporting results:
o
The treatment difference based on the LSM, its SE, the p-value and the associated 
95% confidence interval (CI) will be presented.


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In the event that more than 10% of the ITT subjects are excluded from the full analysis set, 
the following analyses will be performed:
o
Analysis population: Per Protocol Analysis Set;
o
Analysis methodology: The total cough count during 24 hour interval will be 
analyzed using the same negative binomial regression model as the primary 
analysis.
Reporting results:
o
Raw data: the total cough count will be summarized with sample size, mean, 
standard deviation, median, minimum and maximum for each treatment arm. 
o
The rate ratio, p-value, and corresponding 95% confidence limit for DXM HBr vs 
placebo will be obtained and presented.
 
 
 
 
6.2. Secondary Endpoint(s)
6.2.1. Secondary Cough Count Endpoints
o
Endpoints: 
-
Total cough count collected by the cough recording device during the first 
dosing interval on Day 1 (interval between Dose 1 and Dose 2);
-
Total cough count collected by the cough recording device over the dosing 
interval from Dose 2 on Day 1 to Dose 3 on Day 2 (i.e., night time cough 
count);
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-
Total cough count collected by the cough recording device over the first 
dosing interval on Day 2 (interval between Dose 3 and Dose 4);
-
Total cough count collected by the cough recording device over the first 
dosing interval on Day 1 (Dose 1 to Dose 2) and the first dosing interval on 
Day 2 (Dose 3 to Dose 4).  (i.e., daytime cough count).  
These secondary endpoints are derived similarly to the primary endpoint, by counting all 
cough events within each dosing interval.
o
Analysis population: Full Analysis Set;
o
Analysis methodology: The negative binomial regression model will be used, 
which contains treatment, study site (pooled), log-transformed baseline average 
cough count per hour (based on the Baseline Run-in Period), and age group as 
factors, with logarithm of the time over which the cough count is evaluated as the 
offset parameter (specified in Section 5.2.1). 
Reporting results:
o
Raw data: the hourly cough count will be summarized with sample size, mean, 
standard deviation, median, minimum and maximum for each treatment arm. 
o
The rate ratio, p-value, and corresponding 95% confidence limit for DXM HBr vs 
placebo will be obtained and presented.
Additional analysis will be conducted on the first secondary endpoint, i.e., the total cough 
count collected during the first dosing interval on Day 1:
o
Analysis population: Full Analysis Set;
o
Analysis methodology: The hourly cough count collected during the first dosing 
interval, will be log-transformed and analyzed using an ANCOVA model with 
treatment, study site (pooled), log-transformed baseline average cough count per 
hour, and age group terms in the model.
Reporting results:
o
The treatment difference based on the LSM, its SE, the p-value and the associated 
95% confidence interval (CI) will be presented.
6.2.2. Secondary Cough Time Endpoint
This secondary endpoint, derived by adding up all the time when cough events actually 
occurred over a 24-hour period, will be log-transformed and analyzed with ANCOVA model.


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o
Endpoint: Cough time accumulated over a 24-hour period when cough events 
occurred.
o
Analysis population: Full Analysis Set;
o
Analysis methodology: The ANCOVA model will contain treatment, study site 
(pooled), log-transformed baseline cough time (based on the Baseline Run-in 
Period), and age group terms in the model.
Reporting results:
o
The treatment difference based on the LSM, its SE, the p-value and the associated 
95% CI will be presented.
6.3. Other Endpoint(s)
6.3.1. Subjective Cough Assessments 
The defintions of the other
endpoints were specified in Section 3.3.
o
Endpoints: 
-
Cough frequency: change in evaluations in the morning of each day (Days 
2-4) from morning baseline on Day 1, and change in evaluations in 
afternoon of each day (Days 2-4) from afternoon baseline on Day 1.
-
Cough severity: change in evaluations in the morning of each day (Days 2-
4) from morning baseline on Day 1, and change in evaluations in 
afternoon of each day (Days 2-4) from afternoon baseline on Day 1.
-
Impact on sleep: change in evaluations in the morning of each day (Days 
2-4) from morning baseline on Day 1.
o
Analysis population: Full Analysis Set;
o
Analysis methodology: ANOVA model will be used, with treatment, study site
(pooled), the corresponding morning baseline (or afternoon baseline) assessment 
by subject, and age group included in the model.  
Reporting results:
o
Raw data: The categorical answers at each visit will be descriptively summarized 
with count and proportion by treatment. The numerical answers (change from 
baseline) will be summarized with sample size, mean, standard deviation, median, 
minimum and maximum by visit and by treatment. 
o
The treatment difference based on the LSM, its SE, the p-value and the associated 
95% CI will be presented. 
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6.3.2. Child Global Question
o
Endpoint: 
-
Daily assessment of cold:  Change in evaluations in the afternoon of each 
day (Days 2-4) from the afternoon baseline on Day 1. 
o
Analysis population: Full Analysis Set;
o
Analysis methodology: ANOVA model will be used, with treatment, study site
(pooled), the baseline assessment by subject, and age group included in the 
model.  
Reporting results:
o
Raw data: The categorical answers at each visit will be descriptively summarized 
with count and proportion by treatment. The numerical answers (change from 
baseline) will be summarized with sample size, mean, standard deviation, median, 
minimum and maximum by visit and by treatment.
o
The treatment difference based on the LSM, its SE, the p-value and the associated 
95% CI will be presented. 
6.3.3. Global Assessments of Satisfaction
o
Endpoint: Subject and parent/legally acceptable representative global assessments 
of satisfaction with investigational product at the end of the study.
o
Analysis population: Full Analysis Set;
o
Analysis methodology: ANOVA model will be used, with treatment, study site
(pooled), and age group included in the model.  
Reporting results:
o
Raw data: The categorical answers will be descriptively summarized with count 
and proportion by treatment. The numerical answers will be summarized with 
sample size, mean, standard deviation, median, minimum and maximum for each 
treatment arm.
o
The treatment difference based on the LSM, its SE, the p-value and the associated 
95% CI will be presented. 
 
 
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6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
6.5.1.1. Demographic Data
o
Analysis population: Safety population;
o
Analysis methodology: Descripive statistics.
Reporting results:
o
The number and percentage of subjects within each category in gender, race,
ethnicity, and age group will be presented; while for age, height, weight and BMI,
the overall mean, standard deviation, median, minimum, and maximum values 
will be provided. The sample size overall and by treatment will be also listed. 
6.5.1.2. Background Information
o
Endpoints: Medical history, drug allergies;
o
Analysis population: Safety population;
o
Analysis methodology: Descripive statistics.
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Reporting results:
o
Medical history: The sample size, number and percentage of subjects within each 
SOC and preferred term will be presented by treatment and overall in a similar 
manner as adverse events (AEs). The corresponding listing will be also produced.
o
Drug allergies: listing will be provided.
6.5.1.3. Baseline Run-in Cough Counts
o
Endpoint: Baseline average cough count per hour;
o
Analysis population: Full Analysis Set;
o
Analysis methodology: Descripive statistics.
Reporting results:
o
The baseline average cough count per hour will be summarized with sample size, 
mean, standard deviation, Q1, median, Q3, minimum and maximum for each 
treatment arm and overall. 
6.5.1.4. Child Cold Symptom Checklist 
o
Endpoint: Child Cold Symptom Checklist at Screening visit;
o
Analysis population: Full Anlaysis Set;
o
Analysis methodology: Descriptive statistics.
Reporting results:
o
For each question, the number and percentage of subjects in each category will be 
provided overall and by treatment.
6.5.1.5. Child Global Question
o
Endpoint: Child Global Question at the Baseline visit (Visit 2, Day 1);
o
Analysis population: Full Anlaysis Set;
o
Analysis methodology: Descriptive statistics.
Reporting results:
o
The categorical answers will be descriptively summarized with count and 
proportion overall and by treatment. The numerical answers will be summarized 
with sample size, mean, standard deviation, median, minimum and maximum 
overall and by treatment.


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6.5.1.6. Subjective Cough Assessment 
o
Endpoints: The subjective cough assessments at Screening visit (Morning 
Baseline) and Baseline visit (Afternoon Baseline) assessed at Visit 1 and 2 on 
Day 1, respectively;
o
Analysis population: Full Anlaysis Set;
o
Analysis methodology: Descriptive statistics.
Reporting results:
o
For each baseline assessment, the categorical answers will be descriptively 
summarized with count and proportion overall and by treatment. The numerical 
answers will be summarized with sample size, mean, standard deviation, median, 
minimum and maximum overall and by treatment.
6.5.2. Study Conduct and Subject Disposition
Subject disposition and populations groups will be summarized using frequencies and 
percentages. No treatment comparabilities will be assessed.
6.5.3. Concomitant Medications and Non-Drug Treatments
Prior and concomitant medications will be summarized using the preferred drug name from 
WHODrug. No treatment comparabilities will be assessed.  
Concomitant non-drug treatment or procedures will be listed.
6.6. Safety Summaries and Analyses
6.6.1. Adverse Events
Adverse event analyses will include all events collected during the active collection period of 
the study. Adverse events will be summarized by the MedDRA SOC and preferred term, and 
classified according to their severity (mild, moderate, or severe) and relationship (related or 
not related) to study product. For the summary by severity, subjects who have multiple 
occurrences of the same AE will be classified according to the worst reported severity of the 
AE. Similarly, for the summary by relationship to the study product, the AE will be classified 
according to the worst relationship. 
All non-TEAE will be summarized according to the MedDRA preferred term.
No tier-1 events (pre-specified events of clinical importance) are identified in the SRP for the
study product. However, for this study, AEs included in the TME list of the SRP (See 
Appendix 7) will be summarized in a similar manner as Tier-1 events if any are identified. 
Therefore, AEs will additionally be summarized using a 3-tier approach. AEs will be


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classified into 3 tiers as defined in Section 3.5.1. All tier-1, 2, or 3 AEs will be tabulated and 
listed separately in a similar manner as all other AEs. The AEs will be sorted alphabetically 
within a system organ class.   
 
 
 
 
 
6.6.2. Vital Signs
Vital signs (sitting blood pressure, pulse rate, respiratory rate, and temperature) will be 
assessed at screening and Visit 4 (or end of study). 
The values at screening, end of study (or Visit 4), as well as the change from screening for 
the vital signs data will be summarized by descripive statistics, overall and by treatment 
group for the safety population. The number and percentage of subjects with vital sign data 
out-of-normal ranges will be summarized both at screening and end of study.
Corresponding listing will be created and subjects with out-of-normal ranges values will be 
flagged.
6.6.3. Physical Examination
Physical examination data will be summarized both at screening and at end of study for the 
safety population.
6.6.4. Laboratory Data
Laboratory data will not be entered in the database and thus will not be summarized.
7. INTERIM ANALYSES
7.1. Introduction
Protocol Amendment #4 introduced an interim analysis to assess whether or not the study 
would be continued. The rationale is based upon the challenging enrollment in the vulnerable 
subject population (pediatrics) for the trial. The main focus of this interim analysis is the 
primary endpoint (total cough count collected during 24 hour post first dose) and the first 
secondary endpoint (total cough count collected during the first dosing interval), but other 
secondary 
 endpoints may also be considered by the independent committee 
established to review the information as detailed in the committee charter and described in 
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interim statistical analysis plan. Only one interim analysis is planned for this study, and it
will be conducted after at least 50% subjects complete the study or discontinue early.        
7.2. Interim Analyses and Summaries
The methodology used in the interim analysis is based on the calculation of conditional 
power using the weighted z-score test method1,2,3 for the primary endpoint and the first
secondary endpoint. The interim analysis will not consider the control of type-1 error, and 
sample size will not be re-estimated in this interim analysis.
In the interim analysis, the primary endpoint will be analyzed using the primary model 
(negative binomial regression model) as discussed in Section 6.1.1 and the ANCOVA model 
as discussion in Section 6.1.1.1, respectively, based on the FAS. Similar analyses will be 
performed for the first secondary endpoint as discussed in Section 6.2.1. From the two
analyses for each endpoint, the estimate of treatment effect between DXM HBr and placebo 
will be obtained and presented. These treatment differences and corresponding standard 
errors will be used to obtain conditional powers based on the weighted z-score test.
If a conditional power is at least 25% for either analysis of the primary endpoint, or for either 
analysis of the first secondary endpoint, the expected recommendation would be to continue 
the study with the planned sample size (n=150). Otherwise, if all conditional powers lie 
below 25%, the recommendation would be to terminate it early.
8. REFERENCES 
1. Lan, K. K. G. and Zucker, M., Sequential monitoring of clinical trials: the role of 
information and Brownian motion. Statistics in Medicine 1993; 12: 753–765.
2. Fisher, LD. Self-designing clinical trials. Statistics in Medicine 1998; 17:1551-1562.
3. Cui, L, Huang, HMJ, Wang, SJ. Modification of sample size in group sequential clinical 
trials. Biometrics 1999; 55:853-857.


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9. APPENDICES 
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Appendix 5. Global Satisfaction
The global satisfaction question will be self-assessed by the subject at the end of study visit 
after all other activities have been completed.  The corresponding question for the 
parent/legally acceptable representative should be completed after the subject’s assessment 
(within +20 minutes)
GLOBAL SATISFACTION BY SUBJECT
Circle one answer
“How would you rate the study medication for taking away your cough?”
GLOBAL SATISFACTION BY PARENT/LEGALLY ACCEPTABLE 
REPRESENTATIVE
Circle one answer
“How would you rate the study medication for taking away your child’s cough?”
Appendix 6. Statistical Methodology Details
The following SAS code will be used to calculate the rate ratio in negative binomial model 
for count data.
proc genmod data=cough_data;
   class trt agegrp site /param=glm;
   model count= trt  site  agegrp  log(basecough)/dist=nb link=log  offset=logdur type3;
   estimate "log rate ratio Dex vs Pbo" trt 1 -1 / exp;
      0                   1                  2                   3                  4                  5                   6 
Excellent     Very good       Good             Fair             Poor         Very poor       Terrible
    0                   1                  2                   3                  4                  5                   6 
Excellent     Very good       Good             Fair             Poor         Very poor       Terrible


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   lsmeans trt / exp diff cl;
run; 
Where
trt= Treatment (1 and 2 = Treatments being compared)
Appendix 7. Target Medical Event (TME) List
BRAND or TRADE 
Name
TARGET MEDICAL EVENT 
TERM
TME Safety Area of 
Interest  and RATIONALE 
FOR INCLUDING TME
LEVEL (PT, LLT, 
HLT, HLGT & 
SOC?)
Dextromethorphan 
Hydrobromide
Hypersensitivity
Event of PV interest
PT
Nausea
Event of PV interest
PT
Vomiting
Event of PV interest
PT
Dizziness
Event of PV interest
PT
Dysarthria
Event of PV interest
PT
Myoclonus
Event of PV interest
PT
Tremor
Event of PV interest
PT
Somnolence
Event of PV interest
PT
Dysarthria
Event of PV interest
PT
Nystagmus
Event of PV interest
PT
Excitability
Event of PV interest
PT
confusional state
Event of PV interest
PT
psychotic disorders
Event of PV interest
PT
Respiratory depression
Event of PV interest
PT